March 2012 Clinical Advisor by The Clinical Advisor

THE CLINICAL ADVISOR • MARCH 2012

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While there are many diabetes complications,

PAINFUL DPN IS ONE THEY CAN’T IGNORE Help manage your patients’ painful Diabetic Peripheral Neuropathy with LYRICA

ONLY LYRICA IS RECOMMENDED AS LEVEL A by AAN evidence-based guideline for the treatment of painful diabetic neuropathy (PDN)1

“If clinically appropriate, pregabalin should be offered for the treatment of PDN (Level A).”1 The medical organizations that developed this guideline (the AAN, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation) recognize that speciﬁc care decisions are the prerogative of the patient and physician caring for the patient, based on all of the circumstances involved. For full guideline, visit www.aan.com/guidelines. Level A=Established as effective, based on at least 2 Class I studies. Class I level evidence includes a randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population, and other speciﬁed criteria. AAN=American Academy of Neurology.

LYRICA is indicated for the management of neuropathic pain associated with Diabetic Peripheral Neuropathy, management of Postherpetic Neuralgia, as adjunctive therapy for adult patients with Partial Onset Seizures, and management of Fibromyalgia. PBP01859A/291945-01

Selected safety information: LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its other components. There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue LYRICA immediately in patients with these symptoms. There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA. Speciﬁc symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of lifethreatening angioedema with respiratory compromise requiring emergency treatment. Discontinue LYRICA immediately in patients with these symptoms. Antiepileptic drugs (AEDs) including LYRICA increase the risk of suicidal thoughts or behavior in patients taking AEDs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses showed clinical trial patients taking an AED had approximately twice the risk of suicidal thoughts or behavior than placebotreated patients, and estimated the incidence rate of suicidal behavior or ideation was approximately one patient for every 530 patients treated with an AED. The most common adverse reactions across all LYRICA All rights reserved.

clinical trials are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, constipation, euphoric mood, balance disorder, increased appetite, and thinking abnormal (primarily difﬁculty with concentration/attention). Inform patients taking LYRICA that dizziness and somnolence may impair their ability to perform potentially hazardous tasks such as driving or operating complex machinery until they have sufﬁcient experience with LYRICA to determine its effect on cognitive and motor function. Higher frequency of weight gain and edema was observed in patients taking both LYRICA and thiazolidinedione antidiabetic drugs. Exercise caution when coadministering these drugs. Patients who are taking other drugs associated with angioedema such as angiotensin-converting enzyme inhibitors (ACE inhibitors) may be at increased risk of developing angioedema. Exercise caution when using LYRICA in patients who have had a previous episode of angioedema. For Full Prescribing Information and Medication Guide, please visit www.LyricaHCP.com. Please see the Brief Summary of Prescribing Information on adjacent pages. Reference: 1. Bril V, England JD, Franklin GM, et al. Evidence-based guideline: treatment of painful diabetic neuropathy. Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76:1758-1765.

September 2011

LYRICA® (pregabalin) CAPSULES BRIEF SUMMARY: For full prescribing information, see package insert. INDICATION AND USAGE LYRICA is indicated for: • Management of neuropathic pain associated with diabetic peripheral neuropathy DOSAGE AND ADMINISTRATION LYRICA is given orally with or without food. When discontinuing LYRICA, taper gradually over a minimum of 1 week. Neuropathic pain associated with diabetic peripheral neuropathy: • Administer in 3 divided doses per day • Begin dosing at 150 mg/day • May be increased to a maximum of 300 mg/day within 1 week • Dose should be adjusted for patients with reduced renal function Patients with Renal Impairment In view of dose-dependent adverse reactions and since LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function. Base the dose adjustment in patients with renal impairment on creatinine clearance (CLcr), as indicated in Table 1. To use this dosing table, an estimate of the patient’s CLcr in mL/min is needed. CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the Cockcroft and Gault equation: [140 - age (years)] x weight (kg) CLCr =

(x 0.85 for female patients) 72 x serum creatinine (mg/dL) Next, refer to the Dosage and Administration section to determine the recommended total daily dose based on indication, for a patient with normal renal function (CLcr ≥60 mL/min). Then refer to Table 1 to determine the corresponding renal adjusted dose. (For example: A patient initiating LYRICA therapy for postherpetic neuralgia with normal renal function (CLcr ≥60 mL/min), receives a total daily dose of 150 mg/day pregabalin. Therefore, a renal impaired patient with a CLcr of 50 mL/min would receive a total daily dose of 75 mg/day pregabalin administered in two or three divided doses.) For patients undergoing hemodialysis, adjust the pregabalin daily dose based on renal function. In addition to the daily dose adjustment, administer a supplemental dose immediately following every 4-hour hemodialysis treatment (see Table 1).

Table 1. Pregabalin Dosage Adjustment Based on Renal Function Creatinine Clearance Total Pregabalin Daily Dose (CLcr) (mL/min) (mg/day)* ≥60 150 300 450 600 30–60

15–30 <15

Dose Regimen BID or TID

150

225

300

BID or TID

25–50

100–150

150

QD or BID

25–50

50–75

Supplementary dosage following hemodialysis (mg)† Patients on the 25 mg QD regimen: take one supplemental dose of 25 mg or 50 mg Patients on the 25–50 mg QD regimen: take one supplemental dose of 50 mg or 75 mg Patients on the 50–75 mg QD regimen: take one supplemental dose of 75 mg or 100 mg Patients on the 75 mg QD regimen: take one supplemental dose of 100 mg or 150 mg TID = Three divided doses; BID = Two divided doses; QD = Single daily dose. *Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose. †Supplementary dose is a single additional dose. CONTRAINDICATIONS LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its components. Angioedema and hypersensitivity reactions have occurred in patients receiving pregabalin therapy. WARNINGS AND PRECAUTIONS Angioedema There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of life-threatening angioedema with respiratory compromise requiring emergency treatment. Discontinue LYRICA immediately in patients with these symptoms. Exercise caution when prescribing LYRICA to patients who have had a previous episode of angioedema. In addition, patients who are taking other drugs associated with angioedema (e.g., angiotensin converting enzyme inhibitors [ACE-inhibitors]) may be at increased risk of developing angioedema. Hypersensitivity There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue LYRICA immediately in patients with these symptoms. Withdrawal of Antiepileptic Drugs (AEDs) As with all AEDs, withdraw LYRICA gradually to minimize the potential of increased seizure frequency in patients with seizure disorders. If LYRICA is discontinued, taper the drug gradually over a minimum of 1 week. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including LYRICA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. Table 2 Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients Drug Patients Relative Risk: Risk Difference: with Events Per with Events Per Incidence of Events Additional Drug Patients 1000 Patients 1000 Patients in Drug Patients/Incidence with Events Per in Placebo Patients 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing LYRICA or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Inform patients, their caregivers, and families that LYRICA and other AEDs increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Report behaviors of concern immediately to healthcare providers. Peripheral Edema LYRICA treatment may cause peripheral edema. In short-term trials of patients

without clinically significant heart or peripheral vascular disease, there was no apparent association between peripheral edema and cardiovascular complications such as hypertension or congestive heart failure. Peripheral edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function. In controlled clinical trials the incidence of peripheral edema was 6% in the LYRICA group compared with 2% in the placebo group. In controlled clinical trials, 0.5% of LYRICA patients and 0.2% placebo patients withdrew due to peripheral edema. Higher frequencies of weight gain and peripheral edema were observed in patients taking both LYRICA and a thiazolidinedione antidiabetic agent compared to patients taking either drug alone. The majority of patients using thiazolidinedione antidiabetic agents in the overall safety database were participants in studies of pain associated with diabetic peripheral neuropathy. In this population, peripheral edema was reported in 3% (2/60) of patients who were using thiazolidinedione antidiabetic agents only, 8% (69/859) of patients who were treated with LYRICA only, and 19% (23/120) of patients who were on both LYRICA and thiazolidinedione antidiabetic agents. Similarly, weight gain was reported in 0% (0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on LYRICA only; and 7.5% (9/120) of patients on both drugs. As the thiazolidinedione class of antidiabetic drugs can cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, exercise caution when co-administering LYRICA and these agents. Because there are limited data on congestive heart failure patients with New York Heart Association (NYHA) Class III or IV cardiac status, exercise caution when using LYRICA in these patients. Dizziness and Somnolence LYRICA may cause dizziness and somnolence. Inform patients that LYRICA-related dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery. In the LYRICA controlled trials, dizziness was experienced by 31% of LYRICAtreated patients compared to 9% of placebo-treated patients; somnolence was experienced by 22% of LYRICA-treated patients compared to 7% of placebo-treated patients. Dizziness and somnolence generally began shortly after the initiation of LYRICA therapy and occurred more frequently at higher doses. Dizziness and somnolence were the adverse reactions most frequently leading to withdrawal (4% each) from controlled studies. In LYRICA-treated patients reporting these adverse reactions in short-term, controlled studies, dizziness persisted until the last dose in 30% and somnolence persisted until the last dose in 42% of patients. Weight Gain LYRICA treatment may cause weight gain. In LYRICA controlled clinical trials of up to 14 weeks, a gain of 7% or more over baseline weight was observed in 9% of LYRICAtreated patients and 2% of placebo-treated patients. Few patients treated with LYRICA (0.3%) withdrew from controlled trials due to weight gain. LYRICA associated weight gain was related to dose and duration of exposure, but did not appear to be associated with baseline BMI, gender, or age. Weight gain was not limited to patients with edema [see Warnings and Precautions, Peripheral Edema]. Although weight gain was not associated with clinically important changes in blood pressure in short-term controlled studies, the long-term cardiovascular effects of LYRICA-associated weight gain are unknown. Among diabetic patients, LYRICA-treated patients gained an average of 1.6 kg (range: -16 to 16 kg), compared to an average 0.3 kg (range: -10 to 9 kg) weight gain in placebo patients. In a cohort of 333 diabetic patients who received LYRICA for at least 2 years, the average weight gain was 5.2 kg. While the effects of LYRICAassociated weight gain on glycemic control have not been systematically assessed, in controlled and longer-term open label clinical trials with diabetic patients, LYRICA treatment did not appear to be associated with loss of glycemic control (as measured by HbA1C). Abrupt or Rapid Discontinuation Following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache, and diarrhea. Taper LYRICA gradually over a minimum of 1 week rather than discontinuing the drug abruptly. Tumorigenic Potential In standard preclinical in vivo lifetime carcinogenicity studies of LYRICA, an unexpectedly high incidence of hemangiosarcoma was identified in two different strains of mice [see Nonclinical Toxicology, Carcinogenesis, Mutagenesis, Impairment of Fertility]. The clinical significance of this finding is unknown. Clinical experience during LYRICA’s premarketing development provides no direct means to assess its potential for inducing tumors in humans. In clinical studies across various patient populations, comprising 6396 patient-years of exposure in patients >12 years of age, new or worsening-preexisting tumors were reported in 57 patients. Without knowledge of the background incidence and recurrence in similar populations not treated with LYRICA, it is impossible to know whether the incidence seen in these cohorts is or is not affected by treatment. Ophthalmological Effects In controlled studies, a higher proportion of patients treated with LYRICA reported blurred vision (7%) than did patients treated with placebo (2%), which resolved in a majority of cases with continued dosing. Less than 1% of patients discontinued LYRICA treatment due to vision-related events (primarily blurred vision). Prospectively planned ophthalmologic testing, including visual acuity testing, formal visual field testing and dilated funduscopic examination, was performed in over 3600 patients. In these patients, visual acuity was reduced in 7% of patients treated with LYRICA, and 5% of placebo-treated patients. Visual field changes were detected in 13% of LYRICAtreated, and 12% of placebo-treated patients. Funduscopic changes were observed in 2% of LYRICA-treated and 2% of placebo-treated patients. Although the clinical significance of the ophthalmologic findings is unknown, inform patients to notify their physician if changes in vision occur. If visual disturbance persists, consider further assessment. Consider more frequent assessment for patients who are already routinely monitored for ocular conditions. Creatine Kinase Elevations LYRICA treatment was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum value were 60 U/L for LYRICA-treated patients and 28 U/L for the placebo patients. In all controlled trials across multiple patient populations, 1.5% of patients on LYRICA and 0.7% of placebo patients had a value of creatine kinase at least three times the upper limit of normal. Three LYRICA-treated subjects had events reported as rhabdomyolysis in premarketing clinical trials. The relationship between these myopathy events and LYRICA is not completely understood because the cases had documented factors that may have caused or contributed to these events. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaise or fever. Discontinue treatment with LYRICA if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur. Decreased Platelet Count LYRICA treatment was associated with a decrease in platelet count. LYRICA-treated subjects experienced a mean maximal decrease in platelet count of 20 x 10 3/µL, compared to 11 x 10 3/µL in placebo patients. In the overall database of controlled trials, 2% of placebo patients and 3% of LYRICA patients experienced a potentially clinically significant decrease in platelets, defined as 20% below baseline value and <150 x 10 3/µL. A single LYRICA treated subject developed severe thrombocytopenia with a platelet count less than 20 x 103/µL. In randomized controlled trials, LYRICA was not associated with an increase in bleeding-related adverse reactions. PR Interval Prolongation LYRICA treatment was associated with PR interval prolongation. In analyses of clinical trial ECG data, the mean PR interval increase was 3–6 msec at LYRICA doses ≥300 mg/day. This mean change difference was not associated with an increased risk of PR increase ≥25% from baseline, an increased percentage of subjects with on-treatment PR >200 msec, or an increased risk of adverse reactions of second or third degree AV block. Subgroup analyses did not identify an increased risk of PR prolongation in patients with baseline PR prolongation or in patients taking other PR prolonging medications. However, these analyses cannot be considered definitive because of the limited number of patients in these categories. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In all controlled and uncontrolled trials across various patient populations during the premarketing development of LYRICA, more than 10,000 patients have received LYRICA. Approximately 5000 patients were treated for 6 months or more, over 3100 patients were treated for 1 year or longer, and over 1400 patients were treated for at least 2 years. Adverse Reactions Most Commonly Leading to Discontinuation in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all populations combined, 14% of patients treated with LYRICA and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (4%) and somnolence (3%). In the placebo group, 1% of patients withdrew due to dizziness and <1% withdrew due to somnolence. Other adverse reactions that led to discontinuation from controlled trials more frequently in the LYRICA group compared to the placebo group were ataxia, confusion, asthenia, thinking abnormal, blurred vision, incoordination, and peripheral edema (1% each). Most Common Adverse Reactions in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all patient populations combined, dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and “thinking abnormal” (primarily difficulty with concentration/attention) were more commonly reported by subjects treated with LYRICA than by subjects treated with placebo (≥5% and twice the rate of that seen in placebo). Controlled Studies with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy Adverse Reactions Leading to Discontinuation In clinical trials in patients with neuropathic pain associated with diabetic peripheral neuropathy, 9% of patients treated with LYRICA and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (3%) and somnolence (2%). In comparison, <1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the LYRICA group than in the placebo group, were asthenia, confusion, and peripheral edema. Each of these events led to withdrawal in approximately 1% of patients. Most Common Adverse Reactions Table 3 lists all adverse reactions, regardless of causality, occurring in ≥1% of patients with neuropathic pain associated with diabetic neuropathy in the combined LYRICA group for which the incidence was greater in this combined LYRICA group than in the placebo group. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of “mild” or “moderate”.

Table 3 Treatment-emergent adverse reaction incidence in controlled trials in Neuropathic Pain Associated with Diabetic Peripheral Neuropathy (Events in at least 1% of all LYRICA-treated patients and at least numerically more in all LYRICA than in the placebo group) 75 mg/d 150 mg/d 300 mg/d 600 mg/d All PGB* Placebo Body System [N=77] [N=212] [N=321] [N=369] [N=979] [N=459] - Preferred term % % % % % % Body as a whole Asthenia 4 2 4 7 5 2 Accidental injury 5 2 2 6 4 3 Back pain 0 2 1 2 2 0 Chest pain 4 1 1 2 2 1 Face edema 0 1 1 2 1 0 Digestive system Dry mouth 3 2 5 7 5 1 Constipation 0 2 4 6 4 2 Flatulence 3 0 2 3 2 1 Metabolic and nutritional disorders Peripheral edema 4 6 9 12 9 2 Weight gain 0 4 4 6 4 0 Edema 0 2 4 2 2 0 Hypoglycemia 1 3 2 1 2 1 Nervous system Dizziness 8 9 23 29 21 5 Somnolence 4 6 13 16 12 3 Neuropathy 9 2 2 5 4 3 Ataxia 6 1 2 4 3 1 Vertigo 1 2 2 4 3 1 Confusion 0 1 2 3 2 1 Euphoria 0 0 3 2 2 0 Incoordination 1 0 2 2 2 0 1 0 1 3 2 0 Thinking abnormal† Tremor 1 1 1 2 1 0 Abnormal gait 1 0 1 3 1 0 Amnesia 3 1 0 2 1 0 Nervousness 0 1 1 1 1 0 Respiratory system Dyspnea 3 0 2 2 2 1 Special senses 3 1 3 6 4 2 Blurry vision‡ Abnormal vision 1 0 1 1 1 0 *PGB: pregabalin † Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. ‡ Investigator term; summary level term is amblyopia. Other Adverse Reactions Observed During the Clinical Studies of LYRICA Following is a list of treatment-emergent adverse reactions reported by patients treated with LYRICA during all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening. Events are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Events of major clinical importance are described in the Warnings and Precautions section. Body as a Whole – Frequent: Abdominal pain, Allergic reaction, Fever; Infrequent: Abscess, Cellulitis, Chills, Malaise, Neck rigidity, Overdose, Pelvic pain, Photosensitivity reaction; Rare: Anaphylactoid reaction, Ascites, Granuloma, Hangover effect, Intentional Injury, Retroperitoneal Fibrosis, Shock. Cardiovascular System – Infrequent: Deep thrombophlebitis, Heart failure, Hypotension, Postural hypotension, Retinal vascular disorder, Syncope; Rare: ST Depressed, Ventricular Fibrillation. Digestive System – Frequent: Gastroenteritis, Increased appetite; Infrequent: Cholecystitis, Cholelithiasis, Colitis, Dysphagia, Esophagitis, Gastritis, Gastrointestinal hemorrhage, Melena, Mouth ulceration, Pancreatitis, Rectal hemorrhage, Tongue edema; Rare: Aphthous stomatitis, Esophageal Ulcer, Periodontal abscess. Hemic and Lymphatic System – Frequent: Ecchymosis; Infrequent: Anemia, Eosinophilia, Hypochromic anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia; Rare: Myelofibrosis, Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia. Metabolic and Nutritional Disorders – Rare: Glucose Tolerance Decreased, Urate Crystalluria. Musculoskeletal System – Frequent: Arthralgia, Leg cramps, Myalgia, Myasthenia; Infrequent: Arthrosis; Rare: Chondrodystrophy, Generalized Spasm. Nervous System – Frequent: Anxiety, Depersonalization, Hypertonia, Hypesthesia, Libido decreased, Nystagmus, Paresthesia, Stupor, Twitching; Infrequent: Abnormal dreams, Agitation, Apathy, Aphasia, Circumoral paresthesia, Dysarthria, Hallucinations, Hostility, Hyperalgesia, Hyperesthesia, Hyperkinesia, Hypokinesia, Hypotonia, Libido increased, Myoclonus, Neuralgia; Rare: Addiction, Cerebellar syndrome, Cogwheel rigidity, Coma, Delirium, Delusions, Dysautonomia, Dyskinesia, Dystonia, Encephalopathy, Extrapyramidal syndrome, Guillain-Barré syndrome, Hypalgesia, Intracranial hypertension, Manic reaction, Paranoid reaction, Peripheral neuritis, Personality disorder, Psychotic depression, Schizophrenic reaction, Sleep disorder, Torticollis, Trismus. Respiratory System – Rare: Apnea, Atelectasis, Bronchiolitis, Hiccup, Laryngismus, Lung edema, Lung fibrosis, Yawn. Skin and Appendages – Frequent: Pruritus; Infrequent: Alopecia, Dry skin, Eczema, Hirsutism, Skin ulcer, Urticaria, Vesiculobullous rash; Rare: Angioedema, Exfoliative dermatitis, Lichenoid dermatitis, Melanosis, Nail Disorder, Petechial rash, Purpuric rash, Pustular rash, Skin atrophy, Skin necrosis, Skin nodule, Stevens-Johnson syndrome, Subcutaneous nodule. Special senses – Frequent: Conjunctivitis, Diplopia, Otitis media, Tinnitus; Infrequent: Abnormality of accommodation, Blepharitis, Dry eyes, Eye hemorrhage, Hyperacusis, Photophobia, Retinal edema, Taste loss, Taste perversion; Rare: Anisocoria, Blindness, Corneal ulcer, Exophthalmos, Extraocular palsy, Iritis, Keratitis, Keratoconjunctivitis, Miosis, Mydriasis, Night blindness, Ophthalmoplegia, Optic atrophy, Papilledema, Parosmia, Ptosis, Uveitis. Urogenital System – Frequent: Anorgasmia, Impotence, Urinary frequency, Urinary incontinence; Infrequent: Abnormal ejaculation, Albuminuria, Amenorrhea, Dysmenorrhea, Dysuria, Hematuria, Kidney calculus, Leukorrhea, Menorrhagia, Metrorrhagia, Nephritis, Oliguria, Urinary retention, Urine abnormality; Rare: Acute kidney failure, Balanitis, Bladder Neoplasm, Cervicitis, Dyspareunia, Epididymitis, Female lactation, Glomerulitis, Ovarian disorder, Pyelonephritis. Comparison of Gender and Race The overall adverse event profile of pregabalin was similar between women and men. There are insufficient data to support a statement regarding the distribution of adverse experience reports by race. Post-marketing Experience The following adverse reactions have been identified during postapproval use of LYRICA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous System Disorders – Headache. Gastrointestinal Disorders – Nausea, Diarrhea. Reproductive System and Breast Disorders – Gynecomastia, Breast Enlargement. DRUG INTERACTIONS Since LYRICA is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (<2% of a dose recovered in urine as metabolites), and does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein binding displacement. In vitro and in vivo studies showed that LYRICA is unlikely to be involved in significant pharmacokinetic drug interactions. Specifically, there are no pharmacokinetic interactions between pregabalin and the following antiepileptic drugs: carbamazepine, valproic acid, lamotrigine, phenytoin, phenobarbital, and topiramate. Important pharmacokinetic interactions would also not be expected to occur between LYRICA and commonly used antiepileptic drugs. Pharmacodynamics Multiple oral doses of LYRICA were co-administered with oxycodone, lorazepam, or ethanol. Although no pharmacokinetic interactions were seen, additive effects on cognitive and gross motor functioning were seen when LYRICA was co-administered with these drugs. No clinically important effects on respiration were seen. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including lethality, growth retardation, and nervous and reproductive system functional impairment, were observed in the offspring of rats and rabbits given pregabalin during pregnancy, at doses that produced plasma pregabalin exposures (AUC) ≥5 times human exposure at the maximum recommended dose (MRD) of 600 mg/day. When pregnant rats were given pregabalin (500, 1250, or 2500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at ≥1250 mg/kg, and incidences of skeletal variations and retarded ossification were increased at all doses. Fetal body weights were decreased at the highest dose. The low dose in this study was associated with a plasma exposure (AUC) approximately 17 times human exposure at the MRD of 600 mg/day. A no-effect dose for

rat embryo-fetal developmental toxicity was not established. When pregnant rabbits were given LYRICA (250, 500, or 1250 mg/kg) orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed at the highest dose. The no-effect dose for developmental toxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 16 times human exposure at the MRD. In a study in which female rats were dosed with LYRICA (50, 100, 250, 1250, or 2500 mg/kg) throughout gestation and lactation, offspring growth was reduced at ≥100 mg/kg and offspring survival was decreased at ≥250 mg/kg. The effect on offspring survival was pronounced at doses ≥1250 mg/kg, with 100% mortality in high-dose litters. When offspring were tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at ≥250 mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1250 mg/kg. The no-effect dose for pre- and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human exposure at the MRD. There are no adequate and well-controlled studies in pregnant women. Use LYRICA during pregnancy only if the potential benefit justifies the potential risk to the fetus. To provide information regarding the effects of in utero exposure to LYRICA, physicians are advised to recommend that pregnant patients taking LYRICA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www. aedpregnancyregistry.org/. Labor and Delivery The effects of LYRICA on labor and delivery in pregnant women are unknown. In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures ≥50 times the mean human exposure (AUC (0–24) of 123 µg•hr/mL) at the maximum recommended clinical dose of 600 mg/day. Nursing Mothers It is not known if pregabalin is excreted in human milk; it is, however, present in the milk of rats. Because many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for pregabalin in animal studies, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and efficacy of pregabalin in pediatric patients have not been established. In studies in which pregabalin (50 to 500 mg/kg) was orally administered to young rats from early in the postnatal period (Postnatal Day 7) through sexual maturity, neurobehavioral abnormalities (deficits in learning and memory, altered locomotor activity, decreased auditory startle responding and habituation) and reproductive impairment (delayed sexual maturation and decreased fertility in males and females) were observed at doses ≥50 mg/kg. The neurobehavioral changes of acoustic startle persisted at ≥250 mg/kg and locomotor activity and water maze performance at ≥500 mg/kg in animals tested after cessation of dosing and, thus, were considered to represent long-term effects. The low effect dose for developmental neurotoxicity and reproductive impairment in juvenile rats (50 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately equal to human exposure at the maximum recommended dose of 600 mg/day. A no-effect dose was not established. Geriatric Use In controlled clinical studies of LYRICA in neuropathic pain associated with diabetic peripheral neuropathy, 246 patients were 65 to 74 years of age, and 73 patients were 75 years of age or older. In controlled clinical studies of LYRICA in neuropathic pain associated with postherpetic neuralgia, 282 patients were 65 to 74 years of age, and 379 patients were 75 years of age or older. No overall differences in safety and efficacy were observed between these patients and younger patients. In controlled clinical studies of LYRICA in fibromyalgia, 106 patients were 65 years of age or older. Although the adverse reaction profile was similar between the two age groups, the following neurological adverse reactions were more frequent in patients 65 years of age or older: dizziness, vision blurred, balance disorder, tremor, confusional state, coordination abnormal, and lethargy. LYRICA is known to be substantially excreted by the kidney, and the risk of toxic reactions to LYRICA may be greater in patients with impaired renal function. Because LYRICA is eliminated primarily by renal excretion, adjust the dose for elderly patients with renal impairment. DRUG ABUSE AND DEPENDENCE Controlled Substance LYRICA is a Schedule V controlled substance. LYRICA is not known to be active at receptor sites associated with drugs of abuse. As with any CNS active drug, carefully evaluate patients for history of drug abuse and observe them for signs of LYRICA misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior). Abuse In a study of recreational users (N=15) of sedative/hypnotic drugs, including alcohol, LYRICA (450 mg, single dose) received subjective ratings of “good drug effect,” “high” and “liking” to a degree that was similar to diazepam (30 mg, single dose). In controlled clinical studies in over 5500 patients, 4% of LYRICA-treated patients and 1% of placebo-treated patients overall reported euphoria as an adverse reaction, though in some patient populations studied, this reporting rate was higher and ranged from 1 to 12%. Dependence In clinical studies, following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache or diarrhea [see Warnings and Precautions, Abrupt or Rapid Discontinuation], suggestive of physical dependence. OVERDOSAGE Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans There is limited experience with overdose of LYRICA. The highest reported accidental overdose of LYRICA during the clinical development program was 8000 mg, and there were no notable clinical consequences. Treatment or Management of Overdose There is no specific antidote for overdose with LYRICA. If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; observe usual precautions to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient. Contact a Certified Poison Control Center for up-to-date information on the management of overdose with LYRICA. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment. Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50% in 4 hours). NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis A dose-dependent increase in the incidence of malignant vascular tumors (hemangiosarcomas) was observed in two strains of mice (B6C3F1 and CD-1) given pregabalin (200, 1000, or 5000 mg/kg) in the diet for two years. Plasma pregabalin exposure (AUC) in mice receiving the lowest dose that increased hemangiosarcomas was approximately equal to the human exposure at the maximum recommended dose (MRD) of 600 mg/day. A no-effect dose for induction of hemangiosarcomas in mice was not established. No evidence of carcinogenicity was seen in two studies in Wistar rats following dietary administration of pregabalin for two years at doses (50, 150, or 450 mg/kg in males and 100, 300, or 900 mg/kg in females) that were associated with plasma exposures in males and females up to approximately 14 and 24 times, respectively, human exposure at the MRD. Mutagenesis Pregabalin was not mutagenic in bacteria or in mammalian cells in vitro, was not clastogenic in mammalian systems in vitro and in vivo, and did not induce unscheduled DNA synthesis in mouse or rat hepatocytes. Impairment of Fertility In fertility studies in which male rats were orally administered pregabalin (50 to 2500 mg/kg) prior to and during mating with untreated females, a number of adverse reproductive and developmental effects were observed. These included decreased sperm counts and sperm motility, increased sperm abnormalities, reduced fertility, increased preimplantation embryo loss, decreased litter size, decreased fetal body weights, and an increased incidence of fetal abnormalities. Effects on sperm and fertility parameters were reversible in studies of this duration (3–4 months). The no-effect dose for male reproductive toxicity in these studies (100 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately 3 times human exposure at the maximum recommended dose (MRD) of 600 mg/day. In addition, adverse reactions on reproductive organ (testes, epididymides) histopathology were observed in male rats exposed to pregabalin (500 to 1250 mg/kg) in general toxicology studies of four weeks or greater duration. The no-effect dose for male reproductive organ histopathology in rats (250 mg/kg) was associated with a plasma exposure approximately 8 times human exposure at the MRD. In a fertility study in which female rats were given pregabalin (500, 1250, or 2500 mg/kg) orally prior to and during mating and early gestation, disrupted estrous cyclicity and an increased number of days to mating were seen at all doses, and embryolethality occurred at the highest dose. The low dose in this study produced a plasma exposure approximately 9 times that in humans receiving the MRD. A no-effect dose for female reproductive toxicity in rats was not established. Human Data In a double-blind, placebo-controlled clinical trial to assess the effect of pregabalin on sperm motility, 30 healthy male subjects were exposed to pregabalin at a dose of 600 mg/day. After 3 months of treatment (one complete sperm cycle), the difference between placebo- and pregabalintreated subjects in mean percent sperm with normal motility was <4% and neither group had a mean change from baseline of more than 2%. Effects on other male reproductive parameters in humans have not been adequately studied. Animal Toxicology and/or Pharmacology Dermatopathy Skin lesions ranging from erythema to necrosis were seen in repeated-dose toxicology studies in both rats and monkeys. The etiology of these skin lesions is unknown. At the maximum recommended human dose (MRD) of 600 mg/day, there is a 2-fold safety margin for the dermatological lesions. The more severe dermatopathies involving necrosis were associated with pregabalin exposures (as expressed by plasma AUCs) of approximately 3 to 8 times those achieved in humans given the MRD. No increase in incidence of skin lesions was observed in clinical studies. Ocular Lesions Ocular lesions (characterized by retinal atrophy [including loss of photoreceptor cells] and/or corneal inflammation/mineralization) were observed in two lifetime carcinogenicity studies in Wistar rats. These findings were observed at plasma pregabalin exposures (AUC) ≥2 times those achieved in humans given the maximum recommended dose of 600 mg/day. A no-effect dose for ocular lesions was not established. Similar lesions were not observed in lifetime carcinogenicity studies in two strains of mice or in monkeys treated for 1 year. LAB-0294-21.0 June 2011

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2 THE CLINICAL ADVISOR • MARCH 2012 • www.ClinicalAdvisor.com

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CONTENTS MARCH 2012

NEWS AND COMMENT 14

Newsline ■ Metformin shines as diabetes treatment ■ Fiber bad news for diverticulosis ■ Rheumatoid arthritis patients face blood clot risk ■ BP differences might offer a clue to peripheral vascular disease ■ Step up your adult vaccination efforts

Clinical Challenge Dizziness coupled with vomiting send a man to the emergency department.

Legal Advisor A distracted young clinician fails to ensure the safety of a patient.

CME/CE Dermatologic Look-Alikes Two cases of growing skin plaques with scale.

CME/CE Posttest

Alternative Meds Update Hypnotherapy is used to treat pain, anxiety, and behavioral disorders.

Clinicians turn to metformin first 14

Commentary

FEATURES 20

CME/CE Helicobacter pylori:

Toward effective eradication When choosing among the treatment options, consider local prevalence and antibiotic resistance.

ADVISOR FORUM 46

Predisease: A concept whose time has come? There is a temptation to treat patients before they develop a disease, but the adage still applies: First, do no harm.

to pseudogout? ■ Could this be COPD? ■ And more

When to intervene in cases of predisease 33

Clinical Pearls ■ Colder eyedrops mean enhanced relief ■ New pain-management terminology ■ Attitude is everything

Your Comments ■ Toward a more humane source of estrogen

DEPARTMENTS 59

Consultations ■ Is vitamin D deficiency linked

CME/CE Dermatology Clinic ■ Erythematous lichenified plaques develop on a girl’s hands. ■ An elderly woman presents with a

growing verrucous papule on her neck. SPECIAL FEATURE!

Derm Dx Read the clinical descriptions, view the images, and then make your diagnosis at ClinicalAdvisor.com.

MAKING CONTACT

Picture this A pair of photo essays to break up the day 12, 64

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EXCLUSIVE TO THE WEB AT

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Mortality higher among women with MI and no chest pain Clinicians should be aware of gender differences in symptom presentation when caring for patients with heart attack. Microchip effectively delivers osteoporosis drug An implantable microchip that is the size of a flash-memory drive and can be controlled remotely delivered doses of an osteoporosis medication with the same efficacy as injection. Newer pneumonia vaccine could be more cost-effective Thirteen-valent pneumococcal conjugate vaccine might prevent more adult pneumonia than the 23-valent pneumococcal polysaccharide vaccine, at a better price.

Derm Dx Interact with your peers by viewing the images and offering your diagnosis and comments. ClinicalAdvisor.com/DermDx Itchy maceration between the toes A man presents with foul-smelling, itchy, and macerated skin between his third and fourth toes. He is not sure when the condition started.

MAKING CONTACT

Hypertension & Associated Complications One in three U.S. adults has hypertension, the CDC estimates, which increases the risks of heart disease and stroke—the first and third leading causes of U.S. deaths.

The Waiting Room Official Blog of The Clinical Advisor ClinicalAdvisor.com/Blog Katherine Wilkens, PA-C Is Medicare’s 85% reimbursement rule fair? Medicare only reimburses 85% of fees for PA-provided health care, and soon private insurance carriers may do the same. Is it fair to pay less for a PA office visit than an MD visit? Sharon M. O’Brien, MPAS, PA-C Violent sleep bouts: An early sign of Parkinson’s disease? A normally quiet, older man who has been happily married for 50 years fights battles in his sleep and awakes to find his wife beaten and bruised. What could be the cause? Robyn Carlisle, MSN, CNM, WHNP Putting the brakes on drive-by medicine Most patients only need a little bit of their health-care provider’s time and attention to feel that their concerns have been heard. Leigh Montejo, MSN, FNP-BC Overcoming barriers to quality oral health care Transforming the perfect smile from an American status symbol to the status quo begins with primary-care providers. Julee Waldrop, DNP Promoting neonatal health through breast-milk donation Milk banks now provide life-improving and sometimes lifesaving services to many newborns and infants—especially premature infants—around the world.

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8 THE CLINICAL ADVISOR • MARCH 2012 • www.ClinicalAdvisor.com

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Everyone needs a break during the day. So relax with this photo essay, and pretend you’re someplace else.

Picture this

12 THE CLINICAL ADVISOR • MARCH 2012 • www.ClinicalAdvisor.com

In a field in Berkmeer, Netherlands, a windmill and thousands of tulips combine to create a timeless portrait of the Dutch countryside. Every spring, travelers flock to Holland to see the iconic flower in full bloom.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MARCH 2012 13

CME CE

PROGRAM OUTLINE MARCH 2012

0.5 CREDITS

Page 20 FEATURE Helicobacter pylori: Toward effective eradication Susan Collazo, RN, MSN, ACNP ■ LEARNING OBJECTIVES: • Identify the alarm signs for risk of gastric cancer or complicated ulcer disease. • Name the medications to be avoided prior to rapid urease testing for Helicobacter pylori. • Explain why metronidazole is used in the treatment of H. pylori infection. • Describe how long testing should be performed after treatment completion to ascertain H. pylori eradication.

0.5 CREDITS

Page 59 DERMATOLOGY CLINIC Case #1: Thick, leathery, and red skin over the hands Kerri Robbins, MD

Case #2: Slow-growing papule with no pain or itching Esther Stern, NP-C ■ LEARNING OBJECTIVES: • To identify and diagnose dermatologic conditions and review up-to-date treatment.

Page 75 DERMATOLOGIC LOOK-ALIKES Growing skin plaques with scale Joe Monroe, PA-C ■ Learning objective: • To distinguish and properly treat dermatologic conditions with similar presentations.

Page 79 POSTTEST This program has been reviewed and is approved for a maximum of 1 hour of AAPA Category I CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of March 2012. Participants may submit the self-assessment at any time during that period. This program was planned in accordance with AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs. The Nurse Practitioner Associates for Continuing Education (NPACE) is an approved provider of continuing education by the Massachusetts Association of Registered Nurses, Inc. (MARN), an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation (ANCC). NPACE designates this educational activity for a maximum of 1 contact hour of credit. Participants should only claim credit commensurate with the extent of their participation in the activity.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MARCH 2012 11

Newsline

High-fiber diet may raise risk of diverticulosis page 18

M A R C H 2 0 12

Higher BP in one arm may be a clue to PVD page 18

More adults need to be vaccinated page 19

Metformin shines as diabetes treatment

Metformin is the first-line drug of choice for treating type 2 diabetes.

and Jentadueto, a mixture of linagliptin and metformin. Metformin use was also linked with prolonged survival in persons with cancer. A recent analysis of 8,392 people with diabetes and 104,016 without diabetes who developed a first tumor yielded the notable finding that diabetes patients who had been on metformin monotherapy for 90 days before cancer diagnosis had significantly reduced overall mortality (HR 0.85) compared with cancer patients without diabetes (Diabetes Care 2012;35:299-304). Previous research has shown similar results. Among the cancer patients with diabetes, significantly increased mortality was seen in those treated with a sulfonylurea alone (HR 1.48) or with insulin alone (HR1.33) compared with persons on metformin monotherapy.

Percentage of adults being advised to exercise In 2010, about one in three adults who had seen a clinician in the past year was advised to begin or continue to do physical activity. Source: CDC/NCHS, National Health Interview Survey

32.4% 29.4%

30 Percentage

ALTHOUGH MOST oral medications prescribed for diabetes therapy reduce blood glucose levels to a similar degree, metformin does this more effectively than others when used alone or in combination with other antidiabetes agents, while also reducing body weight and improving cholesterol profiles. A new clinical practice guideline from the American College of Physicians (ACP) recommends metformin as the initial drug treatment for most patients with type 2 diabetes once such lifestyle modifications as diet, exercise, and weight loss have failed to adequately improve hyperglycemia (Ann Intern Med. 2012;156:218231). The guideline further advises clinicians to add a second agent to metformin when persistent hyperglycemia cannot be controlled by lifestyle modifications and metformin monotherapy.

The ACP developed these recommendations after reviewing data on several types of oral medications that target high blood glucose in people with type 2 diabetes: metformin, sulfonylureas, meglitinides, th iazol id ined iones, DPP- 4 inhibitors, and GLF-1 receptor antagonists. The evidence for long-term and intermediate outcomes for blood glucose levels, body weight, cholesterol and triglyceride levels, all-cause mortality, cardiovascular disease and death, neuropathy, and kidney function indicated that sulfonylureas carried the highest risk of causing dangerously low blood glucose levels. The FDA recently approved two new metformin-containing tablets for the treatment of type 2 diabetes: Janumet XR, which combines sitagliptin and metformin,

22.6%

20 15 10 5 0

2000

14 THE CLINICAL ADVISOR • MARCH 2012 • www.ClinicalAdvisor.com

2005

2010

Newsline Fiber bad RA patients face blood-clot risk news for diverticulosis

Those with RA had a higher incidence of both DVT and PE.

vs. 1.7%) and pulmonary embolism (4.8% vs. 1.6%). Although persons with RA are known to have an increased incidence of cardiovascular disease in relation to the general population, this research demonstrated that the incidence of noncardiac vascular disease—venous thromboembolic, cerebrovascular, and peripheral arterial events— remained stable from the 19801994 time period through the 1995-2007 time period (Arthritis Rheum. 2012;64:53-61). Consider an individual patient’s risk of thrombosis when deciding for or against the use of preventive therapies for deep vein thrombosis and venous thromboembolism, advise recently released practice guidelines (Chest. 2012;141[2 suppl]:e1S-e801S; available at chestjournal.chestpubs.org/ content/141/2_suppl, accessed February 15, 2012).

BP differences might offer a clue to PVD A difference in BP between a person’s right and left arms could be a useful indicator of risk for vascular disease and death. Analysis of data from 20 studies revealed significant evidence to suggest that a difference in systolic BP of >15 mm Hg between the two arms was associated with a 2.5times increased risk for peripheral vascular disease (PVD) and a 1.6 times increased risk for pre-existing cerebrovascular disease. This difference also raised cardiovascular mortality risk by 70% and all-cause mortality risk by 60%. Risk of PVD was also increased at a difference of >10 mm Hg.

18 THE CLINICAL ADVISOR • MARCH 2012 • www.ClinicalAdvisor.com

The arm that has the higher BP can vary from person to person, but it is the difference in systolic BP between the left and right arm that counts, not which arm has the higher or lower BP, reported Christopher E. Clark, FRCP, PhD, and coinvestigators online ahead of print in The Lancet. “[A] difference in [systolic BP] of 10 mm Hg or more or 15 mm Hg or more between arms could identify patients at high risk of asymptomatic peripheral vascular disease and mortality who might benefit from further assessment,” wrote the researchers.

EARLY R ESULTS from a study of 2,104 patients undergoing outpatient colonoscopy point to a surprising conclusion: Consuming a high-fiber diet may raise a person’s risk of developing diverticulosis. The f indings also linked increased frequency of bowel movements with greater diverticulosis risk, calling into question the commonly held belief that constipation adds to a person’s risk of developing the disease. In the cross-sectional study of persons aged 30 to 80 years, the prevalence of diverticulosis increased with age, as expected. However, high intake of fiber did not reduce prevalence: Instead, the quartile with the highest fiber intake had a greater prevalence of diverticulosis than did the lowest quartile. Constipation was not found to be a risk factor: Compared with individuals with fewer than seven bowel movements per week, those with more than 15 had a 70% greater risk for diverticulosis. Neither physical activity nor intake of fat or red meat was associated with diverticulosis (Gastroenterology. 2012;142:266-272). The causes of diverticulosis remain unknown, but gut flora might play a role. Although these findings offer insights into risk factors, the investigators note that more research is needed before clinicians change their dietary recommendations to patients.

COMPARED WITH persons without rheumatoid arthritis (RA), individuals with the disease are at heightened risk for venous thromboembolism. In a study of 813 RA patients (mean age 55.9 years), those diagnosed as having RA between 1995 and 2007 had a higher incidence of venous thromboembolism than did age- and sex-matched controls (6.7% vs. 2.8%), but similar rates of cerebrovascular and peripheral arterial events, over an average follow-up of 9.6 years. This elevated risk of venous thromboembolism for persons with RA was noted to occur steadily throughout the followup period. When such events were analyzed individually, and patients with RA were compared with those without RA, those with the disease had a higher 10-year cumulative incidence of both deep vein thrombosis (3.1%

Step up your adult vaccination efforts OF F IC E - BA SE D set t i n g s remain a logical focus of efforts to increase adult vaccination, but office-based providers are not meeting their potential in administering and promoting this service. These were the fi ndings of a RAND Corporation report by Katherine M. Harris and colleagues (www.rand.org/pubs/ techn ica l _ repor ts/TR1169. html, accessed February 15, 2012). The report, sponsored by GlaxoSmithKline, indicated that a substantial proportion of clinicians who treat adults appear not to vaccinate at all. The authors cite data from surveys suggesting that only 27% of these practitioners stock all recommended

adult vaccinations. According to the authors, adult vaccination also is infrequently discussed at health-care encounters, despite evidence that the public places a high degree of trust in providers to deliver vaccination information. In a separate study, published online ahead of print by the journal Infection, Farah Ladak and associates found that in a nationally representative sample, 51.4% of high-risk adults remained unvaccinated against the hepatitis B virus and more than 50% had a missed opportunity for vaccination. In its 2012 recommended adult immunization schedule (Ann Intern Med. 2012;156:211-

The public trusts providers to deliver vaccination information.

217), the CDC’s Adv isor y Committee on Immunization Practices (ACIP) counsels that adults younger than age 60 years with diabetes be vaccinated against hepatitis B as soon as possible after diabetes diagnosis. Specif ied older patients with diabetes also should undergo hepatitis B vaccination. The ACIP also now recommends routine HPV vaccination for males aged 11 to 12 years and catch-up vaccination for males aged 13 to 21 years. Among U.S. men and women aged 14 to 69 years, the overall prevalence of oral HPV infection was 6.9%, and the prevalence was higher among men than among women ( JAMA. 2012;307:693-703). ■

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MARCH 2012 19

CME CE FEATURE

■ LEARNING OBJECTIVES : • Identify the alarm signs for risk of gastric cancer or complicated ulcer disease. • Name the medications to be avoided prior to rapid urease testing for Helicobacter pylori. • Explain why metronidazole is used in the treatment of H. pylori infection. • Describe how long testing should be performed after treatment completion to ascertain H. pylori eradication. ■ COMPLETE THE POSTTEST: Page 79 ■ ADDITIONAL CME/CE: Pages 59, 75

SUSAN COLLAZO, RN, MSN, ACNP

Helicobacter pylori: Toward effective eradication When choosing among the available treatment options, consideration must be given to local prevalence and antibiotic resistance.

Helicobacter pylori (green) is one of the most common causes of stomach ulcers.

elicobacter pylori is the cause of one of the most common human infections worldwide. Patients colonized with this gramnegative bacterium can be asymptomatic, or they may experience such significant GI manifestations as chronic gastritis, peptic ulcer disease (PUD), and gastric malignancy. Diagnostic testing and treatment are readily available, but increasing antibiotic resistance has made the bacterium difficult to treat. Primary-care providers need a solid understanding of H. pylori, including prevalence, mode of transmission, diagnostic testing, and effective treatment toward eradication. Background

In 1893, Polish scientist Walery Jarowski first reported observation of a spiral bacterium that he called Vibrio rugula.1 Later researchers called the organism Campylobacter pyloridis. Eventually, the name was changed to H. pylori because of the organism’s helical shape. In 1982, Marshall and Warren confirmed the presence of H. pylori in patients with chronic gastritis 20 THE CLINICAL ADVISOR • MARCH 2012 • www.ClinicalAdvisor.com

Gastric host

Helicobacter pylori

Gastric lymphoma 1. Disrupts mucus layer integrity 2. Inflammatory response Asymptomatic Gastritis Atrophy Peptic ulcer disease

Intestinal metaplasia

Gastric cancer

FIGURE 1. Interaction of H. pylori with host and possible consequences16

and gastric ulcers. At the time, ulcer treatment was focused on chronic reduction of gastric acid. The identification of H. pylori and what it meant for the possible eradication of PUD was significant. The researchers won a Nobel Prize in 2005 for this finding.2

confirmed a correlation between gastric infection and the presence of H. pylori in the mouth. Dental plaque has been reported to be a reservoir for H. pylori.6 Some authors have found H. pylori to be part of the normal flora in the mouth,7 while others feel more studies are needed to confirm this finding.8

Prevalence

Pathogenesis

The prevalence of H. pylori infection increases with age and is highest in immigrants and low socioeconomic groups. In the United States, more than 50% of asymptomatic persons older than age 60 years show evidence of active or past H. pylori infection.3 Worldwide, at least 30% to 50% of the population is colonized by this bacterium, but the rate is declining. For instance, the infection rate in Poland had reached a high of 58.29% of the population. During the past 10 years, widespread application of a test-and-treat strategy has lowered the Polish H. pylori infection rate to 30%. Blaser, who attributes the worldwide decline in H. pylori prevalence to improved standards of living, notes that the reduction has been accompanied by an increase in the occurrence of gastroesophageal reflux disease, Barrett’s esophagus, and esophageal carcinoma.4

The stomach is a remarkable organ: It secretes juices that aid in food digestion, but it does not digest itself. Food entering the stomach initiates a chain of highly complex actions. The secretion of gastrin, production of hydrochloric acid, and conversion of pepsinogen to pepsin are all interconnected. During digestion, the gastric mucosa is injured frequently, but a rapid process called gastric cytoprotection provides repair and multiple layers of defense to prevent any significant disruption of function. The stomach’s protective mechanisms include a well-defined mucus layer that covers the lining; alkaline bicarbonate secretion under the mucus layer; a continuous, insoluble mucus epithelial layer that creates a buffer zone; and a rich blood supply that maintains epithelial integrity. The stomach also contains cytoprotective substances, such as prostaglandins, which provide protection by suppressing gastric acid. The only condition that puts our gastric defenses at risk is inflammation. Colonization of the stomach by H. pylori can cause chronic gastritis, or inflammation of the stomach lining, as the gramnegative, flagellated, and motile H. pylori organisms interact with a gastric host (Figure 1). Specific factors of the susceptible host may influence the manner in which H. pylori will affect

Mode of transmission

The exact mode of H. pylori transmission is still unknown. Transmission has been proposed to occur via contaminated groundwater, food, and human saliva (e.g., from kissing or sharing water bottles).5 The organism has also been found on unsterilized endoscopy equipment. Periodontal disease has recently been associated with H. pylori. Numerous studies have

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MARCH 2012 21

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it; the precise nature of these factors is presently unknown. Similar to other gram-negative bacteria, H. pylori possesses a lipopolysaccharide that acts to disrupt mucosal integrity.9 Once H. pylori invades the host, numerous toxins, enzymes, and/or pathogenic proteins are released, which also disturb the integrity of the gastric layer. One example of a pathologic protein is CagA protein, which is produced by cytotoxic-associated gene A and predisposes the host to more aggressive clinical syndromes, such as PUD, duodenal ulcer, and gastric carcinoma.10 H. pylori damages the gastric mucosa by means of a number of mechanisms (e.g., releasing numerous toxins, enzymes, and pathologic proteins; disrupting the gastric mucous layer; and inciting an inflammatory response). Moreover, H. pylori– produced urease converts urea found in the gastric lumen to ammonia, thereby neutralizing gastric acid. In addition, the organism’s spiral shape and flagella facilitate its passage to the mucoid lining of the stomach.11 In response to H. pylori, the stomach produces more gastrin, which in turn leads to an increase in the amount of acid secreted by parietal cells.12 An assault of excessive acid and pepsin on the stomach lining can cause the lining to erode, leading to development of an ulcer. Where the effects of chronic gastritis are seen determines whether the lesion is a peptic or a duodenal ulcer. H. pylori infection can have various clinical manifestations, including PUD, atrophy, TABLE 1. Alarm signs for risk of gastric cancer or complicated ulcer disease14, 36 • Age >55 years

• Weight loss >10% body weight

• Recurrent vomiting

• Odynophagia

• Rectal bleeding or melena

• Anemia

• Family history of gastric cancer

• Progressive dysphagia

• Early satiety

• Previous esophagogastric malignancy

TABLE 2. American College of Gastroenterology testing guidelines for H. pylori15 Test for H. pylori only if clinical plans are to offer treatment (e.g., can the patient afford treatment?) Testing is indicated in patients with active PUD, a history of PUD, or gastric mucosa-associated lymphoid tissue (MALT) lymphoma. In patients younger than age 55 years who have no alarm symptoms and present with uninvestigated dyspepsia, the test-and-treat approach is a proven management strategy. Decision to test is dependent on whether the patient requires upper endoscopy and on an understanding of the strengths, weaknesses, and costs of each individual test.

gastritis, or gastric lymphoma. Gastric atrophy can cause intestinal metaplasia, which has been found to be a precursor of gastric carcinoma. While overuse of nonsteroidal antiinflammatory drugs (NSAIDs) is often cited as a cause of PUD, 70% to 90% of cases have been attributed to H. pylori infection. Eradication of H. pylori can help prevent recurrence of duodenal ulcer and PUD.13 Regardless of their history of NSAID use, all patients with a peptic ulcer should be tested for the presence of H. pylori. Clinical symptoms

Typical symptoms noted in patients with possible H. pylori infection include epigastric pain/tenderness, nausea/vomiting, dyspepsia, chest discomfort, abdominal bloating, and possible GI bleed. Patients who present with “alarm signs” indicating possible gastric cancer or complicated ulcer should be referred to a gastroenterologist. Such signs include age older than 55 years, jaundice, rectal bleeding or melena, family history of gastric cancer, early satiety, weight loss >10% of body weight, history of peptic ulcer, anemia, progressive dysphagia, or abdominal mass14 (Table 1). Diagnosis

Diagnosis of H. pylori infection can be clinical or based on noninvasive or invasive testing. In 2007, the American College of Gastroenterology published guidelines for H. pylori testing15 (Table 2). Invasive testing. The invasive approaches for diagnosing H. pylori infection rely on biopsy specimens obtained via endoscopy or surgery and include rapid urease testing (RUT), histology, culture, and polymerase chain reaction (PCR) (Table 3). These techniques require expensive equipment, personnel, and time, which may delay patient treatment. Additionally, proton pump inhibitors (PPIs), antibiotics, and bismuth must be avoided for a time prior to testing in order to improve sensitivity.15,16 Although endoscopy may be indicated in patients with clinical symptoms, the presence of an active bleeding ulcer will significantly reduce the sensitivity of the procedure to detect the presence of H. pylori.17 A negative result on RUT and/or histology in the setting of an acute upper-GI bleed should be confirmed with another test, such as a urea breath test (UBT) or fecal antigen testing.15 Noninvasive testing. H. pylori also can be detected noninvasively with serology (identification of antibodies), the UBT, and fecal antigen testing (Table 4). Serology. People infected with H. pylori generally have specific immunoglobulin (Ig)G and IgA antibodies circulating in their blood, and these can be detected by serologic tests.

22 THE CLINICAL ADVISOR • MARCH 2012 • www.ClinicalAdvisor.com

TABLE 3. Invasive diagnostic testing15 Test

Advantage

Disadvantage

RUT

• Fast—results available within 1-24 hours • Simple • Reliable for assessing eradication

• No use of PPI for one week prior to testing • No antibody or bismuth use for four weeks prior to testing

Histology

Obtain pathology results at the same time

Expensive; requires skilled personnel

Culture

Allows for sensitivity testing

• Not as sensitive as RUT or histology • Expensive

PCR

Detects H. pylori in presence of gastritis and mutations

• High false-positive rate • Technically demanding and not standardized across laboratories

Sensitivity

Specificity

96.3%

98.6%

98%

100%

70%–80%

100%

>95%

Sensitivity

Specificity

Key: PCR = polymerase chain reaction; PPI = proton pump inhibitor; RUT = rapid urease test.

TABLE 4. Noninvasive diagnostic testing15 Test

Advantage

Disadvantage

Laboratory serology (ELISA for IgG)

Accurate

• Sensitivity dependent on local prevalence • Not useful for assessing eradication

85%

70%

Point-of-care serology test (ELISA for IgG)

• Office-based • Rapid • Low-cost • CLIA-waived

Not reliable in young symptomatic patients

50%–85%

75%–100%

UBT

• Excellent test reproducibility • Office-based • Reliable for assessing eradication

• Reliability reduced by PPIs, bismuth, antibody therapy • More expensive than ELISA or fecal antigen testing • Reimbursement remains inconsistent

95%

Fecal antigen test

• Rapid, low-cost • Office-based • Reliable for assessing eradication • Ideal for young patients

Collection is unpleasant

94%

86%

Key: CLIA = Clinical Laboratory Improvement Amendments; ELISA = enzyme-linked immunosorbent assay; IgG = immunoglobulin G; PPI = proton pump inhibitor; UBT = urea breath test.

Antibody detection is usually performed using a laboratorybased enzyme-linked immunosorbent assay (ELISA). IgG response is seen in 95% of actively infected patients, and IgA response is seen in 60% to 80% of patients; only 14% of patients produce IgM. IgG antibodies can be detected 21 days after infection.15 Serologic tests must be locally validated because their parameters are adjusted by the test manufacturer to suit the population in which the test is used. In other words, the positive predictive value of antibody testing is influenced by the prevalence of H. pylori infection in that area.18 A small proportion of elderly patients do not mount an IgG response, and up to 31% of elderly patients with positive serology may not have active infection.19 Antibody levels drop very slowly following eradication of the organism, and up to 65% of patients may remain positive for 12 months post-treatment. Therefore, serology is not useful in assessing eradication.20,21 An office-based serology test is currently available. This test offers a rapid method for initial screening of those patients who present with uncomplicated PUD, dyspepsia with no

prior eradication treatment, or undifferentiated dyspepsia without endoscopy.22 Urea breath test. H. pylori produces large quantities of urease, so UBT is a reliable diagnostic procedure. For this test, the patient swallows urea labeled with radioactive carbon (13C or 14C). The urea is then metabolized by the H. pylori organisms, producing ammonia and labeled carbon dioxide. This labeled carbon dioxide can be detected in a patient’s expired breath using mass spectrometry in the clinician’s office. A study examined the validity and accuracy of the 14C UBT and found: sensitivity, 96.3%; specificity, 98.6%; positive predictive value, 98.1%; negative predictive value, 97.2%; and accuracy, 97.6%. Thus, this method is very accurate for detecting H. pylori infection as well as for confirming eradication.23 The downsides are that it is more costly than ELISA and fecal antigen testing; reimbursement remains inconsistent; and reliability/test sensitivity is reduced by numerous medications including PPIs, bismuth, and antibiotics.24 Continues on page 24

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TABLE 5. H. pylori treatment recommendations in the United States Treatment FIRST-LINE THERAPY Clarithromycin triple therapy omeprazole 20 mg b.i.d. + clarithromycin 500 mg b.i.d. + metronidazole 500 mg b.i.d. or amoxicillin 1 g b.i.d.. (If penicillin-allergic) x 10-14 days*** Bismuth quadruple therapy Bismuth subsalicylate 525 mg q.i.d. + metronidazole 250 mg q.i.d. + tetracycline 500 mg q.i.d. + rantidine 150 mg b.i.d. or PPI x 14 days† Above medications with b.i.d. dosing x 14 days SEQUENTIAL THERAPY PPI b.i.d. + amoxicillin 1 g b.i.d. x 5 days followed by PPI b.i.d. + clarithromycin 500 mg b.i.d. + metronidazole 500 mg b.i.d. x 5 days‡

Eradication Rate 70%-85%

75%-90%

92% Not Validated

Consider in penicillin-nonallergic patients; increase sensitivity in patients who never have received metronidazole in the past; substitute metronidazole in penicillin-allergic patients. ** U.S. guidelines recommend 10–14 days although international studies recommend seven days of treatment. † Consider in metronidazole-resistant strains ‡ Not validated in the United States

TABLE 6.Test-and-treat strategy Diagnosis of H. pylori via UBT or fecal antigen testing No endoscopy needed Treat if test is positive for H. pylori

Fecal antigen test. H. pylori antigen in the stool can be identified by enzyme immunoassay with the use of polycolonal or monoclonal anti-H. pylori antibody. Because these tests detect bacterial antigens suggestive of ongoing infection, they can be used to screen for active infection as well as for eradication of H. pylori. Fecal antigen testing for H. pylori eradication can be done as soon as seven days after completion of therapy, with significant positive and negative predictive values (100% and 91%, respectively).25 Note that in the pediatric population, fecal antigen testing and UBT are the diagnostic studies of choice since serology testing has been found to be less accurate.26 Treatment options

Multiple treatment regimens have been studied in numerous randomized trials. Unfortunately, the optimal treatment has not been found because of the ever-changing antibiotic resistance developed by H. pylori. Since the first course of treatment offers the greatest likelihood of eradicating H. pylori infection, clinicians shoulud only use treatments that have proven to be

effective with an eradication rate >90%. Effective eradication typically requires use of two or more antibiotics in conjunction with a PPI and/or bismuth compound. The factors that influence the success of H. pylori treatment include the appropriate drugs, doses, dosing interval, and treatment duration in your local area of practice. A clinician knowledgeable about local susceptibilities and efficacious treatment plans should write a prescription aimed at eradication. PPI-amoxicillin-clarithromycin (PPI-AC) therapy is a key eradication regimen used in many countries worldwide, including the United States.27 France has identified frequent occurrences of clarithromycin resistance that can be attributed to new strains of H. pylori, and such other countries as Brazil are requesting pretreatment susceptibility testing.28,29 The recent recommendations in guidance of effective therapy in the United States include: • Clarithromycin triple therapy—omeprazole 20 mg b.i.d., clarithromycin 500 mg b.i.d., and metronidazole 500 mg b.i.d. (or amoxicillin 1 g b.i.d.) for 10 to 14 days or • Bismuth quadruple therapy—bismuth subsalicylate 525 mg q.i.d. + metronidazole 250 mg q.i.d. + tetracycline 500 mg q.i.d. + ranitidine 150 mg b.i.d. or PPI (dose includes lansoprazole 30 mg b.i.d.; omeprazole 20 mg b.i.d.; esomeprazole 40 mg daily; or rabeprazole 20 mg b.i.d.) ⫻ 14 days (Table 5).15 The mechanisms by which these combinations of medications work include disrupting the cell wall of H. pylori (bismuth and amoxicillin), inhibiting protein synthesis (clarithromycin, tetracycline), decreasing the secretion of acid in the stomach (PPIs, antacids), and/or blocking cell function (metronidazole). When combination therapies are prescribed in this manner, eradication rates can be as high as 90%. Various studies have evaluated numerous treatment regimens to enhance patient compliance and affordability, including reducing the number of therapy days. The eradication rate of 78% achieved with bismuth quadruple therapy administered q.i.d. for 14 days was improved to 92% when the same therapy was administered twice daily for 14 days.30 At its 2009 annual scientific meeting, the American College of Gastroenterology (ACG) acknowledged an open-label study of a new quadruple therapy called LOAD: levofloxacin, omeprazole, the antiparasitic agent nitazoxanide (Alinia), and doxycycline). Researchers compared 10- and seven-day courses of LOAD with a 10-day course of a standard tripletherapy regimen called LAC (lansoprazole, amoxicillin, and clarithromycin). Using a stool antigen assay two weeks after completion of therapy, the team found that the 10-day and

24 THE CLINICAL ADVISOR • MARCH 2012 • www.ClinicalAdvisor.com

seven-day LOAD regimens worked similarly well and were superior to the LAC regimen in treatment-naïve patients.31 When a patient presents with uninvestigated dyspepsia, the test-and-treat strategy is advocated by numerous organizations, including the American Gastroenterological Association and the ACG.32 This strategy involves diagnosing H. pylori via UBT or stool antigen, with subsequent treatment if the result is positive (Table 6). This method includes mass public education on the signs and symptoms of H. pylori infection with access to OTC H. pylori testing. If test results are positive, the patient can receive eradication therapy from the pharmacist without a prescription. Poland has seen a dramatic reduction in the prevalence of H. pylori, from 58% to 30%, using this method of treatment. Follow-up

Patients with PUD, persistent dyspeptic symptoms despite completion of a test-and-treat strategy, or history of gastric carcinoma or MALT lymphoma should undergo post-treatment testing to ascertain eradication of H. pylori. Testing should be done no sooner than four weeks after therapy has been completed. As previously noted, the methods with the highest sensitivity in testing for total eradication of H. pylori include UBT, fecal antigen testing, and endoscopy-obtained RUT. Because of its high cost, endoscopy is typically reserved for patients requiring ulcer or cancer surveillance. 21 Treatment resistance

Up to 20% of patients with H. pylori infection are not cured after completing their first course of treatment and require a second regimen. Retreatment usually calls for the patient to take 14 days of a PPI and two antibiotics. At least one of the antibiotics should differ from those used in the first treatment course. Various strategies can be utilized when attempting to overcome medication resistance, including increasing dose, duration, or number of antibiotics.27 The choice of antibiotic varies from country to country because of the various strains demonstrating medication resistance. In the United States, studies are indicating resistance to two important antimicrobials—clarithromycin and metronidazole. Levels of resistance have been documented to be as high as 40% with metronidazole and higher than 10% with clarithromycin.33

AT A GLANCE ●

Helicobacter pylori may be transmitted via contaminated groundwater, food, and human saliva.

●

GI manifestations of H. pylori infection include gastritis, peptic ulcer disease, and gastric atrophy or lymphoma.

●

Eradictaion may require use of two or more antibiotics in conjuction with a PPI and/or bismuth compound.

●

If necessary, follow-up testing should be done no sooner than four weeks after therapy has been completed.

Because of bacterial resistance, numerous studies have evaluated treatments as alternatives to both the clarithromycin triple therapy and the bismuth quadruple therapy. Levofloxacin-based triple therapy has been studied in other countries as possible second- or third-line therapy in patients with persistent H. pylori infection. This regimen includes a PPI b.i.d., amoxicillin 1 g b.i.d., and levofloxacin 500 mg daily for 10 days and has been found to have an eradication rate of 87%.34 More studies are needed to validate these findings in additional countries. If two therapies fail and H. pylori persists, as indicated by UBT or endoscopy and biopsy analysis, then expert advice is required to evaluate for an H. pylori antibiotic-resistant strain. Gastric biopsy via endoscopy is mandatory at this point to evaluate antibiotic sensitivities and susceptibilities.16 Homeopathic remedies have not been proven to be efficacious in H. pylori treatment. Interestingly, some compounds that are used as natural therapies do suppress H. pylori, but these agents are not curative; one example is the lactobacilli found in yogurt. ■ Ms. Collazo is a nurse practitioner in thoracic surgery at Northwestern Memorial Hospital in Chicago and in internal medicine at Crusader Community Health in Rockford, Ill. The author has no relationships to disclose relating to the content of this article. References 1. Konturek JW. Discovery by Jaworski of Helicobacter pylori and its pathogenetic role in peptic ulcer, gastritis and gastric cancer. J Physio. Pharmacol. 2003;54 Suppl 3:23-41. 2. The Nobel Prize in Physiology or Medicine 2005. www.nobelprize.org/ nobel_prizes/medicine/laureates/2005/index.html.

WHAT DO YOU THINK?

3. Betts R, Chapman S, Penn R. Helicobacter pylori and peptic ulcer dis-

Add your comments to this article —or any article — by going to www.ClinicalAdvisor.com.You will also see what your colleagues are saying.

ease. In: Betts RF, Chapman SW, Penn RL, eds. Reese and Betts: A Practical Approach to Infectious Diseases. 5th ed. New York, NY: Lippincott Williams & Wilkins; 2003: chapter 13. Continues on page 26

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4. Blaser MJ. An endangered species in the stomach. Sci Am. 2005;292:38-45.

22. Meurer LN, Bower DJ. Management of Helicobacter pylori infec-

5. Al-Sulami AA, Al-Taee AMR, Juma’a MG. Isolation and identification

tion. Am Fam Physician. 2002:65;1327-1336. Available at www.aafp.org/

of Helicobacter pylori from drinking water in Basra governorate, Iraq. East

afp/2002/0401/p1327.html.

Mediterr Health J. 2010;16:920-925.

23. Stojković MLj, Durutović DR, Petrović MN, et al. Helicobacter pylori

6. Assumpcão MB, Martins LC, Melo Barbosa HP, et al. Helicobacter pylori

infection in various groups of patients studied, estimated by 14C-urea

in dental plaque and stomach of patients from Northern Brazil. World J

breath test. Acta Chir Iugosl. 2011;58:95-98.

Gastroenterol. 2010;16:3033-3039. Available at www.ncbi.nlm.nih.gov/pmc

24. Gatta L, Vakil N, Ricci C, et al. Effect of proton pump inhibitors and

/articles/PMC2890944/.

antacid therapy on 13C urea breath tests and stool test for Helicobacter

7. Song Q, Lange T, Spahr A, et al. Characteristic distribution pattern of

pylori infection. Am J Gastroenterol. 2004;99:823-829.

Helicobacter pylori in dental plaque and saliva detected with nested PCR.

25. Vaira D, Vakil N, Menegatti M, et al. The stool antigen test for detection of

J Med Microbiol. 2000;49:349-353. Available at jmm.sgmjournals.org/con-

Helicobacter pylori after eradication therapy. Ann Intern Med. 2002;136:280-287.

tent/49/4/349.full.pdf.

26. Versalovic J. Helicobacter pylori. Pathology and diagnostic strategies.

8. Chaudhry S, Iqbal HA, Khan AA, et al. Helicobacter pylori in dental plaque

Am J Clin Pathol. 2003;119:403-412. Available at ajcp.ascpjournals.org/con-

and gastric mucosa: correlation revisited. J Pak Med Assoc. 2008;58:331-334.

tent/119/3/403.long.

9. Moran AP. The role of lipopolysaccharide in Helicobacter pylori patho-

27. Graham DY, Fischbach L. Helicobacter pylori treatment in the era of

genesis. Aliment Pharmacol Ther. 1996:10 Suppl 1:39-50.

increasing antibiotic resistance. Gut. 2010;59:1143-1153.

10. Hardin F, Wright R. Helicobacter pylori: review and update. Hosp

28. Tankovic J, Lamarque D, Lascols C, et al. Clarithromycin resistance of

Physician. 2002;38:23-31. Available at www.turner-white.com/pdf/

Helicobacter pylori has a major impact on the efficacy of the omeprazole-

hp_may02_helio.pdf.

amoxicillin-clarithromycin therapy. Pathol Biol (Paris). 2001;49:528-533.

11. Crowe SE. Pathophysiology of and immune response to Helicobacter

29. Lins AK, Lima RA, Magalhães M. Clarithromycin-resistant Helicobacter

pylori infection. Up-to-date.

pylori in Recife, Brazil, directly identified from gastric biopsies by poly-

12. Schubert ML, Peura DA. Control of gastric acid secretion in health and

merase chain reaction. Arq Gastroenterol. 2010;47:379-382.

disease. Gastroenterology. 2008;134:1842-1860.

30. Graham DY, Belson G, Abudayyeh S, et al. Twice daily (mid-day and

13. Ford AC, Delaney BC, Forman D, Moayyedi P. Eradication therapy

evening) quadruple therapy for H. pylori infection in the United States. Dig

in Helicobacter pylori positive peptic ulcer disease: systematic review and

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economic analysis. Am J Gastroenterol. 2004;99:1833-1855.

31. Brauser D. LAC and LOAD: 4-drug regimen better at eliminat-

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ing H. pylori than standard 3-drug treatment. American College of

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cgi/content/full/161/9/1217.

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All electronic documents accessed February 15, 2012.

26 THE CLINICAL ADVISOR • MARCH 2012 • www.ClinicalAdvisor.com

FEATURE: RONALD L. HOFFMAN, MD, CNS

Predisease: A concept whose time has come? There is a powerful temptation to treat patients before they develop a disease, but the timeworn adage still applies: First, do no harm.

CT shows beginning ostoporosis of the lumbar spine.

nderlying preventive medicine or preventive care are measures taken to stave off diseases (or injuries) rather than curing them or treating their symptoms. The term “predisease” has recently entered the medical lexicon and denotes efforts to set criteria that are action points for averting major causes of sickness or death in asymptomatic individuals. Examples include precancerous lesions, increased intraocular pressure (preglaucoma), prehypertension, hyperlipidemia, prediabetes, and osteopenia. While prevention efforts are laudable, controversy rages over how far we should go in diagnosing prediseases. As Welch and colleagues write: But the truth is that early diagnosis is a doubleedged sword. While it has the potential to help some, it always has a hidden danger: overdiagnosis—the detection of abnormalities that are not destined to ever bother us.1

Others label this “disease-mongering.” In a recent article, Moynihan et al wrote: There’s a lot of money to be made from telling healthy people they’re sick. Some forms of medicalising ordinary life may now be better described as disease-mongering: widening the boundaries of treatable illness in order to expand markets for those who sell and deliver treatments. Pharmaceutical companies are actively involved in sponsoring the definition of diseases and promoting www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MARCH 2012 33

B:8.75” T:7.75” S:6.75”

JEN Sig

JENTADUETO: LINAGLIPTIN AND METFORMIN IN A SINGLE TABLET

FOR ADULT PATIENTS WITH TYPE 2 DIABETES MELLITUS

Adjusted mean change in A1C from baseline at 24 weeks (%)

W VED O N RO P P A

Focusing on what matters Improving glycemic control for adult patients with type 2 diabetes

5 95 5 95 5

25C, 16M, 16Y

5 95

75 25 25 25

M+Y

4 96

25 75 50 50 50

C+Y

25K

4 96 96

80K, 80C, 70M, 70Y

75C, 63M, 63Y

75K 50K

CONTRAINDICATIONS JENTADUETO is contraindicated in patients with: Renal impairment (e.g., serum creatinine ≥1.5 mg/dL for men or ≥1.4 mg/dL for women, or abnormal creatinine clearance). Acute or chronic metabolic acidosis, including diabetic ketoacidosis. History of hypersensitivity reaction to linagliptin (such as urticaria, angioedema, or bronchial hyperreactivity) or metformin. WARNINGS AND PRECAUTIONS LACTIC ACIDOSIS Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with JENTADUETO and is fatal in approximately 50% of cases. The reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years, with

50C, 39M, 39Y

25 25

50K 50 300%

50 3 97 3 97 3 97

75C, 63M, 63Y

75K

5 5

75 25

M+Y

4 4 4 96

3 3

75 50

C+Y

0.5

98 2

99 1

99.5 0.5

98 2

99 1

99.5 0.5

99.5

0.5

99.5

25 50 75 C+M 75 75 75 75

GATF/SWOP Digital Proofing Bar 1

0.5

2 98 2 98 2

99 1 99 1

99.5 0.5 99.5 0.5

98 2

99.5

99 1

0.5

99.5

25 50 75 C+M 75 75 75 75

WARNING: RISK OF LACTIC ACIDOSIS Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspeciﬁc symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspeciﬁc abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate. If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately.

Radiological studies and surgical procedures: Use of JENTADUETO should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or ﬂuids. IMPAIRED HEPATIC FUNCTION Impaired hepatic function has been associated with cases of lactic acidosis with metformin therapy. JENTADUETO tablets should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment. HYPOGLYCEMIA Insulin secretagogues are known to cause hypoglycemia. The use of linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea)

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Important Safety Information

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JENTADUETO should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

25K

JENTADUETO tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate.

approximately 0.015 fatal cases/1000 patient-years. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/ surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal impairment and the patient’s age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in any patients unless measurement of creatinine clearance demonstrates that renal function is not reduced. Metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. MONITORING OF RENAL FUNCTION Before initiation of therapy with JENTADUETO and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and JENTADUETO discontinued if evidence of renal impairment is present.

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JENTADUETO: Significant A1C reductions at 24 weeks*†

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JENTADUETO was approved based on clinical trials that evaluated linagliptin and metformin as separate tablets. Bioequivalence of JENTADUETO to linagliptin and metformin coadministered as individual tablets was demonstrated in healthy subjects.

(n=65) (n=140) Placebo JENTADUETO (Baseline A1C: 8.7%) Linagliptin 2.5 mg/ Metformin 1000 mg Twice Daily ‡ (Baseline A1C: 8.7%)

ALCOHOL INTAKE Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving JENTADUETO.

MACROVASCULAR OUTCOMES There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JENTADUETO or any other antidiabetic drug. ADVERSE REACTIONS In a 24-week factorial design study, adverse reactions reported in ≥5% of patients treated with JENTADUETO and more commonly than in patients treated with placebo are nasopharyngitis and diarrhea. In a 24-week factorial design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin + metformin, 6 (2.1%) of 291 subjects treated with metformin and 1 (1.4%) of 72 subjects treated with placebo. In the placebo-controlled studies hypoglycemia was more commonly reported in patients treated with the combination of JENTADUETO and SU (22.9%) compared with those treated with the combination of placebo, SU, and metformin (14.8%). Pancreatitis was reported more often in patients randomized to linagliptin (1 per 538 person-years versus zero in 433 person-years for comparator).

M+Y

99.5

(n=137) JENTADUETO Linagliptin 2.5 mg/ Metformin 500 mg Twice Daily ‡ (Baseline A1C: 8.7%)

HYPOXIC STATES Cardiovascular collapse (shock) from whatever cause (e.g., acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia) have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JENTADUETO therapy, the drug should be promptly discontinued.

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was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. A lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO.

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*A randomized, double-blind, placebo-controlled, parallel-group study of drug-naïve or previously treated (4 weeks washout and 2 weeks placebo run-in) adult patients with type 2 diabetes and insufficient glycemic control (aged 18-80) who were randomized to placebo (n=72), linagliptin 5 mg once daily (n=142), metformin 500 mg twice daily (n=144), linagliptin 2.5 mg twice daily + metformin 500 mg twice daily (n=143), metformin 1000 mg twice daily (n=147), or linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily (n=143). Primary endpoint was change from baseline A1C at 24 weeks. 29.2% of patients in the placebo group required use of rescue therapy vs 11.1% of patients receiving linagliptin 5 mg once daily, 13.5% of patients receiving metformin 500 mg twice daily, 8.0% of patients receiving metformin 1000 mg twice daily, 7.3% of patients receiving linagliptin 2.5 mg twice daily + metformin 500 mg twice daily, and 4.3% of patients receiving linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily. Full analysis population using last observation on study. † Superiority of both free combination therapies, consisting of the twice daily administration of linagliptin 2.5 mg and metformin (500 mg or 1000 mg), was shown over the individual metformin components (500 mg and 1000 mg, both BID) and over linagliptin 5 mg QD for the change in A1C from baseline at Week 24. Linagliptin 2.5 mg BID + metformin 1000 mg BID was superior to metformin 1000 mg BID (P<0.0001); linagliptin 2.5 mg BID + metformin 1000 mg BID was superior to linagliptin 5 mg QD (P<0.0001); linagliptin 2.5 mg BID + metformin 500 mg BID was superior to metformin 500 mg BID (P<0.0001); linagliptin 2.5 mg BID + metformin 500 mg BID was superior to linagliptin 5 mg QD (P<0.0001). ‡ JENTADUETO studied as coadministered linagliptin and metformin tablets; total daily dose of linagliptin was equal to 5 mg.

DRUG INTERACTIONS Because cationic drugs eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems, careful patient monitoring and dose adjustment of JENTADUETO and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system. The efﬁcacy of JENTADUETO may be reduced when administered in combination with a strong P-glycoprotein inducer and CYP3A4 inducer (e.g., rifampin). Use of alternative treatments is strongly recommended. The concomitant use of carbonic anhydrase inhibitors (e.g., topiramate) and metformin may induce metabolic acidosis. Use these drugs with caution in patients treated with JENTADUETO, as the risk of lactic acidosis may increase. USE IN SPECIFIC POPULATIONS There are no adequate and well-controlled studies in pregnant women, therefore the safety of JENTADUETO in pregnant women is not known. JENTADUETO should be used during pregnancy only if clearly needed. It is not known whether linagliptin is excreted in human milk. Metformin is excreted in human milk in low concentrations. Because of the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Safety and effectiveness of JENTADUETO in patients below the age of 18 have not been established. JENTADUETO should be used with caution as age increases, as aging can be associated with reduced renal function.

Please see adjacent pages for brief summary of full Prescribing Information and Boxed Warning regarding the risk of lactic acidosis.

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Jentadueto™ (linagliptin and metformin hydrochloride) tablets BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for full Prescribing Information. WARNING: RISK OF LACTIC ACIDOSIS Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate. If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately.

INDICATIONS AND USAGE: Indication: JENTADUETO tablets are indicated as

an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate. Important Limitations of Use: JENTADUETO should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. JENTADUETO has not been studied in combination with insulin.

CONTRAINDICATIONS: JENTADUETO is contraindicated in patients with:

• Renal impairment (e.g., serum creatinine ≥1.5 mg/dL for men, ≥1.4 mg/dL for women, or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia [see Warnings and Precautions] • Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin [see Warnings and Precautions] • A history of hypersensitivity reaction to linagliptin (such as urticaria, angioedema, or bronchial hyperreactivity) or metformin [see Adverse Reactions]

WARNINGS AND PRECAUTIONS: Lactic Acidosis: Metformin: Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with JENTADUETO and is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels of >5 µg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years, (with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal impairment and the patient’s age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in any patients unless measurement of creatinine clearance demonstrates that renal function is not reduced. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should be avoided in patients with clinical or laboratory evidence of hepatic impairment. Patients should be cautioned against excessive alcohol intake when taking metformin, since alcohol potentiates the effects of metformin on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids. Use of topiramate, a carbonic anhydrase inhibitor, in epilepsy and migraine prophylaxis may cause dose-dependent metabolic acidosis and may exacerbate the risk of metformin-induced lactic acidosis [see Drug Interactions]. The onset of lactic acidosis is often subtle, and accompanied by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. More severe acidosis may be associated with signs such as hypothermia, hypotension, and resistant bradyarrhythmias. Patients should be educated to recognize and promptly report these symptoms. If present, JENTADUETO should be discontinued until lactic acidosis is ruled out. Gastrointestinal symptoms, which are commonly reported during initiation of metformin therapy are less frequently observed in subjects on a chronic, stable, dose of metformin. Gastrointestinal symptoms in subjects on chronic, stable, dose of metformin could be caused by lactic acidosis or other serious disease. To rule out lactic acidosis, serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be useful. Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be due to other mechanisms, such as poorly-controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a

17989_JD141000PROFA_PI 1 18361_ClinicalAdvisor 3

patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and supportive measures promptly instituted. Metformin is dialyzable (clearance of up to 170 mL/min under good hemodynamic conditions) and prompt hemodialysis is recommended to remove the accumulated metformin and correct the metabolic acidosis. Such management often results in prompt reversal of symptoms and recovery [see Boxed Warning]. Monitoring of Renal Function: Although linagliptin undergoes minimal renal excretion, metformin is known to be substantially excreted by the kidney. The risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Therefore, JENTADUETO is contraindicated in patients with renal impairment. Before initiation of therapy with JENTADUETO and at least annually thereafter, renal function should be assessed and verified to be normal. In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and JENTADUETO discontinued if evidence of renal impairment is present. Linagliptin may be continued as a single entity tablet at the same total daily dose of 5 mg if JENTADUETO is discontinued due to evidence of renal impairment. No dose adjustment of linagliptin is recommended in patients with renal impairment. Use of concomitant medications that may affect renal function or metformin disposition: Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or interfere with the disposition of metformin should be used with caution [see Drug Interactions]. Radiological studies and surgical procedures: Radiologic studies involving the use of intravascular iodinated contrast materials (e.g., intravenous urogram, intravenous cholangiography, angiography, and computed tomography) can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. Therefore, in patients in whom any such study is planned, JENTADUETO should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been confirmed to be normal. JENTADUETO should be temporarily discontinued for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient’s oral intake has resumed and renal function has been evaluated as normal. Impaired Hepatic Function: Because impaired hepatic function has been associated with some cases of lactic acidosis with metformin therapy, JENTADUETO should generally be avoided in patients with clinical or laboratory evidence of hepatic disease [see Warnings and Precautions]. Hypoglycemia: Linagliptin: Insulin secretagogues are known to cause hypoglycemia. The use of linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial [see Adverse Reactions]. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO. Metformin: Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as SUs and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking β-adrenergic blocking drugs. Vitamin B12 Levels: In controlled, 29-week clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of metformin-treated patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia or neurologic manifestations due to the short duration (<1 year) of the clinical trials. This risk may be more relevant to patients receiving long-term treatment with metformin, and adverse hematologic and neurologic reactions have been reported postmarketing. The decrease in vitamin B12 levels appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on JENTADUETO and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurement at 2- to 3-year intervals may be useful. Alcohol Intake: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake while receiving JENTADUETO [see Warnings and Precautions]. Hypoxic States: Cardiovascular collapse (shock) from whatever cause (e.g., acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia) have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JENTADUETO therapy, the drug should be promptly discontinued [see Warnings and Precautions]. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with linagliptin or metformin or any other antidiabetic drug. ADVERSE REACTIONS: Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Linagliptin/ Metformin: The safety of concomitantly administered linagliptin (daily dose 5 mg) and metformin (mean daily dose of approximately 1800 mg) has been evaluated in 2816 patients with type 2 diabetes mellitus treated for ≥12 weeks in clinical trials. Three placebo-controlled studies with linagliptin + metformin were conducted: 2 studies were 24 weeks in duration, 1 study was 12 weeks in duration. In the 3 placebo-controlled clinical studies, adverse events which occurred in ≥5% of patients receiving linagliptin + metformin (n=875) and were more common than in patients given placebo + metformin (n=539) included nasopharyngitis (5.7% vs 4.3%). In a 24-week factorial design study, adverse events reported in ≥5% of patients receiving linagliptin + metformin and were more common than in patients given placebo are shown in Table 1.

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Table 1

Adverse Reactions Reported in ≥5% of Patients Treated with Linagliptin + Metformin and Greater than with Placebo in a 24-week Factorial-Design Study Placebo Linagliptin Metformin Combination of n=72 Monotherapy Monotherapy Linagliptin with n=142 n=291 Metformin n=286 n (%) n (%) n (%) n (%)

Nasopharyngitis

1 (1.4)

8 (5.6)

8 (2.7)

18 (6.3)

Diarrhea

2 (2.8)

5 (3.5)

11 (3.8)

18 (6.3)

Other adverse reactions reported in clinical studies with treatment of linagliptin + metformin were hypersensitivity (e.g., urticaria, angioedema, or bronchial hyperactivity), cough, decreased appetite, nausea, vomiting, pruritus, and pancreatitis. Linagliptin Monotherapy: Nasopharyngitis was reported in ≥5% of patients treated with linagliptin and more commonly than in patients treated with placebo (5.8% vs 5.5%). In the clinical trial program, pancreatitis was reported in 8 of 4687 patients (4311 patient-years of exposure) while being treated with TRADJENTA compared with 0 of 1183 patients (433 patient-years of exposure) treated with placebo. Three additional cases of pancreatitis were reported following the last administered dose of linagliptin. Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperactivity) and myalgia. Metformin Monotherapy: The most common adverse reactions due to initiation of metformin are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption which may very rarely result in clinically significant vitamin B12 deficiency (e.g., megaloblastic anemia) [see Warnings and Precautions]. Hypoglycemia: In a 24-week factorial design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin + metformin, 6 (2.1%) of 291 subjects treated with metformin, and 1 (1.4%) of 72 subjects treated with placebo. When linagliptin was administered in combination with metformin and a sulfonylurea, 181 (22.9%) of 792 patients reported hypoglycemia compared with 39 (14.8%) of 263 patients administered placebo in combination with metformin and sulfonylurea. Laboratory Tests: Changes in laboratory findings were similar in patients treated with linagliptin + metformin compared to patients treated with placebo + metformin. Changes in laboratory values that occurred more frequently in the linagliptin + metformin group and ≥1% more than in the placebo group were not detected. No clinically meaningful changes in vital signs were observed in patients treated with linagliptin. DRUG INTERACTIONS: Drug Interactions with Metformin: Cationic Drugs: Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of JENTADUETO and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system [see Warnings and Precautions]. Carbonic Anhydrase Inhibitors: Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with JENTADUETO, as the risk of lactic acidosis may increase [see Warnings and Precautions]. Drug Interactions With Linagliptin: Inducers of P-glycoprotein and CYP3A4 Enzymes: Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when administered in combination with a strong P-gp inducer or CYP 3A4 inducer. As JENTADUETO is a fixed-dose combination of linagliptin and metformin, use of alternative treatments (not containing linagliptin) is strongly recommended when concomitant treatment with a strong P-gp or CYP 3A4 inducer is necessary. Drugs Affecting Glycemic Control: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving JENTADUETO, the patient should be closely observed to maintain adequate glycemic control. When such drugs are withdrawn from a patient receiving JENTADUETO, the patient should be observed closely for hypoglycemia. USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category B: JENTADUETO: There are no adequate and well controlled studies in pregnant women with JENTADUETO or its individual components, and some clinical data is available for metformin which indicate that the risk for major malformations was not increased when metformin is taken during the first trimester in pregnancy. In addition, metformin was not associated with increased perinatal complications. Nevertheless, because these clinical data cannot rule out the possibility of harm, JENTADUETO should be used during pregnancy only if clearly needed. JENTADUETO was not teratogenic when administered to Wistar Han rats during the period of organogenesis at doses similar to clinical exposure. At higher maternally toxic doses (9 and 23 times the clinical dose based on exposure), the metformin component of the combination was associated with an increased incidence of fetal rib and scapula malformations. Linagliptin: Linagliptin was not teratogenic when administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg and 150 mg/kg, respectively. These doses represent approximately 943 times the clinical dose in rats and 1943 times the clinical dose in rabbits, based on exposure. No functional, behavioral, or reproductive toxicity was observed in offspring of female Wistar Han rats when administered linagliptin from gestation day 6 to lactation day 21 at a dose 49 times the maximum recommended human dose,

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based on exposure. Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits. Metformin Hydrochloride: Metformin has been studied for embryofetal effects in 2 rat strains and in rabbits. Metformin was not teratogenic in Sprague Dawley rats up to 600 mg/kg or in Wistar Han rats up to 200 mg/kg (2-3 times the clinical dose based on body surface area or exposure, respectively). At higher maternally toxic doses (9 and 23 times the clinical dose based on exposure), an increased incidence of rib and scapula skeletal malformations was observed in the Wistar Han strain. Metformin was not teratogenic in rabbits at doses up to 140 mg/kg (similar to clinical dose based on body surface area). Metformin administered to female Sprague Dawley rats from gestation day 6 to lactation day 21 up to 600 mg/kg/day (2 times the maximum clinical dose based on body surface area) had no effect on prenatal or postnatal development of offspring. Metformin crosses the placenta into the fetus in rats and humans. Nursing Mothers: No studies in lactating animals have been conducted with the combined components of JENTADUETO. In studies performed with the individual components, both linagliptin and metformin were secreted in the milk of lactating rats. It is not known whether linagliptin is excreted in human milk. Metformin is excreted in human milk in low concentrations. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of JENTADUETO in pediatric patients have not been established. Geriatric Use: Linagliptin is minimally excreted by the kidney; however, metformin is substantially excreted by the kidney. Considering that aging can be associated with reduced renal function, JENTADUETO should be used with caution as age increases [see Warnings and Precautions]. Linagliptin: Of the total number of patients (n=4040) in clinical studies of linagliptin, 1085 patients were 65 years and over, while 131 patients were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. Therefore, no dose adjustment is recommended in the elderly population. While clinical studies of linagliptin have not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. Metformin: Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. The initial and maintenance dosing of metformin should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function [see Contraindications and Warnings and Precautions].

OVERDOSAGE: In the event of an overdose with JENTADUETO, employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient’s clinical status. Removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely. However, metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful partly for removal of accumulated metformin from patients in whom JENTADUETO overdosage is suspected. Linagliptin: During controlled clinical trials in healthy subjects, with single doses of up to 600 mg of linagliptin (equivalent to 120 times the recommended daily dose), there were no dose-related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans. Metformin: Overdose of metformin has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Boxed Warning and Warnings and Precautions]. Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA Marketed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA and Eli Lilly and Company Indianapolis, IN 46285 USA Licensed from: Boehringer Ingelheim International GmbH Ingelheim, Germany Copyright 2012 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED January 2012

JD/BS/01-12

JD148400PROF

2/10/12 8:20 PM 2/23/12 1:00 PM

PREDISEASE

them to both prescribers and consumers. The social construction of illness is being replaced by the corporate construction of disease.2 The authors point to a mutually reinforcing “alliance of pharmaceutical manufacturers, doctors, and patients groups [who] use the media to frame conditions as being widespread and severe.” They particularly deplore the “seeing of risks as diseases,” claiming that “inappropriate medicalisation carries the dangers of unnecessary labeling, poor treatment decisions, iatrogenic illness, and economic waste, as well as the opportunity costs that result when resources are diverted away from treating or preventing more serious disease.” They allege that “extensive fi nancial ties with leading researchers, [patient groups,] disease foundations, and advertising campaigns (on both drugs and disease) targeted at doctors” expand the boundaries of disease, to society’s detriment. Are we then engaging in a form of medical hubris? Or worse, commercial promotion under the guise of public health? Contentious issues include: Medicalization. Extending the defi nition of disease to comprise millions of additional asymptomatic individuals may create an entire new class of stigmatized “worried well,” with consequent emotional, psychological, and even social ramifications (not to mention concomitant iatrogenic side effects). Cynics argue that the concept of predisease can easily be subverted to vastly expand the reach of the pharmaceutical industry; drugs and tests often conveniently supplant more difficult-to-implement, but potentially more efficacious, lifestyle modifications. Do we run the risk of overtreating our patients? Cost/benefit considerations. Primary disease prevention (preventing illness) is a less clearly cost-effective proposition than secondary prevention (treating the ill). As a country that spends more than twice as much per capita on medical care than comparable industrialized AT A GLANCE ●

Predisease refers to action points for averting major causes of sickness in asymptomatic individuals.

●

There is no evidence that lifestyle changes will prevent stroke in those with prehypertension.

●

According to the American Diabetes Association, about 79 million Americans have prediabetes.

●

Among women aged 65 years and older, 40% have osteopenia, a potential precursor to overt osteoporosis.

nations, can the United States continue to enumerate and treat prediseases? What to measure. In an asymptomatic population, diagnostic tests must be relied upon to highlight disease risk. Are the tests we currently use to predict disease the most reliable and cost-effective we can deploy? Who will be the arbiter of what constitutes “the new normal”? Research design challenges. Because the benefits of intervention in low-risk populations are inherently not clearcut, they are difficult to demonstrate. They require large, expensive, randomized prospective studies to yield statistical validity. Extrapolation from studies demonstrating benefits of pharmaceutical or lifestyle intervention in high-risk populations is logically appealing (e.g., the widespread application of the proven benefits of statin drugs in patients with documented coronary disease to healthy populations with high cholesterol). However, evidence-based literature supporting early intervention in predisease remains scanty. Wary clinicians

Fueling the debate are new signs that the medical profession is disgruntled with escalating imperatives to “do something” for patients. A recent survey of U.S. primary-care clinicians shows that many (48%) believe that their own patients are receiving too much medical care.3 Time constraints, perverse financial incentives, and defensive medicine are felt to be conspiring to put pressure on clinicians to intervene more aggressively than they feel is in their patients’ best interests. Reaching for the prescription pad or the test-requisition form seems an easier expedient than arduously counseling the patient in lifestyle modification. This contributes significantly to soaring medical costs, iatrogenic complications, and patient dissatisfaction. Medicolegal considerations

A recent medical malpractice case illustrates the dilemma facing clinicians. In a chilling precedent, a nurse practitioner was sued for failing to recommend medication for the predisease hyperlipidemia. With the plaintiff ’s expert arguing that the patient should have received statins and the defense arguing that there was no evidence that statins in this case were more effective than diet and exercise, the jury found for the plaintiff (see “Predisease and the law” on the facing page). Lest cases like these prompt clinicians to reflexively default to the most aggressive therapy, lawsuits have also been initiated by plaintiff ’s attorneys alleging precisely the opposite: harm due to side effects caused by unwarranted or indiscriminate use of statins.

38 THE CLINICAL ADVISOR • MARCH 2012 • www.ClinicalAdvisor.com

The “polypill”

The polypill epitomizes the argument for pushing the envelope of disease prevention. In a provocative 2003 article, Wald and Law called for universal prophylaxis for individuals older than age 55 years with a cardiovascular “polypill” consisting of inexpensive, off-patent drugs: aspirin, a beta blocker, an ACE inhibitor, a diuretic, a statin, and folic acid (to combat elevated homocysteine, an intervention no longer thought to prevent or reverse cardiovascular disease [CVD]).4 Their statistical model predicted a whopping 80% reduction in cardiac risk, with a minimum of side effects. The proposal ignited a firestorm of criticism. Opponents argued against a one-size-fits-all approach and pointed out that with a side effect ratio that Wald and Law acknowledged might be as high as 10% to 15%, intervention in tens of millions of otherwise healthy individuals added up to a perilous gamble. Even the modest proposal that all individuals older than age 55 years take an aspirin a day has been undermined by recent trials suggesting that the significant risk of GI bleeding may exceed potential cardioprotective benefits in low-risk individuals.5 In a rhetorical response to Wald and Law, a group of researchers proposed something called the “polymeal.”6 Based largely on the Mediterranean diet, the polymeal incorporates healthy portions of dark chocolate, omega-3-rich fish, olive oil, garlic, red wine, and nuts. Many authorities feel that universal adoption of the polymeal would trump the benefits of the polypill at less expense and without the side effects.

Predisease and the law A man aged 31 years underwent a health screening while attending an auto race. Those results indicated elevations in his lipid profile and BP. The findings of the screening, along with a family history of early heart disease, prompted the man to consult his family practitioner. An NP in his physician’s office evaluated the patient on two occasions. After receiving the results of a second lipid profile, the NP recommended improved diet and exercise to lower the man’s cholesterol. No medications were offered. The man’s wife testified that she asked the NP whether statin therapy was necessary and was specifically told that it was not. Approximately two months later, the man was found dead in his truck. The death was ruled a heart attack secondary to severe coronary artery disease. The plaintiff’s medical expert testified that the NP was negligent because she had not recommended a statin for the treatment of high cholesterol. In the expert’s opinion, statin therapy would have significantly reduced the patient’s risk of heart attack. The defense maintained that a trial of diet and exercise was acceptable medical practice to control the man’s elevated cholesterol. Medical testimony was introduced to demonstrate that statins have not yet been shown to play an incontrovertible role in primary prevention of cardiovascular disease. Nevertheless, the jury awarded the plaintiff’s family a multimillion-dollar award. Mrozinski J. Jury renders record award. Wyoming County Press Examiner. April 11, 2007. Available at wcexaminer.com/index.php/ archives/archives/13876, accessed February 15, 2012.

Number needed to treat

To better appreciate the statistical underpinnings of predisease designations, one must touch on the concepts of relative vs. absolute risk and number needed to treat (NNT). For example, a drug may substantially reduce the risk of a clinical endpoint (disease or death). “Drug X reduces the risk of Disease Y by 50%” may be the claim, backed by clinical research data. But if the patient you are treating has a low risk of contracting the disease to begin with, the change in absolute risk may be negligible (2% vs. 3%, for example). NNT introduces the consideration of how many patients would need to be treated to achieve prevention of a single clinical endpoint (a disease event or death). The lower the NNT, the more beneficial and cost-effective the intervention. The higher the NNT, the greater the number of patients who would need to be subjected to the risk and expense of taking a medication over a specified period of time to achieve prevention in just a single person. When NNTs extend into

the hundreds or even the thousands, the justification for intervention becomes problematic. A recent randomized trial among patients underscored the challenges of decision-making for medical consumers. Regardless of how information about risk/benefit was conveyed—even in this relatively well-educated study population (38% had at least a college degree)—only about one third of participants fully comprehended the implications of data.7 The challenge, the authors asserted, is to make information available to the public in a form that is understandable, and moreover, actionable. To gain a better understanding of the controversies surrounding predisease, consider four prototypical preconditions: prehypertension, hyperlipidemia, prediabetes, and osteopenia. Continues on page 40

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MARCH 2012 39

PREDISEASE

Prehypertension

Hypertension is arguably the first condition for which treatment was proposed for people not suffering from an actual disease. A test parameter—the height achieved by a column of mercury in a sphygmomanometer—was incontrovertibly linked to risks of stroke, heart disease, and kidney failure in otherwise well individuals. The progress made in medicine is laudable when one considers that President Franklin Delano Roosevelt succumbed to the then little-recognized and now largely avoidable effects of poorly controlled hypertension a mere 67 years ago. The benefits of intervening early to treat frank hypertension are indisputable. Also evident, however, is the fact that people with milder abnormalities stand to benefit less from treatment than those with severe abnormalities. Aggressive pharmacologic treatment of borderline increases in BP in patients at high risk for MI, valvular disease, congestive heart failure, stroke, or renal disease might be justified, but indiscriminate drug treatment of prehypertensive patients without concomitant risk factors is not supported by the evidence and might invite unnecessary side effects, particularly in the fragile elderly. In 2003, the National Heart, Lung, and Blood Institute (NHLBI) revised its BP guidelines. The new guidelines state that systolic BP (SBP) levels between 120 and 139 mm Hg or diastolic BP levels (DBP) of 80 to 89 mm Hg indicate prehypertension. By this expanded definition, the prevalence of prehypertension in healthy U.S. adults is 36.3%. This revision means that 100 million Americans whose BP had previously been considered normal now have cause to watch their BP more closely.8 A recent meta-analysis confi rmed that prehypertension appears to be associated with a greater risk of stroke. In a pooled analysis of 12 studies, an SBP of 120 to 139 mm Hg or a DBP of 80 to 89 mm Hg at baseline was associated with a 55% greater risk of incident stroke. The effect was mostly driven by an increased risk in patients whose BP was in the higher range of prehypertension—an SBP of 130 to 139 mm Hg or a DBP of 85 to 89 mm Hg. But the relationship did not reach statistical significance for the lower range of prehypertension (SBP, 120-129 mm Hg; DBP, 80-84 mm Hg).9 The authors of the meta-analysis noted there is no clinical trial evidence that lifestyle changes will prevent stroke in prehypertensive individuals. On the other hand, there is no evidence that drug treatment to lower BP will prevent strokes in this population, either. “It really makes us wonder whether we should be prescribing medications for those

POLL POSITION n=268

Do you think primary-care patients today receive too much unnecessary medical care? 8.2%

60.5%

31.3%

Yes No Other

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individuals,” says Amytis Towfighi, MD. “However, to know for sure, we’d have to do a study to see if prescribing medications will actually lower stroke risk for [them].”10 Correspondingly, NHLBI public pronouncements emphasize nonpharmacologic treatment with diet and exercise. Current guidelines state that prehypertension is best treated with the following measures: • Exercise • Weight loss • Restriction to ≤1,500 mg sodium per day • A diet rich in fruits, vegetables, and low-fat dairy products and reduced consumption of saturated and total fat • Moderate use of alcohol (no more than two drinks a day for men or one drink a day for women, with a drink defined as 12 oz of beer, 4 oz of wine, 1.5 oz of 80-proof spirits, or 1 oz of 100-proof spirits.) Indeed, the potential efficacy of this approach in prehypertension is suggested by the robust results of the Dietary Approaches to Stop Hypertension (DASH) study but remains an extrapolation from research on frank hypertension. The DASH diet reduced BP by 5.5/3.0 mm Hg. That reduction in BP was estimated to reduce coronary heart disease (CHD) by 15% and stroke by 27%.11 Worth noting is that prehypertension may be a powerful prognosticator of metabolic syndrome, which is considered a major pathway to CVD. Therefore, a more selective approach to treatment of prehypertension might factor in recognition of concomitant risk factors pointing to insulin resistance, such as borderline glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and mid-abdominal weight gain. Merely lowering BP with medication would

40 THE CLINICAL ADVISOR • MARCH 2012 • www.ClinicalAdvisor.com

be expected to partially ameliorate risk, but a more comprehensive approach with diet and exercise might more fundamentally address the underlying metabolic dysfunction. Hyperlipidemia

Lipid-lowering therapy is firmly entrenched as a means of preventing CVD. But many researchers and health-care providers argue that lipid-lowering for primary prevention is merely a poorly justified extrapolation of its benefits in patients with established coronary artery disease (CAD). Considerable evidence supports the prescription of statins in patients with proven CAD (status post MI, angioplasty, or coronary artery bypass), angina, or documented plaque burden. But based on a meta-analysis of 14 studies comprising more than 34,000 patients, the prestigious Cochrane Collaboration recently concluded: Widespread use of statins in people with low risk of cardiovascular events—below a 1% all-cause mortality risk or an annual CVD event rate of 2% observed in the control groups in the trials considered here—is not supported by the existing evidence.12 A 2008 article in Bloomberg Businessweek makes the point this way: Citing a direct-to-consumer ad for atorvastatin (Lipitor), which claims a heart disease reduction of 36%, the author notes that by Pfizer’s own admission, this translates at best to a reduction in CVD events from three per 100 untreated controls to two per 100 in the treatment arm.13 This, the article stated, adds up to an NNT of 100: 100 individuals would have to be treated for a minimum of three years to prevent one person from developing CVD. The study often cited in support of using cholesterol drugs is an industrysponsored trial that includes carefully selected, high-risk patients with such risk factors as high BP and smoking. Other government-sponsored trials of statins yield less robust results, pegging the NNT at 250 (or higher) even if patients take the drugs for five years or more. “Anything over an NNT of 50 is worse than a lottery ticket; there may be no winners,” commented Nortin M. Hadler,

PEER PERSPECTIVES

professor of medicine at the University of North Carolina at Chapel Hill.13 The key to better deployment of statins in primary prevention may lie in better risk stratification. Current LDL guidelines, variously adhered to or ignored by clinicians, may be reductive and overly simplistic. In a comprehensive review of CVD prevention strategies, Hobbs wrote: Although high [LDL] may be the most important individual risk factor for [CHD], estimation of an individual’s actual risk for future CHD events must take into account all other coexistent CHD risk factors. Indeed, risk associated with any level of cholesterol is notably influenced by coexistent risk factors. . . [A]n individual with a number of modest risk factors may be at considerably greater risk for CHD than a person with one very high risk factor.14 Accordingly, the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study highlighted another readily measurable parameter as signaling risk and qualifying patients for statin intervention.15 Individuals with elevated levels of high-sensitivity C-reactive protein (hs-CRP) were found to be potential beneficiaries of statins, even when cholesterol levels were normal or low by National Cholesterol Education Program and American Heart Association criteria. If correct, the implication is that an additional 20 million or more Americans without high cholesterol whose hs-CRP level is >2.0 mg/L might be candidates for statins. Still, even in those with elevated hs-CRP values, absolute risk is extremely low. Applying the hazard ratios from the JUPITER study, the NNT with rosuvastatin (Crestor) to prevent one coronary event was unacceptably high. Proponents of noninvasive calcium scanning of coronary arteries using electron-beam tomography or CT imaging suggest this determination might further refi ne the selection process for primary prevention. A considerable number of patients with high cholesterol and/or elevated hs-CRP have little or no evidence of calcific plaque when imaged. During a median follow-up of six years, the 25% of patients with baseline coronary artery

“The answer is yes and no. Patients expect immediate treatment and results, and many do not follow the recommended lifestyle changes. The ability to identify diseases before they are symptomatic certainly improves the care I can provide, provided the patient follows my recommendations.” Sue Floyd, PA [via ClinicalAdvisor.com in response to the Online First poll (see facing page)]

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MARCH 2012 41

PREDISEASE

calcification (CAC) scores >100 accounted for 74% of adverse coronary events. Relatively few events occurred in the 47% of patients with CAC scores of zero. Applying the effect of rosuvastatin treatment from the JUPITER trial to this study population, the NNT to prevent one adverse coronary event was 549 for CAC scores of zero, 94 for scores of 1 to 100, and 24 for scores >100.15 The authors of this analysis argued for low-cost, low-risk, nonpharmacologic intervention in patients with other risk factors but low CAC scores: “These results have important implications for future guidelines and public health discussions aimed at improving the efficiency of statin use in primary prevention.” The researchers acknowledged, however, that the value of routine use of CAC determination for risk stratification remains to be validated by well-designed, large prospective trials. Additionally, critics of CAC screening argue against its cost, the potential harm of radiation exposure, and the risk of unnecessary revascularization procedures when asymptomatic patients are found to have a high plaque burden. Is hyperlipidemia justifiably considered a predisease? At the very least, if the finding of high cholesterol or an unfavorable lipid ratio provides a teachable moment to patients and rallyies them to lifestyle modification centered around diet and exercise, the campaign may do some good. After all, the benefit may not depend on how low patients get their cholesterol levels, but how theydo it. Nonpharmacologic interventions have the advantage of being cheaper and safer, and they are more likely to achieve real, comprehensive risk-factor mitigation. Prediabetes

According to the American Diabetes Association, an estimated 79 million Americans have prediabetes. Once referred to more innocuously as impaired glucose tolerance, prediabetes is defined as: • Fasting blood glucose level between 100 and 125 mg/dL • A two-hour post-challenge blood glucose level of 140 to 199 mg/dL on the oral glucose tolerance test • A hemoglobin A1c reading between 5.7% and 6.4% A constellation of other factors are predictive of prediabetes, including increased BMI; elevated fasting triglyceride, low HDL, and high uric acid levels; gestational diabetes or a history of giving birth to babies of greater-than-normal birthweight; certain ethnicity or racial backgrounds; sedentary lifestyle; polycystic ovary syndrome; or hypertension. Several rationales exist for identifying and developing criteria for prediabetes. Perhaps foremost is that prediabetes is

thought to precede the development of frank diabetes by up to 10 years and heralds its often inevitable natural progression. Additionally, even in the absence of full-blown type 2 diabetes, early pathological changes have been seen in the hearts, brains, kidneys, nerves, and eyes of prediabetic patients. The risk of heart disease, for example, is 1.5 times greater in persons with prediabetes than in those without the disorder. Finally, awareness of prediabetes has the potential to prompt people to delay or prevent the onset of type 2 diabetes through lifestyle changes. The first confirmation that prevention of frank diabetes might be beneficial comes from the Diabetes Prevention Program (DPP), completed in 2000. The DPP was a major multicenter clinical research study aimed at determining whether modest weight loss through dietary changes and increased physical activity or treatment with the oral diabetes drug metformin could prevent or delay the onset of type 2 diabetes in study participants. Patients in the lifestyle-modification arm of DPP were told to eat less fat and fewer calories and to exercise for a total of 150 minutes a week, with the goal of losing 7% of their body weight and maintaining that loss. After receiving intensive training and motivational support, participants in this arm lowered their risk of developing diabetes by 58%. Subjects receiving 850 mg of metformin b.i.d. also reduced their risk of progression to diabetes, on average, by 31%, but significant benefit was seen mostly in patients younger than age 45 years with BMIs >35, meaning that they were at least 60 lb overweight.16 Given these results, one might reasonably think that even more aggressive pharmacologic targeting of high blood glucose in prediabetes would forestall its potential cardiovascular consequences. But results from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study suggest otherwise.17 Intensive therapy lowered blood sugar in diabetic patients but was fraught with risk: 257 patients in the intensive-therapy group died, as compared with 203 patients in the standard-therapy group. Hypoglycemia requiring assistance and weight gain of more than 10 kg

CLINICAL SLIDESHOW Osteoporosis affects about 10 million Americans, and another 40 million are at risk for the disorder. To learn more, visit ClinicalAdvisor.com/OsteoporosisSlideshow.

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PREDISEASE

Awareness of prediabetes has the potential to prompt people to delay or prevent the onset of type 2 diabetes through lifestyle changes. were more frequent in the intensive-therapy group. The study was terminated early. A reappraisal of ACCORD sought to demonstrate an impact of intensive blood glucose control on the accelerated cognitive decline known to occur in diabetic patients; this analysis also showed no benefit of drug therapy. Were it to be applied to prediabetic patients, there is every reason to expect that intensive pharmacotherapy would yield an unacceptable risk/ benefit ratio. Hence, diet modification and exercise remain the only strongly validated treatments for prediabetes. Osteopenia

Forty percent of women aged 65 years and older have osteopenia, a potential precursor to overt osteoporosis, but also in part a mere statistical artifact, since osteopenia is defined as just one standard deviation (SD) below the mean bone density of a healthy 35-year-old woman. With concerns raised over potential risks of hormone replacement, bisphosphonates have come to the forefront of osteoporosis therapy. Among patients with osteopenia, who should be offered medication? Recommendations vary, depending on which organization is consulted. The American Academy of Clinical Endocrinologists (AACE) does not recommend therapy (primary prevention) for osteopenia, except in patients who have already suffered a fracture (secondary prevention). At the T-score threshold of -2.5 SD—at which osteoporosis begins, according to the World Health Organization (WHO) definition—AACE recommends initiation of therapy. The National Osteoporosis Foundation recommends medications if the T score is below -2.5 SD and even for those merely osteopenic patients with T scores of <-1.0 to -2.5 SD if they have a preponderance of concomitant risk factors as calculated by the fracture risk assessment tool, FRAX, developed and endorsed by WHO. Concerns have arisen over the risk of side effects from bisphosphonates: osteonecrosis of the jaw, esophageal irritation, and even atypical femoral fractures. Also, prolonged therapy has unclear benefits and may accentuate problems with bone architecture. Do the potential risks outweigh the benefits for osteopenic patients, who are inherently at lower

MAKING CONTACT

risk of fracture and of possibly requiring longer treatment durations for prevention? A study frequently invoked to support bisphosphonate therapy demonstrated a 50% reduction in risk of hip fracture with alendronate, but only in osteoporotic patients.18 Patients with T scores >-2.5 were not found to benefit in terms of fractures, but they did have enhanced bone density. In absolute terms, the risk reduction was 1.2% fewer hip fractures over three years in women with severe osteoporosis (2.2% of the placebo group had fractures and 1% in the alendronate group), for an NNT of 83. In another study of osteoporosis, actual adherence to a bisphosphonate regimen was found to be very low, with about half of patients discontinuing therapy within the first one to two years. This translates to a not-very-satisfactory NNT of 107 in sporadic users over four years. Moreover, the impact of even stringent compliance with bisphosphonate use was substantially less for fractures other than hip fractures and for younger women (<65 years of age).19 At this point, all we can say about drug intervention for osteopenia is that while it might not be very cost-effective, it may prevent fractures in select instances. Such tools as the FRAX index, which applies a questionnaire-driven formula to enhance the predictive value of bone-density scores, may help better identify a subset of osteopenic patients who deserve more aggressive therapy. The efficacy of lifestyle interventions, such as weight-bearing exercise or supplementation with such bone-supportive nutrients as calcium and vitamin D, remains speculative in osteopenia but surely warrants investigation. Conclusion

There are both advantages and disadvantages to medicine’s embrace of the concept of predisease. To counter the tendency toward unnecessary and harmful diagnostic creep, Viera has proposed that predisease as a category warranting preventive action makes sense only if three criteria are met: 1. Individuals identified as having predisease must have a greater likelihood of developing disease than others not so identified.

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With concerns raised over the potential risks of hormone replacement, bisphosphonates have come to the forefront of osteoporosis therapy. 2. An intervention must exist which, when used, effectively reduces the chance that the predisease will progress to actual disease. 3. The benefits of intervention in patients with predisease must outweigh any harms in the overall population.20 If these intelligent criteria are rigorously and consistently applied—while resisting commercial or policy imperatives that distort objectivity—predisease might evolve into a valuable classification in a new preventive medical paradigm. ■

12. Taylor F, Ward K, Moore TH, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2011;1:CD004816. 13. Carey J. Do cholesterol drugs do any good? Bloomberg Businessweek. January 17, 2008. Available at www.businessweek.com/magazine /content/08_04/b4068052092994.htm. 14. Hobbs FDR. Cardiovascular disease: different strategies for primary and secondary prevention? Heart. 2004;90:1217-1223. Available at heart. bmj.com/content/90/10/1217.long 15. Blaha MJ, Budoff MJ, DeFilippis AP, et al. Associations between C-reactive protein, coronary artery calcium, and cardiovascular events:

Dr. Hoffman is the founder and medical director of the Hoffman Center in New York City.

implications for the JUPITER population from MESA, a population-based cohort study. Lancet. 2011;378:684-692. 16. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the

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cular disease by more than 75% . BMJ. 2004;329:1447-1450. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC535974/. 7. Woloshin S, Schwartz LM. Communicating data about the benefi ts and harms of treatment: a randomized trial. Ann Intern Med. 2011;155:87-96. 8. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572. 9. Lee M, Saver JL, Chang B, et al. Presence of baseline prehypertension and risk of incident stroke: a meta-analysis. Neurology. 2011;77:1330-1337. 10. Towfighi A, Kelley G. The (pre)hypertension limbo: is it time to lower the treatment bar? Neurology. 2011;77:1322-1323. 11. Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med. 1997;336:1117-1124.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MARCH 2012 45

safer, and probably tastier (than the Polypill) strategy to reduce cardiovas-

Advisor Forum These are letters from practitioners around the country who want to share their clinical problems and successes, observations, and pearls with their colleagues. Responding consultants are identified below. We invite you to participate.

Inside the Forum MARCH 2012

Consultations Is vitamin D deficiency linked to pseudogout? . . . . . . . . . . . . . . . .46 Could this be COPD? . . . . . . . . . . . .46 Contraception and breast cancer . . . . .47 How to treat lymphedema . . . . . . . . .47 The benefits of oral contraceptives with folate . . . . . . . . . . . . . . . . . . . .48 How to choose an SSRI . . . . . . . . . .48

Clinical Pearls Colder eyedrops mean enhanced relief . . . . . . . . . . . . . . . .51 New pain-management terminology. . . 51 Attitude is everything. . . . . . . . . . . . .51

Your Comments

Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001. You may also fax (646) 638-6117, or contact us by e-mail at letters@ clinicaladvisor.com. If you are writing in response to a published letter, please indicate so by including the number in parentheses at the end of each item. Letters are edited for length and clarity. The Clinical Advisor’s policy is to print the author’s name with the letter. No anonymous contributions will be accepted.

Toward a more humane source of estrogen . . . . . . . . . . . . . . . . . . .51

CONSULTATIONS IS VITAMIN D DEFICIENCY LINKED TO PSEUDOGOUT? Is there any relationship between calcium pyrophosphate dihydrate disease (pseudogout) and vitamin D deficiency?— JOY GREEN-HADDEN, DNP, RN, FNP-BC, Aurora, Colo. Pseudogout is a form of arthritis that develops in people with calcium pyrophosphate crystal deposition disease. The condition is caused by the buildup of calcium pyrophosphate dihydrate crystals within a joint, and symptoms can mimic gout (caused by urate crystals). A review of literature on both vitamin D deficiency and pseudogout shows no direct connection between the two conditions. There is an indirect link through the parathyroid, in that vitamin D levels help regulate parathyroid activity, which affects calcium levels. Pseudogout is a rare adverse reaction to surgical parathyroidectomy. Theoretically, excessively high levels of vitamin D would decrease the function of the parathyroid.—Rebecca H. Bryan, APRN, CNP (161-1)

COULD THIS BE COPD? A Native American man aged 40 years has a very tender right rib cage cystic formation that measures 2.0 ⫻ 2.0 ⫻ 0.5 cm. Extensive workup has found nothing. He has profoundly clubbed fingers and toes (without abnormal facies), a severely

OUR CONSULTANTS

Rebecca H. Bryan, APRN, CNP,

Eileen Campbell, MSN, CRNP,

Philip R. Cohen, MD,

is a lecturer in the Family Health NP Program, University of Pennsylvania School of Nursing, Philadelphia.

is associate program director, Family Health NP Program, University of Pennsylvania School of Nursing, Philadelphia.

is clinical associate professor of dermatology, University of Texas Medical Center, Houston.

46 THE CLINICAL ADVISOR • MARCH 2012 • www.ClinicalAdvisor.com

Deborah L. Cross, MPH, CRNP, ANP-BC, is associate program

director, Gerontology NP program, University of Pennsylvania School of Nursing, Philadelphia.

Maria Kidner, DNP, FNP-C,

is a nurse practitioner with Cheyenne Cardiology Associates in Cheyenne, Wyo.

congested cough, cachexia, fatigue, and depression. He spends most of every day in bed and tells me that he feels like he’s dying. Thyroid tests, MRI, CT, and x-ray performed two years ago were negative (except to reveal hyper-expanded airways). I have ordered an MRI of the cyst and a repeat chest x-ray. He was sent to me for pain management, and I have initiated duloxetine (Cymbalta) and oxycodone. What are my other options?—JAN MORGAN, ARNP, FAAPM, Bremerton, Wash. This is a challenging clinical scenario. It is not clear if this patient’s symptoms are related or if there is more than one diagnosis to explain his condition. Since you included the dimensions, I assume that the rib cage cystic mass is palpable. If so, despite the fact that the MRI, CT, and x-ray are negative, a biopsy of a palpable mass can be diagnostic. Clubbed fingers and toes can be attributable to a congenital problem or secondary to heart, lung, liver, or thyroid disease. This patient displays many symptoms of chronic obstructive pulmonary disease (COPD), which includes both chronic bronchitis and emphysema. Smoking, genetics, and environmental and occupational exposures are risk factors for COPD. Alpha-1 antitrypsin is a protein that protects the lungs, and a deficiency can result in the development of COPD, especially in a younger person. Classic symptoms of COPD include chronic cough with sputum production, fatigue, and decreased appetite from the increased work of breathing. Patients with COPD may limit their activity in an attempt to avoid exertional dyspnea, a common early symptom of COPD. Depression is often associated with chronic illness and can also account for symptoms of fatigue and loss of interest in activities. Hyper-expanded airways on x-ray are caused by air trapping and are characteristic of emphysema. I would recommend pulmonary function testing for this patient. Pulmonary function tests can make the diagnosis of COPD, determine the severity of the disease, and distinguish it from asthma. Also, consider testing for an alpha-1 antitrypsin deficiency. While there is no cure

for COPD, there are many treatments available to help control the symptoms and improve quality of life.—Eileen F. Campbell, MSN, CRNP (161-2)

CONTRACEPTION AND BREAST CANCER What oral contraceptive pill would you recommend for a woman with a family history of breast cancer? Is medroxyprogesterone (Depo-Provera) considered safe?—MARY JAMES, CNP, Andover, Ohio A family history of breast cancer is not a contraindication to using the combined oral contraceptive pill (nor is such a family history a contraindication to using a progesterone-only contraceptive, such as medroxyprogesterone). Perhaps the confusion stems from the findings of the Women’s Health Initiative that showed an increased risk of breast cancer in postmenopausal women taking estrogen and progesterone; this result cannot be extrapolated to premenopausal women. A woman with a personal history of breast cancer or suspected breast cancer should not be on any hormones whatsoever.—Mary Newberry, CNM, MSN (161-3)

HOW TO TREAT LYMPHEDEMA A man aged 56 years underwent a liver transplant five years ago. He recently presented with bilateral leg swelling that has progressively worsened. He has no deep venous thrombosis or venous insufficiency. A diagnosis of lymphedema has been made. What are the most effective therapies available to treat this condition?—JEANNIE BRENNAN, ANP-C, ACNP-C, Phoenix Complete decongestive therapy (CDT) (also called combined, complex, or comprehensive decongestive therapy) is the gold standard

Debra August King, PHD, PA,

Mary Newberry, CNM, MSN

Claire O’Connell, MPH, PA-C,

Sherril Sego, FNP-C, DNP,

Julee B.Waldrop, DNP,

is senior physician assistant of the Department of Cardiothoracic Surgery, Lenox Hill Hospital, New York City.

provides well-woman gynecologic care as a midwife with Prima Medical Group, Greenbrae, Calif.

teaches in the PA Program at the New Jersey Medical School and Rutgers University, Piscataway, N.J.

is a primary-care nurse practitioner at the Department of Veterans Affairs Medical Center in Kansas City, Mo.

teaches at the University of North Carolina School of Nursing in Chapel Hill and practices pediatrics at UNC Hospitals.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MARCH 2012 47

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FOR ADULT PATIENTS WITH TYPE 2 DIABETES TRADJENTA (LINAGLIPTIN) TABLETS: THE ONLY ONCE-DAILY 1-DOSE DPP-4 INHIBITOR

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*A randomized, multicenter, double-blind, placebocontrolled study of adult patients with type 2 diabetes (aged 18-80) who were randomized to TRADJENTA 5 mg/day (n=336; mean baseline A1C=8.0%) or placebo (n=167; mean baseline A1C=8.0%) for 24 weeks. Primary endpoint was change from baseline in A1C at 24 weeks. 20.9% of patients in the placebo group required rescue therapy vs 10.2% of patients in the TRADJENTA group. Full analysis population using last observation on study. † A randomized, double-blind, placebo-controlled, parallel-group study of adult patients with type 2 diabetes (aged 18-80) with insufﬁcient glycemic control despite metformin therapy who were randomized to TRADJENTA 5 mg/day (n=524; mean baseline A1C=8.1%) or placebo (n=177; mean baseline A1C=8.0%) in combination with metformin ≥1500 mg/day for 24 weeks. Primary endpoint was change from baseline in A1C at 24 weeks. 18.9% of patients in the placebo group required rescue therapy vs 7.8% of patients in the TRADJENTA group. Full analysis population using last observation on study.

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The safety and effectiveness of TRADJENTA in patients below the age of 18 have not been established. References: 1. Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle H-J, Dugi K. Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab. 2011;13:258-267. 2. Data on ﬁle. Boehringer Ingelheim Pharmaceuticals, Inc. 3. Taskinen M-R, Rosenstock J, Tamminen I, et al. Safety and efﬁcacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13:65-74. 4. Barnett AH. Linagliptin: a novel dipeptidyl peptidase 4 inhibitor with a unique place in therapy. Adv Ther. 2011;28:447-459.

Please see brief summary of full Prescribing Information on adjacent page.

There are no adequate and well-controlled studies in pregnant women. Therefore, TRADJENTA should be used during pregnancy only if clearly needed. It is not known whether linagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman.

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Tradjenta™ (linagliptin) tablets BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for full Prescribing Information. INDICATIONS AND USAGE TRADJENTA tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Important Limitations of Use: TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. TRADJENTA has not been studied in combination with insulin. CONTRAINDICATIONS TRADJENTA is contraindicated in patients with a history of a hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity [see Adverse Reactions]. WARNINGS AND PRECAUTIONS Use with Medications Known to Cause Hypoglycemia: Insulin secretagogues are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial [see Adverse Reactions]. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA tablets or any other antidiabetic drug. ADVERSE REACTIONS Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of linagliptin has been evaluated in over 4000 patients with type 2 diabetes in clinical trials, including 12 placebo-controlled studies and 1 active-controlled study with glimepiride. TRADJENTA 5 mg once daily was studied as monotherapy in two placebo-controlled trials of 18 and 24 weeks’ duration. Five placebo-controlled trials investigated linagliptin in combination with other oral antihyperglycemic agents: two with metformin (12 and 24 weeks’ treatment duration); one with a sulfonylurea (18 weeks’ treatment duration); one with metformin and sulfonylurea (24 weeks’ treatment duration); and one with pioglitazone (24 weeks’ treatment duration). In placebo-controlled clinical trials, adverse reactions that occurred in ≥5% of patients receiving TRADJENTA (n = 2566) and more commonly than in patients given placebo (n = 1183) included nasopharyngitis (5.8% vs 5.5%). Adverse reactions reported in ≥2% of patients treated with TRADJENTA 5 mg daily as monotherapy or in combination with pioglitazone, sulfonylurea, or metformin and at least 2-fold more commonly than in patients treated with placebo are shown in Table 1. Following 52 weeks’ treatment in a controlled study comparing linagliptin with glimepiride in which all patients were also receiving metformin, adverse reactions reported in ≥ 5% patients treated with linagliptin (n = 776) and more frequently than in patients treated with a sulfonylurea (n = 775) were arthralgia (5.7% vs 3.5%), back pain (6.4% vs 5.2%), and headache (5.7% vs 4.2%). Other adverse reactions reported in clinical studies with treatment of TRADJENTA were hypersensitivity (e.g., urticaria, angioedema, or bronchial hyperreactivity), and myalgia. In the clinical trial program, pancreatitis was reported in 8 of 4687 patients (4311 patient years of exposure) while being treated with TRADJENTA compared with 0 of 1183 patients (433 patient years of exposure) treated with placebo. Three additional cases of pancreatitis were reported following the last administered dose of linagliptin. Hypoglycemia: In the placebo-controlled studies, 195 (7.6%) of the total 2566 patients treated with TRADJENTA 5 mg reported hypoglycemia compared to Table 1

49 patients (4.1%) of 1183 placebo-treated patients. The incidence of hypoglycemia was similar to placebo when linagliptin was administered as monotherapy or in combination with metformin, or with pioglitazone. When linagliptin was administered in combination with metformin and a sulfonylurea, 181 of 791 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea. Laboratory Tests: Changes in laboratory findings were similar in patients treated with TRADJENTA 5 mg compared to patients treated with placebo. Changes in laboratory values that occurred more frequently in the TRADJENTA group and ≥1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the TRADJENTA group). No clinically meaningful changes in vital signs were observed in patients treated with TRADJENTA. DRUG INTERACTIONS Inducers of P-glycoprotein or CYP3A4 Enzymes: Rifampin decreased linagliptin exposure suggesting that the efficacy of TRADJENTA may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be administered with a P-gp or CYP3A4 inducer. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category B. Reproduction studies have been performed in rats and rabbits. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Linagliptin administered during the period of organogenesis was not teratogenic at doses up to 30 mg/kg in the rat and 150 mg/kg in the rabbit, or approximately 49 and 1943 times the clinical dose based on AUC exposure. Doses of linagliptin causing maternal toxicity in the rat and the rabbit also caused developmental delays in skeletal ossification and slightly increased embryofetal loss in rat (1000 times the clinical dose) and increased fetal resorptions and visceral and skeletal variations in the rabbit (1943 times the clinical dose). Linagliptin administered to female rats from gestation day 6 to lactation day 21 resulted in decreased body weight and delays in physical and behavioral development in male and female offspring at maternally toxic doses (exposures >1000 times the clinical dose). No functional, behavioral, or reproductive toxicity was observed in offspring of rats exposed to 49 times the clinical dose. Linagliptin crossed the placenta into the fetus following oral dosing in pregnant rats and rabbits. Nursing Mothers: Available animal data have shown excretion of linagliptin in milk at a milk-to-plasma ratio of 4:1. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman. Pediatric Use: Safety and effectiveness of TRADJENTA in pediatric patients have not been established. Geriatric Use: Of the total number of patients (n= 4040) in clinical studies of TRADJENTA, 1085 patients were 65 years and over, while 131 patients were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. While this and other reported clinical experience have not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. No dose adjustment is recommended in this population. Renal Impairment: No dose adjustment is recommended for patients with renal impairment. Hepatic Impairment: No dose adjustment is recommended for patients with hepatic impairment. OVERDOSAGE During controlled clinical trials in healthy subjects, with single doses of up to 600 mg of TRADJENTA (equivalent to 120 times the recommended daily dose) there were no dose-related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans. In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Linagliptin is not expected to be eliminated to a therapeutically significant degree by hemodialysis or peritoneal dialysis.

Adverse Reactions Reported in ≥2% of Patients Treated with TRADJENTA and at Least 2-Fold Greater than with Placebo in Placebo-Controlled Clinical Studies of TRADJENTA Monotherapy or Combination Therapy Monotherapy* n (%)

Nasopharyngitis Hyperlipidemia Cough Hypertriglyceridemia† Weight increased

Combination with SU n (%)

TRADJENTA Placebo n = 765 n = 458

Combination with Metformin# n (%) TRADJENTA Placebo n = 590 n = 248

– – – – –

7 (4.3) – – 4 (2.4) –

– – – – –

TRADJENTA Placebo n = 161 n = 84 1 (1.2) – – 0 (0.0) –

Combination with Metformin + SU n (%) TRADJENTA Placebo n = 791 n = 263

Combination with Pioglitazone n (%) TRADJENTA Placebo n = 259 n = 130

– – 19 (2.4)

– 7 (2.7) – – 6 (2.3)

–

– – 3 (1.1) – –

– 1 (0.8) – – 1 (0.8)

SU = sulfonylurea *Pooled data from 7 studies #Pooled data from 2 studies †Includes reports of hypertriglyceridemia (n = 2; 1.2%) and blood triglycerides increased (n = 2; 1.2%)

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is essential at the time of conception, so a woman receiving this supplement in her birth control is assured of adequate levels of this vitamin in the rare case she gets pregnant on the pill or if she were to conceive shortly after discontinuing the pill.—Mary Newberry, CNM, MSN (161-5)

Lymphedema (right) is localized retention of lymph fluid, composed of excess protein, water, bacteria, and waste.

of treatment for lymphedema. The goals of therapy are to decrease swelling, increase lymph drainage from the congested area, reduce skin fibrosis and improve the condition of the skin, enhance the patient’s functional status and quality of life, relieve pain and discomfort, and decrease the risk of cellulitis. Components of CDT include manual lymph drainage, compression bandaging, lymphatic exercise, skin care, and patient education. Lymphedema is a chronic condition, so the patient must be educated in the important areas of risk reduction; self-lymph drainage; skin care; signs and symptoms of infections; proper fit and care of garments; and the importance of a healthy diet, exercise, and weight management. There are lymphedema treatment centers (including one in Scottsdale, Ariz.) that provide expertise in lymphedema management.—Eileen F. Campbell, MSN, CRNP (161-4)

THE BENEFITS OF ORAL CONTRACEPTIVES WITH FOLATE What is the rationale behind the new combined oral contraceptive (COC) that adds folate to the estrogen and progestin (Beyaz)? Assuming that the folate is added to prevent neural tube defects, how is this beneficial in a woman attempting to avoid pregnancy with the use of a COC?—ELIZABETH RASH, PhD, ARNP, FNP-C, Orlando, Fla. According to the manufacturer, folate was added to “lower the risk of having rare neural tube defects in a pregnancy occurring during Beyaz use or shortly after stopping.” A more cynical assessment would assume that the manufacturer reformulated the pill to continue to profit from a branded product that invariably costs the consumer far more than the generic. In any event, it is clear that folic acid

HOW TO CHOOSE AN SSRI How do I choose the appropriate selective serotonin reuptake inhibitor (SSRI) for a newly depressed/anxious patient? What are the differences in side effects and responses to the available SSRIs? I know they behave differently from the clinical responses I see in my patients, but I cannot find a guideline for differentiating among these commonly used drugs.—TRACY POEPPING, NP, Lone Tree, Colo. To my knowledge, there are no studies comparing one SSRI to another, so choosing the most appropriate medication for the new diagnosis of depression and/or anxiety is more of an art than a science. Clinicians can and should read the drug information for each specific medication being prescribed. While a comparison of studies used for FDA approval can provide some guidance, this indirect comparison ranks low on the evidence-based pyramid. Newer SSRIs target the selective serotonin receptors more specifically than the older formulations and thus have fewer unintended consequences. If I have an established patient that I have screened negatively for a mood disorder (i.e., Bipolar I or II), I often choose either citalopram (Celexa) or sertraline (Zoloft) as an initial agent. Citalopram is useful because (1) it is on the formulary at large retail pharmacies for $4/month or $10/three months; (2) dosing is easy—one week of 10 mg daily followed by 20 mg daily; (3) the side effect profile is very neutral (minimal weight gain and fewer sexual side effects than some of the older SSRIs); and (4) it is nonsedating. The benefits of sertraline are (1) it is generic and therefore the lowest copay on insurance; (2) its many dosing increments allow clinicians to fine-tune the dose for more sensitive patients; (3) a side effect of the medication is that it calms abdominal symptoms, and irritable bowel syndrome is common in the anxious/depressed patient. It is important to screen for a mood disorder because bipolar patients often present to primary care during the depressed phase. Treatment with an SSRI can trigger a manic phase and should be avoided. SSRIs take full effect after four weeks. If a patient has marked anxiety, consider a short course of a benzodiazepine (i.e., lorazepam [Ativan] or alprazolam [Xanax]) for prompt initial relief. For followup, speak with the patient via telephone in one week to evaluate initial response, and schedule an office visit in one month to assess effectiveness of the initial dose. Finally, increase the dose of the initial

48 THE CLINICAL ADVISOR • MARCH 2012 • www.ClinicalAdvisor.com

Advisor Forum medication until complete or near-complete resolution of symptoms occurs.—Rebecca H. Bryan, APRN, CNP (161-6)

CLINICAL PEARLS COLDER EYEDROPS MEAN ENHANCED RELIEF I encourage patients using ophthalmic solutions for allergic conjunctivitis to store the drops in the refrigerator for even more soothing results.—DONNA MARIANO, FNP, Wallingford, Ct. (161-7)

NEW PAIN-MANAGEMENT TERMINOLOGY The word “contract” in regard to patients with chronic pain is dated, perceived negatively, and not preferred. Newer and more appropriate terminology with this patient population is “signed patient agreements.” In addition, please consider using the more accurate “opioids” rather than “narcotics.”— SUSAN PENDERGRASS, MSN, MEd, FNP, Columbia, Mo. (161-8)

“Instead of creating life, I’ve decided just to establish an online persona.”

ATTITUDE IS EVERYTHING When a patient complains about everything that is going wrong, encourage him or her to change their way of thinking by focusing on what they can do, like drive, feed, and dress themselves. After all, not everyone is so fortunate. This usually engenders an improved mood.—DONNA M. RICHARDSON, FNP-C, Pineville, La. (161-9)

YOUR COMMENTS TOWARD A MORE HUMANE SOURCE OF ESTROGEN I was happy to see your article, “Making the right choice in hormone therapy” ( January 2012), address the inhumane use of pregnant mare’s urine (PMU) in the manufacturing of conjugated estrogens (Premarin). I am an animal lover and the owner of three horses, one of which was saved from a PMU ranch. I am also an emergency-department physician assistant that advocates educating patients on the source of this medication. Yours was the first article I have seen that addresses this important issue, and I hope more providers will take the time to learn more about it.—HEATHER BARRETT, PA-C, Racine, Wis. (161-10) ■

“You know that thing where you stand like a statue, then move real fast, then stand like a statue again? You totally stole that from me.”

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MARCH 2012 51

Test your clinical acumen with our monthly quiz

CME Dermatology Clinic CE

■ LEARNING OBJECTIVES: To identify and diagnose dermatologic conditions and review up-to-date treatment. ■ COMPLETE THE POSTTEST: Page 79

■ ADDITIONAL CME/CE: Pages 20, 75

CASE #1

Thick, leathery, and red skin over the hands KERRI ROBBINS, MD

A 10-year-old Hispanic girl presented with a rash that had been present for four months. Previous treatment with topical corticosteroids for atopic dermatitis provided no resolution of the rash. Examination of the hands revealed erythematous lichenified plaques distributed over the joints, along with ragged cuticles and periungual telangiectasias. In addition, violaceous patches with areas of hypo- and hyperpigmentation along with telangiectasias were seen around the eyes, bilateral cheeks, and upper trunk. Muscle strength measured of 3/5 on bilateral triceps and 4/5 on bilateral quadriceps. The girl has to sleep on the ground floor because she is too weak to walk upstairs. What is your diagnosis? Turn to page 60

CASE #2

Slow-growing papule with no pain or itching ESTHER STERN, NP-C

A woman aged 85 years presented for evaluation of a slowly growing bump on her neck. The patient explained that the lesion fi rst appeared three months earlier and had grown slowly in the interim to its present size. Although no itching or pain was associated with the lesion, the woman reported bleeding when it got caught on her necklace. Physical exam revealed a flesh-colored 6-mm verrucous papule on the left lateral neck. On gentle paring, the lesion showed pinpoint black dots. What is your diagnosis? Turn to page 61 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MARCH 2012 59

CME CE

CASE #1

Dermatology Clinic

Dermatomyositis

Dermatomyositis is characterized by a cutaneous eruption; it is manifested by an extensor, inflammatory, and symmetric proximal myopathy. Polymyositis is a term used for patients whose skin is spared from disease. In contrast, dermatomyositis sine myositis (also called amyopathic dermatomyositis) is a term used for those patients who have skin disease alone. The disease has a bimodal age distribution, ranging from age 10 to 15 years and age 45 to 57 years. Cases of infantile dermatomyositis also have been observed.1 Gender does not seem to play a role in children, but adult women are twice as likely as men to develop the disease.2 Approximately 25% of adult patients will also have an associated malignancy. Juvenile patients have no increased risk of malignancy but are at higher risk for small-vessel vasculitis and calcinosis. The incidence in various populations ranges from 2 per million to 7 per million.2 Dermatomyositis results from an immune-mediated process in genetically predisposed individuals. It is also believed that a trigger is necessary for the initiation of the disease. Potential triggers include drugs, infectious agents, and malignancy.2 Drug-induced dermatomyositis has been reported due to hydroxyurea (Droxia, Hydrea) in patients with chronic myelogenous leukemia. Other drugs, such as phenytoin (Dilantin), nonsteroidal anti-inflammatories, and lipid-lowering agents, have also been suspected as the trigger for dermatomyositis.2,3 Infectious agents include such viruses as HIV, coxsackievirus-9, echovirus, Escherichia coli, and picornavirus. Genitourinary cancers are the most commonly diagnosed malignancies in adult patients with dermatomyositis.2 A violaceous poikiloderma is one of the most characteristic features of the disease. Poikiloderma is characterized by hyper- or hypopigmentation, telangiectasias, and epidermal atrophy.2 The shawl sign is described as a poikiloderma that is seen in a characteristic distribution on the anterior neck, upper chest, and back area in a V shape. The heliotrope sign, named after its similarity to the heliotrope flower, will be visible when the poikiloderma involves the periorbital skin. Violaceous discoloration that affects such bony prominences as the knuckles, elbows, and knees, is termed Gottron’s sign. When these areas develop a secondary lichenoid quality, they are called Gottron’s papules. Other clinical features include

the photodistributed pattern of the rash and the presence of such nailfold changes as cuticular dystrophy and periungual telangiectasias.3 Well-defined, erythematous plaques with silvery scale may be appreciated on the extensor surfaces of the elbows and knees. Patients may complain of severe pruritus. In children, calcinosis cutis, often at sites of prior trauma, may also be seen. The dermatologic manifestations of dermatomyositis often precede the onset of muscle disease.2 Patients may present with complaints of fatigue and malaise.4 The myositis affects proximal muscle groups in a symmetric fashion. The most commonly affected muscles are the extensors, including the triceps and quadriceps. As the disease advances, all muscle groups may become affected, and muscles may be tender to palpation. The risk for developing a malignancy in adults with dermatomyositis ranges from 10% to 50%.2 It is important for

Once the diagnosis is confirmed histopathologically, the search for possible muscle involvement must follow. clinicians to recognize the signs of dermatomyositis because the rash will often precede the onset of symptoms related to the cancer. Some of the most common malignancies include ovarian, colon, breast, lung, pancreatic, and gastric cancers.2,5 Since the triceps and biceps are often the first to be affected by the disease, muscle biopsy should be taken from one of these areas (typically the triceps).6 The biopsy will often show type II muscle fiber atrophy, necrosis, regeneration, and lymphocytes in a perifascicular and perivascular distribution.2,3 Poikiloderma is a characteristic feature of dermatomyositis but is also seen in such other diseases as lupus erythematosus. However, while the poikiloderma is violaceous in dermatomyositis, it is erythematous in lupus erythematosus.7 Histologically, dermatomyositis and lupus erythematosus may be indistinguishable. Other disorders to consider in the differential diagnosis include psoriasis, atopic dermatitis, airborne or allergic contact dermatitis, photodrug reactions, scleroderma, and cutaneous T-cell lymphoma.6 Once the diagnosis of dermatomyositis is confirmed histopathologically, the search for possible muscle involvement must follow. The evaluation includes assessing the strength of the proximal extensor muscles, obtaining serum levels of muscle enzymes, and performing an electromyogram and a triceps muscle biopsy. MRI or ultrasound of the proximal muscles is often obtained prior to (or instead of ) a muscle

60 THE CLINICAL ADVISOR • MARCH 2012 • www.ClinicalAdvisor.com

biopsy in individuals with classic dermatomyositis.2 Such additional baseline investigations as a CT scan, pulmonary function tests, electrocardiogram, evaluation for overlap connective tissue diseases, and screening for occult malignancy should be done prior to starting systemic therapy. Corticosteroid treatment should be initiated after muscle involvement is confirmed by two positive objective tests. The dose of prednisone is generally 1.0 mg/kg, but this may need to be adjusted depending on the clinical response and/or extent of muscle disease.2 If necessary, such steroidsparing agents as methotrexate (Rheumatrex, Trexall), azathioprine (Azasan, Imuran), chlorambucil (Leukeran), pulse cyclophosphamide (Cytoxan), cyclosporine (Gengraf, Neoral, Sandimmune, Sangcya), fludarabine (Fludara), mycophenolate mofetil (CellCept, Myfortic), tacrolimus (Hecoria, Prograf ), sirolimus (Rapamune), inf liximab (Remicade), and rituximab (Rituxan) may be used alone or in conjunction with the corticosteroid.2 The patient in this case was found to have elevated levels of creatine kinase and aldolase and abnormal electromyography results. A biopsy of the triceps muscle showed changes that were classic for dermatomyositis. Treatment with high-dose prednisone led to resolution of the myositis and no recurrence to date. The dermatologic manifestations of this patient’s disease were treated with triamcinolone 0.1% ointment b.i.d., as needed for pruritus. The rash has improved but has not completely resolved. ■ Dr. Robbins is a resident in the Department of Dermatology at Baylor College of Medicine in Houston. The author has no relationhsips to discolse relating to the content of this aritcle. References 1. Pachman LM, Hayford JR, Chung A, et al. Juvenile dermatomyositis at diagnosis: clinical characteristics of 79 children. J Rheumatol. 1998;25:1198-1204. 2. Bolognia JL, Jorizzo JL, Rapini RP eds. Dermatology. 2nd ed. St. Louis, Mo.: Elsevier-Mosby; 2008:575-583. 3. Habif TP. Skin Disease: Diagnosis and Treatment. 2nd ed., Philadelphia, Pa.: Elsevier Mosby; 2005:350-353. 4. RP Rapini. Practical Dermatopathology. Philadelphia, Pa.: Elsevier Mosby; 2005:228-229. 5. Barnes BE, Mawr B. Dermatomyositis and malignancy. A review of the literature. Ann Intern Med. 1976;84:68-76. 6. Elder DE, Elenitsas R, Johnson BL, et al, eds. Lever’s Histopathology of the Skin. 10th ed. Philadelphia, Pa.: Lippincott Williams & Wilkins; 2009:293-295. 7. Fitzpatrick TB, Johnson RA, Wolff K, Suurmond R, eds. Color Atlas and Synopsis of Clinical Dermatology, 5th ed. New York, N.Y.: McGraw-Hill; 2005:372-374.

CASE #2

Verruca vulgaris

Verruca vulgaris refers to the common wart, a benign neoplasm that is caused by infection with the human papillomavirus (HPV). Verruca vulgaris, as opposed to genital warts, are usually caused by the HPV 1, 2, 4, 27, 57, and 63 strains, which are spread through skin-to-skin contact or via fomites. Warts usually occur during the school-age and youngadult years, but they can appear at any age. Although healthy patients are commonly affected, immunosuppression predisposes to the occurrence of multiple and resistant warts. In addition, adults who handle meat and fish as part of their job or who frequently immerse their hands in water have a higher incidence of common warts. Warts are usually found on the dorsal hands, fingers, and palms. Periungual lesions may cause significant pain and/or paronychia. People who bite their fingernails often present with spread of warts to the vermillion and cutaneous lip, presenting a treatment challenge. Diagnosis of a verruca is almost always clinical. Classically, a wart presents as a rounded papule with a rough grayish surface—this texture is referred to as “verrucous.” Thickening of the infected epidermis and prominence of the dermal papillae cause the verrucous appearance. Flat warts have a more subtle appearance, and the verrucous texture may be difficult to appreciate. The average size of the common wart is 5 mm, but lesions range in size from pinpoint to larger than 1 cm. More than one wart is usually present, and there is often one large wart and several smaller ones grouped nearby. A linear arrangement of warts typically results from autoinoculation, demonstrating the Koebner phenomenon. Verrucae may be difficult to distinguish from seborrheic keratoses, benign lesions seen in the elderly, and palmar or plantar calluses. If the diagnosis is unclear, gentle paring with a surgical blade can remove the verrucous surface keratin painlessly and reveal pinpoint black or purple dots, representing thrombosed capillaries. A wart will also interrupt normal dermatoglyphics, whereas a callus retains the skin lines. More concerning, squamous cell carcinoma and amelanotic melanoma must be ruled out in atypical-appearing lesions. Treatment of warts is often frustrating for both the clinician and the patient. The goal of treatment is resolution of

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MARCH 2012 61

CME CE

Dermatology Clinic

the lesions along with acceptable cosmetic outcome (i.e. minimal or no scarring). Prior to initiating treatment, inform the patient that resolution of a wart does not eradicate the causative virus, which remains latent within the affected squamous epithelial cells, making recurrence common. Also explain that no single treatment method is guaranteed to successfully resolve the warts. Patients should be advised that many warts spontaneously resolve. Literature suggests a 30% clearance rate at three months, 65% to 78% at two years, and 90% over five years.1 As a result, benign neglect is an acceptable option

Resolution of a wart does not eradicate the causative virus, which remains latent within the affected squamous epithelial cells. for warts that are not bothersome to patients and for those that do not interfere with a patient’s social activities. More often, concern regarding the spread of warts prompts many patients—and more commonly, parents of affected children—to request treatment. Physical treatment modalities include cryotherapy, shave removal, electrodessication and curettage, and laser treatment. Cryotherapy with liquid nitrogen is generally considered the first-line treatment option, as this procedure is highly effective and the pain is of short duration.2 Inform the patient that two or three treatments scheduled at two to four weeks’ duration are frequently necessary for eradication. After treatment, the wart will progress to scabbing, crusting, and sometimes blistering. Vigorous treatment may result in scarring. Surgical removal and laser therapy are generally more painful and have a higher likelihood of scarring. Several chemotherapeutic treatment options exist. OTC salicylic acid is an inexpensive albeit time-consuming choice. At-home treatment involves nightly application of the acid. Once the acid has dried, duct tape is applied to occlude the surface of the wart. Removal of the tape the next morning accomplishes gradual and painless debridement. This method may take anywhere from two to 12 weeks for cure. For in-office treatment, cantharidin (Canthacur), a strong blistering agent extracted from the blister beetle, or chloroacetic acid may be carefully applied. Because of their painless application, these are usually the treatments of choice in

children. As with cryotherapy, these also result in blister formation and may require two or three treatments. Imiquimod cream (Aldara) is a biologic agent approved for treatment of external genital warts, but many practitioners prescribe it for daily use in the treatment of common warts. This cream may be used in conjunction with physical destructive techniques. Advise patients of potentially irritating effects, and cease application if any erythema or skin breakdown occurs. Similarly, 5-fluorouracil cream (Efudex) has been shown to be safe and effective for treatment of verruca vulgaris.3 The oral immunomodulating agents cimetidine (Tagamet) and levamisole (Ergamisol), used alone or in combination, have been shown to be effective for recalcitrant warts; however, there is no FDA indication for this use.4 Intralesional injection of bleomycin (Blenoxane) and interferon alfa-2a (Roferon) is reserved for warts resistant to all other standard treatments. The woman described in this case was treated with two rounds of cryotherapy three weeks apart, leading to complete resolution of the lesion. ■ Ms. Stern is a family nurse practitioner at Advanced Dermatology & Skin Surgery, P.C., in Lakewood, N.J. The author has no relationhsips to discolse relating to the content of this aritcle. References 1. James WD, Berger TG, Elston DM. Viral diseases. In: Andrews’ Diseases of the Skin: Clinical Dermatology. 10th ed. Philadelphia, PA.: SaundersElsevier; 2006:404. 2. Lipke MM. An armamentarium of wart treatments. Clin Med Res. 2006;4:273-293. Available at www.clinmedres.org/content/4/4/273.long. 3. Gladsjo JA, Alió Sáenz AB, Bergman J, et al. 5% 5-Fluorouracil cream for treatment of verruca vulgaris in children. Pediatr Dermatol. 2009;26:279285. 4. Parsad D, Pandhi R, Juneja A, Negi KS. Cimetidine and levamisole versus cimetidine alone for recalcitrant warts in children. Pediatr Dermatol. 2001;18:349-352. All electronic documents accessed February 15, 2012.

MORE DERMATOLOGY ON THE WEB Test your diagnostic skills. Our FREE archive of Dermatology Clinic and Dermatologic Look-Alikes is now available online at www.ClinicalAdvisor.com/Derm.

62 THE CLINICAL ADVISOR • MARCH 2012 • www.ClinicalAdvisor.com

Evolving anticoagulation in patients with NVAF, including those at increased stroke risk...

HELP INTERCEPT STROKE RISK

...combining proven protection, a demonstrated safety profile, and convenient once-daily dosing XARELTO® (rivaroxaban) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). There are limited data on the relative effectiveness of XARELTO® and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well controlled.

IMPORTANT SAFETY INFORMATION WARNING A. DISCONTINUING XARELTO® IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION Discontinuing XARELTO® places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO® discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation with XARELTO® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.

Please see additional Important Safety Information and brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

Once-daily XARELTO® delivers... Proven protection Effective reduction in risk of stroke and non-CNS systemic embolism* Results achieved in NVAF patients with multiple comorbidities reflecting increased risk of stroke

A demonstrated safety profile Comparable major bleed rates† versus warfarin: rivaroxaban 3.6, warfarin 3.5 per 100 patient-years In bleeding categories of great concern, such as bleeding into a critical organ‡ and fatal bleeding, fewer events were observed with XARELTO®§ In the categories of transfusions and gastrointestinal bleed, more events were observed with XARELTO®§

Convenient once-daily dosing and administration Oral 20-mg fixed dose taken once daily with the evening meal (15 mg for patients with CrCl 15 mL/min to 50 mL/min) No routine monitoring of INR or other coagulation parameters is required1 If a dose of XARELTO® is not taken at the scheduled time, administer the dose as soon as possible on the same day

E vent rates per 100 patient-years, rivaroxaban versus warfarin: critical-organ bleeding 0.8 versus 1.2; fatal bleeding 0.2 versus 0.5; bleeding resulting in transfusion of ≥2 units of whole blood or packed red blood cells 1.7 versus 1.3; gastrointestinal bleeding 2.0 versus 1.2.

IMPORTANT SAFETY INFORMATION (cont’d) Warning (cont’d) B. SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO® who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: Use of indwelling epidural catheters Concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants, see Drug Interactions A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis. CONTRAINDICATIONS Active pathological bleeding and severe hypersensitivity reaction to XARELTO®. WARNINGS AND PRECAUTIONS Increased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO®, in the absence of adequate alternative

anticoagulation, increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO® to warfarin in clinical trials in atrial fibrillation patients. If XARELTO® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant. Risk of Bleeding: XARELTO® increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO® to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss. Discontinue XARELTO® in patients with active pathological hemorrhage. • A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials. • Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and NSAIDs.

Please see additional Important Safety Information and brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

IMPORTANT SAFETY INFORMATION (cont’d) • Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (eg, ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk. Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis. An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO®. The next XARELTO® dose is not to be administered earlier than 6 hours after the removal of the catheter. Delay the administration of XARELTO® for 24 hours if traumatic puncture occurs. Risk of Pregnancy-Related Hemorrhage: Use with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. The anticoagulant effect of XARELTO® cannot be monitored with standard laboratory testing and is not readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (eg, a drop in

hemoglobin and/or hematocrit, hypotension, or fetal distress). Pregnancy Category C Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO® to reduce the risk of deep vein thrombosis (DVT). Patients who have a history of a severe hypersensitivity reaction to XARELTO® should not receive XARELTO®. DRUG INTERACTIONS Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant administration of XARELTO® with combined P-gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ ritonavir, ritonavir, indinavir/ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk. Drugs That Induce CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant use of XARELTO® with drugs that are combined P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort) due to decreases in rivaroxaban exposure that may decrease efficacy.

CNS = central nervous system; CrCl = creatinine clearance; INR = international normalized ratio.

*A randomized, phase 3, multicenter, active-controlled, double-blind, double-dummy,

event-driven study in more than 14,000 patients with NVAF. Patients received XARELTO® 20 mg once daily (15 mg once daily in patients with CrCl 30 mL/min-50 mL/min) or dose-adjusted warfarin titrated to an INR range of 2.0-3.0.1 † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes were counted as both bleeding and efficacy events. Major bleeding rates excluding strokes were 3.3 for XARELTO® and 2.9 for warfarin per 100 patient-years. ‡ The majority of critical-organ bleeding events were intracranial, and also included intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal.

Learn more at www.XARELTOhcp.com

Please see additional Important Safety Information and brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

CNS = central nervous system; CrCl = creatinine clearance; INR = international normalized ratio.

*A randomized, phase 3, multicenter, active-controlled, double-blind, double-dummy,

Learn more at www.XARELTOhcp.com

IMPORTANT SAFETY INFORMATION (cont’d) NSAIDs/Aspirin: NSAIDs/aspirin are known to increase bleeding; therefore, bleeding risk may be increased when these drugs are used concomitantly with XARELTO®. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs. Clopidogrel: Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with clopidogrel. Drug-Disease Interactions With Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Use in patients with CrCl 15 mL/min to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk. USE IN SPECIFIC POPULATIONS Nursing Mothers: It is not known if rivaroxaban is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO®, taking into account the importance of the drug to the mother. Geriatric Use: In clinical trials the efficacy of XARELTO® in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups. Renal Impairment • Patients with renal impairment taking P-gp and weak to moderate CYP3A4 inhibitors may have significant increases in exposure, which may increase bleeding risk. • For patients with CrCl 15 mL/min to 50 mL/min, the recommended dose of XARELTO® is 15 mg once daily with the evening meal. Avoid use in patients with CrCl <15 mL/min. Periodically assess renal function as clinically indicated (ie, more frequently in

situations in which renal function may decline) and adjust therapy accordingly. Discontinue XARELTO® in patients who develop acute renal failure while on XARELTO®. Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment. Avoid the use of XARELTO® in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy. OVERDOSAGE Overdose of XARELTO® may lead to hemorrhage. A specific antidote for rivaroxaban is not available. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. Discontinue XARELTO® and initiate appropriate therapy if bleeding complications associated with overdosage occur. The use of activated charcoal to reduce absorption in case of XARELTO® overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable. ADVERSE REACTIONS IN CLINICAL STUDIES Hemorrhage: The most common adverse reactions with XARELTO® were bleeding complications. The most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO® versus 3.1% for warfarin. The incidence of discontinuations for nonbleeding adverse events was similar in both treatment groups. In XARELTO®- versus warfarintreated patients, respectively, major bleeding events were 5.6% versus 5.4%. Other Clinical Trial Experience: In an investigational study of acute medically ill patients being treated with XARELTO® 10-mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed. Please see brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

Learn more at www.XARELTOhcp.com

Reference: 1. Patel MR, Mahaffey KW, Garg J, et al; and the ROCKET AF Steering Committee, for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891.

XARELTO® is licensed from Bayer HealthCare AG, 51368 Leverkusen, Germany. © Janssen Pharmaceuticals, Inc. 2011 November 2011 02X11227

Janssen Pharmaceuticals, Inc.

Brief Summary of Prescribing Information for XARELTO® (rivaroxaban) XARELTO® (rivaroxaban) tablets, for oral use See package insert for full Prescribing Information WARNINGS: (A) DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION INCREASES RISK OF STROKE, (B) SPINAL/EPIDURAL HEMATOMA A. DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION Discontinuing XARELTO places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation with XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1) in full Prescribing Information, Warnings and Precautions, and Clinical Studies (14.1) in full Prescribing Information]. B. SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • use of indwelling epidural catheters • concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • a history of traumatic or repeated epidural or spinal punctures • a history of spinal deformity or spinal surgery [see Warnings and Precautions and Adverse Reactions]. Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions]. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions]. INDICATIONS AND USAGE Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation: XARELTO (rivaroxaban) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is wellcontrolled [see Clinical Studies (14.1) in full Prescribing Information]. CONTRAINDICATIONS XARELTO is contraindicated in patients with: • active pathological bleeding [see Warnings and Precautions] • severe hypersensitivity reaction to XARELTO [see Warnings and Precautions] WARNINGS AND PRECAUTIONS Increased Risk of Stroke after Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients. If XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1) and Clinical Studies (14.1) in full Prescribing Information]. Risk of Bleeding: XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss. Discontinue XARELTO in patients with active pathological hemorrhage. A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Clinical Pharmacology (12.3) in full Prescribing Information]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials. Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions]. Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (e.g. ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions]. Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning]. An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO. The next XARELTO dose is not to be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, the administration of XARELTO is to be delayed for 24 hours. Risk of Pregnancy Related Hemorrhage: XARELTO should be used with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing nor readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

XARELTO® (rivaroxaban) tablets Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO to reduce the risk of DVT. Patients who have a history of a severe hypersensitivity reaction to XARELTO should not receive XARELTO [see Adverse Reactions]. ADVERSE REACTIONS Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. During clinical development for the approved indications, 11598 patients were exposed to XARELTO. These included 7111 patients who received XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF) and 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3). Hemorrhage: The most common adverse reactions with XARELTO were bleeding complications [see Warnings and Precautions]. Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups. Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF study. Table 1: Bleeding Events in ROCKET AF* Parameter

XARELTO N = 7111 n (%) 395 (5.6) 91 (1.3)

Event Rate (per 100 Pt-yrs) 3.6 0.8

Warfarin N = 7125 n (%) 386 (5.4) 133 (1.9)

Event Rate (per 100 Pt-yrs) 3.5 1.2

Major bleeding† Bleeding into a critical organ‡ Fatal bleeding 27 (0.4) 0.2 55 (0.8) 0.5 Bleeding resulting in 183 (2.6) 1.7 149 (2.1) 1.3 transfusion of ≥ 2 units of whole blood or packed red blood cells Gastrointestinal bleeding 221 (3.1) 2.0 140 (2.0) 1.2 * For all sub-types of major bleeding, single events may be represented in more than one row, and individual patients may have more than one event. † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥ 2 g/dL, transfusion of ≥ 2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes are counted as both bleeding and efficacy events. Major bleeding rates excluding strokes are 3.3 per 100 Pt-yrs for XARELTO vs. 2.9 per 100 Pt-yrs for warfarin. ‡ The majority of the events were intracranial, and also included intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal. Postmarketing Experience: The following adverse reactions have been identified during post-approval use of rivaroxaban. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: agranulocytosis Gastrointestinal disorders: retroperitoneal hemorrhage Hepatobiliary disorders: jaundice, cholestasis, cytolytic hepatitis Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock Nervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome DRUG INTERACTIONS Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Inhibitors and inducers of these CYP450 enzymes or transporters (e.g., P-gp) may result in changes in rivaroxaban exposure. Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems: In drug interaction studies evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors, increases in rivaroxaban exposure and pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were observed. Significant increases in rivaroxaban exposure may increase bleeding risk. • Ketoconazole (combined P-gp and strong CYP3A4 inhibitor): Steady-state rivaroxaban AUC and Cmax increased by 160% and 70%, respectively. Similar increases in pharmacodynamic effects were also observed. • Ritonavir (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 150% and 60%, respectively. Similar increases in pharmacodynamic effects were also observed. • Clarithromycin (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 50% and 40%, respectively. The smaller increases in exposure observed for clarithromycin compared to ketoconazole or ritonavir may be due to the relative difference in P-gp inhibition. • Erythromycin (combined P-gp and moderate CYP3A4 inhibitor): Both the single-dose rivaroxaban AUC and Cmax increased by 30%. • Fluconazole (moderate CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 40% and 30%, respectively. Avoid concomitant administration of XARELTO with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.

Learn more at www.XARELTOhcp.com

XARELTO® is licensed from Bayer HealthCare AG, 51368 Leverkusen, Germany. © Janssen Pharmaceuticals, Inc. 2011 November 2011 02X11227

Janssen Pharmaceuticals, Inc.

XARELTO N = 7111 n (%) 395 (5.6) 91 (1.3)

Event Rate (per 100 Pt-yrs) 3.6 0.8

Warfarin N = 7125 n (%) 386 (5.4) 133 (1.9)

Event Rate (per 100 Pt-yrs) 3.5 1.2

XARELTO® (rivaroxaban) tablets

Drugs that Induce Cytochrome P450 3A4 Enzymes and Drug Transport Systems: In a drug interaction study, co-administration of XARELTO (20 mg single dose with food) with a drug that is a combined P-gp and strong CYP3A4 inducer (rifampicin titrated up to 600 mg once daily) led to an approximate decrease of 50% and 22% in AUC and Cmax, respectively. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy. Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort). Anticoagulants: In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and XARELTO (10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity. Enoxaparin did not affect the pharmacokinetics of rivaroxaban. In another study, single doses of warfarin (15 mg) and XARELTO (5 mg) resulted in an additive effect on factor Xa inhibition and PT. Warfarin did not affect the pharmacokinetics of rivaroxaban. NSAIDs/Aspirin: In ROCKET AF, concomitant aspirin use (almost exclusively at a dose of 100 mg or less) during the double-blind phase was identified as an independent risk factor for major bleeding. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with XARELTO. In a singledose drug interaction study there were no pharmacokinetic or pharmacodynamic interactions observed after concomitant administration of naproxen or aspirin (acetylsalicylic acid) with XARELTO. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see Warnings and Precautions]. Clopidogrel: In two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and XARELTO (15 mg single dose) were co-administered in healthy subjects, an increase in bleeding time to 45 minutes was observed in approximately 45% and 30% of subjects in these studies, respectively. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. There was no change in the pharmacokinetics of either drug. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with clopidogrel [see Warnings and Precautions]. Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems: Based on simulated pharmacokinetic data, patients with renal impairment receiving full dose XARELTO in combination with drugs classified as combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, quinidine, ranolazine, dronedarone, felodipine, erythromycin, and azithromycin) may have significant increases in exposure compared with patients with normal renal function and no inhibitor use, since both pathways of rivaroxaban elimination are affected. While increases in rivaroxaban exposure can be expected under such conditions, results from an analysis in the ROCKET AF trial, which allowed concomitant use with combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, chloramphenicol, cimetidine, and erythromycin), did not show an increase in bleeding in patients with CrCl 30 to <50 mL/min [Hazard Ratio (95% CI): 1.05 (0.77, 1.42)]. XARELTO should be used in patients with CrCL 15 to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk [see Use in Specific Populations]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C: There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established. Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible. The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing. Animal reproduction studies showed no increased risk of structural malformations, but increased post-implantation pregnancy loss occurred in rabbits. XARELTO should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus [see Warnings and Precautions]. Rivaroxaban crosses the placenta in animals. Animal reproduction studies have shown pronounced maternal hemorrhagic complications in rats and an increased incidence of post-implantation pregnancy loss in rabbits. Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis. This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day. Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg. This dose corresponds to about 14 times the human exposure of unbound drug. Labor and Delivery: Safety and effectiveness of XARELTO during labor and delivery have not been studied in clinical trials. However, in animal studies maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg/day). Nursing Mothers: It is not known if rivaroxaban is excreted in human milk. Rivaroxaban and/or its metabolites were excreted into the milk of rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Geriatric Use: Of the total number of patients in the RECORD 1-3 clinical studies evaluating XARELTO, about 54% were 65 years and over, while about 15% were >75 years. In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years. In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups [see Clinical Pharmacology (12.3) and Clinical Studies (14) in full Prescribing Information]. Females of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.

Renal Impairment: The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in healthy subjects [CrCl ≥80 mL/min (n=8)] and in subjects with varying degrees of renal impairment (see Table 2). Compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased in subjects with renal impairment. Increases in pharmacodynamic effects were also observed. Table 2: Percent Increase of Rivaroxaban PK and PD Parameters from Normal in Subjects with Renal Insufficiency from a Dedicated Renal Impairment Study Renal Impairment Class [CrCl (mL/min)] Parameter Mild Moderate Severe [50 to 79] [30 to 49] [15 to 29] N=8 N=8 N=8 Exposure AUC 44 52 64 28 12 26 (% increase relative to normal) Cmax FXa Inhibition AUC 50 86 100 9 10 12 (% increase relative to normal) Emax PT Prolongation AUC 33 116 144 4 17 20 (% increase relative to normal) Emax PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concentration or effect curve; Cmax = maximum concentration; Emax = maximum effect; and CrCl = creatinine clearance Patients with renal impairment taking P-gp and weak to moderate CYP3A4 inhibitors may have significant increases in exposure which may increase bleeding risk [see Drug Interactions]. Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily. Patients with CrCl 15 to 30 mL/min were not studied, but administration of XARELTO 15 mg once daily is also expected to result in serum concentrations of rivaroxaban similar to those in patients with normal renal function [see Dosage and Administration (2.1) in full Prescribing Information]. Hepatic Impairment: The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in healthy subjects (n=16) and subjects with varying degrees of hepatic impairment (see Table 3). No patients with severe hepatic impairment (Child-Pugh C) were studied. Compared to healthy subjects with normal liver function, significant increases in rivaroxaban exposure were observed in subjects with moderate hepatic impairment (Child-Pugh B). Increases in pharmacodynamic effects were also observed. Table 3: Percent Increase of Rivaroxaban PK and PD Parameters from Normal in Subjects with Hepatic Insufficiency from a Dedicated Hepatic Impairment Study Hepatic Impairment Class (Child-Pugh Class) Parameter Mild Moderate (Child-Pugh A) (Child-Pugh B) N=8 N=8 Exposure AUC 15 127 0 27 (% increase relative to normal) Cmax FXa Inhibition AUC 8 159 0 24 (% increase relative to normal) Emax PT Prolongation AUC 6 114 2 41 (% increase relative to normal) Emax PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concentration or effect curve; Cmax = maximum concentration; Emax = maximum effect Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (ChildPugh C) hepatic impairment or with any hepatic disease associated with coagulopathy [see Dosage and Administration (2.3) in full Prescribing Information and Warnings and Precautions]. OVERDOSAGE Overdose of XARELTO may lead to hemorrhage. A specific antidote for rivaroxaban is not available. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Warnings and Precautions and Clinical Pharmacology (12.3) in full Prescribing Information]. Active Ingredient Made in Germany Finished Product Manufactured by: Janssen Ortho, LLC Gurabo, PR 00778

Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560

Licensed from: Bayer HealthCare AG 51368 Leverkusen, Germany

Derm Dx

EXCLUSIVE TO THE WEB

INTERACT WITH YOUR PEERS by viewing the images and offering your diagnosis and comments. To post your answer, obtain more clues, or view similar cases, visit ClinicalAdvisor.com/DermDx. Learn more about diagnosing and treating these conditions, and see how you compare with your fellow colleagues.

Itchy maceration between the third and fourth toes A 33-year-old otherwise healthy man presents with foul-smelling, itchy, and macerated skin between his third and fourth toes. He is not sure how long ago the condition developed. WHAT IS YOUR DIAGNOSIS?

• • • •

Tinea pedis Erosio interdigitalis blastomycetica Contact dermatitis Erythrasma

● See the full case at ClinicalAdvisor.com/DermDx0312A

Itchy, light-brown patches in the groin An obese man with a history of hypertension and hyperlipidemia complains of light-brown patches accompanied by itching in the groin that has been present for four months. WHAT IS YOUR DIAGNOSIS?

• • • • •

Erythrasma Candidiasis Tinea cruris Inverse psoriasis Irritant contact dermatitis

● See the full case at ClinicalAdvisor.com/DermDx0312B

Have you missed any recent Derm Dx cases? Go to ClinicalAdvisor.com/DermDx for a complete archive of past quizzes as well as additional images of last month’s other cases.

Blisters on the buttock following laparoscopic surgery

Scaly patches after a throat infection

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Everyone needs a break during the day. So relax with this photo essay, and pretend you’re someplace else.

Picture this

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A rising sun lights up the coastal cliffs at Maroubra Beach near Sydney, Australia. Maroubra is a local Aboriginal word that means “place of thunder,” a reference to the wild weather known to strike the area.

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Take the Scavenger Hunt Challenge March edition

Correctly answer the questions below— all of which can be found within this issue of The Clinical Advisor—and you will be entered into a random drawing to win an Apple iPad. To submit your responses, simply go to www.ClinicalAdvisor.com/ScavengerHunt. QUESTIONS 1. What new metformin-containing tablets were recently approved by the FDA? (p. 14) 2. Who reported the first observation of a spiral bacterium called Vibrio rugula? (p. 20) 3. What groups have the highest prevalence of Helicobacter pylori infection? (p. 21) 4. What percentage of patients with H. pylori infection are not cured after completing their first course of treatment? (p. 25) 5. What systolic BP level indicates prehypertension? (p. 40) 6. According to the World Health Organization’s definition, what is the T-score threshold at which osteoporosis begins? (p. 44) 7. Are adult women or men more likely to develop dermatomyositis? (p. 60) 8. What is the average size of the common wart? (p. 61) 9. What three environmental factors seem to influence the course of plaque psoriasis? (p. 76) 10. Who is considered the father of modern hypnosis? (p. 80)

WHO MAY ENTER All nurse practitioners and physician assistants 21 and over who are on The Clinical Advisor’s subscriber list. Employees and families of employees of Haymarket Media Inc., its affiliates, printer, agencies, mailers, and advertisers are not eligible. RULES: No purchase necessary. Entries are limited to one per person. Void where prohibited. All entries must be received by April 15, 2012. Entries become the property of The Clinical Advisor and will not be acknowledged or returned. The Clinical Advisor is not responsible for late or misdirected entries, illegible entries, or electronic malfunctions. Entry constitutes acceptance of all rules. PICKING WINNERS Winners will be randomly selected from all accepted entries received by the deadline. Winners will be notified no later than May 1, 2012. Winners will be required to sign an affidavit of eligibility within 14 days of notification, or another winner will be chosen. Where permitted by law, winners agree to the use of their names, likenesses, and photographs for promotional purposes, without additional compensation. Odds of winning depend on the number of entries received. Winners agree to release and hold harmless The Clinical Advisor and Haymarket Media, Inc. from any liability arising from participation in this contest or acceptance and use of a prize. Names of winners will be published in a future issue of The Clinical Advisor. The winners’ names will be available upon written request after May 1, 2012, to individuals who send a stamped, self-addressed, business-size envelope to Clinical Advisor Contest Winners, 114 W. 26th St., 4th Floor, New York, NY 10001.

Clinical Challenge Severe dizziness, nausea, and vomiting send a man to the emergency room SIEGFRIED EMME, NP-C, CEN, CCRN

The patient’s gait was affected 48 hours after onset and any slight head movement intensified the feeling of imbalance.

Mr. W, aged 57 years, presented to the emergency department complaining of severe dizziness. The man reported that the disequilibrium was with him when he woke up two days ago and was accompanied by vomiting. Mr. W thought the feeling of unsteadiness would go away, but it had not abated. Moving his head or opening his eyes made the dizziness worse.

CASE

1. HISTORY Mr. W was not taking any medications. During consult, Mr.W noted recently battling sinus congestion and an accompanying headache behind his left eye. He had used a Neti pot for relief. No recent fever, ear problem, or tinnitus were reported, and Mr. W had no history of dizziness or head or neck trauma. There was no family history of heart attack, stroke, or diabetes.

2. EXAMINATION Mr.W was afebrile, and his BP was normotensive (117/71 mm Hg). Pulse was 60 beats per minute and respiration 16 breaths per minute. Mr. W was alert and oriented. Ear, nose, and throat all appeared normal. Cranial nerves II through XII were all intact. Horizontal nystagmus to the left was noted, and the Dix-Hallpike test was mildly positive. Finger-to-nose and heel-to-shin movements were normal. Mr.W had no pronator drift. Deep tendon reflexes were a normal 2+ throughout. Mr. W was able to stand at the side of the bed and had a negative Romberg test. Musculoskeletal strength was 5/5 in all four extremities with no numbness or tingling anywhere.

3. DIAGNOSIS AND TREATMENT Vertigo is a common complaint in ambulatory care settings.

66 THE CLINICAL ADVISOR • MARCH 2012 • www.ClinicalAdvisor.com

Mr. W was given promethazine (Phenergan) to control the nausea and vomiting. Complete blood count and electrolytes came back normal 45 minutes later. Although Mr. W’s orthostatic vital signs were normal, a neurological exam was

Clinical Challenge repeated, showing no real changes. As the Dix-Hallpike test was not convincing for vertigo, a CT scan of the head was ordered. The CT was negative for a bleed. As Mr. W tried to walk, staff noticed that his gait was severely affected. A subsequent MRI revealed that Mr. W had an acute left cerebellar infarction. A magnetic resonance angiogram of the head and neck was ordered showing a vertebral artery dissection in the C1-C2 area. He was diagnosed with a cerebellar stroke causing acute vestibular syndrome (AVS). Mr. W was admitted to telemetry and placed on aspirin. Lipids, carotids, and all other workups were negative. Mr. W was discharged two days later and able to walk without assistive devices after physical and occupational therapy. Within two weeks, Mr. W’s gait had returned to normal.

bedside tests are more accurate than an MRI within the first 48 hours. Abnormal results can be remembered by the acronym INFARCT (Impulse Normal, Fast-phase alternating, Refixation on Cover Test).3 Lastly, the Dix-Hallpike test should be performed because despite its low sensitivity, this test does direct to the diagnosis of BPV. If a radiologic exam is necessary, an MRI is first choice, followed by thin-slice CT. A recent study showed that MRI is superior to CT for detection of acute ischemia and for suspected acute stroke.4 Do not completely rely on the diffusion-weighted MRI; one study reported up to a 31 % false-negative rate in the first 24 hours of a stroke, with posterior and brainstem strokes representing the majority missed.5

4. DISCUSSION

The causes of dizziness run the gamut from a small infection to stroke. AVS can safely be worked up to determine whether the cause is central or peripheral. Once you have determined that the patient has a peripheral AVS, the Dix-Hallpike test can be useful in diagnosing BPV despite a 70% sensitivity rate. If there is a central cause to the AVS, then an MRI is the radiologic tool of choice, with the caveat that sensitivity improves with time, especially after 48 hours. ■

Dizziness is a common complaint in ambulatory care, comprising 4% to 5% of all visits. AVS is characterized by rapid onset of vertigo, nausea/vomiting, nystagmus, and head-motion intolerance. Vertigo is a symptom, not a diagnosis. While this case study is only concerned with vestibular (32.9%) and neurologic (11.2%) causes of vertigo, other causes are cardiovascular (21%), respiratory (11%), metabolic (11%), injury/poisoning (11%), GI/genitourinary (12%), and infectious (2.9%).1 The best diagnostic approach is to ascertain the timing and triggers of a patient’s dizziness.1 This will help differentiate between peripheral and central causes of AVS. There are three basic timing patterns of vertigo. Acute spontaneous vertigo slowly improves over days and weeks. The main differentiation here is between vestibular neuritis (peripheral) and a cerebellar or brainstem stroke (central); other concerns are multiple sclerosis, labyrinthitis, neoplasms, and Chiari malformation. Episodic vertigo lasts from minutes to hours. The main differentiation here is between migrainous vertigo and vertebrobasilar transient ischemic attacks. Brief episodes of positional vertigo last from seconds to minutes. The usual cause of this is benign positional vertigo (BPV). With vertigo, a prime concern is to not overlook causes that could be fatal. Not all patients with cerebellar infarction will present with focal neural deficits. A study of persons with cerebellar infarcts identified 10.4 % who presented only with symptoms of isolated vertigo.2 The remainder had more neurologic symptoms, which led to a diagnosis of a cerebellar infarct. We can identify the roughly 10% of patients who have isolated vertigo with the HINTS (Head Impulse, Nystagmus, Test of Skew) tests.3 These simple,

5. CONCLUSION

Mr. Emme is a family nurse practitioner specializing in emergency care at McKee Medical Center in Loveland, Colo. References 1. Newman-Toker DE, Cannon LM, Stofferahn ME, et al. Imprecision in patient reports of dizziness symptom quality: a cross-sectional study conducted in an acute care setting. Mayo Clin Proc. 2007;82:1329-1340. 2. Lee H, Sohn SI, Cho YW, et al. Cerebellar infarction presenting isolated vertigo: frequency and vascular topographical patterns. Neurology. 2006;67:1178-1183. 3. Kattah JC, Talkad AV, Wang DZ, et al. HINTS to diagnose stroke in the acute vestibular syndrome: three-step bedside oculomotor examination more sensitive than early MRI diffusion-weighted imaging. Stroke. 2009;40: 3504-3510. Available at stroke.ahajournals.org/content/40/11/3504.long. 4. Chalela JA, Kidwell CS, Nentwich LM, et al. Magnetic resonance imaging and computed tomography in emergency assessment of patients with suspected acute stroke: a prospective comparison. Lancet. 2007;369:293-298. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC1859855/. 5. Oppenheim C, Stanescu R, Dormont D, et al. False-negative diffusion-weighted MR findings in acute ischemic stroke. Am J Neuroradiol. 2000;21:1434-1440. Available at www.ajnr.org/content/21/8/1434.long. All electronic documents accessed February 15, 2012.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MARCH 2012 71

LEGAL ADVISOR CASE

A clinician breaks the cardinal rule A serious accident during a patient’s discharge leads to potentially life-threatening injuries and a lawsuit.

BY ANN W. LATNER, JD

School doesn’t completely prepare one for professional life—especially when it comes to that critical understanding that talent, in and of itself, is not the only key to professional success. To get ahead, you must work hard and, for the most part, play by the rules, and above all else in medicine, you must ensure the safety of patients entrusted to you. For one eager and talented young trainee, this lesson came at great cost. Ms. V had excelled at a prestigious nursing school, finishing at the top of her class. She further distinguished herself by quickly earning an advanced degree with honors. While in school, Ms. V was a natural leader who was often singled out for awards. After graduating, Ms. V could not wait to practice medicine. However, with heavy school loans weighing her down, she returned to where she grew up—temporarily—to move back in with her parents. Her options for employment were limited there, but Ms. V did manage to land an entry-level position at the main medical center in the community. From the start, the job wasn’t what Ms. V expected. “We are understaffed at this hospital,”

Ms.V was becoming increasingly dissatisfied with what she saw as the lack of opportunity for actual clinical practice.

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the nursing supervisor noted, “and so everyone is expected to pitch in and help—even if technically it isn’t your job. Our goal is to provide the best care for our patients, and that means that sometimes you’ll be doing tasks that you might consider menial. But trust me, nothing here is menial. Even the most minor of assignments is important to our patients.” Ms. V nodded vigorously in agreement. In theory, this made total sense to her. But once reality set in and she was forced to perform tasks she considered beneath her training, Ms. V’s attitude changed. Ms. V had expected to be far more involved in practicing medicine. Instead, she was spending roughly half her time attending to work that she felt was more appropriately suited to an orderly or an aide. Ms. V understood that it was necessary for her to empty a bedpan now and then, but she was becoming increasingly dissatisfied Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

LEGAL ADVISOR with what she saw as the lack of opportunity for actual clinical practice. In frustration, she vented to her supervisor. “I realize that everyone is asked to do things that are not part of our jobs,” said Ms. V, “and I’m perfectly willing to make a bed, or help turn a patient, so he doesn’t get bedsores. But I thought that this job would involve more than that. I think I could be of more value to the center in a clinical capacity.” The supervisor smiled reassuringly. “You’ve only been here a few months. You need to be patient. Look around you; you’ll see that even our most senior nurses do those chores. It’s part of the job here.” Irritated with her supervisor’s answer, Ms. V promised herself she would look for another position. And just as she was fuming over her limited prospects, Ms. V’s supervisor asked her to wheel a patient to the front door for discharge. This request irked Ms. V even more.

Lawsuits are often dismissed on mere technicalities, and the defense in this case argued that an affidavit had not been filed. Mrs. C, the patient assigned to Ms. V for discharge transport, was 59 years old and had been in and out of the hospital for the past 10 years with several serious ailments. Mrs. C clearly wanted to chat on the way down, but Ms. V was taciturn. She was extremely aggravated about her situation. In front of the hospital, Ms. V neglected to fully collapse the footplates on the wheelchair, and as Mrs. C tried to get out of the chair, she tripped over one plate and fell to the ground. Medical staff hurried over when they saw the patient on the ground. Within moments, Mrs. C was rushed back into the hospital and readmitted. Subsequent x-rays showed that she had shattered her left femur in the fall and that surgery was necessary. Following surgery, Mrs. C developed a pulmonary embolism as well as other fall-induced complications. Mrs. C’s family filed a lawsuit against Ms. V and the hospital. The medical center was notified of the suit and Ms. V was placed on mandatory leave while an investigation ensued. Ms. V’s insurance company assigned an attorney to her, and during the initial consultation with the attorney Ms. V laid out the facts of the case. After a careful review of all evidence, the assigned counsel informed Ms. V that he intended to file a motion to dismiss the case, based on the fact that there was no physician affidavit on file. “In this state, in order for a malpractice case to go forward, the plaintiff must file an affidavit from a physician stating that

the incident was malpractice,” the attorney explained. “The plaintiff hasn’t done this, so there’s a chance we can get the case dismissed.” The defense subsequently filed the motion, alleging that the plaintiff failed to submit the requisite affidavit indicating malpractice. The court, however, denied the motion, stating that this case was not a malpractice case, but rather a negligence case. Once it was clear that the case would not be dismissed, it was quickly settled in favor of the plaintiff, Mrs. C, for an undisclosed sum. Ms. V was then formally dismissed from the hospital. Legal background

Differentiating negligence from malpractice can be tricky. Under the letter of the law, malpractice is defined as a failure to follow strict standards of professional care. Negligence, on the other hand, is more tightly defined as breach of duty and/or failure to conform to certain standards—indicating that the professional is in fact following standards, but has been remiss in some aspect of standardized care. The court’s decision in this case summated, “Not every negligent act is malpractice, but a negligent act or omission by a nurse that engages in medical treatment—or that bears a substantial relationship to the rendition of medical treatment by a licensed physician—constitutes malpractice.” The court went on to state, “This action wherein a patient fell while getting out of a wheelchair (operated by a nurse) is more akin to negligence,” and that the facts alleged by the plaintiff as to the manner in which the accident occurred were sufficient to show a potentially meritorious negligence claim. Protecting yourself

Ms. V felt, perhaps justifiably, that she was being undervalued professionally. The fact is that at some point, we are all asked to step in and do something that we feel either isn’t in our job description or we feel overqualified to do. Regardless, if you are going to do a job, it should be done in the best, most responsible way possible. Ms. V, though irate and disgruntled after her conversation with her supervisor, should have given her full attention to discharging Mrs. C. Her carelessness in transporting the patient had drastic results; Mrs. C could have died from pulmonary embolism and Ms. V significantly damaged her professional status and, ultimately, her career. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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CME CE

Dermatologic Look-Alikes ■ LEARNING OBJECTIVE: To distinguish and properly treat dermatologic conditions with similar presentations. ■ COMPLETE THE POSTTEST: Page 79

■ ADDITIONAL CME/CE: Pages 20, 59

Growing skin plaques with scale JOE MONROE, PA-C

CASE #1

CASE #2

A man aged 41 years was referred for evaluation of lesions on his legs, trunk, and forearm. The lesions were first seen several months ago after the man lost his job, was threatened with divorce, began to drink heavily, and gained 30 lbs. All of the lesions had grown in size and developed more scale. Pruritus was minimal but persisted despite OTC clotrimazole recommended by his pharmacist. Examination of the lesions showed several 1- to 8-cm annular, salmon-pink plaques covered with a thick, adherent white scale.

A 50-year-old man noticed a small area of scaling on his forearm. Self-treatment with OTC hydrocortisone 1% cream reduced the itching, but the rash continued to grow over the next year. A pharmacist suggested tolnaftate cream, which only reduced the redness and itching slightly and seemed to worsen the problem. The primary-care clinician prescribed triamcinolone 0.1% cream t.i.d. After two months, the rash had grown to cover almost his entire dorsal forearm and itched even more. The man was then referred to dermatology.

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CME CE

CASE #1

Dermatologic Look-Alikes

Plaque psoriasis

Plaque psoriasis, also known as psoriasis vulgaris, is quite common. The condition affects approximately 1% to 2% of whites, usually presenting in the third to fourth decade of life. Men with mycosis fungoides outnumber women by 2:1. Psoriatic lesions typically first appear on extensor surfaces and truncal skin. Psoriasis is a noncontagious, chronic, multisystem inflammatory disorder. Anywhere from 10% to 30% of those with the disease will also have a related form of arthritis called psoriatic arthropathy (PsA). Psoriasis is a complex multifactorial condition that appears to be influenced primarily by genetic and immune-mediated factors. Environmental factors—especially stress, infection, and medications—seem to influence the course of the disease as well. In many patients, no trigger is ever identified, but once triggered, the disease appears to involve significant leukocyte recruitment to the dermis and epidermis, resulting in the formation of typical psoriatic lesions.1 The activated T-cells infi ltrating the skin appear to be capable of inducing keratinocyte proliferation. Ultimately, this ramped-up, deregulated infl ammatory process also promotes the production of such cytokines as tumor necrosis factor alpha and interleukin-12, which effectively mediate many of the features of plaque psoriasis. In an individual with psoriasis, the turnover time for affected keratinocytes is reduced from 23 days to three to five days. This process greatly interferes with keratinocyte maturation and affects such functions as the adhesion of corneocytes that build up on the surface, accounting for the silvery lamellar scales seen with this disease. Normally, these keratinocytes have time to gradually lose their nuclei as they migrate upward, a phenomenon known as orthokeratosis. In someone with psoriasis, however, the transit time is too short, and the cells retain their nuclei until they are shed. This microscopic fi nding is described as

MORE DERMATOLOGY ON THE WEB Test your diagnostic skills. Our FREE archive of Dermatology Clinic and Dermatologic Look-Alikes is now available online at www.ClinicalAdvisor.com/Derm.

parakeratosis. Superficial vascular engorgement adds to the peculiar redness of the lesions.2 These theories are supported by voluminous research as well as by the positive response to immune-mediating biologic medications that are specifically designed for these functions.3 Histologically, all psoriasis is pustular,4 including spongioform intraepidermal pustules as well as Munro microabscesses within the stratum corneum. Neutrophilic microabscesses are generally seen above multiple small areas of parakeratosis. Cases of well-developed psoriasis feature regular epidermal acanthosis with long, bulbous rete ridges that thin over the dermal papillae but only scant spongiosis, except in the areas immediately surrounding collections of neutrophils. For the most part, the diagnosis of psoriasis is clinical. In this case, the lesions and patient history were a near-perfect fit. The onset or flaring of psoriasis is related to stress, alcohol consumption, and obesity. Psoriasis takes a heavy toll on the patient in terms of stress and depression.5 At times, the diagnosis of psoriasis can be rendered difficult by clinical presentations in which the disease is relegated to inverse areas, nails, scalp, palms, soles, or even the eyes. Especially in early psoriasis, a biopsy can be less than helpful. This is particularly true in cases of chronic psoriasiform spongiotic dermatitis (a major item in the differential). Ideally, biopsy of psoriasis should show a lack of edema; the relative lack of spongiosis; tortuosity of capillary loops; and the presence of neutrophils above foci of parakeratosis, alternating in a rhythmic fashion with orthokeratosis. The differential for psoriasis is extensive and includes such diagnoses as Bowen disease, nummular eczema, tinea corporis, and mycosis fungoides (a form of cutaneous T-cell lymphoma). Early on, mycosis fungoides can manifest as what is termed large plaque parapsoriasis, with psoriasiform lesions ranging in size from 1 cm to 5 cm. These annular lesions feature faint scale, mild surface atrophy, mottled dyspigmentation, and telangiectasia, and appear predominately on the lower abdomen, buttocks, and breasts. Over a considerable amount of time, these lesions can evolve into infi ltrative plaques, which, if left undiagnosed, can develop into a case of full-blown lymphoma. Biopsy and expert examination of the specimen are essential in making the diagnosis.4 Psoriasis can be difficult to treat. Options include topical calcipotriene (Dovonex), intralesional steroid injection, phototherapy, and methotrexate (Rheumatrex, Trexall). Use of such injectible biologics as etanercept (Enbrel) and infl iximab (Remicade) has revolutionized the treatment of this condition. The biologics have the potential to treat

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cutaneous psoriasis as well as PsA but are expensive and possess several potentially dangerous side effects.6 Other types of psoriasis that have been described include guttate, inverse, pustular, and sebopsoriasis (an overlap between psoriasis and seborrheic dermatitis). Psoriatic arthritis is perhaps the most significant type of psoriasis. Left undiagnosed and untreated, PsA can lead to crippling destruction of the joint and must therefore be detected and treated early on. Unfortunately, there is no correlation between the severity or onset of psoriasis and the appearance of PsA. The sheer multiplicity of types of PsA makes diagnosis problematic, so this task is probably best left to a rheumatologist.4 Treatment of this patient’s psoriasis was relatively simple, employing the use of topical clobetasol spray and counseling for to reduce the patient’s weight and alcohol intake.

CASE #2

Dermatophytosis

Dermatophytosis, or tinea, is a fungal infection involving superficial portions of the skin, hair, and nails. The infection is usually caused by one of three genera: Epidermophyton, Microsporum, or Trichophyton. This relatively minor condition can be acquired from animals, humans, or soil. Variations include tinea corporis (body), tinea capitis (head), tinea pedis (feet), tinea unguium (nails), tinea cruris (groin), tinea manus (hands), tinea faciei (face), and tinea barbae (beard).7 The public—and even some medical texts—still use the term “ringworm” to describe this family of infections, but this is misleading provokes unreasonable fear among many patients. Part of this legacy of fear stems from the fact that these infections were quite common many years ago, and effective treatment simply did not exist. Far from having anything to do with worms, dermatophytes are a group of molds that invade and feed only on keratinous tissue, skin, hair, and nails. Increased warmth and moisture encourage dermatophytic infections, which are limited to the upper epidermis by host defense mechanisms and therefore distinct from the so-called deep mycoses. This group of potentially serious diseases affects the deep layers of skin, lungs, and internal organs and includes such

conditions as histoplasmosis, blastomycosis, coccidioidomycosis, and sporotrichosis.8 As this case illustrates, topical and systemic steroids can promote tinea infection because they effectively diminish host defenses. What was missing from this patient’s workup was a definitive diagnosis, which could have been obtained with a biopsy, culture, or KOH preparation to identify fungal elements. The source of this patient’s dermatophyte was not clear, but T. rubrum causes the great majority of this type of tinea corporis (also known as tinea circinata). The active border of dermatophytic infections expands centrifugally, triggering a cell-mediated response. Among other effects, this response causes an increase in epidermal cell proliferation and resultant shedding, leaving new, uninfected cells central to the advancing border. Ultimate elimination is accomplished by the development of cellmediated immunity, but the cell wall of the organisms slows this process, making their treatment difficult. A deeper follicular form of tinea caused by the use of topical and/or systemic steroids is called tinea incognito, because its appearance is atypical enough to render it unrecognizable. Occasionally, under the same but prolonged circumstances, the fungal infection goes even deeper, becomes indurated, and develops pinpoint areas of pustular drainage that resemble a carbuncle. This form of fungal folliculitis, also called Majocchi granuloma, is often KOH- and culturenegative and must be diagnosed with a biopsy.4 Some individuals appear susceptible to dermatophytic infections, either because of the types of lipids their skin produces or because they are able to carry T. rubrum asymptomatically (a tendency possibly inherited autosomally).9 The differential for tinea corporis is vast, so limit it to such annular and/or scaly lesions as seborrhea, eczema, psoriasis, granuloma annulare, lichen planus, erythema annulare centrifigum, nummular eczema, and tinea versicolor. Tinea versicolor is not caused by the dermatophytes and will not necessarily respond to the same antifungal medications used for true tinea. Allylamines like terbinafine (Lamisil, Terbinex) are relatively ineffective against Malassezia furfur, the commensal yeast that causes tinea versicolor. As mentioned, a simple KOH preparation usually distinguishes fungal from nonfungal infection. Punch biopsies are routinely stained for fungal elements. Fungal cultures are simple to obtain and can be incubated at room temperature but take up to two weeks to provide definitive results.7 There are a multitude of effective treatments for tinea corporis. Mild infections can easily be treated with a topical imidazole cream, such as oxiconazole (Oxistat), econazole

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CME CE

Dermatologic Look-Alikes

(Spectazole), or ketoconazole (Feoris, Nizoral), b.i.d. until clear. Other effective topical treatment includes the allylamines terbinafine or ciclopirox (Penlac). Once treated persistently with topical steroids, tinea corporis can be severe enough to require topical and oral antifungals, including terbinafine 250 mg/day for up to one month. In rare cases, terbinafine can cause hepatotoxicity, as can griseofulvin, the most commonly used alternative.10 The patient in this case was successfully treated with oral terbinafine 250 mg daily for two weeks and twice-daily application of oxiconazole lotion. Total resolution occurred one month after treatment was initiated. ■

“I expected it to be awful, but not eternal Zumba.”

Mr. Monroe is a physician assistant specializing in dermatology at Springer Clinic in Tulsa, Okla. The author has no relationships to disclose relating to the content of this article. References 1. Medscape Reference. Psoriasis. Available at emedicine.medscape.com /article/1943419-overview. 2. Dover JS. Cutaneous Medicine and Surgery: Self Assessment and Review. Philadelphia, Pa.: W.B. Saunders; 1996:104-105. 3. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. J Am Acad Dermatol. 2009;60:643-659. Available at www.guidelines.gov /content.aspx?id=14572. 4. James WD, Berger TG, Elston DM. Viral diseases. In: Andrews’ Diseases of the Skin: Clinical Dermatology. 10th ed. Philadelphia, Pa.: SaundersElsevier; 2006:191-201, 297. © The New Yorker Collection 2012 from cartoonbank.com. All Rights Reserved.

5. Sampogna F, Tabolli S, Söderfeldt B, et al. Measuring quality of life of patients with different clinical types of psoriasis using the SF-36. Br J Dermatol. 2006;154:844-849. 6. Callen JP, Krueger GG, Lebwohl M, et al. AAD consensus statement on psoriasis therapies. J Am Acad Dermatol. 2003;49:897-899. 7. Medscape Reference. Tinea corporis. Available at emedicine.medscape .com/article/1091473-overview. 8. Aly R. Ecology and epidemiology of dermatophyte infections. J Am Acad Dermatol. 1994;31(3 Pt 2):S21-S25. 9. Jones HE. Immune response and host resistance of humans to dermatophyte infection. J Am Acad Dermatol. 1993;28(5 Pt 1):S12-S18. 10. Drake LA, Dinehart SM, Farmer ER, et al. Guidelines of care for superficial mycotic infections of the skin: tinea corporis, tinea cruris, tinea faciei, tinea manuum, and tinea pedis. Guidelines/Outcomes Committee. American Academy of Dermatology. J Am Acad Dermatol. 1996; 34(2 Pt 1):282-286. All electronic documents accessed February 15, 2012.

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“Now, Harold, you know you’re not supposed to hibernate angry.”

CME

POSTTEST Expiration date: March 2013

This program has been reviewed and is approved for a maximum of 1 hour of AAPA Category I CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of March 2012. Participants may submit the self-assessment at any time during that period. This program was planned in accordance with AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs. Posttests must be completed and submitted online. PAs may register at no charge at www.myCME.com. To obtain 1.0 hour of AAPA Category I CME credit, you must receive a score of 70% or better on each test taken. CREDITS: 0.5

CREDITS: 0.5

Feature

Dermatology Clinic

Dermatologic Look-Alikes

page 20

page 59

page 75

Helicobacter pylori: Toward effective eradication

Case #1: Dermatomyositis

Case #1: Plaque psoriasis

1. What is considered an alarm sign for risk of gastric cancer or complicated ulcer disease? a. Age younger than 55 years b. Abdominal bloating c. Progressive dysphagia d. Chest discomfort

1. What drug is associated with the development of dermatomyositis in patients with chronic myelogenous leukemia? a. Hydroxyurea (Droxia, Hydrea) b. Methotrexate (Rheumatrex, Trexall) c. Cyclophosphamide (Cytoxan) d. Interferon alfa-2a (Roferon)

5. Where do psoriatic lesions typically first appear? a. Scalp b. Extensor surfaces c. Buttocks d. Nails

2. Which medication must be avoided for a time prior to rapid urease testing for H. pylori? a. Bismuth b. Antibiotics c. Proton pump inhibitors d. All of the above

2. Violaceous discoloration that affects bony prominences such as the knuckles, elbows, and knees is termed a. Auspitz’s sign b. Darier’s sign c. Gottron’s sign d. Nikolsky’s sign

3. Metronidazole is used in the treatment of H. pylori infection because it a. Inhibits protein synthesis b. Blocks cell function c. Disrupts the cell wall d. Decreases acid secretion

Case #2: Verucca vulgaris

6. Annular lesions that feature faint scale, mild surface atrophy, mottled dyspigmentation, and telangiectasia are associated with what condition? a. Bowen disease b. Nummular eczema c. Mycosis fungoides d. Atopic dermatitis Case #2: Dermatophytosis

4. To ascertain H. pylori eradication, how long after treatment completion should testing be performed? a. One week b. Two weeks c. Four weeks d. Six weeks

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/CMEFeatureMar2012

3. What is a feature of verucca vulgaris? a. It is caused by infection with human papillomavirus. b. It usually occurs during school age or young adult years. c. Periungual lesions can cause considerable pain. d. All of the above 4. What is generally the first-line option in the treatment of verucca vulgaris? a. OTC topical salicylic acid b. Cryotherapy with liquid nitrogen c. Oral cimetidine (Tagamet) d. Intralesional bleomycin

7. Which form of tinea requires a biopsy for diagnosis? a. Tinea incognito b. Tinea pedis c. Tinea barbae d. Tinea unguium 8. What is the treatment for mild tinea infections? a. UVB phototherapy b. Topical calcipotriene c. Oral terbinafine d. Topical imidazole

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/DermMar2012

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MARCH 2012 79

ALTERNATIVE MEDS UPDATE What you should know about the herbs and supplements patients use By Sherril Sego, FNP-C, DNP. Ms. Sego is a staff clinician at the VA Hospital in Kansas City, Mo., where she practices adult medicine and women’s health. She also teaches at the nursing schools of the University of Missouri and the University of Kansas.

Hypnosis

“You are getting sleepy...very sleepy.” Everyone has seen the proverbial sketch—with a swinging pocket watch moving before a person’s eyes— where an individual is being hypnotized, but the truth is most people don’t put much stock in hypnotic techniques. Yet several studies examining the use of clinical hypnotherapy have provided interesting results that indicate a viable clinical role for hypnotic suggestion—when it is conducted under the care of a trained therapist or health-care professional. In fact, hypnotherapy is considered a safe complementary and alternative medical treatment.

Background Hypnosis is an altered state of consciousness which lies somewhere between wakefulness and sleep. It can be described as a trance-like state wherein an individual has heightened focus and concentration.1 Under hypnotic suggestion, a person can concentrate intensely on a specific thought, memory, or feeling while blocking out distractions. The term “hypnosis” comes from the Greek word hypnos, meaning sleep. Franz Anton Mesmer, an 18th century Austrian doctor, is widely considered the father of modern hypnosis.2 Mesmer was an ardent believer in the healing powers of an unknown magnetic force that he thought laid within the human body. He was confident he could tap that force and channel it to cure ailments, a practice that became known as “mesmerism” in late-18th-century Europe—and incidentally is the origin of the modern verb “to mesmerize.” Mesmer’s theories and radical therapy are credited with providing the springboard for hypnotherapy today.

By 1847, hypnosis was formally accepted by the Roman Catholic Church.2, 3 It was not until the 1950s, that medical hypnotherapy began to gain acceptance in the United States.4 Researchers at Stanford University were the first to develop a valid method for measuring hypnotized subjects.4 The Stanford Hypnotic Susceptibility Scales showed that at least 95% of people tested could be hypnotized to some degree, and those standards have remained undisputed since the scales’ inception.4

Science Although the mechanism of action in hypnosis is unknown, a number of important theories about hypnotic states provide glimpses into the brain’s inner workings.These theories suggest that in hypnotized individuals there is a contradiction in the level of awareness.Thus, the person receptive to hypnosis must exhibit a decreased awareness of immediate, physical surroundings and, at the same time, a markedly heightened, sensitized awareness of the thoughts and visualizations put forth by the

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ALTERNATIVE MEDS UPDATE Safety in administration Under the care of a licensed therapist or health-care professional, hypnosis is considered a safe alternative medical treatment. However, if a patient is relying on hypnotherapy over mainline therapy, the pros and cons must be clearly elucidated.

Summary More research on clinical hypnotherapy is needed, but clinicians can feel confident in suggesting this alternative form of therapy to patients in need. ■ Hypnosis is a successful tool for people who are trying to quit smoking.

References 1. Anxiety and Panic Disorders Health Center page. WebMD

Hypnotherapy is commonly used for pain management, treatment of anxiety or psychosomatic illness, and treatment of behavioral disorders.

website. Available at www.webmd.com/anxiety-panic /guide/mental-health-hypnotherapy. 2. Stewart JH. Hypnosis in contemporary medicine. Mayo Clin Proc. 2005;80:511-524. 3. Vickers A, Zollman C. ABC of complementary medicine: Hypnosis and relaxation therapies. BMJ. 1999;319:1346-1349. 4. Penn State Probing Questions page. Penn State University website. Available at www.rps.psu.edu/probing/hypnosis.html. 5. Egner T, Jamieson G, Gruzelier J. Hypnosis decouples cognitive control from conflict monitoring processes of the frontal lobe. Neuroimage. 2005; 27:969-978. 6. Castel A, Perez M, Sala J, et al. Effect of hypnotic suggestion on fibromyalgic pain: Comparison between hypnosis and relaxation. Eur J Pain. 2007;11:463-468. 7. Chambless D, Hollon S. Defining empirically supported therapies. J Consult Clin Psychol. 1998;66:7-18. 8. Hammond C. Review of the efficacy of clinical hypnosis with headaches and migraines. Int J Clin Exp Hypn. 2007;55:207-219. 9. Patterson D, Jensen M. Hypnosis and clinical pain. Psychol Bull. 2003;129:495-521. 10. Green J, Lynn S. Hypnosis and suggestion-based approaches to smoking cessation: An examination of the evidence. Int J Clin Exp Hypn. 2000;48:195-224. 11. Ahijevych K,Yerardi R, Nedilksy N. Descriptive outcomes of the American Lung Association of Ohio hypnotherapy smoking cessation program. Int J Clin Exp Hypn. 2000;48:374-387. 12. Kirsch I. Hypnotic enhancement of cognitive-behavioral weight loss treatments: Another meta-reanalysis. J Consult Clin Psychol. 1996;64:517-519. All electronic documents were accessed on February 15, 2012.

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hypnotherapist.5 Studies using functional magnetic resonance imaging and electroencephalography in individuals with high hypnotic susceptibility have demonstrated increased relaxation in muscle tension and auditory stimuli, but also heightened activity in areas of the brain housing deeper memory and autonomic functions.5 Medical hypnotherapy today is most commonly used for pain management, treatment of anxiety or psychosomatic illness, and treatment of behavioral disorders. One study measured the effect of hypnotic suggestion on fibromyalgic pain. In this trial, 45 fibromyalgia patients with uncontrolled pain were randomized to receive either hypnosis with relaxation suggestions, hypnosis with analgesia suggestions, or relaxation training alone.6 Hypnosis with analgesia suggestions provided the greatest relief, and hypnosis with relaxation suggestions were no better than relaxation training alone, data showed.6 In a review study of the clinical efficacy of hypnosis for controlling migraine and tension headaches, a National Institute of Health Technology Assessment Panel determined that hypnotherapy met appropriate criteria to be defined as a “wellestablished therapy.”7,8 This study suggests that the mechanism of analgesia from hypnosis does not involve endorphin-production pathways.8 Prior studies demonstrated similar results through the failure of a posthypnotic administration of naloxone, an opiate antagonist.9 Hypnosis is often used to help control such behaviors as smoking or overeating. In two separate meta-analyses conducted over the course of 10 years examining nearly 700 clinical trials and involving more than 70,000 participants, hypnosis was found to be the most successful smoking-cessation method when compared with unassisted attempts to quit.10, 11 Cessation rates stemming from hypnotherapy ranged from a mean of 36% to greater than 50%, with 12-month abstention levels well over 80%.10,11 Studies of the use of hypnosis to treat obesity have been less positive, but not without merit. When comparing hypnosis alone to hypnosis plus another assistive therapy for weight management—such as behavior modification—combination therapy showed a clear advantage.12

COMMENTARY Marcos A. Vargas, MSHA, PA-C, is an orthopedics physician assistant at Hurley Medical Center in Flint, Mich.

Will we ever belong? Despite the positive inroads and contributions that physician assistants and nurse practitioners have made over the past decades, we still face professional opposition, despite the fact that NPs and PAs have consistently surpassed patient satisfaction and industry expectations with our cost-effectiveness in delivering high-quality, patient-centered care, as shown by third-party researchers over the years. Our impact on the health-care delivery system has been demonstrated and validated. For example, in recent years the PA concept has been exported and implemented by other countries

It does appear we have been losing turf battles and, consequently, professional leverage.

that are seeking to secure and reap the benefits of team-based health-care as practiced here in the United States. So what barriers seem to be stalling PAs and NPs from coming full circle professionally? If asked, I would suggest that we have two major problems. 1. Atrocious self-marketing. We have come a long way in terms of gaining recognition among the different stakeholders (for example, physicians, politicians, patients, and payers) with whom we interact. Yet without a clearly delineated and focused marketing campaign, we’re destined to remain poorly understood and unaccepted as partners. 2. Acceptance of a subservient role. From the beginning, our professional relationship with our physician counterparts was supposed to be one in which we operated as an extension of the services they provided—hence our title of physician extenders. Nowadays we have the semantics game in full force and many of our physician partners are coming to view the professional relationship as one of “master/servant” as the lack of collaboration, support, and acceptance become commonplace. It does appear that we have been losing turf battles and, consequently, professional leverage.

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An example of this confl ict can be found in a letter published by The Wall Street Journal from James Brown, MD, JD, a family medicine physician who became a plaintiff ’s malpractice attorney. Brown wrote that PAs have “lower[ed] the level of primary-care medicine,” and he even proposed closing all PA schools to help resolve this issue (online.wsj.com/article/ SB100014240527487034459045761180611583 24044.html). Obviously this physician is not interested in forging the alliances or fostering the partnerships with other health-care providers that so many of his colleagues have come to appreciate and have used to build their practices. It’s distressing and disheartening to hear the misperceptions of some physicians regarding non-MD clinicians. Relayed under the guise of patient safety and “protecting the unsuspecting patient,” I have noticed a recent surge in these shortsighted sentiments. This subtle monopolization and practice control seem to be targeted to erode our hard-won credibility in this industry. It is my hope that the American Medical Association as well as PA and NP professional organizations will work to promote synergy and to educate those who are uninformed about or opposed to the partnership between physicians and non-physician providers on the benefits of this relationship. ■

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