May 2013 Clinical Advisor by The Clinical Advisor

The Clinical ADVISOR • may 2013

A F O R U M F O R p h y s i c i a n a s s i s t aNTS

NEWSLINE

■■Many can restart statins ■■Fiber intake and stroke ■■Tonsillectomy for adults

advisor forum

■■Diagnosing neutropenia ■■Closed head injury tests ■■Screen for gun ownership

| may 2 0 1 3 | www.ClinicalAdvisor.com

preteen and teen

Immunization Whooping cough is caused by the gram-negative bacteria Bordetella pertussis (shown).

legal advisor

Was a young girl’s suicide caused by her medication?

✶ free cME courses!

n Dermatology Clinic

trunk plaques on a gay man page 67

n Dermatologic Look-Alikes Volume 16, Number 5

Skin-colored thigh papule page 85 Where do you rank in our Salary Survey? To find out the results, turn to page 40.

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Editor Joe Kopcha, editor@clinicaladvisor.com Managing editor Marina Galanakis Senior editor Delicia Yard Web editor Nicole Blazek Contributing editors Bruce D. Askey, MSN, CRNP; Rebecca H. Bryan, APRN, CNP; Eileen F. Campbell, MSN, CRNP; Philip R. Cohen, MD; Deborah L. Cross, MPH, CRNP, ANP-BC; Sharon Dudley-Brown, PhD, FNP-BC; Maria Kidner, DNP, FNP-C; Joan W. Kiely, MSN, CRNP; Debra August King, PhD, PA; Ann W. Latner, JD; Claire B. O’Connell, MPH, PA-C; Kathy Pereira, MSN, FNP-BC; Sherril Sego, FNP, DNP; Julee B. Waldrop, MS, PNP; Kim Zuber, PA-C Art director Andrew Bass Group art director, Haymarket Medical Jennifer Dvoretz Group production manager Kathleen Millea Circulation manager Paul Silver Audience development director John Crewe National accounts manager Alison McCauley, 646.638.6098 alison.mccauley @ haymarketmedical.com Group publisher Thomas P. Hennessy, 646.638.6085 tom.hennessy @ haymarketmedia.com Editorial director Jeff Forster Vice president, medical magazines and digital products Jim Burke CEO, Haymarket Media, Inc. Lee Maniscalco All correspondence to: The Clinical Advisor 114 West 26th Street, 4th Floor, New York, NY 10001 For advertising sales, call 646.638.6085. For reprints, contact Wright’s Reprints at 877.652.5295. Persons appearing in photographs in “Newsline,” “The Legal Advisor,” and “Clinical Challenge” are not the actual individuals mentioned in the articles.They appear for illustrative purposes only. The Clinical Advisor® (USPS 017-546, ISSN 1524-7317), Volume 16, Number 5, is published 12 times a year, monthly, for $75.00 per year in the United States; $85.00 in Canada; $110.00 for all other foreign, in U.S. dollars, by Haymarket Media, Inc., 114 West 26th Street, 4th Floor, New York, NY 10001. Single copy: $20 U.S.; $30 foreign. www.ClinicalAdvisor.com. To order or update your paid subscription, call 800.436.9269. Periodicals postage rate paid at New York, NY, and additional mailing offices. POSTMASTER: Send all address changes to: The Clinical Advisor, c/o DMDData Inc., 2340 River Road, Des Plaines, IL 60018. Call 800.430.5450 to change your address or make other subscription inquiries. Requests for subscriptions from outside the United States must be accompanied by payment. All rights reserved. Reproduction in whole or in part without permission is prohibited. Copyright © 2013.

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LEVE

contents m ay 2 0 1 3

News and comment

Departments

20 Newsline ■■Many patients can restart statin use ■■Fiber intake influences stroke risk ■■Clinical tool calculates medical risks for seniors ■■Surgery for sore throat in adults ■■Biennial mammograms at age 50 ■■Asthma and allergies common in older folks, too ■■And more

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

Glucocorticoids raise risk of VTE 20

67 CME/CE Dermatology Clinic n A homosexual man presents with dark spots on his torso that developed into indurated papules and plaques.

97 Commentary

features 32 Vaccinations to protect adolescents Often at increased risk for disease transmission, many teens and preteens do not receive the recommended immunizations in a timely manner. 40 Special report: Salary survey: How are you doing? The results from our third annual survey of nurse practitioner and physician assistant salaries are in. See how your income measures up.

n Asymptomatic blue discoloration

appears on the arms and legs of a man with a history of rheumatoid arthritis.

Managing declining testosterone levels 50

Continues on page 14

Red palm oil is rich in antioxidants 72

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72 Alternative Meds Update High in beta-carotene and other antioxidants, red palm oil is used to treat hypertension, prevent cancer, and protect against stroke and heart attack. 78 Stat Consult Find out the most recent information on diagnosing, testing, and treating transient ischemic attack.

50 CME/CE Symptoms and treatment of low testosterone in men There is a direct correlation between testosterone and metabolic syndrome, mental function, libido, bone density, erectile dysfunction and overall energy.

making contact

64 Legal Advisor A clinician prescribes an antidepressant to a teenager without immediate follow-up and faces legal action when the patient later commits suicide.

Like us on Facebook facebook.com/TheClinicalAdvisor

www.ClinicalAdvisor.com

Visit us on the web ClinicalAdvisor.com

Go mobile with us mobile.ClinicalAdvisor.com

4/30/13 3:28 PM

85 CME/CE Dermatologic Look-Alikes Two patients present with skin-colored papules—one an intermittently pruritic lesion on the mid-back, the other a bleeding and nonpruritic “mole.”

57 Clinical Pearls ■■Get a grip on dislocated fingers ■■A tongue blade can detect temporomandibular joint disorder ■■Magic hands to soothe a restless child ■■Use a laser to get patients walking

90 CME/CE Posttest

58 Your Comments ■■Screen for gun ownership ■■Derm Dx to the rescue

91 Evidence-Based Medicine n Ciprofloxacin for seven days may be as effective as 14 days for acute pyelonephritis in women n Tiotropium may increase time to

Rubbery, skin-colored papule on the back 85

severe exacerbation in patients with poorly controlled asthma n Prophylactic escitalopram may reduce incidence of interferon-associated depression in patients with chronic hepatitis C and no history of depression

advisor forum 56 Consultations ■■Diagnosing neutropenia ■■Testing for closed head injury ■■When a patient cannot afford specialist treatment

Help for hep C patients with depression 91

“Well, that’s the only song we know, so we can play it another two or three times, or we can cut our losses. Waddya say, Cleveland?”

contents

how to contact us

To contact an editor: • Editor@clinicaladvisor.com • Call 646.638.6077

A FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■ Many can restart statins ■ Fiber intake and stroke ■ Tonsillectomy for adults ADVISOR FORUM

■ Diagnosing neutropenia ■ Closed head injury tests ■ Screen for gun ownership

IMMUNIZATION Whooping cough is caused by the gram-negative bacteria Bordetella pertussis (shown).

Was a young girl’s suicide caused by her medication?

✶ FREE CE COURSES!

■ Dermatology Clinic

TRUNK PLAQUES ON A GAY MAN PAGE 67

■ Dermatologic Look-Alikes

SKIN-COLORED THIGH PAPULE PAGE 85 Where do you rank in our Salary Survey? To find out the results, turn to page 40.

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| M AY 2 0 1 3 | www.ClinicalAdvisor.com

PRETEEN AND TEEN

LEGAL ADVISOR

VOLUME 16, NUMBER 5

To submit an article: • Editor@clinicaladvisor.com • Fax it to 646.638.6117

To submit a clinical question for publication: • w ww.ClinicalAdvisor.com/Advisor Forum • Send it by e-mail to letters@clinicaladvisor.com • Fax it to 646.638.6117 • Mail it to Clinical Advisor, 114 W. 26th St., 4th Floor, New York, NY 10001

THE CLINICAL ADVISOR • MAY 2013

To subscribe: • www.ClinicalAdvisor.com/subscribe

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ENVISION NEW

W B NO ILA A AV

In adults with type 2 diabetes,

POSSIBILITIES Introducing INVOKANATM—the first and only treatment option approved in the United States that reduces the reabsorption of glucose in the kidneys via sodium glucose co-transporter-2 (SGLT2) inhibition1 A1C Reductions as Monotherapy INVOKANATM monotherapy provided statistically signiﬁcant A1C reductions vs placebo at 26 weeks1

Change in A1C (%) from baseline (adjusted mean)

A1C Change From Baseline With INVOKANA™ Monotherapy1

INVOKANA™ (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. INVOKANA™ is not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS >>History of a serious hypersensitivity reaction to INVOKANA™. >>Severe renal impairment (eGFR <30 mL/min/1.73 m2), end stage renal disease, or patients on dialysis. WARNINGS and PRECAUTIONS >>Hypotension: INVOKANA™ causes intravascular volume contraction. Symptomatic hypotension can occur after

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initiating INVOKANA™, particularly in patients with impaired renal function (eGFR <60 mL/min/1.73 m2), elderly patients, and patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (eg, angiotensin-converting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Before initiating INVOKANA™ in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. Please see additional Important Safety Information and Brief Summary of full Prescribing Information on the following pages.

0.2

+0.14

0 DIFFERENCE FROM PLACEBO

DIFFERENCE FROM PLACEBO

–0.4

(95% CI: –1.09, –0.73); P<0.001

(95% CI: –1.34, –0.99); P<0.001

–0.6

–0.77

–0.2

– 0.91

– 1.16

–0.8

–1.03 –1.0 –1.2

Placebo (n=192; mean baseline A1C: 7.97%)

INVOKANATM 100 mg (n=195; mean baseline A1C: 8.06%)

INVOKANATM 300 mg (n=197; mean baseline A1C: 8.01%)

Effect on Weight* Statistically significant weight reductions vs placebo at 26 weeks (P<0.001)1 >> Difference from placebo†: 100 mg: –2.2%; 300 mg: –3.3% Impact on Systolic Blood Pressure (SBP)* Statistically significant SBP lowering vs placebo at 26 weeks (P<0.001)2 >> Difference from placebo†: 100 mg: –3.7 mm Hg; 300 mg: –5.4 mm Hg

A1C Reductions vs Sitagliptin INVOKANATM 300 mg demonstrated greater A1C reductions vs sitagliptin 100 mg, in combination with metformin + a sulfonylurea, at 52 weeks (P<0.05)1 >> Difference from sitagliptin†: –0.37% Incidence of Hypoglycemia Monotherapy over 26 weeks: 100 mg: 3.6%; 300 mg: 3.0%; placebo: 2.6%1 With metformin and a sulfonylurea over 52 weeks: INVOKANATM 300 mg: 43.2%; sitagliptin 100 mg: 40.7%1 >> Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA™ can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue Convenient Once-Daily Dosing1 >> Recommended starting dose: INVOKANA™ 100 mg >> Dose can be increased to 300 mg in patients tolerating 100 mg, who have an eGFR of ≥60 mL/min/1.73 m2 and require additional glycemic control The most common (≥5%) adverse reactions were female genital mycotic infection, urinary tract infection, and increased urination. References: 1. Invokana [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2013. 2. Stenlöf K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15(4):372-382.

Learn more at INVOKANAhcp.com/journal

INVOKANATM is not indicated for weight loss or as antihypertensive treatment. *Prespeciﬁed secondary endpoint. †Adjusted mean.

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ENVISION NEW

W B NO ILA A AV

In adults with type 2 diabetes,

Change in A1C (%) from baseline (adjusted mean)

A1C Change From Baseline With INVOKANA™ Monotherapy1

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0.2

+0.14

0 DIFFERENCE FROM PLACEBO

DIFFERENCE FROM PLACEBO

–0.4

(95% CI: –1.09, –0.73); P<0.001

(95% CI: –1.34, –0.99); P<0.001

–0.6

–0.77

–0.2

– 0.91

– 1.16

–0.8

–1.03 –1.0 –1.2

Placebo (n=192; mean baseline A1C: 7.97%)

INVOKANATM 100 mg (n=195; mean baseline A1C: 8.06%)

INVOKANATM 300 mg (n=197; mean baseline A1C: 8.01%)

Learn more at INVOKANAhcp.com/journal

INVOKANATM is not indicated for weight loss or as antihypertensive treatment. *Prespeciﬁed secondary endpoint. †Adjusted mean.

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IMPORTANT SAFETY INFORMATION (continued from first page)

>> Hyperkalemia: INVOKANA™ can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are more likely to develop hyperkalemia. Monitor serum potassium levels periodically after initiating INVOKANA™ in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions. >> Hypoglycemia With Concomitant Use With Insulin and Insulin Secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA™ can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA™. >> Genital Mycotic Infections: INVOKANA™ increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections. Monitor and treat appropriately. >> Hypersensitivity Reactions: Hypersensitivity reactions (eg, generalized urticaria), some serious, were reported with INVOKANA™ treatment; these reactions generally occurred within hours to days after initiating INVOKANA™. If hypersensitivity reactions occur, discontinue use of INVOKANA™; treat per standard of care and monitor until signs and symptoms resolve. >> Increases in Low-Density Lipoprotein (LDL-C): Doserelated increases in LDL-C occur with INVOKANA™. Monitor LDL-C and treat per standard of care after initiating INVOKANA™. >> Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with INVOKANA™ or any other antidiabetic drug.

DRUG INTERACTIONS >> UGT Enzyme Inducers: Rifampin: Co-administration of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including UGT1A9, UGT2B4, decreased canagliflozin area under the curve (AUC) by 51%. This decrease in exposure to canagliflozin may decrease efficacy. If an inducer of these UGTs (eg, rifampin, phenytoin, phenobarbitol, ritonavir) must be co-administered with INVOKANA™ (canagliflozin), consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA™ 100 mg once daily, have an eGFR greater than 60mL/min/1.73 m2, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer and requiring additional glycemic control. >> Digoxin: There was an increase in the area AUC and mean peak drug concentration (Cmax) of digoxin (20% and 36%, respectively) when co-administered with INVOKANA™ 300 mg. Patients taking INVOKANA™ with concomitant digoxin should be monitored appropriately. USE IN SPECIFIC POPULATIONS >> Pregnancy Category C: There are no adequate and wellcontrolled studies of INVOKANA™ in pregnant women. Based on results from rat studies, canagliflozin may affect renal development and maturation. In a juvenile rat study, increased kidney weights and renal pelvic and tubular dilatation were evident at ≥0.5 times clinical exposure from a 300-mg dose. These outcomes occurred with drug exposure during periods of animal development that correspond to the late second and third trimester of human development. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. INVOKANA™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. >> Nursing Mothers: It is not known if INVOKANA™ is excreted in human milk. INVOKANA™ is secreted in the milk of lactating rats, reaching levels 1.4 times higher than that in maternal plasma. Data in juvenile rats directly exposed to INVOKANA™ showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing

human kidney. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from INVOKANA™, a decision should be made whether to discontinue nursing or to discontinue INVOKANA™, taking into account the importance of the drug to the mother. >> Pediatric Use: Safety and effectiveness of INVOKANA™ in pediatric patients under 18 years of age have not been established. >> Geriatric Use: Two thousand thirty-four (2034) patients 65 years and older, and 345 patients 75 years and older were exposed to INVOKANA™ in nine clinical studies of INVOKANA™. Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with INVOKANA™ (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300-mg daily dose, compared to younger patients; more prominent increase in the incidence was seen in patients who were ≥75 years of age. Smaller reductions in HbA1C with INVOKANA™ relative to placebo were seen in older (65 years and older; -0.61% with INVOKANA™ 100 mg and -0.74% with INVOKANA™ 300 mg relative to placebo) compared to younger patients (-0.72% with INVOKANA™ 100 mg and -0.87% with INVOKANA™ 300 mg relative to placebo).

>> Hepatic Impairment: No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The use of INVOKANA™ has not been studied in patients with severe hepatic impairment and it is therefore not recommended. OVERDOSAGE >> There were no reports of overdose during the clinical development program of INVOKANA™ (canagliflozin). In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ the usual supportive measures, eg, remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis. ADVERSE REACTIONS >> The most common (≥5%) adverse reactions were female genital mycotic infections, urinary tract infections, and increased urination. Adverse reactions in ≥2% of patients were male genital mycotic infections, vulvovaginal pruritis, thirst, nausea, and constipation.

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WARNINGS and PRECAUTIONS (cont’d) >> Impairment in Renal Function: INVOKANA™ (canagliflozin) increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating INVOKANA™. More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2.

Please see Brief Summary of full Prescribing Information on the following pages.

>> Renal Impairment: The efficacy and safety of INVOKANA™ were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to <50 mL/min/ 1.73 m2). These patients had less overall glycemic efficacy and had a higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared to patients with mild renal impairment or normal renal function (eGFR ≥60 mL/min/1.73 m2); patients treated with INVOKANA™ 300 mg were more likely to experience increases in potassium. The efficacy and safety of INVOKANA™ have not been established in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2), with end-stage renal disease (ESRD), or receiving dialysis. INVOKANA™ is not expected to be effective in these patient populations.

Janssen Pharmaceuticals, Inc. Canagliflozin is licensed from Mitsubishi Tanabe Pharma Corporation. © Janssen Pharmaceuticals, Inc. 2013

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April 2013

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IMPORTANT SAFETY INFORMATION (continued from first page)

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Please see Brief Summary of full Prescribing Information on the following pages.

Janssen Pharmaceuticals, Inc. Canagliflozin is licensed from Mitsubishi Tanabe Pharma Corporation. © Janssen Pharmaceuticals, Inc. 2013

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April 2013

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INVOKANA™

(canagliflozin) tablets, for oral use Brief Summary of Prescribing Information. IndIcatIons and Usage INVOKANA™ (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies (14) in full Prescribing Information]. Limitation of Use: INVOKANA is not recommended in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. contraIndIcatIons • History of a serious hypersensitivity reaction to INVOKANA [see Warnings and Precautions]. • Severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end stage renal disease or patients on dialysis [see Warnings and Precautions and Use in Specific Populations]. WarnIngs and PrecaUtIons Hypotension: INVOKANA causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKANA [see Adverse Reactions] particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensinaldosterone system (e.g., angiotensin-converting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Before initiating INVOKANA in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. Impairment in renal Function: INVOKANA increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating INVOKANA [see Adverse Reactions]. More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2. Hyperkalemia: INVOKANA can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are more likely to develop hyperkalemia [see Adverse Reactions]. Monitor serum potassium levels periodically after initiating INVOKANA in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions. Hypoglycemia with concomitant Use with Insulin and Insulin secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions]. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA. genital Mycotic Infections: INVOKANA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections [see Adverse Reactions]. Monitor and treat appropriately. Hypersensitivity reactions: Hypersensitivity reactions (e.g., generalized urticaria), some serious, were reported with INVOKANA treatment; these reactions generally occurred within hours to days after initiating INVOKANA. If hypersensitivity reactions occur, discontinue use of INVOKANA; treat per standard of care and monitor until signs and symptoms resolve [see Contraindications and Adverse Reactions]. Increases in Low-density Lipoprotein (LdL-c): Dose-related increases in LDL-C occur with INVOKANA [see Adverse Reactions]. Monitor LDL-C and treat per standard of care after initiating INVOKANA. Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with INVOKANA or any other antidiabetic drug. adverse reactIons The following important adverse reactions are described below and elsewhere in the labeling: • Hypotension [see Warnings and Precautions] • Impairment in Renal Function [see Warnings and Precautions] • Hyperkalemia [see Warnings and Precautions] • Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions] • Genital Mycotic Infections [see Warnings and Precautions] • Hypersensitivity Reactions [see Warnings and Precautions] • Increases in Low-Density Lipoprotein (LDL-C) [see Warnings and Precautions] clinical studies 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 the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Pool of Placebo-Controlled Trials: The data in Table 1 is derived from four 26-week placebo-controlled trials. In one trial INVOKANA was used as monotherapy and in three trials INVOKANA was used as add-on therapy [see Clinical Studies (14) in full Prescribing Information]. These data reflect exposure of 1667 patients to INVOKANA and a mean duration of exposure to

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INVOKANA™ (canagliflozin) tablets INVOKANA of 24 weeks. Patients received INVOKANA 100 mg (N=833), INVOKANA 300 mg (N=834) or placebo (N=646) once daily. The mean age of the population was 56 years and 2% were older than 75 years of age. Fifty percent (50%) of the population was male and 72% were Caucasian, 12% were Asian, and 5% were Black or African American. At baseline the population had diabetes for an average of 7.3 years, had a mean HbA1C of 8.0% and 20% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 88 mL/min/1.73 m2). Table 1 shows common adverse reactions associated with the use of INVOKANA. These adverse reactions were not present at baseline, occurred more commonly on INVOKANA than on placebo, and occurred in at least 2% of patients treated with either INVOKANA 100 mg or INVOKANA 300 mg. table 1: adverse reactions From Pool of Four 26−Week Placebo-controlled studies reported in ≥ 2% of InvoKana-treated Patients* InvoKana InvoKana Placebo 100 mg 300 mg Adverse Reaction n=646 n=833 n=834 Female genital mycotic 3.2% 10.4% 11.4% infections† ‡ Urinary tract infections 4.0% 5.9% 4.3% Increased urination§ 0.8% 5.3% 4.6% Male genital mycotic 0.6% 4.2% 3.7% infections¶ Vulvovaginal pruritus 0.0% 1.6% 3.0% Thirst# 0.2% 2.8% 2.3% Constipation 0.9% 1.8% 2.3% Nausea 1.5% 2.2% 2.3% * The four placebo-controlled trials included one monotherapy trial and three add-on combination trials with metformin, metformin and sulfonylurea, or metformin and pioglitazone. † Female genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal. Percentages calculated with the number of female subjects in each group as denominator: placebo (N=312), INVOKANA 100 mg (N=425), and INVOKANA 300 mg (N=430). ‡ Urinary tract infections includes the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis. § Increased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia. ¶ Male genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection fungal. Percentages calculated with the number of male subjects in each group as denominator: placebo (N=334), INVOKANA 100 mg (N=408), and INVOKANA 300 mg (N=404). # Thirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia. Abdominal pain was also more commonly reported in patients taking INVOKANA 100 mg (1.8%), 300 mg (1.7%) than in patients taking placebo (0.8%). Pool of Placebo- and Active-Controlled Trials: The occurrence of adverse reactions was also evaluated in a larger pool of patients participating in placebo- and active-controlled trials. The data combined eight clinical trials [see Clinical Studies (14) in full Prescribing Information] and reflect exposure of 6177 patients to INVOKANA. The mean duration of exposure to INVOKANA was 38 weeks with 1832 individuals exposed to INVOKANA for greater than 50 weeks. Patients received INVOKANA 100 mg (N=3092), INVOKANA 300 mg (N=3085) or comparator (N=3262) once daily. The mean age of the population was 60 years and 5% were older than 75 years of age. Fifty-eight percent (58%) of the population was male and 73% were Caucasian, 16% were Asian, and 4% were Black or African American. At baseline, the population had diabetes for an average of 11 years, had a mean HbA1C of 8.0% and 33% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 81 mL/min/1.73 m2). The types and frequency of common adverse reactions observed in the pool of eight clinical trials were consistent with those listed in Table 1. In this pool, INVOKANA was also associated with the adverse reactions of fatigue (1.7% with comparator, 2.2% with INVOKANA 100 mg, and 2.0% with INVOKANA 300 mg) and loss of strength or energy (i.e., asthenia) (0.6% with comparator, 0.7% with INVOKANA 100 mg and 1.1% with INVOKANA 300 mg). In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.9, 2.7, and 0.9 per 1000 patient-years of exposure to comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. In the pool of eight clinical trials with a longer mean duration of exposure to INVOKANA (68 weeks), the incidence rate of bone fracture was 14.2, 18.7, and 17.6 per 1000 patient years of exposure to comparator, INVOKANA

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INVOKANA™ (canagliflozin) tablets

100 mg, and INVOKANA 300 mg, respectively. Upper extremity fractures occurred more commonly on INVOKANA than comparator. In the pool of eight clinical trials, hypersensitivity-related adverse reactions (including erythema, rash, pruritus, urticaria, and angioedema) occurred in 3.0%, 3.8%, and 4.2% of patients receiving comparator, INVOKANA 100 mg and INVOKANA 300 mg, respectively. Five patients experienced serious adverse reactions of hypersensitivity with INVOKANA, which included 4 patients with urticaria and 1 patient with a diffuse rash and urticaria occurring within hours of exposure to INVOKANA. Among these patients, 2 patients discontinued INVOKANA. One patient with urticaria had recurrence when INVOKANA was re-initiated. Photosensitivity-related adverse reactions (including photosensitivity reaction, polymorphic light eruption, and sunburn) occurred in 0.1%, 0.2%, and 0.2% of patients receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Other adverse reactions occurring more frequently on INVOKANA than on comparator were: Volume Depletion-Related Adverse Reactions: INVOKANA results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical studies, treatment with INVOKANA was associated with a dosedependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in patients on the 300 mg dose. The three factors associated with the largest increase in volume depletion-related adverse reactions were the use of loop diuretics, moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2) and age 75 years and older (Table 2) [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Use in Specific Populations]. table 2: Proportion of Patients With at Least one volume depletion-related adverse reactions (Pooled results from 8 clinical trials) comparator InvoKana InvoKana group* 100 mg 300 mg Baseline characteristic % % % Overall population 1.5% 2.3% 3.4% 75 years of age and older† 2.6% 4.9% 8.7% eGFR less than 60 mL/min/1.73 m2† 2.5% 4.7% 8.1% Use of loop diuretic† 4.7% 3.2% 8.8% * Includes placebo and active-comparator groups † Patients could have more than 1of the listed risk factors Impairment in Renal Function: INVOKANA is associated with a dosedependent increase in serum creatinine and a concomitant fall in estimated GFR (Table 3). Patients with moderate renal impairment at baseline had larger mean changes. table 3: changes in serum creatinine and egFr associated with InvoKana in the Pool of Four Placebo-controlled trials and Moderate renal Impairment trial

In a trial carried out in patients with moderate renal impairment with a baseline eGFR of 30 to less than 50 mL/min/1.73 m2 (mean baseline eGFR 39 mL/min/1.73 m2) [see Clinical Studies (14.3) in full Prescribing Information], the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR 30% lower than baseline, was 6.9% with placebo, 18% with INVOKANA 100 mg, and 22.5% with INVOKANA 300 mg. At the end of treatment, 4.6% with placebo, 3.4% with INVOKANA 100 mg, and 3.4% with INVOKANA 300 mg had a significant renal function decline. In a pooled population of patients with moderate renal impairment (N=1085) with baseline eGFR of 30 to less than 60 mL/min/1.73 m2 (mean baseline eGFR 48 mL/min/1.73 m2), the overall incidence of these events was lower than in the dedicated trial but a dose-dependent increase in incident episodes of significant renal function decline compared to placebo was still observed. Use of INVOKANA was associated with an increased incidence of renalrelated adverse reactions (e.g., increased blood creatinine, decreased glomerular filtration rate, renal impairment, and acute renal failure), particularly in patients with moderate renal impairment. In the pooled analysis of patients with moderate renal impairment, the incidence of renal-related adverse reactions was 3.7% with placebo, 8.9% with INVOKANA 100 mg, and 9.3% with INVOKANA 300 mg. Discontinuations due to renal-related adverse events occurred in 1.0% with placebo, 1.2% with INVOKANA 100 mg, and 1.6% with INVOKANA 300 mg [see Warnings and Precautions]. Genital Mycotic Infections: In the pool of four placebo-controlled clinical trials, female genital mycotic infections (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 3.2%, 10.4%, and 11.4% of females treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections on INVOKANA. Female patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrence and require treatment with oral or topical antifungal agents and anti-microbial agents [see Warnings and Precautions]. In the pool of four placebo-controlled clinical trials, male genital mycotic infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.6%, 4.2%, and 3.7% of males treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males and in males with a prior history of balanitis or balanoposthitis. Male patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrent infections (22% on INVOKANA versus none on placebo), and require treatment with oral or topical antifungal agents and anti-microbial agents than patients on comparators. In the pooled analysis of 8 controlled trials, phimosis was reported in 0.3% of uncircumcised male patients treated with INVOKANA and 0.2% required circumcision to treat the phimosis [see Warnings and Precautions]. Hypoglycemia: In all clinical trials, hypoglycemia was defined as any event regardless of symptoms, where biochemical hypoglycemia was documented (any glucose value below or equal to 70 mg/dL). Severe hypoglycemia was defined as an event consistent with hypoglycemia where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained). In individual clinical trials [see Clinical Studies (14) in full Prescribing Information], episodes of hypoglycemia occurred at a higher rate when INVOKANA was co-administered with insulin or sulfonylureas (Table 4) [see Warnings and Precautions]. table 4: Incidence of Hypoglycemia* in controlled clinical studies

Placebo n=646 Creatinine (mg/dL)

0.84

0.82

eGFR (mL/min/1.73 m2)

87.0

88.3

88.8

Week 6 Change

Creatinine (mg/dL)

0.01

0.03

0.05

eGFR (mL/min/1.73 m2)

-1.6

-3.8

-5.0

End of Treatment Change*

Creatinine (mg/dL)

0.01

0.02

0.03

-1.6

-2.3

-3.4

Baseline Pool of Four PlaceboControlled Trials

InvoKana InvoKana 100 mg 300 mg n=833 n=834

eGFR (mL/min/1.73

m2)

InvoKana InvoKana Placebo 100 mg 300 mg n=90 n=90 n=89 Baseline Moderate Week 3 Renal Impairment Change Trial End of Treatment Change*

Creatinine (mg/dL)

1.61

1.62

1.63

eGFR (mL/min/1.73 m2)

40.1

39.7

38.5

Creatinine (mg/dL)

0.03

0.18

0.28

eGFR (mL/min/1.73 m2)

-0.7

-4.6

-6.2

Creatinine (mg/dL)

0.07

0.16

0.18

eGFR (mL/min/1.73 m2)

-1.5

-3.6

-4.0

* Week 26 in mITT LOCF population In the pool of four placebo-controlled trials where patients had normal or mildly impaired baseline renal function, the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR below 80 mL/min/1.73 m2 and 30% lower than baseline, was 2.1% with placebo, 2.0% with INVOKANA 100 mg, and 4.1% with INVOKANA 300 mg. At the end of treatment, 0.5% with placebo, 0.7% with INVOKANA 100 mg, and 1.4% with INVOKANA 300 mg had a significant renal function decline.

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Monotherapy (26 weeks) Overall [N (%)] In combination with Metformin (26 weeks) Overall [N (%)] Severe [N (%)]† In combination with Metformin (52 weeks) Overall [N (%)] Severe [N (%)]† In combination with sulfonylurea (18 weeks) Overall [N (%)] In combination with Metformin + sulfonylurea (26 weeks) Overall [N (%)] Severe [N (%)]†

Placebo (n=192) 5 (2.6) Placebo + Metformin (n=183)

InvoKana 100 mg (n=195) 7 (3.6) InvoKana 100 mg + Metformin (n=368)

InvoKana 300 mg (n=197) 6 (3.0) InvoKana 300 mg + Metformin (n=367)

3 (1.6) 0 (0) glimepiride + Metformin (n=482) 165 (34.2) 15 (3.1) Placebo + sulfonylurea (n=69) 4 (5.8) Placebo + Metformin + sulfonylurea (n=156) 24 (15.4) 1 (0.6)

16 (4.3) 1 (0.3) InvoKana 100 mg + Metformin (n=483) 27 (5.6) 2 (0.4) InvoKana 100 mg + sulfonylurea (n=74) 3 (4.1) InvoKana 100 mg + Metformin + sulfonylurea (n=157) 43 (27.4) 1 (0.6)

17 (4.6) 1 (0.3) InvoKana 300 mg + Metformin (n=485) 24 (4.9) 3 (0.6) InvoKana 300 mg + sulfonylurea (n=72) 9 (12.5) InvoKana 300 mg + Metformin + sulfonylurea (n=156) 47 (30.1) 0

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INVOKANA™ (canagliflozin) tablets

table 4: Incidence of Hypoglycemia* in controlled clinical studies (continued)

UGT1A9, UGT2B4, decreased canagliflozin area under the curve (AUC) by 51%. This decrease in exposure to canagliflozin may decrease efficacy. If an inducer of these UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) must be co-administered with INVOKANA (canagliflozin), consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA 100 mg once daily, have an eGFR greater than 60 mL/min/1.73 m2, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer and require additional glycemic control [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information]. digoxin: There was an increase in the area AUC and mean peak drug concentration (Cmax) of digoxin (20% and 36%, respectively) when co-administered with INVOKANA 300 mg [see Clinical Pharmacology (12.3) in full Prescribing Information]. Patients taking INVOKANA with concomitant digoxin should be monitored appropriately. Use In sPecIFIc PoPULatIons Pregnancy: Teratogenic Effects: Pregnancy Category C: There are no adequate and well-controlled studies of INVOKANA in pregnant women. Based on results from rat studies, canagliflozin may affect renal development and maturation. In a juvenile rat study, increased kidney weights and renal pelvic and tubular dilatation were evident at greater than or equal to 0.5 times clinical exposure from a 300 mg dose [see Nonclinical Toxicology (13.2) in full Prescribing Information]. These outcomes occurred with drug exposure during periods of animal development that correspond to the late second and third trimester of human development. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. INVOKANA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. nursing Mothers: It is not known if INVOKANA is excreted in human milk. INVOKANA is secreted in the milk of lactating rats reaching levels 1.4 times higher than that in maternal plasma. Data in juvenile rats directly exposed to INVOKANA showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from INVOKANA, a decision should be made whether to discontinue nursing or to discontinue INVOKANA, taking into account the importance of the drug to the mother [see Nonclinical Toxicology (13.2) in full Prescribing Information]. Pediatric Use: Safety and effectiveness of INVOKANA in pediatric patients under 18 years of age have not been established. geriatric Use: Two thousand thirty-four (2034) patients 65 years and older, and 345 patients 75 years and older were exposed to INVOKANA in nine clinical studies of INVOKANA [see Clinical Studies (14.3) in full Prescribing Information]. Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with INVOKANA (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger patients; more prominent increase in the incidence was seen in patients who were 75 years and older [see Dosage and Administration (2.1) in full Prescribing Information and Adverse Reactions]. Smaller reductions in HbA1C with INVOKANA relative to placebo were seen in older (65 years and older; -0.61% with INVOKANA 100 mg and -0.74% with INVOKANA 300 mg relative to placebo) compared to younger patients (-0.72% with INVOKANA 100 mg and -0.87% with INVOKANA 300 mg relative to placebo). renal Impairment: The efficacy and safety of INVOKANA were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m2) [see Clinical Studies (14.3) in full Prescribing Information]. These patients had less overall glycemic efficacy and had a higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared to patients with mild renal impairment or normal renal function (eGFR greater than or equal to 60 mL/min/1.73 m2); patients treated with INVOKANA 300 mg were more likely to experience increases in potassium [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Adverse Reactions]. The efficacy and safety of INVOKANA have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2), with ESRD, or receiving dialysis. INVOKANA is not expected to be effective in these patient populations [see Contraindications and Clinical Pharmacology (12.3) in full Prescribing Information]. Hepatic Impairment: No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The use of INVOKANA has not been studied in patients with severe hepatic impairment and is therefore not recommended [see Clinical Pharmacology (12.3) in full Prescribing Information].

In combination with Metformin + sulfonylurea (52 weeks) Overall [N (%)] Severe [N (%)]† In combination with Metformin + Pioglitazone (26 weeks) Overall [N (%)] In combination with Insulin (18 weeks) Overall [N (%)] Severe [N (%)]†

sitagliptin + Metformin + sulfonylurea (n=378) 154 (40.7) 13 (3.4) Placebo + Metformin + Pioglitazone (n=115) 3 (2.6)

InvoKana 100 mg + Metformin + Pioglitazone (n=113) 3 (2.7)

InvoKana 300 mg + Metformin + sulfonylurea (n=377) 163 (43.2) 15 (4.0) InvoKana 300 mg + Metformin + Pioglitazone (n=114) 6 (5.3)

Placebo (n=565) 208 (36.8) 14 (2.5)

InvoKana 100 mg (n=566) 279 (49.3) 10 (1.8)

InvoKana 300 mg (n=587) 285 (48.6) 16 (2.7)

* Number of patients experiencing at least one event of hypoglycemia based on either biochemically documented episodes or severe hypoglycemic events in the intent-to-treat population † Severe episodes of hypoglycemia were defined as those where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained) Laboratory Tests: Increases in Serum Potassium: Dose-related, transient mean increases in serum potassium were observed early after initiation of INVOKANA (i.e., within 3 weeks) in a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information]. In this trial, increases in serum potassium of greater than 5.4 mEq/L and 15% above baseline occurred in 16.1%, 12.4%, and 27.0% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. More severe elevations (i.e., equal or greater than 6.5 mEq/L) occurred in 1.1%, 2.2%, and 2.2% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. In patients with moderate renal impairment, increases in potassium were more commonly seen in those with elevated potassium at baseline and in those using medications that reduce potassium excretion, such as potassium-sparing diuretics, angiotensinconverting-enzyme inhibitors, and angiotensin-receptor blockers [see Warnings and Precautions]. Increases in Serum Magnesium: Dose-related increases in serum magnesium were observed early after initiation of INVOKANA (within 6 weeks) and remained elevated throughout treatment. In the pool of four placebo-controlled trials, the mean change in serum magnesium levels was 8.1% and 9.3% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to -0.6% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information], serum magnesium levels increased by 0.2%, 9.2%, and 14.8% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Increases in Serum Phosphate: Dose-related increases in serum phosphate levels were observed with INVOKANA. In the pool of four placebo controlled trials, the mean change in serum phosphate levels were 3.6% and 5.1% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to 1.5% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information], the mean serum phosphate levels increased by 1.2%, 5.0%, and 9.3% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-HighDensity Lipoprotein Cholesterol (non-HDL-C): In the pool of four placebocontrolled trials, dose-related increases in LDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with INVOKANA 100 mg and INVOKANA 300 mg, respectively. The mean baseline LDL-C levels were 104 to 110 mg/dL across treatment groups [see Warnings and Precautions]. Dose-related increases in non-HDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in non-HDL-C relative to placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with INVOKANA 100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels were 140 to 147 mg/dL across treatment groups. Increases in Hemoglobin: In the pool of four placebo-controlled trials, mean changes (percent changes) from baseline in hemoglobin were -0.18 g/dL (-1.1%) with placebo, 0.47 g/dL (3.5%) with INVOKANA 100 mg, and 0.51 g/dL (3.8%) with INVOKANA 300 mg. The mean baseline hemoglobin value was approximately 14.1 g/dL across treatment groups. At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively, had hemoglobin above the upper limit of normal. drUg InteractIons Ugt enzyme Inducers: Rifampin: Co-administration of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including

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INVOKANA™ (canagliflozin) tablets

“It’s not that I don’t like the job you’re doing— it’s just that I’d like to start seeing other people do it.”

“One large with pepperoni and mushrooms.”

overdosage There were no reports of overdose during the clinical development program of INVOKANA (canagliflozin). In the event of an overdose, contact the Poison Control Center. It is also 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. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis. PatIent coUnseLIng InForMatIon See FDA-approved patient labeling (Medication Guide). Instructions: Instruct patients to read the Medication Guide before starting INVOKANA (canagliflozin) therapy and to reread it each time the prescription is renewed. Inform patients of the potential risks and benefits of INVOKANA and of alternative modes of therapy. Also inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. Advise patients to seek medical advice promptly during periods of stress such as fever, trauma, infection, or surgery, as medication requirements may change. Instruct patients to take INVOKANA only as prescribed. If a dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of INVOKANA at the same time. Inform patients that the most common adverse reactions associated with INVOKANA are genital mycotic infection, urinary tract infection, and increased urination. Inform female patients of child bearing age that the use of INVOKANA during pregnancy has not been studied in humans, and that INVOKANA should only be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Instruct patients to report pregnancies to their physicians as soon as possible. Inform nursing mothers to discontinue INVOKANA or nursing, taking into account the importance of drug to the mother. Laboratory Tests: Due to its mechanism of action, patients taking INVOKANA will test positive for glucose in their urine. Hypotension: Inform patients that symptomatic hypotension may occur with INVOKANA and advise them to contact their doctor if they experience such symptoms [see Warnings and Precautions]. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake. Genital Mycotic Infections in Females (e.g., Vulvovaginitis): Inform female patients that vaginal yeast infection may occur and provide them with information on the signs and symptoms of vaginal yeast infection. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions]. Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis): Inform male patients that yeast infection of penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions]. Hypersensitivity Reactions: Inform patients that serious hypersensitivity reactions such as urticaria and rash have been reported with INVOKANA. Advise patients to report immediately any signs or symptoms suggesting allergic reaction or angioedema, and to take no more drug until they have consulted prescribing physicians. Urinary Tract Infections: Inform patients of the potential for urinary tract infections. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur. Active ingredient made in Belgium Finished product manufactured by: Janssen Ortho, LLC Gurabo, PR 00778 Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Licensed from Mitsubishi Tanabe Pharma Corporation © 2013 Janssen Pharmaceuticals, Inc. 10282400 K02CAN13080B

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“With my condition, does it matter which pain reliever I take?” Your patients may not know the difference between acetaminophen and NSAIDs. And that may have unintended consequences.

TYLENOL® does not interfere with aspirin’s cardioprotective mechanism the way ibuprofen can.1

TYLENOL® does not cause GI irritation the way that aspirin, naproxen sodium, or even ibuprofen can.2

TYLENOL®, when taken at recommended doses, does not compromise renal function in patients with existing kidney dysfunction the way NSAIDs can.3-5

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REFERENCES: 1. Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med. 2001;345(25):1809-1817. 2. Blot WJ, McLaughlin JK. Over the counter non-steroidal anti-inflammatory drugs and risk of gastrointestinal bleeding. J Epidemiol Biostat. 2000;5(2):137-142. 3. Prescott LF, Speirs GC, Critchley JA, Temple RM, Winney RJ. Paracetamol disposition and metabolite kinetics in patients with chronic renal failure. Eur J Clin Pharmacol. 1989;36(3): 291-297. 4. Martin U, Temple RM, Winney RJ, Prescott LF. The disposition of paracetamol and the accumulation of its glucuronide and sulphate conjugates during multiple dosing in patients with chronic renal failure. Eur J Clin Pharmacol. 1991;41(1):43-46. 5. Bugge JF. Renal effects and complications of NSAIDs for routine post-operative pain relief: increased awareness of a real problem is needed. Baillière’s Clinical Anaesthesiology. 1995;9(3):483-492. ©McNEIL-PPC, Inc. 2013

EST-877

Newsline

High fiber intake can prevent first-time stroke page 23

m ay 2 0 13

Tonsillectomy helps adults with pharyngitis page 27

Psoriasis has a role in diabetes mellitus page 28

Many patients can restart statin use

Data suggest that many statin-related events have other causes.

available evidence does not support outcome benefit ( JAMA Intern Med. 2013;173:586-588). Interest ing ly, over use of statins may be driven in part by television commercials. Jeff Niederdeppe, PhD, and colleagues reported in Journal of General Internal Medicine that their analysis of data provided new evidence that direct-to-consumer advertising may promote overdiagnosis of high cholesterol and overtreatment for populations in whom risks of statin use may outweigh benefits. The team estimated that exposure to television ads for statins increased the odds of being diagnosed with high cholesterol by 16% to 20%, and increased statin use by 16% to 22%. The associations were driven almost exclusively by men and women at low risk for future cardiac events.

Number of deaths from 10 leading causes

Suicide

Alzheimer disease

598,000 575,000 138,000 129,000 121,000 83,000

Influenza and pneumonia

Nephritis

100

Unintentional injuries

200

Stroke

300

Chronic lower respiratory diseases

400

Cancer

500

Diabetes

Source: MMWR Morb Mortal Wkly Rep. 2013;62:155.

600

Heart disease

In 2010, heart disease and cancer accounted for nearly 50% of all deaths, according to the CDC.

Causes of death

Most persons who stopped taking statins due to health events attributed to the drugs can tolerate these agents long-term when they try again, a recent study indicates. Researchers investigated the reasons for statin discontinuation and the role of statin-related events in routine care settings (Ann Intern Med. 2013;158:526534). Of 107,835 adults who received statin prescriptions from January 2000 through December 2008, 57,292 stopped using the drugs at least temporarily. Statinrelated events had been documented for 18,778 (17.4%) of those who discontinued use. More than half (6,579) of 11,124 persons who stopped taking statins at least temporarily due to such events were rechallenged with a statin over the subsequent 12 months. Nearly all of the rechallenged patients (92.2%) were still

taking a statin 12 months later. Of the 2,721 patients who were rechallenged with the same statin to which they had a statin-related event, 1,295 were taking the same one 12 months later, and 996 of them were doing so at the same or a higher dose. The findings suggest that many statin-related events may have other causes, are tolerable, or may be specific to individual statins rather than to the entire drug class. Separate research raised the possibility that clinicians are not adequately considering a patient’s cardiovascular risk when prescribing statins in primary prevention. Surveys from 202 physicians showed that when faced with persons at risk for coronary heart disease, practitioners consider medication for persons with low Framingham risk scores for whom

69,000

50,000

38,000

Number of deaths (in thousands)

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Newsline High-fiber foods can prevent the occurrence of first-time stroke, and coronary artery calcification scores help clinicians identify those at risk for this event, indicate recent results from two different studies. In a meta-analysis of eight cohort studies that were published between 1990 and 2012, total dietary fiber intake was inversely associated with risk of hemorrhagic plus ischemic stroke, with every 7-g increase in total dietary fiber reducing first-time stroke risk by 7%. However, wrote Diane E. Threapleton, MSc, and colleagues in the American Heart Association journal Stroke, data were insufficient to draw conclusions regarding the relationship between type of fiber (soluble or insoluble) and stroke.

A separate Stroke study on the occurrence of first-time stroke (2013;44:1008-1013) demonstrated that coronary artery calcification (CAC) is an independent predictor of such events in the general population. CAC is a noninvasive marker of coronary atherosclerotic plaque load; as measured by electron beam– computed tomography, CAC was recently identified as a powerful predictor of MI in the general population. Among 4,180 persons aged 45 to 75 years with no history of stroke, 92 incident strokes occurred (82 ischemic and 10 hemorrhagic). Affected persons had significantly higher CAC values at baseline than did study participants who did not have a stroke (median 104.8 vs. 11.2).

Fiber intake influences stroke risk

A 7-g increase in dietary fiber reduced stroke risk by 7%.

CAC predicted stroke in both men and women, particularly those younger than age 65 years and independent of the presence of atrial fibrillation. It also discriminated stroke risk specifically in persons falling into the low (<10%) and intermediate (10% to 20%) Framingham risk score categories.

A simple checklist can help primary-care providers evaluate the health risks that influence the longevity of older adults and have informed discussions with patients regarding the choice to undergo various screening tests and other health-maintenance measures. “Recent guidelines recommend considering patients’ life expectancy when deciding whether to pursue preventive interventions with long lag times to benefit (≥7 years), such as colorectal cancer screening and intensive glycemic control for diabetes,” wrote Marisa Cruz, MD, and colleagues

Cognitive and motor skills also factor into the calculations.

in a research letter published in JAMA (2013;309:874-876, available at jama.jamanetwork.com/ article.aspx?articleid=1660374, accessed Apr i l 15, 2013). “However, most mortality indices have focused on short-term risk (≤5 years).” The 12-item index operates on a point system, with the total determining the patient’s 10-year risk of mortality. For example, adults aged 60 to 64 years receive one point, whereas those over age 85 years receive seven points. Such health risks as current tobacco use, chronic lung disease, heart disease,

and cancers other than skin cancers are each two points. Cognitive and motor skills also factor into the calculations: The ability to manage one’s finances, walk several blocks, and other such activities are assigned one to two points. “The clinician can ask the patient yes-or-no questions about [the patient’s] health and functional status and then can go over how the patient could benefit from certain medical interventions,” explained Cruz in a statement issued by the University of California–San Francisco, where Cruz is a clinical fellow.

Clinical tool calculates medical risks for seniors

www.ClinicalAdvisor.com • the clinical advisor • may 2013 23

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Newsline Surgery for Biennial mammograms at 50 sore throat in adults

The results held even for women who had high breast density.

through 2008. Compared with women aged 50 to 74 years who undergo screening mammography once a year, women in the same age group who have the test once every two years have similar risk of advanced-stage disease and lower risk of false-positive results. The results held even for women who had high breast density or who used hormone therapy. For women aged 40 to 49 years with extremely dense breasts, biennial vs. annual mammography was associated with increased risk of advanced-stage cancer and large tumors. The probability of a false-positive mammography result among women undergoing annual mammography was high among those with extremely dense breasts who were aged 40 to 49 years or who used estrogen plus progesterone. The probability was lower among women aged 50 to 74 years with scattered fibroglandular densities or fatty breasts who underwent biennial or triennial mammography.

Asthma and allergies common in older folks, too Your older patients with asthma are likely to also have an allergy, advises a new study. Approximately 70% to 80% of children and young adults with asthma are sensitized to at least one allergen (Ann Allergy Asthma Immunol. 2013;110:247-252). Previous studies have suggested that allergic sensitization is significantly lower in older patients, but 2005–2006 data on 2,573 patients (aged 20 to 40 years or 55 years and older) tells a different story.

A total of 108 persons in the younger age group (6.7%) and 43 (4.5%) of the older adults were identified as having asthma. Within those groups, 75.4% of the younger and 65.2% of the older asthmatic patients were sensitized to at least one allergen. Investigators characterized this difference as only moderate and not statistically significant, concluding that allergic sensitization in older patients with asthma may be more common than previously reported.

adults WITH recurrent pharyngitis may be helped by tonsillectomy, with the surgery leading to fewer sore-throat symptoms. As Timo Koskenkorva, MD, and associates explained in CMAJ (available at www.cmaj. ca/content/early/2013/04/02/ cmaj.121852; accessed April 15, 2013), a recent Cochrane review found that tonsillectomy or adenotonsillectomy reduced the number of episodes and days with sore throat in children, but the review yielded limited evidence of tonsillectomy benefit in adults. Koskenkorva’s team randomized 46 adults with recurrent pharyngitis to tonsillectomy and 40 to watchful waiting. The primary outcome was the difference in the proportion of persons with severe pharyngitis (severe symptoms and C-reactive protein level >40 mg/L) within five months. Overall, 32 controls (80%) and 18 tonsillectomy patients (39%) experienced an episode of pharyngitis during follow-up. A total of 17 controls (43%) consulted a physician, compared with two tonsillectomy patients (4%). No significant difference was seen in the number of episodes of severe pharyngitis between the control group and the tonsillectomy group. However, the rate of pharyngitis and the number of symptomatic days were significantly lower among those who underwent tonsillectomy.

Undergoing screening mammography for breast cancer once every two years rather than annually does not increase the risk of advanced-stage or large-size tumors in women aged 50 to 74 years, regardless of their breast density or use of hormone therapy, researchers have determined. In 2009, the United States Preventive Services Task Force recommended that women aged 50 to 74 years undergo mammography every two years rather than every one to two years. Yet as Karla Kerlikowske, MD, and colleagues pointed out in their new report for JAMA Internal Medicine, controversy still surrounds the questions of how often a woman should undergo screening mammography and whether screening interval should vary according to risk factors beyond age. Data were collected from 11,474 women with breast cancer and 922,624 women without the disease. All subjects had undergone mammography from 1994

www.ClinicalAdvisor.com • the clinical advisor • may 2013 27

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Newsline Alr ea dy associated with elevated risk of cardiovascular events and increased prevalence of cardiovascular risk factors, psoriasis now appears to have a role in the development of diabetes mellitus (DM). Among more than 4 million Danish persons aged 10 years and older followed for up to 13 years, 52,613 had psoriasis. Usman Khalid, MD, and fellow investigators reported in Diabetes Care that the overall incidence rates for new-onset DM were 3.67 for the reference population, 6.93 for those with mild psoriasis, and 9.65 for those with severe psoriasis. Compared with the reference population, the incidence rate ratio (IRR) of new-onset DM was increased in all persons with psoriasis: The

IRR was 1.49 for those with mild psoriasis and 2.13 for those with severe psoriasis. Low nighttime secretion of the hormone melatonin was also recently linked with a heightened risk for diabetes. Researchers established an independent association between nocturnal melatonin secretion and type 2 diabetes risk after studying data from 370 participants in the Nurses’ Health Study who developed the disease and 370 control subjects. Compared with women with high levels of nocturnal melatonin secretion, those with low levels had approximately twice the risk of developing type 2 diabetes ( JAMA. 2013;309:1388-1396). In other developments on the diabetes front, the FDA

Psoriasis linked with new-onset diabetes

Psoriasis causes silver-white patches called scales (shown).

has approved the first sodiumglucose co-transporter 2 inhibitor intended to improve glycemic control in adults with type 2 disease. Invokana (canagliflozin) tablets block renal reabsorption of glucose, increase glucose excretion, and lower blood glucose levels.

Clinicians should be aware that systemic glucocorticoids were found to increase the risk of venous thromboembolism (VTE) among new, continuing, and recent users, but not among former users. In JAMA Internal Medicine, Sigrun A. Johannesdottir, BSc, and colleagues identified 38,765 VTE cases diagnosed from 2005 through 2011, and 387,650 population controls. Researchers found that these widely used anti-inflammatory agents increased VTE risk by as much as threefold for all but

Risk rose by as much as threefold for all but former users.

former users, estimating the adjusted incidence rate ratios (IRRs) as follows: • 3.06 for present users (most recent glucocorticoid prescription filled within 90 days of VTE occurrence); • 2.31 for new users (present users who got their first-ever prescription within 90 days of VTE); • 2.02 for continuing users (all present users other than new users); • 1.18 for recent users (most recent prescription filled 91 to 365 days before VTE);

• 0.94 for former users (most recent prescription filled more than 365 days before VTE). The adjusted IRR increased from 1.00 for a prednisoloneequivalent cumulative dose of <10 mg to 1.98 for a dose more than 1,000 mg to 2,000 mg, and to 1.60 for doses >2,000 mg. “New use of inhaled and intestinal-acting glucocorticoids also increased VTE risk,” cautioned the authors. In previous investigations, glucocorticoids have been shown to increase levels of clotting factors and fibrinogen. n

Glucocorticoids present blood-clot threat

28 the clinical advisor • may 2013 • www.ClinicalAdvisor.com

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feature: Christopher Barry, PA-C, MMSc

Vaccinations to protect adolescents Often at increased risk for disease transmission, many teens and preteens do not receive the recommended immunizations in a timely manner.

accines, responsible for controlling and eliminating several conditions that were once commonplace, have been one of the most successful methods of disease prevention in history. Despite the reductions in morbidity and mortality attributable to vaccines, not enough children are being immunized. Although more teens and preteens are getting the recommended vaccines than in previous years, there is still significant room for improvement. According to data from the CDC’s 2011 National Immunization Survey, only 78.2% of eligible children have received the tetanus, diphtheria, acellular pertussis (Tdap) vaccine, and 70.5% have received the meningococcal vaccines. Even more disturbing is the fact that only 53.0% of eligible females had received one dose of the human papillomavirus (HPV) vaccine, and only 34.8% of eligible females had received all three doses.1 More children and young adults need to be immunized, not only for their own well-being but also for the well-being of others in their communities. Providers must be aware of current vaccine recommendations and relay this important information to patients and caretakers to ensure that the number of children who receive these potentially life-saving treatments increases.

Bordetella pertussis (shown) causes whooping cough, mainly in infants.

Which vaccine-preventable diseases (VPDs) are preteens and teenagers most at risk of contracting? Children in their preteen and teenage years are most at risk for contracting, and then spreading,

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ADOLESCENT VACCINATION

meningococcal disease, pertussis (whooping cough), and HPV. Other VPDs include varicella, measles, mumps, rubella, and hepatitis A and B. Children in this age group are in close contact with one another through school, living, and social situations, which facilitates transmission. Vaccination remains one of the most effective methods of disease prevention. Why aren’t more preteens and teenagers being immunized against these VPDs? Children older than age 10 years visit a health-care provider less often than do younger children. The latest data show that only about 16% of teenagers attend an annual well-child visit.2 Clinicians need to do a better job of getting these children into the office. Children and their caretakers also are often unaware of the current vaccine recommendations and the reasons for immunizing. It is up to clinicians to inform patients and their caregivers of the CDC vaccine recommendations and to become strong advocates for vaccination. A provider’s advice is the most influential factor in determining whether a child receives a particular vaccine.

oropharyngeal cancer caused by HPV 16 and 18 is the most common, followed by anal and penile cancers. Why immunize children aged 11 to 12 years against an STI such as HPV? Immunizations are most effective when given prior to exposure to a particular pathogen. Immunizing children routinely at age 11 to 12 years against HPV largely ensures an HPVnaïve patient population. Knowing there is an established link between certain HPV types and cancers, immunizing against a pathogen that is potentially carcinogenic makes sense from public-health and preventive-medicine standpoints. The Advisory Committee on Immunization Practices (ACIP), an expert committee that provides vaccine-use recommendations to the CDC, weighs all of these issues. ACIP also considers cost per quality-adjusted life year, a statistical measure of whether a vaccine’s cost warrants routine or permissive recommendation.

What is the prevalence of HPV? HPV is the most common sexually transmitted infection (STI). The latest estimate is that 20 million people in the United States are currently infected with HPV.3 Up to half of these infections occur in adolescents and young adults aged 15 to 24 years. Estimates place the lifetime prevalence of genital HPV for people living in the United States at greater than 50%. More than 40 HPV types can infect mucosal surfaces, especially genital, anal, and oropharyngeal areas. The body’s immune system will clear most HPV infections, but certain types, notably 16, 18, 31, 33, 45, 52, and 58, are oncogenic.

What is the difference between the two licensed vaccines for HPV? Gardasil (Merck & Co.) and Cervarix (GlaxoSmithKline) were created using technology developed by scientists at the National Cancer Institute. Gardasil (HPV4) protects against HPV types 6, 11, 16, and 18, and was approved for use in 2006. Cervarix (HPV2) protects against HPV types 16 and 18 and was approved for use in 2009. Both vaccines are licensed for females (aged 9 to 26 years for Gardasil and aged 9 to 25 years for Cervarix); Gardasil is also licensed for use in males aged 9 to 26 years. Gardasil and Cervarix are extremely effective against HPV 16 and 18. The CDC expresses no brand preference for females; however, Gardasil is the only licensed HPV vaccine for males.

What is the connection between HPV and cancer? Most people who contract HPV do not know they are infected, and it is possible to contract more than one type of HPV. Certain HPV types have been linked as causative agents for various cancers. Annually, HPV types 16 and 18 are responsible for approximately 15,000 cases of cancer in females and 7,000 cases of cancer in males.4 Cervical cancer represents the majority of these cases in females. In males,

Parents say their child does not need the HPV vaccine because he or she is not sexually active. What reasons do I give for immunizing against an STI at such an early age? To reemphasize, vaccination is most effective before exposure to the pathogen. The HPV vaccine is not active against HPV subtypes previously contracted. Many parents do not realize that HPV can be spread in ways other than direct sexual

To download the CDC’s 2013 recommended immunization schedule for persons aged 0 through 18 years, visit

CliniAd.com/XILcWq. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2013 35

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adolescent vaccination

intercourse; it can also be passed through manual and oral sex. Adolescence is a common time for sexual experimentation. According to a 2012 study, more than half of all individuals aged 13 to 21 years already have HPV—more than 11% of whom have never had sexual intercourse.5 Inform parents that administering the HPV vaccine does not encourage sexual promiscuity.6 Encourage parents to have frank talks with their children about sexual matters. The better the communication at an earlier age, the healthier the parent-child relationship will be throughout the adolescent years. Even if a child never comes in contact with HPV prior to marriage, there is no assurance that this will be the case for his or her eventual sexual partner. Why is there new emphasis on immunizing males against HPV? Data show that Gardasil in males is a very safe vaccine with minimal side effects.7 Gardasil also protects males (as well as females) against genital warts caused by HPV types 6 and 11. In addition, Gardasil provides protection against anal and penile cancers in males, which account for approximately 4,200 new cases combined annually.8 Immunizing males against HPV will reduce spread of the disease, resulting in a lower rate of cervical cancer among females. Many preteens and teens fail to complete the HPV vaccine series. What are some strategies for increasing series completion? HPV vaccination is considered to be complete, and therefore protective, only after receipt of all three doses. According to CDC data, less than one-third of females had completed the HPV vaccine series in 2009.9 For the vaccine to confer herd immunity, a far higher percentage of the eligible population must complete the series. When patients receive the first HPV vaccine, clinicians should inform the child’s caregivers of the recommended series and institute a reminder system to ensure series completion. Consider scheduling return visits at the initial appointment time; sending reminders via telephone, e-mail, and text message; and providing refrigerator magnets that light up when it is time to return for subsequent shots. Is invasive meningococcal disease a major concern? Bacterial meningitis is a potentially deadly disease caused by the gram-negative diplococcus Neisseria meningitidis, also called meningococcus. The peak incidence of bacterial meningitis occurs during the first year of life. However, an increased incidence of N. meningitisdi infection is seen between ages 10 and 20 years. Groups B, C, and Y are responsible

poll position

Do you recommend the HPV vaccine for patients aged 11 and 12 years during well-child visits? n=335

9% Yes No 91%

For more polls, visit CliniAd.com/10TDwDb.

for the majority of bacterial meningitis cases. Bacterial meningitis often presents diagnostic challenges due to its similar presentation to other more common illnesses, such as influenza. In many cases, it is too late to render effective treatment by the time a diagnosis is reached. Even with early diagnosis and treatment, approximately 10% of cases of invasive meningococcal disease—and a staggering 40% of cases of meningococcemia—are fatal.10 Why is it important to immunize preteens and teens against meningococcal disease? Since there is a peak incidence in the early teens, it is crucial that a child receive his or her first meningococcal vaccine by age 12 years. The meningococcal vaccine can only work if given before exposure to the pathogen. What is the difference between the meningococcal vaccines currently on the market? Menactra (Sanofi Pasteur) and Menveo (Novartis), licensed in 2005 and 2010, respectively, are both meningococcal conjugate vaccines. The first meningococcal vaccines, developed in the 1970s, were polysaccharide vaccines. Their protection tended to wane faster than the newer meningococcal conjugate vaccines (MCV4), and they were not able to be boosted. Menactra and Menveo contain serotypes A,C,Y, and W-135. There is no preference for one brand of MCV4 over the other. Is a booster dose of MCV4 necessary? If so, who should be boosted? The need for a booster dose depends on age of the patient. When the MCV4 vaccine was introduced, a booster dose was

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adolescent vaccination

clinical slideshow For additional information on the measles, mumps, and rubella vaccine, view the clinical slideshow at CliniAd.com/15R4nBO.

not thought to be necessary. However, subsequent studies showed that protective antibody levels provided by the MCV4 vaccine decrease significantly three to five years after initial vaccination. Although there are very few cases of meningitis among individuals vaccinated with MCV4, the ACIP has determined that a booster dose is necessary for optimal protection against invasive meningococcal disease. If a child receives his or her first MCV4 vaccination at the recommended age of 11 to 12 years, a booster dose will be required at age 16 years. If a child receives his or her first MCV4 vaccination between ages 13 and 15, a booster dose will be required at age 18 years. If a child receives his or her first MCV vaccination at age 16 years or later, no booster is needed.11 If a patient is entering college and has never received a meningococcal vaccine, when should he or she receive a booster dose of MCV4? Such a patient should receive one dose of MCV4 immediately and will not need a booster dose.11 The booster dose recommendations listed above depend solely on the patientâ&#x20AC;&#x2122;s age at the time of the first MCV4 immunization. What is behind the sudden focus on pertussis? There has been a huge increase in the number of pertussis cases in some states. Wisconsin, Washington, Montana, Vermont, Minnesota, and Iowa had the highest incidence of pertussis in 2012, each having between four and 10 times higher incidences than the general population average. Washington state alone saw a 1,300% increase in pertussis cases through the first six months of 2012 compared with 2011.12 Why is pertussis on the rise? Not all children are receiving a pertussis-containing vaccine on the recommended schedule. In fact, only about 85% of children have received four diphtheria, tetanus, and pertussis (DTaP) vaccines by age 3 years.13 Parents who delay or refuse immunizations have contributed to the pertussis outbreak by weakening herd immunity. Delayed diagnosis is another reason for the rise in pertussis: Pertussis can be difficult to diagnose,

especially when it first presents, as it can mirror a number of other common respiratory illnesses, especially in adolescents and adults. Additionally, not enough teens and preteens have been reached with the Tdap vaccine. In 2010, only 69% of teenagers had received the Tdap vaccine, and only 81% had received either tetanus and diphtheria (Td) or Tdap.9 Finally, and perhaps most disturbingly, we are seeing waning immunity of pertussis vaccines. Children must receive the Tdap booster as close to age 11 to 12 years as possible. At this time, Tdap is approved for a single dose only. However, studies are under way to determine if a booster of Tdap will be needed. What is the difference between the Tdap vaccines on the market? Adacel (Sanofi Pasteur) and Boostrix (GlaxoSmithKline) were approved for use in 2006. Boostrix is approved for individuals aged 10 years and older, and Adacel is approved for those aged 11 to 64 years. Either vaccine may be used without preference for brand. Can a patient who received a Td vaccine within the past two years get a Tdap vaccine? As long as the patient is in the recommended age range and has not received a Tdap vaccine previously, he or she should receive a Tdap vaccine. There is no minimum interval necessary between Td and Tdap vaccines. Is it true that some children aged 7 to 10 years and some adults older than age 65 years should get the Tdap vaccine? In certain circumstances, the ACIP recommends using the Tdap vaccine outside of the FDA-approved age indications. Children aged 7 to 10 years who have not been immunized with DTaP or whose immunization history is unknown should receive a Tdap vaccine. All adults aged 19 years and older who have not previously received a Tdap vaccine should also receive a single dose of Tdap. Even adults aged 65 years and older who need a Tdap vaccine should receive one. The CDC recommends giving Boostrix to adults aged 65 years and older when feasible but permits Adacel to be used as well. This is likely due to licensing restrictions, but the CDC permits off-label use in these circumstances.14 Should pregnant women receive the Tdap vaccine? The ACIP recommends that all pregnant women, regardless of their vaccination history, receive a Tdap vaccine, preferably during the third or late-second trimester. The vaccine will protect the mother from contracting pertussis

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and from transmitting the disease to her baby, and confer some pertussis protection to the infant until he or she can start getting DTaP vaccines.

Pediatr Adolesc Med. 2007;161:252-259. Available at archpedi.jamanetwork. com/article.aspx?articleid=569769. 3. Satterwhite CL, Torrone E, Meites E, et al. Sexually transmitted infections among US women and men: prevalence and incidence estimates,

Who else should get a Tdap vaccine? Vaccination is advisable for anyone who is going to be in close contact with an infant. This includes health-care providers and office staff, grandparents, other family members, daycare employees, nannies, and babysitters.

2008. Sex Transm Dis. 2013;40:187-193. 4. Centers for Disease Control and Prevention (CDC). Human papillomavirus-associated cancers—United States, 2004-2008. MMWR Morb Mortal Wkly Rep. 2012;61:258-261. Available at www.cdc.gov/mmwr/preview/ mmwrhtml/mm6115a2.htm. 5. Widdice LE, Brown DR, Bernstein DI, et al. Prevalence of human

What can be done to increase immunization rates among teens and preteens? Use any office visit as an opportunity for immunization. If a child is due for an immunization and has an injury or minor illness, that child may safely receive an immunization. Be emphatic in your recommendation. Set up a system to get children into the office for their well-child visits. As noted earlier, only a small percentage of preteens and teens present for regular well-child visits. At every appointment, note if the patient has had a well-child visit in the previous 12 months; if not, recommend scheduling one. Use electronic medical records to run a report on children who have not had a well-child visit in the past 12 months. Use postcards, phone calls, and e-mails to remind caretakers to schedule their child’s well-child appointment. The CDC’s Vaccines & Immunizations page (www.cdc. gov/vaccines/) provides excellent information on disease epidemiology. The CDC also offers resources for addressing caregivers and patients who are hesitant about receiving vaccines (www.cdc.gov/vaccines/hcp/patient-ed/conversations/ index.html). The Immunization Action Coalition (www. immunize.org) is a reliable source of easy-to-find information on vaccines and VPDs and current vaccine-information statements in a variety of languages. Finally, the American Academy of Pediatrics Childhood Immunization Support Program (www2.aap.org/immunization/) provides a great deal of useful information for clinicians and caregivers. n

papillomavirus infection in young women receiving the first quadrivalent vaccine dose. Arch Pediatr Adolesc Med. 2012;166:774-776. 6. Liddon NC, Leichliter JS, Markowitz LE. Human papillomavirus vaccine and sexual behavior among adolescent and young women. Am J Prev Med. 2012;42:44-52. 7. Gardasil [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant] package insert. Merck & Co., Inc.; 2011. Available at www.merck.com/product/usa/pi_circulars/g/gardasil/gardasil_pi.pdf. 8. American Cancer Society. Cancer Facts and Figures 2013. Available at www.cancer.org/Research/CancerFactsFigures/CancerFactsFigures/ ACSPC-036845. 9. Centers for Disease Control and Prevention (CDC). National and state vaccination coverage among adolescents aged 13 through 17 years–United States, 2010. MMWR Morb Mortal Wkly Rep. 2011;60:1117-1123. Available at www.cdc.gov/mmwr/preview/mmwrhtml/mm6033a1.htm. 10. Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases. In: The Pink Book: Course Textbook. 12th ed. Available at www.cdc.gov/vaccines/pubs/pinkbook/mening.html. 11. Centers for Disease Control and Prevention (CDC). Updated recommendations for use of meningococcal conjugate vaccines—Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Morb Mortal Wkly Rep. 2011;60:72-76. Available at www.cdc.gov/mmwr/preview/ mmwrhtml/mm6003a3.htm. 12. Centers for Disease Control and Prevention (CDC). Pertussis epidemic– Washington, 2012. MMWR Morb Mortal Wkly Rep. 2012 Jul 20;61(28):517-22. Available at www.cdc.gov/mmwr/preview/mmwrhtml/mm6128a1.htm. 13. Centers for Disease Control and Prevention (CDC). National, state, and local area vaccination coverage among children aged 19-35 months—United

Mr. Barry is a physician assistant in Raleigh, N.C, and the AAPA’s Medical Liaison to the American Academy of Pediatrics.

States, 2009. MMWR Morb Mortal Wkly Rep. 2010;59:1171-7. Available at www.cdc.gov/mmwr/preview/mmwrhtml/mm5936a2.htm. 14. Centers for Disease Control and Prevention (CDC). Updated recom-

References

mendations for use of tetanus toxoid, reduced diphtheria toxoid, and acel-

1. Centers for Disease Control and Prevention (CDC). National and state

lular pertussis (Tdap) vaccine in adults aged 65 years and older—Advisory

vaccination coverage among adolescents aged 13-17 years—United States,

Committee on Immunization Practices (ACIP), 2012. MMWR Morb Mortal

2011. MMWR Morb Mortal Wkly Rep. 2012;61:671-677. Available at www.

Wkly Rep. 2012;61:468-470. Available at www.cdc.gov/mmwr/preview/

cdc.gov/mmwr/preview/mmwrhtml/mm6134a3.htm.

mmwrhtml/mm6125a4.htm.

2. Rand CM, Shone LP, Albertin C, et al. National health care visit patterns of adolescents: implications for delivery of new adolescent vaccines. Arch

All electronic documents accessed April 15, 2013.

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special report: joe kopcha

Salary survey How are you doing?

According to the National Bureau of Economic Research, the Great Recession ended in June 2009, but the recovery has been slow to materialize. Unemployment hover around 8%, and many Americans continue to struggle financially. However, health care is one of the strongest sectors of the economy, a fact that is reflected in the more than 7,000 responses to our annual salary survey. On the whole, nurse practitioners and physician assistants reported higher salaries than last year and strong confidence that such growth will continue as their careers progress.

Practice area

For the third consecutive year, the highest percentage of NP (Table 1) and PA (Table 2) respondents were family/adult medicine practitioners. The only significant change from last year’s survey was psychiatry replacing oncology/hematology at fifth place on the NP list. The order of the PA list remained virtually the same. Salaries were higher in all practice areas listed, with the largest gain seen among pediatric NPs. Table 1. Average NP salary by practice area

Table 2. Average PA salary by practice area

Practice area

Response percent

Average salary 2011

Average salary 2012

Practice area

Response percent

Average salary 2011

Average salary 2012

Family/adult medicine

34.7%

$85,974

$90,629

Family/adult medicine

28%

$89,044

$90,460

Women’s health

9.0%

$77,282

$82,331

Emergency medicine

9.3%

$107,904

$112,825

Pediatrics

6.4%

$78,390

$83,937

Orthopedics

8.8%

$100,265

$105,161

Geriatric medicine

4.1%

$92,503

$97,397

Urgent care

5.1%

$98,331

$99,050

Psychiatry

4.1%

$96,631

Dermatology

4.7%

$110,204

$113,062

Experience

Once again, NP salaries are not significantly affected by experience beyond the first five years of practice (Table 3). PAs see a small but steady growth in income through the first 20 years of employment (Table 4). Table 3. Average NP salary by experience level Years of experience

Response percent

Average salary 2011

Average salary 2012

Table 4. Average PA salary by experience level Years of experience

Response percent

Average salary 2011

Average salary 2012

29.3%

$84,944

$88,200

33.7%

$88,657

$91,512

6-10

20.1%

$89,834

$94,157

6-10

22.2%

$98,031

$100,221

11-15

22.8%

$91,632

$96,011

11-15

17.1%

$100,186

$101,603

16-20

13.3%

$90,693

$93,165

16-20

8.5%

$100,017

$104,955

>20

14.5%

$88,528

$92,243

>20

18.5%

$101,916

$104,011

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salary survey 2013

Sex

Women continue to make up the majority of NP and PA respondents (92.0% and 67.5%, respectively). Some progress was made in narrowing the discrepancy in pay between male and female clinicians, but the differences remain stark. The average male NP earned $104,845 in 2012 ($100,316 in 2011), compared with $94,416 for a female ($87,393 in 2011). For PAs, the average male brought home $109,500 in 2012 ($105,902 in 2011), and women earned $93,365 ($89,728 in 2011). Geographic region

More then one-third of survey respondents reside in the South (Figures 1 and 2). PAs in the West continue to report the highest annual pay. For the first time since this survey began, average salaries of NPs and PAs in all regions climbed above $90,000. Figure 1. Average NP salary by geographic region

Figure 2. Average PA salary by geographic region

West

Midwest

Northeast

West

Midwest

Northeast

14.9% response $98,770 average salary

22.3% response $90,534 average salary

23.8% response $92,084 average salary

21.2% response $103,906 average salary

22.0% response $95,779 average salary

23.2% response $96,060 average salary

South

39.0% response $91,361 average salary

33.6% response $99,365 average salary

Practice setting

The distribution of NPs and PAs by practice setting appears entrenched. Very little movement has been reported by respondents over the past three years. Office-based NPs (Table 5) and PAs (Table 6) remain well-represented in our survey, but hospital-based clinicians earned higher salaries. Table 5. Average NP salary by practice setting Practice setting

Percent response

Average salary 2011

Table 6. Average PA salary by practice setting

Average salary 2012

Practice setting

Percent response

Average salary 2011

Average salary 2012

Office

24.7%

$84,568

$88,698

Hospital

22.6%

$101,568

$106,670

Clinic–standalone

17.1%

$85,418

$90,997

Office

22.3%

$91,833

$94,846

Clinic–hospital

16.3%

$93,421

$95,568

Clinic–standalone

19.9%

$93,023

$94,976

Hospital

14.1%

$98,288

$103,043

Clinic–hospital

15.9%

$95,720

$100,124

Walk-in/ambulatory

4.5%

$85,585

$88,663

Walk-in/ambulatory

4.0%

$92,052

$95,876

Practice location

Urban clinicians continue to earn more than their suburban and rural counterparts, but the gap is narrowing. The largest location-based salary gain in this year’s survey was seen among suburban NPs. The breakdown of NP respondents remained stable, with 40.6% describing their work environment as urban (average salary $93,688, up from $91,295 in 2011), 35.8% as suburban (average salary $93,105, up from $87,561 in 2011), and 23.6% as rural (average salary $89,453, up from $85,579 in 2011). Among PAs, 39.3% worked in an urban setting (average salary $100,190, up from $96,087 in 2011), 41.2% worked in a suburban setting (average salary $98,067, up from $94,734 in 2011), and 19.6% worked in a rural setting (average salary $96,608, up from $95,042 in 2011). www.ClinicalAdvisor.com • the clinical advisor • may 2013 43

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salary survey 2013

Job mobility

The proportion of NPs (Figure 3) and PAs (Figure 4) who work at more than one location was nearly identical to what was shown in the previous surveys. Roughly one out of every three respondents travels from job to job throughout the week. Figure 3. Do you work at multiple locations (NPs)?

37.7% 62.3%

Figure 4. Do you work at multiple locations (PAs)?

37.5%

Yes 62.5%

Yes No

History and the future

Despite an uncertain economic climate, clinicians are optimistic about their financial future. Just over 45% of NPs (Figure 5) and 48% of PAs (Figure 6) reported an increase in income over 2011. Figure 5. Did you earn more money this year (NPs)?

Figure 6. Did you earn more money this year (PAs)?

45.0%

41.6%

37.1%

Less Same

13.4%

48.1% Less Same

14.8%

When asked about their expectations for next year, more than 95% of NPs (Figure 7) and PAs (Figure 8) anticipate that their income would stay the same or increase. Figure 7. Do you expect to earn more money next year (NPs)?

Figure 8. Do you expect to earn more money next year (PAs)?

More 48.5%

47.4% Less

More 41.9%

Same 4.1%

53.2% Less Same

4.9%

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salary survey 2013

Weekly output

As in previous years, the 2013 survey included questions designed to provide some insight into the typical workweek of our readers. No discernible difference was noted in the amount of time NPs and PAs spend on the job. Approximately 80% of all respondents work between 30 and 50 hours per week. There was some diversity with regard to the number of patients seen per week, but the NP (Figure 9) and PA (Figure 10) breakdowns remained similar. Figure 9. Number of patients seen per week (NPs) 3.6%

Figure 10. Number of patients seen per week (PAs)

6.5%

6.0%

9.3%

>125 14.8%

19.5%

>125 9.9%

101-125 76 -100

24.3% 26.2%

51-75

30.1%

25.5%

101-125 76 -100 51-75

26 - 50

26-50

24.3%

≤ 25

Finally, prescription-writing behavior stayed consisted across all disciplines. Approximately two thirds of NPs (Figure 11) and PAs (Figure 12) write fewer than 75 prescriptions per week. Figure 11. Number of prescriptions written per week (NPs) 3.6%

Figure 12. Number of prescriptions written per week (PAs)

7.3%

6.0%

10.1%

201-250+ 17.2%

35.1%

126-200 76-125

201-250+ 29.4%

26-75 36.8%

0-25

19.4%

126-200 76-125 26-75

35.1%

0-25

Congratulations

The randomly chosen winner of the $50 American Express Gift Card is Tamara Love, a nurse practitioner in Sanford, N.C. Thank you to everyone who took the time to participate in this always enlightening project. n Mr. Kopcha is the editor of The Clinical Advisor. 48 the clinical advisor • may 2013 • www.ClinicalAdvisor.com

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CME CE

PROGRAM OUTLINE MAY 2013

0.5 CREDITS

Page 50 FEATURE Symptoms and treatment of low testosterone in men Steven W. Salyer, PA-C Steven W. Salyer, PA-C has no relationships to disclose relating to the content of this article.

Page 67 DERMATOLOGY CLINIC Purple trunk plaques on a homosexual man Navid Malakouti and Julia R. Nunley, MD Navid Malakouti and Julia R. Nunley, MD, have no relationships to disclose relating to the content of this article.

Blue discoloration on both arms and legs Audrey Chan, MD Audrey Chan, MD, has no relationships to disclose relating to the content of this article.

■ LEARNING OBJECTIVES: • To identify and diagnose dermatologic conditions and review up-to-date treatment.

Page 85 DERMATOLOGIC LOOK-ALIKES Skin-colored papules Kerri Robbins, MD Kerri Robbins, MD, ha no relationships to disclose relating to the content of this article.

■ LEARNING OBJECTIVE: • To distinguish and properly treat dermatologic conditions with similar presentations.

Page 90 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 May 2013. 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. Nurse Practitioner Associates for Continuing Education (NPACE) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. 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 • MAY 2013 49

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CME CE FEATURE

■ LEARNING OBJECTIVES: • Identify the symptoms most frequently associated with hypogonadism. • Name the medications that cause a decrease in serum testosterone. • List the contraindications to testosterone replacement therapy. • Name the total testosterone level targeted by replacement therapy. ■ COMPLETE THE POSTTEST: Page 90 ■ ADDITIONAL CME/CE: Pages 67, 85 Turn to page 49 for additional information on this month’s CME/CE courses.

STEVEN W. SALYER, PA-C

Symptoms and treatment of low testosterone in men There is a direct correlation between testosterone and metabolic syndrome, mental function, libido, erectile dysfunction, bone density, and overall energy.

Leydig cells (blue) are involved in the secretion of male sex hormones, including testosterone.

estosterone is a naturally occurring androgenicanabolic steroid that is produced in the Leydig cells of the gonads. The preoptic area and the medial basal region of the hypothalamus monitor testosterone levels and secrete gonadotropin-releasing hormone (GnRH) in a pulsatile manner to the pituitary gland. The periodicity and amplitude of GnRH secretion determine the pattern of secretion of the gonadotrophins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) from the gonadotroph cells of the anterior pituitary.1 In particular, LH controls testosterone production and FSH controls sperm production. Only 1% to 2% of testosterone circulates freely in the blood; the remaining 98% to 99% is bound to albumin (40%–50%) and to sex hormone-binding globulin (SHBG) (50%–60%). Testosterone binds strongly to SHBG; therefore, it is largely the free and albumin-bound testosterone that is available for biologic action.2 As men age, there is a rise in FSH and LH and a decline in testosterone, assuming normal operation of

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the feedback pathway by which low testosterone level signals the hypothalamic-pituitary axis to release FSH and LH. This natural aging process is what affects a man’s total testosterone levels over time.3 Testosterone controls sexual differentiation (stabilization of the Wolfian ducts) and is active on skeletal muscle, libido, and sexual function. Primary hypogonadism

Primary hypogonadism (hypergonadotropic hypogonadism) is a term used to refer to the decrease in testosterone and sperm production. Sperm is made in the seminiferous tubules affected by FSH secretion. FSH regulates spermatogenesis in the basal aspect of the plasma membrane of Sertoli cells in the testis. If testosterone production is low, secondary to dysfunction of the Leydig cells in the testes, this condition is called primary hypogonadism. The diagnosis of primary hypogonadism is made by testing total serum testosterone concentration; testosterone will be below normal, and the serum LH and FSH concentrations typically will be above normal. Secondary hypogondism

Secondary hypogonadism (hypogonadotropic hypogonadism) is caused by low testosterone levels secondary to insufficient stimulation of the Leydig cells by LH. In a man with secondary hypogonadism, the serum testosterone concentration and the sperm count are subnormal, and the serum LH and FSH concentrations are normal or reduced. Secondary hypogonadism is usually caused by hypothalamic and pituitary disorders or lesions; hyperprolactinemia; or Kallmann syndrome, which leads to a GnRH deficiency.4 Causes of low testosterone

The primary cause of decreased testosterone production is a natural decline in rate of production. In the third decade of life, men start losing about 1% of testosterone production per year, unless there is disease of the hypothalamic-pituitarytesticular axis. It has been suggested, but not proven, that neuronal GnRH outflow in healthy men is reduced by 33% to 50% between the second and eighth decades of life. Feedback from testosterone induces a slowing of the hypothalamic pulse generator and a subsequent reduction in the frequency of the LH pulsatile release. LH binds to the LH receptor on the plasma membrane of Leydig cells in the testes, resulting in the synthesis of the enzymes of testosterone. An increase in stress can have a dire t effect on the testes and stimulate the release of glucocorticoids, which can

Table 1. Signs and symptoms of low testosterone Reduced libido

Erectile dysfunction

Decreased muscle mass

Decline in mental function

Fatigue

Loss of bone mineral density

Insulin resistance

Moodiness/irritability

Increased body fat

Metabolic syndrome

Hair loss

Atherosclerosis

Breast discomfort/ gynecomastia

Hot flushes

Sleep disturbance

Decreased vitality

suppress testosterone levels. Obesity, tobacco and alcohol use, obstructive sleep apnea, diabetes, chromosomal abnormalities, HIV/AIDS, disease, and illness can all affect a man’s testosterone levels. Low testosterone can also be caused by Klinefelter syndrome and other chromosomal abnormalities, mutation in the FSH and LH receptor genes, cryptorchidism, variocele, mytonic dystrophy, and disorders of androgen synthesis. Some medications may cause a decrease in serum testosterone as well, including suramin (Germanin), ketoconazole (Nizoral), glucocorticoids, and alkylating agents. Chronic opioid use is a common cause of low testosterone and will be discussed in detail later in this report. The symptom most associated with hypogonadism is low libido. Other common signs include fatigue, decreased muscle mass, erectile dysfunction, and weight gain (Table 1).5 Cardiovascular effects of testosterone

Human observational studies have uncovered no association between high testosterone levels and coronary artery disease. Testosterone has been shown to dilate the coronary arteries both in vitro and in vivo. Some studies have demonstrated that testosterone can be considered to have a positive effect on reducing cardiovascular risk factors; for example, inverse relationships have been shown between testosterone levels and BMI, waist circumference, and waist-to-hip ratio, as well as levels of serum leptin, LDL cholesterol, triglycerides, and fibrinogen. Low testosterone is associated with dyslipidemia, hypertension, obesity, and diabetes, all of which increase the risk of cardiovascular disease and are features of the metabolic syndrome.6 Studies indicate that low testosterone levels are associated with atherosclerosis in all major vessels. Animal experiments have shown that testosterone inhibits plaque development in rabbits and rodents fed a high-fat diet.7 Continues on page 52

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Diabetes, metabolic syndrome, and obesity

Low testosterone is associated with type 2 diabetes. A man with diabetes is approximately twice as likely to be hypogonadal than a man without diabetes.8 Low testosterone concentrations predict the development of type 2 diabetes: Data from the National Health and Nutrition Examination Survey (NHANES) III survey indicated that men with the lowest levels of free testosterone were four times as likely to have diabetes as those with the highest levels.9 Evidence suggests a direct bidirectional and physiologic link between hypogonadism and metabolic syndrome in males. Data show that there is improvement in the symptoms of patients with metabolic syndrome who receive testosterone replacement therapy.10 Hyperinsulinemia and obesity may inhibit testicular testosterone production.11 Testosterone replacement therapy in hypogonadal men improves lean body mass and reduces fat mass, and may improve some symptoms of metabolic syndrome and type 2 diabetes.12 Bone density

Testosterone levels also affect bone density. Osteopenia, osteoporosis, and fracture prevalence rates are greater in hypogonadal men.13 A positive direct relationship between serum testosterone and bone mineral density increments was seen in a 36-month study.14 The prevalence of osteoporosis is estimated to be 18% in men, but 30% of all fractures occur in men with low testosterone. With age, men experience a gradual decline in testosterone production and bone density. The rate of trabecular bone loss in the lumbar spine in men older than age 50 years with low testosterone is double the rate of loss in men younger than age 50 years.15 Erectile dysfunction and decreased libido

As men get older, there is a natural decline in testosterone and thus a corresponding decline in libido. Testosterone is essential for the regulation of erectile physiology by multiple mechanisms.16 In one study, after four testosterone injection intervals, the percentage of patients with “low” or “very low” levels of sexual desire/libido decreased from 64% at baseline to 10%; moderate, severe, or extremely severe erectile dysfunction decreased from 67% to 19%.17 Testosterone regulates nerve structure and function in areas of the spinal cord that are involved in erections. The hormone is critical for the maturation and maintenance of terminal axon density and neuropeptide expression in the vas deferens. Acting peripherally to the spinal cord, testosterone enhances

the erectile response of the cavernous nerve. Testosterone also regulates nitric oxide synthase expression and activity in the corpus cavernosum. It may restore erectile function in men with diabetes.16 There is growing evidence that testosterone has profound effects on penile tissues involved in the mechanism of erection and that testosterone deficiency impairs the anatomical and physiologic/biochemical substrate of erectile capacity. These effects have been shown to be reversible on androgen treatment. Treatment with transdermal testosterone resulted in improved tumescence and rigidity of nocturnal erections, spontaneous erections, and sexually related erections in men with androgen deficiency.18 Effects on mental function

Low testosterone levels have an effect on cognition in men. Higher bioavailable testosterone levels are associated with better performance in cognitive tests. Often men with low testosterone complain of mental “fogginess” or forgetfulness. As testosterone levels normalize with replacement therapy, this decline in mental function reverses. In the Veterans Affairs Puget Sound Health Care System cohort study, 278 hypogonadal men (total testosterone level ≤200 ng/dL) aged 45 years and older without previous depressive diagnosis showed an approximate fourfold increase in risk of incident depression during the two-year follow-up. Veterans with low testosterone developed depression over time. Men with depression who received testosterone therapy had improved scores on depression scales.19 In a randomized, placebo-controlled, double-blind, phase III trial, 184 men suffering from metabolic syndrome and hypogonadism were treated for 30 weeks with either parenteral testosterone undecanoate (1,000 mg intramuscularly) or placebo. Depression was assessed at baseline and at 18 and 30 weeks using the Beck Depression Inventory. At baseline, depression significantly correlated with the total testosterone level. Over time, a significant improvement in depression was seen in the testosterone undecanoate group (mean difference after 30 weeks: −2.5 points). Effects were strongest in men with the lowest baseline total testosterone (<222 ng/dL).20 Chronic opioid use

Long-acting opioid analgesics suppress the hypothalamicpituitary-gonadal axis in men, thus producing symptomatic androgen deficiency and an increased risk of osteoporosis. The high prevalence of opioid-induced hypogonadism in both sexes is not widely recognized.21 Opioids, both endogenous and exogenous, modulate gonadal function

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is converted to two active metabolites, 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT), which mediate some actions of testosterone in target tissues. Most of the circulating E2 is derived from peripheral aromatization of testosterone in adipose tissue, and DHT is derived by 5α-reduction of testosterone.23 Estradiol is a metabolite of testosterone that causes many of the side effects of testosterone replacement therapy. As the testosterone is replaced, estradiol levels will also increase. Rising estradiol levels can increase such side effects as gynecomastia, enlarged prostate, elevated hematocrit count, and increased moodiness. Estradiol levels should be followed along with total testosterone and free testosterone in any patient receiving testosterone replacement therapy.

Table 2. Potential risks of testosterone replacement therapy Stimulate growth of prostate cancer and breast cancer Worsen symptoms of benign prostatic hypertrophy Cause liver toxicity and liver tumor Cause gynecomastia Cause erythrocytosis Cause testicular atrophy and infertility Cause skin diseases Cause or exacerbate sleep apnea

Table 3. Contraindications to testosterone replacement therapy Metastatic prostate cancer

Testosterone replacement therapy

Breast cancer Undiagnosed prostate nodule or induration Unexplained elevation of prostate-specific antigen (>3 ng/mL) Erythrocytosis (hematocrit >50%) Severe benign prostatic hyperplasia (International Prostate Symptom Score >19) Unstable severe congestive heart failure (class III or IV) Untreated obstructive sleep apnea

primarily by acting on opioid receptors in the hypothalamus. This action leads to the decreased release or disruption to the normal pulsatility of GnRH secretion, resulting in a reduction of the release of LH and FSH from the pituitary gland, and of testosterone or estradiol from the gonads.22 With the prevalent use of opioids in the treatment of acute and chronic pain, the effect on the hypothalamus is often overlooked. Fatigue, low libido, and decline in mental function are frequently associated with chronic opioid use. Any man on opioid therapy, especially methadone (Dolophine, Methadose, Westadone), who complains of chronic fatigue should have his total testosterone level checked. Long-term replacement of testosterone can induce a general improvement of the male chronic pain patient’s quality of life, an important clinical aspect of pain management. The administration of testosterone in chronic pain patients with low testosterone improved their pain-rating indexes. The Aging Males’ Symptoms Scale was used in the referenced study along with a sexual dimension index. Both scales showed significant improvement over time. Estradiol

The female hormone estrogen can be synthesized from testosterone in many tissues throughout the body. Testosterone

Morbidity and mortality are higher in men with belownormal serum testosterone. The goal of testosterone replacement therapy is to relieve the symptoms of low testosterone and restore testosterone levels to the mid-to-normal range. Testosterone therapy can be administered through injection, cream, or patch. The half-life of injectable testosterone is approximately eight days. A testosterone injection every seven to 10 days is recommended for a stable therapeutic level. The absorption rate of testosterone cream is unpredictable, and the cream can be transferred to others who come in contact with the applicant. The testosterone patch can get wet and may come off. There is currently no oral testosterone replacement therapy available in the United States. Testosterone undecanoate, which is absorbed predominantly through the lymphatic system, is widely used outside the United States and has the best safety data. However, this form of testosterone is unlikely to raise levels above the mid-range.5 Testosterone replacement therapy is not without its risks (Table 2). Users may be at risk for prostate cancer, worsening symptoms of benign prostatic hypertrophy, liver toxicity and tumor, worsening symptoms of sleep apnea and congestive heart failure, gynecomastia, infertility, and skin diseases. Because exogenous testosterone will suppress the hypothalamic–pituitary–thyroid axis, testosterone replacement therapy is not appropriate for men who wish to father a child.5 The severity of these risks depends on the man’s age, life circumstances, and other medical conditions.24 Contraindications to testosterone replacement therapy include metastatic prostate cancer, breast cancer, undiagnosed prostate nodule or induration, unexplained prostate-specific antigen (PSA) elevation, erythrocytosis, severe benign prostatic

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low testosterone

hyperplasia symptoms, unstable severe congestive heart failure, and untreated obstructive sleep apnea (Table 3).5 Testosterone monitoring

Serum testosterone levels vary significantly as a result of circadian and circannual rhythms, episodic secretion, and measurement variations. Concentrations may be affected by illness and certain medications. Total testosterone concentrations are also influenced by alterations in SHBG concentrations.24 On initial evaluation for testosterone replacement therapy, obtain a complete blood count (CBC) and total chemistry panel and measure levels of thyroid-stimulating hormone (TSH), LH, FSH, total testosterone, free testosterone, PSA, prolactin, and estradiol. If the testosterone level is <150 ng/dL on two morning visits, obtain an MRI to rule out pituitary adenoma or disease. After the fourth injection, evaluate the total testosterone, free testosterone, and estradiol levels and adjust the testosterone dose accordingly. The goal of testosterone replacement therapy is total testosterone between 400 ng/dL and 600 ng/dL and a free testosterone between 15 ng/dl and 20 ng/dl. At these normal levels, symptoms of hypogonadism resolve. A digital rectal examination should be performed and PSA should be tested prior to initiating testosterone replacement therapy; a follow-up PSA test should be performed every three months. If the PSA value is increasing over time, refer the patient to urology for evaluation. All abnormal PSA results on the first visit should be referred for evaluation, and testosterone replacement therapy should not be started until cleared by a urologist. Men with hypothyroidism will almost always have low testosterone, but not all patients with low testosterone will have hypothyroidism. If the patient has low testosterone on screening, a TSH should be performed to rule out hypothyroidism. LH and FSH are used to rule out disease of the hypothalamus-pituitary axis. A prolactin level should also be obtained if disease of the pituitary gland is suspected. During testosterone replacement therapy, a CBC (specifically a hematocrit) as well as total testosterone, free testosterone, LH, FSH, estradiol, and PSA levels should be obtained every 90 days. Testosterone replacement therapy can thicken the blood. If the hematocrit is >50%, testosterone therapy should be stopped or the dose reduced.

prescribe anastrozole (Arimidex) 1 mg, one half to one tablet every morning of testosterone injection. If estradiol levels continue to rise and symptoms are present, the dose can be increased to one tablet three times a week. Antibiotic soap should clear up any acne that occurs as a result of treatment. Conclusion

Testosterone replacement therapy is associated with significant improvement in the physical and mental function of men diagnosed with low testosterone. The natural decline in testosterone with age is the most prevalent cause of this condition. The main complaints of men with low testosterone are fatigue, decreased muscle mass, erectile dysfunction, waning libido, and weight gain. A known association exists among the triad of low testosterone, metabolic syndrome, and erectile dysfunction. Testosterone replacement to normal levels also has positive effects on depression and bone density. Chronic opioid use can lower total testosterone, but replacement has a positive effect on overall pain levels. Mental function and cognition is also improved with testosterone replacement in those who have low testosterone. A normal testosterone level most likely provides cardiovascular protection. The major contraindication for androgen supplementation is the presence of a prostatic carcinoma.5 Response to testosterone replacement therapy must be assessed regularly. If no symptom improvement is noted, treatment should be discontinued and the patient investigated for other possible causes of the clinical presentation. n Mr. Salyer is a practicing emergency-medicine physician assistant in San Antonio, Tex. References 1. Araujo AB, Wittert GA. Endocrinology of the aging male. Best Pract Res Clin Endocrinol Metab. 2011;25:303-319. Available at www.ncbi.nlm.nih.gov /pmc/articles/pmid/21397200/. 2. Kaufman JM, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev. 2005;26:833876. Available at edrv.endojournals.org/content/26/6/833.long. 3. Bagatell CJ, Bremner WJ. Androgens in menâ&#x20AC;&#x201D;uses and abuses. N Engl J Med. 1996;334:707-714. 4. Seftel A. Male hypogonadism. Part II: etiology, pathophysiology, and diagnosis. Int J Impot Res. 2006;18:223-228. Available at www.nature.com/

Side effects of testosterone replacement therapy

ijir/journal/v18/n3/full/3901365a.html.

If gynecomastia, nipple tenderness, enlarged prostate, increased hematocrit, fluid retention, and/or increased moodiness occur in a patient with increased estradiol levels,

5. Bassil N, Alkaade S, Morley JE. The benefits and risks of testosterone replacement therapy: a review. Ther Clin Risk Manag. 2009;5:427-448. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC2701485/.

54 the clinical advisor â&#x20AC;˘ may 2013 â&#x20AC;˘ www.ClinicalAdvisor.com

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6. Shabsigh R, Katz M, Yan G, Makhsida N. Cardiovascular issues in hypo-

20. Kalinchenko SY, Tishova YA, Mskhalaya GJ, et al. Effects of testosterone

gonadism and testosterone therapy. Am J Cardiol. 2005;96:67M-72M.

supplementation on markers of the metabolic syndrome and inflammation

7. Hanke H, Lenz C, Hess B, et al. Effect of testosterone on plaque

in hypogonadal men with the metabolic syndrome: the double-blinded

development and androgen receptor expression in the arterial vessel

placebo-controlled Moscow study. Clin Endocrinol (Oxf). 2010;73:602-612.

wall. Circulation. 2001;103:1382-1385. Available at circ.ahajournals.org/con-

21. Daniell HW. Hypogonadism in men consuming sustained-action oral

tent/103/10/1382.long.

opioids. J Pain. 2002;3:377-384.

8. Mulligan T, Frick MF, Zuraw QC, et al. Prevalence of hypogonadism in

22. Mehmanesh H, Almeida OF, Nikolarakis KE, Herz A. Hypothalamic

males aged at least 45 years: the HIM study. Int J Clin Pract. 2006;60:762-

LH-RH release after acute and chronic treatment with morphine studied

769. Available at www.ncbi.nlm.nih.gov/pmc/articles/pmid/16846397/.

in a combined in vivo/in vitro model. Brain Res. 1988;451:69-76.

9. Selvin E, Feinleib M, Zhang L, et al. Androgens and diabetes in men:

23. Simpson ER. Sources of estrogen and their importance. J Steroid

results from the Third National Health and Nutrition Examination Survey

Biochem Mol Biol. 2003;86:225-230.

(NHANES III). Diabetes Care. 2007;30:234-238. Available at care.diabetes-

24. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men

journals.org/content/30/2/234.long.

with androgen deficiency syndromes: an Endocrine Society clinical practice

10. Bhattacharya RK, Khera M, Blick G, et al. Effect of 12 months of testoster-

guideline. J Clin Endocrinol Metab. 2010;95:2536-2559. Available at jcem.

one replacement therapy on metabolic syndrome components in hypogonad-

endojournals.org/content/95/6/2536.long.

al men: data from the Testim Registry in the US (TRiUS). BMC Endocr Disord. 2011;11:18. Available at www.ncbi.nlm.nih.gov/pmc/articles/pmid/22044661/.

All electronic documents accessed April 15, 2013.

11. Zitzmann M. Testosterone deficiency, insulin resistance and the metabolic syndrome. Nat Rev Endocrinol. 2009;5:673-681. 12. Wang C, Swerdloff RS, Iranmanesh A, et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab. 2000;85:28392853. Available at jcem.endojournals.org/content/85/8/2839.long. 13. Meier C, Nguyen TV, Handelsman DJ, et al. Endogenous sex hormones and incident fracture risk in older men: the Dubbo Osteoporosis Epidemiology Study. Arch Intern Med. 2008;168:47-54. Available at archinte .jamanetwork.com/article.aspx?articleid=413728. 14. Aversa A, Bruzziches R, Francomano D, et al. Effects of long-acting testosterone undecanoate on bone mineral density in middle-aged men © The New Yorker Collection 2013 from cartoonbank.com. All Rights Reserved.

with late-onset hypogonadism and metabolic syndrome: results from a 36 months controlled study. Aging Male. 2012;15:96-102. 15. Martin AC. Osteoporosis in men: a review of endogenous sex hormones and testosterone replacement therapy. J Pharm Pract. 2011;24:307-315. 16. Traish AM, Goldstein I, Kim NN. Testosterone and erectile function: from basic research to a new clinical paradigm for managing men with androgen insufficiency and erectile dysfunction. Eur Urol. 2007;52:54-70. Available at www.ncbi.nlm.nih.gov/pmc/articles/pmid/17329016/. 17. Zitzmann M, Mattern A, Hanisch J, et al. IPASS: a study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men. J Sex Med. 2013;10:579-588. 18. Shabsigh R, Arver S, Channer KS, et al. The triad of erectile dysfunction, hypogonadism and the metabolic syndrome. Int J Clin Pract. 2008;62:791798. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC2327081/. 19. Shores MM, Sloan KL, Matsumoto AM, et al. Increased incidence of diagnosed depressive illness in hypogonadal older men. Arch Gen Psychiatry. 2004;61:162-167. Available at archpsyc.jamanetwork.com/article. aspx?articleid=481955.

“Look at the picture I took of the thing we’re looking at.”

www.ClinicalAdvisor.com • the clinical advisor • may 2013 55

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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 M ay 2 0 1 3

Consultations Diagnosing neutropenia. . . . . . . . . . . 56 Testing for closed head injury. . . . . . . 56 When a patient cannot afford specialist treatment. . . . . . . . . . . . . . 57

Clinical Pearls Get a grip on dislocated fingers . . . . . 57 A tongue blade can detect temporomandibular joint disorder. . . 57 Magic hands to soothe a restless child . . . . . . . . . . . . . . . . . . 58 Use a laser to get patients walking. . . . 58

Your Comments Screen for gun ownership. . . . . . . . . . 58

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.

Derm Dx to the rescue . . . . . . . . . . . 58

Consultations Diagnosing neutropenia What constitutes a reasonable workup for neutropenia in an otherwise healthy young person?—DEBORAY KAY LANIUS, FNP, Fredericksburg, Va. Neutropenia is defined as a deficiency of circulating neutrophils or an absolute neutrophil count <1,500 µL. This condition can be attributable to a reduction in bone-marrow production or increased loss of bone marrow from the circulation. A thorough history is the best place to start in your evaluation of a healthy child with a low neutrophil count. A viral infection is the most common cause in children (not infants). The neutropenia develops during the illness and persists for up to one week after resolution. Measles, mumps, and rubella vaccine as well as varicella vaccine can also trigger transient neutropenia. Another possible cause is bacterial infection. Nutritional deficits in folic acid, vitamin B12, or copper can also lead to a drop in neutrophils. Lastly, look carefully at any drugs the patient is currently taking or may have recently finished taking. Herbal therapies and supplements also deserve evaluation.—Julee B. Waldrop, DNP (175-1)

Testing for closed head injury What is a good screening test for evaluation of closed head injury? What cases require overnight observation? How do I know which patients to send to the emergency

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.

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.

56 the clinical advisor • may 2013 • www.ClinicalAdvisor.com

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department (ED)?—BEVERLY GREENFIELD, BSN, Great Barrington, Mass. The standard neurologic assessment is still the best test. Pay specific attention to focal neurologic changes (e.g., pupil reactivity and equality), gait, level of consciousness, and basic vital signs. More advanced indications of increasing intracranial pressure include vomiting and decreased level of consciousness. Given their inherent increase in capillary fragility, older individuals would most likely require a trip to the ED. The same goes for any patient on any sort of anticoagulant (including aspirin).—Sherril Sego, FNP-C, DNP (175-2)

When a patient cannot afford specialist treatment A pressing question for all health-care providers is, “How do I do what is best for the patient if the patient cannot afford a higher level of treatment?” For example, I work in primary care, and many of my mental-health patients need a consult with a psychiatrist or ongoing counseling. A patient on a limited income cannot afford to pay $300 for the psychiatrist visit and another $100 for counseling sessions. When the choice boils down to eating or becoming mentally well, patients are going to choose to eat.—JENNY WILLMORE, PA-C, Anthony, Idaho Inequality to health-care access, especially access to mental-health treatment, is rampant in this country. The United States is the only industrialized nation that continues to have a health-care system established on employee-based private health insurance programs that are for-profit industries with an obligation to shareholders above the obligation to individual patient care. The health-insurance industry continues to reap substantial profits and to divest funds into lobbying against any movement to a single-payer or government-sponsored

Debra August King, PhD, PA,

is senior physician assistant at New York-Presbyterian Hospital, New York City.

Mary Newberry, CNM, MSN,

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

nonprofit system. Employers can no longer afford to offer the healthinsurance plans once universally provided to employees and have either stopped providing insurance or switched their workforce to part-time workers who do not meet the criteria for health insurance and cannot afford to purchase insurance on their own. It is outrageous that the cost of getting ill accounts for roughly two-thirds of all personal bankruptcies in the United States. Adequate health care should be available to all residents, regardless of socioeconomic class or employment status. To help patients like the one described, familiarize yourself with the resources in your community, including any local, state, or federally subsidized programs. Programs are also available through some of the large pharmaceutical companies to get reduced prices for patients without prescription plans. Charity care is available in most states, but waiting lists are quite long. Finally, form a relationship with local clinics and caregivers and, most important, with your legislators and regulators, and encourage them to expand existing programs to those with need.—Claire Babcock O’Connell, MPH, PA-C (175-3)

Clinical Pearls Get a grip on dislocated fingers When performing a closed reduction on a dislocated finger, improve your grip by first placing some tincture of benzoin on the distal finger.—ANNETTE O’GORMAN, FNP-C, Yarmouth, Maine (175-4) A tongue blade can detect temporomandibular joint disorder If a patient complains of chronic headaches, ear, or jaw pain and you suspect temporomandibular joint (TMJ) disorder, perform the tongue blade test. Rest a tongue blade on the bottom teeth on either side. Instruct the patient to bite

Claire O’Connell, MPH, PA-C,

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

Sherril Sego, FNP-C, DNP,

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

Julee B.Waldrop, DNP,

is associate professor at the University of Central Florida (UCF), and practices pediatrics at the UCF Health Center.

www.ClinicalAdvisor.com • the clinical advisor • may 2013 57

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Advisor Forum down. If there is malocclusion of the bite (a common cause of TMJ), the patient will not be able to hold both blades in place.—KRISTEN JOHNSON, NP, Savannah, Ga. (175-5)

Magic hands to soothe a restless child To complete a thorough abdominal assessment on a squirmy toddler, tell the child you are going to use your hands to guess what he or she has had to eat. I can generally palpate for as long as I need by reporting what I am feeling (e.g., bananas, spaghetti, Cheerios, etc.).—JEAN GALE, NP, South Beloit, Ill. (175-6) use a laser to get patients walking A laser pointer can be used to get patients with Parkinson disease or dementia to ambulate. Such patients will often follow the red beam of light as it moves across the floor.— BELINDA KINCAID, FNP, Corfu, N.Y. (175-7)

“She thinks it’s a touchscreen.”

Screen for gun ownership The tragedy at Sandy Hook Elementary School in Newtown, Conn., demonstrates the need to address gun issues in the health-care setting. I ask the following questions in every mental-status exam: (1) Are you suicidal? (2) Are you homicidal? (3) Do you have a gun in the house? The answers inform further evaluation and treatment and provide an opportunity to discuss risks to the gun owner, family, and community. Such discussion is even more relevant when children—especially teens—are in the home and the patient is depressed.—PAT HURTZELER, APRN-BC, Haverhill, Mass. (175-8) The following comment was written in response to our monthly dermatology quiz, Derm Dx. To view our archive of similar cases, visit CliniAd.com/10KIbCF.

Derm Dx to the rescue While working in Haiti, I saw cases similar to your presentation of elephantiasis nostras verrucosa (“A woman with ‘mossy’ legs, available at CliniAd.com/SCwoHs). I suspected filarial (parasitic worms) etiology, but had no means of testing. Thank you for the explanation.—REX EVANS, PA-C, Dubois, Pa. (175-9) n

Your comments

58 the clinical advisor • may 2013 • www.ClinicalAdvisor.com

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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 CliniAd.com/ZqK3Cm. Learn more about diagnosing and treating these conditions, and see how you compare with your fellow colleagues.

A red, rapidly growing bump on the tongue An otherwise healthy woman presents with a rapidly growing tongue lesion that started as a red bump months earlier. The lesion is asymptomatic with the exception of occasional minor bleeding. What is your diagnosis?

• Pyoderma gangrenosum • Granuloma annulare • Pyostomatitis vegetans • Pyogenic granuloma

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A painful sore on the inner lip A healthy Asian man complains of painful sores in his mouth that appear every few months. Each eruption produces approximately two to five lesions and lasts about 10 days. What is your diagnosis?

• Primary herpetic gingivostomatitis • Recurrent aphthous stomatitis • Recurrent intraoral herpes simplex infection • Eosinophilic ulcer of the oral mucosa ● See the full case at CliniAd.com/13bNYri

Have you missed any recent Derm Dx cases? Go to CliniAd.com/ZqK3Cm for a complete archive of past quizzes as well as additional images of last month’s other cases.

Pink flat papules on the face

Progressive nose enlargement

60 the clinical advisor • may 2013 • www.ClinicalAdvisor.com

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LEGAL ADVISOR CASE

Teen suicide prompts an investigation

By Ann W. Latner, JD

Ms. F was a nurse practitioner working in a clinic that had a steady stream of patients. Ms. F, as well as the other NPs working at the clinic, had broad authority to examine and treat patients. One day, Ms. C, aged 15 years, arrived at the clinic with her father. She had been seen two days earlier in the emergency department (ED) of the local hospital with complaints of nausea, abdominal pain, and vomiting. The clinician in the ED attributed her condition to a virus and advised the young patient to follow up with her family physician if she did not improve in a few days. Ms. C did not have a family physician, so her father took her to Ms. F’s clinic when the teenager was still nauseated after 48 hours. Ms. F examined the patient while the father waited in the reception area. Ms. C’s vital signs were normal, but the patient appeared fatigued and drained. She complained of nausea and reported that she felt “down.” Ms. F watched the clock carefully. Her superiors frowned on appointments that lasted longer than 15 or 20 minutes, and she had violated this policy on more than one occasion.

A clinician prescribes an antidepressant to a young woman without immediate follow-up.

A friend told the patient’s parents about a story saying antidepressants were known to cause teenagers to think about suicide.

“Explain what you mean when you say you are feeling down?” Ms. F asked the girl. “You know, tired. Just sort of sad for no good reason,” responded Ms. C. “How are you sleeping?” “It seems like I either sleep too much, or I can’t sleep at all,” answered the patient. Ms. F spent a few more minutes questioning Ms. C, and then remembered the packed waiting room and knew she had to wrap up the exam. “I’m giving you two prescriptions,” said Ms. F. “One is for an antinausea drug to help with the queasiness, and the other is an antidepressant to help with feeling down. Come back in four weeks so we can see how you’re doing.” Ms. F wrote prescriptions for the antinausea medication and for fluoxetine (Prozac, Rapiflux, Sarafem, Selfemra) on a pad that had been pre-signed by the supervising physician, and handed them to the 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.

64 the clinical advisor • may 2013 • www.ClinicalAdvisor.com

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LEGAL ADVISOR patient. “I’ll see you in one month,” she told her, and the girl and her father left. Ms. F noted in the patient’s file which drugs had been prescribed and that the fluoxetine was for depression. Ms. C scheduled an appointment for four weeks later, but never showed up. Three weeks after her appointment with Ms. F, Ms. C attempted to hang herself. She was discovered by her mother and was rushed to the hospital, but she had already suffered catastrophic brain injury and would now require permanent around-the-clock care. Ms. F was shocked and troubled when she heard the news, but as time passed she began to forget about Ms. C, whom she had only seen once. Ms. C’s parents were heartbroken and distraught, but eventually their sorrow turned to anger. A friend mentioned to them that he had heard on the news that antidepressants were known to cause suicidal thoughts in teenagers. The girls parents decided to contact a plaintiff’s attorney and see whether they might have a case. The attorney studied the medical records and then asked the father whether Ms. F had spoken to him about prescribing an antidepressant for his daughter. “No,” replied the father, “but I knew she was taking it because I filled the prescription for her.” “But the clinician never told you to watch your daughter for signs of worsening depression?” “No.” The attorney accepted the case and filed a malpractice lawsuit against Ms. F, her supervising physician, and the clinic. Ms. F quickly scheduled a meeting with her defense attorney. The attorney looked at the records and asked Ms. F why she had prescribed the fluoxetine. Ms. F explained that the girl was exhibiting signs of clinical depression, which she’d noted in the file, and she thought it was the proper treatment. The case moved toward trial. Depositions were taken, records were produced, and experts were hired. In the meantime, Ms. C passed away from her injuries (two years after the suicide attempt). More than ever, her parents were anxious for what they considered to be justice. At trial, the parents tearfully testified about their love for their daughter and the impact her loss had on the family. The jury was obviously moved by their testimony. Experts testified that fluoxetine was known to cause suicidal ideation in children and adolescents, which is why the FDA had mandated a black-box warning on the packaging. The defense argued that the medication was legitimately prescribed for clinical depression, as Ms. F had noted in the patient’s file. Using information gained during depositions, the defense contended that Ms. C’s attempted suicide was caused by

an argument with her father and a breakup with her boyfriend, not by the medication prescribed by Ms. F. After deliberating for several hours, the jury found Ms. F, the physician, and the clinic liable, and awarded more than $3 million in damages to the family. Legal background

A jury is made up of ordinary people, and sympathy for the plaintiff can sway jurors, even if it should not. In this case, the jurors heard about a suicide attempt by a teenage girl. They saw the impact this had on the family and heard testimony that the medication prescribed by Ms. F was known to be dangerous for a small subset of patients (a group that included Ms. C). The defense’s tactic of trying to blame the suicide attempt on an argument with the father or a breakup with a boyfriend actually might have worked against Ms. F by making her appear unsympathetic. While it is reasonable to expect and hope that jurors can be unbiased, the fact is that they may be moved by the tragedy of the situation. Protecting yourself

Ms. F probably should not have prescribed fluoxetine to Ms. C. She had no history with the patient and could only make an assessment based on a 15- or 20-minute appointment. The medication does have significant warnings regarding its use in children and young adults, yet Ms. F never spoke to the patient’s father to make sure he was aware of a possible worsening of the condition. Most teenagers feel depressed at one point or another, but these feelings often resolve in time. Ms. C had not gone to the clinic for depression; she had been seeking treatment for a stomach virus. Even if Ms. F believed the teen was depressed, a far safer course of action would have been to have her return to the clinic in two weeks and reassess her for depression at that time. If Ms. F suspected clinical depression, she should have referred the teenager to a psychiatric professional rather than try to make such a quick assessment after having just met the patient. Even if Ms. C did suffer from depression, it is not clear that medication was the proper treatment. Ms. F could have suggested counseling or a combination of medication and counseling. Prescribing a medication that is known to cause suicidal thoughts in some young people—without further dialogue with a parent and without a referral to a mental-health professional—was a tragic error in judgment. n Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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CME CE

Dermatology Clinic n Learning objectives: To identify and diagnose dermatologic conditions and review up-to-date treatment. n complete the posttest: Page 49

n additional CME/CE: Pages 50, 85

Turn to page 90 for additional information on this month’s CME/CE courses.

CASE #1

Purple trunk plaques on a homosexual man Navid Malakouti and Julia R. Nunley, MD

A white man, aged 35 years, was referred to dermatology for treatment of a rash of several weeks’ duration. The man initially noted dark spots on his torso that subsequently developed into firm bumps. His medical history was negative, and he was taking no medications; social history revealed a homosexual lifestyle with no illegal drug use. Physical examination revealed numerous elliptical-to-round, violaceous, and indurated papules and plaques of various sizes. Laboratory testing showed the presence of the HIV virus with a CD4+ T-lymphocyte count of 200 cells/µL. A punch biopsy was performed. What is your diagnosis? Turn to page 68

CASE #2

Blue discoloration on both arms and legs Audrey Chan, MD

A white man, aged 67 years, sought treatment for the insidious onset of discoloration of his arms and legs. The patient reported that these areas were asymptomatic with no preceding history of rash. Medical history was notable for rheumatoid arthritis, hypertension, and hyperlipidemia. The man’s current medications included minocycline, metoprolol (Lopressor, Toprol), simvastatin (Zocor), and aspirin. No history of cancer, mycobacterial infections, arrhythmias, or use of alternative medicines or bleaching agents was reported. Physical exam was notable for blue-black macules coalescing into patches on bilateral dorsal forehands and forearms and pretibial legs. What is your diagnosis? Turn to page 69 www.ClinicalAdvisor.com • the clinical advisor • may 2013 67

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CME CE

CASE #1

Dermatology Clinic

Kaposi sarcoma

The punch biopsy revealed a spindle-cell tumor that was comprised of proliferated, dilated blood vessels and vascular slits blended with erythrocytes and a mixed inf lam mator y inf iltrate. These findings are characteristic of a vascular neoplasm called Kaposi sarcoma (KS), an AIDS-defining illness in an HIV-positive individual. AIDS-related KS was highly prevalent in the 1990s; however, the introduction and widespread use of highly active antiretroviral therapy (HAART) in the United States allowed stabilization of the immune system in many HIVinfected individuals and dramatically reduced the incidence of KS. Nevertheless, KS remains a common malignancy in AIDS patients, second only to non-Hodgkin lymphoma.1 First described in 1872 by Hungarian dermatologist Moritz Kaposi,2 KS is now known to be caused by an infectious organism, human herpesvirus 8, also referred to as Kaposi sarcoma-associated herpesvirus (HHV-8/KSHV).3 Although KS is indelibly linked with HIV and AIDS in the Western world, three of its four variants are not HIV-related: Classic KS, as described by Moritz, affects mainly elderly men of eastern European and Mediterranean descent; endemic KS (also referred to as African KS) occurs most commonly in children in sub-Saharan Africa; immunosuppressed KS develops in patients on immunosuppressive therapy following a solid-organ transplant; and epidemic KS (also referred to as AIDS-related KS), first reported in 1981, is most common in HIV-positive homosexual men.4 Present in blood, saliva, and other bodily fluids, the precise mode of transmission for KSHV remains obscure. However, epidemic KS is most prevalent in those who acquire the HIV virus through homosexual contact.4,5 Cutaneous lesions occur in virtually all individuals who have KS, but the presentation and course can be highly variable. In some individuals, the skin lesions will spontaneously remit, whereas the disease will take a more aggressive course in other patients, in part related to the individual’s immune system. Systemi involvement occurs in approximately 50% of affected patients, some of whom develop widespread disease affecting the hematopoietic and lymphatic systems, visceral internal organs, mucosal surfaces, and subcutaneous tissues.6,7

Lesions assocated with AIDS-related KS can occur anywhere but are more common on the head and neck, upper torso, and extremities. Lesions are typically asymptomatic and pigmented with a wide variety of colors, ranging from pink to purple or brown to black. Lesions may be innumerable or single, discrete or confluent, flat or elevated, plaque-like or nodular. They can vary greatly in size from 1 mm to 2 mm to several centimeters in diameter.7 Mucosal surfaces are frequently affected. The differential diagnosis for lesions of KS includes bacillary angiomatosis (BA), angiosarcoma, hemangioma, and lichen planus (LP); of these, BA and LP can also be associated with HIV. A biopsy readily differentiates between these conditions. Of the 50% of patients with KS who develop internal organ involvement, the GI tract is the most common site afflicted. Although frequently asymptomatic and detected solely by examination of the oral cavity, these patients may develop diarrhea, with or without blood, or abdominal pain.7 Pulmonary involvement is the next most prevalent site of organ involvement and may be life-threatening. Patients may note shortness of breath, cough, hemoptysis, and chest pain.7,8 Other organs may be similarly affected, and autopsy studies have revealed KS to develop in nearly every organ system. Staging of KS is based on a tumor, immunologic status, and systemic illness system. Earlier stages have a better prognosis, with skin-limited disease having a better prognosis than systemic disease. GI and pulmonary involvement adversely affect morbidity and mortality. Other poor prognostic factors include the presence of an opportunistic infection, thrush, and the constitutional symptoms of fever, night sweats, and weight loss.9 Data suggest that aggressive treatment with HAART, even in patients with lung disease, may be associated with a more favorable prognosis.10 As an AIDS-defining illness, KS is an indication to initiate therapy in an otherwise asymptomatic HIV-positive patient.7 HAART is considered first-line therapy to treat AIDS-related KS and may result in a 20% to 80% remission rate if an adequate immune status can be re-established. A paradoxical flare of KS can occur with the initiation of HAART. This flare is called the “immune reconstitution syndrome” and is a result of a rising CD4+ count with reactivation of the immune system and associated inflammatory response. Other treatment approaches are only palliative in nature and include various regimens for localized disease and systemic cytotoxic drugs. Local therapy options include radiation, cryosurgery, laser surgery, excisional surgery, electrocauterization, topical

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alitretinoin, and intralesional injection of various chemotherapeutic agents. Of the listed ablative modes, radiation is the most effective and most widely used; electron-beam radiation may even be effective for widespread cutaneous disease. Topical alitretinoin may reduce tumor size in up to 50% of patients. Intralesional injections of vinca alkaloids (vinblastine, vincristine) may also minimize tumors, but significant localized adverse effects, including ulceration and pain, are common. Unfortunately, all local treatment options are inconsequential for systemic disease. Various systemic cytotoxic drugs can induce rapid tumor regression but are typically reserved for extensive or lifethreatening KS.11 Unfortunately, these agents carry significant side effects, including neuropathy, pulmonary fibrosis, depression, cardiotoxicity, and bone-marrow suppression, which may be unacceptable for some patients due to HIV status, age, immunosuppression, or other comorbidities. Systemic agents include bleomycin, etoposide, paclitaxel, pegylated liposomal doxorubicin, pegylated interferon, the vinca alkaloids, and anthracyclines (doxorubicin and daunorubicin).7,11,12 Studies have shown a synergistic effect with adding zidovudine when treating epidemic KS with interferon.1 In this case, a treatment-naïve HIV patient with a low CD 4+ count, HAART was indicated. In addition to tripledrug HAART, short-term prophylactic trimethoprim/ sulfamethoxazole was initiated to combat opportunistic infections during the immune reconstitution phase. Several months into therapy, the cutaneous lesions slowly involuted, and the man’s CD4+ count rose to 500 cells/µL, with an undetectable HIV viral load. Mr. Malakouti is a third-year medical student at Medical College of Virginia Hospitals, Virginia Commonwealth University, in Richmond, where Dr. Nunley is professor of dermatology. References 1. Aversa SM, Cattelan AM, Salvagno L, et al. Treatments of AIDS-related Kaposi’s sarcoma. Crit Rev Oncol Hematol. 2005;53:253-265. 2. Kaposi M. Idiopatisches multiples Pigmentsarkom der Haut. Arch Dermatol Syphilis. 1872;4:265-73. 3. Nawar E, Mbulaiteye SM, Gallant JE, et al. Risk factors for Kaposi’s sarcoma among HHV-8 seropositive homosexual men with AIDS. Int J Cancer. 2005;115:296-300. 4. Friedman-Kien AE, Laubenstein LJ, Rubinstein P, et al. Disseminated Kaposi’s sarcoma in homosexual men. Ann Intern Med. 1982;96:693-700. 5. Biggar RJ, Rabkin CS. The epidemiology of AIDS-related neoplasms. Hematol Oncol Clin North Am. 1996;10:997-1010.

6. Sanders CJ, Canninga-van Dijk MR, Borleffs JC. Kaposi’s sarcoma. Lancet. 2004;364:1549-1552. 7. Levine AM, Tulpule A. Clinical aspects and management of AIDS-related Kaposi’s sarcoma. Eur J Cancer. 2001;37:1288-1295. 8. Aboulafia DM. The epidemiologic, pathologic, and clinical features of AIDS-associated pulmonary Kaposi’s sarcoma. Chest. 2000;117:1128-1145. 9. Krown SE, Testa MA, Huang J. AIDS-related Kaposi’s sarcoma: prospective validation of the AIDS Clinical Trials Group staging classification. AIDS Clinical Trials Group Oncology Committee. J Clin Oncol. 1997;15:3085-3092. 10. Holkova B, Takeshita K, Cheng DM, et al. Effect of highly active antiretroviral therapy on survival in patients with AIDS-associated pulmonary Kaposi’s sarcoma treated with chemotherapy. J Clin Oncol. 2001;19:3848-3851. 11. Di Lorenzo G, Konstantinopoulos PA, Pantanowitz L, et al. Management of AIDS-related Kaposi’s sarcoma. Lancet Oncol. 2007;8:167-176. 12. Sgadari C, Bacigalupo I, Barillari G, Ensoli B. Pharmacological management of Kaposi’s sarcoma. Expert Opin Pharmacother. 2011;12:1669-1690.

CASE #2

Minocycline-induced hyperpigmentation

Minocycline is a tetracyclinederivative antibiotic that is widely used for its antimicrobial and anti-inflammatory properties. The use of minocycline for infections is usually for short courses, with the exception of mycobacterial infections, which typically require several months of treatment. Long-term therapy with minocycline is generally used for such inflammatory conditions as acne, rosacea, and rarely, rheumatoid arthritis (RA). The three types of minocycline-induced pigmentation are characterized as follows: type I features blue-black pigmentation in sites of scars, most commonly on the face; type II has blue-gray pigmentation on previously normal skin, most commonly on the anterior legs; and type III is diffuse brown pigmentation on sun-exposed sites.1 The symptoms in the patient in this case were most consistent with the type II reaction. Minocycline causes cutaneous hyperpigmentation because it is highly lipid-soluble, allowing the medication to become concentrated in the patient’s skin, mucous membranes, bones, teeth, nails, and internal organs.1 On oxidation,

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CME CE

Dermatology Clinic

minocycline pigment turns black.1 Although minocyclineinduced hyperpigmentation typically develops at a cumulative dose of >50 g, type I can occur regardless of dose or duration of treatment.2 The incidence of minocyclineinduced hyperpigmentation varies with disease, as it develops in 14% of patients treated for facial dermatoses and in 41% of patients treated for RA.3,4 It is likely that this difference in incidence reflects higher doses and longer durations of minocycline regimens used for rheumatologic conditions. The three types of minocycline-induced hyperpigmentation have distinct histologic findings explaining the variable clinical appearance. Type I demonstrates intra-and extracellular iron-containing pigment in the dermis. Type II reveals deeper melanin- and iron-containing pigment granules in the dermis and subcutis. Type III is notable for superficial melanin deposition in the basal layer of the epidermis and in dermal macrophages (melanophages). Diagnosis is aided by the use of Prussian blue histopathology stain, which

Chloroquine, hydroxychloroquine, and quinacrine are common causes of drug-induced hyperpigmentation. stains iron pigment in hemosiderin, and Fontana-Masson, which stains melanin.1 The differential diagnosis includes other medicationinduced causes of hyperpigmentation. Diagnosis based on physical examination alone can be difficult, as the differences in color pigmentation from these medications are subtle. There are, however, some helpful clinical clues. In a patient with a history of cancer, a careful review of chemotherapies should be conducted. Bleomycin has a unique pattern of flagellate hyperpigmentation, with linear bands on the chest and back likely correlating with where the patient scratches. This pattern is not specific for bleomycin, as it may also be seen with ingestion of shiitake mushrooms and with dermatomyositis. Topical fluorouracil (Cara, Efudex, Fluoroplex) is also a common cause of hyperpigmentation in sun-exposed skin, as seen in type III minocycline-induced hyperpigmentation. However, fluorouracil can also cause a unique pattern of hyperpigmentation overlying veins. Other chemotherapy-induced causes of hyperpigmentation in sun-exposed sites include daunorubicin (Cerubidine) and methotrexate (Rheumatrex, Trexall). Generalized

hyperpigmentation can be seen with busulfan (Myleran), cyclophosphamide (Cytoxan), dactinomycin (Cosmegen), and mechlorethamine (Mustargen). The use of antimalarial drugs—namely chloroquine (Aralen), hydroxychloroquine (Plaquenil), and quinacrine (Atabrine) —is another common cause of drug-induced hyperpigmentation. Aside from the prevention and treatment of malaria, antimalarials are commonly used in rheumatology and dermatology practices for the treatment of connectivetissue diseases, including systemic and cutaneous lupus erythematosus and dermatomyositis. Hydroxychloroquine and chloroquine classically present with blue-black to ecchymoses-like pigmentation on the pretibial legs. This can be difficult to distinguish clinically from type II minocycline-induced hyperpigmentation; histologically, hydroxychloroquine-induced pigmentation will not stain for Prussian blue as it would with minocycline. Quinacrine causes a readily distinguishable yellow-brown color. Hyperpigmentation with heavy metals is now rare, as the use of gold and silver has fallen out of favor in mainstream medical practice. However, use of heavy metals may still be found in alternative medicine, so patients should be questioned regarding alternative or nontraditional medicines. Gold-induced hyperpigmentation (chrysiasis) is notable for blue-gray pigmentation in sun-exposed sites, especially the periorbital areas. Argyria is caused by silver deposition and has a unique slate-gray color. Because silver is excreted in sweat, the histology uniquely demonstrates silver granules in the membrana propria of eccrine glands in addition to the basement membrane. In a patient with a history of cardiac arrhthymias, the use of amiodarone (Cordarone, Pacerone) should be ruled out. Amiodarone-induced hyperpigmentation is characterized by slate-gray to violaceous discoloration in sun-exposed areas, most commonly the face. Although type I minocycline-induced hyperpigmentation also has a predilection for the face, it is only seen in scar tissue or in areas of prior inf lammation. Histology demonstrates yellow-brown granules that do not stain with Prussian blue or FontanaMasson, which helps distinguish from minocycline-induced hyperpigmentation. HIV-positive patients on zidovudine (Retrovir) may develop hyperpigmentation of the skin, especially in sunexposed areas and in areas of friction. This medication is also known to cause longitudinal, horizontal, or diffuse discoloration of the nails. Used to treat leprosy, rhinoscleroma, and rarely other inflammatory dermatoses, clofazimine (Lamprene) may

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cause a reddish discoloration of skin and conjunctivae that is easily distinguished from minocycline-induced-hyperpigmentation. Clofazimine may cause a second pattern of hyperpigmentation with violet-brown pigmentation in sites of inflammation that may be confused with minocyclineinduced hyperpigmentation; however, the histology of these two entities is distinct. Hydroquinone is a topical bleaching agent that may paradoxically cause blue-black pigmentation at the application site, most commonly the face. This reaction is known as exogenous ochronosis. Hydroquinone is a phenol available in a number of prescription and OTC products, so patients may be unaware that they are using this medication. Exogenous ochronosis typically develops when hydroquinone is used for longer than six months.5 The relative risk of exogenous ochronosis based on concentration of hydroquinone is unknown, but can occur at concentrations as low as 1% to 2%.6 Once the diagnosis of minocycline-induced hyperpigmentation has been made by history, physical exam, and/ or histology, minocycline must be discontinued. For most patients, the hyperpigmentation is reversible, but this process takes months to years. Laser therapy may be helpful in cases of persistent hyperpigmentation.1 Such bleaching agents as hydroquinone are ineffective. In this case, the patient’s minocycline was discontinued, but he was not concerned with the discoloration and chose not to undergo laser therapy. n

Dr. Chan is a second-year resident in the Department of Dematology at Baylor College of Medicine in Houston. References 1. Bolognia JL, Jorizzo JL, Rapini RP eds. Dermatology. 2nd ed. St. Louis, Mo.: Elsevier-Mosby; 2008:943-946. 2. Wilde JL, English JC 3rd, Finley EM. Minocycline-induced hyperpigmentation. Treatment with the neodymium:YAG laser. Arch Dermatol. 1997;133:1344-1346. 3. Dwyer CM, Cuddihy AM, Kerr RE, et al. Skin pigmentation due to minocycline treatment of facial dermatoses. Br J Dermatol. 1993;129: 158-162. 4. Roberts G, Capell HA. The frequency and distribution of minoc ycline induced hyperpigmentation in a rheumatoid arthritis population. J Rheumatol. 2006;33:1254-1257. 5. Merola JF, Meehan S, Walters RF, Brown L. Exogenous ochronosis. Dermatol Online J. 2008;14:6. 6. Levitt J. The safety of hydroquinone: a dermatologist’s response to the 2006 Federal Register. J Am Acad Dermatol. 2007;57:854-872.

“It keeps me from looking at my phone every two seconds.”

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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.

Red palm oil

Red palm oil, or Elaeis guineensis, is far from a new discovery in alternative therapy. This ancient botanical, generally agreed to have existed since the earth’s inception, began as a consumer product in West Africa. Although red palm oil sounds like a luxurious suntan lotion, its utility is far more important. Red palm oil, so named for its deep red-orange hue, is high in beta-carotene. It is rich in other antioxidants as well, especially those that assist in healthy metabolism of serum lipids. Carotenoids, phytosterols, vitamin E, and vitamin A are particularly abundant in red palm oil.1

Background Elaeis guineenis, or the oil palm tree, has been cultivated in more than 20 countries, all of them tropical with warm, moist environments.1 Statistics on worldwide production of vegetable oils for human consumption show palm oil recently surpassed soybean oil as the most widely produced.2 Although there has been some concern regarding the saturated fat content of red palm oil, multiple clinical trials have failed to support that concern. There appears to be a near balance of saturated fatty acids to unsaturated, and an equally high level of potent antioxidants.3 In combination, these are credited with numerous health benefits for patients who use this nutrient.

Science Any discussion of a consumable fat-based product prompts consideration of atherogenic risk. Consequently, given the

fatty-acid content of red palm oil, further attention needs to be paid to this possible complication. Biochemical studies of the specific compounds found in red palm oil highlight the abundance of antioxidants known as carotenoids and vitamin E (both tocopherol and tocotrienoid).4 Laboratory research has shown that daily intake of a tocopherol- and tocotrienolenriched palm oil not only promotes a reduction in LDL, but also regulates the expression of thromboxane, platelet aggregatory chemicals, and glucose in the human system.4 In another study, hypertensive rats showed significant reductions in both systolic and diastolic BP readings while being fed a red palm oil supplement.5 This was attributed to the oleic fatty acid in the oil, which promotes vasodilatation and restricts vasoconstriction. Among the predominant antioxidants found in red palm oil, tocotrienol is one of eight naturally occurring isomers in the vitamin E family. This lipid-soluble vitamin possesses other unique protective actions in brain tissue. Brain tissue membranes are particularly rich in polyunsaturated

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alternative meds update fatty acids (PUFAs). Tocotrienol penetrates and stabilizes these PUFA membranes, theoretically preventing the advance of disease. Researchers have theorized that a number of neurodegenerative conditions in the human brain are associated with disturbed PUFA metabolism of tocotrienol.6 One of the most intensely studied benefits of red palm oil is protection against cancer. Cancer cells have the ability to grow uninhibited, live longer than normal cells, and resist outside attack. The tocotrienol in red palm oil has been shown not only to protect normal cells from the signals that disrupt routine metabolism and growth, but actually to sabotage the cancer cell so as to promote early cell death.7 In addition, red palm oil is possibly the world’s most widely available source of vitamin A. The World Health Organization estimates that more than 190 million school-aged children and 19 million pregnant women suffer from vitamin A deficiencies in the underdeveloped nations of Africa and southeast Asia. Red palm oil is considered the richest, most readily available source of provitamin A, yielding 15 times more beta-carotene than carrots.8 Red palm oil beta-carotene is also more bioavailable, as it is already in oil form, thus the red palm oil readily penetrates lipophilic membranes.

oil, it can be purchased in capsule form for approximately $12 for a one-month supply.

Summary When used as a part of one’s daily fat intake, red palm oil is proven to help prevent various illnesses. Combined with its availability, ease of use, and antioxidant concentration, it is a definite asset in the world of health foods and supplements. n References Red palm oil is thought to have an impact in reducing hypertension.

Red palm oil is considered the richest, most readily available source of provitamin A, yielding 15 times more beta-carotene than carrots.

Safety, interactions

1. Obahiagbon, FI. A review: Aspects of the african oil palm (Elaeis guineensis jacq.) and the implications of its bioactives in human health. Am J Biochem Mol Biol. 2012;3:106-119. 2. Mukherjee S, Mitra A. Health effects of palm oil. J Hum Ecol. 2009;26:197-203. 3. Oguntibeju O, Esterhuyse A, Truter E. Red palm oil: Nutritional, physiological and therapeutic roles in improving human wellbeing and quality of life. Br J Biomed Sci. 2009;66:216-222. 4. Song BL, DeBose-Boyd RA. Insig-dependent ubiquitination and degradation of 3-hydroxy-3-methylglutaryl coenzyme A reductase stimulated by delta-and gamma-tocotrienols. J Biol Chem. 2006;281:25054-25061. Available at www.jbc.org/content/281/35/25054.long. 5. Boon CM, Ng MH, Choo YM, Mok SL. Super, red palm, and palm oleins improve the blood pressure, heart size, aortic media thickness and lipid profile in spontaneously hypertensive rats. PLOS One. 2013;8:e55908. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3569425/. 6. Sen CK, Rink C, Khanna S. Palm oil-derived natural

Dose, how supplied, cost

vitamin E alpha-tocotrienol in brain health and disease. J Am Coll Nutr. 2010;29:314S-323S. Available at www.ncbi .nlm.nih.gov/pmc/articles/pmid/20823491/. 7. Shah SJ, Sylvester PW. Tocotrienol-induced cytotoxicity is unrelated to mitochondrial stress apoptotic signaling in neoplastic mammary epithelial cells. Biochem Cell Biol. 2005;83:86-95. 8. Rice AL, Burns JB. Moving from efficacy to effectiveness: Red palm oil’s role in preventing vitamin A deficiency. J Am Coll Nutr. 2010;29:302S-313S. Available at www.jacn .org/content/29/3_Supplement_1/302S.long. 9. Edem DO. Palm oil: Biochemical, physiological, nutritional, hematological and toxicological aspects: A review.

To determine appropriate dosage, consideration of the patient’s other medications is warranted. In addition to red palm oil’s availability as cooking

Plant Foods Hum Nutr. 2002;57:319-341. All electronic documents accessed April 15, 2013.

Red palm oil is generally safe for consumption. There is some concern over the damage that may occur if the oil is consumed in an oxidized state.9 Its health benefits come from the antioxidants, which can be destroyed if the oil is poorly or improperly processed. Allergic reactions are always a possibility, but there is rare mention of this in the literature. Highly antioxidant supplements also potentiate the anticoagulant effect of warfarin so caution is urged in concomitant use.

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Acetaminophen or Ibuprofen?

You Decide. We Provide Both—and more.

Use only as directed.

For samples, dosing sheets, and more, go to TylenolProfessional.com

“Two steaks, cruelly raisd and brutally slaughtered. Enjoy!” www.ClinicalAdvisor.com • the clinical advisor • may 2013 77

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Stat Consult

A quick review of common conditions, using the best global evidence

Description

Transient ischemic attack

• According to the American Heart Association/ American Stroke Association 2009 guidelines, the definition of transient ischemic attack (TIA) is a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction on neuroimaging. Also called

By Alan Drabkin, MD

Dr. Drabkin is a clinical editor for DynaMed (www.ebscohost.com/ dynamed), a database of comprehensive updated summaries covering more than 3,200 clinical topics, and Assistant Clinical Professor of Population Medicine at Harvard Medical School.

• Acute neurovascular syndrome ICD-9 codes

• 435 transient cerebral ischemia ——435.0 basilar artery syndrome ——435.1 vertebral artery syndrome ——435.2 subclavian steal syndrome ——435.3 vertebrobasilar artery syndrome ——435.8 other specified transient cerebral ischemias ——435.9 unspecif ied transient cerebral ischemia • 436 acute, but ill-defined, cerebrovascular disease • V12.54 personal history of TIA and cerebral infarction without residual deficits

Incidence/Prevalence

• Prevalence of TIA in older Americans (Cardiovascular Health Study) ——Men aged 65-69 years—2.7% ——Men aged 75-79 years—3.6% ——Women aged 70-74 years—1.6% ——Women aged 75-79 years—4.1% Causes

Micrograph shows that blood vessel calcification has reduced the lumen (black) by 75%.

• Cardiogenic emboli • Carotid or vertebral artery disease • Hematologic disorders Risk factors

• Metabolic conditions • Modifiable lifestyle factors ——Dietary factors ——Poor physical function

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Stat Consult ——Smoking ——Heavy alcohol use ——Substance abuse • Lower income • Genetic • Biomarkers ——High cholesterol ——High C-reactive protein ——Proteinuria ——Hypokalemia ——Hyperuricemia • Cardiovascular conditions ——History of TIA ——Hypertension ——MI ——Atrial fibrillation ——Left atrial enlargement • Carotid stenosis • Hormone replacement therapy • Oral contraceptives Associated conditions

• 3% to 10% risk of stroke in first 48 hours • Increased long-term risk for MI and vascular death Chief concern

General physical

• BP in each arm • Pulse rate and rhythm • Carotid and supraclavicular bruits • Emboli on fundoscopic exam • Arrhythmia (such as atrial fibrillation) and murmurs • Evidence of focal neurologic deficits that should resolve Making the diagnosis

• Transient episode of neurologic dysfunction • Absence of acute infarction found on neuroimaging, preferably MRI • Return to baseline neurologic status Rule out

• Stroke and/or focal seizure • Complex migraine or migraine equivalents • Metabolic abnormalities • Multiple sclerosis • Myasthenia gravis • Periodic paralysis • Thoracic outlet syndrome • Subdural hematoma • Transient global amnesia • Acute radial nerve palsy • Isolated third-nerve palsy

• Focal transient neurologic deficit Testing to consider History

• Most TIAs are brief ——<1 hour in 60% ——<2 hours in 71% ——>6 hours in 14% • Duration of symptoms lasting ≤24 hours does not accurately identify which patients will have infarction and not TIA. Medications

• Interruption of aspirin therapy may be associated with increased risk of ischemic stroke or TIA • Hormone or oral contraceptive use Ask about history of

• Recent head or neck trauma • Thrombotic disorders • Miscarriages • Migraine • Cocaine abuse

• Complete blood count • Chemistry panel • Coagulation tests ——Prothrombin time/partial thromboplastin ——Consider specialized coagulation studies in younger patients with TIA, especially if no vascular risk factors or underlying identifiable cause • Fasting lipid panel • Neuroimaging within 24 hours of symptom onset ——MRI including diffusion-perfusion-weighted imaging preferred ——If MRI not available, computed tomography • Electrocardiogram • Echocardiography • Holter monitor or continuous telemetry • Evaluation of carotid arteries ——Ultrasound ——Computed tomographic angiography ——Magnetic resonance angiography ——Intracranial stenosis confirmed by catheter angiography

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nociceptive or neuropathic? knowing the differenceâ&#x20AC;&#x201D;makes a difference.

Register at www.painweek.org Global Education Group (Global) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education to physicians. Global Education Group designates this live activity for a minimum of 32.0 AMA PRA Category 1 Credit(s) TM. This activity will be approved for continuing pharmacy, psychology, nurse practitioner, nursing and dentistry education. Applications for certification of social work NASW and family physician AAFP hours will be applied for. For more information and complete CME/CE accreditation details, visit our website at www.painweek.org.

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PW13 CLINICAL ADVISOR 3.29.indd 3

3/29/13 12:14 PM

Stat Consult • ABCD2 score appears to be the most predictive for stroke risk after TIA. Treatment

• If the patient does not return to baseline, diagnosis may be stroke rather than TIA. • Inpatient vs. outpatient management ——Reasonable to hospitalize patients with TIA if ■■ Presenting within 72 hours of event and »»ABCD2 score ≥3 »»Unclear if outpatient workup can be completed within two days. ■■ Suspected focal ischemia ——If not admitting the patient to the hospital, same-day evaluation for TIA or minor stroke is associated with reduced risk of recurrent stroke at 90 days. • Medication ——Anticoagulation therapy ■■ Following noncardioembolic TIA-antiplatelet agents recommended over anticoagulation »»Options include -- Aspirin 50-325 mg/day -- Combination of aspirin 25 mg plus extendedrelease dipyridamole (Permole, Persantine) 200 mg b.i.d. -- Clopidogrel (Plavix) 75 mg once daily -- Cilostazol (Pletal) -- Triflusal ■■ Following cardioembolic TIA, anticoagulation preferred over antiplatelet therapy »»With atrial fibrillation, long-term oral anticoagulation with target international normalized ratio 2.5 (range 2-3) »»With contraindications to anticoagulant therapy, use aspirin 75-325 mg/day ——Statins ■■ Reduce subsequent cerebrovascular events in adults with history of stroke or TIA ■■ Intensive lipid-lowering recommended if LDL is ≥100 mg/dL. ■■ Reasonable targets are ≥50% reduction in LDL or LDL cholesterol <70 mg/dL. ■■ Insufficient evidence to evaluate efficacy and safety of statins within two weeks of acute ischemic stroke or TIA ——Perindopril (Aceon) plus indapamide (Lozol) may reduce risk of stroke in patients with stroke or TIA.

• Carotid endarterectomy ——Indicated in patients with recent TIA or ischemic stroke and ipsilateral severe (70%-99%) carotid stenosis if performed by a surgeon with perioperative morbidity and mortality <6% ——Benefits of surgery are lower with ipsilateral moderate (50%-69%) carotid stenosis. ——Carotid artery angioplasty and stenting is alternative to carotid endarterectomy. ——Addition of percutaneous transluminal angioplasty and stenting to aggressive medical management increases risk of stroke in patients with intracranial arterial stenosis. ——Insufficient evidence to recommend angioplasty in patients with intracranial artery stenosis Prevention

• Treatment of patients with atrial f ibrillation with anticoagulation • Long-term follow-up (risk-factor reduction) ——Optimization of ■■ Lipids ■■ BP »»Lifestyle modifications (including weight loss; diet high in fruits, vegetables, and low-fat dairy products; regular aerobic physical activity, limited alcohol consumption, salt restriction) are reasonable parts of comprehensive BP management. »» Optimal medication is unclear, but evidence suggests diuretics or combination of diuretics and angiotensin-converting enzyme inhibitor are useful. ■■ Weight ——Avoidance of tobacco use ——Avoidance of heavy alcohol use ——Maintenance of physical activity. n

“Trust me, at this point it’s the only way we can boost your numbers on likability.”

Prognosis

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CME CE

Dermatologic Look-Alikes n Learning objective: To distinguish and properly treat dermatologic conditions with similar presentations. n complete the posttest: Page 90

n additional CME/CE: Pages 50, 67

Turn to page 49 for additional information on this month’s CME/CE courses.

Skin-colored papules Kerri Robbins, MD

CASE #1

CASE #2

A man, aged 34 years, presented with an intermittently pruritic lesion on his left mid-back. The lesion had been present for years and was slowly enlarging. The patient desired an elective excision of the lesion to alleviate repeated irritation from clothing. Review of systems was otherwise negative. The man’s medical and family histories were unremarkable. On physical examination, a 7-mm rubbery, skin-colored papule was appreciated on the left mid-back. The remainder of the examination was within normal limits.

A woman, aged 33 years, presented with what she described as a mole that had been present for more than 10 years. She complained of repetitive trauma and bleeding to the lesion and desired elective excision. The lesion had not been changing in size and/or color, and there was no associated pruritus. Review of symptoms was otherwise negative. Medical and family histories were unremarkable. Physical examination revealed a 6-mm skin-colored to tan papule on the left lateral thigh. A similar lesion was noted on the trunk.

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CME CE

CASE #1

Dermatologic Look-Alikes

Neurofibroma

Neurof ibromas were f irst described as fibrous tumors. Verocay later suggested a neuroectodermal origin, which was ultimately confirmed by immunohistochemical and ultrastructural studies.1 In 1882, von Recklinghausen provided the medical community with the first in-depth clinical and pathologic description of the physically devastating condition of neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease. However, it was not until the mid-20th century that Crowe, Schull, and Neel compiled a comprehensive description of the manifestations of NF1 that is still in use today. The two main categories of neurofibromas are the solitary type and the plexiform type. Both types occur equally in males and females. Solitary cutaneous neurofibromas are relatively common and usually arise around puberty. However, multiple cutaneous neurofibromas, along with other characteristic stigmata to be discussed later, should alert the clinician to the diagnosis of neurofibromatosis. Plexiform-type neurofibromas are probably congenital in origin but do not become physically apparent until age 4 or 5 years. The presence of a plexiform neurofibroma almost always indicates that the patient has NF1. The exact pathogenesis of solitary neurofibromas is unclear. However, the basic process involves proliferation of the entire neuromesenchyme, which includes Schwann cells, perineural cells, endoneurial fibroblasts, mast cells, and cell types with intermediate features.2 The extent of proliferation of each cell line varies. Hence, the resulting histologic composition and architecture is variable. Neurofibromas are usually solitary; soft or rubbery; skin-colored to pink, tan, or brown papulonodules that range in size from 0.2 cm to 2 cm. The growths are most commonly seen on the head or trunk and may become pedunculated. Neurofibromas are usually slow-growing and asymptomatic, but some patients complain of pruritus. The “buttonhole sign” (i.e., effortless invagination of the tumor after gentle external pressure) is a characteristic feature. Plexiform neurofibromas are usually seen on the trunk and proximal extremities and present as tender, firm, dermal, or subcutaneous nodules or masses that may become baggy or pedunculated. Both hyperpigmentation

and hypertrichosis may overlie plexiform neurofibromas. Recognition of these lesions is important because they are considered pathognomonic for NF1, and approximately 3% to 15% may transform into malignant peripheral-nerve sheath tumors. The onset of rapid growth or pain in a previously stable plexiform neurofibroma may indicate malignant transformation. Cutaneous neurof ibromas are composed of a wellcircumscribed but unencapsulated dermal collection of small nerve fibers and haphazardly arranged slender spindle cells. The spindle cells represent a mixture of Schwann cells, perineural cells, and fibroblasts. The collagenous stroma has varying amounts of mucin and scattered mast cells. Mitotic figures are absent or rare. Plexiform neurofibromas are composed of large, irregularly expanded, twisted nerve fascicles composed of spindle-shaped fibroblasts and Schwann cells in a myxoid matrix. Solitary neurofibromas may be mistaken for intradermal nevi, compound nevi, soft fibromas, dermatofibromas, and neuromas. Plexiform neurofibromas with overlying hyperpigmentation and hypertrichosis may be mistaken for a congenital melanocytic nevus. Multiple neurofibromas or a single plexiform neurofibroma warrants further investigation because these may be a clinical manifestation of the systemic disorder NF1. The incidence of NFI is thought to be approximately 1 in 3,000. Although NF1 is an autosomal-dominant disorder, as many as 50% of NF1 patients harbor spontaneous mutations. The NF1 gene is located on chromosome 17q11.2, and mutations lead to inactivation of the GAP-related protein neurofibromin. One of the functions of neurofibromin is to negatively regulate the proto-oncogene, ras. The ras protein is a G-protein, which like all other G-proteins, requires GTP. GAPs, including neurofibromin, hydrolize GTP to GDP, thereby terminating the ras signal and halting cellcycle progression, survival, and cytoskeletal reorganization. Thus, neurofibromin has tumor-suppressor properties. To make the diagnosis of NF1, two or more of the following must be present: (1) six or more café-au-lait macules (>5 mm in prepubertal individuals and >15 mm in postpubetral individuals); (2) two or more neurofibromas of any type or one plexiform neurofibroma; (3) freckling in the axillary or inguinal regions (Crowe’s sign); (4) optic gliomas; (5) two or more Lisch nodules (iris hamartomas); (6) osseous lesions (sphenoid wing dysplasia or thinning of the long bone cortex); (7) a first-degree relative with NF1. Individuals with NF1 may also have neurologic or cardiovascular manifestations. Management of those who

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are found to have NF1 requires a multidisciplinary approach dictated by the patient’s specific NF1 concerns. Neurofibromatosis type 2 (NF2) is genetically distinct from NF1 and is characterized by café-au-lait macules, neurofibromas, schwannomas, and a variety of intracranial tumors, including bilateral schwannomas of the acoustic nerves. Patients should be reassured of the benign nature of solitary neurofibromas. If desired, simple excision is curative. Laser ablation has also been used to eradicate neurofibromas.3,4 Patients who have a plexiform neurofibroma should be periodically followed, and rapid growth or pain within the lesion should merit immediate evaluation to exclude malignant transformation. In this case, a punch excision was performed per the patient’s request. The remainder of the cutaneous examination did not reveal any characteristic stigmata suggestive of NF1.

CASE #2

Intradermal nevus

Intradermal, compound, and junctional nevi are classified as common acquired melanocytic nevi. They are also known by the terms “nevocellular nevi,” or more simply put, “moles.” Not much is known about the history of acquired melanocytic nevi. This is largely attributable to the fact that acquired melanocytic nevi are so common that they are considered a normal variant. Nevi are seen equally in both males and females. The prevalence is related to age, race and genetic and environmental factors. During early childhood, only a few nevi are present. With time, however, nevi slowly increase in number, rapidly develop at the onset of puberty, and then peak between ages 20 and 29 years. Following this peak, the nevi begin to disappear as the individual gets older. Genetic factors also play a role in the development of melanocytic nevi. Parents with increased numbers of nevi have been shown to have children with a similar affinity. Whites have a greater number of nevi than do to darker-skinned individuals. Nevi are also more prevalent in whites and fair-skinned individuals. However, such darker-skinned individuals as African-Americans and Asians have a higher

prevalence of melanocytic nevi on the palms, soles, nail bed, and conjunctivae than do whites. Some evidence also points to such environmental influences as UV exposure in the development of nevi.5 Individuals who live in warm and sunny climates tend to have more nevi than do individuals who live in more temperate climates. Melanocytic nevi originate from melanoblasts, which are cells that arise in the neural crest and migrate to the epidermis. The nevi are thought to represent hamartomas, or benign proliferations of melanocytes that possess some growth advantage over surrounding basilar melanocytes. These slightly altered nevus cells, or melanocytes, go on to produce a junctional nevus within the epidermis. It is hypothesized that these melanocytes subsequently migrate into the dermis, thereby producing a compound nevus.6 When the melanocytic cells are no longer seen in the epidermis, an intradermal nevus is formed. Common acquired melanocytic nevi are typically round or ovoid lesions that measure approximately 2 mm to 6 mm in diameter. Benign nevi tend to be symmetric with well-defined borders and regular color variation throughout. Clinically, junctional nevi are medium-to-dark-brown macules. Under the dermatoscope, one can appreciate that the pigment tends to fade toward the periphery. Compound nevi vary in elevation and tend to be lighter shades of brown. The most common dermatoscopic features are multiple round ovoid globules that resemble a cobblestone pattern. Intradermal nevi are usually more elevated and are either light tan or skin-colored. These lesions show focal globules and/or pale structureless areas and comma vessels under the dermatoscope. Common acquired melanocytic nevi contain nests of melanocytes in the epidermis ( junctional nevi), dermis (intradermal nevi), or both (compound nevi). In the superficial dermis, the cells generally have an epithelioid appearance and contain abundant cytoplasm. These melanocytes contain moderate amounts of melanin. As the cells mature and travel deeper into the dermis, they lose cytoplasm and the cells become smaller, resembling lymphocytes. These melanocytes rarely produce melanin. Junctional nevi must be distinguished from ephelides, simple lentigines, solar lentigines, café-au-lait macules, and macular seborrheic keratosis. Compound nevi may be differentiated from seborrheic keratoses by their lack of verrucous surface and pseudo-horn cysts. Dermatofibromas may also be mistaken for compound nevi. Neurofibromas and fibroepithelial polyps may be indistinguishable from skin-colored or slightly pigmented and/or pedunculated dermal nevi. Continues on page 88

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CME CE

Dermatologic Look-Alikes

Benign melanocytic nevi are distinguished from atypical nevi and melanoma by their overall symmetry, regular borders, homogenous color, smaller diameter, and stable clinical appearance. However, a significant proportion of patients with melanoma have reported the existence of a longstanding melanocytic nevus at the site of melanoma development. In fact, it is estimated that approximately onethird of melanomas are associated with a prior melanocytic nevus; the other two-thirds are thought to arise de novo. Interestingly, individuals with an increased number of melanocytic nevi are at higher risk of developing melanoma. Common acquired melanocytic nevi are benign and are not normally excised unless the physician and/or patient has noticed a change in appearance, there is clinical concern for melanoma, for cosmetic reasons, or if the patient complains of repetitive trauma. A shave biopsy often is performed to remove junctional nevi completely or to remove the protruding portion of compound and intradermal nevi. Since the melanocytic nests are present in the dermis of compound and intradermal nevi, these lesions may return after simple shave excision. A punch excision or simple excision is a better method to assure complete removal but may result in a more noticeable scar. To address this woman’s complaints of repetitive trauma, punch excision was used to remove her intradermal nevus. n

“Whoa, Galahad—you’ve got a bad case of knight face.”

Dr. Robbins is a resident in the Department of Dermatology at Baylor College of Medicine in Houston.

1. Verocay J. Zur kenntnis der Neurofibrome. Beitr Pathol Annat Allg Pathol. 1910;48:1-69. 2. Scheithauer BW, Woodruff JM, Erlandson RA. Tumors of the peripheral nervous system. In: Atlas of Tumor Pathology, 3rd series, Fascicle 24. Washington, D.C.: Armed Forces Institute of Pathology; 1999:1-415. 3. Kriechbaumer LK, Susani M, Kircher SG, Happak W. Vaporization of cutaneous neurofibromas with an erbium: yttrium-aluminum-garnet laser: a comparative histologic evaluation. Plast Reconstr Surg. 2012;129:602e-604e. 4. Kim HJ, Lee KG, Yi SM, et al. Successful treatment of multiple cutaneous neurofibromas using a combination of shave excision and laser photothermocoagulation with a 1,444-nm neodymium-doped yttrium aluminum garnet laser. Dermatol Surg. 2012;38:960-963. 5. Karlsson MA, Wahlgren CF, Wiklund K, Rodvall Y. Parental sunprotective regimens and prevalence of common melanocytic naevi among 7-year-old children in Sweden: changes over a 5-year period. Br J Dermatol. 2011;164:830-837. 6. Brodell R, Sims DM, Zaim MT. Natural history of melanocytic nevi. Am

References

Fam Physician. 1988;38:93-101.

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posttest Expiration date: May 2014

Nurse Practitioner Associates for Continuing Education (NPACE) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. The Nurse Practitioner Associates for Continuing Education designates this educational activity for a maximum of 1.0 contact hours of credit. Participants should only claim credit commensurate with the extent of their participation in the activity. Posttests must be completed and submitted online. NPs may register at no charge at www.mycme.com.You must receive a score of 70% or better on each test taken to obtain credit.

credits: 0.5

Feature

Dermatology Clinic

Dermatologic Look-Alikes

page 50

page 67

page 85

Symptoms and treatment of low testosterone in men

Case #1: Kaposi sarcoma (KS)

Case #1: Neurofibroma

1. What is the most common site of internal organ involvement with KS? a. Brain b. GI tract c. Lungs d. Kidney

1. What is a feature of neurofibromatosis type 1 (NF1)? a. Freckling in the axillary or inguinal regions b. Six or more café-au-lait macules c. First-degree relative with NF1 d. All of the above

1. Which medication causes a decrease in testosterone? a. Clomiphene (Clomid, Milophene, Serophene) b. Ketoconazole (Nizoral) c. Docetaxel (Docefrez, Taxotere) d. Tamoxifen (Nolvadex, Soltamox) 2. What symptom is most frequently associated with hypogonadism? a. Low libido b. Fatigue c. Decreased muscle mass d. Weight gain 3. What is a contraindication to testosterone replacement therapy? a. Erythrocytosis b. Undiagnosed prostate nodule c. Breast cancer d. All of the above 4. The goal of testosterone replacement therapy is total testosterone between a. 100 ng/dL and 200 ng/dL b. 200 ng/dL and 400 ng/dL c. 400 ng/dL and 600 ng/dL d. 600 ng/dL and 1,200 ng/dL

2. What is the most widely used and effective ablative treatment for KS? a. Cryosurgery b. Electrocauterization c. Radiation d. Topical alitretinoin (Panretin) CASE #2: Minocycline-induced hypopigmentation

2. What is the curative treatment of choice for a single neurofibroma? a. Cryosurgery b. Radiation c. Simple excision d. Deep excision CASE #2: Intradermal nevus

3. Which medication used to treat 3. Common acquired melanocytic nevi cardiac arrhythmias causes a hyperare typically pigmentation most common on a. Round or ovoid lesions approxithe face? mately 2 mm to 6 mm in diameter a. Amiodarone (Cordarone, b. Symmetric with well-defined borPacerone) ders with regular color variation b. Propranolol (Inderal, InnoPran, c. Medium-to-dark macules with fading Pronol) pigment at the periphery c. Quinidine d. Varied in elevation and tend to be d. Lidocaine (Lidoderm) lighter shades of brown 4. Which medication causes a reaction that is known as exogenous ochronosis? a. Daunorubicin (Cerubidine) b. Zidovudine (Retrovir) c. Clofazimine (Lamprene) d. Hydroquinone

To take the Posttest please go to CliniAd.com/16iBoqW

4. Which nevi are symmetric with regular borders, homogenous color, and a stable clinical appearance? a. Junctional nevi b. Benign melanocytic nevi c. Compound nevi d. Intradermal nevi

To take the Posttest please go to CliniAd.com/ZQDjAs

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CME

posttest Expiration date: May 2014

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 May 2013. 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 50

page 67

page 85

Symptoms and treatment of low testosterone in men

Case #1: Kaposi sarcoma (KS)

Case #1: Neurofibroma

1. What is the most common site of internal organ involvement with KS? a. Brain b. GI tract c. Lungs d. Kidney

1. What is a feature of neurofibromatosis type 1 (NF1)? a. Freckling in the axillary or inguinal regions b. Six or more café-au-lait macules c. First-degree relative with NF1 d. All of the above

2. What is the curative treatment of choice for a single neurofibroma? a. Cryosurgery b. Radiation c. Simple excision d. Deep excision CASE #2: Intradermal nevus

To take the Posttest please go to CliniAd.com/16iBoqW

4. Which nevi are symmetric with regular borders, homogenous color, and a stable clinical appearance? a. Junctional nevi b. Benign melanocytic nevi c. Compound nevi d. Intradermal nevi

To take the Posttest please go to CliniAd.com/ZQDjAs

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Evidence-Based Medicine This department uses the best available scientific findings to offer practice guidance on a wide range of conditions seen in primary care.The author, Alan Ehrlich, MD, is a deputy editor for DynaMed, Ipswich, Mass., and assistant clinical professor in Family Medicine, University of Massachusetts Medical School in Worcester. DynaMed (www.ebscohost.com/dynamed/) is a database that provides evidence-based information on more than 3,200 clinical topics and is updated daily through systematic surveillance covering more than 500 journals.The most important evidence identified is summarized here.

Ciprofloxacin for seven days May Be as Effective as 14 days for Acute Pyelonephritis in Women Level 2: Mid-level evidence Oral ciprofloxacin (Cipro, Proquin) administered for seven to 10 days is a first-line treatment for uncomplicated acute pyelonephritis in nonpregnant women, recommended by the Infectious Diseases Society of America and European Society for Microbiology and Infectious Diseases. This recommendation is based in part on a randomized trial that compared ciprof loxacin for seven days vs. co-trimoxazole (Bactrim, Septra, Sulfatrim) for 14 days ( JAMA. 2000;283:1583-1590; available at jama.jamanetwork.com/article. aspx?articleid=192526, accessed April 15, 2013). That trial enrolled young women (median age 25 years) with mild-to-moderate illness, and the study population was found to have a high prevalence of co-trimoxazole resistance. Treatment duration of more than seven days remains common, but longer treatment is associated with increased risk of developing resistance. A new randomized noninferiority trial evaluated the generalizability of seven-day treatment with ciprofloxacin in an older and sicker population (Lancet. 2012;380:484-490). A total of 248 women (median age 43 years) with a preliminary diagnosis of acute pyelonephritis were randomized to receive ciprofloxacin 500 mg orally b.i.d. for seven days vs. 14 days. The first week of treatment was open-label, and the second week was placebo-controlled. Initially, 69 women were excluded from the study for incorrect diagnosis, drug resistance, or other ineligibility, and an additional 23 women were excluded from analysis for loss to follow-up

Tiotropium was associated with significant improvements in forced expiratory volume in one second, forced vital capacity, and peak expiratory flow.

or other protocol violations. Bacteremia was present in 27%. The primary outcome was clinical cure, defined as complete resolution of symptoms during treatment with no recurrence of symptoms or signs of urinary tract infection during follow-up. The clinical cure rates at 10-14 days were 97% with seven-day treatment and 96% with 14-day treatment (noninferiority established). At 42-63 days, both groups had a clinical cure rate of 93% (noninferiority established). There was no significant difference in overall rates of adverse events, but seven-day treatment was associated with lower incidence of mucosal candida infection after the first week (0% vs. 5%, p=0.036).

Tiotropium May Increase Time to Severe Exacerbation in Patients with Poorly Controlled Asthma Level 2: Mid-level evidence Many patients with asthma have poorly controlled disease despite combined use of inhaled glucocorticoids and long-acting beta-2 agonists (LABAs), and for these patients, few treatment options exist. Anticholinergic agents, such as tiotropium (Spiriva HandiHaler), have been widely used for bronchodilation in chronic obstructive pulmonary disease (COPD), but have been less commonly used for asthma. A recent report of two identical randomized trials The quality of the evidence supporting each item is rated from Level 1 (highest) to Level 3 (lowest). Absolute risk reductions are presented as the number needed to treat (NNT) for one patient to benefit. Absolute risk increases are presented as the number needed to harm (NNH).

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evaluated the efficacy of tiotropium for controlling exacerbations in patients with poorly controlled asthma (N Engl J Med. 2012;367:1198-1207; available at www.nejm.org/doi/ full/10.1056/NEJMoa1208606, accessed April 15, 2013). A total of 912 patients (mean age 53 years) who were taking inhaled glucocorticoids and LABAs were randomized to inhaled tiotropium 5 µg (in two puffs) vs. placebo by Respimat Soft Mist Inhaler once daily for 48 weeks. All patients had an Asthma Control Questionnaire score ≥1.5 (on a seven-point scale) and had at least one exacerbation treated with systemic glucocorticoids within the last year. The primary outcome was time to severe asthma exacerbation, defined as either the initiation of systemic glucocorticoids for three or more days or a doubling of systemic glucocorticoid dose for three or more days in patients with ongoing or preexisting systemic treatment. Data from the two trials were pooled for analysis. Median time to severe exacerbation was not reached in either the tiotropium or the placebo group. The time until 25% of the group had a severe exacerbation was 282 days with tiotropium vs. 226 days with placebo (hazard ratio 0.79, 95% CI 0.62-1). The tiotropium group had 0.53 severe exacerbations per patient year, compared to 0.66 with placebo (p=0.046). Tiotropium was associated with significant improvements in forced expiratory volume in one second, forced vital capacity, and peak expiratory flow in both trials. There were no significant differences in hospitalizations for asthma or adverse events, and no deaths occurred in either group. It should be noted that tiotropium delivered via Respimat Soft Mist Inhaler has previously been associated with increased risk of all-cause and cardiovascular mortality in patients with COPD (BMJ. 2011;342:d3215; available at www. ncbi.nlm.nih.gov/pmc/articles/PMC3114950/, accessed April 15, 2013).

Prophylactic Escitalopram May Reduce Incidence of InterferonAssociated Depression in Patients with Chronic Hepatitis C and No History of Depression Level 2: Mid-level evidence Peginterferon alfa-2a (Pegasys) plus ribavirin (Copegus, Rebetol, Ribasphere, Virazole) is the standard treatment for patients with chronic hepatitis C, but depression and other psychiatric adverse events are common complications of interferon treatment. Previous trials on depression prophylaxis with antidepressants have shown inconsistent

Evidence-Based Medicine

Depression may be alleviated in patients with hepatitis C and symptomatic jaundice (shown).

results, but most of these trials have been limited by either small sample size or short follow-up duration. In the largest trial conducted to date, prophylactic escitalopram (Lexapro) was evaluated in adults with chronic hepatitis C and no history of psychiatric illness (Ann Intern Med. 2012;157:94-103; available at annals.org/article. aspx?articleid=1216554, accessed April 15, 2013). A total of 208 patients were randomized to receive escitalopram 10 mg once daily vs. placebo beginning two weeks before the initiation of antiviral treatment with peginterferon alfa-2A plus ribavirin. Antiviral therapy lasted for 24 or 48 weeks depending upon genotype. Escitalopram treatment continued for the duration of antiviral therapy. Patients were followed for incident depression for 48 to 72 weeks (24 weeks after end of treatment). All patients were observed for development of depressive symptoms for 12 weeks prior to the start of allocated treatment. During this period, 17% of the escitalopram group and 9% of the placebo group dropped out. The remaining 181 patients were included in the analysis, including 9 patients who were lost to follow-up. Depression was defined as a score of 13 or more points on the Montgomery-Asberg Depression Rating Scale (range 0-60 points). Depression developed in 32% of patients taking escitalopram vs. 59% with placebo (p<0.001, NNT 4). Major depression developed in 8% vs. 19% (p=0.031, NNT 9). There were no significant differences in sustained virologic response, treatment discontinuation, or serious adverse events. Peginterferon treatment is contraindicated in patients with preexisting depression or other psychiatric illness. n

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myCME.com

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For inquiries contact Dr. Nicole, PA Recruiters at: 803-467-4346 or fax CV to: 803-774-7004 or 803-403-8483 PA WANTED

PA/NP WANTED

North Country Emergency Medical Consultant’s PC is recruiting a Physician Assistant or Nurse Practitioner to join our current group of 9 physicians, 5 physician assistants and 2 nurse practitioners. NC-EMC, P.C. contracts with Samaritan Medical Center to staff the ED which has an annual volume of 53,000. The PAs work closely with the MDs and staff the ED in both the Urgent Care and Rapid Clinical Evaluation area. SMC recently opened a new ED 11/10 which has in-ED radiology, CT scan, ED Ultrasound and point of care testing. The compensation package includes $120,000.00 salary, plus benefits for approximately 144 hours/month. A RVU-based productivity bonus is awarded quarterly. Upstate New York is an outdoor enthusiast’s paradise with 4-season recreation in the world famous Thousand Islands, Lake Ontario region and the Adirondack Mountains. Montreal, Toronto, Finger Lakes region and NYC are a short drive away. Syracuse International Airport is within a one hour drive. If this opportunity interests you AND you have a minimum of 3 years Emergency Medicine/Urgent Care experience, please send your CV and cover letter to: Dr. Maja Lundborg-Gray President, North Country Emergency Medical Consultants, P.C. Emergency Department 830 Washington Street Watertown, New York 13601 Fax: 315-785-4314 Email: MLGRAY@shsny.com (preferred route)

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PA WANTED

MEDICAL EDUCATION

PA/NP WANTED

ONCOLOGY

PA/NP for busy privately owned Primary Care office, Palm Beach Gardens, Florida. M-F 8a-5p, no hospital. Must have Primary Care experience. No peds/gyn. Benefits Available.

PHYSICIAN ASSISTANT OR NURSE PRACTITIONER FRESNO, CALIFORNIA Central California Faculty Medical Group (CCFMG) affiliated with the University of California San Francisco Fresno Medical Education Program has an excellent opportunity for a licensed Physician Assistant or Nurse Practitioner in the Oncology Department at Community Regional Medical Center (CRMC) in Fresno. The selected applicant will evaluate new oncology patients, see follow-up consults, write chemotherapy orders, manage toxicities and diagnose/treat incidental problems that may arise during chemotherapy. The successful applicant will participate in the delivery of specialized patient care, including, direct patient care, assessment, documentation, treatment intervention and patient/family education and support. This position may include responsibility for education, research, and administrative services. Two years experience in oncology chemotherapy required. Competitive salary and benefit package. EOE E-mail or fax CV plus 3 references to: CCFMG Recruiting, E-Mail: diane.oconnor@ccfmg.org Fax #: (559) 443-2691

CLASSIFIEDS

Call Dr. Mitchell Marks: (561) 512-4246 or fax resume: (561) 296-1642.

Mountain Medical Services URGENT CARE is looking to hire Practitioners to work in a fast paced medical facility in upstate New York. • Positions in primary care or urgent care settings • Four great locations - Lake Placid, Saranac Lake, Massena & Malone • Full-time, Part-time & Per Diem Positions • Salay dependent on experience • Prefer 1 - 2 years experience Please contact Lindsay LaPointe for more information. To apply please email: llapointe@mountainmedical.net

Email for ad info: ca@russelljohns.com

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CLASSIFIEDS

MEDICAL EDUCATION

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COMMENTARY Kelly Anderson, RDH, MHS, is an associate professor in the Department of Dental Hygiene at Wichita State University, Wichita, Kan.

Brush up on oral-health screening A large majority of people who have dental pain contact their primary-care provider (PCP) for help. Untreated periodontal disease is the most common cause of tooth loss among adults, and dental care is often cited as the greatest unmet health need of children, which points to access-to-care issues for the general population that can be improved by PCPs with adequate oral-health screening techniques. Nurse practitioners (NPs) and physician assistants (PAs) should be aware that oral health is linked to many systemic diseases, including cardiovascular disease and diabetes, as well as to preterm labor. The connection stems from the inflammation response from the gingiva to the rest of the body.

Many health providers have difficulty recognizing the initial signs of periodontal disease.

The mouth can also exhibit pathological markers for medical problems such as leukemia, bleeding disorders, and sexually transmitted diseases. Many health providers have difficulty recognizing the initial signs of periodontal disease, including chronically bleeding gingiva, bad odor from the mouth, and loosening of the teeth. Even when providers do note the presence of periodontal disease and understand its connection to diabetes and cardiovascular disease, the intervention is often to refer the patient to a dentist rather than initiating a shared treatment plan to co-manage the condition. The American Cancer Society estimates that about 36,000 new cases of oral cancer will be diagnosed this year in the United States, and approximately 6,850 people will die of these cancers (www.cancer.org/cancer /o r a l c av i t y a n d o r o ph a r y n g e a l c a n c e r/ detailedguide/oral-cavity-and-oropharyngealcancer-key-statistics, accessed April 15, 2013). As noted by the National Cancer Institute, most lip and oral-cavity cancers are squamous cell carcinomas, which arise from the oral mucosal lining (www.cancer.gov/cancertopics/pdq/ treatment/lip-and-oral-cavity/Patient/page1, accessed April 15, 2013). Despite the fact that the oral cavity is highly accessible for direct examination, these malignancies often are not detected until a late stage. Oral mucosal changes can be subtle, and NPs and PAs who

can recognize these changes can make timely and appropriate referrals to increase the patient’s chance of survival. Patients should be screened for tobacco and alcohol use, as these are risk factors for oral problems. NPs and PAs also may encounter persons who develop oral lesions as a result of chemotherapy and radiation treatment. With appropriate training, the NP and PA could be instrumental in detecting early tooth decay and administering preventive services such as applying fluoride varnish. Fluoride varnish is a professionally applied, highly concentrated topical fluoride that prevents decay. In the past decade, it has become more widely available in the United States and is used on children in many settings, such as pediatric practices and public-health centers. Fluoride varnish treatment, which has high reimbursement rates among Medicaid recipients, is an attractive option for the primary-care setting as it takes less than five minutes to paint the solution onto the person’s teeth, is generally acceptable to patients, and requires no special preparation of the teeth or expensive equipment. Many health facilities and organizations are making oral screening a crucial component of the general patient assessment. This effort will ultimately promote health and prevent disease as well as foster collaboration between medical and dental professionals. n

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