May 2018 Clinical Advisor by The Clinical Advisor

A P E E R - R E V I E W E D 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

■■Skin cancer prevention ■■Antibiotic-resistant bacteria ■■Allergic disease risk ■■IBD and DPP-4 inhibitors FEATURE Oral Anticoagulation

Advances in reversal agents key for preventing bleeding LEGAL ADVISOR

A patient dies after a missed diagnosis

DERMATOLOGY CLINIC

A pink rash with fine scale in a 7-year-old boy

FREE CME COURSE

Rheumatoid arthritis: a journey toward remission

M AY 2 01 8

| www.ClinicalAdvisor.com

DEEP VEIN THROMBOSIS

Emergence of NOACs expands treatment options for patients DVT typically consists of pain and swelling in a lower extremity.

Editor Colby Stong editor@clinicaladvisor.com Associate editor Madeline Morr Assistant editor Rita Aghjayan Contributing editors Mark P. Brady, PA-C; Philip R. Cohen, MD; Deborah L. Cross, MPH, CRNP, ANP; Sharon Dudley-Brown, PhD, FNP; Abimbola Farinde, PharmD; Laura A. Foster, CRNP, FNP; Abby A. Jacobson, PA; Maria Kidner, DNP, FNP; Joan W. Kiely, MSN, CRNP; Debra August King, PhD, PA; Ann W. Latner, JD; Mary Newberry, CNM, MSN; Claire Babcock O’Connell, MPH, PA; Kathy Pereira, DNP, FNP; Sherril Sego, DNP, FNP; Ann Walsh, PA-C, SCT(ASCP); Kim Zuber, PA-C Production editor Kim Daigneau Group art director, Haymarket Medical Jennifer Dvoretz Production manager Krassi Varbanov Circulation manager Paul Silver National accounts manager Alison McCauley, 973.224.6414 alison.mccauley @ haymarketmedical.com Publisher Kathleen Hiltz, 201.774.1078 kathleen.hiltz@haymarketmedia.com Editorial director Kathleen Walsh Tulley General manager, medical communications Jim Burke, RPh CEO, Haymarket Media, Inc. Lee Maniscalco All correspondence to: The Clinical Advisor 275 7th Avenue, 10th 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 21, Number 5, is published 12 times a year, monthly, by Haymarket Media, Inc., 275 7th Avenue, 10th Floor, New York, NY 10001. For Advertising Sales & Editorial, call (646) 638-6000 (M–F, 9am–5pm, ET). The Clinical Advisor is available on a paid subscription basis at the following annual rates: $75 USA, $85 Canada, $110 for all other foreign, in U.S. dollars, Single copy price: USA $20, Foreign $30. To order or update a paid subscription visit our website at www. ClinicalAdvisor.com or call (800) 436-9269. Periodicals postage rate paid at NewYork, NY, and additional mailing offices. Postmaster: Send changes of address to The Clinical Advisor, c/o Direct Medical Data, 10255 W. Higgins Rd., Suite 280, Rosemont, IL 60018. All rights reserved. Reproduction in whole or in part without permission is prohibited.

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EXPERTS If a patient has you stumped, write us and we’ll forward your query to one of our consultants and publish the response in Advisor Forum.You can also use this space to contribute a clinical pearl of your own or comment on another letter.

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.

CLINICAL PEARLS

It cannot be beat.—TERRI JORDAN, ARNP, Daytona Beach, Fla. (202-2)

NEUTROPHILS AND LYMPHOCYTES In interpreting a complete blood count with differential, anytime the neutrophils and lymphocytes are numerically close, it is a viral cause; when the neutrophils and lymphocytes are numerically distant, it is a bacterial cause. This is very helpful in determining treatment.—DONNA CARTER, FNP-C, Scottsburg, Ind. (202-1) GENERIC “CAINE” IS EFFECTIVE FOR WOUND CARE For pain relief, most pharmacies offer a “caine” at 2-510%, and basically nothing higher, for between $5 and $30 per tube. I work in wound care and use Walmart’s

INTRA-ARTICULAR INJECTIONS FOR SEVERE OSTEOARTHRITIS Patients with severe osteoarthritis in the knees seem to do better with intra-articular injections if you have them sit up and dangle their legs off the examination table and distract the knee slightly when administering the injection.—ROSEMARY LEDBETTER, PhD, PA, Troy, Ill. (202-3)

YOUR COMMENTS SLIPPED CAPITAL FEMORAL EPIPHYSIS IN OBESE ADOLESCENTS I just read the CME/CE article by Marilou Shreve, DNP, APRN, entitled, “Assessing and treating pediatric obesity” [ June 2015]. I was concerned regarding the oversight of a critical issue in obese adolescents: the increased risk of slipped capital femoral epiphysis (SCFE). This was not addressed in the article. The case study (p. 55) gave incomplete advice regarding the evaluation of an obese adolescent male with knee pain. The most common etiology of the insidious onset of knee pain in children is the hip, due to referred pain from the

Equate brand—vagicaine 20% benzocaine. When using this before debriding a wound, give it three minutes to sedate the nerves, then perform the procedure. I get good results, as patients say. It relieves pain and burning for $1.88.

Advisor F

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 contact us by e-mail at editor@ 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.

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These are lette and successe rs from practitioners s, observat around the below. We ions, and country who OUR CONSULTANTS pearls with invite you want to shar to participa their colle e their clinic agues. Resp te. al problems onding cons ultants are identified CON SULTAT IONS

TREATM ENT FOR INFECT URINAR ION SGLT2 REC MALE CHI S IN THE UNC Y TRACT IRCUMCI LD FOR DIA EPTOR BLOCKE If a male SED child conti Deborah L. Cross, MPH, CRNP, Laura A.BET Foster,ES CRNP, FNP, Abby A. Jacobson, PA-C, RS Abimbola Farinde, PhD, PharmD, With the nues toassociate ANP-BC, is practices family medicine is a physician assistant is a professor redevprogram adven t ofPrimary circu SGLT2 recep at Delaware Valley urinaryattract director, Gerontology NP elop Program, mcisi Columbia Southern moda litywith Palmetto on be perfo for type tor infecPhysicians Dermatology University of Pennsylvania School blockersGroup University 2 diabe rmed? regarding inCare as a treatm in Wilmington, Del. in Orange Beach, Ala. useCharleston, S.C. tes, is there ent urology is of Nursing, Philadelphia. any evide NATHAN in patients with to protect the is well advise nce or data type 1 diabe GARDNE d tes mellitus?— R, PA-C, continues to to recommend a circum upper tracts, the kidne CPAAPA, ys. develo cision It p recurr•ent 44 THE ADVISOR AUGUST 2015 •on www.ClinicalAdvisor.com Castleton, severaCLINICAL l consideration urinary tract the male child who As it currently stands N.Y. , SGLT2 s that infections. for glycemic impede the receptor blocke There are control in ability to cleansenter into this decisio rs are FDA adults with n. Poor hygien should the e and quell -approved child have e may appro diet and exercise, but with type 2 diabetes phimosis, simpl infection potential. appropriate the in ved conjun FDA for use in patien Moreover, AdvisorForum_CA0815.indd urine 44 9/29/15ction 2:38 PM e cathet culture can ts with type has stated that they ketoacidosi steroid cream be a challenge. erization to obtain s, or those are not may tempo an FAR with severe 1 diabetes, patients with Having a short tion of the rarily solve renal functi diabetic steroid the trial of informINDE, PhD, Pharm these issues tenden , though after for infection D (See bottom on.—ABIMBOL ation about once again.—C cy redevelops, placin cessaA Dr. Farinde.) of this page Milwaukee g (203-2) for more , Wis. (203- OLEEN ROSEN, the child at risk 1) DNP, FNP -C, CLI Philip R. Cohen, MD,

is clinicaltions associate professor , shou ld of dermatology, University a of Texas Medical Center, The focus of Houston.

NICAL

Send us your letter Advisor Forum, The s with questions New York, and comm Clinical Advisor ents to: , 114 clinicaladvisoNY 10001. You may contacWest 26th Street , please indicatr.com. If you are writing in t us by e-mail at 4th Floor, each item. e so by including response editor@ to a the Letters are policy is edited for number in parent published letter, to heses at length and contribution print the author ’s name with clarity. The Clinicathe end of s will be accepted. l Advisor the letter. No anonym ’s ous

Write us today.

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VAGINA L RESULT DISCHARGE AND ING FRO If a female M TAMPON ODOR patient has USE a ask if she uses tamp history of vaginal disch ons. If she the pelvic arge with says “yes,” exam when cond odor, that you woul , do not enter ucting the rotating of d to take a pap smea vagina in the same the specu way r. Instead, the cervix. lum Most retain from side to side start shallow until reach ed tampons ing are lodge d in the fold

Philip R.

Cohen, MD, is clinical associa te profess of dermat or ology, of Texas MedicaUniversity l Center, Houston.

SEND TO The Clinical Advisor 275 7th Avenue, 10th floor New York, NY 10001

62 THE CLINI

Deborah L. Cross, MPH, ANP-B

CRNP, C, is associa te program director, Geronto logy NP Program University of Pennsyl vania School , of Nursing , Philadelphia.

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is a profess PharmD, or at Columb ia Souther n Univers in Orange ity Beach, Ala.

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Laura A.

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practices familyCRNP, FNP, with Palmett medicine o Primary Care Physicia ns in Charles ton, S.C.

Abby A.

Jacobso

is a physicia n, PA-C, n at Delawa assistant re Dermatology Valley in Wilmington,Group Del.

.indd 62

9/29/15

2:44 PM

E-MAIL editor@clinicaladvisor.com

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2018 1

CONTENTS M AY 2 0 1 8

NEWS AND COMMENT 16 Newsline ■■Skin cancer prevention: behavioral counseling ■■Antibiotic-resistant bacteria in US healthcare facilities ■■Antidepressant types and adverse events ■■Acid suppressors, antibiotics in infants tied to allergic disease ■■IBD risk is linked to DPP-4 inhibitor use 16 Skin cancer prevention recommendations

FEATURES 20 Deep vein thrombosis: history and evolution of treatment NOACs have emerged as a leading treatment for DVT 18 Antidepressant types and adverse events

34 Oral anticoagulation: reversing the current view Advances in reversal agents are key for managing patients who use direct oral anticoagulants 42 CME Case: A 49-year-old recently diagnosed with rheumatoid arthritis A patient’s journey toward remission in a treat to target approach 51 CME Feature posttest

34 Reversal agents in oral anticoagulation

Continues on page 10

63 Legal Advisor: Liability after a clinician misses a diagnosis and a patient dies

Like us on Facebook facebook.com/TheClinicalAdvisor Visit us on the web ClinicalAdvisor.com Download the app ClinicalAdvisor.com/App

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MORE WAYS TO FIND US!

CONTENTS M AY 2 0 1 8

DEPARTMENTS, cont’d A P E E R - R E V I E W E D 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

■ Skin cancer prevention ■ Antibiotic-resistant bacteria ■ Allergic disease risk ■ IBD and DPP-4 inhibitors FEATURE Oral Anticoagulation

Advances in reversal agents key for preventing bleeding

THE CLINICAL ADVISOR • MARCH 2018

THE CLINICAL ADVISOR • APRIL 2018

Web Roundup A summary of our most recent opinion, news, and multimedia content from ClinicalAdvisor.com

THE CLINICAL ADVISOR • MAY 2018

MA AYPEER-REVIEWED 2 01 8 | www.ClinicalAdvisor.com FORUM FOR NURSEAPRACTITIONERS PEER-REVIEWED FORUM | APRIL FOR 2 018 NURSE | www.ClinicalAdvisor.com PRACTITIONERS | MARCH 2018

NEWSLINE DEEP VEIN THROMBOSIS

■ Type 2 diabetes guideline ■ Adolescent depression ■ Varicose veins and DVT

STAT CONSULT

Clinical Pearl ■ Phantom knee pain

Case File ■ Cat scratch disease

FREE CME COURSE

Rheumatoid arthritis: a journey toward remission

Stenosis of the blood vessels resulting from atherosclerosis.

■ Dermatologic Look-Alikes

PAINFUL PLAQUES ON THE ELBOWS PAGE 45

ERYTHEMATOUS PLAQUES PAGE 61

✶ FREE CE COURSE!

■ Feature

VOLUME 21, NUMBER 3

ADVISOR FORUM

■ Dermatology Clinic

A pink rash with fine scale in a 7-year-old boy

VOLUME 21, NUMBER 4

Legal Advisor Liability after a missed diagnosis

Campylobacter jejuni infection can lead to food poisoning and diarrhea.

swelling in a lower extremity.

DERMATOLOGY CLINIC

VOLUME 21, NUMBER 5

Dermatology Clinic ■ Inflammatory papulopustules in a young woman ■ A pink rash with fine scale in a 7-year-old boy

LEGAL ADVISOR

LEGAL ADVISOR A clinician shares incorrect patient information with A clinician attempts to voidDVT typically and government agency. a noncompete clauseconsists of painanother

A patient dies after a missed diagnosis

RISK FACTORS DIARRHEA ■ Immunization schedules ■ Stroke guidelines ■ Obesity surgery outcomes ■ Gestational diabetes ■ Septic shock mortality

Sudden cardiac death

LEGAL ADVISOR

| www.ClinicalAdvisor.com

A NEWSLINE CLINICAL APPROACH FOR CORONARY ARTERY DISEASE

Emergence of NOACs expands treatment options for patients

POSTOPERATIVE PAIN MANAGEMENT PAGE 34

■ Feature

SMOKING CESSATION STRATEGY PAGE 32

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“It isn’t exactly my idea of a corner office.”

For first-line constipation therapy, stick with the leader

The AGA recommends PEG laxatives (like MiraLAX) as a first-line constipation treatment1

✔ 96% patient satisfaction rate* ✔ #1 GI-recommended laxative for over 10 years Start with MiraLAX for proven relief of occasional constipation. *Survey of 300 consumers, 2017. Use as directed on product labeling or as directed by your doctor. Reference: 1. Clinical decision support tools. American Gastroenterological Association website. http://campaigns.gastro.org/algorithms/constipation/index.html. Accessed May 12, 2017. Bayer, the Bayer Cross, and MiraLAX are trademarks of Bayer. © 2017 Bayer May 2017 68522-PP-MLX-BASE-US-0328

1003669ha_a.indd 1

Doctor recommended, patient approved

6/2/17 10:21 AM

EXCLUSIVE TO THE WEB AT

ClinicalAdvisor.com

NEWS ClinicalAdvisor.com/News

In utero exposure to multiple AEDs, sodium valproate, linked to poor educational attainment in childhood

THE WAITING ROOM

Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom Sharon M. O’Brien, MPAS, PA-C Discrepancy of sleep in patients with paradoxical insomnia In patients with paradoxical insomnia, also called sleep state misperception (SSM), there is a significant discrepancy between objective sleep quality and subjective perception of sleep.

In utero exposure to AEDs in combination, or sodium valproate alone, is associated with a significant decrease in attainment in national educational tests for 7-year-old children.

Pink eye: prevention and treatment tips from the CDC Pink eye, also known as conjunctivitis, is an inflammation of the conjunctiva that makes blood vessels more visible and gives the eye a pink or reddish color.

NCCN’s anticancer drug recommendations based on weak evidence The National Comprehensive Cancer Network expands indications of FDAapproved drugs based on weak evidence.

Colorectal cancer screening doubled with use of a digital health program The use of the Mobile Patient Technology for Health-CRC digital health program doubles the proportion of patients who completed colorectal cancer screening.

Daytime drowsiness and increased risk of ß-amyloid build-up in elderly Excessive daytime sleepiness in elderly persons without dementia is linked to risks for elevated β-amyloid accumulation, which may lead to a greater risk for developing Alzheimer disease.

Frightening parasomnias of childhood sleep Parasomnias usually occur in healthy children, but the differential can include neurologic, psychiatric, and mental disorders, so careful observation and a good history and physical are important.

CASE STUDY IN URGENT CARE ClinicalAdvisor.com/CaseStudy Brady Pregerson, MD Abdominal pain, distention, and constipation A 64-year-old man presents to the emergency department with abdominal pain and distention, as well as constipation of 8 days’ duration. He denies vomiting, fever, diarrhea, or dysuria. Except for hypertension, he is otherwise healthy with no prior surgeries. Read the full case at: ClinicalAdvisor.com/CaseAbdominalPain Headache, back pain, and fever A 25-year-old woman presents to the emergency department with a chief complaint of headache, back pain, and fever, while also experiencing some vaginal itching and discharge. Read the full case at: ClinicalAdvisor.com/HeadacheBackPain George Marzouka, MD Syncope, dizziness, and fatigue on a camping trip A 52-year-old man presents to the emergency department with dizziness and fatigue after a syncopal episode on a camping trip. Read the full case at: ClinicalAdvisor.com/CaseCampingTrip

12 THE CLINICAL ADVISOR • MAY 2018 • www.ClinicalAdvisor.com

Advisor Dx Interact with your peers by viewing the images and offering your diagnosis and comments. To post your answer, obtain more clues, or view similar cases, visit ClinicalAdvisor.com/AdvisorDx. Learn more about diagnosing and treating these conditions, and see how you compare with your fellow colleagues. Check out some of our latest cases below!

DERM DX

Elastic skin and scattered scars A 10-year-old boy presents for evaluation of scattered scars on his ankles and back, which are slightly atrophic and violaceous. According to his parents, the scars were the result of minor trauma incurred months ago. The boy’s parents were concerned because of his abnormal healing. Highly elastic skin was noted during the examination. The patient also demonstrated joint hypermobility, as did his father but to a lesser degree. CAN YOU DIAGNOSE THIS CONDITION?

• Marfan syndrome • Ehlers-Danlos syndrome

• Loeys-Dietz syndrome • Osteogenesis imperfecta

● See the full case at ClinicalAdvisor.com/DermDx_May18

ORTHO DX

In partnership with

TheJopa.org

Journal of Orthopedics for Physician Assistants

Posterior hip dislocation after an accident A 34-year-old man presents to the emergency department after a motor vehicle accident with severe left hip pain and a lower extremity rotational deformity. He was the driver when he lost control and hit a pole. On examination, he has a shortened and externally rotated left lower extremity. Radiographs of the left hip show a posterior hip dislocation. WHAT IS THE BEST TREATMENT OPTION?

• Closed reduction then CT • Closed reduction then MRI • CT then closed reduction • Open reduction and internal fixation ● See the full case at ClinicalAdvisor.com/OrthoDx_May18

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2018 13

Newsline THE US PREVENTIVE Services Task Force (USPSTF) has updated the 2012 recommendation on behavioral counseling for the primary prevention of skin cancer and the 2009 recommendation on screening for skin cancer with skin self-examination, as published in JAMA. The task force reviewed the evidence on whether counseling patients about sun protection reduces intermediate outcomes (eg, sunburn or precursor skin lesions) or skin cancer; the link between counseling and behavior change, the link between behavior change and skin cancer incidence, and the harms of counseling or changes in sun protection behavior; and the link between counseling patients to perform skin self-examination and skin cancer outcomes, as well as the harms of skin selfexamination. These recommendations

apply to asymptomatic persons with no history of skin cancer. The USPSTF recommends counseling young adults, adolescents, children, and parents of young children about minimizing exposure to ultraviolet (UV) radiation for persons aged 6 months to 24 years with fair skin types to reduce their risk of skin cancer (B recommendation). Existing evidence indicates that the net benefit of counseling all adults older than 24 years is small; therefore, physicians are advised to selectively offer individualized counseling to adults older than 24 years based on the presence of risk factors for skin cancer (C recommendation). The USPSTF concludes that current evidence is insufficient to assess the balance of benefits and harms of counseling adults about skin self-examination to prevent skin cancer.There is no evidence

Skin cancer prevention: Behavioral counseling guideline

supporting an incremental benefit that might occur with skin self-examination above the benefit from counseling for sun protection behaviors and from current levels of skin examinations being performed by clinicians. In a related editorial, Robert Sidbury, MD, MPH, stated,“Though the recommendations are limited to individuals with fair skin types, it is important to remember that skin type is a continuum like skin cancer risk.”

Antibiotic-resistant bacteria found in 221 US healthcare facilities in 2017 A TOTAL of 221 cases of carbapenem-resistant Enterobacteriaceae (CRE) were confirmed in US healthcare facilities in 2017, according to the Centers for Disease Control and Prevention (CDC). These virulent pathogens, described by the CDC as “nightmare bacteria,” are very difficult to treat and control. “While antibiotic resistance threats vary nationwide, [antibiotic resistance] has been found in every state,” the CDC stated. Using preventive measures for antibiotic-resistant strains is the most effective treatment. The CDC reported that aggressive, early approaches to each case of infection can hinder high-resistance microbes from spreading, which could be untreatable if left uncontrolled. Since virulent microorganisms rapidly spread at exponential rates,

such tactics could prevent 1600 CRE-related cases per state during the course of 3 years. Healthcare facilities are strongly encouraged to contact their state/local lab support when resistant microorganisms are detected. Labs should send the proper isolates out immediately for testing and generate protocols to inform the proper departments about the microbe of interest and validate new tests to confirm and control the spread of the pathogen. Health departments and healthcare facilities should enforce infection control within their facilities and monitor patients with these nightmare bacteria, according to the CDC. Ongoing colonization screenings and infection control should be a priority until pathogenic spreading is controlled.

16 THE CLINICAL ADVISOR • MAY 2018 • www.ClinicalAdvisor.com

Newsline SELECTIVE SEROTONIN reuptake inhibitor use is associated with a higher rate of fracture than tricyclic and related antidepressant use and lower mortality and adverse drug reaction rates than other antidepressant drug classes, according to a study published in BMC Medicine. A total of 238,963 eligible patients aged 20 to 64 years (61% women) were included, and the mean age was 39.5 years. A majority of patients (209,476, 87.7%) were treated with antidepressants in the followup, during which 4,796 had fractures, 1,066 had upper gastrointestinal bleeds, 3,690 had road traffic accidents, 1,058 had experienced adverse drug reactions, and 3,181 patients died. Fracture rates were significantly increased for selective serotonin reuptake inhibitor use (adjusted hazard ratio [HR], 1.30) and other antidepressants (HR, 1.28), compared with periods when antidepressants were not used. Rates of adverse drug reactions were significantly higher for tricyclic and

related antidepressants (HR, 1.54) and other antidepressants (HR, 1.61), compared with selective serotonin reuptake inhibitors.Trazodone was associated with a significantly increased risk of upper gastrointestinal bleed.All-cause mortality rates were significantly higher for tricyclic and related antidepressants (HR, 1.39) and other antidepressants (HR, 1.26) than for selective serotonin reuptake inhibitors over 5 years but not 1 year, and were significantly reduced after 85 or more days of treatment with selective serotonin reuptake inhibitors.

IBD risk linked to DPP-4 inhibitor use IN PATIENTS WITH type 2 diabetes, the use of dipeptidyl peptidase-4 (DPP4) inhibitors is linked to an elevated risk for inflammatory bowel disease, according to a study published in the BMJ. Researchers designed a populationbased group analysis to understand the association between DPP-4 inhibitor use and inflammatory bowel disease incidence in patients with type 2 diabetes. Participants older than age 18 who started antidiabetic medication between January 2007 and December 2016 were eligible.The group consisted of 141,170 individuals, and a follow-up was assigned until June 2017. The main outcome measured was the incidence of inflammatory bowel disease

among patients with type 2 diabetes taking a DPP-4 inhibitor. By the 552,413 person years follow-up, the investigators reported 208 cases of inflammatory bowel disease, a crude incidence rate of 37.7 per 100,000 person years. The hazard ratio (HR) of inflammatory bowel disease associated with DPP-4 use was 1.75. This risk was positively correlated with length of DPP-4 usage, with the greatest reported risk after 3 to 4 years of use (HR, 2.90). After 4 years, the risk was reduced (HR, 1.45). “The results of this large population based cohort study indicate that the use of dipeptidyl peptidase-4 inhibitors is associated with an overall 75% increase in the risk of inflammatory bowel disease in patients with type 2 diabetes,” the authors stated.

18 THE CLINICAL ADVISOR • MAY 2018 • www.ClinicalAdvisor.com

Acid suppressors, antibiotics in infants tied to allergic disease CHILDREN WHO RECEIVE acidsuppressive medications or antibiotics within the first 6 months after birth may have an elevated risk for developing allergic disease, according to a study published in JAMA. In the study, 792,130 children with birth medical records between 2001 and 2013 were administered either a histamine-2 receptor antagonist (H2RA), proton pump inhibitor (PPI), or antibiotics. Half of the participants were girls (n= 395,215). The percentage of the cohort receiving prescribed H2RA, PPI, and antibiotics was 7.6%, 1.7%, and 16.6%, respectively. Adjusted hazard ratios (HR) associated with food allergies were 2.18 for H2RA and 2.59 for PPIs. H2RA and PPI ratios were further calculated for medication allergies (HR, 1.70 and 1.84, respectively), anaphylaxis (HR, 1.5 and 1.45, respectively), allergic rhinitis (HR, 1.50 and 1.4, respectively), and asthma (HR, 1.25 and 1.41, respectively). The ratios for infants 6 months and younger were also recorded for those who were prescribed antibiotics: asthma (HR, 2.09), allergic rhinitis (HR, 1.75), anaphylaxis (HR, 1.51), and allergic conjunctivitis (HR, 1.42). “This study found associations between the use of acid-suppressive medications and antibiotics during the first 6 months of infancy and subsequent development of allergic disease,” reported the authors. “Acidsuppressive medications and antibiotics should be used during infancy only in situations of clear clinical benefit.” ■

Antidepressants and adverse events

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FEATURE: JOHN B. HURT, MPAS, PA-C, KRISTOPHER R. MADAY, MS, PA-C, MICHELLE BROWN, PhD, PAUL M. HARRELSON, MSPAS, PA-C

Deep vein thrombosis: History and evolution of treatment DVT is a significant source of morbidity and mortality, so it is imperative that clinicians understand how to recognize and treat patients with the disorder.

Deep vein thrombosis in the lower leg (on left) of a 61-year-old man.

20 THE CLINICAL ADVISOR • MAY 2018 • www.ClinicalAdvisor.com

lood clotting functions primarily to repair and prevent bleeding from an injured vessel. However, because of the triad of inflammation, hypercoagulability, and endothelial injury, clots can form within blood vessels.1,2 Venous thrombosis accounts for more than 600,000 hospitalizations annually.1,2 If left untreated, venous thrombosis in large vessels can lead to pulmonary embolism, so that it a significant cause of morbidity and mortality.2 Although the pathophysiology of blood clotting is well understood, the treatment has varied greatly over time. In the early days, vessel ligation was a common practice, although swelling and pain in the affected extremity were frequent complications. Later, immobilization of the extremity was the standard of care, although it left the patient immobile, further increasing the risk for clot formation.3 It was many years later that anticoagulation therapy evolved as the standard of care for patients with blood clots and deep vein thrombosis (DVT). Anticoagulation was initially accomplished by administering heparin along with warfarin, a vitamin K–dependent anticoagulant.3 Although heparin and warfarin were and still are a good option for anticoagulation, ongoing monitoring of the patient’s prothrombin time (PT) and international normalized ratio (INR) is required to identify and maintain the appropriate dosage. Within the last few years, medications belonging to another class, the non–vitamin K antagonist oral anticoagulants (NOACs), have emerged as safe alternatives to warfarin and do not entail the

right-hand column like this one does at the top

requirement for intermittent measurement of the PT and INR. It is essential that physician assistants understand the pathophysiology of clot formation and DVT, recognize the signs and symptoms of DVT in clinical practice, and be knowledgeable about the new anticoagulants and evidence-based treatments for DVT. History of the study of coagulation

The study of coagulation can be traced as far back as Hippocrates, the father of medicine. It was around 400 BC that he observed the blood of a wounded soldier “congealing” as it cooled.4,5 At about the same time, it was noted that placing skin over a bleeding wound halted further bleeding.4 Later, Aristotle noted that blood removed from the body “decayed,” resulting in clotting, which was thought to be due to cooling.4,5 In the 1600s, Mercurialis observed clots forming in blood vessels at normal body temperature.4,5 It was not until the early 1900s that Paul Marowitz organized coagulation factors into a scheme, or coagulation pathway, hypothesizing that multiple clotting factors act together to form a fibrin plug.4 Over the next 100 years, additional proteins involved in the coagulation process were discovered. These proteins all play an integral role in clotting and fibrinolysis.4 Coagulation is a vital process that prevents excessive bleeding when a blood vessel is injured. Multiple coagulation factors, together with platelets, function together to form a clot, preventing further bleeding. Although clotting is essential to prevent bleeding, clots can form within the lining of a vein with or without obvious injuries.1,2,4-6 The first documented case of DVT

The first well-documented case of DVT was reported during the middle ages.3 In 1271, unilateral swelling and edema developed in the leg and ankle of Raoul, a 20-year-old Norman cobbler.3 When a leg ulcer subsequently formed, Raoul was advised to visit the tomb of King Louis IX of France to seek his healing power. (King Louis had died in 1270 and was canonized in 1297 as a Roman Catholic saint.) There, Raoul rubbed dust from the stone covering the king’s tomb into the wound. Miraculously, the wound healed, and Raoul lived for 11 more years; his recovery was thought to be a result of applying the dust.3 After this report, the identification and documentation of cases of DVT began to increase.They were primarily noted in pregnant and postpartum women.3 The clots were believed to be a consequence of the retention of “evil humors” during pregnancy.2,3 It was also thought that postpartum DVT was due to the presence of unconsumed breast milk within the legs.3 In the 17th century, the humoral theory was gradually abandoned, and in 1676,Wiseman hypothesized that blood clots were due to abnormalities within the blood.3 Later, in 1793, Hunter proposed that DVT was a venous occlusion caused by clots.3 After his discovery, Hunter performed many venous ligations above the thrombosis, thus

preventing fatal pulmonary thromboembolism (PTE).3 Although vena cava ligation was controversial, this technique became more widely used at the end of the 19th century.3 The ligation could be placed at the level of the femoral vein, common iliac vein, or inferior vena cava.3 Along with ligation, the mainstay of DVT treatment was strict bed rest.3 This was often prescribed because of fear of migration of the thrombus.The patient’s limbs were often splinted to preclude clot movement. Other treatments for DVT included bloodletting, the administration of antiinflammatory agents, the application of warm compresses, and elevation of the extremity to promote venous return.3 Pathophysiology of DVT and blood clot formation

As the diagnosis of blood clots became more common, clinicians began to realize that DVT formation was actually a complex process involving the interaction of multiple genetic and environmental factors.1-3,6,7 In the 1930s, a consensus was reached that three factors contribute to thrombosis: venous stasis, vessel wall damage, and hypercoagulability.1-3,6,7 These factors comprise the Virchow triad: hypercoagulability, hemodynamic change, and endothelial injury. Multiple other risk factors are known to increase the incidence of DVT (Table 1)6-9; however, it should be noted that many times DVT develop with no known cause.1,2 Signs and symptoms of DVT

The presentation of DVT can vary but typically consists of pain and swelling in a lower extremity.1,2,6-9 This is often described as a feeling of fullness or dullness that worsens with walking.1,2,7,9 In many cases, mild redness and tenderness of the calf on palpation may be noted, which are due to thrombophlebitis caused by the clot. DVT may also be associated with pain in the calf elicited by passive dorsiflexion of the foot (the Homans sign).1,7,9 However, the sensitivity and specificity of this test are low.1,2 Often, the diameter of each tibia tubercle is measured and the two measurements are compared.A difference of 2 cm or more at 10 cm below the tibia tubercle increases the likelihood of DVT TABLE 1. Risk factors for DVT • Advanced age • Obesity • Recent surgery • Major trauma • Active cancer • Acute medical illness • Stroke or immobilization • Previous clot

• Congenital venous malformation • Varicose veins • Central venous catheter or IVC filter • Long distance travel • Oral contraceptives • Pregnancy • Antiphospholipid syndrome • Inherited thrombophilia

Modified from Kline1 and Wells et al.8

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2018 21

DEEP VEIN THROMBOSIS

Contrast venography remains the gold standard in diagnosing DVT; however, it has been largely replaced by ultrasonography in most institutions. by a factor of 2.1,2 A proximal DVT can lead to complete venous obstruction and increased compartmental pressures.1 Typically, the presentation consists of a swollen, painful limb, which can be dusky or blue in color. A proximal DVT in a pale or white painful limb is known as phlegmasia alba dolens, and a proximal DVT in a dusky or blue limb is known as phlegmasia cerulea dolens.1,2 Either can cause limb loss and warrants aggressive therapy, including thrombolysis or catheter-guided thrombectomy.1 In clinical practice, pretest scoring systems may be used to assist clinicians in diagnosing DVT. One scoring system in frequent use, the Wells criteria, looks at multiple risk factors and assigns a risk score accordingly.1,7,8 The calculation is then used before testing to determine the probability of DVT.The score should be used to guide subsequent diagnostic testing and workup. Because many patients may fall into the moderate- or intermediate-risk category, clinical judgment continues to be an important factor in diagnosing DVT.8-10 Diagnostic studies

A physical examination is of little help in diagnosing DVT, nor should it be used to rule out DVT. Contrast venography remains the gold standard in diagnosing DVT; however, it has been largely replaced by ultrasonography in most institutions.1,2,7-10 Contrast venography has a sensitivity and specificity of nearly 100% and can detect DVT in the calf, iliac vessels, and inferior vena cava that ultrasonography may miss.2 Ultrasonography is the most accurate

POLL POSITION Which of the following tests do you most frequently recommend when you suspect a patient may have DVT? 2.64% ■ Ultrasound ■ Blood test ■ Venography

88.65%

8.18%

0.53%

■ CT or MRI scan

For more polls, visit ClinicalAdvisor.com/Polls.

noninvasive tool for diagnosing DVT of the lower extremity, with a sensitivity of 93% to 100% and a specificity of 97% to 100% in detecting proximal DVT.1,2,8-10 However, it should be noted that ultrasonography has several limitations. It is somewhat limited in the detection of calf and pelvic DVT, and its accuracy can be subjective and depend on the skill of the operator.Another drawback is that it cannot differentiate between an old and a new clot.10 A D-dimer test is often ordered as well to check for breakdown products resulting from fibrin degradation by plasmin.10 Several laboratory techniques are used to check the D-dimer level; however, the enzyme-linked immunoassay (ELISA) is the most accurate.The quality of the blood specimen affects the D-dimer assay. Lipemia and hemolysis can interfere with a photo-optical assay. Hemolysis also implies the ex vivo activation of platelets and coagulation factors, rendering laboratory results invalid.The combination of ELISA and ultrasonography has a negative predictive value for DVT of nearly 100%.1,2 In a recent study, patients with a Wells score of less than 2 and a negative D-dimer test were less likely than those with a negative ultrasonography examination to have DVT on follow-up.7,8-10 Treatment options for DVT

Heparin The first anticoagulants can be traced back to the 1800s. In 1884, a scientist named Haycraft extracted a pure anticoagulant, known at the time as hirudin, from the saliva of leeches.1,11 Hirudin could not be used as a potent anticoagulant until 1986, when it was produced by genetic engineering.1,3,11 In 1916, a medical student named McLean, while studying the procoagulant activity of crude ether and alcohol extracts of the brain, liver, and heart, noticed the anticoagulant activity of heparphosphatide.1,12 McLean observed that as heparphosphatide was exposed to air, it began to act like an anticoagulant.1,12 After McLean’s discovery, his mentor, Howell, worked further with heparphosphatide and after mixing it with phospholipids named it heparin.12 In 1933, Charles Scott produced the first purified heparin, and it was used in humans in 1935.12,13 The first clinical use of heparin was for chemoprophylaxis in surgical patients. In 1937, Murray and Crafoord published data evaluating surgical patients who received prophylaxis for DVT.14 Despite the lack of randomized, placebo-controlled clinical trials, the effectiveness of heparin was obvious.Therefore, in the 1940s, heparin began to be used to treat and prevent venous thrombosis.14 Today, heparin and its low-molecular-weight derivatives are still effective medications for the prevention and treatment of DVT and PTE. Heparin is a sulfated polysaccharide that works

22 THE CLINICAL ADVISOR • MAY 2018 • www.ClinicalAdvisor.com

The advantages of warfarin are its relatively low cost and the fact that if needed its effects can be reversed with vitamin K and fresh frozen plasma. primarily by inactivating thrombin and activated factor X.15,16 This occurs through an antithrombin-dependent mechanism. The binding of heparin to antithrombin III (ATIII) causes a conformational change that results in the activation of ATIII when the loop at the reactive site becomes more flexible.15 The activated molecule binds to thrombin, factor X, and other proteases involved in clotting, thus inhibiting clot formation.15,16 Optimal amounts of heparin have been known to accelerate these reactions up to 2000-fold.16 Unfractionated heparin may be injected intravenously or subcutaneously and is rapidly effective. Low-molecular-weight heparins (LMWHs) are manufactured derivatives of unfractionated heparin in which the molecules are much smaller. Less protein and cellular binding result in pharmacokinetics that are much more predictable than those of unfractionated heparin. LMWHs are given subcutaneously and often used in the initial treatment of DVT, as well as in DVT prophylaxis. Peak activity is achieved approximately 4 hours after administration.15,16 LMWHs have mostly anti-Xa activity, so they are generally monitored with an anti-Xa assay. LMWHs are cleared by the kidneys; therefore, monitoring is required in patients with renal disease, obese patients, young children, and pregnant women.15,16 The multiple anticoagulants within this class, which vary in molecular weight, include enoxaparin, parnaparin, dalteparin, and many others.17 See Table 2 for dosing. Vitamin K–dependent anticoagulants, warfarin The vitamin K–dependent coagulation factors were first discovered in the prairies of North Dakota and Alberta, Canada. Here, at the beginning of the 20th century, cattle were dying in large numbers of “hemorrhagic disease” or “sweet clover disease.”3,18,19 In 1924, a Canadian veterinary pathologist named Schofield discovered that the disease was caused by a moldy type of sweet clover. Although he determined that Aspergillus

organisms were the cause of the mold, they were not the cause of the prolonged bleeding times occurring in the cattle.3,18,19 The bleeding issues were easily treated by removing the clover from the diet of the cattle and transfusing the animals with bovine blood.1,18,19 Paul Link and his colleagues later discovered that a nontoxic substance, coumarin, was oxidized to dicoumarol in moldy hay. It was this substance that caused the bleeding in the cattle.18 These investigators also demonstrated that the effects of dicoumarol could be reversed with vitamin K.After 2 years, vitamin K was used to treat DVT.14,20 Later, Link and his colleagues discovered the existence of a more potent analogue of dicoumarol.This chemical analogue, named warfarin, was used later, in 1948, as a pesticide in rodents.3,18,20 In 1950, Link recommended that warfarin be used in clinical medicine.3,18,20 After some hesitation on the part of clinicians about using in humans a substance that was designed to exterminate rats, warfarin began to gain acceptance within the medical community, and in 1954 it was approved by the Food and Drug Administration (FDA) for human use.3 Although the anticoagulant effect of warfarin begins within 24 hours, the peak effect takes 72 to 96 hours. Therefore, unfractionated heparin or LMWH is used in conjunction with warfarin until a therapeutic INR of 2.5 to 3.0 can be achieved.The INR is used to evaluate the extrinsic pathway of coagulation, indicating how fast a patient’s blood clots.Warfarin is known to prolong the PT and INR by inhibiting the synthesis of vitamin K–dependent clotting factors.These include factors II,VII, IX, and X, as well as the anticoagulant proteins C and S. Warfarin has been used as an anticoagulant for many years.The advantages of warfarin are its relatively low cost and the fact that if needed its effects can be reversed with vitamin K and fresh frozen plasma.21 Its major disadvantages are that continual monitoring is required, certain foods interfere with its anticoagulant effects, and it may cause episodes of either gastrointestinal or Continues on page 31

TABLE 2. Dosing of LMWH and indications Indication

Enoxaparin Dose

Acute DVT without PE administered in conjunction with warfarin

1 mg/kg subcu, q12 or 1.5 mg/kg subcu daily

Abdominal surgery

40 mg subcu daily initiate 2 hours preop

Hip replacement/surgery

30 mg subcu q12, starting 9-15 hours after surgery for 10-15 days

Modified from Weitz,15 Fogarty and Minichiello,16 and Gray and Mulloy.17

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2018 23

DEEP VEIN THROMBOSIS

TABLE 3. NOACs and dosing recommendations Drug

Dosage in treatment of DVT

Dabigatran (Pradaxa)

After 5–10 days of parenteral anticoagulation, 150 mg po bid for CrCl > 30

Apixiaban (Eliquis)

10 mg po bid for 7 days, then 5 mg po bid

Rivaroxaban (Xeralto)

15 mg po q12 for 21 days, then 20 mg po qd for 6 months If CrCl < 30 ml/min avoid use

Edoxaban (Savaysa)

After 5–10 days of parenteral anticoagulation > 60 kg - 60 mg po qd, < 60 kg - 30 mg po qd Do not use with CrCl >95ml/min

Modified from Holden et al,21 Fenger-Eriksen et al,22 ROCKET AF Study Investigators,23 and Avezum et al.24

intracranial bleeding.21 It should also be noted that many medications interact with warfarin, so that even closer follow-up of the patient’s INR and consult with the pharmacy are required. NOACs For decades, vitamin K antagonists, such as warfarin, have been the mainstay of DVT treatment. NOACs, developed to optimize the management of DVT, have helped to overcome some of the limitations of traditional DVT management.21,22 Over the last 5 years, four NOACs have been approved to treat DVT.21,22 These include direct thrombin inhibitors as well as inhibitors of factor Xa.22 After extensive testing in clinical trials, rivaroxaban, dabigatran, apixaban, and edoxaban have been approved by the FDA for the treatment of DVT or venous thromboembolism (VTE). These medications have the advantage of more predictable effects, so that the need for continual monitoring is eliminated.22 The NOACs also have a shorter half-life than that of warfarin, which is an advantage if anticoagulation must be abruptly stopped.21 Although more costly, the new medications have provided a safe form of anticoagulation that requires less monitoring and follow-up in comparison with other anticoagulants. Direct thrombin inhibitors. Dabigatran (Pradaxa) is a direct, reversible, potent competitive inhibitor of thrombin. Inhibition of thrombin prevents the conversion of fibrinogen to fibrin and thus prevents clot formation.22 The primary route of elimination is via the kidneys, which clear about 85% of the drug. In the treatment of DVT with dabigatran, it is recommended that initially the drug be administered parenterally for 5 to 10 days. Peak activity occurs within 1 to 6 hours, and the drug has a half-life of 12 to 17 hours.21,22 The dose should be adjusted in patients with renal failure, defined as creatinine clearance below 30 mL/min.22 The disadvantages of dabigatran include a higher cost compared with warfarin, the need for twice-daily dosing, and a slightly

increased risk for gastrointestinal bleeding (6.1% with dabigatran vs 4% with warfarin).21,22 Initially, another disadvantage of dabigatran was the lack of a true reversal agent, although in October 2015, idarucizumab (Praxbind) was approved as a reversal agent for dabigatran. Despite the few disadvantages, dabigatran has proved to be a safer anticoagulant than warfarin.22 The RE-LY study evaluated dabigatran relative to warfarin in more than 18,000 patients over a 2-year span. The investigators found a significant reduction in the overall incidence of stroke (relative risk [RR] 0.64%, 95% confidence interval [CI] 0.51-0.81, P <0.001) and intracranial hemorrhage (RR 0.40, 95% CI 0.27-0.60, P < 0.001) when dabigatran was compared with warfarin, showing it to be a safe alternative to warfarin therapy.21,22 Two other large studies, ROCKET-AF (rivaroxaban) and ARISTOTLE (apixaban), compared these medications with warfarin.The studies showed rivaroxaban and apixaban to be superior to warfarin, with similar or lower rates of hemorrhage.23,24 Factor Xa inhibitors. Apixaban (Eliquis), rivaroxaban (Xerelto), and edoxaban (Savaysa) are all direct factor Xa inhibitors.They keep factor Xa from binding to its substrate, prothrombin, thus preventing clot formation. Multiple clearance mechanisms exist for this class of oral anticoagulants. Approximately 30% of the drug is excreted by the kidneys, with the remainder metabolized by the liver. The factor Xa inhibitors are currently used for stroke prevention and the treatment of nonvalvular atrial fibrillation as well as DVT and VTE.21,22 The major disadvantages of factor Xa inhibitors include the lack of a true reversal agent, the need for twice-daily dosing, and increased cost. Despite these few disadvantages, the NOACs have begun to replace warfarin in the treatment of DVT and VTE. NOAC dosing and treatment for DVT are summarized in Table 3.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2018 31

DEEP VEIN THROMBOSIS

Conclusion

8. Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pre-

DVT and thromboembolism are a significant source of morbidity and mortality. It is imperative that clinicians understand how to recognize and treat DVT. Over the years, the treatment of DVT has evolved to include a new class of medications, the NOACs. Although the use of NOACs presents some disadvantages, such as increased cost, a lack of antidotes, and a limited number of laboratory methods available to monitor their activity, there are clear advantages to prescribing NOACs to patients at risk for DVT. These medications have a wide therapeutic window and cause fewer drug-drug interactions than the older agents; in addition, because of their shorter halflife, it easier to discontinue treatment abruptly with NOACs than with warfarin.These features, along with the lack of the need for continual monitoring of the INR, make NOACs a safe and reasonable treatment option for patients with DVT. ■

test probability of deep-vein thrombosis in clinical management.” Lancet. 1997;350(9094):1795-1798. 9. Gens DR,Tortorich A. Chapter 30. Deep venous thrombosis. In: Farcy DA, Chiu WC, Flaxman A, Marshall JP, eds. Critical Care Emergency Medicine. New York, NY: McGraw-Hill; 2012. http://accessemergencymedicine.mhmedical.com/ content.aspx?bookid=522&Sectionid=41291788. Accessed April 3, 2018. 10. Ramzi DW, Leeper KV. DVT and pulmonary embolism: part I. Diagnosis. Am Fam Physician. 2004;69:2829-2836. http://www.aafp.org/afp/2004/0615/ p2829.html. Accessed April 3, 2018. 11. Whitaker I, Rao J, Izadi D, Butler P. Historical article: Hirudo medicinalis: ancient origins of, and trends in the use of medicinal leeches throughout history. Br J Oral Maxillofacl Surg. 2004;42:133-137. doi:10.1016/s0266-4356(03)00242-0 12. Mclean J. The discovery of heparin. Circulation. 1959;19:75-78. doi:10.1161/01.cir.19.1.75 13. Charles AF, Scott DA. Studies on heparin: observations on the chemistry of heparin. Biochem J. 1936;30:1927-1933. doi:10.1042/bj0301927

John B. Hurt, MPAS, PA-C, is an assistant professor and director of clinical education, Department of Physician Assistant Studies, Samford University, in Birmingham, AL; Kristopher Maday, MS, PA-C, is the program director and associate professor, University of Tennessee Health Science Center, Physician Assistant Program, in Memphis; Paul M. Harrelson, MPAS, PA-C, is a program director at Samford University; and Michelle Brown, PhD, MS, MLS (ASCP), is an assistant professor at the University of Alabama Birmingham.

14. Murray GD, Best CH. The use of heparin in thrombosis. Ann Surg. 1938;108:163-177. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1386890. Accessed April 3, 2018. 15. Weitz JI. Antiplatelet, anticoagulant, and fibrinolytic drugs. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; 2015. http://accessmedicine.mhmedical. com/content.aspx?bookid=1130&Sectionid=79732627. Accessed April 3, 2018. 16. Fogarty PF, Minichiello T. Disorders of hemostasis, thrombosis, & antithrombotic therapy. In: Papadakis MA, McPhee SJ, Rabow MW, eds. Current

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Medical Diagnosis & Treatment 2016. New York, NY: McGraw-Hill; 2016.

1. Kline JA. Venous thromboembolism. In: Tintinalli JE, Stapczynski J, Ma J,

17. Gray E, Mulloy B. Biosimilar low molecular weight heparin products.

Yealy DM, Meckler GD, Cline DM, eds. Tintinalli’s Emergency Medicine: A

J Thromb Haemost. 2009;7:1218-1221. doi:10.1111/j.1538-7836.2009.03461.x

Comprehensive Study Guide. 8th ed. New York, NY: McGraw-Hill; 2016.

18. Copeland CE, Six CK. A tale of two anticoagulants: warfarin and heparin.

https://accessmedicine.mhmedical.com/content.aspx?bookid=1658&Section

J Surg Educ. 2009;66:176-181. doi:10.1016/j.jsurg.2009.03.035

id=109429015. Accessed April 3, 2018.

19. Wardrop D, Keeling D. The story of the discovery of heparin and warfarin.

2. Fritz DA. Chapter 40. Vascular emergencies. In: Stone C, Humphries RL, eds.

Br J Haematol. 2008;141:757-763. doi:10.1111/j.1365-2141.2008.07119.x

Current Diagnosis & Treatment Emergency Medicine. 7th ed. New York, NY:

20. Link KP. The discovery of dicumarol and its sequels. Circulation. 1959;19:97-

McGraw-Hill; 2011. http://accessemergencymedicine.mhmedical.com/content.

107. doi:10.1161/01.cir.19.1.97

aspx?bookid=385&Sectionid=40357256. Accessed April 3, 2018

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3. Galanaud J, Laroche J, Righini M.The history and historical treatments of deep

vular atrial fibrillation. JAAPA. 2015;28:28-34. doi:10.1097/01.jaa.0000471615.92278.1c

vein thrombosis. J Thromb Haemost. 2013;11:402-411. doi:10.1111/jth.12127

22. Fenger-Eriksen C, Münster A, Grove EL. New oral anticoagulants: clinical

4. Owen CA, Nichols WL., Bowie EJ. A History of Blood Coagulation. Rochester,

indications, monitoring and treatment of acute bleeding complications. Acta

MN: Mayo Foundation for Medical Education and Research; 2001.

Anaesthesiol Scand. 2014;58:651-659. doi:10.1111/aas.12319

5. Hougie C. Thrombosis & Bleeding: An Era of Discovery. Victoria, BC, Canada:

23. ROCKET AF Study Investigators. Rivaroxaban—once daily, oral, direct factor

Trafford Publishing; 2004.

Xa inhibition compared with vitamin K antagonism for prevention of stroke

6. Chesnutt MS, Prendergast TJ. Pulmonary disorders. In: Papadakis MA,

and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF

McPhee SJ, Rabow MW, eds. Current Medical Diagnosis & Treatment 2016.

study. Am Heart J. 2010;159:340-347. doi:10.1016/j.ahj.2009.11.025

New York, NY: McGraw-Hill; 2016.

24. Avezum A, Lopes RD, Schulte PJ, et al. Faculty of 1000 evaluation for

7. Goldhaber SZ. Deep venous thrombosis and pulmonary thromboem-

apixaban in comparison with warfarin in patients with atrial fibrillation and

bolism. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J, eds.

valvular heart disease: findings from the Apixaban for Reduction in Stroke

Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill;

and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial.

2015. https://accessmedicine.mhmedical.com/content.aspx?bookid=1130&Sec

Circulation. 2015;132:624-632. doi:10.3410/f.725585376.793515796. Aronow

tionid=79744095&jumpsectionID=98723657. Accessed April 3, 2018.

W. (n.d.) F1000 - post-publication peer review of the biomedical literature.

32 THE CLINICAL ADVISOR • MAY 2018 • www.ClinicalAdvisor.com

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Oral anticoagulation: reversing the current view in bleeding events Advances in new reversal agents will be key for managing patients treated with DOACs to prevent major bleeding events.

Spontaneous bruising caused by use of warfarin.

34 THE CLINICAL ADVISOR • MAY 2018 • www.ClinicalAdvisor.com

ral anticoagulation is a clinical therapeutic that is frequently prescribed by numerous providers in many medical settings. There are two different types of oral anticoagulation, including vitamin-K antagonists (VKAs), such as warfarin, and the new class of direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, apixaban, and endoxaban.1 Until recently, warfarin has been the standard therapy for oral anticoagulation.2 However, according to the most recent CHEST guidelines on antithrombotic therapy for venous thromboembolism (VTE), experts in the field of anticoagulation agreed that DOACs provide advances in efficacy, overall safety, and patient and provider simplicity as the preferred anticoagulant when compared with warfarin in patients without cancer.3 This expert consensus was largely driven by multiple recent, large clinical trials that have established the efficacy and safety of DOACs for stroke prevention and VTE treatment and prevention. Since 2009, four large multicenter, randomized, double-blind, placebo-controlled trials demonstrated that DOACs were noninferior in the prevention of stroke in patients with nonvalvular atrial fibrillation and had a lower risk of bleeding compared with warfarin.4-7 Several other large phase 3 clinical trials have shown that DOACs were noninferior to warfarin regarding acute VTE treatment and prevention of recurrent VTE. In addition, DOACs had a lower risk of

bleeding and similar risk of major fatal bleeding compared with warfarin.4,8-14 Furthermore, a recent systematic review and meta-analysis of 13 randomized control trials evaluated mortality data and showed that DOACs were associated with lower rates of fatal bleeding, cardiovascular mortality, and all-cause mortality compared with warfarin.15 These trials have even led to the recent update in guidelines on antithrombotic therapy for VTE released by the CHEST Guideline and Expert Panel in January 2016. The panel suggests that a DOAC should be used preferably over a VKA for initial and long-term therapy of VTE in patients without cancer (Grade 2B).3 Reversal agents for DOACs

Given these recent new guidelines, expert consensus statements, and multiple promising large trials, DOACs will be at the forefront of antithrombotic therapy. However, despite their noninferior efficacy and lower risk of bleeding compared with warfarin, there is still a bleeding risk with any anticoagulant drug and a paucity of data regarding reversal agents for the new DOACs.16 Idarucizumab recently received accelerated approval to reverse the anticoagulant effects of dabigatran in patients requiring emergent surgery/urgent procedures or life-threatening/uncontrolled bleeding based on findings from the Reversal Effects of Idarucizumab on Active Dabigatran trial (RE-VERSE AD).17,18 Early trial results for idarucizumab

Schiele et al presented the first report of a specific antidote for DOACs, referred to as aDabi-Fab, now known as idarucizumab.18,19 The research group characterized aDabi-Fab as a monoclonal antibody fragment that binds and neutralizes the anticoagulant effects of dabigatran. They showed that the antidote exhibited a high affinity for dabigatran, roughly 350 times greater than for thrombin in vitro and in vivo. Additionally, the researchers showed that aDabi-Fab demonstrated quick reversal of dabigatran as measured by thrombin time (TT) and activated partial thromboplastin (aPTT) time in vivo in a rat model.19 These key findings were essential in the translation of idarucizumab as a humanized clinical therapeutic for future studies. In March 2015, Glund et al conducted a two-part randomized, double-blind, placebo-controlled phase 1 trial on humanized idarucizumab. In the first part of the study, the group investigated the safety, tolerability, and pharmacokinetics of different doses of idarucizumab in 110 healthy male volunteers aged 18 to 45.They concluded that idarucizumab was safe and tolerable at all doses administered in the study. In addition, maximum concentrations of idarucizumab were

achieved at the end of infusion followed by quick elimination without any effect on coagulation parameters.20 In the second part of the study, the group investigated the safety, tolerability, and efficacy of idarucizumab as a reversal agent for dabigatran in 47 men from the first part of the study.They showed that idarucizumab exhibited quick reversal of dabigatran with persistent effect at all doses tested without any major adverse events.21 Also, Glund et al concluded that idarucizumab was safe, tolerable, and exhibited persistent effect at all administered doses in elderly and renally impaired patients.22 REVERSE-AD trial

Following the promising results from several studies on the safety, tolerability, and efficacy of idarucizumab, Pollack et al developed a multicenter, prospective cohort study, referred to as REVERSE-AD, to evaluate the safety of 5 grams of idarucizumab, which was given as two separate 2.5-gram infusions, and its ability to reverse dabigatran in patients who had serious bleeding (group A) or required an urgent procedure/surgery that could not be delayed for at least 8 hours and required hemostasis (group B).The study began in June 2014 and completed enrollment in July 2016. The primary outcome of the study was maximum reversal of dabigatran’s anticoagulant effects as measured by direct thrombin time (dTT) and ecarin clotting time (ECT) in the first 4 hours after initial infusion. The maximum reversal was calculated as a percentage using the following equation: percentage reversal = (predose test result [in seconds] − minimum postdose test result [in seconds] ∕ (predose test result [in seconds] − upper limit of normal range [in seconds]) × 100. In an interim analysis of the first 90 patients enrolled, 68 patients with elevated dTT and 81 patients with elevated ECT at baseline were found to have maximum reversal of dabigatran’s anticoagulant effects of 100%, immediately after infusion of idarucizumab. Furthermore, dTT normalized in 98% of patients in group A and 93% of patients in group B. ECT normalized in 89% of patients in group A and 88% of patients in group B.The study found that similar maximum reversal and normalization findings of aPTT and TT were seen among each group. Furthermore, following the administration of idarucizumab, the concentration of unbound dabigatran was decreased to a level that produces little to no anticoagulant effect in all patients but one in the cohort. There were no safety concerns with administration of idarucizumab at the study dose.17 In August 2017, Pollack et al published the full cohort analysis of 503 patients from the REVERSE-AD trial.The robust findings validated the initial results from the interim analysis of 90 patients. In those patients receiving dabigatran

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2018 35

ORAL ANTICOAGULATION

Anticoagulation reversal: take home points 1. DOACs provide advances in efficacy, overall safety, and patient and provider simplicity compared with warfarin.

2. There is a paucity of data regarding reversal agents for the new DOACs.

3. Idarucizumab completely and quickly reversed dabigatran’s anticoagulant effects in the REVERSE-AD trial.

4. Idarucizumab (Praxbind®) recently received accelerated approval as a reversal agent for dabigatran in patients requiring emergent surgery/urgent procedures or life-threatening/ uncontrolled bleeding.

5. Other potential reversal agents for dabigatran include renal replacement therapy and prothrombin complex concentrate.

with prolonged dTT and uncontrollable bleeding or need for an urgent procedure, idarucizumab reversed the anticoagulant activity of dabigatran in more than 98% of patients. The 30-day and 90-day mortality data were similar between the groups and were concluded to be due to the initial event or comorbid conditions and less likely as a result of idarucizumab effects.23 Following the interim analysis findings from the REVERSE-AD trial, idarucizumab received accelerated approval on October 16, 2015, for patients requiring emergent surgery/urgent procedures or life-threatening/uncontrolled bleeding. The recommended dose is 5 grams, given as two separate vials each containing 2.5 grams/50 milliliters.18 The wholesale acquisition cost of two vials of 2.5 grams of idarucizumab is about $3500.24 Even though the data have high impact, there are limitations to the study. First, most hospitals do not routinely use dTT or ECT levels, complicating the ability to measure the effects of idarucizumab on dabigatran reversal.The reason for their use in this study was based on their high correlation with unbound dabigatran levels.21 However, hospitals do routinely order aPTT as a coagulation parameter. Given that the study showed maximum reversal within the first few minutes and normalization of aPTT after idarucizumab administration, aPTT may be a potential coagulation parameter for monitoring idarucizumab. Second, there was no control group in the study; however, the authors acknowledge this limitation and state that it would be unethical to randomly assign patients to a placebo group given there are no approved alternatives to idarucizumab.

Third, the REVERSE-AD trial did not evaluate any other specific indications for idarucizumab other than uncontrollable bleeding or need for urgent procedure.These data will need to be explored in future studies. Potential alternative reversal agents

Three other potential methods have been evaluated as reversal agents for dabigatran. Khadzhynov et al conducted an open label, single center, phase 1 study to evaluate the elimination of dabigatran with renal replacement therapy in patients with end-stage renal disease. Their study findings showed that intermittent hemodialysis decreased plasma dabigatran concentrations by 48.8% to 59.3%.25 In 2011, Erenberg et al conducted a randomized, double-blind, placebo-controlled study evaluating the reversal effects of prothrombin complex concentrate (PCC) on rivaroxaban and dabigatran.They concluded that PCC quickly and completely reversed the effects of rivaroxaban but had no effect on dabigatran.26 In contrast, in 2012, Pragst et al conducted an open-label, placebo-controlled study evaluating the reversal effects of PCC among rabbits treated with dabigatran.They concluded that PCC decreased blood loss and increased hemostasis in a variety of dabigatran doses. Importantly, the doses used were similar to those used in clinical practice.27 Lastly, Lange et al showed that dabigatran can be removed via activated charcoal; 75% to 80% of circulating dabigatran was reduced after 1 hour and levels were undetectable after 2 hours. However, the maximum binding capacity for activated charcoal is 30 mg of drug, far less than the current recommended dose of dabigatran.28 Even though these studies may have promising potential, future large human randomized studies are warranted to determine their efficacy in reversing the effects of dabigatran as well as their efficacy when compared with idarucizumab. Given the recent updates on oral anticoagulation in the literature and findings from multiple large clinical trials showing the efficacy of DOACs, these drugs will become the leaders in antithrombotic therapy.Therefore, advances in new reversal agents will be a key piece to the puzzle for managing patients treated with DOACs to prevent major bleeding events.The promising data from the interim and full cohort analysis of the REVERSE-AD trial has put idarucizumab in the spotlight as the first approved DOAC reversal agent. However, future studies on idarucizumab are warranted to establish its potential indications in different patient populations. n Zachary Lavender, PA-C, MHS, and Peter S. Sandor, RRT, MHS, PA-C, DFAAPA, are critical care physician assistants based in Hartford, Conn., and faculty members at Quinnipiac University in Hamden, Conn.

36 THE CLINICAL ADVISOR • MAY 2018 • www.ClinicalAdvisor.com

References

16. Reilly PA, Lehr T, Haertter S, et al. The effect of dabigatran plasma

1. Barnes GD, Ageno W, Ansell J, Kaatz S. Subcommittee on the Control

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of Anticoagulation. Recommendation on the nomenclature for oral anti-

stroke and major bleeding in atrial fibrillation patients: The RE-LY trial

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2015;13:1154-1156. doi: 10.1111/jth.12969.

Cardiol. 2014;63:321-328. doi: 10.1016/j.jacc.2013.07.104.

2. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy:

17. Pollack CV,Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran

Antithrombotic therapy and prevention of thrombosis, 9th ed: American

reversal. N Engl J Med. 2015;373:511-520. doi: 10.1056/NEJMoa1502000.

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18. Praxbind (idarucizumab) [package insert]. Ridgefield, CT: Boehringer

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Ingelheim Pharmaceuticals, Inc.; revised October 2015.

3. Kearon C, Akl E, Ornelas J, et al. Antithrombotic therapy for VTE

19. Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran:

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4. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin

20. Glund S, Moschetti V, Norris S, et al. A randomised study in healthy

in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151. doi:

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5. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in

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nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891. doi: 10.1056/

21. Glund S, Stangier J, Schmohl M, et al. Safety, tolerability, and efficacy

NEJMoa1009638.

of idarucizumab for the reversal of the anticoagulant effect of dabi-

6. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin

gatran in healthy male volunteers: A randomised, placebo-controlled,

in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992.

double-blind phase 1 trial. Lancet. 2015;386:680-690. doi: 10.1016/

doi: 10.1056/NEJMoa1107039.

S0140-6736(15)60732-2.

7. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin

22. Glund S, Stangier J, Schmohl M, et al. Idarucizumab, a specific

in patients with atrial fibrillation. N Engl J Med. 2013;369:2093-2104.

antidote for dabigatran: immediate, complete and sustained reversal

doi: 10.1056/NEJMoa1310907.

of dabigatran induced anticoagulation in elderly and renally impaired

8. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin

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2014 (abstract).

9. Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous

23. Pollack CV, Reilly RA, van Ryn J, et al. Idarucizumab for Dabigatran

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Reversal – Full Cohort Analysis. N Engl J Med. 2017;377:431-441.

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doi.10.1056/NEJMoa1707278

CIRCULATIONAHA.113.004450.

24. Buchheit J, Reddy P, Connors JM. Idarucizumab (Praxbind)

10. Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran,

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25. Khadzhynov D, Wagner F, Formella S, et al. Effective elimination

11. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al. Oral

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26. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR,

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27. Pragst I, Zeitler SH, Doerr B, et al. Reversal of dabigatran

14. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment

anticoagulation by prothrombin complex concentrate (beriplex P/N)

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28. Lange J, Thiel C, Thiel K, Klingert W, Klingert K, et al. Acceleration of

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www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2018 37

Stat Consult

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

Parenteral nutrition issues ALAN DRABKIN, MD

Dr Drabkin is a senior clinical writer for DynaMed (www.ebscohost. com/dynamed), a database of comprehensive updated summaries covering more than 3,200 clinical topics, and assistant clinical professor of population medicine at Harvard Medical School.

Mechanical complications • catheter or venous thrombosis — incidence varies (3.9% with peripherally inserted central catheters (PICC) to 38% with hemodialysis — prophylactic heparin does not significantly reduce risk of thrombosis — PICC associated with higher rates of thrombophlebitis and difficulty of insertion compared with standard subclavian catheters • catheter occlusion — more common with PICC than non-PICC — increased risk with addition of syrups, medications with low pH, or oleaginous liquid medication — treatments include ■ 70% ethanol may clear lipid-related occlusion ■ 0.1-N sodium hydroxide for mineral or drug occlusion ■ tissue plasminogen activator (tPA) for thrombus-related obstruction • catheter-related infection (higher risk than enteral nutrition or IV dextrose) • catheter dislodgement or fracture (rare) Central vascular access complications

• • • • •

pneumothorax hemothorax air embolism arterial puncture line malposition

Compatibility issues:

Parenteral nutrition is introduced otherwise than through the intestines.

• formation of precipitates (calcium gluconate may decrease risk) • if high-dose vitamin C (up to 2,000 mg per day) needed, use separate infusion • many medications not compatible with 3-in-1 parenteral nutrition solutions Stability (degradation of nutritional components over time)

• not typically seen in acute care settings due to daily compounding of solutions 38 THE CLINICAL ADVISOR • MAY 2018 • www.ClinicalAdvisor.com

• more commonly seen in home care settings with bulk home delivery of solutions • avoid degradation by adding vitamins just prior to infusions

limit lipid infusion to < 0.12 g/kg/hour in critically ill patients or if impaired lipid clearance • goal serum triglyceride < 400 mg/dL (4.5 mmol/L) in adult patients on continuous TPN

Hyperglycemia

Gastrointestinal complications

• primary cause is excess dextrose infusion • balanced regimen should include 50%-60% of total calories from dextrose (infusion 4-5 mg/kg/minute optimal) • critically ill patients at increased risk • advance dextrose concentration slowly to meet caloric goal with insulin adjustments per blood glucose levels • consider using IV insulin drip instead of sliding scale in ICU

• intestinal atrophy may result from ——lack of stimulation from luminal nutrients ——absent fuel source ——impaired gastric hormonal response ——increased intestinal permeability and bacterial translocation • gastroparesis • may be limited by gut stimulation from oral or enteral intake

Reactive hypoglycemia

Parenteral nutrition-associated liver disorders

• reactive hypoglycemia can occur 15-60 minutes after cessation of parenteral nutrition due to prolonged insulin response to caloric load • increased risk with ——renal and liver disease ——severe malnutrition ——sepsis ——hyperthyroidism • prevention strategies include ——adequate oral intake to sustain blood glucose levels ——if oral intake is not resumed, consider ■■ infusion of 10% dextrose immediately after discontinuation of parenteral nutrition ■■ gradual tapering of parenteral solution for 1-2 hours

• hepatic steatosis ——characterized by elevated serum aminotransferases and hepatomegaly ——may occur within first few weeks of treatment ——reversible with discontinuation of TPN ——more common in adults ——may be limited by reduction in carbohydrate load in patients with elevated LFTs • biliary complications ——long-term TPN associated with cholecystitis and biliary sludge ——may be prevented by oral or enteral intake • cholestasis ——typically occurs with long-term TPN ——often chronic and irreversible, may lead to liver failure and death ——more common in infants ——prevention strategies include ■■ initiation of enteral feeding and weaning of parenteral nutrition ■■ avoiding overfeeding ■■ providing balanced source of energy ■■ cyclic parenteral nutrition infusions ■■ avoidance of sepsis ■■ limiting manganese if long-term TPN used ——ursodiol (ursodeoxycholic acid) reported effective for treatment

Hyperlipidemia

• causes ——excessive lipid load ——impaired lipid clearance ■■ obesity ■■ diabetes ■■ sepsis ■■ pancreatitis ■■ liver disease ■■ renal failure ——prolonged use of high-dose corticosteroids • prevention and treatment ——reduce dextrose load, especially with hypertriglyceridemia ——reduce lipid load; if hyperlipidemia is not corrected by reduced dextrose load ■■ consider cycling lipid as 250 mL of 20% IV fat emulsion twice weekly if serum triglyceride > 400 mg/dL (4.5 mmol/L)

■■

Low bone mineral density

• common • many patients are asymptomatic • may present with ——pain (bone, back)

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2018 39

Stat Consult •

• •

•

— atraumatic fractures — loss of height monitoring should include — serum calcium, phosphorous, magnesium, acetate, 25-hydroxyvitamin D (all may be normal) — 24-hour urine collection (calcium, magnesium) — baseline DEXA scan, repeated every 1–2 years if abnormal (T-score < -1 diagnostic) adequate intake of calcium and phosphorus essential for prevention aluminum toxicity associated with development of parenteral nutrition-associated bone disease — infants at higher risk due to reduced renal function — sources of aluminum in parenteral solutions include multivitamins, sodium phosphate, and calcium gluconate — serum aluminum level > 100 mcg/dL or urine aluminum/ creatinine ratio > 0.3 may indicate contamination of parenteral solution management in parenteral solutions for adults — calcium > 15 mEq/day — phosphorus > 15 mmol/day — magnesium (maintenance) — acetate — decrease protein to 1 g/kg/day if nutritionally stable treatment strategies — calcium supplementation 500-1,000 mg/day for adults at risk, total daily intake ≥ 1,500 mg — vitamin D supplementation if deficient — consider estrogen replacement if postmenopausal — limit steroid use — smoking cessation — exercise refeeding syndrome — severe fluid and electrolyte disturbances caused by rapid nutritional repletion if severely malnourished — characterized by hypophosphatemia, hypokalemia, and hypomagnesemia — may be life-threatening if not promptly treated — patients at risk should have parenteral nutrition advanced slowly to goal over 3-5 days with close monitoring of relevant tests — additional supplementation often required in addition to repletion hypercapnia — excessive CO2 production caused by overfeeding total kcal and dextrose — may result in difficulty weaning from mechanical ventilation

— may be reduced by decreasing caloric load • other deficiencies — essential fatty acids (avoid by providing 2%-4% of total kilocalories as linoleic acid and not using lipid-free parenteral solutions for > 2 weeks) — selenium — copper • renal complications — hyperoxaluria — hypercalciuria — renal tubular defects Prevention of complications

• inspect solutions at time of compounding and prior to administration and discard if any of — gross particulate contamination — discoloration—yellow-brown oil layer or marbling • delay of supplemental parenteral nutrition for 8 days reduces new infections and length of stay compared with immediate initiation in critically ill children in pediatric ICU • ethanol locks associated with decreased risk of catheterassociated bloodstream infection compared with heparin locks in children with intestinal failure and chronic parenteral nutrition dependence • addition of selenium to parenteral nutrition for ≥ 5 days may reduce risk of new infection in critically ill adults. ■

40 THE CLINICAL ADVISOR • MAY 2018 • www.ClinicalAdvisor.com

Case Study Library Check out all of our case studies in obesity, diabetes, and other important topics in primary care — along with our clinical challenges — by visiting us at: ClinicalAdvisor.com/Case-Study

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 on the latest information about conditions seen in everyday practice. Running approximately 2,500 to 5,000 words, including the references, 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. Charts, tables, and algorithms are also encouraged. Please include your title and affiliation. 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. The length should be about 1,500 words, and accompanying images are encouraged. Please include your title and affiliation. Dermatology Clinic CASE #1

Fingernail dystrophy in a young child SIMO HUANG, BS, CHRISTOPHER RIZK, MD

The patient is a 12-year-old Hispanic girl who presents with a 6-month history of nail dystrophy involving all of her fingernails. On examination, all 10 of her fingernails exhibit longitudinal ridging, pitting, fragility, thinning, and distal notching. The patient’s mother is very concerned about the cosmesis of her daughter’s nails. The patient has no systemic symptoms. On review of systems, the patient’s mother noted that her daughter has started to develop circular patches of hair loss that appear to resolve on their own. The patient has no relevant social or family history and does not take any medications. What is your diagnosis? Turn to page 54

CASE #2

Headache, malaise, and a rash ZACHARY SOLOMON, BS, DAVID RIZK, BA, CONNIE WANG, MD

A 42-year-old man presents with a four-day history of experiencing headache, malaise, and stabbing right-sided headache. Two days after his initial symptoms appeared, he developed a rash over the area of pain. He reports that he went hiking through the Texas hill country prior to becoming ill. The patient is otherwise in good health and has an unremarkable medical history. Physical examination reveals unilateral erythematous, thin, raised plaques over the right forehead. In addition, he has no relevant social or family history. What is your diagnosis? Turn to page 55 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2017 53

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 75-to-100-word description of the patient 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, an explanation of how the correct diagnosis was reached, 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. Please include your title and affiliation. COMMENTARY is our guest editorial page. It gives you the opportunity to sound off on an issue of importance to your colleagues nationwide. A typical Commentary runs about 600 words in length. Please include your title and affiliation. To discuss your editorial ideas, contact us by phone at 646.638.6078; by e-mail to editor@ClinicalAdvisor.com; or by mail to The Clinical Advisor, 275 7th Avenue, 10th Floor, New York, NY 10001. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2018 41

CME

Release Date: January 31, 2018 Expiration Date: May 31, 2019 Estimated Time to Complete: 30 minutes Accredited Provider: This activity is provided by Haymarket Medical Education (HME).

FEATURED COURSE EDUCATIONAL OBJECTIVES After completing the activity, the participant should be better able to: • Recognize the full spectrum of RA manifestations, including the impact on functional ability, quality of life, and elevated risk for myocardial infarction and stroke • Implement guidelinesdirected, treat to target strategies to achieve RA remission or low disease activity • Incorporate shared decision-making strategies in RA treatment decisions • Individualize RA treatment plans with consideration for patient-centric issues such as tolerability and likelihood of adherence in addition to efficacy and safety COMPLETE THE POSTTEST: Page 51

Commercial Supporter: This activity is supported by an educational grant from Sanofi Genzyme and Regeneron Pharmaceuticals. Program Description: Timely diagnosis of rheumatoid arthritis (RA) allows for prompt initiation of treatment—an important component in increasing the likelihood of clinical remission. Attaining clinical remission, or the secondary goal of low disease activity, in turn helps limit joint damage and subsequent disability as well as other unwelcome consequences of RA.This case presentation depicts a patient’s journey toward remission, using the “treat to target” approach advocated by American and European RA management guidelines. Intended Audience: Rheumatologists, physician assistants, and nurse practitioners Conflict of Interest Disclosure Policy: In accordance with the ACCME Standards for Commercial Support, HME requires that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any commercial interest. HME resolves all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational activities. Faculty Roy Fleischmann, MD, MACR - Chair Medical Director Metroplex Clinical Research Center Clinical Professor of Medicine University of Texas Southwestern Medical Center Dallas,TX, USA Dr. Fleischmann reports that he is a consultant for AbbVie Inc., Amgen Inc., Eli Lilly, GlaxoSmithKline plc, Pfizer Inc., and Sanofi USA and receives fees for non-CME services from Pfizer Inc. He also receives research grants from AbbVie Inc., Amgen Inc., Eli Lilly, GlaxoSmithKline plc, Novartis, Pfizer Inc., Regeneron Pharmaceuticals Inc., Sanofi USA, Samumed LLC, and UCB Inc. Bernard Combe, MD, PhD Professor of Rheumatology Montpellier University Head, Bone and Joint Department Montpellier University Hospital Montpellier, France Dr. Combe reports that he is a consultant for and is on the speakers’ bureaus of AbbVie Inc., BristolMyers Squibb Company, Chugai Pharmaceutical Co. Ltd., Janssen, Lilly, Merck Sharp & Dohme Corp., Pfizer Inc., and UCB Inc. He also receives research funds from Chugai Pharmaceutical Co. Ltd., Merck Sharp & Dohme Corp., and Pfizer Inc.

Accredited Provider Disclosures: Haymarket Medical Education staff involved in the planning and content review of this activity have no relevant financial relationships to disclose. Publishing Staff Disclosures: Lori Marrese and Jill Rovitzky Black have nothing to disclose in regard to commercial support. Accreditation Statement: Haymarket Medical Education is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Designation Statement: Haymarket Medical Education designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credit(s)TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Disclosure of Unlabeled Use: This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options for a specific patient’s medical condition. Disclaimer: The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of Haymarket Medical Education, Sanofi Genzyme, and Regeneron Pharmaceuticals. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Instructions: There are no fees for participating in and receiving CME credit for this activity. During the period January 31, 2018, through May 31, 2019, participants must: 1) read the learning objectives and faculty disclosures; 2) complete the pre-assessment test; 3) study the educational activity; 4) respond to all polling questions and watch all patient video clips in the online version of the activity; and 5) complete the post-test and evaluation form and submit it online. A statement of credit will be issued only upon receipt of the above elements and a post-test score of 70% or higher. All components must be completed and submitted online at ClinicalAdvisor.com/May18feature. If you have any questions relating to your certificate or other issues with the activity, please contact myCME.Support@haymarketmedical.com.

Provided by

CME FEATURED COURSE: ROY FLEISCHMANN, MD, MACR; BERNARD COMBE, MD, PHD

Case: A 49-year-old recently diagnosed with rheumatoid arthritis Timely diagnosis of rheumatoid arthritis is critical. This case highlights a patient’s journey toward remission using a “treat to target” approach.

atrick, a 49-year-old man, presented to a rheumatologist for evaluation. His primary care physician (PCP) diagnosed him with rheumatoid arthritis (RA) about 3 months ago, following complaints about multiple tender, swollen joints; general fatigue; and morning stiffness lasting about 1 hour each day. He had experienced symptoms for 6 weeks prior to the PCP’s diagnosis. Patrick’s medical history is significant for overweight (body mass index 28 kg/m2), dyslipidemia treated with atorvastatin, and seasonal allergic rhinitis treated as needed with fluticasone nasal spray. Patrick has a 19-year history of smoking cigarettes; he quit smoking at age 40 upon retiring from an army career. He is anxious because his pain and stiffness are interfering with his ability to perform his work as an electrician.

■ VIDEO CLIP 1: Go to ClinicalAdvisor. com/May18feature to listen to Patrick explain his symptoms and concerns.

RA typically involves tender, warm, and swollen joints in the hands and feet.

Physical examination identified 8 tender and 7 swollen small joints in the hands and feet, with a total of 10 joints affected. Laboratory findings were significant for elevated C-reactive protein (CRP), 20 mg/L; rheumatoid factor (RF), 2 times the upper limit of normal (ULN); and anticitrullinated protein antibody (ACPA); 4 times the ULN. Complete blood count (CBC), renal www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2018 43

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Historically, 20% to 30% of patients became unable to work within the first 2 to 3 years after having a diagnosis of rheumatoid arthritis. measures, and hepatic function were normal. Hand, wrist, and feet X-rays revealed no erosions. His functional status, as measured by the Health Assessment Questionnaire (HAQ), was 1.5, indicating moderate disability.1 Patrick’s Disease Activity Score (DAS) 28-CRP was 5.2. Confirming the diagnosis and classifying early RA

The 2010 criteria for classifying early-stage RA that would benefit from early therapeutic intervention, developed by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR), are intended for the evaluation of patients displaying at least 1 swollen joint not better explained by a disease other than RA. Table 1 lists the classification criteria and score-based algorithm for evaluating whether a patient has definite RA. A score of 6 out of 10 qualifies as definite RA.2 Patrick has a score of 8 out of 10: 3 points for his 10 small involved joints, 3 points for his high-positive ACPA, 1 point for his abnormal CRP, and 1 point for his symptom duration. This finding confirms the diagnosis of RA. The international guidelines for the treatment of RA advise measuring disease activity “in a majority of (patient) encounters.”3 Acceptable assessment tools include the Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index

(SDAI), or Disease Activity Score with 28-joint counts (DAS28) and erythrocyte sedimentation rate (ESR) or CRP.3-5 (Note that the use of DAS28 using CRP is not interchangeable with DAS28 using ESR; cutoff points to establish low disease activity or remission differ between them.6) Patrick’s DAS28CRP score of 5.2 signals high disease activity.6,7 He displays multiple negative prognostic factors, with high levels of CRP, RF, and ACPA.5 The ACR guidelines also recommend measuring functional status at least annually, and more often in patients with active disease.3 The HAQ is one acceptable instrument; others include the Multidimensional Health Assessment Questionnaire, Patient-Reported Outcomes Measurement Information System (PROMIS; available at www.assessmentcenter.net), Physical Function 10-item, PROMIS Physical Function 20-item, and PROMIS Physical Function Computerized Adaptive Tests (PROPFCAT).3 Impact of RA Work disability. Measurement of functional status is important because RA is associated with high rates of work disability. Historically, 20% to 30% of patients became unable to work within the first 2 to 3 years after diagnosis.8 A median of 66% of patients with RA who were employed experienced

TABLE 1. Classification criteria for rheumatoid arthritis2 Score-based algorithm: Add score of categories A through D; a score of ≥6 out of 10 is needed for classification of a patient as having definite RA. Joint involvementa

Serology (≥1 test required)b

a. 1 large joint—0 points b. 2–10 large joints—1 point c. 1–3 small joints (with or without large joint involvement)—2 points d. 4–10 small joints (with or without large joint involvement)—3 points e. >10 joints with ≥1 small joint—5 points

a. Negative RF and negative ACPA—0 points b. Low-positive RF or low-positive ACPA—2 points c. High-positive RF or high-positive ACPA—3 points

Acute-phase reactants (≥1 test required)c a. Normal CRP and normal ESR—0 points b. Abnormal CRP or abnormal ESR—1 point

Duration of symptoms a. <6 weeks—0 points b. ≥6 weeks—1 point

ACPA, anti-citrullinated protein antibody; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; RF; rheumatoid factor. a

ny tender or swollen joint on physical examination except the distal interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal joints. These joints are typically A involved in osteoarthritis. Large joints are the shoulders, elbows, hips, knees, and ankles. Small joints are the metacarpophalangeal joints, proximal interphalangeal joints, second to fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists.

egative serology: no higher than the upper limit of normal (ULN) for the laboratory and assay. Low-positive is defined as >ULN but <3 times ULN for laboratory and assay. N High-positive: >3 times ULN for laboratory and assay. If RF is reported as only positive or negative, then a positive result should be scored as low-positive.

Determine by local laboratory standards.

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ACR and EULAR guidelines recommend a shared patient–clinician decision-making approach to choice of therapy for rheumatoid arthritis. some disease-related work loss within the prior 12 months, according to a systematic review of 38 studies. More severe RA, older age, and physically demanding work predicted subsequent work disability in this analysis.9 Data from a nationwide registry in Finland indicate that although the rate of RA-related work disability has decreased over time in general, it still exceeds work disability rates among the general population.10 Also, analysis suggests that work disability rates remain elevated for patients with RA whose jobs are physically demanding.9 Risk of cardiovascular disease (CVD). Inflammation underlies the pathology of both RA and CVD. Numerous studies document an increased risk of CVD in patients with RA. Patients with RA face a 50% increased risk of CV death compared to those without the disease, according to a metaanalysis of 24 observational studies.11 RA was associated with roughly double the risk of myocardial infarction and stroke and a 30% higher rate of CV death in a cohort study among all adults in British Columbia.12 Mortality. For many years (1965-2005), RA has been associated with an overall mortality rate higher than that of the general population (2.4 and 2.5 per 100 person-years, women and men with RA, respectively; and 0.2 and 0.3 per 100 person-years, women and men in the general white population of Minnesota, respectively).13 A more recent analysis found that patients with low disease activity had levels of mortality similar to those of the general population.14 Consecutive patients with RA starting any of 9 biologics or other new therapies in Germany and enrolled from 2001 to 2011 were included in this study.14 Economic impact. People with RA have significantly higher medical costs than those without the disease, according to an analysis of data from the 2008 Medical Expenditure Panel Survey, a nationally representative survey of the US civilian noninstitutionalized population. Adjusted average annual medical expenses were $13,012 (95% CI $1737-$47,081) for patients with RA (5.8 million) and $4950 (95% CI $567$17,425) for controls (190 million).15 Analysis of Swedish national databases revealed that the total direct and indirect cost of RA (inpatient and outpatient care, pharmaceuticals, sick leave, and disability pensions) rose from 1990 to 2010, primarily due to increased drug costs (from 3% to 33%) following the introduction of biologics. RA-related inpatient care, sick leave, and disability pension costs declined over the study period.The share of RA costs traced to indirect costs (sick leave and disability pension) fell from 75% in 1990

to 58% in 2010. The total direct and indirect costs of RA, following adjustment for inflation, rose by 32%. Disability pensions remained the major cost driver.16 POLLING QUESTION

How would you treat Patrick? a. Monotherapy with a tumor necrosis factor (TNF) inhibitor b. Monotherapy with a conventional disease-modifying antirheumatic drug (DMARD), preferably oral methotrexate 10 mg per week c. Oral methotrexate 15 mg per week, titrating up to 25 mg per week within 2 to 3 months if tolerated, and oral glucocorticoids 10 mg per day to give Patrick rapid relief, then tapering and discontinuing the glucocorticoids after 3 months of therapy d. Monotherapy with tofacitinib, as you prefer to start with a biologic or targeted synthetic (ts) DMARD and find that patients prefer an oral therapy Choosing initial therapy

The most recent ACR guidelines for treating RA recommend monotherapy with a traditional/conventional DMARD for symptomatic patients with early RA and moderate to high disease activity,3 like Patrick. Methotrexate is considered firstline therapy, both as monotherapy and in combination with other agents.3,5 It was associated with a 70% reduced risk of death over 25 years in a prospective observational study of 5626 patients with RA.17 The EULAR recommendations advise considering the addition of short-term glucocorticoids when starting a conventional DMARD, and tapering the steroids as quickly as possible.3,5 Both ACR and EULAR guidelines recommend a shared patient–clinician decision-making approach to choice of therapy. This includes informing the patient about the disease, with its risks and prognosis, and treatment options with their potential benefits, risks, and monitoring requirements.3,5 The goal of therapy should be clinical response at 3 months and full remission—or at least low disease activity—within 6 months.5 Initial therapy for Patrick: Shared decision-making The rheumatologist explained to Patrick that RA is a chronic inflammatory disease affecting the joints and other areas of the body.18 He indicated that although RA cannot be cured, many therapies are available and that starting treatment early in the disease course—as they are doing—can reduce the risk of joint

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The goal of therapy is to achieve full remission within 6 months, with low disease activity a second goal if full remission is not attainable. damage.5 He underlined the importance of taking medications as prescribed and adhering to follow-up procedures. Patrick expressed concern about his hand function and the pain in his feet when he stands for long periods or rises from a squatting position. He asked whether he will be able to continue working as an electrician. He stressed his need for rapid relief so that he can function on the job. The rheumatologist acknowledged these concerns. He noted that Patrick is starting therapy before joint damage has occurred and expressed optimism that treatment can lead to remission.The rheumatologist explained that the goal of therapy is to achieve full remission within 6 months, with low disease activity a secondary goal if full remission is not attainable.5 He stressed that Patrick will need to return for visits often during that time while they monitor the safety and effect of the treatment and adjust therapy as needed. Patrick agreed to do whatever is needed to restore his function and prevent damage. The rheumatologist recommended initiating therapy with oral methotrexate at 10 mg per week, increasing to 15 mg at 2 weeks, 20 mg at 4 weeks, and 25 mg at 8 weeks, if tolerated and beneficial. He explained that this agent is a common first therapy for RA and is used alone and with other agents.5 Some relief of swelling and tenderness may occur as early as 3 to 6 weeks.19 Folic acid supplementation was prescribed to reduce the risk of methotrexate toxicity, such as nausea and other gastrointestinal (GI) side effects as well as liver enzyme elevations.20 Patrick received a single 120-mg intramuscular glucocorticoid injection at this visit as well as a prescription for daily oral glucocorticoid medication (prednisone 10 mg/day) to provide rapid symptom relief.5 The rheumatologist indicated that the plan is to lower the steroid dose each month—to 7.5 mg per day for month 2 and to 5 mg per day for month 3—and to eliminate glucocorticoids at the end of 3 months, consistent with current guidelines.3,5 He asked Patrick to return in 1 month for laboratory work and evaluation of safety and effectiveness. Patrick expressed concern about taking oral steroids and asks about their side effects. The rheumatologist indicated that the risk-benefit profile of oral glucocorticoids in early RA is favorable as long as the dose is low (the equivalent of prednisone ≤10 mg/day) and the duration of therapy is short—less than 6 months. Glucocorticoids are used as a bridge therapy until the benefit of DMARD therapy is realized3 and are intended to provide the rapid relief that Patrick desires. A recent study examining the safety of lowdose glucocorticoids in early RA over 7 years of follow-up

reported no significant difference in the rates of death, CVD, infections, severe infections, or fractures in patients with RA who did and did not use very low-dose glucocorticoid therapy (average of <5 mg/day).21 The rheumatologist informed Patrick that blood pressure increases, weight gain, fluid retention, and infections are potential side effects of glucocorticoids. He advised him to minimize use of sugar and salt (the latter to reduce fluid retention) during therapy. Infection, including serious infection, is a risk while taking methotrexate. GI side effects and lung disease (signaled by a dry, nonproductive cough) may occur during methotrexate therapy.The rheumatologist will monitor Patrick’s blood pressure, weight, liver and kidney function, and blood levels during therapy. Patrick should stop taking methotrexate and notify the rheumatologist office immediately if he develops mouth sores, fever, dehydration, cough, shortness of breath, infection, or skin rash.19,22 He vaccinated Patrick for pneumococcal pneumonia and influenza prior to starting methotrexate therapy, consistent with ACR guidelines.3

■ VIDEO CLIP 2: Go to ClinicalAdvisor.com/ May18feature to listen to Patrick respond to his rheumatologist about treatment options. Optimizing methotrexate dose

A systematic review of 38 publications examining methotrexate use in RA concluded that the best regimen began with an initiation dose of 15 mg per week orally, with escalation by 5 mg per month up to 25 mg to 30 mg per week oral dose as tolerated. Patients with an inadequate response to the maximum tolerated oral dose can be switched to subcutaneous (SC) administration.23 Other studies have reached similar conclusions.24 Optimizing methotrexate dose was associated with a more than 4-fold greater likelihood of achieving ACR-EULAR remission at 1 year and normal functioning (HAQ <0.5) in an analysis of individuals with early RA prescribed methotrexate as a first DMARD in the French ESPOIR cohort. Optimal methotrexate dose in this study was defined as ≥10 mg per week during the first 3 months, with escalation to ≥20 mg per week at 6 months in the absence of remission. Only 26.4% of the patients in this analysis received an optimized dose.25 US data also indicate that methotrexate dose is not optimized in RA prior to adding a biologic agent. An analysis of claims data showed that the mean oral dose of methotrexate prior

46 THE CLINICAL ADVISOR • MAY 2018 • www.ClinicalAdvisor.com

A treat-to-target strategy should be used for all patients with RA. Therapy should not be changed until the conventional DMARD has been optimized. to adding a biologic agent was 15.3 mg per week in 2009 and 15.9 mg per week in 2012. There are some suggestions that patients who do not experience an adequate response to methotrexate tablets may do better with an SC formulation. Only 16% of patients who failed oral methotrexate were switched to the SC formulation in 2012.26 Patients should be directed to take a folate supplement during methotrexate therapy. A recent Cochrane review found that concomitant use of folate during methotrexate therapy for RA significantly reduced the risk of GI side effects (relative risk reduction [RRR], 26.0%; P=.008), serum transaminase elevations (RRR, 76.9%; P<.00001), and patient withdrawal from methotrexate (RRR, 60.8%; P<.00001).20

TABLE 2.Treat to target: International Task Force overarching principles and recommendations4 Overarching principles

A. The treatment of RA must be based on a shared decision between patient and rheumatologist B. The primary goal of treating patients with RA is to maximize long-term health-related quality of life through control of symptoms, prevention of structural damage, normalization of function, and participation in social and work-related activities C. Abrogation of inflammation is the most important way to achieve these goals D. Treatment to target by measuring disease activity and adjusting therapy accordingly optimizes outcomes in RA

Treat to target

All patients with RA should be managed using a treat-to-target (T2T) strategy, with the target being clinical remission or low disease activity (Table 2). The latter may be an alternative goal for patients with long-standing disease.4 Validated composite measures of disease activity should be used to guide clinical decisions.4 Acceptable measures of disease activity include the DAS/ DAS28, CDAI, and SDAI.7,27 The ACR and EULAR definition of remission is that the swollen joint count, CRP (in mg/dL), and patient global assessment (0-10 scale) are all no higher than 1, or that the SDAI is no higher than 3.3.28 For DAS28 ESR, remission is defined as <2.6 and low disease activity as ≥2.6 and ≤3.2.7 The T2T international task force recommends documenting disease activity according to the chosen measure regularly, as often as monthly for those with moderate to high disease activity and every 6 months for those in low disease activity or remission.4 Therapy should not be changed until the conventional DMARD (eg, methotrexate) has been optimized.5 Many practices do not apply T2T. Evaluation of 11 US rheumatology practice sites, 9 of which were affiliated with academic medical centers, revealed a mean T2T implementation score of 11%. Following a 9-month intervention (9 educational sessions for clinicians) to promote the application of T2T in RA, the T2T implementation score rose to 57%.29 Adherence to T2T was higher in 2 clinical trials including 20 and 12 hospitals, respectively, in the Netherlands (86% and 70% adherence over 5 years in the 2 studies).30 Applying a T2T approach with remission as the goal led to a 50% greater probability of attaining remission 3 months later and a 64% greater likelihood of attaining sustained remission (>6 months), compared with not applying T2T, in a 10-country prospective cohort study (RA BIODAM).31

Recommendations 1. The primary target for treatment of RA should be a state of clinical remission 2. Clinical remission is defined as the absence of signs and symptoms of significant inflammatory disease activity 3. While remission should be a clear target, low disease activity may be an acceptable alternative therapeutic goal, particularly in established long-standing disease 4. The use of validated composite measures of disease activity, which include joint assessments, is needed in routine clinical practice to guide treatment decisions 5. The choice of the (composite) measure of disease activity and the target value should be influenced by comorbidities, patient factors, and drug-related risks 6. Measures of disease activity must be obtained and documented regularly, as frequently as monthly for patients with high/moderate disease activity or less frequently (such as every 6 months) for patients in sustained low-disease activity or remission 7. Structural changes, functional impairment, and comorbidity should be considered when making clinical decisions, in addition to assessing composite measures of disease activity 8. Until the desired treatment target is reached, drug therapy should be adjusted at least every 3 months 9. The desired treatment target should be maintained throughout the remaining course of the disease 10. The rheumatologist should involve the patient in setting the treatment target and the strategy to reach this target RA, rheumatoid arthritis.

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1-month follow-up

Treatment intensification

Patrick’s methotrexate dose was increased to 20 mg per week. He also was taking 10 mg per day of prednisone. He reported “a little less” morning stiffness and some relief from the pain and swelling in his hands and feet. Laboratory findings (CBC, liver enzymes, and creatinine—monitored as recommended by the ACR guidelines)3 are within normal limits, with no evidence of methotrexate intolerance. Patrick’s blood pressure was 120/80 mm Hg, similar to that of his first visit. He gained 1 lb. Patrick was instructed to reduce the prednisone dose to 7.5 mg per day immediately and to 5 mg in 1 month. At 1 month, he also should raise the methotrexate dose to 25 mg per week. He was scheduled to return in 2 months (that is, 3 months from treatment initiation).

At least 10 biologic (b) DMARDs and 1 tsDMARD (tofacitinib) are approved by the US Food and Drug Administration (FDA) for the treatment of RA (Tables 3 and 4).The European Medicines Agency (EMA) has also approved the Janus kinase (JAK) 1/JAK 2 inhibitor baricitinib for the treatment of RA, but that tsDMARD is not approved for use in the US. The EULAR treatment guidelines indicate that “among bDMARDs, there is no difference in outcomes, irrespective of their target. This conclusion rests on head-to-head trials, meta-analyses, the results of the SLRs [systemic literature reviews] and indirect comparison (the latter being less reliable and therefore least informative).”5 The choice of agent therefore is based on considerations such as comorbidities, concurrent medications, safety, insurance coverage, and patient preferences about administration route and dosage frequency. The EULAR guidelines advise combining a bDMARD or tsDMARD with a conventional DMARD such as methotrexate.5 The rheumatologist recommends adding one of the TNF inhibitors, explaining that they have the longest history of use for RA and the most safety data and are usually the first bDMARD used in RA. Patrick indicates that because his work demands make it difficult for him to come to the office for an infusion, he would rather self-inject, preferably as infrequently as possible. Based on these concerns, the rheumatologist recommends golimumab, a TNF inhibitor that is self-injected once a month. After ascertaining that Patrick

3-month follow-up

Patrick’s medications were 25 mg per week of methotrexate and 5 mg per day of prednisone. His DAS28-ESR count has fallen to 3.9, representing a significant improvement from the initial value of 5.2 and moderate disease activity. He reported less hand stiffness, hand and foot pain, and morning stiffness (about 30 to 40 minutes each day). Laboratory values were within normal limits, with no evidence of methotrexate intolerance; CRP was 8 mg/L. Patrick gained 1 lb since his 1-month follow-up visit. His blood pressure was unchanged. The rheumatologist instructed Patrick to stop the prednisone. 6-month follow-up

Patrick reported taking 25 mg per week of methotrexate with no glucocorticoid. He described experiencing more pain and stiffness in his hands and feet. His DAS28-ESR was 4.6, indicating moderate disease activity,6,7 and his CRP was 15 mg/L. X-rays of the hands and feet reveal 3 erosions, 1 in the hand and 2 in the wrist. Laboratory values remained consistent with tolerance of methotrexate.The patient expressed concern about his ability to work as his symptoms worsen. POLLING QUESTION

What would be your next step for Patrick’s therapy? a. Stop the methotrexate and start a TNF inhibitor b. Continue oral methotrexate and start a biologic or tsDMARD, listening to patient preferences before choosing the specific new agent c. Continue methotrexate and restart an oral glucocorticoid d. Continue oral methotrexate and choose the biologic or tsDMARD with the best outcomes data

The rheumatologist indicated that it is time to add a biologic agent.

TABLE 3.Tumor necrosis factor inhibitors for the treatment of RA Agent

Dose and route of administration

Adalimumab

SC: 40 mg qow

Certolizumab

SC: 400 mg at weeks 0, 2, and 4, then 200 mg qow

Etanercept

SC: 50 mg/week

Golimumab

SC: 50 mg/month

Infliximab

IV: 3 mg/kg at weeks 0, 2, and 6, then q8w

IV, intravenous; q8w, every 8 weeks; qow, every other week; RA, rheumatoid arthritis; SC, subcutaneous. All agents are approved by the US Food and Drug Administration (FDA) for RA. Dosage information is taken from FDA prescribing information. Prescribing information for some medications includes alternative dosing regimens for certain patients; consult prescribing information for details.

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TABLE 4. Non-TNF biologic and targeted synthetic agents for the treatment of RA Agent

MOA

Dose and route of administration

Abatacept

Selective T-cell co-stimulation modulator

IV: Weight-based dosing*; weeks 0, 2, and 3, then q4w SC: Weekly with or without IV loading dose; if IV loading dose, then 125 mg SC within a day of loading dose, followed by q4w

Anakinra

IL-1 receptor antagonist

SC: 100 mg qd

Baricitinib

JAK inhibitor

Oral: 4 mg qd

Rituximab

Anti–B-cell agent; CD20-directed cytolytic antibody

IV: 1000 mg at weeks 0 and 2 every 24 weeks, based on clinical evaluation; to be used concomitantly with methotrexate Methylprednisolone 100 mg IV or equivalent recommended 30 min prior to each infusion

Sarilumab

IL-6 receptor antagonist

SC: 200 mg q2w

Tocilizumab

IL-6 receptor antagonist

IV: 4 mg/kg IV q4w; can raise to 8 mg/kg q4w SC: 162 mg qow (<100 kg body weight) or qw (≥100 kg body weight)

Tofacitinib

JAK inhibitor

Oral: 5 mg bid For XR version, 11 mg qd

bid, twice a day; EMA, European Medicines Agency; IL, interleukin; IV, intravenous; JAK, Janus kinase; MOA, mechanism of action; q2w, every 2 weeks; q4w, every 4 weeks; qd, every day; qow, every other week; qw, every week; SC, subcutaneous; TNF, tumor necrosis factor; XR, extended release. *See prescribing information for details. All agents except baricitinib are approved by the US Food and Drug Administration (FDA) for RA. Dosage information is taken from FDA prescribing information except for baricitinib, which is taken from the EMA Summary of Product Characteristics. Prescribing information for some medications includes alternative dosing regimens for certain patients; consult prescribing information for details.

tests negative for tuberculosis and for hepatitis B and C,3 the rheumatologist prescribed golimumab while continuing methotrexate. He scheduled a follow-up visit and laboratory work in 3 months. Data indicate that TNF inhibitors are more efficacious in combination with methotrexate than as monotherapy.32 Use of methotrexate with a biologic has been associated with greater persistence with biologic therapy, according to an analysis of a Medicare claims database.33 Nevertheless, biologic registries and US claims databases indicate that about 30% of patients taking biologics use them as monotherapy.32 3 months later

Patrick’s tender and swollen joint count has fallen to 3. His CRP is 1 mg/L and the patient global assessment score is 1.5. With a DAS28-ESR score of 2.38, he is considered in remission.7 Laboratory values are within normal limits and he has had no infections. Patrick reported experiencing minimal pain and stiffness, with little difficulty injecting himself once he overcame some initial reluctance. He expressed relief at being able to work effectively again and function with minimal symptoms.

■ VIDEO CLIP 3: Go to ClinicalAdvisor.com/ May18feature to listen to Patrick’s conclusion. Summary

Early diagnosis and early, intensive treatment of newly diagnosed RA is important to increase the likelihood of achieving clinical remission and preventing joint damage and disability. Methotrexate is the cornerstone of therapy for RA, used alone or in combination with bDMARD or tsDMARD treatment. Optimizing methotrexate dose prior to adding another therapy is an important component of treatment.Treating to an objective, measurable target with frequent evaluation to assess whether the target has been met (“T2T”) increases the proportion of patients who attain remission.31 ■ This activity is part of a series.To access 2 additional courses, go to myCME.com/myRA. References 1. Bruce B, Fries JF. The Health Assessment Questionnaire (HAQ). Clin Exp Rheumatol. 2005;23(5 suppl 39):S14-S18.

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2. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification

19. Label: Methotrexate- methotrexate sodoim tablet: drug label informa-

criteria: an American College of Rheumatology/European League Against

tion. DailyMed, National Institutes of Health (NIH), US National Library

Rheumatism collaborative initiative. Ann Rheum Dis. 2010;69(9):1580-1588.

of Medicine website. https://dailymed.nlm.nih.gov/dailymed/drugInfo.

3. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of

cfm?setid=8f1260de-b60c-4f0e-8af6-0e957b0a281b. Updated October 18,

Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis

2017. Accessed January 23, 2018.

Care Res (Hoboken). 2016;68(1):1-25.

20. Shea B, Swinden MV, Tanjong Ghogomu E, et al. Folic acid and folinic acid

4. Smolen JS, Breedveld FC, Burmester GR, et al. Treating rheumatoid arthritis

for reducing side effects in patients receiving methotrexate for rheumatoid

to target: 2014 update of the recommendations of an international task force.

arthritis. Cochrane Database Syst Rev. 2013;(5):CD000951.

Ann Rheum Dis. 2016;75(1):3-15.

21. Roubille C, Rincheval N, Dougados M, et al. Seven-year tolerability profile

5. Smolen JS, Landewe R, Bijlsma J, et al. EULAR recommendations for the man-

of glucocorticoids use in early rheumatoid arthritis: data from the ESPOIR

agement of rheumatoid arthritis with synthetic and biological disease-modifying

cohort. Ann Rheum Dis. 2017;76(11):1797-1802.

antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76(6):960-977.

22. Label: Prednisone- prednisone tablet: drug label information. DailyMed,

6. Fleischmann RM, van der Heijde D, Gardiner PV, et al. DAS28-CRP and

National Institutes of Health (NIH), US National Library of Medicine website.

DAS28-ESR cut-offs for high disease activity in rheumatoid arthritis are not

https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3115aef0-fd50-4ec8-

interchangeable. RMD Open. 2017;3:e000382. http://rmdopen.bmj.com/

a064-3effb695f3f2. Updated January 23, 2017. Accessed January 23, 2018.

content/rmdopen/3/1/e000382.full.pdf.

23. Visser K, van der Heijde D. Optimal dosage and route of administration

7. Anderson J, Caplan L, Yazdany J, et al. Rheumatoid arthritis disease activity

of methotrexate in rheumatoid arthritis: a systematic review of the literature.

measures: American College of Rheumatology recommendations for use in

Ann Rheum Dis. 2009;68(7):1094-1099.

clinical practice. Arthritis Care Res (Hoboken). 2012;64(5):640-647.

24. Goodman SM, Cronstein BN, Bykerk VP. Outcomes related to methotrex-

8. Sokka T. Work disability in early rheumatoid arthritis. Clin Exp Rheumatol.

ate dose and route of administration in patients with rheumatoid arthritis: a

2003;21(5 suppl 31):S71-S74.

systematic literature review. Clin Exp Rheumatol. 2015;33(2):272-278.

9. Burton W, Morrison A, Maclean R, Ruderman E. Systematic review of

25. Gaujoux-Viala C, Rincheval N, Dougados M, et al. Optimal methotrexate

studies of productivity loss due to rheumatoid arthritis. Occup Med (Lond).

dose is associated with better clinical outcomes than non-optimal dose in

2006;56(1):18-27.

daily practice: results from the ESPOIR early arthritis cohort. Ann Rheum Dis.

10. Rantalaiho VM, Kautiainen H, Jarvenpaa S, et al. Decline in work disability

2017;76(12):2054-2060.

caused by early rheumatoid arthritis: results from a nationwide Finnish regis-

26. Rohr MK, Mikuls TR, Cohen SB, et al. Underuse of methotrexate in the

ter, 2000-8. Ann Rheum Dis. 2013;72(5):672-677.

treatment of rheumatoid arthritis: a national analysis of prescribing practices

11. Avina-Zubieta JA, Choi HK, Sadatsafavi M, et al. Risk of cardiovascular mor-

in the US. Arthritis Care Res (Hoboken). 2017;69(6):794-800.

tality in patients with rheumatoid arthritis: a meta-analysis of observational

27. Aletaha D, Landewe R, Karonitsch T, et al. Reporting disease activity in

studies. Arthritis Rheum. 2008;59(12):1690-1697.

clinical trials of patients with rheumatoid arthritis: EULAR/ACR collaborative

12. Solomon DH, Goodson NJ, Katz JN, et al. Patterns of cardiovascular risk in

recommendations. Arthritis Rheum. 2008;59(10):1371-1377.

rheumatoid arthritis. Ann Rheum Dis. 2006;65(12):1608-1612.

28. Felson DT, Smolen JS, Wells G, et al. American College of Rheumatology/

13. Gonzalez A, Maradit Kremers H, Crowson CS, et al. The widening mortal-

European League Against Rheumatism provisional definition of remission in

ity gap between rheumatoid arthritis patients and the general population.

rheumatoid arthritis for clinical trials. Ann Rheum Dis. 2011;70(3):404-413.

Arthritis Rheum. 2007;56(11):3583-3587.

29. Solomon DH, Losina E, Lu B, et al. Implementation of treat-to-target in

14. Listing J, Kekow J, Manger B, et al. Mortality in rheumatoid arthritis: the

rheumatoid arthritis through a learning collaborative: results of a randomized

impact of disease activity, treatment with glucocorticoids, TNFalpha inhibitors

controlled trial. Arthritis Rheumatol. 2017;69(7):1374-1380.

and rituximab. Ann Rheum Dis. 2015;74(2):415-421.

30. Akdemir G, Markusse IM, Goekoop-Ruiterman YP, et al. Rheumatologists’

15. Kawatkar AA, Jacobsen SJ, Levy GD, et al. Direct medical expenditure

adherence to a disease activity score steered treatment protocol in

associated with rheumatoid arthritis in a nationally representative sample

early arthritis patients is less if the target is remission. Clin Rheumatol.

from the medical expenditure panel survey. Arthritis Care Res (Hoboken).

2017;36(2):317-326.

2012;64(11):1649-1656.

31. Ramiro S, Landewé R, van der Heijde D, et al. Is treat-to-target really

16. Kalkan A, Hallert E, Bernfort L, et al. Costs of rheumatoid arthritis dur-

working? A longitudinal analysis in Biodam [poster THU0067]. Ann Rheum Dis.

ing the period 1990-2010: a register-based cost-of-illness study in Sweden.

2016;75(suppl 2):202-203. http://ard.bmj.com/content/75/Suppl_2/202.2.

Rheumatology (Oxford). 2014;53(1):153-160.

32. Emery P, Sebba A, Huizinga TWJ. Biologic and oral disease-modifying

17. Wasko MC, Dasgupta A, Hubert H, et al. Propensity-adjusted association

antirheumatic drug monotherapy in rheumatoid arthritis. Ann Rheum Dis.

of methotrexate with overall survival in rheumatoid arthritis. Arthritis Rheum.

2013;72(12):1897-1904.

2013;65(2):334-342.

33. Zhang J, Xie F, Delzell E, et al. Impact of biologics with and without con-

18. Young A, Koduri G. Extra-articular manifestations and complications of

comitant MTX and at reduced doses in older rheumatoid arthritis patients.

rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2007;21(5):907-927.

Arthritis Care Res (Hoboken). 2015;67(5):624-632.

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CME

POSTTEST Expiration date: May 31, 2019

A statement of credit will be issued only upon receipt of a completed pre-assessment test, polling questions, activity evaluation form, and posttest with a score of 70% or higher. All components must be completed and submitted online at ClinicalAdvisor.com/May18feature.

CREDITS: 0.50 | Case: A 49-year-old recently diagnosed with rheumatoid arthritis

1. Which of the following statements is most accurate about the disease burden of rheumatoid arthritis (RA)? a. Rates of work disability in patients with RA have decreased over time, while remaining higher than those of the general population. b. With improved treatment, the risk of cardiovascular death associated with RA has fallen to that of the general population. c. Patients with RA face a substantially higher risk of death regardless of the level of disease activity. d. Data analysis suggests that the rates of work disability in patients with RA have declined for patients, regardless of the type of job they hold. 2. According to the treatment guidelines for RA, the goal of therapy should be: a. Clinical response at 6 months b. Full remission or low disease activity at 3 months c. Clinical response at 3 months and full remission—or at least low disease activity—within 6 months d. Normal functional status at 3 months, as measured by the Health Assessment Questionnaire (HAQ) or other validated instrument 3. A treat-to-target (T2T) strategy for managing patients with RA involves: a. Using low disease activity as the primary target for most patients b. Documenting disease activity as often as monthly for those with moderate to high disease activity and less frequently (eg, every 6 months) for those in sustained remission or low disease activity c. Documenting disease activity through swollen and tender joint count only d. Adjusting drug therapy at least every 6 months until the desired target is achieved

4. An example of involving the patient in treatment decisions while adhering to treatment guidelines is: a. Using biologic monotherapy as initial therapy for RA in a newly diagnosed patient with early disease because the patient expresses concern about the side-effect profile of methotrexate b. Not intensifying therapy in a patient with moderate disease activity on optimized methotrexate monotherapy because the patient does not wish to inject herself or receive an infusion c. Intensifying therapy with long-term, low-dose glucocorticoids rather than using a biologic agent in a patient who is impressed with the relief offered by the former therapy d. Considering patient preference regarding route and frequency of administration and drug cost when choosing a biologic (if the treatment target has not been achieved with optimized methotrexate and short-term glucocorticoid therapy) 5. Which of the following statements is true of optimized methotrexate therapy in RA? a. Maximum dose of oral methotrexate is 15 mg per week if tolerated. b. Maximum dose of oral methotrexate is 25 mg to 30 mg per week if tolerated. c. Optimized methotrexate therapy that reduces disease activity but does not yield remission should be stopped prior to treatment intensification. d. Optimized methotrexate therapy has been associated with a more than 4-fold greater likelihood of achieving remission at 1 year in patients with early RA prescribed methotrexate as a first disease-modifying anti-rheumatic drug (DMARD).

TO TAKE THE POSTTEST please go to: ClinicalAdvisor.com/May18feature

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2018 51

CLINICAL PEARL

Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 275 7th Avenue, 10th Floor, New York, NY 10001.You may contact us by e-mail at editor@ 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.

PHANTOM KNEE PAIN About 2.5 weeks following a total knee arthroplasty in 2016, I became troubled by persistent nighttime pain at the operative site. Daytime pain was minimal, and daytime need for opiates had ceased completely. Despite this, approximately 4 hours after retiring at night, with a dose of oxycodone as prescribed by my surgeon, I would awaken with pain that prevented me from further sleep. This was relieved after 30 minutes or so by walking about and changing position of the affected limb frequently. Subsequent attempts to sleep were terminated approximately hourly by recurrence of this pain. Opioids were helpful for a short time for this pain that occurred only when I was immobile for a prolonged period, such as at night. The pain seemed to disappear when additional sensory input regarding the affected joint was received, as opposed to nighttime when I remained still, inactive, and asleep. A search of the internet revealed mention of the possibility of “phantom limb pain” in the setting of TKA, as well as other nonlimb loss settings, but no formal studies. Suspecting that this phenomenon might be the source of my nighttime pain, causing significant REM sleep deprivation, I reasoned that a neuromodulator such as a gabapentinoid might be helpful. I requested and received from my orthopedic surgeon a prescription for gabapentin 300 mg at h.s. The first bedtime dose allowed me to sleep for 8 hours without pain and without waking. I continued this regimen, trying unsuccessfully to discontinue the gabapentin after 1 month, then ultimately being able to discontinue with no further symptoms after 2 months. Literature searches have thus far failed to reveal any studies of this phenomenon or of the use of gabapentin in this specific setting (although it is often used in other situations involving phantom

56 THE CLINICAL ADVISOR • MAY 2018 • www.ClinicalAdvisor.com

limb pain and has been studied perioperatively for early postoperative pain). After sharing my experience with a few other healthcare professionals, I have been made aware of 3 other cases in which late postoperative atypical TKA pain has been alleviated partially or completely by gabapentin. I am making my experience known in the hope that it will be helpful to other providers and patients in similar clinical settings. It seems to me to be a potentially interesting subject for formal study.—RICHARD EDWARDS, PA-C Emeritus, Englewood, FL (235-1)

CASE FILE CAT SCRATCH DISEASE Contributed by Sherril Sego, FNP-C, DNP A normally healthy 7-year-old female complained of “not feeling good.” She had no fever, nausea, or diarrhea. She was lethargic but continued to attend school. Her mother took her to their pediatrician. Upon examination, he noted a unilateral lymphadenopathy in her right axilla. The rest of the examination was normal. Lab testing showed mildly elevated liver function tests and a Westergren sedimentation rate of 65 mm/hr. She was then referred to an infectious disease specialist for further evaluation.The answer was found in an in-depth history. She had 3 young cats in her home that she always played with. Although no specific bite or scratch was found, the presumed diagnosis was cat scratch disease (CSD). Caused by the bacterium Bartonella henselae, CSD is typically benign, so no treatment was considered necessary. Though occasional severe side effects are possible, they are rare. Most cases are found in children. Follow-up lab work at 6 weeks showed resolution of the previous abnormalities, and the child had recovered completely as is usually the case. (235-2) ■

Dermatology Clinic CASE #1

Inflammatory papulopustules in a young woman HILLARY HENDLEY AND ALICIA ELAM, PharmD

A 24-year-old Caucasian woman presented with intermittent, inflammatory papulopustules and nodules on the face, neck, chest, and back. The lesions would appear 1 week premenstrually and resolve 1 week postmenstrually with normal menstrual cycles. She has a history of adolescent acne that is only responsive to isotretinoin 6 years ago. Examination revealed scarring and postinflammatory hyperpigmentation diffusely on her face. What is your diagnosis? Turn to page 58

CASE #2

A pink rash with fine scale in a 7-year-old boy EMMA WEISS AND JESSICA BOULAVSKY, MD

A 7-year-old healthy boy is brought to the dermatology clinic by his parents after having had a 3-week history of a rash. The patient’s rash was slightly pruritic, and it involved predominantly the trunk, starting as one larger pink patch with fine scale and subsequently spreading with smaller similar macules and patches.The boy’s palms and soles were spared of the rash. What is your diagnosis? Turn to page 60 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2018 57

Dermatology Clinic CASE #1

Acne vulgaris in women

Acne vulgaris, known for its high prevalence in adolescents, was reported to occur in more than half of women older than age 25 years.1 Postadolescent acne appears more in adult women than in men.2-8 Due to the time of onset of adolescent acne, the age of occurrence in adults is not clearly defined.9 There are three subtypes of adult female acne. Most commonly, persistent acne begins in adolescence and continues into adulthood. According to most sources, late-onset acne occurs after 18 to 25 years. Least commonly, relapsing acne initially occurs during adolescence, resolves for a few years, then reappears during adulthood.8 Acne vulgaris derives from a combination of inflammatory reactions, hyper-seborrhea, differentiation of keratinocytes, hyper-keratinization of the pilosebaceous follicles, and increased anaerobic Gram-positive bacteria, Propionibacterium acnes, which survives on sebum and

Female adult acne most commonly presents as mild to moderate, and severe acne is rare in adult women. stimulates inflammation.8,10,11 Androgens are also believed to play a role in the etiology of postadolescent female acne and can increase the size of sebaceous glands to stimulate sebum production.12 Additionally, most female adults with acne complain of premenstrual flares, coupled with menstrual cycles, typically described as being the most aggravating factor. The exact mechanism responsible for premenstrual flares is unknown, though it has been proposed that reduced openings of the pilosebaceous follicle produce excessive sebum in the sebaceous glands.11,13,14 Stress, diets inclusive of dairy products, exercise, cosmetics, and genetics may all be contributing factors.8,9,15-17 Female adult acne most commonly presents as mild to moderate, and severe acne, indicating a high number of lesions, is rare in adult women.8 Acne in postadolescent women mainly appears on the face, but the chest, neck, and back can be affected.8 Similar to adolescent acne, female adult acne can present as inflammatory lesions, such as

papules, pustules, and nodules, as well as noninflammatory lesions, such as open and closed comedones, and cysts.18 There are two clinical presentations of female adult acne, retentional and inflammatory.The retentional form consists of numerous comedones with a few inflammatory lesions that appear on multiple zones of the face.The inflammatory form is comprised of papulopustules and nodules appearing mainly on the lower face, chin, and mandibular region. An explanation regarding the presentation of inflammatory acne is unknown.8,19 Lesions localized to the mandible are the stereotypical presentation of female adult acne.9 While some studies support this appearance, others have found that mandibular localized acne is only a small subtype of female adult acne and the majority of cases involve multiple facial areas.8,9,20 More than half of the participants with perimenstrual acne in one study complained of worsening acne 1 week before menstruation, though there were also complaints of worsening symptoms during menses, postmenstruation, or continuously throughout their entire cycle.11 Female adult acne is a clinical diagnosis. Laboratory evaluation may be indicated to rule out an underlining endocrine disorder if the patient presents with symptoms of hyperandrogenism, signs of virilization, or subcutaneous signs such as abrupt onset of severe acne, hirsutism, acanthosis nigricans, and alopecia.15,20 The most common cause of hyperandrogenism is polycystic ovary syndrome.20 Another common differential diagnosis for acne vulgaris is rosacea. Rosacea is an inflammatory disorder that presents with inflammatory papulopustules, telangiectasia, or erythema in the centrofacial location.21 Some patients have rosacea and acne simultaneously.22 Several signs can differentiate rosacea from acne, such as the hallmark rosacea characteristic of facial flushing, worsened by heat, alcohol, or spicy food. Additionally, rosacea occurs in older patients, with the typical age of onset between 30 and 60 years.22,23 More than half of rosacea patients also have ocular manifestations.24 Unlike acne, rosacea does not appear with comedones, nodules, cysts, and scarring, and rarely has lesions on the trunk.21, 22 Typical treatment regimens such as antibiotics and topical or systemic retinoids can be used in postadolescent female acne.Topical retinoids include tretinoin, adapalene, tazarotene, and isotretinoin (not available in the US).Topical antimicrobials include benzoyl peroxide, clindamycin, erythromycin, and dapsone.Topical combination products include benzoyl peroxide/clindamycin, benzoyl peroxide/erythromycin, clindamycin/tretinoin, and benzoyl peroxide/adapalene. Azelaic acid and salicylic acid are also options. Oral antibiotics include tetracycline, doxycycline, minocycline, erythromycin, trimethoprim-sulfamethoxazole, and azithromycin. Hormonal

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agents include combination oral contraceptives (estrogen/ progestin) and spironolactone. Furthermore, the oral retinoid to treat acne is oral isotretinoin.25 Hormonal therapy can improve acne in patients with and without hyperandrogenism. In patients with androgen levels in the normal range, hormonal therapy is usually indicated for postmenarchal women with moderate to severe acne who are not planning to become pregnant, and those unresponsive to topical treatment. Hormonal therapy for pregnancy prevention has an additional benefit of improving mild acne, but topical regimens will also treat mild acne.25

References 1. Rademaker M, Wishart J, Birchall N. Isotretinoin 5 mg daily for low-grade adult acne vulgaris—a placebo-controlled, randomized double-blind study. J Eur Acad Dermatol Venereol. 2014;28:747-754. 2. Yentzer BA, Hick J, Reese EL, et al. Acne vulgaris in the United States: a descriptive epidemiology. Cutis. 2010;86:94-99. 3. Shen Y, Wang T, Zhou C, et al. Prevalence of acne vulgaris in Chinese adolescents and adults: a community-based study of 17,345 subjects in six cities. Acta Derm Venereol. 2012;92:40-44. 4. Poli F, Dreno B, Verschoore M. An epidemiological study of acne in female adults: results of a survey conducted in France. J Eur Acad Dermatol Venereol. 2001;15:541-545.

Major systemic treatment options for women include oral antibiotics, hormonal therapy, and oral isotretinoin.

5. Goulden V, Clark SM, Cunliffe WJ. Post-adolescent acne: a review of clinical features. Br J Dermatol. 1997;136:66-70. 6. Seirafi H, Farnaghi F, Vasheghani-Farahani A, et al. Assessment of androgens in women with adult-onset acne. Int J Dermatol. 2007;46:1188-1191. 7. Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol.1999;41:577-580. 8. Preneau S Dreno B. Female acne: a different subtype of teenager acne?

Major systemic treatment options for women include oral antibiotics, hormonal therapy, and oral isotretinoin. There are not enough studies to compare the effectiveness of oral antibiotics and hormonal therapy, but they are both considered first line for moderate to severe acne in women. It is suggested that women with normal serum androgen levels who present with acne involving the lower face and premenstrual acne flares may be more likely to respond to hormonal agents than oral antibiotics. Hormonal therapy is usually adjuvant, given in conjunction with topical or oral antibiotics, as well as topical retinoids. However, hormonal therapy does not deliver immediate results. Improvement requires at least 3 to 6 months of treatment.25 The prevalence of acne decreases with age, which suggests spontaneous resolution.26 Women, however, may experience acne for many years. In one study, the average duration for adult female acne was 20.4 years.16 Also, acne can cause scarring and postinflammatory hyperpigmentation, and there is a high correlation of depression, anxiety, lack of confidence, self-consciousness, and an inability or lack of focus in women with acne.9,27 Although our patient continued hormonal therapy, topical tretinoin was discontinued due to intolerable skin irritation. Patient education included topical tretinoin compliance, strategies to decrease inflammation, length of therapy (6 to 12 weeks) before improvement, stress management, and follow-up in 12 weeks.

J Euro Acad Dermatol Venereol. 2011;26:277-282. 9. Dréno B, Thiboutot D, Layton A, Berson D, Perez M, Kang S. Large-scale international study enhances understanding of an emerging acne population: adult females. J Eur Acad Dermatol Venereol. 2015;29:1096-1106. 10. Jeremy AH, Holland DB, Roberts SG, et al. Inflammatory events are involved in acne lesion initiation. J Invest Dermatol. 2003;121:20-27. 11. Geller L, Rosen J, Frankel A, Goldenberg G. Perimenstrual flare of adult acne. J Clin Aesthetic Dermatol. 2014;7:30-34. 12. Yildiz BO. Diagnosis of hyperandrogenism: clinical criteria. Best Pract Res Clin Endocrinol Metab. 2006;20:167-176. 13. Burton JL, Cartlidge M, Shuster S. Variations in sebum excretion during the menstrual cycle. Acta Derm Venereol. 1973;53:81-84. 14. Williams M, Cunliffe WJ. Explanation for premenstrual acne. Lancet. 1973;2:1055-1077. 15. Williams C, Layton AM. Persistent acne in women: implications for the patient and for therapy. Am J Clin Dermatol. 2006;7:281-290. 16. Shaw JC, White LE. Persistent acne in adult women. Arch Dermatol. 2001;137:1252-1253. 17. Goulden V, McGeown CH, Cunliffe WJ. The familial risk of adult acne: a comparison between first-degree relatives of affected and unaffected individuals. Br J Dermatol. 1999;141:297-300. 18. Ramos-e-Silva M, Ramos-e-Silva S, Carneiro S. Acne in women. Br J Dermatol. 2015;172(Suppl 1):20-26. 19. Capitanio B, Sinagra JL, Bordignon V, et al. Underestimated clinical features of postadolescent acne. J Am Acad Dermatol. 2010;63:782-788. 20. Kamangar FShinkai K. Acne in the adult female patient: a practical approach. Int J Dermatol. 2012;51:1162-1174.

Hillary Hendley is a student at Augusta University, and Alicia Elam, PharmD, is associate admissions director, Physician Assistant Department, Augusta University, in Georgia.

21. Reszko A, Berson D. Postadolescent acne in women. July 15, 2016. Available from: http://www.uptodate.com/contents/postadolescentacne-in-women

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Dermatology Clinic 22. Archer CB, Cohen SN, Baron SE; British Association of Dermatologists and Royal College of General Practitioners. Guidance on the diagnosis and clinical management of acne. Clin Exp Dermatol. 2012;37 (Suppl 1):1-6. 23. Habif T. Clinical dermatology. St Louis: Mosby; 1996:182-183. 24. Dakovic Z, Vesic S, Vukovic J, et al. Ocular rosacea and treatment of symptomatic Helicobacter pylori infection: a case series. Acta Dermatovenerol Alp Pannonica Adriat. 2007;16:83-86. 25. Graber E. Hormonal therapy for women with acne vulgaris. July 15, 2016. Available from: http://www.uptodate.com/contents/ hormonal-therapy-for-women-with-acne-vulgaris 26. Perkins AC, Maglione J, Hillebrand GG, et al. Acne vulgaris in women: prevalence across the life span. J Womens Health (Larchmt). 2012;21:223-230. 27. Tanghetti EA, Kawata AK, Daniels SR, Yeomans K, Burk CT, Calledner VD. Understanding the burden of adult female acne. J Clin Aesthet Dermatol. 2014;7:22-30.

CASE #1

Pityriasis rosea

Pityriasis rosea (PR) is an acute, self-limited dermatosis characterized by oval, erythematous lesions located primarily on the trunk. Robert Willan first described PR in 1798.1 Since then, several other names have been used to describe PR’s clinical presentation, including pityriasis circinata, roseola annulata, and herpes tonsurans maculosus. In 1860, a French dermatologist, Camille Melchior Gilbert, gave PR its current name.2 Pityriasis rosea most commonly affects individuals in late childhood and early adulthood, with the majority of cases occurring between ages 10 and 35.3 PR exhibits some seasonal variation with increased occurrence in colder seasons. The overall prevalence of PR has been estimated to be 1.31%, which is likely an underestimation, as it does not take into account cases diagnosed by nondermatologists and atypical cases that are often misdiagnosed.4 The etiology is thought to be infectious; however, its exact cause remains unknown. Support for an infectious etiology comes from its distinct presentation and clinical course, lack of recurrence, seasonal variation, and its association with prodromal symptoms.There is some evidence that human herpes virus (HHV) is associated with PR. Drago et al demonstrated

HHV-7 as a probable causative agent by detecting HHV-7 in peripheral blood and saliva of patients with PR but not in the control group.5 The association between HHV-7 and PR is controversial, as other studies have failed to replicate similar results. Furthermore, experiments attempting to transmit the disease using isolated HHV-7 have been unsuccessful. Pityriasis rosea has a characteristic clinical course that makes diagnosis rather straightforward.Traditionally, PR begins with a herald patch: a single, oval-shaped scaly plaque ranging from 2 cm to 5 cm, often on the patient’s trunk. The initial lesion is then followed by the eruption of numerous, smaller lesions, typically within days to a couple weeks.These smaller lesions are salmon-pink, oval to round in shape with a delicate scale, resembling the original herald patch.The generalized rash tends to occur along lines of cleavage of the trunk and neck and is often described as a “Christmas tree” distribution.The lesions may be pruritic, ranging in severity from mild to moderate.6 Constitutional symptoms are usually absent; however, prodromal symptoms of fever, headache, cough, and arthralgia have been found in as many as 59% of patients.7 Most cases resolve in 4 to 6 weeks and rarely last 6 months. Postinflammatory hyperpigmentation is commonly seen in dark-skinned individuals but usually resolves after 6 to 12 months. Recurrence is rare, seen in approximately 2% of patients.5 Atypical clinical presentations of PR can be found in up to 20% of patients.These variations include vesicular, inverse, acral, limb-girdle, and erythema multiforme-like PR. Children often have atypical presentations of PR in both distribution and character of the lesions. The lesions can be folliculopapular, vesicular, or pustular and can involve the face and distal extremities, sometimes sparing the patient’s trunk.8 The differential diagnosis for pityriasis rosea includes drug eruptions, secondary syphilis, guttate psoriasis, small plaque parapsoriasis, erythema migrans with secondary lesions, erythema multiforme, and tinea corporis.Tinea corporis usually presents with few lesions and can be definitively differentiated by simple KOH scraping. Guttate psoriasis can also present with an acute eruption of small lesions located on the trunk. However, psoriasis has a thicker scale and extended clinical course. Drug eruptions are an important consideration, especially in the context of recent medication changes. Unlike PR, drug eruptions are confluent, brightly erythematous, and more pruritic. Secondary syphilis is an essential diagnosis to consider in atypical presentations of pityriasis rosea. Traditionally, secondary syphilis involves the palms and the soles in the setting of unprotected sexual intercourse and a remote history of a painless chancre. Traditionally, secondary syphilis presents on the palms and soles in patients who report a remote history of a painless chancre.9

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Diagnosis of pityriasis rosea is made clinically by history and physical examination revealing the typical clinical presentation of an initial herald patch followed by eruptions of several other pruritic lesions in the absence of other symptoms. Currently, no noninvasive tests are available to confirm the diagnosis of PR. KOH scraping and syphilis serology can easily be obtained and can help rule out other diseases with similar presentations. Skin biopsies are not recommended for diagnosis as PR has nonspecific

3. Chuang T-Y, Ilstrup DM, Perry H, Kurland LT. Pityriasis rosea in Rochester, Minnesota, 1969 to 1978. J Am Acad Dermatol. 1982;7:80-89. doi:10.1016/ S0190-9622(82)80013-3. 4. Chuh AA, Dofitas BL, Comisel GG, et al. Interventions for pityriasis rosea. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD005068. 5. Drago F, Broccolo F, Rebora A. Pityriasis rosea: An update with a critical appraisal of its possible herpesviral etiology. J Am Acad Dermatol. 2009;61: 303-318. doi:10.1016/j.jaad.2008.07.045. 6. Eisman S, Sinclair R. Pityriasis rosea. BMJ. 2015;351:h5233. 7. Özyürek GD, Alan S, Çenesizoglu E. Evaluation of clinico-epidemiological

The differential diagnosis includes drug eruptions, secondary syphilis, guttate psoriasis, and small plaque parapsoriasis.

and histopathological features of pityriasis rosea. Postepy Dermatol Alergol. 2014;31:216-221. doi:10.5114/pdia.2014.40641. 8. Chuh AAT. Quality of life in children with pityriasis rosea: a prospective case control study. Pediatr Dermatol. 2003;20:474-478. 9. Marks JG, Miller JJ. Lookingbill and Marks’ Principles of Dermatology. 5th ed. Philadelphia: Saunders; 2013. 10. Chuh A, Zawar V, Sciallis G, Kempf W. A position statement on the management of patients with pityriasis rosea. J Eur Acad Dermatology Venereol. 2016;30:1670-1681. doi:10.1111/jdv.13826.

Emma Weiss is a medical student at the University of Texas– McCombs School of Business and the Baylor College of Medicine. Jessica Boulavsky, MD, is a dermatology resident at the Baylor College of Medicine in Houston. References 1. Mahajan K, Relhan V, Relhan A, Garg V. Pityriasis rosea: An update on etiopathogenesis and management of difficult aspects. Indian J Dermatol. 2016;61:375-384. doi:10.4103/0019-5154.185699. 2. Chuh A, Chan H, Zawar V. Pityriasis rosea—evidence for and against an infectious aetiology. Epidemiol Infect. 2004;132:381-390. doi:10.1017/ S0950268804002304.

Unexpected Help for the Colonists at the Boston Tea Party www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2018 61

histopathology that is characteristic but not pathopneumonic. If needed for atypical cases, a skin biopsy would show epidermal focal parakeratosis, a lessened granular layer, spongiosis, spongiotic vesicles, perivascular infiltrate of lymphocytes and histiocytes, and occasionally extravasation of red cells. The characteristic biopsy findings of epidermal dyskeratotic cells and extravasated erythrocytes in the dermis are found in 60% of patients.5 PR is a self-limited disease and spontaneously resolves within 3 months. Therefore, interventions are often not necessary. Treatment includes patient education, reassurance, and symptom management if needed. Medium potency topical corticosteroids can be applied to pruritic areas 2 or 3 times per day for up to 3 weeks if the patient is symptomatic. Topical anti-itch creams containing pramoxine and oral antihistamines may also alleviate pruritus.10 There is limited evidence that oral acyclovir and UVB light may accelerate clinical improvement in severe cases of PR. The patient and family were reassured. He was given a prescription for fluocinolone oil to use up to twice daily for symptomatic relief, and the rash regressed within several weeks. ■

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LEGAL ADVISOR CASE

Liability after a missed diagnosis

BY ANN W. LATNER, JD

Mr N was a 38-year-old nurse practitioner working for a small practice that included his supervising physician, Dr S, and a physician assistant. Mr N had been working at the practice for close to a decade. He and his supervisor, Dr S, had a good working relationship. When Mr N started at the practice, Dr S had been very careful to go over his patients’ charts with him, to make suggestions when necessary, and to follow up on more intricate cases. As the years passed, however, her involvement with his day-to-day work gradually decreased, until she rarely looked at his patients’ charts and they only discussed things if there was a particular question. Mr N worked mostly independently. Most of his patients made appointments directly to see him. One of his patients was Mr P, a 45-year-old man with a history of gout. Mr P was what Mr N thought of as an anxious patient. Every new pain caused him great worry and concern, and he frequently feared the worst. One afternoon Mr P came into the office complaining of a flare-up of his gout.The patient described his pain with great animation and concern. After a brief exam, Mr P prescribed prednisone and gave the patient a steroid injection in his left leg.

A patient dies after a clinician fails to act on signs of a potential case of deep vein thrombosis. A patient dies from a pulmonary embolism after seeing a clinician who did not believe that the situation had been that urgent.

The patient left but returned 3 weeks later.“My left calf is all swollen,” he told the clinician. “It hurts behind my knee. I can barely limp around! Do you think this is serious? Do I need an X-ray or something?” Mr P’s anxiety was palpable. Mr N measured the patient’s left calf, which was 42 cm.The patient’s right calf measured 40.5 cm. Mr N considered the situation. He knew that deep vein thrombosis (DVT) was a possible cause of swelling and pain, but he doubted this was the case and he noted this in the patient’s file. Instead, he stated in the file that he believed the pain was due to the patient’s gout, Baker’s cyst, or radiculopathy. “I don’t think this is anything to be worried about,” he told the patient in what he hoped was a calming voice.“I’m going to give you another prednisone injection in your left ankle. If your calf continues to swell, then I will order an ultrasound so we can get a better idea of what is going on.” He did 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.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2018 63

LEGAL ADVISOR not mention to the patient that the purpose of the ultrasound was to rule out DVT, nor did he explain to the patient what a DVT was to not alarm him more than necessary. The patient went home but called the office later that day complaining of increased swelling and pain in his left calf and knee area. Mr N ordered an ultrasound to be performed the next day.The following day, after the ultrasound was performed, the results were called into Mr N’s office, and they revealed that the patient did have a DVT. The patient was called and told to come to Mr N’s office for an evaluation. When he arrived, Mr N measured his left calf and it was larger than it had been the previous day, so Mr N advised him to go right to the emergency department immediately.

The defense expert stated that the best practice would have been to immediately send the patient for an ultrasound. Mr P and his wife rushed to the emergency department, but shortly after arriving there the patient underwent cardiac arrest. Resuscitation efforts were unsuccessful, and the patient was declared dead.An autopsy revealed a pulmonary embolism. Mr N was shocked when he heard about Mr P’s passing. He had not believed that the patient’s situation had been that urgent. He felt terrible about the patient’s death, and that feeling was only compounded when he received notice that both he and the practice he worked for were being sued for medical malpractice by the patient’s widow. Mr N met with the defense attorney provided by his malpractice insurance.The attorney had the patient’s records reviewed by his own medical experts. After the experts expressed some criticism about how Mr N handled the case, the attorney advised settling, but a settlement could not be worked out and the case proceeded to trial.

The defense introduced an expert who said that Mr N’s actions were within the standard of care, but on cross-examination, the expert stated that the best practice in this case would have been to immediately send the patient for an ultrasound. The jury deliberated and returned with a $2 million verdict for the patient. Protecting yourself

Although Mr N clearly knew what the signs of DVT are because he did consider it when the patient returned complaining of calf swelling, he did not act on it. He noted that it was a possibility, but doubted it was the correct one.This was his first missed opportunity. He should have sent the patient for an ultrasound immediately, understanding that DVT can be fatal and that it should be decisively ruled out right away. His second missed opportunity was failing to explain to the patient what a DVT is, and what symptoms to look for so that the patient could go straight to the emergency department if necessary. His third missed opportunity was when his office was notified that the patient had a DVT and instead of directing him immediately to the emergency room, he had him come to the office for an evaluation. Once he was aware that the patient had a DVT, it was now an emergency and the patient should have been directed to the emergency department immediately. Mr N had been concerned about exacerbating the patient’s anxiety over his health by providing information which could seem frightening, but by doing so, he did his patient a great disservice. Before jumping to any other diagnosis, be sure to eliminate the possibility of an emergency condition, such as this one. Err on the side of caution, and treat patients like adults by explaining symptoms about which they need to be aware. ■ Ms Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

At trial, the patient’s widow introduced medical experts who testified about the standard of care in the case.The experts stated that Mr N should have ruled out the potential DVT by ordering the ultrasound as soon as the patient first complained of swelling in his calf. “An earlier diagnosis would likely have resulted in a better outcome for the patient,” testified one of the experts. “There was no reason for Mr N to have even delayed a day.” The plaintiff ’s experts were also critical of Mr N’s supervising physician, saying that she failed to provide adequate oversight of his work. 64 THE CLINICAL ADVISOR • MAY 2018 • www.ClinicalAdvisor.com

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