August 2013 Clinical Advisor by The Clinical Advisor

The Clinical ADVISOR • august 2013

A F O RU M F O R N U R S E P R AC T I T I O N E R S

NEWSLINE

■■NSAID improves glycemia ■■Who needs ear tubes? ■■A new tickborne illness

advisor forum

■■Generic asthma inhalers ■■Fruit juice and diabetes ■■Lab evaluation of pruritus

| au g ust 2 013 | www.ClinicalAdvisor.com

Diagnosis of malignant

melanoma

Asymmetry is one indication that a lesion (dark area) may be cancerous.

legal advisor

A clinician accidentally reveals a man’s HIV status

✶ free cE courses!

n Dermatology Clinic

Dome-shaped facial lesions page 79

Volume 16, Number 8

n Dermatologic Look-Alikes

urticating papules on the back page 87 Expanded job listings! www.ClinicalAdvisor.com/Jobs

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Writers’ Guidelines The Clinical Advisor welcomes submissions from its readers. Writing for us is an opportunity to share your knowledge and experience with your colleagues — and to collect a fee in the bargain! We pay an honorarium for every submission we accept. We’ll be glad to work with you to develop your ideas into compelling articles. As for length, that depends on which kind of article you submit. CLINICAL FEATURES update our readers with the latest information about conditions seen in everyday practice. Running no more than 3,000 words, features can be written either as regular narratives or as a series of questions and answers. Topics should be selected with the busy primary-care clinician in mind; specialists should review specialty topics from the primary-care point of view. If at all possible, articles should be accompanied by clinical photos, for which we pay extra. Charts, tables, and algorithms are also encouraged. References are optional; if you opt not to use any, please provide a recommended reading list of books, articles, and Web sites. In addition, include your curriculum vitae, which should list all current titles and affiliations. CLINICAL CHALLENGE is our popular department comprising histories of difficult cases. Each case is presented as a step-by-step, chronological account, revealing the author’s thought processes along the way. It is divided into sections in this order: the patient presentation; the patient history; the twists and turns eventually leading to a diagnosis; the treatment and outcome; and a discussion of the lessons learned or of the condition in general. We pay extra for any photographs or images that we use. The length should be about 1,500 words. Please include your title, affiliations, and curriculum vitae. DERMATOLOGY CLINIC is a department that presents photos of actual cases and asks readers to identify the condition. Each case opens with one or two color photos and a brief description of the patient and/or his presentation, without giving away the diagnosis. This is followed by a 750- to 1,000-word summary that includes a fuller description of the ailment, how the correct diagnosis was achieved, a general review of the condition along with a differential diagnosis, and a description of the patient’s treatment and outcome. Topics must be approved by the editor prior to submission. COMMENTARY is our guest editorial page. It gives you the opportunity to sound off on an issue of importance to your colleagues nationwide. Support your views with as many facts, statistics, studies, and personal anecdotes as possible. A typical Commentary runs about 700 words in length. To discuss your editorial ideas, contact us by phone at 646.638.6077; by e-mail to editor@ClinicalAdvisor.com; or by mail to: The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001. www.ClinicalAdvisor.com • the clinical advisor • august 2013 5

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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 Production director 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 8, 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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6 the clinical advisor • august 2013 • www.ClinicalAdvisor.com

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LEVEL

contents august 2013

News and comment

departments

24 Newsline ■■NSAID improves glycemia in diabetes ■■Guide identifies kids who need ear tubes ■■Estrogen in younger postmenopausal women ■■More supplement talk needed ■■Steroid injections for back pain weaken vertebrae ■■August is the peak season for vitamin D ■■Clopidogrel plus aspirin may reduce stroke ■■New tickborne illness found in the Northeast

76 Derm Dx Read the clinical descriptions, view the images, and make your diagnosis at ClinicalAdvisor.com. 77 Legal Advisor An inadvertent mistake in transferring a patient’s records reveals his HIV status to his employer. Tympanostomy tubes in children 27

nA woman’s white, dome-shaped facial papules grow in number and size.

99 Commentary

84 Alternative Meds Update Botulinum toxin is used to treat a number of conditions, including muscle spasms, strabismus, and hyperhidrosis.

features 36 Early diagnosis of malignant melanoma Surveillance in primary care is critical to the timely identification of cancerous lesions in at-risk individuals.

How to recognize a malignant melanoma 36

48 Improving geriatric cancer survivorship Since most patients are treated by a number of clinicians, the primary-care provider must act as the gatekeeper. 66 CME/CE Treatment options for shift work disorder Behavioral, nonpharmacologic, and pharmacologic interventions are available to facilitate restorative sleep.

making contact

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79 CME/CE Dermatology Clinic n A young boy develops a painless and bleeding nodule on his shoulder.

87 CME/CE Dermatologic Look-Alikes Two patients present with urticating papules—one a man whose eruption began on the trunk, and the other a woman with firm lesions on her back. 91 CME/CE Posttest Continues on page 18

Exophytic nodule on the shoulder 79

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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.

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ENVISION NEW

W BLE 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 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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IMPORTANT SAFETY INFORMATION (continued from first page)

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. >>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.

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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

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>>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.

K02CAN13149

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.

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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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 3.2% 10.4% 11.4% Female genital mycotic infections† ‡ Urinary tract infections 4.0% 5.9% 4.3% Increased urination§ 0.8% 5.3% 4.6% 0.6% 4.2% 3.7% Male genital mycotic 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 2† 2.5% 4.7% 8.1% 60 mL/min/1.73 m 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

eGFR (mL/min/1.73 m2)

-1.6

-2.3

-3.4

Baseline Pool of Four PlaceboControlled Trials

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

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.

137193_L01.indd 7

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

137193_L01.indd 8

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INVOKANA™ (canagliflozin) tablets

“Think this is bad? You should see the inside of my head.”

“Worst budget cuts ever!”

“But if you were a real boy you wouldn’t be allowed to work such long hours.”

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

www.ClinicalAdvisor.com • the clinical advisor • august 2013 17

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contents 92 Evidence-Based Medicine n Extended anticoagulation with apixaban or dabigatran reduces recurrent VTE and mortality without increasing major bleeding n Increasing radiation exposure of the heart is associated with increasing cardiovascular risk in women with breast cancer treated with radiation therapy n Initial treatment with physical therapy for meniscal tear is associated with functional improvement similar to surgery and may lower surgery rates in patients with knee osteoarthritis.

Botulinum toxin is used for more than reducing wrinkles 84

advisor forum 72 Consultations ■■Where are the generic inhalers? ■■Fruit juice and diabetes ■■And more 74 Clinical Pearls ■■Alleviating diarrhea subsequent to radiation ■■Abdominal exams can be ticklish ■■Craving ice may signal anemia 74 Your Comments ■■Disputing the facts about Plan B

Radiation exposure during therapy for breast cancer 92

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Guideline for tympanostomy tubes in children page 27

a u g u s t 2 0 13

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NSAID improves glycemia in diabetes

A glucometer can help track fluctuations in blood glucose.

Prescription painkiller overdoses among women Women between the ages of 25 and 54 years are most likely to go to the emergency department because of prescription painkiller misuse or abuse.

50,000

ED visits per 100,000 persons

Salsalate, a nonsteroidal anti-inf lam mator y dr ug (NSAID), reduced hemoglobin (Hb) A1c levels by a mean of 0.37% over the course of a year in persons with type 2 diabetes. However, this prodrug form of salicylate still needs to be evaluated for cardiac and renal safety in these patients. The trial focused on 286 persons who had fasting glucose levels no higher than 225 mg/dL and HbA1c levels of 7.0% to 9.5%. In addition to continuing with their current therapies, 146 participants were randomized to 48 weeks of salsalate 3.5 g/day, with another 140 receiving placebo (137 of the placebo users were included in the analysis). Over the course of 48 weeks, the mean HbA1c level was 0.37% lower in the salsalate group than in the placebo group. Fasting glucose concentration fell by

patient population (Ann Intern Med. 2013;159[1]:1-12). They did caution, however, that the cardiac and renal effects of salsalate require further evaluation. Nonpharmaceutical approaches to glycemic control demonstrated mixed results in two recent studies. Thomas P.J. Solomon, PhD, and fellow researchers wrote in a JAMA Internal Medicine research letter that although aerobic exercise training significantly improved average changes in body weight, whole-body fat, fasting plasma glucose, and twohour oral glucose tolerance test results in older persons with impaired glucose tolerance or type 2 diabetes, these benefits were reduced in those who went into the aerobic exercise training with ambient hyperglycemia, particularly in persons with type 2 diabetes.

15 mg/dL more among the salsalate users, who also required fewer additional medications to control glucose levels than did the placebo users. Salsalate use also reduced triglyceride levels and uric acid while increasing adiponectin and hematocrit levels, but the NSAID also raised low LDL cholesterol levels as well as body weight. Urinary albumin levels increased with salsalate, but fell again upon discontinuation of the drug. Although the study authors deemed the trial too short and the number of patients too few to accurately determine the long-term risks and benef its of salsalate in type 2 diabetes, they concluded that the agent improves glycemia and decreases inflammatory mediators (having reduced leukocyte, neutrophil, and lymphocyte counts) in this

40,000 30,000 20,000 10,000 0

Source: Drug Abuse Warning Network, 2010

<18

18-24

25-34

35-44

45-54

55-64

>65

Age group

24 the clinical advisor â&#x20AC;˘ august 2013 â&#x20AC;˘ www.ClinicalAdvisor.com

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Newsline The American Academy of Otolaryngology–Head and Neck Surgery has issued the first evidence-based guideline for tympanostomy tube placement, the most common reason for outpatient surgery performed on children in the United States. The guideline offers 12 recommendations developed to address patient selection as well as surgical indications for and management of tympanostomy tubes in children aged 6 months to 12 years. Tympanostomy tubes are placed in the eardrum to treat middleear effusion and frequent or persistent ear infections by allowing air to circulate in the middle ear. The tubes usually fall out on their own after a year or two. Among the significant points made in the executive summary

of the guideline (Otolaryngol Head Neck Surg. 2013;149[1]:8-16; available at oto.sagepub.com/ content/149/1/8.long, accessed July 15, 2013) is the recommendation that children who have persistent otitis media with effusion (OME) in the middle ear for three months or longer undergo an age-appropriate hearing test. Tympanostomy tubes should be offered to children who have OME in at least one ear for at least three months plus symptoms that are likely caused by OME, such as ear discomfort, balance problems, and poor school performance. Children were also the focus of another recently released clinical practice guideline, this one centering on acute bacterial sinusitis in youths aged 1 to 18 years (Pediatrics. 2013;132:e262; available

Guide identifies kids who need ear tubes

Ear tubes keep the middle ear aerated and free of mucus.

at pediatrics.aappublications. org/content/132/1/e262.long, accessed July 15, 2013). As reported on ClinicalAdvisor.com (available at CliniAd.com/18gndUC, accessed July 15, 2013), this is the first time the American Academy of Pediatrics has updated this guideline since 2001.

Although postmenopausal hormone therapy with conjugated equine estrogens (CEEs) may adversely affect cognitive function in older women, these treatments produced no overall sustained benefit or risk to cognitive function when administered to postmenopausal women aged 50 to 55 years, indicates recent research. The Women’s Health Initiative Memor y Study of Younger Women was designed to test whether prescribing CEE-based hormone therapy to postmenopausal women aged 50 to 55 years

Estrogen therapy had no effect on cognitive function.

had longer-term effects on cognitive function. The 1,326 study participants had started treatment in two randomized, placebo-controlled trials when they were aged 50 to 55 years. The trials compared CEE 0.625 mg with or without medroxyprogesterone acetate 2.5 mg. Mark Espeland, PhD, and colleagues evaluated data from an annual telephone-administered cognitive battery that included measures of global and domainspecif ic cognitive functions, conducted over an average of 7.2 years after the trials ended.

Global cognitive function scores were similar for women who had been assigned to CEEbased therapies and to those assigned to placebo. In addition, no overall differences were found for any individual cognitive domain. Subgroup analyses indicated that CEE-based therapies may have adversely affected verbal f luency among women who had undergone prior hysterectomy or prior use of hormone therapy; however, the researchers noted in JAMA Internal Medicine that this observation may have been a chance finding.

Estrogen in younger postmenopausal women

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Newsline More Steroids weaken vertebrae supplement talk needed

The risk of fracture increased by 21% with each successive injection.

in patients who are at risk for osteoporotic fractures. In other bone-and-joint news, the Amer ican Academy of Orthopaedic Surgeons (AAOS) has released a revised clinical practice guideline on osteoarthritis of the knee (available at www. aaos.org/research/guidelines/ GuidelineOAKnee.asp; accessed July 15, 2013). There are two key revisions from the 2009 version. First, the recommended dosage of acetaminophen was reduced from 4,000 mg/day to 3,000 mg/day. This change was not made by the AAOS specifically for persons with osteoarthritis, but ref lects an overall change made by the FDA. Second, intraarticular hyaluronic acid is no longer recommended as a treatment for persons with symptomatic osteoarthritis of the knee, after a meta-analysis showed that the evidence of this therapy’s effectiveness did not meet the minimum thresholds of clinically important improvement.

August is the peak season for vitamin D A NEW study shows that blood levels of 25-hydroxyvitamin D, or 25(OH)D, in the U.S. population are at their highest in August and at their lowest in February. In an evaluation of data from 3.44 million blood samples of 25(OH)D, spanning 287 consecutive weeks, researchers analyzed the proportion of sera that were vitamin D– sufficient, defined as 25(OH)D ≥25 ng/mL. In the temperate northern hemisphere, vitamin D levels show a “lag of the seasons”

pattern, peaking in August and troughing in February. Although the correlation between the seasons and vitamin D has been known for some time, the new findings have added precision to the estimates of vitamin D seasonality. This information can help establish statistical associations between vitamin D levels and the development of a given disease (PLoS One. 2013;8[6]:e65785; available at www.ncbi.nlm.nih.gov/pmc/articles/ PMC3689782/, accessed July 15, 2013).

Primary-care clinicians are not having thorough enough discussions with patients on the use of dietary supplements. Content from 1,477 recorded office visits to 102 primary-care physicians was analyzed along with responses from patient and provider surveys. Providers discussed a total of 738 dietary supplements in encounters with 357 patients (24.2% of all encounters included in the data). Providers mentioned the following topics during these discussions: (1) reason to take the supplement, for 46.5% of dietary supplements discussed; (2) how to take the supplement, for 28.2%; (3) risks, for 17.3%; (4) effectiveness, for 16.7%; and (5) cost or affordability, for 4.2%. Less than 25% of these topics were discussed during office visits, and an average of only 1.13 of these five topics were discussed for each supplement. More of the five topics were reviewed for nonvitamin, non-mineral supplements (mean: 1.47) than for vitamin/ mineral supplements (mean: 0.99). The former have a greater potential for adverse interactions with medication than do the latter. The investigators concluded that providers could more frequently address topics that may influence patient dietary-supplement use, such as the risks, effectiveness, and costs of these products (Patient Educ Couns. 2013;91[3]: 287-294).

Lumbar epidural steroid injections (LESIs) administered to relieve back pain may lead to greater bone fragility, according to the results of a retrospective study in which such injections were associated with an increasing likelihood of vertebral fractures. Although LESIs are frequently prescribed for the treatment of radiculopathy or neurogenic claudication arising from compression of spinal nerves, evidence suggests that corticosteroids diminish new bone formation and increase bone resorption ( J Bone Joint Surg Am. 2013;95[11]:961-964). Compared with controls, patients who had received LESIs for spine-related problems exhibited a greater risk for vertebral body fractures, with each successive injection increasing the risk of fracture by 21%. The f indings suggest that because the added exposure to glucocorticoids resulting from LESIs may carry greater risk than previously thought, these injections should be used cautiously

www.ClinicalAdvisor.com • the clinical advisor • august 2013 33

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Newsline Th e com bination of clopidogrel (Plavix) and aspirin has been found to be superior to aspirin alone in reducing the risk of stroke in the first 90 days after a minor stroke or a transient ischemic attack (TIA), without increasing the risk of hemorrhage. A total of 5,170 patients across 114 centers in China were randomized to the combination therapy or to aspirin plus placebo for 90 days within 24 hours after the onset of minor ischemic stroke or high-risk TIA (N Engl J Med. 2013;369:11-19). Stroke, which is common during the first few weeks after a minor ischemic stroke or TIA, occurred in 8.2% of patients receiving clopidogrel plus aspirin, compared with 11.7% in the aspirin-only users. Moderate or severe hemorrhage

rates were 0.3% in each group, as was hemorrhagic stroke rate. In a separate study, Michael W. Cullen, MD, and colleagues evaluated the association between stroke risk and bleeding risk on rates of oral anticoagulant use based on data from 10,098 outpatients (mean age: 73 years; 58% men) with atrial fibrillation. They reported in Circulation: Cardiovascular Quality and Outcomes that overall, 76% of the patients used war far in (Coumadin, Jantoven) or dabigatran (Pradaxa). Oral anticoagulant use increased with higher CHADS2 stroke-risk scores, from 53% among those with a score of zero to 80% among those with a score of 2 or higher. Anticoagulant use dropped slightly as ATRIA bleeding-risk score rose, from 81% for an ATRIA

Clopidogrel plus aspirin may reduce stroke

Clopidogrel prevents cells in the blood from clumping together.

score of 3 to 73% for an ATRIA score of 5 or higher. Among persons with low bleeding risk, oral anticoagulant use rose significantly with increasing stroke risk. Among those with high bleeding risk, CHADS2 stroke risk had a smaller impact on oral anticoagulant use.

Bor r eli a miyamotoi infection is being reported as a newly recognized tickborne illness, observed in patients originally thought to have human granulocytic anaplasmosis (HGA). In a case report presented in Annals of Internal Medicine (2013;159[1]:21-27), Hanumara Ram Chowdri, MD, and colleagues explained that the diverse tickborne infections of the northeastern United States can present as undifferentiated flulike illness. When patients in areas known for Lyme disease and other tickborne diseases develop acute febrile

Tickborne infections can present as flulike illness.

illness with myalgia, headache, neutropenia, thrombocytopenia, and elevated hepatic aminotransferase levels, they often are presumed to have HGA. Two patients with fever presented to primary-care medical centers, one in Massachusetts and one in New Jersey. They each received a diagnosis of HGA but did not respond quickly to doxycycline therapy, nor was there any laboratory evidence of Anaplasma phagocytophilum infection. Polymerase chain reaction and DNA sequencing led to the detection of B. miyamotoi in the

peripheral blood of both patients. No evidence of infection with other tickborne pathogens common to the area was found, although Chowdri’s team noted that one of the patients may have had concurrent Lyme disease. The authors advised that clinicians should carefully analyze samples from tick-exposed patients who have acutely presented with signs of HGA but who have a delayed response to doxycycline or negative confirmatory test results for HGA. These patients may in fact be infected with B. miyamotoi. n

©thinkstock

New tickborne illness found in the Northeast

34 the clinical advisor • august 2013 • www.ClinicalAdvisor.com

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Now Available

...it’s time.

For more information, including clinical data, visit BELVIQ.com.

BELVIQ® is a registered trademark of Arena Pharmaceuticals GmbH. LORC0127

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Printed in USA.

1/2013

6/13/13 5:18 PM

feature: Leah Springer, PA-C, and Laura Gunder McClary DHSc, MHE, PA-C

Early diagnosis of malignant melanoma Surveillance on the part of primary-care clinicians is critical to the timely identification of cancerous lesions in at-risk individuals.

Malignant melanomas (dark area) usually grow from an existing nevus after prolonged UV exposure.

alignant melanoma is a type of skin cancer that originates in melanocytes. Although these pigment-producing cells are found primarily in the basal layer of the skin, they are also located in the GI tract, eyes, ears, and the oral and genital mucosal membranes.1 Melanoma is the leading cause of skin-cancerrelated death worldwide.1 In the United States, melanoma is the fifth most common cancer in men and the sixth most common cancer in women.2,3 It is projected that 1 in 52 Americans will develop cutaneous malignant melanoma at some point.4 Melanoma incidence is increasing worldwide faster than any other neoplasm outside of lung cancer in women.5 This continuing rise in incidence is becoming a public-health crisis that mandates early recognition of suspicious lesions. Early detection of melanoma is critical to patient prognosis and survival.5 A recent study on the evidence-based staging system for melanoma found that tumor thickness and ulceration were two of the most powerful independent predictors of survival in cases of localized disease.6 Earlier detection has boosted the five-year survival rate for invasive melanoma from 82.6% of cases diagnosed between 1975 and 1979 to 93.1% of cases diagnosed in 2002.7 Nevertheless, invasive melanoma remains very difficult to treat, with no proven therapy plan and poor long-term prognosis. Early detection and diagnosis of melanoma before metastasis is critical to improving patient outcomes.5 Primary-care

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malignant melanoma

Table 1. Personal history predictive of melanoma risk

Table 3. Pertinent family history predictive of melanoma

UV exposure

Pancreatic cancer

Melanoma in first- or second-degree relative

Multiple sunburns

Retinoblastoma

Multiple melanoma cases on one side of the family

Melanoma

Li-Fraumeni syndrome

Multiple primary-stage melanomas in one parent

Dysplastic nevi

Xeroderma pigmentosa

Table 2. Phenotypic characteristics predictive of melanoma

Multiple primary-stage melanomas in any family member Melanoma in a family member at a young age (<40 years) Melanoma in a family member with previous dysplastic nevi Pancreatic adenocarcinoma

Fair complexion

Number of nevi (>10)

Astrocytoma

Blue or green eye color

Anatomic location of nevi

Central nervous system cancers

Light or red hair color

Inability to tan

Breast cancer

Freckles

clinicians are often the first line of defense against melanoma and must be educated in the correct identification of cancerous lesions. Identifying at risk patients

Personal history. One of the most significant contributors to the development of melanoma is sunlight exposure, particularly exposure to UVB radiation (Table 1).8 UVB radiation is most notably a risk in those with phenotypic susceptibility (Table 2). A history of sunburns and excessive sun exposure in young children dramatically increases the risk of developing melanoma. The risk of melanoma in people with a history of sunburn is twice that of those who have never sunburned.5 In addition to a history of UV exposure and multiple sunburns, a personal history of melanoma or dysplastic nevi is highly predictive of melanoma risk. Personal history of other associated diseases, including pancreatic cancer, retinoblastoma, Li-Fraumeni, or xeroderma pigmentosa, are also associated with increased risk of developing melanoma.5,9 Phenotypic features. The presence of certain phenotypic characteristics approximately doubles the risk of developing melanoma and include fair complexion, blue or green eye color, light or red hair color, presence of freckles, location of nevi, and an inability to tan.5,8,9 One possible mechanism for this risk is a variation in the melanocortin-1 receptor, resulting in the development of sporadic cutaneous melanomas. The risk of developing melanoma has also been directly correlated with the total number of benign nevi on the body. Individuals with 11 to 25 nevi are approximately 1.5 times more likely to develop melanoma than are those with fewer than 10 nevi. This risk doubles with every increase of 25 nevi. Dysplastic nevi also significantly increase the risk of developing melanoma.5

Nonmelanoma skin cancer (i.e., squamous cell carcinoma, basal cell carcinoma)

Family history. Genetics have also been shown to have a clear role in the development of melanoma and may explain the variations in age- and gender-specific incidence rates (Table 3).8 A family history of melanoma is one of the strongest predictive factors for the development of the disease. Persons with a first-degree relative with melanoma have twice the risk of developing melanoma than those without a positive family history. Several genetic conditions—including dysplastic nevus syndrome or familial atypical multiple mole and melanoma (FAMMM) syndrome—have been found to significantly increase the risk of developing melanoma. FAMMM syndrome should be suspected when a family history of pancreatic cancer or astrocytoma is present. Patients with FAMMM syndrome may present at a younger age (<40 years), have multiple primary melanomas, or have a history of dysplastic nevi. History of other familial cancer syndromes, including familial retinoblastoma, Li-Fraumeni syndrome, and Lynch syndrome type II, also increases an individual’s melanoma risk.5 Family history of breast cancer and nonmelanoma skin cancers also raises the risk of developing melanoma.9 Patients without a family history of melanoma may still have a genetic predisposition to the disease from a new mutation to the CDKN2A gene or the CDK4 gene.5 Diagnosis

The ABCD(E)s of melanoma. The original ABCD criteria (Asymmetry, Border irregularity, uneven Color, and Diameter >6 mm) was devised in 1985 to provide primary-care practitioners and the general public with an easy-to-remember algorithm to aid in the early diagnosis of malignant melanoma.10 Prior to the addition of the final criterion (E [Evolution]), the specificity was 75% and sensitivity was 84% with a diagnostic

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malignant melanoma

accuracy of 76%.7 Assessing for evolving lesions optimizes diagnostic sensitivity and specificity.11 Table 4 lists the sensitivity and specificity for each criterion.11 Benign pigmented lesions are characteristically small, round, and symmetric with regular borders and uniform pigmentation. Lesions demonstrating characteristics of malignancy are described as large (>6 mm) and asymmetrical lesions, with grossly irregular borders and variant pigmentation ranging from tan to black.12 These clinical features led to the development of the ABCDs of diagnosing melanoma. Evaluating the diameter criterion. There has been some debate regarding the diameter criterion, as the incidence of smalldiameter (<6 mm) malignant melanomas has increased. Small melanomas comprise 3% to 14% of all invasive melanomas and rarely result in metastasis and death.13 Researchers have concluded that although the incidence of small-diameter melanomas may be on the rise, there is currently not enough evidence to revise the criteria.10,13 Specifically, the percentage of small-diameter lesions that are melanoma compared with those that are benign pigmented lesions must be more thoroughly investigated.10 Evolving lesions. A history of change in a preexisting nevus or the growth of a new nevus in at-risk patients may signal malignancy. Change noted in a preexisting nevus occurs at a higher frequency in malignant lesions than in benign lesions. Studies have indicated that growing melanomas tend to exhibit observable changes in a three-to-six-month period. These alterations include changes in lesion size, shape, color, elevation, and such symptoms as itching or bleeding. The addition of evolution to the established ABCD criteria for the detection of melanoma has increased both the sensitivity and the specificity of the guidelines and has significantly enhanced the ability of clinicians to diagnose melanoma earlier. This development is particularly important for the diagnosis of nodular melanoma, which frequently presents at advanced stages. In one study, lesion change was associated with 78% of nodular melanomas and 71% of superficial spreading melanomas.14 Evolution has been found to have the highest specificity and sensitivity of all diagnostic criteria, at 90% and 84%, respectively.11 The “ugly duckling.” An outlier nevus that does not match the patient’s other nevi is often identified as the “ugly duckling” sign. The term was coined by researchers describing the clinical manifestation of melanoma in two different patients. One case of melanoma presented as a brown-black lesion in an individual with mainly red-brown nevi, while the other melanoma presented as a uniformly dark lesion in a patient whose nevi predominately displayed multiple

Table 4. Specificity and sensitivity of the ABCDEs Characteristic

Specificity

Sensitivity

Asymmetry

72%

57%

Border

71%

57%

Color

59%

65%

Diameter

63%

90%

Evolution

90%

84%

Adapted from Thomas L, Tranchand P, Berard F, et al. Semiological value of ABCDE criteria in the diagnosis of cutaneous pigmented tumors. Dermatology. 1998;197:11-17.

pigments and irregular borders. The investigators’ observations led to the conclusion that the ugly-duckling nevus can be described as atypical in a patient with multiple typical nevi, or as typical in a patient with multiple atypical nevi. Several clinical studies have demonstrated the efficacy of this method in differentiating cases of melanoma from benign nevi.14,15 One such study described a 100% positive identification of melanoma and a 2.1% false-positive finding of benign lesions, making the sensitivity of the ugly duckling sign for melanoma 90%.15 The ugly duckling sign is highly sensitive in the detection of melanoma even among nondermatologists, thereby improving the early detection rate of melanoma and patient prognosis.14,15 The gold standard in diagnosis

Skin biopsy followed by histopathologic examination remains the gold standard in diagnosing melanoma.14 Current guidelines recommend full-thickness excisional biopsy of lesions clinically suspected of melanoma with a margin of 1 mm to 2 mm. Full-thickness excisional biopsy allows complete histopathologic assessment, providing more accurate diagnosis and staging of the tumor.16 Partial biopsies using the punch or shave techniques result in a higher frequency of misdiagnosis and microstaging inaccuracy through unrepresentative tissue sampling.17 Microstaging inaccuracy is attributable to the increased possibility of transecting the base of the lesion, resulting in an inconclusive Breslow depth. In one study, inaccurate staging was observed in 34% of punch biopsies, 19% of shave biopsies, and 9.1% of excisional biopsies.17 Punch biopsy is associated with the highest rates of melanoma histopathologic misdiagnosis and inaccurate microstaging. Primary-care clinicians and dermatologists alike must be aware of these findings when interpreting pathology reports.17 Summary

The worldwide incidence of melanoma continues to rise.1 To address this growing public-health crisis, practitioners

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malignant melanoma

The ugly-duckling sign has been shown to have high specificity and sensitivity among dermatologists and primary-care practitioners. must be vigilant and identify suspicious lesions, particularly in patients at risk for developing melanoma. Early detection is crucial to patient prognosis and long-term survival.5 The ABCDE criteria are a memorable and effective algorithm for assessing nevi and continue to be used globally to educate clinicians and the public in an effort to improve early diagnosis of cancerous lesions.10 The ugly-duckling sign can be used when evaluating atypical nevi and has been shown to have high specificity and sensitivity among dermatologists and primary-care practitioners.14,15 Clinicians and patients must be educated in these criteria to evaluate nevi accurately. Biopsy of suspicious lesions is the only way to accurately diagnose melanoma. Full-thickness excisional biopsy remains the recommended procedure because of its ability to completely assess the lesion and provide information on tumor thickness and prognosis.16 n

10. Abbasi NR, Shaw HM, Rigel DS, et al. Early diagnosis of cutaneous melanoma: revisiting the ABCD criteria. JAMA. 2004;292:2771-2776. Available at jama.jamanetwork.com/article.aspx?articleid=199929. 11. Thomas L, Tranchand P, Berard F, et al. Semiological value of ABCDE criteria in the diagnosis of cutaneous pigmented tumors. Dermatology. 1998;197:11-17. 12. Friedman RJ, Rigel DS, Kopf AW. Early detection of malignant melanoma: the role of physician examination and self-examination of the skin. CA Cancer J Clin. 1985;35:130-151. 13. Abbasi NR, Yancovitz M, Gutkowicz-Krusin D, et al. Utility of lesion diameter in the clinical diagnosis of cutaneous melanoma. Arch Dermatol. 2008;144:469-474. Available at archderm.jamanetwork.com/article. aspx?articleid=419627. 14. Goodson AG, Grossman D. Strategies for early melanoma detection: Approaches to the patient with nevi. J Am Acad Dermatol. 2009;60:719735. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC2690513/. 15. Scope A, Dusza SW, Halpern AC, et al. The “ugly duckling” sign: agree-

Ms. Springer is a physician assistant in the family medicine department at The Longstreet Clinic in Oakwood, Ga. Dr. Gunder McClary is associate clinical professor at Georgia Regents University in Augusta and associate professor at Nova Southeastern University in Fort-Lauderdale-Davie, Fla.

ment between observers. Arch Dermatol. 2008;144:58-64. Available at archderm.jamanetwork.com/article.aspx?articleid=419304. 16. Tadiparthi S, Panchani S, Iqbal A. Biopsy for malignant melanoma— are we following the guidelines? Ann R Coll Surg Engl. 2008;90:322-355. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC2647196/. 17. Ng JC, Swain S, Dowling JP, et al. The impact of partial biopsy on histo-

References

pathologic diagnosis of cutaneous melanoma: experience of an Australian

1. Medscape Reference. Cutaneous melanoma. Available at emedicine.

tertiary referral service. Arch Dermatol. 2010;146:234-239. Available at

medscape.com/article/1100753.

archderm.jamanetwork.com/article.aspx?articleid=209747.

2. Centers for Disease Control and Prevention. Top 10 cancers among women. Available at www.cdc.gov/Features/dsWomenTop10Cancers/.

3. Centers for Disease Control and Prevention. Top 10 cancers among men. Available at www.cdc.gov/Features/dsMenTop10Cancers/. 4. National Cancer Institute. SEER stat fact sheets: Melanoma of the skin. Available at seer.cancer.gov/statfacts/html/melan.html. 5. Markovic SN, Erickson LA, Rao RD, et al. Malignant melanoma in the 21st century, part 1: epidemiology, risk factors, screening, prevention, and diagnosis. Mayo Clin Proc. 2007;82:364-380. 6. Balch CM, Soong SJ, Atkins MB, et al. An evidence-based staging system for cutaneous melanoma. CA Cancer J Clin. 2004;54:131-149. 7. Rigel DS, Russak J, Friedman R. The evolution of melanoma diagnosis: 25 years beyond the ABCDs. CA Cancer J Clin. 2010;60:301-316. 8. Meyskens FL Jr, Farmer PJ, Anton-Culver H. Etiologic pathogenesis of melanoma: a unifying hypothesis for the missing attributable risk. Clin Cancer Res. 2004;10:2581-2583. Available at clincancerres.aacrjournals.org/ content/10/8/2581.long. 9. Gunder LM, Update on familial melanoma: Understanding risk, surveillance and the role of genetic testing. J Derm Physician Assistants. 2008;2:16-21.

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46 the clinical advisor • august 2013 • www.ClinicalAdvisor.com

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feature: Meghan Routt, GNP/ANP, AOCNP

Improving geriatric cancer survivorship Since most older cancer patients are treated by a number of clinicians in different specialties, the primary-care provider must act as the gatekeeper.

Collaboration between primary care and oncology ensures adequate supportive care.

ancer is the second leading cause of adult death in the United States.1 Approximately 60% of people diagnosed with cancer are aged 65 years and older.2 The median age of cancer diagnosis is 65 years; the median age of cancer-related death is 73 years.3 Incidence rates of breast cancer, the most common cancer among females in the United States, have increased in women aged 50 years and older.4 Women aged 70 years and older are two times more likely to develop cancer than those aged 50 years or younger. While statistics on the anticipated number of cancer survivors in the United States vary, it is estimated that at least 6.5 million survivors are older than age 65 years.5 As the population continues to grow older and life expectancy extends, these estimated numbers have the potential to increase exponentially: According to the CDC, more than half of all invasive cancers occur in individuals aged 65 and older (Table 1).6 The term “older adult” has been defined many ways. Government services confer senior citizen status at age 65 years. The U.S. population of older adults is heterogeneous, accounting for 41.1 million individuals.7 To combat age-related generalization, geriatric specialists have divided this population further into three categories: young-old (aged 65-74 years), old (aged 75-84 years), and oldest-old (aged 85 years and above). It is important to note within those older than age 65 years, the fastest growing subgroup of older adults is those aged 85 and above. However, chronologic age is not

48 the clinical advisor • August 2013 • www.ClinicalAdvisor.com

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Download the new app for the iPhone, iPad,and Android— created specifically for nurse practitioners and physician assistants from the publishers of the highest rated journal for these health-care professionals. With the Clinical Advisor app you can: • Take Derm Dx quizzes to learn about difficultto-identify dermatology conditions, and then see how you performed against your peers. • Use medical calculators to do things like assess liver function, convert HbA1C to mean plasma glucose, evaluate BP, determine BMI and more. • Read the latest news about breakthrough treatments, disease outbreaks, drug approvals and recalls, and clinical research.

• Use the medical slideshows to educate patients in-office about clinically relevant topics, including the detrimental effects of smoking, the benefits of breastfeeding, diabetes complications and healthy lifestyle tips, etc. • Access hundreds of NP- and PA-specific accredited courses from the myCME education library and claim your certificate instantly. • Search the NPPR/PAPR drug database

The best part? IT’S FREE! So don’t wait. Download the Clinical Advisor app today to start experiencing the benefits of this essential resource at the point-of-care.

geriatric cancer

TABLE 1. Incidence of invasive cancers by age group Age group (years)

Rate (per 100,000 population)

Number

<19

16.9

14,023

20-49

155.5

192,055

50-65

843.2

477,087

65-74

1902.5

385,233

>75

2223.3

408,106

Adapted from Centers for Disease Control and Prevention. Invasive cancer incidence— United States, 2009. MMWR Morb Mortal Wkly Rep. 2013;62:113-118. Available at www.cdc. gov/mmwr/preview/mmwrhtml/mm6207a1.htm. Accessed July 15, 2013.

always indicative of physiologic age. Physiologic age takes into account functional status, comorbidity, frailty, and the presence of geriatric syndromes.2 Cancer survival in advanced age

In general, advanced age is associated with inadequate cancer diagnosis and treatment and can translate into shorter survival time.8 Age is not considered a primary risk for surgery. Research demonstrates that older adults tolerate surgery as well as their younger counterparts.9 Controversy exists among practitioners in regard to older adults and recommended treatment for cancer. Those controversies include appropriateness for surgery, ability to tolerate chemotherapy, screening for and prevention of other cancers, end-of-life-care initiation, and the participation of older adults in clinical trials. To address these concerns, the National Comprehensive Cancer Network (NCCN) established senior adult oncology recommendations for practitioners.10 The NCCN guidelines emphasize estimating life expectancy based on function and comorbidities. The guidelines also state that any treatment that diminishes an individual’s quality of life with no significant survival benefit should be avoided. Preservation of function should be the ultimate goal of treating older adult oncology patients. Function is primarily assessed by the patient’s ability to perform activities of daily living (ADLs) and instrumental activities of daily living (IADLs). Examples of ADLs include continence, eating, and grooming. IADLs include managing money, shopping, preparing meals, and using a telephone. The role of the primary-care provider

The primary-care provider (PCP) is considered the gatekeeper and the main source of health information for the geriatric patient. Most older adults are managed by clinicians of many different specialties, with the PCP coordinating all

care. Screening patients for cancer also falls within the realm of services provided by the PCP. Screening guidelines for the older adult are controversial; however, most incorporate an anticipated age expectancy of at least 10 years. Many guidelines emphasize the importance of the individualized relationship between the PCP and the patient. The PCP is charged with explaining risks and benefits of screening, possible treatment options, and ramifications of testing positive for cancer. Collaborative, shared care between PCPs and oncologists may change depending on the stage of care. The continuum of care ranges from the newly diagnosed to end-of-life care or survivorship. Once the patient receives a diagnosis of cancer, there is a perceived hand-off from the PCP to the oncology team.11 Under this scenario, the patient not only has to deal with the anxiety of a new diagnosis, but also with a new multiple-member team (e.g., surgery, radiation, medical oncology). Patients identify the PCP as an important source of information about cancer treatment and as a potential source of support for themselves and their families.12 Ensuring continuity of care

In 2005, the Institute of Medicine released a report outlining the numerous challenges of providing comprehensive cancer care.13 The overall conclusion of this report was the need for better care integration between primary- and cancercare systems as a way of ensuring continuity of care and improving support for patients. Collaboration between the PCP and the oncology team may enhance three features of care for cancer patients during the primary treatment phase: (1) continuity of care; (2) identification and management of preventive-care needs and comorbid conditions; and (3) provision of appropriate supportive care. Continuity of care can help smooth the transition between providers and ensures all providers have the most current information on the patient’s health. It has been shown that communication between providers, which is essential, is often insufficient. Previous research on this topic unfortunately predates the electronic medical record (EMR). Ideally, full implementation of the EMR will result in a list of all current providers of care and allow for automatic drafting of consultation notes. However, not all practices have incorporated the EMR, and gaps in communication continue to exist. Treating comorbidities

Optimizing treatment of comorbid conditions is vital when treating a patient with cancer. Specifically, the geriatric

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patient will have multiple comorbidities, which will often be exacerbated by cancer treatment. Again, the PCP is the cornerstone in managing these comorbid conditions and ensuring that the patient is in the best health possible. Ongoing consultation regarding anticoagulation start and stop times, maintenance of tight glycemic control, and BP management are just a few examples of the PCP’s responsibilities throughout the continuum of the older patient’s cancer care. Older adults with cancer have unique needs during all aspects of their survivorship. Although it is safe for older adults to receive treatment for cancer, proper assessment and careful consideration of all options is paramount. The ultimate goal of treatment is the preservation of physical and psychosocial function. It is vital that geriatric cancer survivors be continually assessed for the presence of geriatric syndromes, as these syndromes can limit treatment and quality of life. Geriatric syndromes are most likely to be identified and treated by the PCP.

As the aging population continues to grow, the quality of geriatric cancer survivorship will depend on accurate assessment of risk facwtors influencing prognosis. Functionality should be preserved at all costs by utilizing interventions that promote independence in ADLs. Clinicians have the responsibility of ongoing assessment of geriatric cancer survivors across the survivorship continuum. A collaborative approach to treatment, incorporating the entire oncology team and the PCP, provides the best outcomes for quality patient care. n Ms. Routt is an inpatient surgical oncology nurse practitioner at James Cancer Hospital, The Ohio State University Medical Center, Columbus. References 1. Centers for Disease Control and Prevention. United States cancer statistics. Available at apps.nccd.cdc.gov/uscs/. 2. Carreca I, Balducci L. Cancer chemotherapy in the older cancer patient. Urol Oncol. 2009;27:633-642. 3. Hanson LC, Muss HB. Cancer in the oldest old: making better treatment

Supportive care

decisions. J Clin Oncol. 2010;28:1975-1976. Available at jco.ascopubs.org/

Providing supportive care to the geriatric oncology patient is of utmost importance. Because of the long-term relationship between the PCP and the patient, the PCP is sensitive to any potential psychosocial issues that may arise during the patient’s cancer treatment. The PCP is privy to family dynamics, previous discussions regarding advance directives, and treatment preferences of which the oncology team may not be aware. Conversely, the oncology team may be aware of available social services that are specific to the oncology patient’s needs. Working collaboratively will ensure the patient has adequate supportive care.

content/28/12/1975.long. 4. American Cancer Society. Cancer facts & figures 2009. Available at www. cancer.org/research/cancerfactsstatistics/cancerfactsfigures2009/index. 5. National Cancer Institute. Cancer statistics. Available at seer.cancer.gov/ statistics/. 6. Centers for Disease Control and Prevention. Invasive cancer incidence—United States, 2009. MMWR Morb Mortal Wkly Rep. 2013;62:113118. Available at www.cdc.gov/mmwr/preview/mmwrhtml/mm6207a1.htm. 7. Centers for Disease Control and Prevention. Older person’s health. Available at www.cdc.gov/nchs/fastats/older_americans.htm. 8. Wedding U, Röhrig B, Klippstein A, et al. Age, severe comorbidity and functional impairment independently contribute to poor survival in

poll position

What cancer do you most commonly see in your patients aged 65 years and older?

cancer patients. J Cancer Res Clin Oncol. 2007;133:945-950. 9. Petrakis IE, Paraskakis S. Breast cancer in the elderly. Arch Gerontol Geriatr. 2010;50:179-184. 10. Balducci L, Cohen HJ, Engstrom PF, et al. Senior adult oncology clinical

n=169

1.5% n Skin: 34.8% n Breast: 24.6% n Colon: 17.4% n Lung: 13.0% n Prostate/uterus: 8.7% n Other: 1.5%

8.7% 13.0%

practice guidelines in oncology. J Natl Compr Canc Netw. 2005;3:572-590. 11. O’Toole E, Step MM, Engelhardt K, et al. The role of primary care phy-

34.8%

sicians in advanced cancer care: perspectives of older patients and their oncologists. J Am Geriatr Soc. 2009;57 (Suppl 2):S265-S268. 12. Canadian Health Services Research Foundation. An evaluation of con-

17.4% 24.6%

tinuity of cancer care through regional supportive care networks. Available at www.cfhi-fcass.ca/Migrated/PDF/ResearchReports/OGC/whelan_e.pdf. 13. Institute of Medicine. From Cancer Patient to Cancer Survivor: Lost in Transition. Available at books.nap.edu/openbook.php?record_id=11468.

For more polls, visit CliniAd.com/10TDwDb. All electronic documents accessed July 15, 2013.

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CME CE

program outline August 2013

0.5 credits

Page 66 Feature Treatment options for shift work disorder Suzanne Salamanca, MSN, PMHNP-BC Suzanne Salamanca, MSN, PMHNP-BC has no relationships to disclose relating to the content of this article.

■■ Learning objectives: • List comorbid conditions that contribute to poor sleep hygiene. • Name the treatment that promotes daytime sleep among night-shift workers. • Explain what makes armodafinil (Nuvigil) convenient for patients with shift work disorder. • Describe the common side effects associated with modafinil (Provigil). 0.5 credits

Page 79 Dermatology Clinic A painless, bleeding nodule on the shoulder Audrey Chan, MD Audrey Chan, MD, has no relationships to disclose relating to the content of this article.

White dome-shaped facial papules Allison Pagano and Julia R. Nunley, MD Allison Pagano and Julia R. Nunley, MD, have 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 87 Dermatologic Look-Alikes Urticating papules Kerri Robbins, MD Kerri Robbins, MD, has no relationships to disclose relating to the content of this article.

■■ Learning objective: • To distinguish and properly treat dermatologic conditions with similar presentations.

Page 91 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 August 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.

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CME CE feature

n Learning objectives: • List comorbid conditions that contribute to poor sleep hygiene. • Name the treatment that promotes daytime sleep among night-shift workers. • Explain what makes armodafinil (Nuvigil) convenient for patients with shift work disorder. • Describe the common side effects associated with modafinil (Provigil). n complete the posttest: Page 91 n additional CME/CE: Pages 79, 87 Turn to page 65 for additional information on this month’s CME/CE courses.

Suzanne Salamanca, MSN, PMHNP-BC

Treatment options for shift work disorder Behavioral, nonpharmacologic, and pharmacologic interventions are available to facilitate restorative sleep and ensure sustained alertness.

Caption here

he Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text-Revision, defines circadian rhythm sleep disorder (CRSD) of the shift work type as, “insomnia during the major sleep period or excessive sleepiness during the major awake period associated with night-shift work or frequently changing shift work.”1 The American Academy of Sleep Medicine (AASM) refers to the condition consisting of symptoms of insomnia or excessive sleepiness that occur in transient phenomena in relation to work schedules as shift work disorder (SWD). For simplicity’s sake, this article will refer to the condition as SWD, as individuals often seek treatment for sleep disturbances in a primary-care rather than a mental-health setting. Appropriate management strategies and specific interventions for SWD as delineated by the AASM will be presented (Table 1). The economic burden and risks associated with SWD are clearly documented in the literature and will not be addressed herein.

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It is vital for clinicians to recognize and address any comorbid conditions that may contribute to poor sleep hygiene and/or decreased alertness. The circadian system

The circadian rhythm describes the cyclical changes involving body temperature, hormone levels, and sleep that occur over a 24-hour period and are driven by the body’s biological clock.2 The cycle is synchronized by rhythmic environmental cues, known as zeitgebers.3 The primary zeitgebers are the environmental light-dark cycle and the secretion of melatonin, both of which can be manipulated to induce a phase shift in an individual’s circadian rhythm.4 CRSDs occur when there is a misalignment between a person’s current sleep pattern and the sleep pattern desired, which results in symptoms of sleepiness and insomnia.5 SWD is considered an extrinsic or exogenous circadian rhythm disorder because, in individuals with SWD, the circadian system functions adequately under normal circumstances.6 Excessive sleepiness often occurs during the shift work, thus impairing alertness. Over time, improvement of symptoms is observed; however, these symptoms tend to persist to some degree for the duration of the shift work, only alleviating once a regular daytime-shift pattern is resumed.5 Prevalence and diagnostic issues

An estimated 20% of U.S. workers are involved in some form of shift work (i.e., permanent or intermittent night work, early morning work, and rotating schedules).7 The percentage of those who meet criteria for the diagnosis of SWD is unclear, as diagnostic criteria are soft and will most likely remain so due to the subjective nature of the individual’s experience and intensity of symptoms. The majority of practice recommendations in the literature have been evaluated in shift workers at large and not specifically in those with SWD. Treatment goals

The primary goals of treatment for individuals with SWD are to facilitate restorative and high-quality sleep when appropriate and to ensure sustained alertness when alertness is required. These goals can be met through nonpharmacologic and, when necessary, pharmacologic interventions or a combination of both, as recommended by the AASM guidelines.7 Addressing comorbid conditions

It is vital for clinicians to recognize and address any comorbid conditions that may contribute to poor sleep hygiene and/or decreased alertness or excessive fatigue during required periods of wakefulness. Comorbid conditions may include,

but are not limited to, other sleep disorders (e.g., obstructive sleep apnea), mood disorders (e.g., depression), and a variety of medical disorders (e.g., peptic ulcers, cardiovascular disease, obesity). Consultation with a sleep specialist may be indicated for individuals with suspected or confirmed comorbid sleep disorders. Psychiatric consultation is preferred for the treatment of complex mood disorders. Behavioral and nonpharmacologic interventions

Improvement of sleep hygiene. Clinicians should counsel patients on positive sleep hygiene practices using a commonsense approach. The bedroom should be quiet, cool (68°F), darkened, and reserved for sleep and sex only. Bedclothes should be kept to a minimum. The use of technologic devices should be discouraged when attempting to sleep. Large meals, alcohol, and psychostimulants—including caffeine—should be avoided before planned sleep sessions. Alcohol consumption has been shown to cause fragmented sleep patterns and disruption of REM sleep.8 Some individuals may attempt to induce sleep by ingesting alcohol, unaware of its effects. Scheduled naps. The AASM asserts that planned napping before or during works improves alertness and performance among night-shift workers. This recommendation is based on the results of five studies utilizing shift work laboratory simulations as well as field investigations.9-13 Scheduled naps TABLE 1. Recommended treatments of CRSDs Therapy

Effect

Planned napping

Improves alertness and performance among night-shift workers.

Timed light exposure

Decreases sleepiness and improves alertness during night-shift work.

Administration of melatonin

Promotes daytime sleep among night-shift workers.

Hypnotic medications

Promotes daytime sleep among nightshift workers; carryover of sedation to the nighttime shift with potential adverse consequences for night-time performance and safety must be considered.

Modafinil (Provigil)

Enhances alertness during the night shift.

Caffeine

Enhances alertness during the night shift.

Adapted from Morgenthaler TI, Lee-Chiong T, Alessi C, et al. Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American Academy of Sleep Medicine report. Sleep. 2007;30:1445-1459. Available at www.ncbi.nlm.nih.gov/pmc/ articles/PMC2082098/. Accessed July 15, 2013.

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A moderate amount of exercise, which can be obtained through brisk walking or resistance training, is sufficient to improve sleep quality. also improved reaction times and decreased accidents during night-shift work in these studies. The length or frequency of the naps is not specified in the literature. The studies were performed using night-shift workers and not specifically individuals with SWD. Although napping may prove to be beneficial in terms of performance and risk reduction, it may not be practical or even permitted during work hours in certain environments. Timed exposure to light. Based on the results of several studies, the AASM concludes that timed light exposure in the work environment and light restriction in the morning, when feasible, decreases sleepiness and improve alertness during night-shift work.14-20 A study that simulated a night-shift work pattern comprising four day shifts and three night shifts over the course of 10 days showed that a combination of afternoon/evening sleep (between 2 p.m. and 10 p.m.) and phase-advancing light therapy (between 3 a.m. and 7 a.m.) may be optimal for maintaining workplace alertness.21 Exercise. The current literature indicates that a moderate amount of exercise, which can be obtained through a variety of means, such as brisk walking or resistance training, is sufficient to improve sleep quality.22 Further research is needed to fully define the benefits of exercise among individuals with SWD. Additionally, optimal timing and regimens will need to be clearly delineated before exercise is considered a treatment guideline for SWD. In the meantime, clinicians should continue making recommendations for exercise regimens based on the patientâ&#x20AC;&#x2122;s health profile until new guidelines emerge in this arena. Evaluation of shift pattern. A 2003 study demonstrated that safety declines over successive night shifts, with increasing hours on duty, and between successive rest breaks.23 Working more than four consecutive eight-hour shifts should be avoided due to risk for decreased cognitive performance and increased risk of accidents on the job. Some shift patterns are more detrimental than others in terms of effects on performance. Researchers have shown that it is easier to change the sleep/wake cycle to clockwise shift rotation (i.e., a work schedule in which shifts move forward, from days to evenings to nights), as this follows the natural adaptive pattern of delay in the sleep period.24,25 Whenever possible, those on rotating shifts should be encouraged to rotate in a clockwise rather than a counterclockwise manner (i.e., a work schedule in which the shifts move backward, from nights to evenings to days).24

Pharmacologic interventions

Wakefulness-promoting agents. Modafinil (Provigil) and its R-enantiomer armodafinil (Nuvigil) have been evaluated specifically in patients with excessive sleepiness (ES) associated with SWD and are currently the only two drugs approved by the FDA as wakefulness-promoting agents for this indication. FDA approval of modafinil was based on the findings of two controlled clinical trials.26,27 Modafinil significantly improved wakefulness, as measured using patient diaries and changes on the Multiple Sleep Latency Test in those who had ES as a consequence of SWD. Attention was also significantly improved in the modafinil group compared with placebo, and significantly fewer participants treated with modafinil reported accidents or near-accidents while commuting home than did those who received placebo. Additionally, modafinil use was associated with significantly improved self-reports of functioning (in terms of alertness and vigilance) and quality of life in individuals with SWD.27 In both studies, the two most commonly reported adverse events with modafinil were headache and nausea. Investigators found that more patients treated with modafinil experienced insomnia compared with the placebo group (6% vs. 0%, respectively).27 Armodafinil was shown to improve wakefulness in individuals with ES associated with SWD in a 12-week randomized controlled study. A total of 254 individuals with SWD from 42 sleep-research facilities were enrolled in the trial. Armodafinil significantly improved mean sleep latency from 2.3 minutes at baseline to 5.3 minutes at final visit, compared with a change from 2.4 minutes to 2.8 minutes in the placebo group. Clinical condition ratings improved in more patients receiving armodafinil (79%) than in those receiving placebo (59%). As reflected by patient diaries, armodafinil significantly reduced sleepiness during laboratory nights, night shifts at work, and the commute home. Armodafinil also improved performance on standardized memory and attention tests compared with placebo. Armodafinil was well-tolerated and did not affect daytime sleep as measured by polysomnography. Headache and nausea were again the most common treatment-related adverse events in patients with SWD who took part in the study.28 A recent clinical trial compared the efficacy and safety of armodafinil (150 mg) with modafinil (200 mg) in individuals with SWD.29 Although both modafinil and armodafinil significantly improved mean sleepiness grades compared

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Caffeine may be useful in promoting wakefulness during the work period, but it may have some residual effects on daytime sleep. with baseline, no differences in efficacy or safety were found between the drugs. However, these two agents have different pharmacokinetic profiles.30 Compared with modafinil, armodafinil takes longer to reach its peak plasma concentration and is present at higher concentrations for a longer period after administration, causing its wakefulness-promoting effects to last throughout the day.31 The longer duration of the effects of armodafinil and its potential for once-daily dosing make this drug an appropriate and convenient choice for patients with SWD.32 Armodafinil’s low potential for abuse or tolerance also adds to its appeal.33 Stimulants. Such stimulants as methamphetamine have been shown to enhance wakefulness in individuals undergoing simulated night-shift work.34 However, amphetamines can induce rebound insomnia and this, combined with their adverse cardiovascular effects and potential for abuse, makes these medications less than ideal options for any chronic condition.35 Methamphetamine has not been evaluated as an intervention for individuals with a diagnosis of SWD, and although effective at improving performance and mood during one or more night shifts after a single dose, its usefulness in managing SWD on numerous sequential nights is questionable.36 A number of studies among individuals undergoing simulated night-shift work suggest that caffeine may be useful in promoting wakefulness during the work period; however, it may have some residual effects on daytime sleep depending on the caffeine-containing substance selected.37-39 It has been suggested that low-dose repeated caffeine administration may improve performance at the expense of increasing subjective ES during periods of extended wakefulness.40 As mentioned previously, caffeine in combination with other wakefulness-promoting strategies—including scheduled napping and bright-light therapy—has proved to be a promising intervention under simulated shift work conditions.41,42 However, the appropriate dose and timing of caffeine intake to optimize performance and mood during a night shift has not yet been determined. Higher caffeine doses may induce a state of hyperstimulation and can even be toxic.43 To date, regular and moderate caffeine intake has not been specifically assessed among individuals with SWD. Sleep-mediating hormone. Administration of melatonin can promote daytime sleep.44 However, while some studies have reported that melatonin is helpful for inducing daytime sleep in simulated and real-world work conditions,45-47 others have

failed to exhibit any subjective or objective benefit of taking melatonin after night-shift work.48 Single doses of melatonin taken before the required sleep period in simulated shift work studies of healthy subjects have been shown to decrease sleep latency and increase sleep duration.45 Melatonin doses in the studies ranged from 0.5 mg to 10 mg.45,46 In the resultant data, effectiveness did not appear to correlate with dosage strength or form. With that being said, however, simulation studies using melatonin doses ranging from 1.8 mg to 3 mg have shown a positive effect on sleep quality.7,45,46 Sleep-promoting agents (hypnosedatives). Zolpidem (Ambien, Edluar, Intermezzo, Zolpimist), zopiclone, triazolam (Halcion), and temazepam (Restoril) have all been shown to increase sleep duration during the day and to improve wakefulness during the night shift.34, 49-52 Only zopiclone has been evaluated among shift workers. In a study of 29 shift workers suffering from insomnia, a single 7.5-mg dose of zopiclone was found to increase the duration of sleep significantly over the baseline duration after the first and second nights on duty. Subjective estimation of sleep was better in patients taking zopiclone who exhibited a smaller number of shorter awakening episodes.53 No studies of hypnosedatives have been conducted among individuals with SWD. AASM advises clinicians to take care when prescribing hypnosedatives, as these medications might worsen such comorbid conditions as sleep-related breathing disorders.7 Conclusion

Although interventions specifically designed for individuals with SWD remain scarcely reported in the literature, there are a number of appropriate treatment options from which clinicians can choose when this diagnosis is suspected. Recognition of and appropriate referral for comorbidities is of paramount importance. From the outset, patients with SWD should be counseled on behavioral measures that may enhance sleep quality and prevent insomnia and excessive sleepiness. Such nonpharmacologic interventions as use of bright-light therapy (either before or during a night shift) and reduction of exposure to daylight on the commute home from work may be helpful.54-57 The use of certain melatonin agents before a required sleep period may also be beneficial. Whenever possible to execute, adjust shift schedules (clockwise-rotating shifts and avoiding shifts longer than 12 hours) and appropriately timed naps may contribute to better outcomes. Continues on page 70

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Wakefulness-promoting therapy should be introduced early in the management of individuals with SWD. Modafinil and armodafinil remain the only pharmacologic interventions with FDA approval for use in individuals with SWD. The clinician should integrate both nonpharmacologic interventions and pharmacologic therapies judiciously until more research is available that speaks specifically to those with SWD. n

14. Stewart KT, Hayes BC, Eastman CI. Light treatment for NASA shiftworkers. Chronobiol Int. 1995;12:141-151. 15. Yoon IY, Jeong DU, Kwon KB, et al. Bright light exposure at night and light attenuation in the morning improve adaptation of night shift workers. Sleep. 2002;25:351-356. 16. Boivin DB, James FO. Circadian adaptation to night-shift work by judicious light and darkness exposure. J Biol Rhythms. 2002;17:556-567. 17. Budnick LD, Lerman SE, Nicolich MJ. An evaluation of scheduled bright light and darkness on rotating shiftworkers: trial and limitations. Am J Ind

Ms. Salamanca is a psychiatric nurse practitioner at Hackensack University Medical Center in Hackensack, N.J.

Med. 1995;27:771-782. 18. Costa G, Ghirlanda G, Minors DS, Waterhouse JM. Effect of bright light on tolerance to night work. Scand J Work Environ Health. 1993;19:414-420.

References

19. Lowden A, Akerstedt T, Wibom R. Suppression of sleepiness and

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental

melatonin by bright light exposure during breaks in night work. J Sleep Res.

Disorders, Fourth Edition, Text Revision. Washington, D.C.: American Psychiatric

2004;13:37-443.

Association; 2000.

20. Bjorvatn B, Kecklund G, Akerstedt T. Bright light treatment used for

2. Bonnefont X. Circadian timekeeping and multiple timescale neuroendo-

adaptation to night work and re-adaptation back to day life. A field study at

crine rhythms. J Neuroendocrinol. 2010;22:209-216.

an oil platform in the North Sea. J Sleep Res. 1999;8:105-112.

3. Moore-Ede MC, Czeisler CA, Richardson GS. Circadian timekeeping in

21. Santhi N, Aeschbach D, Horowitz TS, Czeisler CA. The impact of sleep

health and disease. Part 1. Basic properties of circadian pacemakers. N Engl J

timing and bright light exposure on attentional impairment during night

Med. 1983;309:469-476.

work. J Biol Rhythms. 2008;23:341-352. Available at www.ncbi.nlm.nih.gov/

4. Waterhouse J, Reilly T, Atkinson G, Edwards B. Jet lag: trends and coping

pmc/articles/PMC2574505/.

strategies. Lancet. 2007;369:1117-1129.

22. Buman MP, King AC. Exercise as a treatment to enhance sleep. Am J

5. American Academy of Sleep Medicine. The International Classification

Lifestyle Med. 2010;4: 500-514.

of Sleep Disorders, 2nd ed.: Diagnostic and Coding Manual. Westchester, Ill.:

23. Folkard S, Tucker P. Shift work, safety and productivity. Occup Med (Lond).

American Academy of Sleep Medicine; 2005.

2003;53:95-101. Available at occmed.oxfordjournals.org/content/53/2/95.long.

6. Sack RL, Auckley D, Auger RR, et al. Circadian rhythm sleep disorders:

24. D’Alonzo GE, Krachman SL. Circadian rhythm sleep disorders.

part I, basic principles, shift work and jet lag disorders. An American

J Am Osteopath Assoc. 2000;100(8 Suppl):S15-S21. Available at www.jaoa.

Academy of Sleep Medicine review. Sleep. 2007;30:1460-1483.

org/content/100/8_suppl/15S.long.

7. Morgenthaler TI, Lee-Chiong T, Alessi C, et al. Practice parameters for

25. Son M, Kong JO, Koh SB, et al. Effects of long working hours and the

the clinical evaluation and treatment of circadian rhythm sleep disorders. An

night shift on severe sleepiness among workers with 12-hour shift systems

American Academy of Sleep Medicine report. Sleep. 2007;30:1445-1459.

for 5 to 7 consecutive days in the automobile factories of Korea. J Sleep Res.

8. Landolt HP, Gillin JC. Sleep abnormalities during abstinence in alcohol-

2008;17:385-394.

dependent patients. Aetiology and management. CNS Drugs. 2001;15:413-425.

26. Erman MK, Rosenberg R, Modafinil Shift Work Sleep Disorder Study

9. Schweitzer PK, Randazzo AC, Stone K, et al. Laboratory and field studies

Group. Modafinil for excessive sleepiness associated with chronic shift work

of naps and caffeine as practical countermeasures for sleep-wake problems

sleep disorder: effects on patient functioning and health-related quality of

associated with night work. Sleep. 2006;29:39-50.

life. Prim Care Companion J Clin Psychiatry. 2007;9:188-194. Available at www.

10. Sallinen M, Härmä M, Akerstedt T, et al. Promoting alertness with a

ncbi.nlm.nih.gov/pmc/articles/PMC1911168/.

short nap during a night shift. J Sleep Res. 1998;7:240-247.

27. Czeisler CA, Walsh JK, Roth T, et al. Modafinil for excessive sleepiness

11. Purnell MT, Feyer AM, Herbison GP. The impact of a nap opportunity

associated with shift-work sleep disorder. N Engl J Med. 2005;353:476-486.

during the night shift on the performance and alertness of 12-h shift workers.

Available at www.nejm.org/doi/full/10.1056/NEJMoa041292.

J Sleep Res. 2002;11:219-227.

28. Czeisler CA, Walsh JK, Wesnes KA, et al. Armodafinil for treatment of

12. Garbarino S, Mascialino B, Penco MA, et al. Professional shift-work driv-

excessive sleepiness associated with shift work disorder: a randomized

ers who adopt prophylactic naps can reduce the risk of car accidents during

controlled study. Mayo Clin Proc. 2009;84:958-972.

night work. Sleep. 2004;27:1295-1302.

29. Tembe DV, Dhavale A, Desai H, et al. Armodafinil versus modafinil in

13. Bonnefond A, Muzet A, Winter-Dill AS, et al. Innovative working

patients of excessive sleepiness associated with shift work sleep disorder:

schedule: introducing one short nap during the night shift. Ergonomics.

a randomized double blind multicentric clinical trial. Neurol Res Int. 2011;

2001;44:937-945.

2011:514351. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3135062/.

70 the clinical advisor • August 2013 • www.ClinicalAdvisor.com

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30. Darwish M, Kirby M, Hellriegel ET, Robertson P Jr. Armodafinil and

47. Burgess HJ, Sharkey KM, Eastman CI. Bright light, dark and melatonin can pro-

modafinil have substantially different pharmacokinetic profiles despite

mote circadian adaptation in night shift workers. Sleep Med Rev. 2002;6:407-420.

having the same terminal half-lives: analysis of data from three

48. Wright SW, Lawrence LM, Wrenn KD, et al. Randomized clinical trial of

randomized, single-dose, pharmacokinetic studies. Clin Drug Investig.

melatonin after night-shift work: efficacy and neuropsychologic effects. Ann

2009;29:613-623.

Emerg Med. 1998;32(3 Pt 1):334-340.

31. Darwish M, Bond M, Ezzet F. Armodafinil and modafinil in patients with

49. Bonnet MH, Dexter JR, Gillin JC, et al. The use of triazolam in phase-

excessive sleepiness associated with shift work disorder: a pharmacokinetic/

advanced sleep. Neuropsychopharmacology. 1988;1:225-234.

pharmacodynamic model for predicting and comparing their concentration-

50. Casagrande M, Ferrara M, Curcio G, Porcù S. Assessing nighttime vigi-

effect relationships. J Clin Pharmacol. 2012;52:1328-1342.

lance through a three-letter cancellation task (3-LCT): effects of daytime

32. Darwish M, Kirby M, Hellriegel ET, et al. Pharmacokinetic profile of

sleep with temazepam or placebo. Physiol Behav. 1999;68:251-256.

armodafinil in healthy subjects: pooled analysis of data from three random-

51. Hart CL, Ward AS, Haney M, Foltin RW. Zolpidem-related effects

ized studies. Clin Drug Investig. 2009;29:87-100.

on performance and mood during simulated night-shift work. Exp Clin

33. Bogan RK. Armodafinil in the treatment of excessive sleepiness. Expert

Psychopharmacol. 2003;11:259-268.

Opin Pharmacother. 2010;11:993-1002.

52. Moon CA, Hindmarch I, Holland RL. The effect of zopiclone 7.5 mg on

34. Hart CL, Haney M, Nasser J, Foltin RW. Combined effects of meth

the sleep, mood and performance of shift workers. Int Clin Psychopharmacol.

amphetamine and zolpidem on performance and mood during simulated

1990;5 Suppl 2:79-83.

night shift work. Pharmacol Biochem Behav. 2005;81:559-568.

53. Quera-Salva MA, Philip P, Taillard J, et al. [Study of the real situation of

35. Darke S, Kaye S, McKetin R, Duflou J. Major physical and psychological

improvement by Zopiclone in treatment of insomnia among persons work-

harms of methamphetamine use. Drug Alcohol Rev. 2008;27:253-262.

ing during night shifts]. Rev Neurol (Paris). 2002;158:1102-1106.

36. Comer SD, Hart CL, Ward AS, et al. Effects of repeated oral

54. Crowley SJ, Lee C, Tseng CY, et al. Complete or partial circadian re-

methamphetamine administration in humans. Psychopharmacology (Berl).

entrainment improves performance, alertness, and mood during night-shift

2001;155:397-404.

work. Sleep. 2004;27:1077-1087.

37. Jay SM, Petrilli RM, Ferguson SA, et al. The suitability of a caffeinated

55. Eastman CI, Stewart KT, Mahoney MP, et al. Dark goggles and bright light

energy drink for night-shift workers. Physiol Behav. 2006;87:925-931.

improve circadian rhythm adaptation to night-shift work. Sleep. 1994;17:535-543.

38. Muehlbach MJ, Walsh JK. The effects of caffeine on simulated night-shift

56. Crowley SJ, Lee C, Tseng CY, et al. Combinations of bright light, sched-

work and subsequent daytime sleep. Sleep. 1995;18:22-29.

uled dark, sunglasses, and melatonin to facilitate circadian entrainment to

39. Walsh JK, Muehlbach MJ, Humm TM, et al. Effect of caffeine on

night shift work. J Biol Rhythms. 2003;18:513-523.

physiological sleep tendency and ability to sustain wakefulness at night.

57. Revell VL, Burgess HJ, Gazda CJ, et al. Advancing human circadian rhythms

Psychopharmacology (Berl). 1990;101:271-273.

with afternoon melatonin and morning intermittent bright light. J Clin Endocrinol

40. Wyatt JK, Cajochen C, Ritz-De Cecco A, et al. Low-dose repeated caf-

Metab. 2006;91:54-59. Available at jcem.endojournals.org/content/91/1/54.long.

feine administration for circadian-phase-dependent performance degradation during extended wakefulness. Sleep. 2004;27:374-381.

All electronic documents accessed July 15, 2013.

41. Schweitzer PK, Randazzo AC, Stone K, et al. Laboratory and field studies of naps and caffeine as practical countermeasures for sleep-wake problems associated with night work. Sleep. 2006;29:39-50. 42. Berson DM, Dunn FA, Takao M. Phototransduction by retinal ganglion cells that set the circadian clock. Science. 2002;295:1070-1073. 43. Haller C, Kearney T, Bent S, et al. Dietary supplement adverse events: report of a one-year poison center surveillance project. J Med Toxicol. 2008;4:84-92. 44. Hughes RJ, Badia P. Sleep-promoting and hypothermic effects of daytime melatonin administration in humans. Sleep. 1997;20:124-131. 45. Sharkey KM, Fogg LF, Eastman CI. Effects of melatonin administration on daytime sleep after simulated night shift work. J Sleep Res. 2001;10:181-192. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3679650/. 46. Sharkey KM, Eastman CI. Melatonin phase shifts human circadian rhythms in a placebo-controlled simulated night-work study. Am J Physiol Regul Integr Comp Physiol. 2002;282:R454-R463. Available at ajpregu.physiology.org/content/282/2/R454.long.

“Have you tried taking long walks?”

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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 august 2013

Consultations Where are the generic inhalers?. . . . . 72 Fruit juice and diabetes . . . . . . . . . . . 72 Red wine for menstrual cramps. . . . . 73 Lab evaluation for pruritus. . . . . . . . . 73

Clinical Pearls Alleviating diarrhea subsequent to radiation. . . . . . . . . . . . . . . . . . . 74 Abdominal exams can be ticklish . . . . 74 Craving ice may signal anemia . . . . . . 74

Your Comments Disputing the facts about Plan B. . . . . 74

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.

Consultations Where are the generic inhalers? Will a generic albuterol hydrofluoroalkane (HFA) inhaler or a cortisone HFA inhaler ever be available? Many patients choose not to treat their asthma until they have an acute exacerbation. These same patients often cannot or are unwilling to pay the higher copayment for nongeneric medication.—JANET WAFER, FNP-C, Purchase, N.Y. In its final ruling, the FDA established that production and sale of single ingredient albuterol metered-dose inhalers that contain chloro fluorocarbons stop as of December 31, 2008 (available at www.fda. gov/Drugs/DrugSafety/InformationbyDrugClass/ucm080446. htm, accessed July 15, 2013). Ever since, patients have been forced to purchase brand-name HFA inhalers. The first of those patents expired in 2009 and 2010, but no generic versions have yet to appear in the marketplace. Speculation indicates that the next round of patent expirations will take place in 2014 and 2015. In the meantime, individuals with no insurance coverage may benefit from specific pharmaceutical company patient-assistance programs.— Sherril Sego, FNP-C, DNP (178-1)

Fruit juice and diabetes I have read that drinking too much sweetened soda and fruit punch, but not fruit juice, raises the likelihood of developing

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.

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diabetes. Fruit juices are still a basic sugar (fructose) and are quantity-restricted on diabetic diets. If there is evidence that their consumption does not carry the same risk as the other drinks listed, I would love to get back to enjoying at least one glass of orange juice.—WAYNE TAMBERELLI, PA-C, Roanoke Rapids, N.C.

Red wine is known to contain high levels of the potent antioxidant resveratrol. This polyphenol, combined with the wine’s alcohol content, exerts smooth-muscle relaxation and prostaglandin-inhibitory actions on the system that might logically mitigate dysmenorrhea.—Sherril Sego, FNP-C, DNP (178-3)

The amount of sugar in the diet does not cause diabetes. Type 2 diabetes is caused by a combination of genetic predisposition, environmental exposures, and overall imbalance of caloric intake and expenditure. Avoiding fruit juice throughout life will not prevent the development of diabetes. All individuals should be encouraged to maintain a balanced diet and to exercise to prevent diabetes, heart disease, cancer, and a number of chronic diseases. Once a patient has developed diabetes, it is advisable to restrict all sources of natural sugars and carbohydrates to <50% of caloric intake. Patients should be encouraged to increase fiber intake, especially whole grains, legumes, vegetables, and fruits. The overall caloric intake is what matters most. For additional information on meal planning and exchanges, refer to the American Diabetes Association website (www.diabetes.org). Another way to look at intake is with the glycemic index, which is a measure of how quickly a carbohydrate is digested and metabolized, thereby releasing glucose into the bloodstream. Foods with a high glycemic index will result in a rapid rise in blood glucose. Glycemic indices above 50 are considered high (e.g., honey 91, table sugar 64). Orange juice is in the 53-to-58 range, depending on the source. Fresh fruits, such as apples (38), are lower.—Claire Babcock O’Connell, MPH, PA-C (178-2)

Lab evaluation for pruritus How useful is blood work in finding the cause of pruritus that has few apparent primary skin changes and is unresponsive to topical steroids, pramoxine, lidocaine, and doxepin (Prudoxin, Zonalon)? What tests should be ordered?— MELISSA RAUE, PA-C, Pound Ridge, N.Y.

Red wine for menstrual cramps A patient was told by her gynecologist to drink 4 oz. of red wine to prevent menstrual cramps. Is there any evidence for this? – TERRIE ESTES, MSN, ANP, Colleyville, Tex.

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.

A thorough history and review of systems focusing on the onset, duration, and nature of the pruritus may help to establish its cause. Chronic, progressive, generalized pruritus in the absence of primary skin lesions may be secondary to an underlying systemic disease. Conservative symptomatic treatment is reasonable for the initial management of “pruritus of unknown origin.” If there is no response after two weeks, however, laboratory evaluation should be considered to exclude a possible systemic etiology, neurologic disorders, lymphoreticular neoplasms, visceral malignancies, and other conditions. Initial screening laboratory studies should include complete blood cell counts with differential WBC count and platelets; serum chemistries with particular attention to blood urea nitrogen, creatinine, alkaline phosphatase, bilirubin, and glucose; thyroid function tests (i.e., thyroxine, triiodothyronine resin uptake, and thyroid-stimulating hormone); stool examination for occult blood; and a chest roentgenogram. Depending on the results from the initial laboratory screening, additional tests to consider are serum iron and ferritin; serum protein electrophoresis and serum immunoelectrophoresis; skin biopsy for routine staining (i.e., hematoxylin and eosin stains) and special stains (i.e., toluidine blue or Giemsa to exclude

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.

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Editor’s note: This comment was written in response to a post in The Waiting Room, our collection of expert blogs. To read more, visit the website at CliniAd.com/VwgfCl.

When treating a patient for pruritus of unknown origin, rule out dermatitis herpetiformis (shown) with a skin biopsy.

mastocytosis); skin biopsy for direct immunofluorescence (to exclude dermatitis herpetiformis and bullous pemphigoid); stool examination for ova and parasites; urine collection for 5-hydroxyindoleacetic acid and mast-cell metabolites (i.e., histamine, histamine metabolites, and prostaglandin D2 metabolites); and additional radiologic studies. —Philip R. Cohen, MD (178-4)

Clinical pearls Alleviating diarrhea subsequent to radiation For individuals with intractable diarrhea related to pelvic radiation, alternate loperamide with diphenoxylate/ atropine (Lomotil) before moving on to tincture of opium or octreotide (Sandostatin).—JOAN ZAMPIERI, PA-C, Houston (178-5)

Disputing the facts about Plan B I want to comment on Ms. Carlisle’s statement that “contrary to widespread misinformation Plan B is NOT an abortion pill.” (“The facts about Plan B,” available at CliniAd. com/15XOze1). If one defines an abortion as the removal of a fetus or embryo from the uterus before viability, Plan B potentially falls into this category. For many patients, life begins at conception. A woman’s choice to use Plan B (or recommend that her daughter use Plan B) would be affected by the knowledge that a fertilized egg would not be allowed to implant. To allow patients to make informed decisions, clinicians need to provide accurate and complete information. It is a disservice to presume that everyone believes life begins at implantation (or after) or to use a personal definition of what constitutes an abortion. It is better to err on the side of too much information than to simplify something that could lead an individual to compromise on his or her morals. —JANNA WILLHAUS, Prairie Village, Kan.

Abdominal exams can be ticklish Enlist the help of a ticklish child when palpating his or her abdomen. I find having the child place his or her hand over mine and help guide it as I examine the various regions reduces the child’s squirming.—RENEE BARALL, FNP, Colorado Springs, Colo. (178-6)

The primary mechanism of action of emergency contraception is to prevent ovulation. Plan B may cause changes to the endometrium that would inhibit implantation of a fertilized egg, but there is not enough evidence to support this theory. Furthermore, the FDA, National Institutes of Health, and American Congress of Obstetricians and Gynecologists define pregnancy as beginning with implantation. Based on that widely accepted definition, Plan B is not an abortion. If we are truly providing complete information to our patients, we must also counsel them that all hormonal contraceptive methods may also prevent pregnancy by inhibiting ovulation or fertilization or by preventing implantation of a fertilized egg. This even includes the method of lactational amenorrhea (exclusive breastfeeding for the first six months postpartum). I do not know any provider who considers this method of contraception to be an abortion.—Robyn Carlisle, MSN, CNM, WHNP (178-8)

Craving ice may signal anemia When assessing for fatigue, inquire about an abnormal craving for ice, which may be a sign of iron-deficiency anemia. Patients on blood thinners may experience a similar craving.—TERRI GRIFFIS, RN, FNP-S, Southlake, Tex. (178-7)

Correction: The July 2013 Advisor Forum mistakenly provided outdated information. Because of the potential risk of serious and life-threatening hematologic reactions, quinine sulfate is no longer recommended as a treatment for nocturnal leg cramping (Item 177-4). The editor apologizes for the error. n

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XXXX13_AANP SpecConf ClinicalAdv Ad 7/8/13 2:46 PM Page 1

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/10KIbCF. Learn more about diagnosing and treating these conditions, and see how you compare with your colleagues.

Small annular plaques on the legs A woman in her 60s presents with a progressinve rash consisting of multiple small annular plaques on her legs. No pruritus or pain was noted. According to the patient, her mother had the same condition. What is your diagnosis?

• Annular lichen planus • Actinic keratosis • Annular psoriasis • Disseminated actinic porokeratosis

● See the full case at CliniAd.com/1bV4zDo

A linear lesion on the anterior frontal scalp Several years ago, a woman from Mexico developed a lesion that started on the frontal scalp and progressed down her forehead. The lesion is currently stable and has not changed or progressed for at least two years. What is your diagnosis?

• CREST syndrome • Linear morphea • Atrophoderma of Pasini and Pierini • Generalized systemic sclerosis ● See the full case at CliniAd.com/1aDT7ZG

Have you missed any recent Derm Dx cases? Go to CliniAd.com/10KIbCF for a complete archive of past quizzes as well as additional images of last month’s other cases.

Red, scaly rash all over the body

Itchy blister between the toes

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LEGAL ADVISOR CASE

Facets of HIPAA compliance

By Ann W. Latner, JD

Mr. D had been employed as a physician assistant in a small suburban office under the supervision of Dr. G, a general practitioner, for the three years. When Mr. D was hired, Dr. G explained to him that since she was a solo practitioner and the office had little in the way of staff, Mr. D would be expected to perform a variety of duties, including some administrative work. Although he wasn’t too keen on the prospect, Mr. D accepted the responsibility. As it turned out, Mr. D’s office duties were largely confined to a half-day, once a week. The office manager worked only in the morning each Friday, so if any recordkeeping or some other office duty needed to be handled on a Friday afternoon, Mr. D would take care of those administrative tasks that needed immediate attention. Mr. D’s principal responsibilities, however, involved treating patients on his own or providing a preliminary clinical evaluation before Dr. G saw the patient. The office work structure kept things running smoothly, and the staff seemed to be happy with this setup.

An inadvertent mistake in transferring a patient’s records reveals his HIV status to his employer.

Instead of personalized fax cover sheets, the clinic used blank forms that required the sender to fill in the “to” and “from” sections.

Early one Friday morning, the office manager got a call from Mr. M, a 45-year-old, HIVpositive man who had been seeing Dr. G for routine care for more than a decade. Although Mr. M was happy with the treatment he had been receiving, his company was transferring him to another town. He called to ask Dr. G’s office to fax his medical records to his new health-care provider. The office manager had not gotten around to faxing the records by the time she left on Friday afternoon, so this task was one of a score of jobs Mr. D needed to attend to that day. Instead of personalized fax cover sheets, the clinic used forms that the office manager printed off once a week, with blank spaces requiring the sender to complete the “to” and “from” sections. Mr. D quickly filled in the form and sent the fax to Mr. M’s new clinician before his next 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.

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LEGAL ADVISOR patient arrived. He did not give the fax another thought until the following Monday, when the office manager came into the back office to speak to him. She was pale and looked shaken, and Mr. D immediately asked her if she was okay. “It’s about Mr. M,” the office manager explained. “He just called, and he is absolutely furious. Apparenly, someone faxed his medical records to his current employer rather than to his new clinician. This means that his company is now aware of his HIV status. Needless to say, Mr. M is extremely upset with us right now.” “I don’t believe it,” said Mr. D, feeling a swell of rising panic. “I sent that fax out late last week. I must have accidentally copied the wrong fax number from his file. What should we do?” Both Mr. D and the office manager looked to Dr. G for guidance.

The Office for Civil Rights issued a letter of warning and referred the office staff for HIPAA privacy training. Dr. G rubbed her forehead, trying to figure out the best way to remedy the situation. “The first thing we are going to do is call Mr. M and apologize,” she announced. “Then we’ll take it from there.” Both practitioners called Mr. M and apologized profusely for the mistake. Mr. M understood that this had not been done maliciously, but he was still not satisfied, and ultimately reported the incident to the U.S. Department of Health and Human Services (HHS) Office for Civil Rights (OCR). A preliminary investigation determined that the incident was not criminal, so the case was handled by the OCR rather than being referred to the Department of Justice. After a more thorough on-site investigation, the OCR issued a letter of warning to Mr. D and ordered the office staff to undergo privacy training. The OCR also had the office revise the format of the practice’s fax cover sheets to underscore the confidentiality of the communication for the intended recipient. Legal background

The Health Insurance Portability and Accountability Act of 1996 (HIPAA) was created to protect the personal health information of patients and specifies to providers how such information may be used. In the time since HIPAA took effect, the HHS has received a total of almost 80,000 complaints. Of those complaints, more than 44,000 were

dismissed, more than 19,000 were investigated and resolved with changes to privacy practice, and more than 9,000 were investigated and found no violation. According to HHS, private medical practices were most often required to take corrective action as a result of enforcement. The top two compliance issues most frequently investigated are the impermissible use and disclosure of protected health information and a lack of safeguards for protected health information. When a HIPAA complaint is filed with HHS, investigators attempt to determine if there is a possible privacy violation and whether or not it is of a criminal nature. If a violation is determined to be criminal, the case is referred to the Department of Justice for investigation and possible prosecution. When the offense is not considered to be criminal, the OCR is charged with investigating the matter. Once a HIPAA violation is confirmed, the OCR can either obtain voluntary compliance from the offender or take corrective action (often requiring the offender to engage in mandatory changes). Finally, the OCR can issue a formal finding of violation and force the offender to change its practices. In this case, Mr. D and Dr. G immediately took corrective action by apologizing to the patient. As a result of the official investigation, Dr. G’s office agreed to two OCR recommendations: (1) to have the staff undergo special HIPAA compliance training, and (2) to change office faxing procedures, specifically indicating when faxed materials are confidential. Protecting yourself

This situation was the result of a careless error. Mr. D was doing too much at once and not paying attention to the task at hand. While anyone can make a careless error, one such as this could cause irreparable harm to the patient, if his employer were to view or treat him differently because of the revelation of his HIV-positive status. Confidential patient records must be treated with the greatest of care, as they often contain sensitive information. Many HIPAA cases have involved the unintentional divulging of the HIV status of a patient. In a similar case, a dental practice was reported to HHS for using red stickers and stamping the word “AIDS” on the outside of patient folders. And in a case that took place in a hospital, a nurse and an orderly lost their jobs for discussing a patient’s HIV status within earshot of other patients. Always remember to treat a patient’s confidential information as you would want yours to be treated, and then add a little extra security for good measure. n

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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 91

n additional CME/CE: Pages 66, 87

Turn to page 65 for additional information on this month’s CME/CE courses.

CASE #1

A painless bleeding nodule on the shoulder Audrey Chan, MD

A 9-year-old boy came in for an evaluation of a lesion on his right posterior shoulder that developed approximately three months prior to presentation. The lesion was not painful, but it bled with minimal contact. No prior trauma to the area was reported, and there was no personal or family history of similar lesions. A review of systems was negative for fever, chills, malaise, and unusual weight loss. On physical examination, the patient was noted to have a 4-cm exophytic nodule covered by dried heme crust. A shave biopsy was performed. What is your diagnosis? Turn to page 80

CASE #2

White dome-shaped facial papules Allison Pagano and Julia R. Nunley, MD

A white woman, aged 43 years, presented for facial lesions. The lesions were first noted approximately 10 years ago and had since grown in number and in size. She had previously been prescribed a number of acne medications and topical steroids, but nothing proved to be effective. The woman’s father and paternal grandmother had similar lesions. Medical history revealed three episodes of spontaneous pneumothoraxes as a young adult. Family history was significant for renal cancer in her father. Physical examination revealed numerous firm, white, smooth, and dome-shaped papules across the cheeks and forehead. What is your diagnosis? Turn to page 81 www.ClinicalAdvisor.com • the clinical advisor • august 2013 79

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CME CE

CASE #1

Dermatology Clinic

Pyogenic granuloma

A shave biopsy of the skin revealed a pyogenic granuloma. Pyogenic granuloma, also known as lobular capillary hemangioma, is a benign vascular lesion of the skin and mucosa. These lesions are relatively common. Although pyogenic granulomas can occur at any age, they are more common in children and young adults, representing 0.5% of all skin nodules in children.1 Males and females are affected equally. There is no known racial predilection. Pyogenic granulomas on the gingiva are more common in pregnant women.2 The pathophysiology of pyogenic granuloma is unknown but is likely the result of reactive neovascularization.2 Onethird of cases have a history of preceding trauma or irritation. Recent genetic studies demonstrate increased protein expression in the nitric oxide pathway and FLT4 (a tyrosine kinase receptor), which is related to hypoxia-induced angiogenesis and vascular injury.3 Pyogenic granulomas may develop during pregnancy, so hormonal influences may also be a factor in the onset of this condition. Medications that have been associated with the development of pyogenic granuloma include the following: antineoplastics (paclitaxel [Abraxane, Onxol, Taxol], docetaxel [Docefrez, Taxotere], capecitabine [Xeloda], mitoxantrone [Novantrone]), antiretrovirals (indinavir [Crixivan], lamivudine [Epivir], zidovudine [Retrovir]), epidermal growth factor receptor inhibitors (cetuximab [Erbitux], erlotinib [Tarceva], gefitinib [Iressa]), immunosuppressants (cyclosporine [Gengraf, Neoral, Sandimmune), and retinoids (acitretin [Soriatane], etretinate [Tegison], isotretinoin).4 Pyogenic granulomas present as a solitary red papule or polyp. There is often a history of rapid growth over weeks to months, after which time the lesion stabilizes. Pyogenic granulomas rarely grow larger than 1 cm, making the size in the case described here an unusual feature. The most common sites in decreasing order of frequency are the gingiva, fingers, lips, face, and tongue.5 Frequent and easy bleeding is often the presenting complaint when patients seek care for these lesions. Pyogenic granulomas can very rarely present in extracutaneous sites, including the GI tract, subcutaneous tissue, or within the veins. There is a case report of pyogenic

granuloma developing in the stomach presenting with melena.6 Subcutaneous pyogenic granulomas can present as a painful or a painless protruding nodule in the finger with easy bleeding on contact.7 Intravenous pyogenic granulomas (IVPG) usually occur in the veins of the neck and upper extremities. Unlike cutaneous pyogenic granulomas, this condition is usually seen in adults. IVPG can present with an asymptomatic mass with or without focal swelling distal to the lesion secondary to venous occlusion.8 Although pyogenic granulomas are usually solitary, disseminated and eruptive forms on the skin have occurred in the settings of burns and drug hypersensitivity reactions, within congenital vascular lesions, and in otherwise healthy patients.9-11 The diagnosis of pyogenic granuloma can usually be made by clinical exam. A skin biopsy can confirm the diagnosis and is often curative. The characteristic feature on skin biopsy is a well-circumscribed and exophytic proliferation of small capillaries that are divided into lobules by thick bands of fibrous tissue. The lateral margins of the papule are often defined by epithelial collarettes from either peripheral adnexal hyperplasia or downward growth of rete ridges.2 Because these lesions are easily traumatized, there is often secondary ulceration. Pyogenic granuloma will demonstrate positive Wilms tumor 1 protein expression, a marker for vascular tumors.12 Ultrasound findings of subcutaneous pyogenic granuloma have been described as hypoechoic and homogeneous masses with marked vascularity.7 In infants, the differential diagnosis includes an infantile hemangioma. Hemangiomas are usually more plaquelike and often have a deeper-blue subcutaneous component. In adults, pyogenic granulomas may rarely be confused with angiolymphoid hyperplasia with eosinophilia or amelanotic melanoma; however, these lesions can be distinguished from pyogenic granuloma by the lack of intense red color typically seen in vascular lesions. In an immunosuppressed patient, bacillary angiomatosis or Kaposi sarcoma could be difficult to distinguish from a pyogenic granuloma. On the hands, the differential diagnosis includes acquired digital fibrokeratoma or glomus tumor. An acquired digital fibrokeratoma is usually skin-colored, unlike pyogenic granulomas, which are red and vascular in appearance. Glomus tumors usually present as small blue papules, most commonly in subungual sites. With any of these entities, if a diagnosis cannot be made on clinical grounds, a skin biopsy is diagnostic. Subcutaneous pyogenic granulomas might be confused with such other subcutaneous tumors as giant cell tumor of the tendon sheath, but the latter is hard and fixed to underlying structures. Since subcutaneous

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lesions are usually too deep to be sampled by skin biopsy, ultrasound and other imaging studies may be useful. Treatment of pyogenic granulomas can easily be achieved by shave, punch, or scalpel excision. Frequently, the shave biopsy is deep enough to also be curative; however, the rate of recurrence may be as high as 9.55%.13 Although full-thickness excision has the lowest risk of recurrence among surgical options (2.94%), this must be weighed against the fact that excisions are more expensive, more time-consuming, and have the potential for more morbidity than a simple shave removal. Nonsurgical options include cryotherapy with liquid nitrogen, laser therapy (CO2 laser, flashlamp-pumped pulsed dye laser), and topical imiquimod (Aldara, Zyclara).13 Cryotherapy was noted to have a low recurrence rate (1.62%), but required two sessions on average for removal of the lesion. Both CO2 laser and flashlamp-pumped pulsed dye laser had recurrence rates of less than 5%, but the majority of patients undergoing flashlamp-pumped pulsed dye laser required more than one treatment for clearance. Patients who underwent CO2 laser only required one treatment. Topical imiquimod 5% cream was used in a study of five pediatric patients with resolution of lesions within two to four weeks; however, imiquimod cream commonly causes significant local irritation that may limit patient compliance in general practice.14 Although the nonsurgical options demonstrated low recurrence rates,13 shave removal is still the most common modality to treat pyogenic granulomas, as it is relatively inexpensive and requires only one clinic visit. The patient in this case was anesthetized with local injections of lidocaine, and his lesion was shave-removed and electrodesiccated with successful resolution.

5. Kerr DA. Granuloma pyogenicum. Oral Surg Oral Med Oral Pathol.

Dr. Chan is a second-year resident in the Department of Dermatology at Baylor College of Medicine in Houston.

The histologic evaluation of a biopsy of a papule was diagnostic for a fibrofolliculoma, a rare and benign follicular hamartoma. The presence of a fibrofolliculoma in an individual with a history of spontaneous pneumothorax and family history of renal cancer led to the diagnosis of Birt-Hogg-Dubé (BHD) syndrome. First described in 1977, this syndrome is a multisystem disorder characterized by the cutaneous triad of fibrofolliculomas, trichodiscomas, and acrochordons.1 Patients with BHD have an increased risk of internal malignancy and spontaneous pneumothorax.

References 1. Patrice SJ, Wiss K, Mulliken JB. Pyogenic granuloma (lobular capillary hemangioma): a clinicopathologic study of 178 cases. Pediatr Dermatol. 1991;8:267-276. 2. Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd ed. St. Louis, Mo.: Elsevier-Mosby; 2008:1776-1777. 3. Godfraind C, Calicchio ML, Kozakewich H. Pyogenic granuloma, an impaired wound healing process, linked to vascular growth driven by FLT4 and the nitric oxide pathway. Mod Pathol. 2013;26:247-255. 4. Paul LJ, Cohen PR. Paclitaxel-associated subungual pyogenic granuloma: report in a patient with breast cancer receiving paclitaxel and review of drug-induced pyogenic granulomas adjacent to and beneath the nail. J Drugs Dermatol. 2012;11:262-268.

1951;4:158-176. 6. Kusakabe A, Kato H, Hayashi K, et al. Pyogenic granuloma of the stomach successfully treated by endoscopic resection after transarterial embolization of the feeding artery. J Gastroenterol. 2005;40:530-535. 7. Lee GK, Suh KJ, Lee JH, et al. Lobular capillary hemangioma in the soft tissue of the finger: sonographic findings. Skeletal Radiol. 2010;39:1097-1102. 8. Ceyhan AM, Basak PY, Akkaya VB, et al. A case of multiple, eruptive pyogenic granuloma developed on a region of the burned skin: can erythromycin be a treatment option? J Burn Care Res. 2007;28:754-757. 9. Ghekiere O, Galant C, Vande Berg B. Intravenous pyogenic granuloma or intravenous lobular capillary hemangioma. Skeletal Radiol. 2005;34:343-346. 10. Palmero ML, Pope E. Eruptive pyogenic granulomas developing after drug hypersensitivity reaction. J Am Acad Dermatol. 2009;60:855-857. 11. Baselga E, Wassef M, Lopez S, et al. Agminated, eruptive pyogenic granuloma-like lesions developing over congenital vascular stains. Pediatr Dermatol. 2012;29:186-190. 12. Lawley LP, Cerimele F, Weiss SW, et al. Expression of Wilms tumor 1 gene distinguishes vascular malformations from proliferative endothelial lesions. Arch Dermatol. 2005;141:1297-1300. Available at archderm.jamanetwork.com/article.aspx?articleid=399310. 13. Lee J, Sinno H, Tahiri Y, Gilardino MS. Treatment options for cutaneous pyogenic granulomas: a review. J Plast Reconstr Aesthet Surg. 2011;64:1216-1220. 14. Fallah H, Fischer G, Zagarella S. Pyogenic granuloma in children: treatment with topical imiquimod. Australas J Dermatol. 2007;48:217-220. All electronic documents accessed July 15, 2013.

CASE #2

Birt-Hogg-Dubé syndrome

Continues on page 82

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CME CE

Dermatology Clinic

BHD is a genetic condition that is inherited in an autosomaldominant fashion with high penetrance; however, sporadic mutations have been described. In 2002, the genetic defect was identified as a germline defect in the folliculin (FLCN) gene on chromosome 17p11.2.2 This is the only gene known to be associated with BHD and is found in 88% of affected individuals.7 Current evidence suggests that the FLCN gene may have tumor-suppressor effects within the skin, kidneys, and lungs. As a result, the clinical constellation of BHD includes fibrofolliculomas, multiple pulmonary cysts, pneumothorax, and renal tumors that are often bilateral or multifocal. The spectrum of cutaneous hamartomas associated with BHD includes fibrofolliculomas, angiofibromas or tricho discomas, perifollicular fibromas, and acrochordons.3 However, the fibrofolliculoma is the only true hallmark specific for BHD. Lesions generally arise during the third decade of life and may be single or innumerable; areas typically affected include the scalp, forehead, face, and neck.4 A punch biopsy is necessary to confirm the diagnosis.5 The histologic pattern of a fibrofolliculoma demonstrates a hair follicle filled with multiple anastomosing epithelial strands surrounded by a well-circumscribed proliferation of mucin-rich stroma.6,7 The

Some suggest that fibrofolliculomas and trichodiscomas are opposite ends of the spectrum of the same disorder. histologic pattern of a trichodiscoma, which is similar to an angiofibroma, shows a hamartomatous proliferation of fibrous and vascular stroma in the reticular dermis.7 Some suggest that fibrofolliculomas and trichodiscomas are opposite ends of the spectrum of the same disorder, with the trichodiscoma being the more mature form and the fibrofolliculoma the more immature.8 Although the conditions may be related, only the fibrofolliculoma is diagnostic for BHD; however, the presence of a trichodiscomas should raise one’s suspicion.7 Treatment for any of these lesions is limited. Several case reports have shown that laser ablation provides temporary improvement, but relapse is common.7 Alternative options include shave and cautery or curettage and hyfrecation.3 Lesion removal or destruction may leave unacceptable scarring. A modality to halt lesion development or growth has not yet been found. The most life-threatening consequence of BHD is renal cancer. First documented in 1993, this association is now

well-established. Kindred studies have indicated that most renal cancers occur later than the cutaneous findings; however, renal cancers have been described in the rare 20-year-old patient.9 Various histologic subtypes of renal cancer have been described, but a hybrid of chromophobe and oncocytoma renal carcinoma appears to be the most predominant.1 When associated with BHD, renal tumors are found to be bilateral and multifocal in more than half of those affected.5 In addition to renal carcinoma, benign renal cysts are also found, although the prevalence is largely unknown. There are currently no set guidelines regarding surveillance of BHD. An annual renal MRI may be the best screening option; ultrasound is not sensitive enough to detect small lesions, and annual CT scans would subject the patient to an unacceptably high cumulative radiation dose.10 More than 80% of patients with BHD have pulmonary cysts detectable on CT.7 The number of reported cysts ranges widely, from zero to a staggering 166, with a mean count of 16 per patient. Although most of these lesions are asymptomatic, a cyst may be the presenting sign of this syndrome. In general, spontaneous pneumothorax is more frequently associated with cysts in the pulmonary apices; in BHD cases, most cysts are in the basal layer. Interestingly, Toro reported one or more pneumothoraces to develop in 24% of patients with BHD.7 Despite cystic changes, lung function in most BHD patients appears to be largely unaffected.3 Routine screening for pulmonary cysts is not indicated, but an individual with BHD should be educated as to the risk in addition to the signs and symptoms so that he or she may seek appropriate attention if necessary.2 Patients with BHD should also be encouraged not to smoke and to avoid unnecessary changes in external air pressure, which may cause rupture of pulmonary cysts.3 Alternatively, BHD should be suspecgted in patients who develop presumed idiopathic, spontaneous pneumothoraces. However, because of the clinical subtleties of BHD, practitioners must have a high index of suspicion to make the diagnosis. Other genetic conditions with cutaneous lesions need to be in the differential diagnosis of BHD. Tuberous sclerosis, which has such overlapping clinical features as angiofibromas, cysts, and renal tumors, must be excluded. Additional conditions to be considered include familial trichoepitheliomas, multiple endocrine neoplasia type 1, and Cowden syndrome.7 Diagnostic criteria include the presence of five or more cutaneous papules with at least one histologically confirmed fibrofolliculoma.3 Although the original criteria for the diagnosis was based on skin pathology, recent investigations

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have shown that some individuals with BHD have pulmonary and renal involvement without skin findings.7 Genetic testing is now available. Once the diagnosis is made, a systemic evaluation is warranted. Current recommendations include a thorough history and physical, an MRI scan of the abdomen to evaluate for renal lesions, and possibly a chest x-ray to assess for lung cysts. Since recent studies have suggested an association with intestinal polyps, surveillance for colorectal neoplasia should also be considered in all patients with BHD. Fortunately, no malignancy was detected on evaluation in this case. Serial imaging studies will follow on a periodic basis. The woman declined genetic testing. n Ms. Pagano is a fourth-year student at Medical College of Virginia Hospitals, Virginia Commonwealth University, in Richmond, where Dr. Nunley is a professor of dermatology.

“It’s interpret-your-own-test-results day today.”

References 1. Lindor NM, Hand J, Burch PA, Gibson LE. Birt-Hogg-Dube syndrome: an autosomal dominant disorder with predisposition to cancers of the kidney, fibrofolliculomas, and focal cutaneous mucinosis. Int J Dermatol. 2001;40:653-656. 2. Reese E, Sluzevich J, Kluijt I, et al. Birt-Hogg-Dubé Syndrome. In: RiegertJohnson DL, Boardman LA, Hefferon T, et al., eds. Cancer Syndromes. Bethesda, Md.: National Center for Biotechnology Information; 2009. Available from www.ncbi.nlm.nih.gov/books/NBK45326/. 3. Menko FH, van Steensel MA, Giraud S, et al. Birt-Hogg-Dubé syndrome: diagnosis and management. Lancet Oncol. 2009;10:1199-1206. 4. Mahto A. Birt-Hogg-Dubé syndrome. J Am Acad Dermatol. 2012;66 (Suppl 1):AB92.

5. Garg A, Herts BR. Birt-Hogg-Dube syndrome. J Urol. 2012;188:1343-1344. 6. Vincent A, Farley M, Chan E, James WD. Birt-Hogg-Dubé syndrome: a review of the literature and the differential diagnosis of firm facial papules. J Am Acad Dermatol. 2003;49:698-705. 7. Toro JR. Birt-Hogg-Dubé Syndrome. In: Pagon RA, Adam MP, Bird TD, et al, eds. GeneReviews. Seattle, Wa.: University of Washington, Seattle; 19932013. Available from www.ncbi.nlm.nih.gov/books/NBK1522/. 8. Scalvenzi M, Argenziano G, Sammarco E, Delfino M. Hereditary multiple fibrofolliculomas, trichodiscomas and acrochordons: syndrome of BirtHogg-Dubè. J Eur Acad Dermatol Venereol. 1998;11:45-47. 9. Fahmy W, Safwat AS, Bissada NK, et al. Multiple/bilateral renal tumors in patients with Birt-Hogg-Dubé syndrome. Int Urol Nephrol. 2007;39:995-999. 10. López V, Jordá E, Monteagudo C. [Birt-Hogg-Dubé syndrome: an update]. Actas Dermosifiliogr. 2012;103:198-206. Available at www .actasdermo.org/en/birthoggdube-syndrome-an-update/articulo/90140428/. All electronic documents accessed July 15, 2013.

“He’s perfectly nice, but sort of boring, like good cholesterol or something.”

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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.

Botulinum toxin

Botulinum toxin (BoNT), often referred to as a “miracle poison,” is one of the deadliest biological substances known to man.1 BoNT is a neurotoxin produced by Clostridium botulinum. A rod-shaped anaerobic bacterium, C. botulinum is commonly found in the soil. The bacterium has been known to cause botulism—a rare but serious, and sometimes fatal, paralytic illness. While the danger of this BoNT is very real, it has found its way into modern medicine as a treatment for a wide array of conditions ranging from strabismus to muscle spasms to hyperhidrosis.

Background BoNT was identified for therapeutic use more than a century ago.2 The toxin’s first effects on neuromuscular transition were discovered in the 1940s. In the late 1960s, ophthalmologists began experimenting with chemodenervation in monkeys. The 1980s saw the first human use of the toxin to treat two ophthalmic conditions, strabismus and blepharospasm. In 2002, the FDA approved BoNT as a wrinkle-reducing agent, licensed and marketed under the tradename Botox.2 In 2004, the FDA approved Botox for the treatment of primary hyperhidrosis.2 By 2007 the use of Botox to diminish facial wrinkles was the most common cosmetic procedure performed in the United States.2

Science BoNT acts by binding to receptor sites on the cholinergic nerve terminals. This action results in a decrease in the

release of acetylcholine, causing a neuromuscular blockade.3 The chemodenervation experiments in the 1960s were initially conducted using Rhesus monkeys with strabismus. By injecting a tiny amount of BoNT into the horizontal rectus muscles in the stronger eye, the toxin caused minor muscular paralysis and strengthened the use of the other eye. Subsequent human experiments showed that injecting BoNT into the extraocular muscles of 42 strabismus patients had a uniformly beneficial effect that lasted up to 411 days without systemic or local complications.4 Botox is also used in the treatment of muscle spasms. The muscle-weakening effect produced by BoNT lessens the spams and can last for 60 to 70 days.5 Two large Cochrane systematic reviews of 16 randomized, placebo-controlled trials overwhelmingly supported both the safety and the efficacy of Botox for the relaxation of persistent cervical muscle contraction.6 Botox represents the only true semi-ablative therapy for the treatment of primary hyperhidrosis.This condition—which

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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

“Is there anything sadder than an underfunded wax museum?”

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alternative meds update typically involves the palms, soles, and axillae— causes excessive, drenching perspiration.Affecting an estimated 2% to 3% of the population in the United States, hyperhidrosis has, to date, had no other satisfactory or effective treatment.7 In one randomized, placebo-controlled, double blinded study, 145 patients with severe hyperhidrosis (rates of axillary sweat production >50 mg per minute) were given an injection of BoNT type A (BoNT/A) into the axilla.8 Two weeks after the initial injections, the mean (+/- SD) rates of sweat production were 24±27 mg per minute in the axillae treated with BoNT/A and 144±113 mg per minute in the axillae treated with placebo.8 Botox is also widely used for the treatment and management of migraine headaches. In a doubleblind, controlled study, 123 patients known to have frequent, severe migraines were monitored after receiving injections of either BoNT/A or an inert liquid for three months.9 At the trial’s end, patients who received the active toxin showed a greater than 50% reduction in both the frequency and severity of migraine episodes.9 Another common but debilitating condition that responds well to Botox therapy is temporomandibular joint syndrome (TMJ). According to the National Institutes of Health, 10 million people in the United States suffer from TMJ, a condition that was responsible for 17 million lost working days in 2001.10 In a literature review, researchers found sufficient evidence for the safety and efficacy of Botox treatment in TMJ.6

requiring localization of a very small muscle are usually guided by electromyography.11

Summary BoNT now plays a significant role in the management of a wide variety of medical conditions, and the list of possible new indications is rapidly expanding. Unfortunately, cost may be a significant barrier since many insurance plans do not cover BoNT treatment. n Botulinum toxin is an effective treatment for strabismus.

In 2002, the FDA approved botulinum toxin as a wrinklereducing agent, licensed and marketed under the trade name Botox.

Safety concerns

References 1. Erbguth FJ. Historical notes on botulism, Clostridium botulinum, botulinum toxin, and the idea of the therapeutic use of the toxin. Mov Disord. 2004;19 Suppl 8:S2-S6. 2. Münchau A, Bhatia KP. Uses of botulinum toxin injection in medicine today. BMJ 2000;320:161. Available at www.bmj.com /content/320/7228/161. 3. Drugs, Diseases & Procedures: Botulinum Toxin page. Medscape Reference web ite. Available at emedicine.medscape .com/article/325451-overview#aw2aab6b4. 4. Scott AB, Miller JM, Shieh KR.Treating strabismus by injecting the agonist muscle with bupivacaine and the antagonist with botulinum toxin. Trans Am Ophthalmol Soc. 2009;107:104-109. 5. Bihari, K. Safety, effectiveness, and duration of effect of BOTOX after switching from Dysport for blepharospasm, cervical dystonia, and hemifacial spasm dystonia, and hemifacial spasm. Curr Med Res Opin. 2005;21:433-438. 6. Persaud R, Garas G, Silva S, et al. An evidence-based review of botulinum toxin (BOTOX) applications in non-cosmetic head and neck conditions. JRSM Short Rep. 2013;4:10. 7. PubMed Health website. Hyperhidrosis page. Available at www.ncbi.nlm.nih.gov/pubmedhealth/PMH0004518. 8. Heckmann M, Ceballos-Baumann AO, Plewig G, et al. Botulinum toxin A for axillary hyperhidrosis (excessive sweating).

Botox therapy is generally safe when administered by a trained health-care professional. Pain and excessive muscle weakness (in the injected area) are the most commonly noted side effects.

How supplied, dose

N Engl J Med. 2001;344:488-493. Available at www.nejm.org/doi /full/10.1056/NEJM200102153440704. 9 Silberstein S, Mathew N, Saper J, Jenkins S. Botulinum toxin type A as a migraine preventive treatment. For the BOTOX migraine clinical research group. Headache. 2000;40:445-450. 10. National Institutes of Health website: National Institute of Dental and Craniofacial research:TMJ Disorders page. Available at www.nidcr.nih.gov/OralHealth/Topics/TMJ/TMJDisorders.htm. 11. Nigam PK, Nigam A. Botulinum toxin. Indian J Dermatol. 2010,55:8-14. All electronic records accessed on July 15, 2013.

BoNT is injected into the designated area with a fine-gauge needle.Total dose is determined largely by muscle mass at the injection site.The injections are administered directly into the targeted muscle through hollow Teflon-coated needles. Cases 86 the clinical advisor • august 2013 • www.ClinicalAdvisor.com

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Dermatologic Look-Alikes

CME CE

n Learning objective: To distinguish and properly treat dermatologic conditions with similar presentations. n complete the posttest: Page 91

n additional CME/CE: Pages 66, 79

Turn to page 65 for additional information on this month’s CME/CE courses.

Urticating papules Kerri Robbins, MD

CASE #1

CASE #2

A man, aged 43 years, presented with a pruritic eruption that had been present for three months. The eruption began on his trunk and then spread to the proximal extremities. Extreme temperature changes and alcohol consumption aggravated the lesions. A review of systems was otherwise normal. Medical and family histories were unremarkable. Physical exam revealed reddish-brown macules and papules on the trunk and proximal extremities that would urticate when stroked. No lymphadenopathy or hepatosplenomegaly was appreciated.

A 22-year-old woman presented to the clinic complaining of “lumps” on her back. The lesions had been present for five months and were occasionally associated with pain, especially in cold weather. There was no associated pruritus. A review of systems was otherwise negative. Medical and family histories revealed a prior diagnosis of uterine leiomyomas in the woman and her mother. On physical examination, a group of erythematous firm papules was appreciated on the left mid-back. After gentle stroking, the lesions appeared to urticate.

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CME CE

CASE #1

Dermatologic Look-Alikes

Mastocytosis

Mastocytosis is a term used to describe a spectrum of clinical disorders that have local and/ or systemic accumulations of mast cells. In 1869, Nettleship and Tay first described mastocytosis in a young girl with hyperpigmented papules that urticated.1 Eight years later, Erlich discovered the mast cell. Unna was the first to identify mast cells as the responsible entity in cutaneous mastocytosis. However, it was not until nearly 60 years later, in 1949, that Ellis reported the first patient with systemic disease. The World Health Organization classifies mastocytosis into cutaneous and systemic forms. These include cutaneous mastocytosis (urticaria pigmentosa, diffuse cutaneous mastocytosis, and mastocytoma of the skin), indolent systemic mastocytosis, systemic mastocytosis with an associated clonal hematologic non-mast cell lineage disease, aggressive systemic mastocytosis, mast-cell leukemia, mast-cell sarcoma, and extracutaneous mastocytoma.2 If extracutaneous involvement is present, the skeletal system, bone marrow, lymph nodes, spleen, liver, GI system, and central nervous system are the most commonly affected organs. This article will primarily address cutaneous mastocytosis. Mastocytosis may be present at birth or develop anytime thereafter. Approximately 55% of patients develop the disease prior to age 2 years, and another 10% develop the disease between age 2 years and age 15 years. Most patients with mastocytosis have no family history of the disease; however, a small number of familial cases have been described.3 Women and men are equally affected, and there is no racial predilection. There are both childhood and adult forms of mastocytosis, and they vary in clinical presentation, prognosis, and pathogenesis. Many cases of adult mastocytosis result from a neoplastic proliferation of mast cells caused by a mutation at codon 816 in the c-KIT gene. c-KIT is a proto-oncogene whose protein product is the transmembrane tyrosine kinase KIT receptor (CD117) and whose ligand is stem-cell factor. This mutation leads to constitutive activation of KIT, thereby causing continued mast-cell development. Childhood mastocytosis is defined as disease onset prior to puberty. Interestingly, childhood and familial cases of mastocytosis do not usually harbor the c-KIT mutation. Childhood disease is thought to arise from mutations other

than the 816 type, from cytokine-derived hyperplasias, or from other yet unidentified mutations. Urticaria pigmentosa represents 60% to 90% of childhood cases of cutaneous mastocytosis. The most common clinical presentation is that of tan, brown, or rose-colored macules and papules that have a predilection for the trunk, sparing the central face, scalp, palms, and soles. Solitary mastocytomas, which present as a yellow-brown papule or plaque, comprise 10% to 40% of childhood mastocytoses. Diffuse cutaneous mastocytosis is a rare form of childhood mastocytosis in which the entire skin is thickened and infiltrated with mast cells. The skin often has a peau dâ&#x20AC;&#x2122;orange appearance, and generalized bullae and erosions may develop. In children, systemic involvement is rarely seen. Most cases of early-onset, skin-limited disease will resolve spontaneously or markedly improve by adolescence. Individuals who have lesions that persist into adulthood are thought to possess the c-KIT activating mutation and have the same prognosis as adult-onset mastocytosis patients. Adult-onset mastocytosis most commonly presents as a generalized eruption that favors the trunk and proximal extremities. Characteristic lesions are pink or reddish-brown macules and papules that measure 1 cm or less in diameter. Telangiectasia macularis eruptive perstans is a form of adult mastocytosis that most commonly presents with persistent, asymptomatic, reddish-brown macules and patches with telangiectasias that usually measure less than 0.5 cm. Erythrodermic mastocytosis presents as generalized erythroderma and the skin has a leather-grain appearance. In adults with the c-KIT activating mutation, lesions tend to persist throughout life and the likelihood of systemic involvement is higher. Histologically, an increased number of mast cells, which have a fried-egg appearance with granules in an amphophilic cytoplasm, will be appreciated. If needed, such special stains as Giemsa, toluidine blue, and Leder or monoclonal antibodies that recognize tryptase or CD117 (KIT) can help to identify tissue mast cells. Lesions of mastocytosis often exhibit a positive Darier sign (urtication on stroking). Other diseases that may exhibit a positive Darier sign include juvenile xanthogranulomas, histiocytosis X, leukemia cutis, and lymphoma. A pseudoDarier sign, defined as transient piloerection and elevation or increased induration of a lesion after rubbing, clinically resembles Darier sign and may be seen in leiomyomas or smooth-muscle hamartomas. Other diseases in the clinical differential diagnosis include pigmented nevi, juvenile xanthogranuloma, xanthomas, arthropod bites, and bullous disorders.

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Once a diagnosis of mastocytosis is reached, the decision to assess for bone marrow involvement must be made. In general, all adult patients and children with an unexplain able abnormal complete blood count (CBC), hepatomegaly, splenomegaly, lymphadenopathy, or a baseline serum tryp tase >20 ng/mL should be offered a bone-marrow biopsy. In adults who do not meet the above criteria, yearly CBC and serum tryptase testing should be performed, along with a complete history and physical examination. Those with symptomatic mastocytosis should identify and avoid such triggers as temperature extremes, alcohol, and certain medications, including aspirin, nonsteroidal antiinflammatory drugs, narcotics (e.g. morphine, codeine), anticholinergic medications, polymyxin B sulfate, and some systemic anesthetics. Local injection of lidocaine can be used safely. If needed for symptom control, local therapy includes potent or superpotent topical steroids and intralesional corticosteroids. Systemic therapy for symp tom control includes oral H1 and H2 receptor antagonists, oral cromolyn sodium (Gastrocrom), oral corticosteroids, and oral PUVA. Systemic therapy for severe mastocytosis includes interferon α-2b (Intron A), cladribine (Leustatin), hydroxyurea (Droxia, Hydrea), and specific tyrosine kinase inhibitors, such as imatinib mesylate (Gleevec) (depending on the type of c-KIT mutation).4 In this case, a biopsy confirmed the diagnosis of masto cytosis. History, physical examination, CBC, and serum tryptase were all within normal limits. The patient continues to be followed annually to monitor for disease progression.

CASE #2

Piloleiomyoma

L eiomyom a s were f i r st described by Rudolf Virchow in 1854. The three distinct va r ia nt s of leiomyom a s include piloleiomyomas, genital leiomyomas, and angi oleiomyomas. Cutaneous leio myomas are rare neoplasms, and their exact incidence is unknown. One general surgi cal pathology practice reported the incidence to be as low as 0.04% in approximately 85,000 cases.5 Men and women are equally affected, and there is no racial predilection. Most patients develop the tumors during adolescence or

early adulthood; however, rare congenital or pediatric cases have been described. Cutaneous leiomyomas are benign dermal tumors. Piloleiomyomas are derived from the arrector pili mus cles. Genital leiomyomas arise from the dartoic, vulvar, or mammary smooth muscles. The smooth muscles that envelop dermal blood vessels give rise to angioleiomyomas. Individuals with multiple cutaneous leiomyomas may have multiple cutaneous and uterine leiomyomatosis (MCUL) syndrome. This syndrome is also known as multiple leio myomatosis, Reed’s syndrome, and leiomyomatosis cutis et uteri. MCUL is an autosomal dominant disorder with germline mutations in the fumarate hydratase gene, located on chromosome 1q42.3-43.6 Fumarate hydratase is an enzyme of the mitochondrial Krebs cycle that catalyzes fumarate to malate. Individuals who have this germline mutation are at high risk for developing MCULs. A small number of these patients are also at risk of developing earlyonset papillary renal cell carcinoma.5,6 When associated with renal cell carcinoma, these patients are said to have hereditary leiomyomatosis and renal cell cancer (HLRCC). Piloleiomyomas present as skin-colored, pink, or reddishbrown dermal papules or nodules that are small and firm and that can be solitary or multiple. Solitary piloleio myomas are most commonly located on the extremities, whereas multiple piloleiomyomas are most commonly seen on the trunk, with a predilection for the shoulder. Solitary piloleiomyomas tend to be bigger than those of multiple piloleiomyomas but rarely grow larger than 2 cm in diameter. Piloleiomyomas are frequently associated with spontaneous or induced pain. Known triggers include pres sure, trauma, emotion, and cold temperatures. The exact pathogenesis of the pain is unknown. However, several hypotheses have been proposed, including contraction of smooth muscle, compression of nearby nerves, or an increased number of nerve bundles.7 Genital leiomyomas usually present as solitary interdermal papules or nodules that may be pedunculated and are usually smaller than 2 cm in diameter. Genital leiomyomas can be located on the labia majora, the vulva, the scrotum, and occasionally the nipple. In contrast to other leiomyomas, most genital lesions are asymptomatic. Angioleiomyomas usually present as firm subcutaneous nodules on the lower extremities. These nodules are usually solitary and do not exceed 4 cm in diameter. In all leiomyomas, the major constituent cell is the myocyte. Myoctes are fusiform and have centrally located elongated nuclei with blunt ends (cigar-shaped). Often, perinuclear

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CME CE

Dermatologic Look-Alikes

vacuoles can be appreciated. If smooth-muscle differentiation is not obvious on hematoxylin-and-eosin-stained tissue, Masson trichrome stain (which will stain muscle red) or immunohistochemistry that demonstrates antibodies against smooth-muscle actin and/or desmin may prove helpful. Piloleiomyomas tend to be poorly demarcated and are composed of intersecting smooth-muscle bundles centered in the reticular dermis with varying amounts of intermingled collagen at the periphery. The tumors can extend into the fat and the overlying epidermis may be normal, effaced, or hyperplastic. Genital leiomyomas are often larger and better circumscribed than are piloleiomyomas. Tumors of the scrotum are usually homogeneous spindle cell tumors, whereas tumors involving the vulva can show hyalinization, myxoid change, or epithelioid cytology. Nipple leiomyomas most closely resemble piloleiomyomas. Angioleiomyomas are usually encapsulated and well-circumscribed nodules located in the lower reticular dermis and subcutis. These tumors contain smooth-muscle bundles that surround numerous thick-walled vessels. Because of the wide spectrum of clinical presentations (solitary, linear, clustered, and so forth) the differential diagnosis

offer genetic counseling, and arrange for additional screening for uterine leiomyomas and renal cell cancer in those at risk for MCUL and HLRCC. In this case, an excisional biopsy revealed the diagnosis of piloleiomyoma. The woman was referred to genetics and advised to undergo regular screenings for uterine leiomyomas and renal cell cancer. n Dr. Robbins is an instructor in the Department of Dermatology at Baylor College of Medicine in Houston. Reference 1. Nettleship E, Tay W. Rare forms of urticaria. Br Med J. 1869;2:323-324. 2. Valent P. Diagnostic evaluation and classification of mastocytosis. Immunol Allergy Clin North Am. 2006;26:515-534. 3. Longley BJ Jr, Metcalfe DD, Tharp M, et al. Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. Proc Natl Acad Sci USA. 1999;96:1609-1614. Avaialable at www.pnas.org/content/96/4/1609.long. 4. Pardanani A. Systemic mastocytosis: disease overview, pathogenesis, and treatment. Hematol Oncol Clin North Am. 2012;26:117-28. 5. Stewart L, et al: Association of germline mutations in the fumararte

Since leiomyomas are benign tumors, the extent of treatment will be solely dependent on the severity of symptoms.

hydratase gene and uterine fibroids in women with hereditary leiomyo matosis and renal cell cancer. Arch Dermatol. 2008;144:1584-1592. 6. Choudhary S, McLeod M, Torchia D, Romanelli P. Multiple cutaneous and uterine leiomyomatosis syndrome: a review. J Clin Aesthet Dermatol. 2013;6:16-21. Available at www.ncbi.nlm.nih.gov/pmc/articles/ PMC3638850/. 7. Raj S, Calonje E, Kraus M, et al. Cutaneous pilar leiomyoma: clinicopathologic analysis of 53 lesions in 45 patients. Am J Dermatopathol. 1997;19:2-9. 8. Christenson LJ, Smith K, Arpey CJ. Treatment of multiple cutaneous leiomyomas with CO2 laser ablation. Dermatol Surg. 2000;26:319-322. All electronic documents accessed July 15, 2013.

is broad. Dermal neoplasms, including dermatofibromas, dermatofibrosarcoma protuberans, schwannomas, neurofibromas, adnexal tumors, and cutaneous metastases, are often considered. Leiomyomas may present with a pseudo-Darier sign due to muscle-fiber contraction, which may help to differentiate these tumors from other entities in the differential. If needed, a biopsy will provide a definitive diagnosis. Since leiomyomas are benign tumors, the extent of treatment will be solely dependent on the severity of symptoms. Solitary or limited tumors may be surgically removed. Tumors that are not amenable to surgical excision may be treated with such off-label therapies as nitroglycerin (Nitrolingual, Nitromist, Nitrostat), nifedipine, doxazosin (Cardura), phenoxybenzamine (Dibenzyline), topical 9% hyoscine hydrobromide, gabapentin (Horizant, Neurontin), or CO2 laser ablation.6,8 Malignant transformation of cutaneous leiomyomas is rare, and the prognosis is generally good. However, the clinician must not forget to take a detailed family history,

“Someday, son, all this will be yours.”

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posttest Expiration date: August 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 66

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page 87

Treatment options for shift work disorder

Case #1: Pyogenic granuloma

Case #1: Mastocytosis

1. What is the most common site of pyogenic granulomas? a. Gingiva b. Tongue c. Fingers d. Face

1. What type of lesions are characteristic of adult-onset mastocytosis? a. Areas of erythema with exudative lesions b. Solid, firm, thick plaques with scaling c. Pink or reddish-brown macules and papules d. Raised papules and plaques with silvery scales

1. What is a comorbid condition that contributes to poor sleep hygiene? a. Obstructive sleep apnea b. Depression c. Obesity d. All of the above 2. Which of the following promotes daytime sleep among night-shift workers? a. Planned napping b. Timed light exposure c. Administration of melatonin d. Consumption of caffeine

2. What is the most frequent treatment of pyogenic granulomas? a. Topical imiquimod (Aldara, Zyclara) b. Shave removal c. CO2 laser d. Liquid nitrogen

3. What characteristic of armodafinil (Nuvigil) makes it a convenient choice for patients with shift work disorder? a. Once-daily dosing b. Lack of side effects c. Quick achievement of peak plasma concentration d. Superior efficacy

Case #2: Birt-Hogg-Dubé (BHD) syndrome

4. What is a common side effect of modafinil (Provigil)? a. Diarrhea b. Ataxia c. Dizziness d. Headache

4. BHD is associated with which malignancy? a. Renal cancer b. Lymphoma c. Pancreatic cancer d. Chronic myelogenous leukemia

To take the Posttest please go to CliniAd.com/18xXKUh

3. Patients with BHD have an increased risk of a. Cardiac arrhythmias b. Stroke c. Spontaneous pneumothorax d. Esophageal ulcers

2. What is a trigger for symptomatic mastocytosis? a. Temperature extremes b. Alcohol c. Aspirin d. All of the above Case #2: Piloleiomyoma 3. Solitary piloleiomyomas are most commonly located on the a. Extremities b. Trunk c. Scalp d. Groin 4. What is a treatment for solitary or limited tumors? a. Intralesional corticosteroids b. UVB phototherapy c. Cryotherapy d. Surgical excision

To take the Posttest please go to CliniAd.com/15GcnCA

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CME

posttest Expiration date: August 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 August 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 66

page 79

page 87

Treatment options for shift work disorder

Case #1: Pyogenic granuloma

Case #1: Mastocytosis

1. What is the most common site of pyogenic granulomas? a. Gingiva b. Tongue c. Fingers d. Face

2. What is the most frequent treatment of pyogenic granulomas? a. Topical imiquimod (Aldara, Zyclara) b. Shave removal c. CO2 laser d. Liquid nitrogen

Case #2: Birt-Hogg-Dubé (BHD) syndrome

4. What is a common side effect of modafinil (Provigil)? a. Diarrhea b. Ataxia c. Dizziness d. Headache

4. BHD is associated with which malignancy? a. Renal cancer b. Lymphoma c. Pancreatic cancer d. Chronic myelogenous leukemia

To take the Posttest please go to CliniAd.com/18xXKUh

3. Patients with BHD have an increased risk of a. Cardiac arrhythmias b. Stroke c. Spontaneous pneumothorax d. Esophageal ulcers

To take the Posttest please go to CliniAd.com/15GcnCA

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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 3,000 clinical topics and is updated daily through systematic surveillance covering more than 500 journals.The most important evidence identified is summarized here.

Extended Anticoagulation with Apixaban or Dabigatran Reduces Recurrent VTE and Mortality without Increasing Major Bleeding Level 1: Likely reliable evidence Anticoagulation treatment for individuals with venous thromboembolism (VTE) is generally recommended for at least three months (Eur Heart J. 2008;29:2276-2315; available at eurheartj .oxfordjournals.org/content/29/18/2276. long, accessed July 15, 2013; Chest. 2012;141[2 Suppl]:e419S-e494S; available at www.ncbi .nlm.nih.gov/pmc/articles/PMC3278049/, accessed July 15, 2013), but there is a high risk of recurrence. Extended treatment decreases the risk of recurrence, but can increase the risk of major bleeding (Cochrane Database Syst Rev. 2006;1:CD001367). Therefore, the decision concerning how long to continue anticoagulation can be complicated, especially in patients with unprovoked VTE. Two new trials evaluated the safety and efficacy of extended anticoagulation treatment with either apixaban (AMPLIFY-EXT) (N Engl J Med 2013;368:699-708) or dabigatran (RE-SONATE) (N Engl J Med 2013. 21;368:709-718). In the AMPLIFY-EXT trial, 2,486 patients with VTE who had already completed 6-12 months of anticoagulation therapy were randomized to apixaban (2.5 mg vs. 5 mg) orally twice daily vs. placebo for an additional 12 months. Previous treatments included warfarin, apixaban, or enoxaparin. All patients were recurrence-free during previous treatment, and were eligible for either continuation or cessation of anticoagulation therapy.

Dabigatran was associated with a reduced risk of clinically-relevant bleeding, and with a nonsignificant reduction in major bleeding.

Symptomatic or fatal VTE occurred in 1.7% in each apixaban group (2.5 mg and 5 mg doses) and in 8.8% in the placebo group (p <0.001, NNT=14 for each apixaban dose). There were no significant differences in the rates of major bleeding among groups (0.1%-0.2% with apixaban vs. 0.5% with placebo). The higher apixaban dose was associated with an increase in clinically relevant nonmajor bleeding compared with placebo (4.2% vs. 2.3%, p <0.05, NNH 52). The difference between the rates of clinically relevant bleeding between the lower dose and placebo (0.7%) was not significant. In the RE-SONATE trial, 1,353 patients with VTE who had completed six to 18 months of anticoagulation therapy were randomized to dabigatran 150 mg orally twice daily vs. placebo for six months. Recurrent or fatal VTE occurred in 0.4% with dabigatran vs. 5.6% with placebo (p <0.001, NNT=20). Clinically relevant bleeding occurred in 5.3% vs. 1.8% (p=0.001, NNH 28), but there was no significant difference in the rates of major bleeding. An additional noninferiority trial (RE-MEDY) comparing dabigatran with warfarin was reported in the same article. The rates of recurrent or fatal VTE were similar for the two active drugs, but dabigatran was associated with a reduced risk of clinically relevant bleeding (5.6% vs. 10.2%, p <0.001, NNT=22), and with a nonsignificant reduction in major bleeding (0.9% vs. 1.8%, p=0.06). Continues on page 94

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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Evidence-Based Medicine

Increasing Radiation Exposure of the Heart is Associated with Increasing Cardiovascular Risk in Women with Breast Cancer Treated with Radiation Therapy Level 2: Mid-level evidence Incidental exposure of the heart to radiation is a common unintended consequence of radiation therapy for breast cancer. The association between cardiac radiation exposure and the development of ischemic heart disease was investigated in a recent population-based case-control study with women from Swedish and Danish cancer registries (N Engl J Med. 2013;368:987-998). A total of 2,168 women younger than age 75 years who had radiation therapy for breast cancer between 1958 and 2001 were analyzed. The cases were 963 women who had a major coronary event (myocardial infarction, revascularization, or death from ischemic heart disease) before breast cancer recurrence or diagnosis of a second cancer. The controls were 1,205 women (matched to cases on age and year of diagnosis) who also had radiation therapy, but who did not have a major coronary event before the time to event of the matched case. The women were assessed for incidental radiation exposure of whole heart and left anterior descending coronary artery based on reviews of their treatment fields and dose plans. The estimated mean radiation exposure of the heart was 4.9 Gy overall (cases and controls). For each 1-Gy increase in heart exposure, the risk of a major coronary event was increased by 7.4% (95% CI 2.9%-14.5%) overall. The increase in risk was highest within the first four years following radiation treatment (16.3%, 95% CI 3%-64.3%) and fell to 8.2% (95% CI 0.4%-26.6%) at ≥20 years after treatment. Cases had higher rates of baseline cardiovascular factors than did controls, and women with risk factors had higher absolute event rates than did women without, but the increase in risk per radiation dose was independent of underlying risk.

Other options for long-term prophylaxis against VTE recurrence include rivaroxaban (N Engl J Med. 2010;363:24992510; available at www.nejm.org/doi/full/10.1056/ NEJMoa1007903, accessed July 15, 2013) and aspirin (N Engl J Med. 2012;366:1959-1967; available at www.nejm. org/doi/full/10.1056/NEJMoa1114238, accessed July 15, 2013). In the absence of head-to-head trials comparing the different possible treatments, the decision as to whether to give additional treatment and the decision as to which agent to use must be individualized, based on risks for bleeding and risks for recurrence of VTE.

Incidental cardiac radiation exposure is a common consequence of radiotherapy for breast cancer (shown).

The treatment period of this study spans many decades, and breast-radiation techniques have evolved to limit the exposure of the heart and left anterior descending coronary artery, although radiation exposures may not be eliminated entirely. Current data suggest that there is no threshold level of radiation at which cardiovascular risk begins to increase. Therefore, these findings may be useful in deciding what treatment for breast cancer is most appropriate, taking into account the woman’s underlying cardiovascular risk profile. They also may help guide the care of women who were treated before improved radiation methods were in use and may have increased risks comparable to the women in this study.

Initial Treatment with Physical Therapy for Meniscal Tear is Associated with Functional Improvement Similar to Surgery and May Lower Surgery Rates in Patients with Knee Osteoarthritis Level 2: Mid-level evidence Meniscal tears are common in patients with osteoarthritis of the knee, and symptomatic tears are frequently treated with arthroscopic surgery. Existing data from randomized trials show arthroscopic debridement is not effective for treating knee osteoarthritis (N Engl J Med. 2008;359:1097-1107, N Engl J Med 2002;347:81-88), but these trials have not specifically addressed meniscal tears. A new trial compared initial physical therapy vs. initial arthroscopic surgery for symptomatic meniscal tears in this population (N Engl J Med. 2013;368:1675-1684). Continues on page 97

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Evidence-Based Medicine

A total of 351 patients with mild-to-moderate osteoarthritis and symptomatic meniscal tear were randomized to one of two treatments and followed for one year. The first group began treatment with a standardized physical therapy regimen but had the option for surgery at the discretion of patient and surgeon. The second group had immediate arthroscopic partial meniscectomy followed by the same standardized physical therapy. The physical therapy regimen for both groups included interventions to address inflammation, range of motion, muscle strength, aerobic conditioning, functional mobility, and balance. There were one or two weekly sessions plus home exercises for approximately six weeks, depending on patient progress. All patients could have acetaminophen or NSAIDs as needed, and intra-articular glucocorticoid injections were permitted. The primary outcome was change in physical function as measured by the Western Ontario and McMaster Universities Osteoarthritis Index scale (WOMAC score, 0-100 scale with higher scores indicating more severe symptoms). The mean WOMAC scores at baseline were 37.5 in the physical therapy group and 37.1 in the surgery group. A change in WOMAC score of eight points was considered clinically meaningful. Patients who did not complete follow-up (6% at six months and 9% at one year) were excluded from the analyses. Both groups showed significant improvement in physical function by WOMAC score at six months (decrease in score 18.5 vs. 20.9) and one year (decrease in score 22.8 vs. 23.5). There were no significant differences in improvement between groups at either time point. Nearly one-third of the physical therapy group crossed over to surgical treatment in the first six months. In the physical therapy group, 44% had clinically relevant improvement at six months without crossing over, compared with 67% in the surgery group (p <0.001). There were no significant differences in adverse events or pain at six or 12 months. Most of the patients in the physical therapy group who had surgery in the first six months had little functional improvement prior to crossover. However, their one-year outcomes were similar to those seen in the immediate-surgery group, suggesting that delaying surgery did not have a detrimental effect. It should be noted that the WOMAC questionnaire is a valid measure of physical function during basic activities of daily living, but it does not assess high-level function as may be required for work or sports. Nevertheless, these results suggest that physical therapy may be an appropriate first option for many patients with osteoarthritis and meniscal tears and that it may be possible to reserve surgery for those who do not benefit from physical therapy alone. n

“I forget—are you not speaking to me or just not listening to me?”

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COMMENTARY Judi Greif, RN, MS, APN-C, is a family nurse practitioner currently residing in East Brunswick, N.J.

Retail medicine: A final sale? It is 7:00 p.m. on a weeknight as I walk into my local pharmacy. I sign in at a kiosk to get my annual flu shot. Waiting for the nurse practitioner to call my name prompts me to think about how convenient it is to take care of this in 20 minutes—less than the time it takes to drive to my doctor’s office, let alone sit in her waiting room or wait the week it might take to get an appointment. On the surface, the emergence of so-called “retail medicine” fills a niche; in reality, the concept may be more controversial. Furthermore, I ponder what the future holds for these unique providers of health care, especially as the Affordable Care Act becomes a reality.

Concerns about the quality of care in retail clinics have not come to fruition, but physicians continue to harbor worries.

The first retail clinic opened in Minnesota in 2000, and now more than 1,200 pepper the landscape, mainly in retail stores such as chain pharmacies. Retail clinics treat a limited menu of acute conditions, such as sore throats and minor skin problems, in addition to offering preventive services including cholesterol screenings and vaccinations. Staffed primarily by nurse practitioners and physician assistants, these venues achieve a high level of patient satisfaction, most likely attributable to their convenience and low cost. Some see retail clinics as a threat to the financial viability of private practices, and to the continuity and quality of care that private practices offer. The opposing view is that retail clinics may take the strain off of overwhelmed physicians, and that traditional health-care settings still serve as resources when follow-ups and referrals are needed. Although concerns about the quality of the care rendered by retail clinics—as would be evidenced by such indicators as the need for repeat visits, the overprescribing of antibiotics, and missed opportunities for preventive care— have not come to fruition, physicians and their professional societies continue to harbor worries regarding fragmentation of care, coordination of electronic medical records, and the lack of formal oversight. Not surprisingly, the American Academy of Pediatrics (AAP) and the American Academy

of Family Physicians (AAFP) have issued statements speaking out against retail clinics, whereas the American Association of Nurse Practitioners has endorsed these setups. The AAP and AAFP have raised concerns about loss of the medical home and continuity of care, particularly for chronically ill patients. The AANP points to the provision of highquality, timely, evidence-based care being made available to those who might not otherwise be able to see a health-care practitioner. All organizations, including the American Medical Association, have made recommendations to assure that care is collaborative with a physician and is carefully monitored. Retail clinics may branch out into chronicdisease management or weight loss or smoking cessation counseling, and make services available in the workplace or through telemedicine. However, it must be made clear that there are limitations to the types of patients and illnesses that can be adequately and appropriately triaged to such venues, and that collaboration with and referral to traditional primary-care settings will only strengthen—not hamper—the relationship between retail clinics and conventional medical practices as we struggle to provide primary-care services to all who require them. As I wait to be called in for my flu vaccine, how can I deny that there is a place for retail clinics? n

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