January 2017 Clinical Advisor

THE CLINICAL ADVISOR • JANUARY 2017

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■ Statin recommendations ■ Restless legs syndrome ■ Diabetes/psychosocial care FEATURE Raynaud Phenomenon

Digital vasospasm caused by cold weather and stress

|

JANUARY 2017

| www.ClinicalAdvisor.com

A CLINICIAN’S GUIDE FOR

PALLIATIVE CARE Palliative care is an important component of standard health care.

LEGAL ADVISOR

Fatal meningitis that was misdiagnosed as migraine

n Dermatologic Clinic

A FLESHY TUMOR ON THE TOE PAGE 60

✶ FREE CME COURSE!

VOLUME 20, NUMBER 1

n Feature

OPTIMIZING LDL-C MANAGEMENT PAGE 40

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Editor Colby Stong, editor@clinicaladvisor.com Senior editor Sandhya George Associate editor Lauren Grygotis Assistant editor Madeline Morr 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 director Ada Figueroa 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 Senior vice president, digital products and medical magazines 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.

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Unsure about a diagnosis or treatment?

Ask our

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.

orum

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.

OUR CO

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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.

CAL ADVI

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Abimbo la Farinde

, PhD,

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

• www.Clinic

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Laura A.

Foster,

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

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CONTENTS JANUARY 2017

NEWS AND COMMENT 14

40 CME Optimizing the management of LDL-C and ASCVD risk Pharmacotherapies for LDL-C lowering with differing mechanisms of action are helping optimize patients’ ASCVD risk management plans.

Newsline ■■USPSTF releases final statin

recommendations for CVD prevention.

■■Managing peripheral artery disease: an updated guideline ■■Restless legs syndrome: a new practice guideline ■■AAP issues recommendations for behavioral and emotional problems in young children.

■■An online calculator can estimate the chance of live birth during courses of in vitro fertilization.

■■ADA publishes guidelines for psychosocial care in diabetes patients.

■■The combination of a statin and PCSK9 inhibitor is effective for lowering cholesterol in patients with angiographic coronary disease.

54 CME Feature posttest

Raynaud phenomenon: finger discoloration 33

DEPARTMENTS 12

55 Case Study: Obesity Vision changes after bariatric surgery 60

FEATURES

A case of misdiagnosed meningitis 69

20 A clinician’s guide for palliative care By initiating a conversation, primary care providers can identify specific end-of-life needs and goals, manage symptoms, and coordinate care.

TOC_CA0117.indd 4

Follow us on Twitter @ClinicalAdvisor

Dermatology Clinic n An asymptomatic, fleshy tumor on the base of the toe n A woman with diabetes and a sore on her leg

65 Dermatologic Look-Alikes A pink nodule Continues on page 10

33 Raynaud phenomenon: a cold-weather condition A thorough work-up can differentiate between primary and secondary forms, mitigating progression of a more severe underlying disease.

MAKING CONTACT

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

Alt Meds Update: Kratom 71

Like us on Facebook facebook.com/TheClinicalAdvisor

www.ClinicalAdvisor.com

Visit us on the web ClinicalAdvisor.com

Download the app ClinicalAdvisor.com/App

12/28/16 2:18 PM

CONTENTS 69

Legal Advisor A case of misdiagnosed meningitis

71

Alternative Meds Update Kratom

ADVISOR FORUM 58

Consultations ■ Treating premenopausal women with fibroids and dysmenorrhea ■ Prostate biopsies and cancerous cells

58

Clinical Pearls ■ Converting pounds to kilograms ■ A tip for treating minor lacerations

59

Case Files ■ An enlarging mass on the calf

“If WikiLeaks releases my email about Kevin, I’ll just die!”

“That’s bass with broccoli and mushrooms. Stop calling it animal, vegetable, and fungus.”

Top: © Harley Schwadron, 2017. Bottom: © The New Yorker Collection 2017 from cartoonbank.com. All Rights Reserved.

DEPARTMENTS cont’d

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■ Statin reco mmendatio ns ■ Restless legs syndrom e ■ Diabetes /psychosoci al care

FEATURE

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LEGAL AD VISOR

Fatal meningit misdiagnose is that was d as migrain e

• Send it by e-mail to editor@ClinicalAdvisor.com

| www.Clin icalA

dvisor.com

PALLIATIVE CARE IDE FOR

Palliative care is an important component of standard health care .

■ Dermatolo gic Clini

c A FLESH TUMOR ON THE Y TOE PAGE

60

SE!

ER 1

• Mail it to The Clinical Advisor, 275 7th Avenue, 10th Floor, New York, NY 10001

2017

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Phenomeno

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Raynaud

n Digital vaso spas cold weather m caused by and stress

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RS

A CLINIC

■ Feature

OPTIMIZIN MANAGEMEG LDL-C NT

PAGE 40

12/28/16 2:22 PM

EXCLUSIVE TO THE WEB AT

ClinicalAdvisor.com Web Exclusives

Multimedia

ClinicalAdvisor.com/News

ClinicalAdvisor.com/Multimedia

Statins may reduce risk of Alzheimer’s disease Depending on race, sex, and ethnicity, the right statin type may lower the risk of developing Alzheimer’s disease.

CDC: Influenza vaccine rate is low in US this season Approximately 2 of 5 individuals in the United States have received the influenza vaccine for the 2016 to 2017 season.

Life expectancy in the United States declined in 2015 Between 2014 and 2015, the age-adjusted death rate for the total US population increased by 1.2%, according to a report from the CDC.

USPSTF: Statin recommendations released for cardiovascular disease prevention The US Preventive Services Task Force has released its final recommendations for low- to moderate-dose statins in adults who are at risk for cardiovascular disease. Watch the video here: ClinicalAdvisor.com/USPSTFStatinVideo VA hospital offers hepatitis, HIV screenings after improper dental care A VA hospital urges veterans to be screened for hepatitis B, hepatitis C, and HIV after a dentist at the center did not follow standard infection control procedures. Watch the video here: ClinicalAdvisor.com/VAMedicalCenterVideo

The Waiting Room Official Blog of The Clinical Advisor

Cartoon Archive

ClinicalAdvisor.com/WaitingRoom

The Clinical Advisor’s monthly cartoons are also available online.

Jim Anderson, MPAS, PA-C, DFAAPA Team-based medicine, freeway style Citizen responders and medical care providers assess and comfort two patients in the aftermath of a traumatic incident.

ClinicalAdvisor.com/cartoons

© Harley Schwadron, 2017

Jillian Knowles, MPAS, PA-C Lidocaine patches as an alternative pain solution Lidocaine patches may be effective for patients who are in pain but are looking to avoid drugs that could potentially be addictive.

“I’ve just listened to all the political news. I think I’m going back to sleep.”

MAKING CONTACT

Follow us on Twitter @ClinicalAdvisor

Sharon M. O’Brien, MPAS, PA-C Shortened sleep increases the risk of diabetes Shortened sleep is associated with endocrine and metabolic changes and may be one reason for the increase in diabetes in the United States.

Like us on Facebook facebook.com/TheClinicalAdvisor

Visit us on the web ClinicalAdvisor.com

Go mobile with us mobile.ClinicalAdvisor.com

12 THE CLINICAL ADVISOR • JANUARY 2017 • www.ClinicalAdvisor.com

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Advisor Dx

EXCLUSIVE TO THE WEB

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

Ortho Dx

In partnership with

TheJopa.org

Journal of Orthopedics for Physician Assistants

What are the grade and type of this spondylolisthesis?

A 55-year-old woman presents with a 2-year history of lower back pain. Over the last 6 months, she has begun to have bilateral lower extremity pain and weakness. She has also noticed numbness in both feet and has felt unsteady while walking because of lower extremity weakness.

WHICH BEST DESCRIBES THE DIAGNOSIS?

• Grade 2 dysplastic spondylolisthesis • Grade 1 degenerative spondylolisthesis • Grade 1 isthmic spondylolisthesis • Grade 2 pathologic spondylolisthesis ● See the full case at ClinicalAdvisor.com/OrthoDx_Jan17

Derm Dx A rash on the axillae that sometimes itches or burns A 45-year-old moderately obese man presents with a rash affecting both axillae. The eruption has been present for months and on occasion either itches or burns.

Examination reveals well-demarcated erythematous patches of the axillae. An erythematous patch with scale is also noted on his scalp.

CAN YOU DIAGNOSE THIS CONDITION?

• Inverse psoriasis • Guttate psoriasis • Glucagonoma syndrome • Tinea incognito ● See the full case at ClinicalAdvisor.com/DermDx_Jan17

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2017 13

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Newsline J A N U A R Y 2 017

Practice guideline for restless legs syndrome page 16

Behavioral problems in young children page 16

Guideline for psychosocial care in diabetes page 18

THE US PREVENTIVE Services Task Force (USPSTF) gives a B grade recommendation for the use of low- to moderate-dose statins in adults between 40 and 75 years of age at risk for cardiovascular disease (CVD) and a C grade recommendation for the selective use of low- to moderate-dose statins in adults who are not at risk for CVD, according to the recommendation statement published in JAMA. The USPSTF notes that there is insufficient evidence to assess the benefits and harms of initiating statin therapy in adults older than 76 years of age.

The task force reviewed evidence regarding the benefits and harms of screening and treatment for dyslipidemia in adults older than 21 years of age and the benefits and harms of statin use in reducing CVD events or mortality in adults without a history of CVD. They also examined whether the benefits vary by patient subgroup, clinical characteristics, or dosage, and examined the benefits of various treatments for adults older than 40 years of age without a history of CVD. The updated recommendation replaces the USPSTF 2008

© THINKSTOCK

USPSTF releases final statin recommendations for CVD prevention Low- to moderatedose statins are advised in adults between the ages of 40 and 75 for CVD prevention.

recommendation on screening for lipid disorders in adults.

The USPSTF found that adults without a history of CVD should use a low- to moderate-dose statin to prevent CVD events when they are between 40 and 75 years of age, have more than 1 CVD risk factor including dyslipidemia, diabetes, hypertension, or smoking, and have a calculated 10-year risk of an adverse event of 10% or greater.

Managing peripheral artery disease: an updated guideline THE AMERICAN HEART ASSOCIATION and American College of Cardiology (AHA/ACC) have released an updated guideline regarding the diagnosis and management of patients with lower extremity peripheral artery disease (PAD).

The previous recommendations on lower extremity in PAD were published by the AHA/ACC in 2005.

The guideline includes recommendations for the clinical assessment of PAD, which should begin with a review of clinical history, review of symptoms, and a physical examination. In patients with symptoms of PAD, the resting ankle-brachial index (ABI) should confirm the diagnosis. The ABI should be obtained by measuring systolic blood pressure at the arms and ankles in a supine position. Patients with an ABI ≤0.90 should be diagnosed with PAD. Patients who are diagnosed with PAD should receive a program of guideline-directed management and therapy, which should include structured exercise and lifestyle modification to reduce cardiovascular events. Smoking cessation is critical to PAD

management, and patients should also receive a program of pharmacology customized to individual risk factors, such as diabetes, to reduce cardiovascular ischemic events and limb-related events.

The AHA/ACC recommends statin treatment for all patients with PAD, and recommends antiplatelet therapy with aspirin or clopidogrel for patients with symptomatic PAD to reduce myocardial infarction, stroke, and vascular death.

A supervised exercise program is recommended for patients with claudication to improve functional status and quality of life and to reduce leg symptoms. This should be considered as a treatment option before possible revascularization. In addition, a community or home-based exercise program with behavioral change techniques can help patients with PAD improve walking ability and functional status.

Patients with PAD who have claudication, critical limb ischemia, or acute limb ischemia may require endovascular or surgical revascularization to establish in-line blood flow or minimize tissue loss.

14 THE CLINICAL ADVISOR • JANUARY 2017 • www.ClinicalAdvisor.com

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Newsline THE AMERICAN Academy of Neurology (AAN) has released a new practice guideline for treating adults with restless legs syndrome, as published in Neurology.

Researchers used articles classified by the 2004 (AAN) evidence rating scheme to make evidencebased recommendations for RLS management in adults. For RLS efficacy, the International Restless legs Syndrome Study Group rating scale (IRLS) was the preferred outcome.

In moderate to severe primary RLS, clinicians should consider prescribing medication specifically to reduce RLS symptoms.

Stronger evidence supports pramipexole, rotigotine, cabergoline, and gabapentin enacarbil use (Level A); moderate evidence supports ropinirole, pregabalin, and IV ferric carboxymaltose use

For symptom relief in patients with moderate to severe primary restless legs syndrome, medication should be considered.

(Level B). Clinicians may also consider prescribing levodopa (Level C). Augmentation risks with dopaminergic agents should be considered.

When treating PLMS, clinicians should consider prescribing ropinirole (Level A) or pramipexole, rotigotine, cabergoline, or pregabalin (Level B). For other subjective sleep measures, they should

consider cabergoline or gabapentin enacarbil (Level A) or ropinirole, pramipexole, rotigotine, or pregabalin (Level B). For patients failing other treatments for RLS symptoms, clinicians may consider prolonged-release oxycodone/naloxone where available (Level C).

When non-pharmacologic approaches are desired, clinicians should consider prescribing pneumatic compression (Level B) and may consider near-infrared spectroscopy or transcranial magnetic stimulation (Level C). Clinicians may consider prescribing vibrating pads to improve subjective sleep (Level C). In patients on hemodialysis with secondary RLS, clinicians should consider vitamin C and E supplementation (Level B) and may consider prescribing ropinirole, levodopa, or exercise (Level C).

© PHILIPPE GARO / SCIENCE SOURCE

Restless legs syndrome: a new practice guideline

THE AMERICAN Academy of Pediatrics has released recommendations for primary care pediatricians and specialty care providers regarding preschool-aged children with emotional, behavioral, and relationship problems. The recommendations include the following: • Pediatricians should advocate for: funding programs that increase dissemination and implementation of evidencebased treatments, such as pharmacologic and nonpharmacologic therapies, especially in areas with limited resources;

addressing the early childhood mental health workforce shortage by providing incentives for training in these professions; decreasing third-party payer barriers to accessing mental health services to very young children; promoting accountable care organization regulations that protect early childhood mental health services.

• Pediatricians should advocate for more research that will enhance the evidence base for treatment of very young children with emotional, behavioral, and relationship issues.

Intervention is lacking in children with emotional problems.

• Pediatricians should collaborate with local governmental and private agencies to identify local and national clinical services that can serve young children and explore opportunities for innovative service delivery models such as consultation or co-location.

• Primary care pediatricians and developmental-behavioral pediatricians, together with early childhood mental health providers can create educational materials for trainees and providers to enhance the care that young children receive.

© THINKSTOCK

Recommendations for behavioral and emotional problems

16 THE CLINICAL ADVISOR • JANUARY 2017 • www.ClinicalAdvisor.com

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Newsline Predicting birth ADA publishes guidelines for success after IV psychosocial care in diabetes patients fertilization patient-appropriate standardized THE AMERICAN Diabetes Association has released a position statement to provide diabetes care providers with guidelines for psychosocial assessment and care of patients with diabetes.

The statement focuses on the most common psychosocial factors, including environmental, social, behavioral, and emotional factors, that affect individuals with diabetes. The researchers note that providers should consider the context of the person with diabetes when practicing psychosocial care. The recommendations include the following: • Psychosocial care should be provided to all individuals with diabetes, with the goals of optimizing health outcomes and health-related quality of life. Grade A • Providers should assess symptoms of diabetes distress, depression, anxiety, and disordered eating and of cognitive capacities using

Psychosocial care should be provided to all patients with diabetes to optimize health outcomes.

tools at the initial visit, at periodic intervals, and when there is a change in disease, treatment, or life circumstance. Grade B • Monitor patient performance of self-management behaviors and psychosocial factors that could affect the patient’s selfmanagement. Grade E • Consider the assessment of life circumstances that affect physical and psychological health outcomes and their incorporation into intervention strategies. Grade E • Individuals with diabetes should be evaluated and receive training until they attain competence in diabetes self-care skills and the use of technology at the time of diagnosis, annually, and if transitions in care occur. The diabetes care team should directly and regularly assess these self-management behaviors. Grade B

Statin, PCSK9 inhibitor combo for cholesterol IN PATIENTS WITH angiographic coronary disease who have been treated with a statin, the addition of evolocumab, a PCSK9 inhibitor, led to greater low-density lipoprotein cholesterol (LDL-C) lowering and atheroma regression compared with placebo after 76 weeks of treatment, according to a study in JAMA. The participants had a mean age of 59.8 years, 269 (27.8%) were women, and the mean LDL-C level was 92.5 mg/dL. A total of 846 had evaluable imaging at follow-up.

Compared with placebo, those who received evolocumab had lower mean, time-weighted LDL-C levels (93.0 vs 36.6 mg/dL, respectively). PAV increased 0.05% with placebo and decreased 0.95% with evolocumab. Normalized TAV decreased 0.9 mm3 with placebo and 5.8 mm3 with evolocumab. Evolocumab induced plaque regression in a greater percentage of patients compared with placebo (64.3% vs 47.3%, respectively, for PAV and 61.5% vs 48.9%, respectively, for TAV). n

© THINKSTOCK

AN ONLINE calculator can estimate the chance of live birth during courses of in vitro fertilization (IVF), before treatment and after the first fresh embryo transfer, according to a study in BMJ. Researchers identified 113,873 women undergoing cycles of IVF using their own eggs and partner’s sperm. Also included were women who received intracytoplasmic sperm injection (ICSI).

Two clinical prediction models were used to estimate the chance of a first live birth over a maximum of 6 complete cycles of IVF. The total number of women who participated in the study had 184,269 complete cycles of IVF. A total of 33,154 (29.1%) had a live birth after the first complete cycle and 48,925 (43.0%) had a live birth after 6 complete cycles.

However, the chances of a live birth over 6 complete cycles were lower after transfer of a single cleavage stage fresh embryo compared with double cleavage stage fresh embryo. Thirty percent of all live births resulted in multiples.

Couples with a diagnosis of tubal or male factor infertility had a 10% reduced chance of a live birth, whereas couples with unexplained infertility or anovulation had a slightly increased chance of success. Couples without a previous pregnancy had slightly decreased odds of live birth, and couples who underwent ISCI had a 24% increased chance of live birth as opposed to IVF alone.

18 THE CLINICAL ADVISOR • JANUARY 2017 • www.ClinicalAdvisor.com

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FEATURE: JOANNE STEVENS, PHD, FNP-BC, ARNP, MEGAN FLANAGAN, FNP-BC, ARNP, AND TRESSA PEDROFF, MSN, RN

A clinician’s guide for palliative care By initiating a conversation, primary care providers can identify specific end-of-life needs and goals, manage symptoms, and coordinate care.

© PHOTO ILLUSTRATION: J. DVORETZ

Many patients want their primary care provider to take the lead in end-of-life care.

W

hen primary care providers are working with very ill patients, initiation of the palliative care dialogue can be difficult for the patients and caregivers as well as for the clinicians. Starting the conversation on palliative and end-of-life (EOL) care is essential, particularly as the number of older US adults with complex chronic comorbidities increases.

Consider the effect of the baby boomers alone (individuals born between 1946 and 1964). At present, there are 47.6 million people in the United States aged older than 65 years, a number that is predicted to increase to 72.8 million by the year 2030.1 As the incidence of chronic illnesses, such as chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), diabetes, dementia, and cancer, increases, individuals are living longer but with substantially more chronic illnesses than in the past.1 Little has changed since the publication of the Institute of Medicine (IOM) report on the state of EOL care in 2014,2 which warned of increasing medicalization, the depersonalization of death, and exorbitant costs. Singer et al recently reported that after more than a dozen years, patient and family suffering and quality of life are worse than formerly, with more pain, depression, and confusion occurring in patients currently than in the 1990s.3 According to the IOM report, many US adults have not addressed how to manage their own personal EOL care.2 The report calls for a national effort to implement quality EOL care,

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recommending that not only physicians but also other providers, including the healthcare community and healthcare organizations, reach out to patients about evidence-based advanced care planning for personalized and quality EOL care. The US health system requires major reform to address quality care that is affordable and sustainable.2 Nurse practitioners, physician assistants, and nurses, along with primary care physicians, are in a unique position to implement quality standardized care and coordinate the EOL processes best suited for their primary care patients.

Better access to palliative care is associated with a decreased symptom burden and better quality of life for patients at the EOL.4 Such access is also associated with a lower likelihood of dying in intensive care, an increase in care consistent with preferences, an increase in hospice use, and significant reductions in healthcare costs.5 According to the IOM report, Americans prefer to die at home with control over their healthcare decisions.2 Nonetheless, at present, there is little or no advanced care planning in place.2 Palliative care vs hospice care

It is essential that primary care providers be able to educate their patients about palliative care as a standard component of overall health care. Furthermore, both providers and patients and their families benefit if they understand that palliative care and hospice are not synonymous.

Hospice is a type of care and a philosophy designed to provide comprehensive, interdisciplinary, team-based palliative care for patients with “life-limiting illness with a prognosis of six months or less if the disease follows its natural course.”6 The palliative approach to care shares the holistic philosophy of hospice care but is broader in that care is provided to patients who may not be dying or who are unable to obtain or not interested in hospice services. Therefore, hospices overall deliver palliative services, but not all palliative care is delivered in hospices.6 The differences between palliative care and hospice care are summarized in Table 1.

Establishing goals of care is of extreme importance when older adults with life-limiting illnesses are being treated. A patient’s basic understanding of palliative care is foundational as disease progresses and as available treatments become more and more burdensome. Palliative care is given when a serious or life-threatening illness or disease is diagnosed, with care ensuing at any point in time.7 It is defined as “patientand family-centered care that optimizes quality of life by anticipating, preventing, and treating suffering. Palliative care throughout the continuum of illness involves addressing physical, intellectual, emotional, social, and spiritual needs

and to facilitate patient autonomy, access to information, and choice.”7 It is now recognized that palliative care can be offered at any time during a life-threatening illness, even together with life-prolonging therapies.8 Challenges in palliative care

Multiple challenges for quality EOL care in the United States include the increasing numbers of aging Americans, the enormous cultural diversity in the United States, obtaining access to the right care in complex systems, and the lack of availability of palliative care services, especially in smaller healthcare facilities.2,3 In the United States, health care is costly in a system focused on curative rather than supportive care, and there is a lack of communication and coordination for EOL processes.1 Beyea et al4 found that even though they are available in some areas, hospital and palliative care programs and services are underutilized, especially by lowincome patients. Early dialogue is necessary to honor the preferences of dying patients and their families.1 Head et al9 reported additional challenges for palliative care, including patients with complex medical comorbidities, financial challenges, and language barriers.

A recent study found that the quality of EOL care differs by diagnosis, with significantly better EOL care given to patients who have cancer or dementia than to those with end-stage renal disease (ESRD), cardiopulmonary failure, or frailty.10 Khan et al11 reported that even after hospitalization for CHF, patients experience prolonged symptoms of fatigue, dyspnea, pain, and anxiety, with fewer than 10% of them receiving palliative care.

TABLE 1. Palliative care vs hospice care Palliative care • is centered on relieving the symptoms, pain, and stress of an illness to improve the quality of life of patients and family caregivers; • is provided in conjunction with disease-modifying or life-prolonging treatments; and • may be initiated at any stage of an illness or disease; the diagnosis of a terminal illness or projection of limited life expectancy is not required.

Hospice care • is a form of palliative care; • provides care to relieve the symptoms, pain, and stress of an illness; • is given to those with a limited life expectancy of 6 months or less; and • consists of comfort measures only.

From National Hospice and Palliative Care Organization. An explanation of palliative care. http://www.nhpco.org/palliative-care-4. Accessed November 23, 2016; Hospice FAQs. http:// www.nhpco.org/about-hospice-and-palliative-care/hospice-faqs. Updated July 23, 2015.

Accessed November 23, 2016.

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It is important to have an ongoing dialogue with patients regarding care options and preferences, including conversations with family members.

The primary care provider’s role

Many patients expect their primary care providers to take the lead and rely on their expertise for guidance in making decisions for the best care. Unfortunately, many primary care practices are not proactive in addressing such needs.2,3 It is important not only to inform patients about the trajectory of their illness(es) and treatment plans but also to have an ongoing dialogue with them regarding care options and preferences, including conversations with family members.

Key questions, according to Beyea et al,4 include the following: What is your understanding of your current condition? If your health gets worse, what are your goals? What are your fears? Do you have opinions about treatments?

These questions need to be explored, preferences should be documented, and follow-up should be provided (Table 2).

Phillips12 emphasizes that some primary care providers look upon palliative care as services rather than as an approach, a perception that creates barriers in communicating with patients. Using an “approach” to palliative care in primary practice means that practitioners, over the course of a career, embrace and integrate the concept of palliative care with services as part of comprehensive care. Of note is the study

by Obermeyer et al,13 which found that physician characteristics are the strongest predictor of whether a patient will be referred to hospice, outweighing even patient age and comorbidities. The take-home message is that primary care TABLE 2. Key questions about palliative care that practitioners should ask their patients 1. If you became seriously ill, how confident are you that you would be treated according to your wishes and values?

2. Do you have someone who can make healthcare decisions for you if you become unable to speak for yourself?

3. Do you have opinions about how you would want to be treated if you become seriously or terminally ill?

4. Are your opinions about how you would want to be treated understood by your healthcare physicians/providers?

5. Have you put your opinions in writing?

6. Are you experiencing symptoms that affect your quality of daily life?

7. How confident are you that you know how to get help if symptoms worsen?

Adapted from Beyea et al.4

providers’ opinions and recommendations matter for patients as they decide on palliative care by addressing patients’ goals and EOL options. Communication and relationships between providers and patients and their families are key.

O’Neill and Morrison8 describe how palliative care can be appropriately offered to patients at any time and can certainly include restorative and life-prolonging therapies. According to these authors, the primary principles of palliative care include the following: establishing goals of care that are consistent with the patient’s values and preferences; managing symptoms; arranging for ongoing communication between the patient and those involved in the patient’s care; providing psychosocial, spiritual, and common sense support to patients and caregivers; and offering coordination across sites of care.

Advance directives

Weinberg and Stason14 offer practical information for initiating advance directives (ADs) in a primary care practice.

A provider who knows what a patient’s AD goals are and uses them when making clinical decisions improves the patient’s outcomes, according to numerous studies.1,14 These authors provide specific actionable advice related to ADs. For example, they encourage providers to integrate ADs within their primary care practices by including scheduled sequenced visits (eg, primary care visit and follow-up visit).

The primary care visit consists of 30 minutes of face-to-face time with the patient, family members, and/or surrogates to introduce the topic and explain key information; the second visit is for following up, answering questions, and documenting ADs. The ADs are then reviewed at regular intervals.14 Patients learn about their illnesses and develop ADs with their primary care provider. The visits occur no later than after a serious illness or terminal illness has been diagnosed.

Worsening symptoms, increasing disability, and complications after medical events commonly indicate the need for an AD.14 Weinberg and Stason14 carefully point out the importance of communication and collaboration among primary care providers, patients and families, specialists, hospitalists, skilled nursing facilities (SNFs), and emergency departments (EDs).

They recommend 24/7 access to patient information in the medical record (eg, the electronic medical record [EMR]) for covering healthcare proxies, with the patient’s goals always considered for consistent patient management.

It is essential that providers take ADs into consideration when making clinical decisions. Having ADs available in the

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Research suggests that frank disclosure of terminal status to patients and their caregivers is a critical first step in advanced care planning.

EMR is especially important for clinicians who are managing and coordinating the care of patients who are chronically ill.

Improving communication

Beyea et al4 reported on a statewide intervention in which case managers were assigned to increase the utilization of palliative care and hospice for Medicaid patients. They found that the intervention, based on the use of training components and engagement with local hospice and palliative care providers, was effective in improving communication and referrals for hospice and palliative care.

It has been reported that a stigma is associated with terms like palliative care and hospice, whereas terms like supportive care and care of the critically ill are more readily accepted.15 In 2012, Bernacki and colleagues created a systematic intervention called the Serious Illness Care Program,16 which included provider training, an EMR prompt, and a system for identifying patients for whom services were appropriate. With the intervention, EOL discussions occurred more frequently and earlier (after approximately 3 months), resulting in less anxiety among patients and improved satisfaction with their quality of life. Patients further reported better discussions with family and physicians going forward.

The study of An et al17 suggests that frank disclosure of terminal status to both patients and their caregivers is a critical first step in advanced care planning. Patients who recognize the terminal nature of their illness were more likely to receive symptom-directed care.17 Nettina18 discusses the roles of primary care providers in regard to initiating discussions about ADs or living wills, preferences for life-sustaining treatment (including out-of-hospital orders), and the role of a health care proxy. Glatter and Mirarchi19 further emphasize the importance of physician orders for lifesustaining treatment (POLST), which are specific instructions for management after a catastrophic event or desired care during the last stages of a terminal disease, including out-of-hospital events. Murray et al15 produced a toolkit of innovative strategies for promoting palliative care in the community.

How patients deal with their illness is also significant. A study of patients with chronic heart failure lasting 6 months or longer demonstrated that those who had come to terms with their disease were more likely to have a good quality of life.20 These patients reported more energy; less pain; better emotional reactions, quality of sleep, and mobility; and less social isolation.20 In a recent study, only one in four patients were familiar

with palliative care.11 Investigators in this prospective study of individuals hospitalized for heart failure at their center from 2013 to 2014 found that the patients thought palliative care was actually hospice and mistakenly believed that palliative care was just for those with cancer.11 It is important that education about palliative care, including frank disclosure regarding terminal disease status to both patients and their caregivers,17 be conducted in a sensitive and supportive dialogue. Primary providers are in a unique position to offer education, support, and palliative management.

Insurance coverage for EOL discussions

A new policy, implemented on January 1, 2016, allows doctors, nurses, nurse practitioners, and physician assistants to bill for discussions about EOL care.21 This means that older adults will likely have more opportunities to schedule EOL discussions because they will be reimbursable. The Centers for Medicare & Medicaid Services (CMS)22 included this new provision for financial coverage in its regulation package introduced during the summer of 2015. The two Current Procedural Terminology (CPT) codes are 99497 and 99498.22 During the summer of 2016, the CPT codes were activated, and CMS has now approved payment for voluntary EOL counseling as part of its 2016 Medicare payment schedule.

Making EOL counseling reimbursable represents a major policy change and will undoubtedly result in more providers offering such visits.

For this reason, it is essential that primary care providers be familiar with the principles of palliative care because they are responsible for the coordination of care of their patients with serious, complex, or life-threatening disease and illness.23 Consider a patient with CHF whose disease progression is marked by periods of exacerbation and stability. Guidelines for palliative care are essential not only during periods of exacerbation but also during the early stages of treatment as part of the overall treatment modality.23 Review Table 3 as you think through the following case.

A case study

Mrs W is a 73-year-old African American woman who presents to your primary care office as a new patient. She is accompanied by her eldest daughter, with whom she resides.

Mrs Whalen currently receives Medicare benefits and has recently moved to Florida from Buffalo, NY. Her daughter Continues on page 28

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Guidelines for palliative care are essential not only during periods of exacerbation but also during the early stages of patients’ treatment. is now exploring local SNFs, given her mother’s frailty and declining health. The patient can no longer walk or stand for any length of time without experiencing chest pain and shortness of breath. She is having trouble with activities of daily living (ADLs) and instrumental activities of daily living (IADLs). She has been experiencing extreme fatigue and weakness for more than 3 weeks.

Mrs W has been hospitalized three times in the last 6 months, with the most recent hospitalization occurring 2 weeks ago.

At that time, she was discharged from the hospital to a cardiac rehabilitation unit, but because of her inability to tolerate physical therapy, she was discharged home with recommendations for hospice. Currently, a home health aide helps Mrs W with ADLs and acts as a constant companion while the daughter works. Mrs W’s previous medical provider indicated that she did not have any ADs and suggested that the patient develop a living will after further discussion with her daughter. No further EOL discussions or referrals for assistance with this matter ever occurred, nor was a living will ever completed.

The patient’s medical history includes hypertension (1997), diabetes mellitus type 2 (1999), and coronary artery disease with myocardial infarction/bypass (2013). CHF was diagnosed in 2014. Data obtained from the medical record reveal that she has “not gotten around to completing a living will but does not want machines keeping her alive.” She denies having a health care proxy but would elect her daughter over her son. There are no ADs in her EMRs. She concedes to avoiding the topic of EOL care but admits that confronting this issue probably would help her to get things in order.

POLL POSITION

Who most frequently initiates the discussion of palliative care with your patients? n = 217

■ I do ■ The patient

4.15% 86.64%

9.22%

■ A family member of the patient

For more polls, visit ClinicalAdvisor.com/Polls.

After moving in with her daughter 2 weeks ago, she was transported to the ED when the daughter found her to be short of breath and having chest pain. This last CHF exacerbation began with a dry cough and then shortness of breath for approximately 2 days, with worsening swelling from feet to face and “all over chest pain.” She describes the pain as constant and nonradiating, and she rates it as 7 on a scale of 10. A non-ST segment elevation myocardial infarction (NSTEMI) is diagnosed, and the patient is admitted to the cardiac care unit with intravenous heparin, analgesics, aspirin, and clopidogrel.

Vitals are taken. The patient’s weight is 157 lb and her height is 5 ft 4 in. The heart rate is 78 beats/min, respiratory rate is 88/min, blood pressure is 184/93 mm Hg, and oxygen saturation is 93% on room air. The heart sounds are S1 and S2 with S3 gallop, with no murmurs or rubs. On auscultation, she has rales in the lung bases. She has bilateral pitting edema at 3+.

Her current medications consist of furosemide (60 mg twice a day), potassium chloride (20 mEq every morning), lisinopril (10 mg every morning), aspirin (81 mg daily), and metformin.

During her hospitalization 2 weeks ago, she had a full evaluation for heart failure, resulting in a New York Heart Association (NYHA) categorization of class III (marked limitation of physical activity) and a classification of stage C (structural heart disease and symptoms of heart failure) per the American College of Cardiology (ACC)/American Heart Association (AHA) staging system. Her treatment and discharge plan included oxygen and noninvasive positivepressure ventilation, dietary sodium and fluid restriction, physical activity as tolerated, and attention to weight gain.

Her medications were adjusted, lifestyle changes were addressed, and she was offered the option of home hospice care. Mrs W reported that she wanted “to talk with my new Florida doctor first. I don’t want hospice to be involved— that’s giving up. This all is in God’s hands anyways.”

When asked what an overall goal for care would be, she stated “I’d like to have my remaining days to be good ones and not have tubes keeping me alive. I want to live without pain and suffering, and when the time comes, to be at home with my children at my side.”

Comfort care at home needs to be the principal goal of care in this case. If the patient had established ADs with her past primary provider, she might have avoided unnecessary hospitalizations and the transfer to rehabilitative services. Her current health status in conjunction with her ADs would have served

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Experienced palliative clinicians know that it is never too early to begin educating patients about the palliative approach and EOL conversations. as a guideline for making healthcare decisions and coordinating best care. Pain and suffering might have been avoided.

Initiating the palliative care dialogue

Experienced palliative clinicians know that it is never too early to begin educating patients about the palliative approach and with time, to transition into EOL conversations. For providers, the idea of what palliative care is should be introduced early in the trajectory of a patient’s illness. When standard EOL discussions are incorporated into primary care early on, patients and families can develop ADs that provide a foundation for an open dialogue on EOL goals.

Mrs W was an excellent candidate for supportive care at home with a palliative component. She described her ordeal at the hospital, saying that the hospitalist suggested palliative care, but she was not ready for hospice. This patient needed a better understanding of palliative care as an approach, with hospice as an option.

Her new primary care provider explained that palliative care is patient- and family-centered and that it is a holistic approach to overall health care that addresses symptoms and quality of life. Furthermore, the provider described palliative care as an important and necessary component of standard health care and that curative and restorative treatment is available. In addition, hospice was described to Mrs W as quality care for those with less than 6 months to live, and it was explained that hospice services result in improved patient satisfaction during the last months of life and during the dying process. Mrs W was given a handout on palliative and hospice care, including web links and literature on available resources. The patient felt better after understanding that palliative care meant relief of pain and stress but also included standard treatment for her CHF and diabetes. Mrs W was also able to verbalize that hospice is a service for everyone who needs it during the later stages of life.

Voicing another common misunderstanding, Mrs W said that she thought this type of special help was reserved for

Testing your knowledge on palliative care 1. A 76-year-old woman cared for her 80-year-old husband in their home until he died of chronic and serious congestive heart failure. Which of the following best predicts an uncomplicated bereavement? a. The woman’s strong dependence on her husband before his illness b. The provision of palliative care and/or hospice during his illness c. The woman’s agnostic beliefs d. The woman’s mild dementia, which will mitigate her grief 2. Research indicates that patients want to communicate with their healthcare providers about end-of-life issues.

Therefore, according to current recommendations, which of the following should clinicians address with patients at the onset of a terminal illness? Choose all that apply. a. Preparing advance care directives. b. Choosing a health care proxy or surrogate decision maker c. Describing in detail the end-stage signs and symptoms of the patient’s most problematic chronic illness d. Documenting patient decisions and updating them regularly

3. Choose from the following type(s) of advance legal directives that are available for individuals determined not to have decision-making capacity. Choose all that apply. a. The family lawyer c. Hospice team consensus b. A living will d. A health care proxy or surrogate 4. Which is the most accurate statement concerning palliative care and hospice? a. Hospice is provided for those with a life expectancy of 6 months or less. b. Palliative care can be initiated only for a patient with a terminal illness. c. Both palliative care and hospice can include curative treatments. d. Palliative care provides comfort measures only.

5. Which are the chronic illnesses least likely to receive palliative care and good-quality end-of-life care? a. Cancer and dementia b. End-stage renal disease and congestive heart failure c. Frailty and chronic obstructive pulmonary disease d. Frailty and end-stage renal disease

Answers: 1) b. 2) a, b, d. 3) b, d. 4) a. 5) b.

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TABLE 3. Provider checklist for quality palliative care 1. Provide care that is patient-centered (goals and values) and familyoriented.2 2. Educate patients about their severe and/or chronic/acute illnesses in a frank manner.17 3. Designate the palliative care team representatives in your primary care practice who implement evidence-based practice and remain current in palliative education.

4. Set up standard palliative care consultation visits (eg, primary and follow-up visits)14 that address the following components: • Provide fact-based information on AD planning for informed choices.2 • Ask key questions and incorporate quality curriculum for palliative visits (Table 2).4 • Address the patient's and caregiver's goals for ADs, including information and decision making regarding living wills, health care proxies, and MOLST/POLST. • Document ADs in the patient's medical record (preferably in EMR format for best coordination among providers).

• At regular intervals, reassess the patient’s AD goals, medical status, and changes to the care plan, including necessary referrals.2 5. Use resources and research for best evidence-based practice (Table 4).

6. Always consider ADs while making healthcare decisions.

7. Communicate and collaborate with SNFs, EDs, the patient's physician, specialists, and hospitalists for AD implementation congruent with best care.

8. Be knowledgeable about local hospital discharge practices and associated resources.

9. Develop and regularly assess palliative outcome measures (eg, scheduled consultations, patient satisfaction data, safe EOL care measures, code status, and record settings for death).2 10. Network and use available community palliative care teams.23 AD, advance directive; ED, emergency department; EMR, electronic medical record; EOL, end-of-life; MOLST, medical orders for life-sustaining treatment; POLST, physician orders for life-sustaining treatment; SNF, skilled nursing facility.

patients with terminal cancer or dementia, and she was happy to learn of extended services for patients with chronic and complicated illnesses such as ESRD and CHF. The provider emphasized that palliation is meant to manage symptoms and pain and to improve the quality of life of all patients with illness or disease. The provider reiterated that neither palliative nor hospice care is required (and can be withdrawn at any time), but studies have clearly indicated that quality of life is improved by such an approach with services.

Because the new provider’s practice offered palliative services, Mrs W and her daughter were scheduled for an initial visit to establish how she viewed her own disease and what her goals were. This service was conducted by a provider and nurse

team, with the practice social worker available as needed. Mrs W was frank, stating “I know I’m sick and getting weak. I am having more and more difficulty even walking a few steps.

My big fear is that my symptoms, especially the shortness of breath, will be such a struggle.” Mrs W had her provider document that she desired her daughter to be her health care proxy if she became unable to make decisions about her care.

At this patient’s practice, the primary care palliative team members were certified and experienced in providing palliative services. They completed continuing education on an ongoing basis and educated staff regularly. A primary care practice goal of theirs was to support palliative and EOL dialogue and to become actively involved in patients’ advanced care planning. The practice worked collaboratively with the front office staff, providers, and technicians and nurses to systematize and integrate this approach with all the patients.

Palliative care resources and specialized community palliative teams were consulted for more challenging patients.

A palliative care checklist

Incorporating good communication skills in delivering tough news, describing palliative care, setting patient goals, and involving caregivers are essential for patient-centered care.17,18,24 Patients need to understand the expected trajectory of their serious illness and the types of advanced care planning that should be considered. The SPIKES (setting, perception, invitation or information, knowledge, empathy, summarize or strategize) acronym25 is a helpful tool for providers delivering bad news early in the course of a life-threatening illness. Primary care providers should have discussions about ADs no later than at the time of the first diagnosis of a serious illness. Alternatively, standard visits can be considered beginning at age 65 years, and many suggest having discussions with primary care patients earlier.4,8,17,18,26 Besides ADs, in various scenarios, a surrogate decision maker and out-of-hospital orders for life-sustaining treatment should be included for comprehensive information.

A checklist for incorporating a palliative approach into a primary care practice appears in Table 3. It is derived from the IOM report2 as well as current studies examining palliative care in primary practice.4,14,17,23 Besides best practices to initiate primary and follow-up appointments with patients, the checklist emphasizes the need to consider ADs with clinical decision making, and it reinforces the need for communication and collaboration with SNF coordinators, specialists, hospitalists, and EDs.14 In addition, the checklist includes an ongoing assessment of a practice’s palliative care outcome measures, such as completed consultations and patient and family satisfaction surveys.2

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TABLE 4. Palliative care resources for healthcare professionals Center to Advance Palliative Care (CAPC): www.capc.org Education in palliative and end-of-life care: www.epec.net Hospice & palliative nurses association: www.hpna.org The Joint Commission—Certification for palliative care programs: http:// www.jointcommission.org/certification/palliative_care.aspx National Hospice and Palliative Care Organization: www.nhpco.org Get palliative care: www.getpalliativecare.org US National Library of Medicine—Palliative care: https://medlineplus.gov/ palliativecare.html The Conversation Project: http://theconversationproject.org American Academy of Hospice and Palliative Medicine: http://aahpm.org National Consensus Project: http://www.nationalconsensusproject.org Supportive Care Coalition: http://www.supportivecarecoalition.org

TABLE 5. Advanced care planning websites for patients and families Prepare: http://www.prepareforyourcare.org Aging with dignity—Five wishes: https://www.agingwithdignity.org/fivewishes/about-five-wishes ACP (advanced care planning) decisions: http://www.acpdecisions.org Coalition to Transform Advanced Care (C-TAC): http://www.thectac.org

The best resources for information on palliative care to be used in primary care practice are listed in Table 4. Table 5 lists websites for patients. These are especially relevant for primary care providers who are building palliative care processes aimed at helping patients develop evidence-based EOL ADs.

The palliative process requires standardization and a “kick start,” particularly in primary care practices and clinics.

Developing a palliative care team and incorporating EOL visits into a primary care practice provide a solid beginning.

Demonstrated competency (eg, continuing education units) and/or certification in discussing ADs is certainly important and will undoubtedly become required for providers.

EOL care should become part of standard medical, nursing, physician assistant, and nurse practitioner curricula,4,19,24 so that providers become comfortable and more seasoned in providing information and ongoing management.

Advanced care planning has been shown to improve patient and family satisfaction and allow care that is evidence-based, with fewer hospitalizations.2 It is essential that primary care providers address the many unmet needs of patients and families during the patients’ later years.

By initiating the palliative care dialogue, the primary care team can identify specific needs and goals, manage symptoms, coordinate care, and determine when additional resources are necessary. When incorporating EOL care into primary care, providers need to consider the process as “the beginning of a journey,” with treatment geared to provide the highest quality of life possible for the longest possible time. An interdisciplinary approach will provide a holistic focus and address comprehensive care for patients and families.18,27 Primary care providers have tremendous potential for ensuring access to and delivery of palliative care by reaching patients with all life-threatening illnesses, meeting their needs across all domains (physical, spiritual, social, and emotional), and providing care and support in a variety of primary care settings. Let the journey begin. n Joanne Stevens, PhD, FNP-BC, ARNP, is an associate professor of nursing, Megan Flanagan, FNP-BC, ARNP, is an alumna, and Tressa Pedroff, MSN, RN, is a clinical instructor at University of Tampa in Florida. Megan Flanagan, FNP-BC, ARNP, practices at Lifetime Obstetrics and Gynecology in Tampa.

References

Conclusions and future recommendations

1. Centers for Disease Control and Prevention. The state of aging and

All primary care providers (not just those treating patients with chronic illnesses or the dying) are responsible for teaching their patients about palliative care. Providers should have quality EOL discussions with their patients in a timely and ongoing manner. Doing so affords patients the necessary information, consistent good-quality management, and (when required) transitions in care (eg, transfer to hospice services). The earlier the introduction to the palliative care approach, the better.

health in America 2013. http://www.cdc.gov/features/agingandhealth/ State_of_aging_and_health_in_america_2013.pdf. Published 2013.

Accessed November 23, 2016.

2. Institute of Medicine. Dying in America: improving quality and honoring individual preferences near the end of life. Washington, DC: The National Academies Press, 2014.

3. Singer AE, Meeker D, Teno JM, Lynn J, Lunney JR, Lorenz KA. Symptom trends in the last year of life from 1998 to 2010: a cohort study. Ann Intern Med. 2015;162:175-183.

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4. Beyea A, Fischer J, Schenck A, Hanson L. Integrating palliative care information

21. Centers for Medicare & Medicaid Services. Medicare care choices

and hospice referral in Medicaid primary care. J Palliat Med. 2013;16:376-382.

model. https://www.cms.gov/Newsroom/MediaReleaseDatabase/Fact-

5. Morrison RS, Dietrich J, Ladwig S, et al. Palliative care consultation teams cut

sheets/2014-Fact-sheets-items/2014-03-18.html. Published March 18,

hospital costs for Medicaid beneficiaries. Health Aff (Millwood). 2011;30:454-463.

2014. Accessed November 23, 2016.

6. Meier DE, McCormick E, Lagman R. Hospice: philosophy of care and

22. Centers for Medicare & Medicaid Services. Proposed policy,

appropriate utilization in the United States. UpToDate. https://www.uptodate.

payment, and quality provisions changes to the Medicare Physician Fee

com/contents/hospice-philosophy-of-care-and-appropriate-utilization-in-the-

Schedule for Calendar Year 2016. https://www.cms.gov/newsroom/

united-states. Updated May 5, 2016. Accessed November 23, 2016.

mediareleasedatabase/fact-sheets/2015-fact-sheets-items/2015-07-08.

7. National Hospice and Palliative Care Organization. Key hospice

html. Published July 8, 2015. Accessed November 23, 2016.

messages. http://www.nhpco.org/press-room/key-hospice-messages.

23. Meier DE, McCormick E. Palliative care: benefits, services, and models

Accessed November 23, 2016.

of subspecialty palliative care. UpToDate. https://www.uptodate.com/

8. O’Neill L, Morrison R. Palliative care: issues specific to geriatric patients.

contents/benefits-services-and-models-of-subspecialty-palliative-care.

UpToDate. http://www.uptodate.com/contents/palliative-care-issues-specific-

Updated November 15, 2016. Accessed November 23, 2016.

to-geriatric-patients. Updated May 29, 2015. Accessed November 23, 2016.

24. Pelayo-Alvarez M, Perez-Hoyos S, Agra-Varela Y. Clinical effectiveness

9. Head BA, La Joies S, Augustine-Smith L, et al. Increasing access to community-

of online training in palliative care of primary care physicians. J Palliat Med.

based palliative care for Medicaid patients. Prof Case Manage. 2010;15:206-217.

2013;16:1188-1196.

10. Wachterman MW, Pilver C, Smith D, Ersek M, Lipsitz SR, Keating NL.

25. Ruben DB, Herr K, Pacala J, Pollock BG, Potter JF, Semia TP, eds.

Quality of end-of-life care provided to patients with different serious

Geriatrics at Your Fingertips. 18th ed. New York, NY: The American

­illnesses. JAMA Intern. Med. 2016;176:1095-1102.

Geriatrics Society; 2016.

11. Khan RF, Feder S, Goldstein NE, Chaudry SI. Symptom burden

26. Peereboom K, Coyle N. Facilitating goals-of-care discussions for

among patients who were hospitalized for heart failure. JAMA Intern Med.

patients with life-limiting disease-communication strategies for nurses.

2015;175:1713-1715.

J Hospice Palliat Nurs. 2012;14:251-258.

12. Phillips J. A service versus an approach: the importance of building

27. Kelly AS, Morrison RS. Palliative care for the seriously ill. N Engl J Med.

primary palliative care. Int J Palliat Nurs. 2014;20:471.

2015;373:747-755.

13. Obermeyer Z, Powers BW, Makar M, Keating NL, Cutler DM. Physician characteristics strongly predict patient enrollment in hospice. Health Aff (Millwood). 2015;34:993-1000.

14. Weinberg N, Stason WB. End-of-life planning in primary care practice.

Consultant. 2015;55:999-1005.

15. Murray SA, Firth A, Schneider N, et al. Promoting palliative care in the community: production of the primary palliative care toolkit by the © The New Yorker Collection 2017 from cartoonbank.com. All Rights Reserved.

European Association of Palliative Care Taskforce in primary palliative care. Palliat Med. 2015;29:100-111.

16. Bernacki R, Hutchings M, Vick J, et al. Development of the Serious Illness Care Program: a randomised controlled trial of a palliative care communication intervention. BMJ Open. 2015;5:e009032.

17. An A, Lee J, Yun Y, Heo D. Terminal cancer patients’ and their primary caregivers’ attitudes toward hospice/palliative care and their effects on actual utilization: a prospective cohort study. Palliat Med. 2014;28:976-985.

18. Nettina S. Bringing palliative care to primary care. The Maryland Nurse News and Journal. 2015;February-April:17.

19. Glatter R, Mirarchi F. What physicians and other healthcare providers need to know about end-of-life care. Medscape. http://www.medscape.com/ viewarticle/852655. Published October 22, 2015. Accessed November 23, 2016.

20. Obieglo M, Uchmanowicz I, Wieklik M, Jankowska-Polanska B, Kusmier M. The effect of acceptance of illness on the quality of life in patients with chronic heart failure. Eur J Cardiovasc Nurs. Published January 8, 2015.

Accessed November 23, 2016.

“No caffè latte? And you call yourselves a bookstore?”

32 THE CLINICAL ADVISOR • JANUARY 2017 • www.ClinicalAdvisor.com

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FEATURE: MACY COOK, PA-C

Raynaud phenomenon: a cold-weather condition A thorough work-up can differentiate between primary and secondary forms, mitigating progression of a more severe underlying disease.

© VOISIN / PHANIE / SCIENCE SOURCE

A

Raynaud phenomenon is marked by reversible bouts of digital vasospasm.

s the colder months approach and the temperatures drop, Raynaud phenomenon (RP) will most likely be seen in an increasing number of patients in the primary care setting. RP is characterized by reversible bouts of digital vasospasm that are an exaggerated response to physical, chemical, or emotional stress.

The condition is primary in 80% of cases and secondary in 20%.1 The primary form is idiopathic—that is, not linked to any other comorbid condition or disease. The secondary form is diagnosed when an underlying condition is causing the symptoms of RP. The secondary form is most commonly caused by one of the autoimmune connective tissue diseases. The underlying disease is most frequently systemic sclerosis; RP is seen in 96% of patients with this condition.1 The secondary form can also be due to a vibration injury, medication, hematologic disorder, or an endocrine disorder.2 The differences between the two forms are imperceptible to the naked eye. Therefore, during the work-up of a patient with RP, laboratory studies are an important tool for differentiating between the primary and secondary forms.

The etiology and pathogenesis of RP have yet to be explained or understood completely, but several factors are thought to have a role. The average age of patients is 47.2 years in European countries and 53.5 years in the United States.1 In a randomized trial conducted in California that analyzed 162 patients with RP, 80.5% were found to be non-Hispanic whites, 0.6% were Native Americans/Alaskans, and 1.2% were Asian/Pacific

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RAYNAUD PHENOMENON: A COLD-WEATHER CONDITION

Most clinicians can make the general diagnosis of Raynaud phenomenon by taking a history of the patient’s symptoms.

Islanders.1 As for gender patterns within the United States, the prevalence is 9.6% in women and 5.8% in men.1 A heightened prevalence of RP has also been noted in male smokers and in women with a high rate of alcohol intake.1 Most clinicians can make the general diagnosis of RP by taking a history of the patient’s symptoms. The more challenging aspect is deciding whether the symptoms are arising independently or because of another condition. In other words, does the patient have the primary or secondary form? A patient with RP will present with either a “triple” or “double” color change in the affected digits. The triple color change includes pallor (indicating ischemia), cyanosis (indicating deoxygenation), and erythema (indicating reperfusion); the double color change may present as pallor plus cyanosis or cyanosis plus erythema. The average length of a vasospastic episode is 20 minutes, but an episode has the potential to last TABLE 1. Nailfold capillary patterns in Raynaud phenomenon associated with various disease states Disease

Nailfold capillaroscopy patterns or characteristics

Scleroderma (early)

Few giant capillaries, few capillary hemorrhages, relatively well-preserved capillary distribution, and no evident loss of capillaries5

Scleroderma (active)

Frequent giant capillaries, frequent capillary hemorrhages, moderate loss of capillaries, mild disorganization of capillary architecture, and absent or mild ramified capillaries5

Scleroderma (late)

Irregular enlargement of capillaries, few or absent giant capillaries and hemorrhages, severe loss of capillaries with extensive avascular areas, disorganization of normal capillary array, and ramified capillaries5

Polymyositis/ dermatomyositis

Two or more of the following findings in at least two nailfolds: enlargement of capillary loops, loss of capillaries, disorganization of normal distribution of capillaries, “bushy” capillaries, twisted enlarged capillaries, and capillary hemorrhages6

Systemic lupus erythematosus

Morphologic changes in capillary loops, venular visibility, and sludging of blood with variability of capillary loop length7

Mixed connective Presence of dystrophic, extremely convoluted, branched tissue disease capillaries, sometimes termed pseudoglomeruli or bushy capillary formation8 Nonspecific abnormalities

Abnormal nailfold capillary findings with no patterns suggestive of scleroderma, polymyositis/dermatomyositis, systemic lupus erythematosus, or mixed connective tissue disease8

for several hours. Symptoms typically subside with return to a warm room or placement of the affected body part in warm water. The patient may describe sensory changes such as numbness, decreased range of motion, decreased sensation, and aching pain.2 Numbness is most likely to coincide with ischemia, whereas pain is most likely to be associated with deoxygenation/cyanosis and reperfusion.3 Work-up of the patient with Raynaud phenomenon

It is imperative to determine whether a patient has primary RP or the secondary form with an underlying cause.

Nailfold capillaroscopy and specific serologic testing are the most commonly used tools in the work-up of a patient with vasospastic attacks. The morphology of nailfold capillaries is examined by placing a drop of immersion oil onto the cuticle and viewing the region with a high-power magnification device.2 In a study of nailfold capillary patterns and connective tissue diseases among 67 patients with RP, Wu et al found that a patient with enlarged capillary loops or certain capillary patterns is likely to have a secondary form of RP.4 The capillary patterns differ depending on which autoimmune connective tissue disease affects the patient.

Characteristics of various patterns, identified based on quantitative nailfold capillaroscopic observation, are listed in Table 1.5-8 Primary RP often exhibits a normal nailfold capillary pattern, which consists of a “parallel arrangement of hairpin-like capillaries in appropriate caliber and shape,” and therefore the diagnosis of secondary RP is excluded.4 Depending on a practitioner’s ability to discern these characteristics, consistent findings on nailfold capillaroscopy make it possible not only to detect the presence of an underlying connective tissue disease but also to diagnose a specific connective tissue disease.4 Systemic sclerosis, systemic lupus erythematosus, polymyositis/dermatomyositis, and mixed connective tissue disease are all possible causes of RP and were the connective tissue diseases noted in this study. Within all the disease states, the study showed that nailfold capillaroscopy used for identifying a connective tissue disease is highly specific but is highly sensitive only for identifying systemic sclerosis and polymyositis/dermatomyositis. Therefore, nailfold capillaroscopy has potential value as a diagnostic tool in secondary RP. However, careful training and considerable practice at identifying these capillary patterns are needed, which may be unrealistic goals for primary care practitioners dealing with Continues on page 37

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RAYNAUD PHENOMENON: A COLD-WEATHER CONDITION

The first-line treatment includes life-style modifications, such as avoidance of smoking, exposure to cold, and emotional stress. a disease that has a prevalence of only approximately 10% in women and 6% in men in the United States.1 In addition to using nailfold capillaroscopy to detect abnormal patterns, the practitioner should look for other abnormal physical examination findings suggestive of an underlying condition. These may include, among others, the following: diminished pulses in the extremities, malar rash, swollen joints, telangiectasia, skin tightening, and digital ulceration.2 Additional features that can suggest the presence of an underlying rheumatic disease include age older than 30 years, relatively intense episodes, unilateral involvement, abnormal nailfold capillaries, and abnormal results of serology tests, such as antinuclear antibody (ANA), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR).9 What are the treatment options?

In all patients with RP, the first-line treatment involves lifestyle modifications, such as avoidance of smoking, exposure to cold, emotional stress, medications that cause vasoconstriction, and occupational use of vibratory equipment. Proper care of the hands and feet is important because wounds are generally slow to heal, making infection hard to manage.2 For patients with relatively severe symptoms or symptoms not relieved by lifestyle modifications, drug therapy can be initiated. Calcium channel blockers are used for severe primary RP (they are less effective in secondary RP) and have

been shown to reduce both the frequency and severity of attacks. Generally, 30 to 90 mg of nifedipine daily has been shown to be effective.10 Other drugs that have shown some benefit include the selective serotonin reuptake inhibitor fluoxetine, topical nitroglycerin, phosphodiesterase inhibitors (sildenafil, tadalafil, and vardenafil), sympatholytic agents, angiotensin-converting enzyme (ACE) inhibitors, endothelin receptor inhibitors, statins, antiplatelet agents, and prostaglandins.2 The medication and dosage recommendations for a patient with RP are listed in Table 2.11 In patients with secondary RP due to an underlying connective tissue disease, quality of life is more likely to decrease and management is more difficult. These patients experience relatively frequent, intense, painful exacerbations of their disease. The increased severity of the attacks can lead to the development of skin ulcerations, which may eventually result in scarring, necrosis, or gangrene of the affected area.

Surgery may be indicated if the ischemia is so severe that it causes bone necrosis and self-amputation of the fingertips.12 Along with skin manifestations, several body systems are likely to be involved by disease, and patients need to be managed on several different levels.1 Conclusion

RP does not greatly affect a patient’s quality of life unless it is secondary to an underlying cause and leads to gangrene

TABLE 2. Medications used for the treatment of Raynaud phenomenon11 Medication

Dosage forms

Therapy

Other information

Nifedipine (or other dihydropyridine calcium channel blockers)

Capsule: 10 mg, 20 mg, Tablet, extended release: 30 mg, 60 mg, 90 mg

Initiate at lowest dose available and titrate upward as tolerated, with goal of diminishing frequency and/or severity of attacks.

Most effective first-line treatment after nonpharmacologic therapy; extended-release form most often used

Selective serotonin reuptake inhibitors (fluoxetine)

Capsule: 10 mg, 20 mg, 40 mg Initiate at 20 mg daily and may progress to Tablet: 10 mg, 20 mg, 60 mg 60 mg.

Nitroglycerin (topical)

1%

Apply locally for vasodilator effects.

Phosphodiesterase inhibitors (sildenafil, tadalafil, and vardenafil)

Various

• Sildenafil: dosage ranges from 25 mg 3 times daily to 50 mg 2 times daily • Tadalafil: dosage ranges from 20 mg daily to 20 mg 3 times per week • Vardenafil: dosage is 10 mg 2 times daily

May need to adjust tadalafil dosage for hepatic or renal impairment

Iloprost (or other prostaglandins)

Single-use ampule: 10 mcg/mL (1 mL) 20 mcg/mL (1 mL)

• Initial dose: 2.5 mcg inhaled; if well tolerated, THEN 5 mcg subsequently • Maintenance dose: 2.5–5 mcg, not to exceed 45 mcg/d

Inhaled or given intravenously; approved for pulmonary arterial hypertension but also used in secondary form of Raynaud phenomenon

Less effective than calcium channel blockers; used in primary form of Raynaud phenomenon

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RAYNAUD PHENOMENON: A COLD-WEATHER CONDITION

or digital necrosis. In most cases, primary RP is a moderate nuisance that patients can tolerate by modifying their environment or stress level, and it is doubtful that further investigation will have a major effect on their overall health.

On the other hand, secondary RP may very well be the first clinical manifestation of a connective tissue disease.

If the progression of a more severe underlying disease can be mitigated, then a patient work-up and assessment of the disorder will be well worth the time. n Macy A. Cook, PA-C, is a critical care physician assistant for Piedmont Healthcare in Atlanta.

References 1. Prete M, Fatone MC, Favoino E, Perosa F. Raynaud’s phenomenon: from molecular pathogenesis to therapy. Autoimmun Rev. 2014;13:655-667.

“Good news. The government has downgraded our emissions from ‘toxic’ to ‘smelly.’ ”

2. Papadakis MA, McPhee SJ, Rabow MW, eds. Current Medical Diagnosis & Treatment 2013. 52nd ed. New York, NY: McGraw-Hill; 2013.

3. Sunderkotter C, Riemekasten G. Pathophysiology and clinical consequences of Raynaud’s phenomenon related to systemic sclerosis.

Rheumatology. 2006;45:33-35.

4. Wu PC, Huang MN, Kuo YM, Hsieh SC, Yu CL. Clinical applicability tissue diseases with Raynaud’s phenomenon. J Formos Med Assoc.

2013;112:482-488.

5. Cutolo M, Sulli A, Pizzorni C, Accardo S. Nailfold videocapillaroscopy assessment of microvascular damage in systemic sclerosis. J Rheumatol.

2000;27:155-160.

6. Klyscz T, Bogenschutz O, Junger M, Rassner G. Microangiopathic changes and functional disorders of nailfold capillaries in dermatomyositis [in German]. Hautarzt. 1996;47:289-293.

7. Candela M, Pansoni A, De Carolis ST, et al. Nailfold capillary microscopy in patients with antiphospholipid syndrome [in Italian]. Recent Prog Med. 1998;89:444-449.

8. Granier F, Vayssairat M, Priollet P, Housset E. Nailfold capillary microscopy in mixed connective tissue disease. Comparison with systemic sclerosis and systemic lupus erythematosus. Arthritis Rheum. 1986;29:189-195.

9. Chikura B, Moore T, Manning J, Vail A, Herrick AL. Thumb involvement in Raynaud’s phenomenon as an indicator of underlying connective tissue disease. J Rheumatol. 2010;37:783-786.

10. Butendieck RR, Murray PM. Raynaud disease. J Hand Surg Am. 2013;39:121-123.

11. Hansen-Dispenza H. Raynaud phenomenon medication. Medscape. http://emedicine.medscape.com/article/331197-medication. Updated November 17, 2015. Accessed December 8, 2016.

12. Amanzi I, Braschi F, Fiori G, et al. Digital ulcers in scleroderma: staging, characteristics and sub-setting through observation of 1614 digital lesions.

Rheumatology (Oxford). 2010;49:1374-1382.

Top, Middle: © Harley Schwadron, 2017. Bottom: © The New Yorker Collection 2017 from cartoonbank.com. All Rights Reserved.

of quantitative nailfold capillaroscopy in differential diagnosis of connective

38 THE CLINICAL ADVISOR • JANUARY 2017 • www.ClinicalAdvisor.com

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CME FEATURED COURSE

■ EDUCATIONAL OBJECTIVES At the conclusion of this activity, participants should be better able to: • Describe pathophysiologic pathways of LDL-C metabolism and targets for pharmacologic therapy • Compare the efficacy and safety of statins, ezetimibe, and PCSK-9 inhibitors in lowering LDL-C • Identify patients who are candidates for intensification of LDL-C therapy, including dosage optimization, improving adherence, and combination regimens • Individualize treatment plans to increase the population of patients achieving LDL-C goals ■ COMPLETE THE POSTTEST: Page 54

Release Date: September 22, 2016 Expiration Date: September 22, 2017 Estimated Time to Complete: 1 hour Accredited Provider: This educational activity is jointly provided

by Postgraduate Institute for Medicine and Consultants in Medical Education (CiME).

Commercial Supporter: This activity is supported by an independent educational grant from Amgen Inc. Program Description: Currently in the US, one-third of all deaths occur as a result of cardiovascular disease (CVD). Despite many clinical studies into hypercholesterolemia and dyslipidemia, only low-density lipoprotein cholesterol (LDL-C) has been definitely established as a robust surrogate parameter for atherosclerotic CVD (ASCVD), and today a low percentage of patients at high risk of ASCVD are attaining the LDL-C goal of at least a 50% reduction recommended by the ACC/AHA, NLA and other national and international guidelines. Supplementary to diet and lifestyle changes, the increasing number of pharmacologic agents available with differing mechanisms of action means that clinicians have a better armamentarium of options to help patients achieve LDL-C goals and have a positive impact on cardiovascular disease risk. This activity uses a combination of casebased and didactic methodologies along with supporting audio insights to assist learners in developing management plans that maximize reduction of both LDL-C, and ASCVD risk, in their patients.

Intended Audience: Primary care physicians and other health care clinicians involved in the treatment of patients with hypercholesterolemia and dyslipidemias Conflict of Interest Disclosure Policy: Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.

Faculty Eliot A. Brinton, MD, FAHA, FNLA Immediate Past-President, American Board of Clinical Lipidology President, Utah Lipid Center Salt Lake City, UT Faculty Disclosure: Dr. Brinton discloses that he has served on the Advisory Board (for scientific information) for Alexion, Amarin, Amgen, Aralez, Kowa, Merck, PTS Diagnostics, Regeneron, and Sanofi. He has served on the Speakers’ Bureau for Alexion, Amarin, Amgen, AstraZeneca, Genzyme, Janssen, Kowa, Merck, Regeneron, Sanofi, and Takeda.

interest related to the content of this activity of any amount during the past 12 months.

CiME manager, Chris Blagden, PhD, hereby states that he or his spouse do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.

Accreditation Statement: This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Postgraduate Institute for Medicine and Consultants in Medical Education (CiME). The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Designation Statement: The Postgraduate Institute for Medicine designates this enduring material for a maximum of 1.00 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Disclosure of Unlabeled Use: This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer: Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

Instructions: There are no fees for participating in and receiving CME credit for this activity. During the period September 22, 2016 through September 22, 2017, participants must: 1) read the learning objectives and faculty disclosures; 2) complete the pre-assessment test; 3) study the educational activity; 4) complete the poll questions; and 5) complete the post-test and submit it online.

A statement of credit will be issued only upon receipt of the above elements and a post-test score of 75% or higher. All components must be completed and submitted online at ClinicalAdvisor.com/Jan17feature.

Jointly provided by

Planner and Manager Disclosures: The following PIM planners and managers, Judi Smelker-Mitchek, RN, BSN, Trace Hutchison, PharmD, Samantha Mattiucci, PharmD, CHCP, and Jan Schultz, MSN, RN, CHCP, hereby state that they or their spouse/life partner do not have any fi nancial relationships or relationships to products or devices with any commercial

CA_CME_1.17_v10_adjusted.indd 40

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CME

FEATURED COURSE: ELIOT A. BRINTON, MD, FAHA, FNLA

Optimizing the management of LDL-C and ASCVD risk Pharmacotherapies for LDL-C lowering with differing mechanisms of action are helping clinicians optimize their patients’ ASCVD risk management plans.

© HENNING DALHOFF / SCIENCE SOURCE

C

Drawing showing the interior of an artery affected by atherosclerosis.

ardiovascular disease (CVD) is the leading cause of death worldwide, accounting for 17.3 million deaths per year with the number expected to increase to more than 23.6 million by 2030. In the US, according to the American Heart Association, approximately 800,000 people died from heart disease, stroke, and other cardiovascular diseases in 2013, accounting for about one-third of all deaths. More than 85 million people in the US are currently living with clinical atherosclerotic CVD (ASCVD).1 Clinical ASCVD is defined as acute coronary syndromes, history of myocardial infarctions (MIs), stable or unstable angina, coronary or other arterial revascularization, stroke or transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin.2 Among all modifiable risk factors for ASCVD, abnormal lipid levels are both highly prevalent and strongly associated with the highest population attributable risk (~50%) for the occurrence of MI worldwide.3 The impact of improved lipid control is unquestioned; a series of studies across the US, Canada, and Europe from 1980 to 2010 have shown that an estimated 19% to 46% of the reduction in coronary heart disease (CHD) mortality during that time period occurred as a result of lowering total cholesterol by both lifestyle changes and statin pharmacotherapy (Table 1).4 Elevated low-density lipoprotein cholesterol (LDL-C) levels, or non–high-density lipoprotein cholesterol (non–HDL-C) levels, as measurable

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CME

FEATURED COURSE

lipid parameters are well-recognized risk factors for the occurrence of ASCVD and have largely replaced total cholesterol in this regard. The Framingham Heart Study showed that both men and women were more than 1.5 times more likely to develop CHD if they had LDL-C >160 mg/dL compared to a control population with LDL-C <130 mg/dL.5 The ARIC (Atherosclerotic Risk in Communities) study demonstrated the risk of a CHD event was increased by roughly 40% for every 39 mg/dL increase in LDL-C.6 As a result, most national and international guidelines include LDL-C or non–HDL-C as primary targets for clinical management due to the presence of atherogenic lipoproteins.2,7-9

of cholesteryl-ester transfer protein, CETP) and gives up triglycerides (TG) via CETP and lipolysis, to form IDL, which undergoes these same processes to form LDL.10,11 Circulating VLDL, IDL, and LDL are removed from the bloodstream in 3 ways:

Cholesterol transport and the pathophysiology of ASCVD

Diffusion of lipoproteins across the vascular endothelium into the arterial wall is a passive, gradient-driven process, and the rate increases as the circulating levels of LDL-C increase.11 Once they reach the subendothelial space (or subendothelium, SE), lipoprotein particles are bound to an extracellular matrix of proteoglycans, which greatly prolongs their retention there. Most lipoprotein oxidation takes place in the SE and it is oxidized LDL and related lipoproteins that are primary drivers of inflammation and macrophage activation, which in turn promotes foam-cell formation and drives injury to the overlying endothelium and cells in the SE. Through these mechanisms, persistent elevations of plasma levels

Cholesterol is transported around the body by 5 major types of lipoproteins: chylomicrons (CMs), very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), LDL, and HDL. The critical organ for cholesterol metabolism and regulation is the liver; cholesterol synthesis occurs there and the portion of cholesterol in the intestinal lumen that is absorbed from the gut also passes through it (Figure 1). The liver assembles VLDL from cholesterol—mainly cholesteryl ester (CE)—phospholipids, triglycerides, and apolipoproteins (apo B-100 and others).

Once in the plasma, VLDL receives more CE (via action

• Hepatic uptake via the LDL-receptor (LDL-R) and related receptors • Uptake by various body organs for use or storage of core lipid (also via the LDL-R but constituting only a minor pathway) • Entry into the arterial wall through the endothelium

TABLE 1. Attributable reduction in CHD mortality risk from total cholesterol via statin treatment and other causes, such as dietary and exercise interventions, in different developed countries (adapted from [4]) Attributable risk reduction (%) Study

Statin therapy

Other causes

Total risk

Ford 2007

8.5

24.2

32.7

Bjorck 2009

6.2

39.5

45.7

Wijeysundera 2010

15.4

22.8

38.2

Aspelund 2010

0.5

32.0

32.5

Palmieri 2010

6.4

23.4

29.8

Flores-Mateo 2011

5.6

31.1

36.7

Bandosz 2012

3.4

39.0

42.4

Bajekal 2012

13.9

5.5

19.4

Hughes 2013

8.7

25.8

34.5

Hotchkiss 2014

13.3

8.9

22.2

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of atherogenic particles (mainly LDL, IDL, and VLDL) cause early-stage fatty streaks that may then progress to become lipid-rich atherosclerotic plaques.12,13 The next section will discuss practical assessment of ASCVD risk based on LDL-C levels and other clinical parameters.

PATIENT CHALLENGE 1

Which of the following patients would benefit from LDL-C– lowering therapy, based on current evidence and guidelines?

A. A 48-year-old Hispanic man released from the hospital following a stroke, current LDL-C = 90 mg/dL B. A 65-year-old White woman, a cigarette smoker with no personal or family history of ASCVD, BP = 121/81, LDL-C = 140 mg/dL, HDL-C = 56 mg/dL, TG = 125 mg/dL, TC = 221 mg/dL, no diabetes C. An 82-year-old Black man, post-MI, with type 2 diabetes (T2DM) and stage 2 chronic kidney disease, current BP = 155/110, LDL-C = 165 mg/dL

a. All 3 patients meet guideline recommendations for LDL-C– lowering therapy b. Only patient A c. Patients A and C d. Patients B and C e. None of the patients meet guideline recommendations for LDL-C–lowering therapy

Determining ASCVD risk in primary care patients

LDL-C lowering is associated with improving clinical outcomes, both in patients with clinical ASCVD (secondary prevention) and for primary prevention in patients without ASCVD. Data from the IMPROVE-IT study showed a further ASCVD risk reduction with LDL-C– lowering from 69 to 53 mg/dL.14 Based on the associated risk of elevated LDL-C and the proven clinical efficacy of treatment, antihyperlipidemic therapy is recommended to lower LDL-C levels in both primary and secondary

FIGURE 1. Cholesterol transport and atherosclerosis Adapted from Goldstein JL, Brown MS. Science. 2001;292:1310-1312.

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prevention, with the LDL-C goal and treatment intensity dependent on the degree of underlying ASCVD risk.2,7 Assessing ASCVD risk can be challenging, as many factors interconnect to influence any particular patient’s risk of heart disease. In 2013, the American Heart Association (AHA) and American College of Cardiology (ACC) revised their risk stratification approach to a drug treatment-based evaluation in conjunction with a calculator to estimate any patient’s 10-year risk for primary prevention purposes (available at http://tools.acc.org/ASCVD-RiskEstimator/). Although somewhat controversial, this risk estimator is very useful in that it: • Provides race-specific risk for individuals of African descent • Adds stroke to coronary heart disease risk (total ASCVD risk being about 50% higher than coronary risk alone) • Utilizes lifetime risk in addition to the standard 10-year risk Although contemporary to the risk estimator, the 2013 cholesterol guidelines from the ACC/AHA were much more controversial. These guidelines were created using a novel approach to evidence inclusion and exclusion. The writing panel was allowed to review only the very highest-quality evidence: the results for the primary question of top-quality randomized clinical trials. All other evidence—including subgroup analyses from the top-quality trials, results from lesser-quality randomized trials, observational data, mechanistic data, and expert opinion—was excluded from deliberations and was used only when absolutely necessary, such as in the absence of any other applicable data. This unusual evidence exclusion process resulted in the exclusion of the evidence on which lipid goals had always been based. Having excluded that evidence, no such evidence

could be found and so no recommendation regarding goals could be given. This unprecedented approach resulted in an implied repudiation of the centerpiece of US cholesterol guidelines for the prior 25 years, lipid goals. The exclusion of goals caused much confusion on the part of primary care providers, who did not understand the rationale for the change and were left without clear guidance for follow-up of lipid therapy.

The guidelines appropriately identified four “statin-benefit groups”: prior ASCVD (≤75 y/o), LDL-C ≥190 mg/dL, diabetes mellitus (40 to 75 y/o), and a 10-year ASCVD risk ≥7.5%.2 They also correctly focused on higher doses of higher-efficacy statins (“high- or moderate-intensity” statin treatment) as noted in Table 2. And they correctly recommended regular follow-up LDL-C level measurements, but they omitted any specific recommendations regarding what the on-treatment levels should be.2 Since there is a wide range of LDL-C levels seen with a given dose of a given statin,15,16 and since lower on-treatment LDL-C associates with lower on-treatment risk of ASCVD,15 it was unfortunate that lipid goals, central to all prior lipid guidelines worldwide, were removed in the 2013 ACC/ AHA guidelines. This abandonment of on-treatment LDL-C goals was rejected by most US-based lipidologists and indeed by lipidologists worldwide.17–19 In light of this controversy it is fortunate that, despite common perception, the 2013 ACC/AHA cholesterol guidelines are not the official US lipid guidelines. Although the data collection and review process was sponsored by the National Heart, Lung, and Blood Institute, they disassociated themselves from the guideline process near its end, and instead requested that the document be published as an “evidentiary review,” which was supposed to serve as the basis of a later consensus guideline writing process to be

TABLE 2. AHA/ACC recommendations for statin therapy (adapted from [2]) High-intensity statin therapy should be initiated in patients who are:

Moderate-intensity statin therapy should be initiated in patients who are:

• Between 21 and 75 years of age with clinical ASCVD

• Older than 75 years of age with clinical ASCVD

• 21 years of age or older with LDL-C ≥190 mg/dL

• Between 40 and 75 years of age with no ASCVD but have diabetes and LDL-C 70–189 mg/dL with <7.5% 10-year ASCVD risk

• Between

40 and 75 years of age with no ASCVD but who have diabetes and LDL-C 70–189 mg/dL with ≥7.5% 10-year ASCVD risk

• B etween 40 and 75 years of age with no ASCVD, no diabetes, but who have LDL-C 70–189 mg/dL with ≥7.5% 10-year ASCVD risk

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led by the ACC and AHA.20 Instead, the ACC and AHA published the review the very next month as a guideline, without going through any further guideline development.

Shortly after the release of the 2013 ACC/AHA cholesterol guidelines, the International Atherosclerosis Society released goal-based guidelines and soon thereafter the Joint British Societies and the National Lipid Association (NLA) did the same.7,21,22 All of these continued in the tradition of having treatment goals for LDL-C and/or non–HDL-C. The NLA directly built on the framework established previously by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) Guidelines.7,23 Not only was the NLA risk assessment similar (very high, high, moderate, or low risk depending on certain risk factors), but also treatment thresholds and goals were similar, again based on LDL-C and non–HDL-C levels (Tables 3 and 4).7,23

Both the 2013 ACC/AHA guidelines and the 2014 NLA recommendations focus on patient-centered decision-making, regardless of risk assignment, meaning that clinicians discuss the pros and cons of LDL-C– lowering therapy with patients where it may be beneficial.2,7 Assignment of patients to specific ASCVD risk categories differs between the ACC/AHA guidelines and the NLA recommendations as noted above. The pool of patients recommended for statin treatment expanded notably in the ACC/AHA guidelines, particularly among the elderly, due to ASCVD risk being driven by increased age, although only 25% of primary care practices had adopted these particular guidelines for many of their patients, according to a 2015 survey.24,25 Despite all this, significant therapeutic inertia exists currently in the US with regard to both primary and secondary prevention of ASCVD using LDL-C–lowering therapy:

TABLE 3. NLA risk assignment algorithm for ASCVD. GFR = glomerular filtration rate (adapted from [7]) STEP 1: Identify patients at high risk or very high risk • Very high risk — Clinical ASCVD — Diabetes plus ≥2 other major ASCVD risk factors or end organ damage • High risk — Diabetes plus 0/1 other major ASCVD risk factors — Chronic kidney disease stage ≥3B (GFR ≤44 mL/min/1.73m2) — LDL-C ≥190 mg/dL STEP 2: Count major ASCVD risk factors • If 0/1 major risk factors, assign to low-risk category • If ≥3 major risk factors, assign to high-risk category STEP 3: If 2 major risk factors, consider risk scoring* or additional testing to make individual patient determination • If risk scoring* reaches threshold for high risk, assign to high-risk category • If ≥1 of the following risk indicators are present, assign to high-risk category: — Severe level of a major ASCVD risk factor (eg, high-quantity smoker, multiple first-degree relatives with premature CHD) — LDL-C ≥160 mg/dL or non–HDL-C ≥190 mg/dL — High-sensitivity C-reactive protein ≥2.0 mg/L — Urine albumin/creatinine ratio ≥30 mg/g — Lipoprotein(a) ≥50 mg/dL — Other indicators of subclinical disease, such as coronary artery calcium ≥300 Agatston units • Based on above steps, if no underlying reason exists to warrant high-risk category, assign to moderate-level category * R isk scoring can be performed using any available risk calculator, but clinicians should be aware that such calculators vary in their outputs, clinical factors used to make risk predictions, and time frame associated with that risk. Adapted from [7].

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• Among almost 1.13 million patients in US cardiovascular practices included in the National Cardiovascular Data Registry Practice Innovation and Clinical Excellence registry, less than 70% of statin-eligible patients (as defined by the ACC/AHA 2013 guidelines) were actually on statin therapy26 • In a study evaluating almost 28,000 patients with CHD or a CHD risk equivalent, more than half of patients remained on their initial statin monotherapy dosage regimen despite only 72% achieving an LDL-C <100 mg/dL and only 24% achieving an LDL-C <70 mg/dL27 • Among Medicare patients who were given a prescription for a high-intensity statin after hospital discharge for a CHD event, only 27% of patients filled the initial prescription and only 11.5% of those whose first postdischarge prescription was for a low- or moderate-intensity statin filled a high-intensity statin prescription within the first year after discharge28 • The net number of patients taking statins in the US does not appear to have increased since the publication of the 2013 ACC/AHA guidelines29 These data suggest that many patients who should be taking LDL-C–lowering therapy are either not doing so TABLE 4. Major risk factors associated with the NLA patient-centered ASCVD risk assessment algorithm described in Table 3 (adapted from [7]) Major risk factors for ASCVD • Age — Men ≥45 years — Women ≥55 years • Family history of premature MI, coronary death, or coronary revascularization procedure — <55 years of age in a first-degree male relative, or <65 years of age in a first-degree female relative • Cigarette smoker • Hypertension — Untreated ≥140/≥90 mm Hg — Controlled on antihypertensive pharmacologic therapy • Low HDL-C — Men <40 mg/dL — Women <50 mg/dL

at all, or are taking statins at a lower-than-recommended intensity. In either case, they are falling short of their potential therapeutic benefit. As such, achieving effective LDL-C lowering is still a challenge in primary care.

The next section will discuss approaches to attaining LDL-C goals.

PATIENT CHALLENGE 2

Which of the following patients would be a candidate for high-intensity statin therapy based on the 2013 ACC/AHA guidelines?

A. A 48-year-old Hispanic man released from the hospital following a stroke, current LDL-C = 90 mg/dL B. A 65-year-old White woman, a cigarette smoker with no personal or family history of ASCVD, BP = 121/81, LDL-C = 140 mg/dL, HDL-C = 56 mg/dL, TG = 125 mg/dL, TC = 221 mg/dL, no diabetes C. An 82-year-old Black man, post-MI, with T2DM and stage 2 chronic kidney disease, current BP = 155/110, LDL-C = 165 mg/dL a. All 3 patients are candidates for high-intensity statin therapy b. Only patient A c. Patients A and C d. Patients B and C e. None of the patients are candidates for high-intensity statin therapy PATIENT CHALLENGE 2 EXPLANATION

Only patient A is a candidate for high-intensity statin therapy, due to a diagnosis of clinical ASCVD. Patient B does not have sufficiently high LDL-C to meet guideline criteria; using the online risk calculator patient B also has a 10-year risk of 9.6%, greater than the recommended 7.5% threshold, but does not have diabetes, which would make her a candidate for moderate-intensity statin therapy only. Patient C is older than 75 years, and therefore does not meet criteria for high-intensity therapy.

PATIENT CHALLENGE 3

Which of the following patients has an LDL-C goal <70 mg/ dL according to the 2014 NLA lipid recommendations?

A. A 48-year-old Hispanic man released from the hospital following a stroke, current LDL-C = 90 mg/dL B. A 65-year-old White woman, a cigarette smoker with no personal or family history of ASCVD, BP = 121/81, LDL-C = 140 mg/dL, HDL-C = 56 mg/dL, TG = 125 mg/dL, TC = 221 mg/dL, no diabetes

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C. An 82-year-old Black man, post-MI, with T2DM and stage 2 chronic kidney disease, current BP = 155/110, LDL-C = 165 mg/dL a. All 3 patients have an LDL-C goal <70 mg/dL b. Only patient A c. Patients A and C d. Patients B and C e. None of these patients have an LDL-C goal <70 mg/dL PATIENT CHALLENGE 3 EXPLANATION

According to the NLA risk assessment algorithm, patients B and C are at “high” risk, and therefore both have LDL-C goals of <100mg/dL. Patient A is the only one at “very high” risk by NLA recommendations, with a recommended target LDL-C goal of <70mg/dL. Getting LDL-C to goal in patients with first-line therapy: LDL-C–lowering strategies and target goals

Three basic approaches exist to reduce the circulating concentrations of LDL-C [reviewed in (4)]. First, all commonly used treatments work by upregulation of hepatic LDL-receptors. In the past, this was done almost entirely by depleting the liver of cholesterol, which provides a strong signal for upregulation of LDL-receptor synthesis. Statins deplete hepatic cholesterol by blocking cholesterol synthesis.

The cholesterol-absorption-inhibitor class, consisting solely of ezetimibe, does this by blocking cholesterol absorption (mainly reabsorption of biliary cholesterol, less so absorption of dietary cholesterol) in the intestine. The bile-acid sequestrants (such as colesevelam) do this by blocking bileacid reabsorption in the intestine, which depletes hepatic

cholesterol by requiring that more cholesterol be used for more bile-acid synthesis. A newly available way of upregulating hepatic LDL receptors is to block their destruction by proprotein convertase subtilisin/kexin type 9 (PCSK9), a recently discovered hepatic protein that promotes LDL receptor destruction within hepatocytes. Monoclonal antibodies against PCSK9 have been recently approved, and they are the only LDL receptor-mediated treatments more effective in LDL lowering than the statins. The second general mechanism, uncommonly to rarely used, is to reduce hepatic production of VLDL, which is the substrate for LDL production in the plasma. Niacin probably exerts its modest LDL-lowering effect via this mechanism, and the 2 medications indicated solely for homozygous familial hypercholesterolemia (FH), lomitapide and mipomersen, work by blocking the hepatic assembly of VLDL or the synthesis of apo B-100, respectively. A third mechanism, rarely used, is to remove LDL via extracorporeal circulation of plasma through columns that trap LDL, called LDL apheresis.

The NLA recommendations list LDL-C levels above which to consider pharmacologic therapy (“treatment thresholds”), along with treatment goals, linked to the risk classification described in the previous section. In addition, guidance regarding the sequence of diet and lifestyle treatment versus medical therapy is given (Table 5).

Nonpharmacologic interventions

Dietary and lifestyle interventions remain a critical component of first-line interventions for patients at any level of ASCVD risk. The NLA recommends a tiered approach to the application of lifestyle therapies7:

TABLE 5. NLA recommendations for initiating LDL-C–lowering pharmacotherapy, treatment targets, and when to begin lifestyle therapies in relation to pharmacologics (adapted from [7]) Consider initiating pharmacologic therapy

Treatment goal

LDL-C mg/dL

LDL-C mg/dL

Initiate lifestyle therapies

Low

≥160

<100

First

Moderate

≥130

<100

First

High

≥100

<100

First or concurrently

Very high

≥70

<70

Concurrently

Risk category

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• For patients at low to moderate risk, lifestyle therapies should be given an adequate therapeutic trial prior to initiation of pharmacologic therapy; the recommended length of trial is at least 3 months • For patients at very high risk, pharmacologic therapy may be started concurrently with lifestyle therapies • For patients at high risk, clinicians should use their judgment as to whether initiating lifestyle therapies alone will be sufficient to attain goals; this judgment may be affected by the presence of a high-risk condition such as diabetes, where it is unlikely that patients will attain goals without concurrent pharmacotherapy In any case, balance is needed between under- and over-reliance on diet and lifestyle. These must never be skipped but often they are insufficient, in which case long postponement of medical treatment is inappropriate. Recommended lifestyle interventions are listed in Table 6. Patients with metabolic syndrome or those who are overweight or obese have a high potential to benefit from lifestyle therapies. Overall, improvements in diet and exercise have been shown to lower LDL-C by anywhere from 10% to 15%.30 Where appropriate, clinicians should consider referral or coordinated care with a registered dietitian to develop culinary plans and goals and a physical therapist for guided and safe levels of exercise tailored to the individual patient.

Statin therapy as first-line LDL-C–lowering pharmacotherapy

Statin therapy is recommended by all major guidelines as the standard of care for first-line therapy in LDL-C reduction. In the ACC/AHA guidelines, no specific treatment targets are provided for clinicians, but anticipated therapeutic responses to high- and moderate-intensity statin therapy are mentioned.

As noted above, this approach is a marked departure from NCEP ATP III and all other major lipid guidelines.2,23 Aggressive LDL-C lowering is a universal recommendation of all guidelines, with a 50% reduction being desired in higher-risk patients. Decreasing LDL-C levels to <40 mg/dL are linearly related to decreasing ASCVD risk,15 and cost-benefit analyses suggest that treating even patients with ≥3.0% 10-year ASCVD risk (instead of the ACC/AHA’s recommended ≥7.5%) might be cost-effective, if using inexpensive generic medications.32 Central to the statin treatment is the concept of using the maximally tolerated statin dose, if needed, before going to non-statin treatments.

In patients with a prior history of statin intolerance or with

concerns about statin safety, a “start-low go-slow” approach is desirable, and choice of dosing regimen and LDL-C– lowering goals must always consider patient preference.

The cost of statins is now no longer an issue since all but one statin has gone generic. Moderate- and high-intensity statin regimens are presented in Table 7.

Clinicians should be aware of several precautions and contraindications to statin use2,7: • A history of previous statin intolerance or muscle disorders (always a contraindication if a true allergy, but also very concerning if the patient has had rhabdomyolysis with any statin) • Impaired renal or hepatic function • A history of hemorrhagic stroke (precaution) • Age >75 years (precaution, use half of typical dose) • Concomitant use of drugs that affect statin metabolism Medications that can affect statin metabolism include azole antifungal agents, cimetidine, macrolide antibiotics (eg, clarithromycin, erythromycin), and cyclosporine. All but fluvastatin interact adversely with gemfibrozil and there are mild adverse interactions of all with fenofibrate. Fluvastatin has little or no adverse interaction with cyclosporine. All but pitavastatin can interact adversely with HIV protease inhibitors. Pravastatin and pitavastatin tend to have the fewest overall adverse interactions. Pravastatin and pitavastatin are also the only two that do not appear to increase risk of new-onset diabetes, especially in the prediabetic, insulin-resistant, or metabolic syndrome patient.33 Clinicians should be vigilant for treatment-emergent adverse events, TABLE 6. Lifestyle therapies for LDL-C lowering.

DASH = Dietary Approaches to Stop Hypertension (adapted from [4], [7], and [31]) Intervention • Diet — Should be low in saturated fats (<7% of caloric intake) — Recommended DASH diet, Mediterranean diet, or equivalent • Physical activity — ≥150 minutes per week of moderate- to high-intensity exercise • Weight loss — 5% to 10% of body weight for patients who are overweight or obese

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particularly fall risk and other issues that specifically affect older patients. Effective communication about risks with patients is critical to avoid therapy discontinuation without clinical consultation. Ongoing lipid profile monitoring for patients who have attained LDL-C goals is recommended every 4 to 12 months to ensure maintenance of patient adherence to chronic disease therapy and continued target LDL-C levels.7 The next section discusses strategies for patients with inadequate LDL-C control or those who may be unable to take statin therapy.

PATIENT CHALLENGE 4

A 48-year-old man is released from the hospital following an atherothrombotic stroke with an LDL-C of 160 mg/dL. His discharge prescription is for rosuvastatin 20 mg/day. At a 3-month follow-up visit with primary care, his LDL-C is now 120 mg/dL and he has only 5 doses remaining from 3 months of treatment.

The primary care physician decides to increase the rosuvastatin dose to 40 mg/day.

What is your opinion regarding this clinical decision?

• Strongly disagree—LDL-C levels are meaningless once a patient is on a statin.

• Disagree—there is no point in uptitrating or adding any LDLlowering medication because the patient is already on high-intensity therapy.

• Agree—but adding ezetimibe is likely to be more effective for LDL-C lowering as it has good evidence for reducing ASCVD when added to a statin, and might reduce the risk of statin intolerance.

• Strongly agree—this is clearly the best approach; no other medication class lowers ASCVD events.

TABLE 7. Sample dosages of daily statin therapy (data taken from [7]) High-intensity statin therapy LDL-C reduction ≥50%

Moderate-intensity statin therapy LDL-C reduction 30%–50%

Atorvastatin 40–80 mg

Atorvastatin 10–20 mg

Rosuvastatin 20–40 mg

Rosuvastatin 5–10 mg Simvastatin 20-40 mg Pravastatin 40–80 mg Pitavastatin 2–4 mg

PATIENT CHALLENGE 5

Following an additional 3 months of LDL-C–lowering therapy that has included both lifestyle therapies and 40-mg/day rosuvastatin, our patient returns to the primary care office with an LDL-C of 100 mg/dL. He reports no adverse effects from the increased dose and brings in his medications to confirm good adherence to therapy. A carotid ultrasound and angiogram show diffuse atherosclerotic plaque, although no high-grade stenosis. What is the best next step? a. Make no changes to the regimen and observe for an additional 3 months b. Switch to another statin c. Add ezetimibe d. Add a PCSK9 inhibitor PATIENT CHALLENGES 4 AND 5 EXPLANATION

The patient’s rosuvastatin dose is already maximal; 80 mg was investigated but never approved, and replacing with another statin is unlikely to improve LDL-C lowering.

Ezetimibe’s mechanism of action is complementary to that of statins, and it has evidence for both LDL-C lowering and ASCVD risk reduction. Although a prior trial of ezetimibe is not required in the label for either PCSK9 inhibitor, ezetimibe has a more robust evidence base and history along with fewer side effects. It is usually best in most patients to add ezetimibe before considering a PCSK9 inhibitor.

PATIENT CHALLENGE 6

Six months after his last visit, our patient is on rosuvastatin 40 mg/day and ezetimibe 10 mg/day, and his LDL-C has increased to 110 mg/dL, verified by retesting. The patient is convincing in his claims of nearly 100% medication compliance. His blood pressure remains well controlled and his fasting glucose is 81 mg/dL. To attempt to further reduce LDL-C and minimize his risk of another ASCVD event, what is the best choice now? a. Recheck the patient’s compliance, continue the current regimen, and don’t worry further. b. Switch to another statin. c. Add a bile-acid sequestrant and continue his other meds. d. Add a PCSK9 inhibitor and continue his other meds. e. Add a PCSK9 inhibitor, after which you will be able to discontinue his statin.

PATIENT CHALLENGE 6 EXPLANATION

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of <70 mg/dL; therefore options A and B, while possible, are not preferred. Adding a bile-acid sequestrant is a reasonable option, but the average LDL-C lowering is only 10% to 15%, which is very unlikely to bring him below the goal of 70 mg/dL. Further, a trial of bile-acid sequestrant treatment is rarely considered required before the addition of PCSK9 inhibitor therapy, which has potential for better LDL-C lowering and ASCVD risk reduction. Since the patient appears not to have responded adequately to ezetimibe, its discontinuation might be considered in this case. However, clinicians must resist the temptation to discontinue a statin, since statins are far better proven to reduce ASCVD risk in long-term use and they are far more cost-effective than PCSK9 inhibitors.

Optimizing pharmacotherapy in patients with inadequate LDL-C control

Despite the recommendation for aggressive lipid lowering in patients at risk, a large proportion of patients do not achieve

adequate LDL-C lowering with statin therapy, even when high-intensity statin therapy is employed. For example, in a study of high-risk patients, only 79% of patients who were switched to high-intensity therapy (rosuvastatin 20 mg/day) achieved an LDL-C concentration of <100 mg/ dL and only 37% achieved an LDL-C concentration of <70 mg/dL.34 In another study involving a large number of patients from an academic practice of family and internal medicine physicians, only 43% of high-risk patients met their LDL-C goals, despite aggressive therapy.35 There are numerous reasons for the lack of adequate LDL-C lowering with statins. Rarely, patients may have resistance to statins that is caused by the presence of genetic polymorphisms in the gene(s) responsible for lipid transport.36 A major barrier to treatment outcomes is nonadherence to therapy. Nonadherence may result from adverse events or from concerns from internet searches or comments from friends or family, increasing a patient’s reluctance to continue therapy.37 Clinicians must carefully and

FIGURE 2. Pharmacologic LDL-C—lowering strategies Adapted from Goldstein JL, Brown MS. Science. 2001;292:1310-1312; Wadhera RK, et al.

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empathetically listen to patient complaints and concerns and then work with the patient to maximize adherence to the optimal regimen.

Clinicians should work to ensure that each patient’s statin regimen either is sufficient to bring the patient to LDL-C goal or is increased to maximally tolerated dosage. At that point, ezetimibe or other treatments should be considered if the patient’s LDL-C is still above goal.7 Beyond dose increases, a switch to another statin may often be beneficial or clinicians may consider the addition of another agent of a different class that may work cooperatively with statins to reduce LDL-C levels further.7 As illustrated in Figure 2, additional FDA-approved LDL-lowering agents are available that have the potential to work cooperatively with statins to improve lipid control.

When dealing with nonadherent patients, patients with apparent significant statin intolerance, patients with progressive atherosclerosis despite statin plus ezetimibe therapy, or patients remaining well above LDL-C goal despite statin plus ezetimibe therapy, a primary provider may need to consider referral to a lipidologist.

Lipidologists need not have been trained formally in Lipidology (few such fellowships exist) and are as often in Family Medicine or general Internal Medicine as they are in Cardiology or Endocrinology. Indeed, not all endocrinologists are truly lipidologists, and most cardiologists are not lipidologists either. A lipidologist is someone who has sought extra knowledge in lipid management and who is competent and confident in both ASCVD risk assessment (by risk scoring and advanced lipid testing, as needed) and in treatment of dyslipidemia. A primary care provider may either refer difficult patients to a lipidologist or may choose to become a lipidologist, at least for certain types of advanced lipid cases.

Ezetimibe

Ezetimibe inhibits the function of the NPC1L1 cholesterol transporter protein, which moves cholesterol from the intestinal lumen into the luminal epithelium.

Ezetimibe can reduce the net absorption of cholesterol by about 50% (Figure 2). Ezetimibe was approved to reduce LDL-C, either alone or in combination with a statin,38 and in the IMPROVE-IT study was shown to decrease ASCVD when added to statin monotherapy.14 When ezetimibe was started soon after an acute coronary syndrome, patients with an LDL-C averaging 69 mg/dL on statin monotherapy achieved an LDL-C averaging 53 mg/dL (a further 24% decrease) with the addition of 10

mg/day ezetimibe. This was associated with a decrease in the relative risk of ASCVD (primary composite endpoint of CV death, major coronary events, or nonfatal stroke) at 7 years by 6.4% over statin therapy alone. Ezetimibe is the first LDL-C–lowering therapy to demonstrate improvements in ASCVD outcomes in patients well controlled on statin therapy, and these studies have suggested that LDL-C lowering as a clinical goal, not statin therapy per se, is the critical metric that results in improved ASCVD outcomes.

These findings have also suggested that the ASCVD risk reduction per mg/dL LDL-C reduction of ezetimibe is similar to that of statins.4,14 Although ezetimibe was not officially FDA approved for ASCVD, likely because the risk reduction in IMPROVE-IT was modest, learners should note there was no benefit during the first year post-ACS, but the risk reduction was 10% afterward. Also, clinicians should understand that the relationship between ASCVD and percent LDL-C lowering is curvilinear, and so it is likely (although not absolutely proven) that if ezetimibe were added to patients with LDL-C elevation residual after statin monotherapy, say in the 100 to 160 mg/dL range instead of the <70 mg/dL range in the IMPROVE-IT study, that the ASCVD risk reduction would be far better and more clinically robust.

PCSK9 inhibitors

PCSK9 is a circulating enzyme that binds to hepatic cell surface LDL receptors. It does not interfere with the interaction between LDL and its receptor, but prevents their dissociation after internalization into the hepatocyte, thus causing lysosomal degradation of the LDL receptor along with LDL itself. This greatly reduces LDL-receptor activity since LDL receptors ordinarily make an average of 150 trips when not degraded by PCSK9.4 Two inhibitors of PCSK9 have been recently FDA approved. Both are monoclonal antibodies that block PCSK9 binding to the LDL receptor, thus preserving it and allowing it to remove more LDL particles from the bloodstream (Figure 2).4 The 2 PSCK9 inhibitors, alirocumab and evolocumab, are given by subcutaneous injection using autoinjector pens and have shown roughly comparable efficacy at reducing LDL-C by 40% to 60% (no head-to-head data exist yet) at 12 weeks when added to a statin. Their FDA-approved indication is for patients with clinical ASCVD or heterozygous FH who require additional LDL-C lowering despite maximally tolerated statin therapy. Alirocumab comes in a half-dose strength (75 mg) as well as a full-dose 150-mg size, both in identical pens and for administration every 2

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weeks. Evolocumab also comes in 2 doses, a 140-mg pen for injection every 2 weeks and a new 420-mg autoinjector for use every month. Evolocumab is the only one of the two with study data and an indication for use in homozygous FH. Although definitive evidence for ASCVD reduction is lacking, phase 3 data with both medications suggest ASCVD risk reduction: • ODYSSEY LONG TERM assessed alirocumab in highASCVD-risk patients on statin therapy; after 78 weeks, the incidence of major CV events was reduced by 48% in the alirocumab study arm over statin therapy alone39 • OSLER I and II evaluated the efficacy and safety of evolocumab when added to standard-of-care therapy; over a maximum of a 1-year exploratory analysis, the incidence of major CV events was reduced by 53% in the evolocumab study arm over standard of care alone40

• High-intensity statin therapy typically reduces LDL-C by ~50%; moderate-intensity therapy reduces LDL-C by 30% to 50%.

• For patients unable to attain sufficient LDL-C lowering with maximally tolerated statin therapy, ezetimibe and PCSK9 inhibitors are efficacious options at lowering LDL-C and have evidence supporting their ability to reduce ASCVD risk. n References 1. Mozaffarian D, Benjamin EJ, Go AS, et al. Hear t disease and stroke statistics--2015 update: a repor t from the American Hear t Association.

Circulation. 2015;131:e29-322.

2. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63 (25 Pt B):2889-934.

Both of these agents have long-term cardiovascular outcome trials in progress that will assess the impact of treatment on CV outcomes in patients with established clinical ASCVD well controlled on statins and that will conclude in 2017. Both agents are well tolerated; major adverse events for clinicians to be aware of are nasal stuffiness, injection-site reactions, and flu-like symptoms, but neurocognitive events are not increased.39,40 Patient adherence to oral chronic disease therapy is usually low regardless of disease state, and the fact that both PCSK9 inhibitors come with adherence reminder systems holds the possibility, as yet not documented, of improving adherence to therapy (and therefore patient outcomes) compared with other lipid treatments.

3. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364: 937–952.

4. Wadhera RK, Steen DL, Khan I, Giugliano RK, Foody JM. A review of low-density lipoprotein cholesterol, treatment trategies, and its impact on cardiovascular disease morbidity and mor tality. J Clin Lipidol.

2016;10:472-489.

5. Wilson PW, D’Agostino RB, Levy D, et al. Prediction of coronary hear t disease using risk factor categories. Circulation.

1998;97:1837–1847.

6. Sharrett AR, Ballantyne CM, Coady SA, et al. Coronary hear t disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions:the Atherosclerosis Risk in Communities (ARIC) study.

Circulation. 2001;104:1108–1113.

Summary and clinical takeaways

7. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association

• There is a linear risk reduction with LDL-C– lowering therapy and ASCVD risk down to LDL-C levels <40 mg/dL. • Dietary and lifestyle interventions remain a critical component of first-line interventions for patients at any level of ASCVD risk.

• Statins, ezetimibe, and PCSK9 inhibitors have all demonstrated efficacy at LDL-C lowering in individuals with ASCVD risk; these agents all act by upregulation of LDL-receptor activity, albeit at different points in the cholesterol metabolism pathways.

• Statin therapy is recommended by all major guidelines as the standard of care for first-line therapy in LDL-C reduction.

recommendations for patient-centered management of dyslipidemia: par t 1-executive summary. J Clin Lipidol. 2014;8:473–488.

8. Catapano AL, Reiner Z, De Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis. 2011;217 (Suppl 1):S1–S44.

9. Exper t Dyslipidemia Panel of the International Atherosclerosis Society Panel members. an International Atherosclerosis Society position paper: global recommendations for the management of dyslipidemia—full repor t. J Clin Lipidol. 2014;8:29–60.

10. Feingold KR, Grunfeld C. Introduction to lipids and lipoproteins.

In: De Groot LJ, Beck-Peccoz P, Chrousos G, et al, eds. Endotext.

South Dar tmouth, MA: MDText.com, Inc; 2000.

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11. Weissberg PL, Rudd JH. Textbook of Cardiovascular Medicine. 2nd ed.

25. Jame S, et al. The new lipid guidelines: what do primary care

Philadelphia, PA: Lippincott Williams & Wilkins; 2002:3-14.

clinicians think? Am J Med. 2015;128:914.e5-914.e10

12. Ross R. Atherosclerosis is an inflammatory disease. Am Heart J.

26. Maddox TM, Borden WB, Tang F, et al. Implications of the

1999;138:S419–S420.

2013 ACC/AHA cholesterol guidelines for adults in contemporary

13. Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque

cardiovascular practice: insights from the NCDR PINNACLE registry.

formation and rupture. Circ Res. 2014;114:1852–1866.

J Am Coll Cardiol. 2014;64:2183-92.

14. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added

27. Toth PP, Foody JM, Tomassini JE, et al. Therapeutic practice

to statin therapy after acute coronary syndromes. N Engl J Med.

patterns related to statin potency and ezetimibe/simvastatin

2015;372:2387–2397.

combination therapies in lowering LDL-C in patients with

15. Wiviott SD, Cannon CP, Morrow DA, et al. Can low-density

high-risk cardiovascular disease. J Clin Lipidol. 2014;8:107–16.

lipoprotein be too low? The safety and efficacy of achieving very

28. Rosenson RS, Kent ST, Brown TM, et al. Underutilization of

low low-density lipoprotein with intensive statin therapy:

high-intensity statin therapy after hospitalization for coronary hear t

a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol. 2005; 46:1411-6.

disease. J Am Coll Cardiol. 2015;65:270-7.

16. Boekholdt SM, Hovingh GK, Mora S, et al. Very low levels

29. Tran JN, Kao TC, Caglar T, et al. Impact of the 2013

of atherogenic lipoproteins and the risk for cardiovascular events:

Cholesterol Guideline on patterns of lipid-lowering treatment

a meta-analysis of statin trials. J Am Coll Cardiol. 2014;64:485-94.

in patients with atherosclerotic cardiovascular disease or

17. Ray KK, Kastelein JJ, Boekholdt SM, et al. The ACC/AHA 2013

diabetes after 1 year. J Manag Care Spec Pharm. 2016; 22:901-8.

guideline on the treatment of blood cholesterol to reduce atheroscle-

30. Scirica BM, Cannon CP. Treatment of elevated cholesterol.

rotic cardiovascular disease risk in adults: the good the bad and the

Circulation. 2005;111:e360–e363.

uncer tain: a comparison with ESC/EAS guidelines for the management

31. Champagne CM. Dietary interventions on blood pressure: the

of dyslipidaemias 2011. Eur Heart J. 2014;35:960-8.

Dietary Approaches to Stop Hyper tension (DASH) trials. Nutr Rev.

18. Civeira F, Ascaso J, Masana L. Should we forget about low-density

2006;64:S53-6.

lipoprotein cholesterol? J Am Coll Cardiol. 2014;63:1228-9.

32. Pandya A, Sy S, Cho S, et al. Cost-effectiveness of 10-year risk

19. Anderson TJ, Grégoire J, Hegele RA, et al. Are the ACC/AHA

thresholds for initiation of statin therapy for primary prevention of

guidelines on the treatment of blood cholesterol a game changer?

cardiovascular disease. JAMA. 2015;314:142–150.

A perspective from the Canadian Cardiovascular Society

33. Ahmad Z. Statin intolerance. Am J Cardiol. 2014;113:1765–71.

Dyslipidemia Panel. Can J Cardiol. 2014;30:377-80.

34. Ballantyne CM, Ber tolami M, Hernandez Garcia HR, et al.

20. Gibbons GH, Shurin SB, Mensah GA, Lauer MS. Refocusing

Achieving LDL cholesterol, non-HDL cholesterol, and

the agenda on cardiovascular guidelines: an announcement from

apolipoprotein B target levels in high-risk patients: Measuring

the National Hear t, Lung, and Blood Institute. J Am Coll Cardiol.

Effective Reductions in Cholesterol Using Rosuvastatin therapY

2013;62:1396-8.

(MERCURY) II. Am Heart J 2006;151:975 e971–9.

21. JBS3 Board. Joint British Societies’ consensus recommendations

35. Schoen MW, Salas J, Scherrer JF, Buckhold FR. Cholesterol

for the prevention of cardiovascular disease (JBS3). Heart. 2014;100

treatment and changes in guidelines in an academic medical

Suppl 2:ii1-ii67.

practice. Am J Med. 2015;128:403–9.

22. Exper t Dyslipidemia Panel of the International Atherosclerosis

36. Reiner Z. Resistance and intolerance to statins. Nutr Metab

Society Panel members. An International Atherosclerosis Society

Cardiovasc Dis. 2014;24:1057–66.

position paper: global recommendations for the management of

37. Cohen JD, Brinton EA, Ito MK, Jacobson TA. Understanding

dyslipidemia—full repor t. J Clin Lipidol. 2014;8:29-60.

Statin Use in America and Gaps in Patient Education (USAGE):

23. NCEP. National Cholesterol Education Program (NCEP) Exper t

an internet-based survey of 10,138 current and former statin users.

Panel on Detection, Evaluation, and Treatment of High Blood

J Clin Lipidol. 2012;6:208–215.

Cholesterol in Adults (Adult Treatment Panel III). Third repor t of

38. Vytorin [package inser t]. Whitehouse Station, NJ:

the National Cholesterol Education Program (NCEP) Exper t Panel

Merck & Co., Inc.; 2015.

on Detection, Evaluation, and Treatment of High Blood Cholesterol

39. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety

in Adults (Adult Treatment Panel III) final repor t. Circulation.

of alirocumab in reducing lipids and cardiovascular events.

2002;106:3143-421.

N Engl J Med. 2015;372:1489–1499.

24. Pencina MJ, Navar-Boggan AM, D’Agostino RB Sr, et al.

40. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and

Application of new cholesterol guidelines to a population-based

safety of evolocumab in reducing lipids and cardiovascular events.

sample. N Engl J Med. 2014;370:1422–1431.

N Engl J Med. 2015;372:1500–1509.

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CME

POST-TEST Expiration date: September 22, 2017

Credit Designation: The Postgraduate Institute for Medicine designates this enduring material for a maximum of 1.00 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

A statement of credit will be issued only upon receipt of a completed pre-assessment test, polling questions, activity evaluation form, and post-test with a score of 75% or higher. All components must be completed and submitted online at ClinicalAdvisor.com/Jan17feature.

CREDITS: 1.00 | Optimizing the management of LDL-C and ASCVD risk

1. Moderate-intensity statin therapy typically reduces LDL-C by how much? a. 10% to 20% b. 20% to 30% c. 30% to 50% d. 50% to 70% 2. Which of the following statements about statin-dependent new-onset diabetes is true? a. New-onset diabetes is a significant class-wide effect with all statins. b. Patients taking rosuvastatin or pitavastatin have a dose-dependent increased risk of new-onset diabetes. c. Pravastatin and pitavastatin are the only statins that do not appear to increase the risk of new-onset diabetes. d. Patients taking statins have no documented increased risk of new-onset diabetes.

4. Which of the following is not considered an atherogenic lipid? a. LDL b. IDL c. VLDL d. HDL 5. For a patient at moderate risk of ASCVD with an LDL-C of 160 mg/dL, what is the NLA’s recommended treatment target? a. 130 mg/dL b. 100 mg/dL c. 70 mg/dL d. 50 mg/dL

3. For patients at high risk of ASCVD, when should lifestyle therapies be initiated? a. Before starting pharmacotherapy b. Concurrently with pharmacotherapy c. After initiating pharmacotherapy d. Patients at high risk of ASCVD should be managed with only pharmacologic agents.

TO TAKE THE POST-TEST please go to: ClinicalAdvisor.com/Jan17feature

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Case Study | OBESITY EXAMINATION Weight history

• Baseline weight: 166.8 kg • Weight at the time of bariatric surgery: 141.8 kg • Weight at approximately 1 year postbariatric surgery: 76.6 kg • Weight today: 85.3 kg.

Current diet

Vision changes after bariatric surgery A patient has difficulty transitioning from light to dark 4 years post-surgery.

Presence of GI symptoms

He notes having loose stools 3 to 4 times per day, typically 2 to 3 times in the morning, and up to 2 times in the evening. He also notes having gas, which is often more common at night.

Exercise/activity

He tries to walk as much as he can at work. He is also very active during the summer months doing yard work, housework, and paddleboarding on the weekends. Last winter, he participated in a daily workout video course with his wife.

JULIA JURGENSEN, APRN, CNP

THE CASE

© THINKSTOCK

He typically consumes 3 meals with occasional snacks and between 70 and 75 g of protein daily.

He plans to add a protein shake to get closer to 90 g of protein daily. He also consumes about 32 ounces of water per day.

Paul, age 35, presents for a 4-year follow-up visit after undergoing a laparoscopic biliopancreatic diversion with a duodenal switch 4 years ago. He was last seen for a follow-up for bariatric surgery about 2 years ago.

He notes concerns with his vision. Specifically, he has difficulty transitioning from light to dark and from dark to light. He often notices a yellow hue at sunset throughout his entire vision field.

He denies having any difficulty with driving at night but has not done it frequently. He has had to strain his eyes at work while working on the computer, so he has been wearing “cheater” glasses for the past few months. Recently, he noticed a possible blind spot in both eyes. He was seen by an ophthalmologist within the last month. He has a new mild refractive error and was given a prescription, but nothing else was noted of significance during that visit.

Pre-existing weight-related comorbidities

• Impaired fasting glucose, which resolved within 3 months of bariatric surgery • Dyslipidemia • Obstructive sleep apnea—no longer requires CPAP Multivitamin use

He is not currently taking any multivitamins, calcium, or vitamin B12 and stopped taking all supplements 1 year ago.

Laboratory results

• Hemoglobin 13.9 g/dL (reference range 13.5-17.0 g/dL)

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Case Study • Ferritin 33 mcg/L (reference range, 11 to 307 mcg/L) • Vitamin D 22 ng/mL (reference range, 20 to 50 ng/mL) • Vitamin A 4.4 mcg/dL (reference range, 32.5 to 78.0 mcg/dL) • Vitamin E 4.2 mg/L (reference range, 5.5 to 17 mg/L) • Calcium 8.7 mg/dL (reference range, 8.9 to 10.1 mg/dL) • Albumin 4.1 g/dL (reference range, 3.5 to 5 g/dL) • Cholesterol 99 mg/dL (reference range, <200 mg/dL is ideal) • Triglycerides 42 mg/dL (reference range, <150 mg/dL is ideal) • HDL 45 mg/dL (reference range, >40 mg/dL) • LDL 46 mg/dL (reference range, <100 mg/dL is ideal) • Bone alkaline phosphatase 25 mcg/L (reference range, 0 to 20 mcg/L) • 24-hour urine calcium 123 mg/24 hours (reference range, 80 to 200 mg/24 hours) • 24-hour urine volume 2453 mL (reference range, >1500 mL)

Q&A

■ QUESTION 2 Which vitamin deficiency is possibly linked to the patient’s vision changes?

A. Vitamin A deficiency B. Hypovitaminosis D C. Vitamin E deficiency D. Vitamin E deficiency Answer: A. Vitamin A deficiencies are rare in the United States.

However, they can occur in patients with disorders associated with fat malabsorption, such as cystic fibrosis and other causes of pancreatic insufficiency, celiac disease, cholestasis liver disease such as primary biliary cholangitis, small bowel Crohn disease, or short bowel syndrome, and in patients who have undergone certain types of bariatric surgery (biliopancreatic diversion with duodenal switch). If patients with these conditions have difficulty with fat absorption and are experiencing vision changes, particularly in low light or at night, they should be evaluated for vitamin A deficiency.

■ QUESTION 1

■ QUESTION 3

Which of the following types of bariatric surgery puts the patient at the greatest risk for developing nutritional deficits?

What is the current recommended treatment of vitamin A deficiency?

A. Vitamin A 100,000 units orally or IM daily for 3 days, followed by 50,000 units daily for 2 weeks, then 10,000 to 20,000 units orally daily for additional 2 months B. Vitamin A 900 mcg/day for life C. Vitamin A 100,000 units orally or IM daily for 2 weeks, then 900 mcg/day for life D. Vitamin A 50,000 units orally for 2 weeks, then 10,000 units orally daily for 2 months

A. Roux-en-Y gastric bypass B. Biliopancreatic diversion with duodenal switch C. Sleeve gastrectomy D. Lap band Answer: B. This procedure begins with the surgeon removing a large part of the patient’s stomach. The valve that releases food to the small intestine remains afterward, along with the duodenum.

The surgeon then closes off the middle section of the intestine and attaches the last part directly to the duodenum. This is the duodenal switch. The separated section of the intestine is not removed from the body. Instead, it is reattached to the end of the intestine, allowing bile and pancreatic digestive juices to flow into this part of the intestine. This is the biliopancreatic diversion. As a result of these changes, food bypasses most of the small intestine, limiting the absorption of calories and nutrients.

The patient in this case stopped taking his recommended twicedaily multivitamins, twice-daily calcium, and vitamin B12, and as a result, several of his vitamin levels were deficient.

Answer: D. Paul was treated with vitamin A 100,000 units orally for 3 days, followed by 50,000 units daily for 2 weeks, then 20,000 units orally daily for an additional 2 months. His vitamin A level at 6 weeks after the start of treatment was 24.6 mcg/dL, and at 3 months after treatment it was 33.4 mcg/dL. He was able to discontinue the large-dose vitamin A supplementation at that time. However, he was instructed that he must not stop his strict vitamin regimen again. Patients who have undergone biliopancreatic diversion with duodenal switch have a greater risk of developing vitamin deficiencies. They must be

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on lifelong daily multivitamins, calcium, and vitamin B12 (at least once monthly if injected or daily sublingual). The amounts of these vitamins that the patients require are individualized, and sometimes additional supplements such as vitamin D and iron are also needed. Regular surveillance should be conducted to ensure that these patients do not have vitamin deficiencies. ■

Julia Jurgensen, APRN, CNP, practices at the Mayo Clinic in Rochester, Minnesota, in the department of endocrinology, specializing in diabetes management and obesity.

References 1. Bariatric surgery procedures. American Society for Metabolic and Bariatric Surgery. Available at: http://asmbs.org/patients/bariatric-surgeryprocedures (Accessed December 20, 2016).

“You have to let other people into your life.”

2. Mechanick JI, Youdim A, Jones DB, Garvey WT, Hurley DL, McMahon MM, et al. Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient—2013 update: cosponsored by American Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic & Bariatric Surgery. Endocr Pract. 2013;19(2):337-372.

3. Pazirandeh S, Burns D. Overview of vitamin A. UpToDate. 2016.

Available at: http://www.uptodate.com/contents/overview-of-vitamin-a

The Clinical Advisor

“This one’s just like being at a real theatre.”

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

“This book you took out on speed reading is 12 months overdue.”

Top, middle: © The New Yorker Collection 2017 from cartoonbank.com. All Rights Reserved. Bottom: Harley Schwardron, 2017

(Accessed December 20, 2016).

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

CONSULTATIONS TREATING PREMENOPAUSAL WOMEN WITH FIBROIDS AND DYSMENORRHEA What is the standard of care for a premenopausal woman with fibroids, heavy bleeding, and dysmenorrhea?—DEBORAH DONNELL, BSN, RN, Jackson, Miss.

If the patient does not wish to have any further pregnancies, the standard of care is hysterectomy. If, however, continued fertility is desired, there is a lack of rigorous trials evaluating the effectiveness of management options. Hormonal treatments may provide relief of heavy bleeding and/or reduction in uterine size, but results are mixed and the effects of long-term use on future pregnancies are unknown. Myomectomy, uterine artery embolization, and magnetic resonance–guided, focused ultrasound surgery are options. The most recent practice guidelines from the American College of Obstetricians and Gynecologists were issued in 2008. More recent guidelines were published by French researchers in the European Journal 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.

of Obstetrics & Gynecology and Reproductive Biology (2012;165[2]:156-164).—CLAIRE O’CONNELL, MPH, PA-C (See photo at bottom of page 57 for more information about Ms. O’Connell.) (219-1)

ARE PROSTATE BIOPSIES LINKED TO THE SPREAD OF CANCEROUS CELLS? Do prostate biopsies spread cancerous cells?—OSCAR RAMIREZ, NP, Valley Park, Mo. Transrectal ultrasound–guided biopsy of the prostate is generally without complications, provided adequate antibiotic prophylaxis is given prior to the procedure. Seeding of cancerous cells is a concern, but to date there have been only isolated cases. These cases are rare and are more often associated with a transperineal approach rather than a transrectal one.—CLAIRE O’CONNELL, MPH, PA-C (219-2)

CLINICAL PEARLS CONVERTING POUNDS TO KILOGRAMS My first supervising physician in pediatrics in 1993 taught me a quick and easy way to convert pounds to kilograms in your head when you are dosing by weight antibiotics for kids in the outpatient clinical setting. Subtract the first number from the total if the weight in pounds is two digits; subtract

OUR CONSULTANTS

Philip R. Cohen, MD,

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

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

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

Abimbola Farinde, PhD, PharmD,

is a professor at Columbia Southern University in Orange Beach, Ala.

Laura A. Foster, CRNP, FNP,

Abby A. Jacobson, MS, PA-C,

practices family medicine with Palmetto Primary Care Physicians in Charleston, S.C.

is an assistant professor at Thomas Jefferson University and a dermatology PA at Family Dermatology of Reading, Pa.

58 THE CLINICAL ADVISOR • JANUARY 2017 • www.ClinicalAdvisor.com

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the first two digits as a whole number if the weight is three digits. Then subtract that from the total, and divide by half, which gives you the weight in kg.

Example 1: 57 pounds: 57 − 5 = 52 52 ÷ 2 = 26 kg (actual conversion, 25.9 kg) Example 2: 113 pounds: 113 − 11 = 102 102 ÷ 2 = 51 kg (actual conversion, 51.3 kg).

As you progress to higher adult weights (150 to 200 pounds), the actual value can vary by a few kg, so it is not as accurate.—CATHERINE DOCOUS, PA, CNS, Oneida, N.Y. (219-3)

TIP FOR TREATING MINOR LACERATIONS With minor lacerations suitable for Dermabond, I clean the area, dry well, and then apply Mastisol or benzoin. When it dries, apply a minimum of tiny Steri-Strips and then the Dermabond to cover. This holds the laceration line closed first for good approximation and provides a double cover in the patient, especially children.—MONICA GRIFFITH, MSN, APRN, FNP/PNP, Louisville, Kent. (219-4)

CASE FILES AN ENLARGING MASS ON THE CALF Contributed by Sherril Sego, FNP-C, DNP (See photo at bottom of this page for more information about Dr. Sego.)

A 62-year-old Caucasian woman presented to her primary care provider with a recent notation of a lump in her right calf. She denies tenderness, but it bothers her. She has an 80–pack year history of smoking. She has COPD but is otherwise in average health. On initial examination, the lump was palpable, smooth, firm, and fixed. There were no

Debra August King, PhD, PA,

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

Mary Newberry, CNM, MSN,

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

abnormalities in the surrounding area of her lower extremity. She was scheduled for Doppler imaging, which revealed a solid mass with suggestion of increased vascularity. She was then sent for an MRI and subsequent consultation by both orthopedics and medical oncology. Surgical excisional pathology revealed a poorly differentiated leiomyosarcoma (LMS). Otherwise known as “soft tissue sarcoma,” LMS originates in the smooth or involuntary muscle. LMS is considered “treatable” when caught early.

LMS is rare but highly aggressive. This patient began radiation therapy but ultimately removed herself from treatment. She died within one year of her first presentation. (219-5)

A CASE OF ACUTE SEVERE EMPHYSEMATOUS PANCREATITIS A 55-year-old man with diabetes presented to the hospital after having recent onset of acute abdominal pain and recurrent vomiting [Balani, et al. BMJ Case Reports. 2016; Dec 15]. He was immediately admitted to the intensive care unit for ionotropic and invasive respiratory support.

He had an acutely tender abdomen with distension, and a hematologic examination revealed leukopenia (880/mm3), thrombocytopenia (64,000/mm 3), elevated C reactive protein (68 mg/mL), metabolic acidosis (pH: 6.88) with a severely elevated blood lactate (14 mmol/L), estimated creatinine clearance <14 mL/min, hyperlipidemia (1280 U/L), and serum amylase levels of 5134 U/L. Plain CT showed extensive gas in the pancreatic bed that extended into the lesser sac and adjacent retroperitoneal space. The clinicians made a diagnosis of acute severe emphysematous pancreatitis. Aggressive treatment was begun, but the patient died. Retrospective blood cultures were positive for Enterobacter aerogenes. (219-6) n

Claire O’Connell, MPH, PA-C,

an associate professor at the Rutgers University Physician Assistant Program, Piscataway, N.J.

is

Katherine Pereira, DNP, FNP,

is assistant professor, Duke University School of Nursing, Durham, N.C.

Sherril Sego, FNP-C, DNP,

is an independent consultant in Kansas City, Mo.

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Dermatology Clinic CASE #1

An asymptomatic, fleshy tumor on the base of the toe MELINDA LIU, BA, AND MAURA HOLCOMB, MD

A healthy 30-year-old man presents with a 3-year history of an asymptomatic, fleshy papule at the base of his great toe. He denies any new lesions during this time, a history of trauma to the area, or a family history of similar skin lesions. He was treated previously by another dermatologist with cryotherapy; however, he returns to the clinic with recurrence of the lesion. Examination reveals a pedunculated, flesh-colored, well-demarcated tumor on the plantar surface of the base of his great toe.

What is your diagnosis? Turn to page 62

CASE #2

A woman with diabetes and a sore on her leg MERRICK D. KOZAK, BA, AND JULIA R. NUNLEY, MD

A 45-year-old woman with insulin-dependent diabetes mellitus presents with a sore on her right leg. She describes a long-standing history of asymptomatic lesions on her shins but had only recently injured her leg, causing the sore, which is slow to heal. Despite a 15-year history of diabetes, she has no systemic complications. She has large, well-circumscribed plaques on her anterior shins bilaterally, which are yellowbrown with telangiectasias and minimally violaceous borders.

What is your diagnosis? Turn to page 63 60 THE CLINICAL ADVISOR • JANUARY 2017 • www.ClinicalAdvisor.com

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Dermatology Clinic CASE #1

Acquired digital fibrokeratoma

Acquired digital fibrokeratoma (ADFK) is a rare, benign, f ibrous tumor that usually occurs as a solitary lesion in adults.1,2 This lesion has been reported in patients of all races aged from 12 to 70 years.1,3 Although it appears to be slightly more common in men, as of yet, too few cases exist to determine statistical significance.1,3 Trauma is thought to predispose individuals to the development of ADFKs; however, this lesion has also been reported in patients lacking a history of trauma.4 Other factors that may play a role in the development of ADFK include local factors that result in epidermal–dermal interactions, fibroblast-induced neoformation of collagen, and infectious causes.1,2,4 Clinically, ADFK presents as a small, solitary, well-defined nodule surrounded by a hyperkeratotic collar.1,2,5 The lesion presents most commonly on the fingers and toes, but in rare instances, it may also occur on the nose, lower lip, arms, and legs.2,6 Although the lesion is typically < 5 mm in size, a few cases of giant ADFK > 1 cm have been reported in the literature.1,2 Usually, the lesion is asymptomatic and is not associated with malignancy.1,6 Diagnosis is based on a combination of clinical and histopathologic features. Classic histologic features include a core of thick, densely packed collagen bundles oriented Take-away points for acquired digital fibrokeratomas Clinical presentation

• Small, solitary, well-defined nodule surrounded by a hyperkeratotic collar, most commonly on the fingers and toes • Typically asymptomatic and benign

Differential diagnosis

• Cutaneous horn, neurofibroma, pyogenic granuloma, supernumerary digit, and Koenen tumor

Diagnosis

• Diagnosed through a combination of clinical and histologic features • The characteristic histologic features are thick, densely packed collagen bundles oriented parallel to the longitudinal axis of the dermis

Management

• Complete surgical resection is the only definitive treatment • Lesions do not spontaneously resolve

parallel to the longitudinal axis of the dermis.1,3,4,7 The epidermis is characterized by hyperkeratosis and irregular acanthosis, and the rete ridges are thickened and branching.7 Vessels of varying diameters are also scattered throughout the tumor, which is often highly vascular. 3,7 Based on clinicohistopathologic findings, ADFK can be categorized into three different types.1,8 Classic dermoscopic findings include clumps of homogenous red lacunae divided by a white reticular septal wall.7 The adjacent skin is surrounded by telangiectasias.7 The differential diagnosis includes cutaneous horn, neurofibroma, pyogenic granuloma, supernumerary digit, and Koenen tumors.1,9 Although these lesions may appear similar clinically, they can be differentiated from ADFK through histology. For example, cutaneous horn lacks the prominent core of outgrowing connective tissue and often has epidermal neoplasia at the base; neurofibromas consist of loosely spaced spindle cells and wavy collagenous strands in the dermis, and supernumerary digits contain neural bundles in the dermis.1,9 Koenen tumors typically

Acquired digital fibrokeratoma presents as a small, solitary, well-defined nodule surrounded by a hyperkeratotic collar. have atypical stellate myofibroblasts, are multilobulated, and are associated with tuberous sclerosis.1,5 In rare cases, ADFKs may also ulcerate and mimic aggressive neoplasms.8 The treatment of choice of ADFK is surgical excision, because these lesions do not spontaneously resolve. 2,6 Recurrence is rare following complete excision.2,5,9 In our case, the patient was treated with complete surgical removal without recurrence at the 1-year follow-up visit.

Melinda Liu, BA, is a medical student and Maura Holcomb, MD, is a dermatology resident at Baylor College of Medicine in Houston.

References 1. Ali M, Mbah CA, Alwadiya A, Nur MM, Sunderamoorthy D. Giant fibrokeratoma, a rare soft tissue tumor presenting like an accessory digit, a case report and review of literature. Int J Surg Case Rep. 2015; 10:187-190.

2. Bulam H, Şencan A, Bozkırlı BA, Sezgin B, Tuncer S. Giant acquired periungual fibrokeratoma of the thumb: case report and review. Hand (N Y). 2015;10:140-142.

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3. Frydman AF, Mercer SE, Kleinerman R, Yanofsky VR, Birge MB. Acquired fibrokeratoma presenting as multiple plantar nodules. Dermatol Online J. 2010;16:5.

4. Carlson RM, Lloyd KM, Campbell TE. Acquired periungual fibrokeratoma: a case report. Cutis. 2007;80:137-140.

5. Longhurst WD, Khachemoune A. An unknown mass: the differential diagnosis of digit tumors. Int J Dermatol. 2015;54:1214-1225.

6. Yu D, Morgan RF. Acquired digital fibrokeratoma: a case report. Ann Plast Surg. 2015;74:304-305.

7. Hayashi K, Matori S, Kariya Y, et al. Dermoscopic observation of acquired digital fibrokeratoma developed on the dorsum of the fourth left toe. J Dermatol. 2016;43:107-108.

8. Plaza JA, Suster S, Prieto VG, Sangueza M. Acquired reactive digital fibroma: a clinicopathologic report of 5 cases of a new entity. J Am Acad Dermatol. 2013;69:603-608.

9. Choi JH, Jung SY, Chun JS, et al. Giant acquired digital fibrokeratoma occurring on the left great toe. Ann Dermatol. 2011;23:64-66.

CASE #2

Necrobiosis lipoidica

Necrobiosis lipoidica (NL) is an indolent, chronic, granulomatous, cutaneous disorder.

Although it is most commonly seen in those with insulindependent diabetes mellitus, it has also been described in patients with other conditions, such as sarcoidosis, inflammatory bowel disease, and rheumatoid arthritis, and also in otherwise healthy individuals.1 It has a strong predominance in women, with a 3:1 ratio of women to men.

The condition is rare, even in individuals with type 1 diabetes, in whom incidence ranges from 0.3% to 1.2%.1,2 Development of NL precedes the diagnosis of diabetes mellitus in approximately 14% of patients and is found simultaneously in 24%, but more commonly develops well after the diagnosis of diabetes mellitus has been established, accounting for 62% of cases.3 Typically, NL lesions begin as painless, small, red-brown papules on the shins, unilaterally or bilaterally, which enlarge over time, evolving into one or more variably sized plaques.4 Although the shins are most commonly affected, lesions may occur anywhere, especially on the arms, back, and (peculiarly) within the periorbital areas.4 The increased

incidence on the shins may be a result of the Koebner phenomenon1—induction of skin lesions following minor trauma. Eventually the color of the plaques evolves to a yellow-brown, although active lesions maintain a persistently violaceous rim. As a result of collagen degeneration, the central areas of the plaques are often atrophic and appear waxy; telangiectasia can be visible through the atrophic dermis. Approximately 30% of patients will develop ulcers, most frequently as a result of localized trauma. Although NL itself is usually asymptomatic, ulcerative NL may be painful and very difficult to manage. In rare cases, an area within a plaque of NL may degenerate into a squamous cell carcinoma.5 The diagnosis of NL can typically be made by clinical inspection alone. If necessary, a biopsy will confirm the diagnosis; however, NL is poor to heal, and a biopsy should only be done if the diagnosis is in question. Histologic changes of NL consist of palisading granulomas, aligned parallel to the skin surface and extending deep into the subcutaneous tissue. Degeneration of collagen fibers (necrobiosis) is noted within the granulomas. A diffuse perivascular infiltrate is often present, consisting mostly of lymphocytes and plasma cells, although eosinophils may also be present.4 The pathogenesis of NL remains unknown. Although, there are several theories, each has both supportive and contradictory data. Some investigators propose NL to be a result of the same microangiopathic changes that cause diabetic nephropathy and retinopathy. However, a large retrospective study found no correlation between nephropathy, retinopathy, and the development of NL; although those

Necrobiosis lipoidica lesions begin as painless, small, red-brown papules on the shins, unilaterally or bilaterally. who developed NL did have a higher glycated hemoglobin level (8.7% vs 8.3%; P = .0065).2 Celiac disease has been found to be more prevalent among individuals with type 1 diabetes and with NL than in those without (1% vs 3.4%; P = .0035), which lends credence to the theory that the pathogenesis could be an autoimmune phenomenon.2 Further supporting an immune mechanism is the finding of immune complexes in the vascular walls of vessels in the deep dermis of lesions of NL. However, it is debated whether these immune complexes cause the collagen degeneration

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Dermatology Clinic or occur as a result of the collagen degeneration.3,4 Thus far, the pathogenesis is speculative at best.

The differential diagnosis of NL includes conditions such as granuloma annulare (GA), sarcoidosis, necrobiotic xanthogranuloma (NXG), and diabetic dermopathy. Although the clinical appearance of a GA lesion may be somewhat similar, the distribution is not; GA is more common over joints, especially on the hands and elbows, but lesions may be found over ankles as well. Sarcoidosis is the great imitator, but its lesions usually do not have telangiectasias, which are classically seen in NL. NXG is a rare, chronic

The differential diagnosis of necrobiosis lipoidica includes granuloma annulare, sarcoidosis, and diabetic dermopathy. granulomatous disorder with predilection for the periorbital area; however, the yellowish hew of lesions is more suggestive of a xanthomatous process. Although diabetic dermopathy is atrophic and present on the shins, it is usually hyperpigmented and lacks telangiectasia.4 If the diagnosis is still in doubt, histologic findings on biopsy will differentiate these various conditions. A biopsy of GA will uniquely demonstrate mucin deposition within the granulomas.4,6 Sarcoidosis lacks the necrobiosis seen in GA, NL, and NXG. Histology of NXG reveals cholesterol clefts, which are absent in the other conditions, and no granulomas or necrobiosis are seen histologically with diabetic dermopathy.

Given the rarity of NL, there are no randomized controlled trials to determine the optimal therapy. Only case reports and case series exist to support the various treatment regimens, which include lifestyle modifications to minimize trauma, optimizing glucose control, and several medications.

Corticosteroids, administered topically or intralesionally, are the most common initial medicinal intervention. However, care should be taken to minimize the risk of further atrophy. Topical tretinoin may be a good alternative, as it promotes collagen formation and angiogenesis.1,7 Intravenous immunoglobulin, topical immune modulators, and systemic methylprednisone have shown some efficacy for recalcitrant, ulcerative NL. Unfortunately, recurrence is common when these agents are discontinued, and retreatment often yields disappointing results.7 Psoralen with ultraviolet A phototherapy reduces inflammation at the dermal-subepidermal junction, which may

improve the granulomatous inflammation of NL but has no effect on atrophic areas.2,7 Systemic immune modulators, such as methotrexate, mycophenolate mofetil, and cyclosporine, have anecdotally improved NL; however, numerous side effects can occur with these medications and, despite treatment success, recurrence rates are disappointingly high upon cessation of treatment.1,2,7 If a squamous cell carcinoma develops, surgical removal is indicated; however, this may be complicated by Koebnerization of NL, or by causing ulcerative NL; at times, a split thickness skin graft may be beneficial.1,5 In our case, the diagnosis was made on the classic clinical findings: bilateral plaques on the anterior shins of an individual with type 1 diabetes and an ulcer following minimal trauma. The ulcer was treated with intralesional triamcinolone acetate and a 5-week taper of prednisone; wound care consisted of petroleum-impregnated gauze and a light pressure dressing. Her fluctuating blood sugar levels, associated with the steroid taper, were managed by her primary care provider. This treatment regimen managed to heal the ulcer but had little effect on the established plaque of NL. She was educated about the risk associated with minimal trauma and the high recurrence rate of the ulcer. n Merrick D. Kozak, BA, is a medical student and Julia R. Nunley, MD, is a professor of dermatology and program director of dermatology at the Medical College of Virginia Hospitals of Virginia Commonwealth University in Richmond.

References 1. Reid SD, Ladizinski B, Lee K, et al. Update on necrobiosis lipoidica: a review of etiology, diagnosis, and treatment options. J Am Acad Dermatol.

2013;69:783-791.

2. Hammer E, Lilienthal E, Hofer SE, et al. Risk factors for necrobiosis lipoidica in type 1 diabetes mellitus. Diabet Med. 2016 Apr 21. doi: 10.1111/ dme.13138. [Epub ahead of print] 3. Sibbald C, Reid S, Alavi A. Necrobiosis lipoidica. Dermatol Clin.

2015;33:343-360.

4. Reisenauer A, White KP, Korcheva V, White CR. Non-infectious granulomas. In: Bolognia J, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed.

Philadelphia, PA: Elsevier Saunders; 2012:93-94.

5. Lim C, Tschuchnigg M, Lim J. Squamous cell carcinoma arising in an area of long-standing necrobiosis lipoidica. J Cutan Pathol. 2006;33:581-583.

6. Rupley KA, Riahi RR, Hooper DO. Granuloma annulare and necrobiosis lipoidica with sequential occurrence in a patient: report and review of literature. Dermatol Pract Concept. 2015;5:29-34.

7. Feily A, Mehraban S. Treatment modalities of necrobiosis lipoidica: a concise systematic review. Dermatol Reports. 2015;7:5749.

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Dermatologic Look-Alikes A pink nodule ESTHER STERN, NP

CASE #1

CASE #2

A 17-year-old adolescent girl presents for treatment of a lesion on her index finger. She reports that the lesion was present for approximately 2 years. Initially, it grew quickly, but recently, it has remained stable in size. A friend told her that it was a wart and she could have it frozen. The patient denies any pain, itching, or bleeding from the lesion. She denies having any other similar lesions elsewhere. Physical examination reveals a light pink, 3-mm, well-circumscribed dome-shaped nodule on the right index finger over the proximal interphalangeal joint. There is no associated erythema or tenderness.

A 74-year-old man presents for his biannual skin examination. After questioning him regarding any new or changing lesions, the clinician learns that he had a new pink growth that appeared on his left elbow 2 weeks earlier. The patient denies having any pain from the lesion, although he noted that it bled a lot when it got caught on his clothing. The patient has a history of extensive actinic damage, as well as a history of a basal cell carcinoma on his chin. Physical examination of the left elbow reveals a firm, rubbery, pink papule with a small black crust at the lateral margin.

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Dermatologic Look-Alikes CASE #1

Spitz nevus

Spitz nevus is a benign melanocytic nevus named after the pathologist Sophie Spitz, who first described this lesion in 1948. Spitz nevi, although in herently ben ig n, may mimic malignant melanomas both clinically and histologically. For this reason, Spitz nevi are often referred to as benign juvenile melanoma. More concerning, however, is that there have been cases of atypical Spitz nevi that have metastasized and caused death.1 This has caused tremendous confusion among researchers and clinicians, leading to great uncertainty and variability regarding the ideal treatment of these lesions. More recent literature2 recommends that Spitz tumors be viewed on a spectrum, with the common Spitz tumor on the benign end and its highly atypical counterpart, which cannot be distinguished from melanoma, on the other end of the spectrum.

They appear most commonly in the first and second decades of life, although new onset occurs in adulthood about 30% of the time.3 Both sexes are affected equally. The diagnosis is more common in fair-skinned and white people, although cases have been reported in the Hispanic population.4 Classic clinical presentation of a Spitz nevus is a fleshy, red-brown, erythematous or pigmented, hairless papule or nodule, ranging in size from 5 to 10 mm in diameter.

Dermoscopy may aid in identifying pigment in an otherwise nonpigmented-appearing lesion. In children, these lesions most commonly occur on the face,5 although Spitz nevi have been seen on the arms and legs. These lesions appear suddenly and grow quickly over the course of several months to years, at which point they stabilize in size and appearance.

The differential diagnosis of Spitz nevus includes all pink, fleshy, or pigmented solitary lesions. Examples of these include intradermal nevus, molluscum contagiosum, juvenile xanthogranuloma, verruca vulgaris, amelanotic melanoma, dysplastic nevus, and pigmented basal cell carcinoma.

Biopsy technique is crucial to making the correct diagnosis. A small incisional shave or punch biopsy will not allow the pathologist to fully evaluate the architectural pattern for symmetry and circumscription of the lesion,6 possibly leading to a false and devastating diagnosis of malignancy.

For this reason, conservative excisional biopsy is appropriate for lesions suspicious for Spitz nevus.

Biopsy samples should be examined by a dermatopathologist experienced with pigmented and Spitz nevi. The three most important histologic factors that may predict a poorer outcome are mitotic activity, mitoses near the base, and inflammation.2 There are no clear guidelines to direct the clinician in appropriate treatment of a Spitz nevus. Consideration must be given to the clinical scenario and histopathologic attributes of the lesion. Generally, Spitz nevi in the adult population are excised, whereas similar tumors in the pediatric population are usually managed nonsurgically with close observation,7 as several studies have found that younger age is more likely to be associated with benign Spitz nevus.8 Close communication between the clinician and dermatopathologist allows for collaborative discussion to determine the best treatment.

In our case, biopsy of the lesion on the young womanâ&#x20AC;&#x2122;s index finger revealed a Spitz nevus with unusual features.

Risks and benefits of close observation versus surgical excision were discussed with the patient and her mother.

They elected to see a plastic surgeon to undergo surgical excision, which was performed without any complication.

In addition, the patient was instructed on the importance to return for annual skin examination.

CASE #2

Amelanotic melanoma

Amelanotic melanoma (AMM) refers to a malignant melanoma tumor that lacks the presence of the characteristic melanin in classic melanomas. True amelanotic melanomas are rare9; more commonly, AMM refers to tumors that are mostly devoid of pigment, and close inspection reveals flecks of pigment at the periphery of the lesion. All forms of cutaneous melanoma, including the metastatic type, can have an amelanotic variant, although subungual and desmoplastic melanomas appear amelanotic at a significantly greater rate.10 AMM is the typical variant seen in albinism.3 AMM accounts for about 2% of all melanotic melanomas, affecting middle-aged women more commonly, with a 5:1 female:male ratio.11 Because of their relatively benign appearance, diagnosis of this melanoma is often delayed. For this reason, AMM is often referred to as the great masquerader.9 A history of a new pink growth or change in a pink, fleshy lesion should

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raise concern for malignancy, particularly in higher-risk patients, such as those with a personal or family history of melanotic melanoma and dysplastic nevi. Clinical presentation of AMM is a pink, erythematous, or flesh-colored macule, papule, patch, or plaque. The lesion may be smooth or scaly.

Most AMMs will have flecks of pigment.

The differential diagnosis of AMM is vast. Mimickers include basal cell carcinoma, actinic keratosis, pyogenic granuloma, Spitz nevus, intradermal nevus, neurofibroma, molluscum contagiosum, eczema, psoriasis, and discoid lupus erythematosus.

Although dermoscopy is tremendously valuable in the evaluation of pigmented lesions, its use is limited in the evaluation of amelanotic melanomas. When using a dermoscope, care should be taken not to apply too much pressure to the lesion so as not to conceal the vascular pattern of the lesion. Pizzichetta and colleagues12 concluded that abnormal vascular patterns, such as milky-red dotted vessels, hairpin vessels, and linear irregular vessels were clues to the diagnosis of melanoma. Definitive diagnosis of AMM requires a skin biopsy for histopathologic evaluation. When AMM is suspected, excisional biopsy is the gold standard diagnostic test.13 Histopathologic examination of AMM reveals a host of changes including architectural disturbance and striking cytologic atypia. The majority of melanoma cells in AMM are of the epithelioid variety,14 presenting with abundant eosinophilic cytoplasm, prominent vesicular nuclei, and large nucleoli; others are of the spindle and desmoplastic morphology.

Despite the absence of clinically apparent pigmentation, AMM may reveal the presence of pigment on biopsy by use of special stains. The Fontana and the S-100 stain are helpful; however, electron microscopy is considered the most definitive method for diagnosis of AMM.15 The prognosis of AMM is the same as that of its pigmented counterpart in the same stage of growth. Morbidity and mortality depend on thickness and invasion of the tumor, as well as the patient’s age and sex.16 A higher mitotic index predicts a worse prognosis. Unfortunately, AMM is usually more advanced than pigmented melanotic melanoma at the time of diagnosis, likely due to the high rate of diagnostic confusion; therefore, prognosis is poorer.

The treatment of amelanotic tumors is the same as the treatment of pigmented melanotic melanoma. Wide local excision is the treatment of choice for AMM in situ.

Depending on the stage of invasive AMM, treatment may involve wide local excision, lymph node dissection, radiation, immunotherapy, or other treatments.

In our case, the patient was referred to the local cancer center for treatment of his stage T1 AMM. He underwent

wide local excision with negative margins. The patient was instructed regarding the need for monthly self-skin checks as well as clinical full skin examination every 3 months for the first years and then biannually thereafter. n Esther Stern, NP, is a family nurse practitioner at Advanced Dermatology & Skin Surgery, P.C., in Lakewood, N.J. References 1. Gelbard SN,Tripp JM, Marghoob AA, et al. Management of Spitz nevi: a survey of dermatologists in the United States. J Am Acad Dermatol. 2002;47(2):224-230.

2. Luo S, Sepehr A, Tsao H. Spitz nevi and other Spitzoid lesions part I. Background and diagnoses. J Am Acad Dermatol. 2011;65(6):1073-1084.

3. James WD, Berger TG, Elston DM. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, PA: Saunders-Elsevier; 2011.

4. Berlingeri-Ramos AC, Morales-Burgos A, Sánchez JL, Nogales EM. Spitz nevus in a Hispanic population: a clinicopathological study of 130 cases. Am J Dermatopathol. 2010;32(3):267-275.

5. Paller AS, Mancini AJ. Hurwitz Clinical Pediatric Dermatology: A Textbook of Skin Disorders of Childhood and Adolescence. 4th ed. Philadelphia, PA; Elsevier Saunders; 2011.

6. Ackerman AB. Spitz nevus. J Am Acad Dermatol. 1981;4(5):609-610.

7. Luo S, Sepehr A, Tsao H. Spitz nevi and other Spitzoid lesions part II. Natural history and management. J Am Acad Dermatol. 2011;65(6):1087-1092.

8. Vollmer RT. Patient age in Spitz nevus and malignant melanoma: implication of Bayes rule for differential diagnosis. Am J Clin Pathol. 2004;121(6):872-877.

9. Koch SE, Lange JR. Amelanotic melanoma: the great masquerader. J Am Acad Dermatol. 2000;42(5):731-734.

10. Baran R, Haneke E, Drapé JL, Zook EG. Tumours of the nail apparatus and adjacent tissues. In: Diseases of the Nails and Their Management. Baran R, Dawber RPR, de Berker DAR, Haneke E, Tosti A, eds. Oxford, United Kingdom; Blackwell Scientific; 1994.

11. Conrad N, Jackson B, Goldberg L. Amelanotic lentigo maligna melanoma: a unique case presentation. Dermatol Surg. 1999;25(5):408-411.

12. Pizzichetta MA,Talamini R, Stanganelli I, et al. Amelanotic/­hypomelanotic melanoma: clinical and dermoscopic features. Br J Dermatol. 2004;150(6):1117-1124.

13. Ming ME. The histopathologic misdiagnosis of melanoma: sources and consequences of “false positives” and “false negatives.” J Am Acad Dermatol. 2000;43(4):704-706.

14. Cheung WL, Patel RR, Leonard A, et al. Amelanotic melanoma: a detailed morphologic analysis with clinicopathologic correlation of 75 cases. Cutan Pathol. 2012;39(1):33-39.

15. Gibson LE, Goellner JR. Amelanotic melanoma: cases studied by Fontana stain, S-100 immunostain, and ultrastructural examination. Mayo Clin Proc. 1988;63(8):777-782.

16. Schuchter L, Schultz DJ, Synnestvedt M, et al. A prognostic model for predicting 10-year survival in patients with primary melanoma. The Pigmented Lesion Group. Ann Intern Med. 1996;125(5):369-375.

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LEGAL ADVISOR CASE

A case of misdiagnosed meningitis

ANN W. LATNER, JD

Correctly diagnosing a patient, often in a very short period of time and sometimes with little background information on the patient, is one of a clinician’s most challenging jobs. Symptoms can often be attributed to numerous medical conditions, making diagnosis difficult.

Ms. R was a 32-year-old nurse practitioner (NP) who worked in an on-campus health clinic at a college. The clinic was staffed with 2 rotating NPs who were employed by a medical practice that provided healthcare services to students at several college clinics. A physician in the practice was responsible for reviewing the NPs’ notes, and for answering any questions and acting as a consultant or backup for the NPs should they encounter anything complicated. Ms. R had previously worked for a family practitioner for a year, and before that she worked in an OB/GYN office.

In most cases, the students would come in with colds, influenza, sore throats, rash, or other minor ailments. Occasionally, they would have a small accident that resulted in cuts, bruises, or a burn. Periodically, Ms. R received questions from embarrassed students about sexually

© THINKSTOCK

A student’s headaches, lethargy, vomiting, and photophobia are misdiagnosed as migraine.

The patient’s symptoms should have prompted an immediate referral to the emergency department for further screening.

transmitted diseases and birth control. She was often asked about antidepressants and ways to minimize anxiety. Some students seemed to appear in the clinic every other day, often just to talk, whereas many students completed their 4 years without ever visiting the health center.

Ms. R had been working on campus for 6 months when Mr. J, an 18-year-old male freshman student came in to see her. Ms. R had never seen Mr. J before and had no medical records for him. The student told Ms. R that he had had severe headaches for the past 4 days and that he felt lethargic. A brief examination revealed that the patient’s temperature and blood pressure were normal.

Ms. R asked the student whether he was experiencing any unusual stress.

“Well, we’re in the finals period, and this was my first time with college finals,” said the young Cases presented are based on actual occurrences.

Names of participants and details have been changed.

Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

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LEGAL ADVISOR man. He commented that he was on a scholarship and had to maintain passing grades to continue receiving the money to go to school. Ms. R nodded, sympathetically.

“The first year can be especially tough,” she told the student.

“Stress can cause physical problems, including headaches.”

She gave the young man some tips for reducing stress, recommended an over-the-counter pain reliever for his headache, and told him to come back if he did not improve. “Oh, and good luck on the rest of your finals!” she added.

She noted “stress-related headache” in his chart and filed it away where it was looked at but not remarked on by the supervising physician.

A week later, on a Friday, the young man returned to the health center. Again, Ms. R was on duty.

“What are you doing back here again?” she joked to the student. “Anything to avoid those finals, right?”

But the student was not in the mood for joking. His headaches and lethargy had continued, and now he was complaining about new symptoms, vomiting and photophobia.

After a short discussion of his symptoms and a brief physical examination, Ms. R diagnosed Mr. J as having migraines. She prescribed an anti-migraine medication and recommended that he see a neurologist on Monday if the symptoms continued. The student thanked her, took his prescription, and left. Ms. R noted the diagnosis in his chart and filed it away.

Because the early symptoms of meningitis can resemble something less threatening, it can easily be misdiagnosed.

The next morning, the student was found dead in his dorm room. After an autopsy, the medical examiner determined that the cause of death was bacterial meningitis.

Mr. J’s devastated parents knew that he had been to the school’s health clinic for the headaches, and they sought the counsel of a plaintiff’s attorney to decide whether they might have a case. The attorney, after having the medical records reviewed by an expert, told the parents that he believed they did have a case, and he recommended suing the practice that employed the NPs and the physician who was supposed to be overseeing the work of the NPs. Ms. R was not personally sued, but because the case was based on her alleged negligence, she was called as a witness and had to give a deposition prior to the case going to trial.

During the deposition, she was asked why she had not referred

the student to a hospital emergency department for head imaging when he returned a week later still complaining of severe headaches. Ms. R had no answer.

Her supervising physician was questioned about why he had not intervened, and it became apparent that he had not even looked at the notes from the second visit before the patient died. The case was ultimately settled prior to trial, out of court, for an undisclosed amount.

Legal background

Although Ms. R committed the actual negligent act in this case, it was her employer that was sued. This is common in cases against physician extenders, although that is starting to change. In general, the physician or practice will have deeper pockets (and better professional insurance) than an NP, and so the practice or supervising physician is often the one sued in such cases, particularly, as in this case, where there should have been more supervision.

Although Ms. R was not personally sued, once the case was settled she was let go from her employment based on what had happened to her patient.

Protecting yourself

Because the early symptoms of meningitis can resemble something less threatening, such as the flu, it can easily be misdiagnosed. Bacterial meningitis requires early diagnosis and treatment, or there can be tragic consequences. The three main symptoms—sudden fever, severe headache, and stiff neck—only all occur together in less than half of bacterial meningitis cases, meaning that if 1 of the 3 symptoms is present, it is worth ruling out meningitis because the consequences of the disease are so great.

In addition, Ms. R should have considered the setting in which she was practicing. Outbreaks of meningococcal disease, particularly those caused by Neisseria meningitidis, tend to spread where large groups of people are living together in close quarters, such as college campuses. Even if Mr. J’s first visit had not been enough to cause Ms. R to consider meningitis, his second visit should have. Vomiting and photophobia are also signs of meningitis, and those combined with his severe and long-lasting headaches should have prompted Ms. R to refer him to the emergency department immediately for further screening. Her supervising physician should have given her better instruction on recognizing the signs of meningitis— particularly considering the setting that she was working in. n Ms Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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ALTERNATIVE MEDS UPDATE

What you should know about the herbs and supplements patients use

By Sherril Sego, FNP-C, DNP Ms. Sego is an independent consultant in Kansas City, Mo.

Kratom

© THINKSTOCK

A complex, poorly understood plant product, kratom, or Mitragyna speciosa, has recently burst onto the American stage in a big way and gained the attention of the US Food and Drug Administration (FDA), as well as the Drug Enforcement Administration (DEA). Mitragynine, the dominant alkaloid in the compound, has been found to have some opioid-like activity, and some believe that it is useful in assisting patients who are withdrawing from either licit or illicit narcotic use. The debate about potential DEA regulation of this compound is, more than likely, just beginning.

Background Kratom grows naturally in much of Southeast Asia, more specifically, in Malaysia.1 This evergreen tree can reach a height of more than 80 feet with a trunk diameter of 3 feet.1 The large, dark glossy green leaves yield the extract that is the active component of the tree. Kratom has been used in its native environment for centuries for purposes ranging from religious ceremonies to wound healing. Its action as an opium substitute, however, was reported in 1836.2 Official notation of this plant and its action was first made by Dutch botanist Pieter Korthals in 1839.3 The compound has been relatively slow to develop a following in the United States, but that appears to be changing.

Science Kratom’s main mechanism of action is due largely to 1 of more than 25 alkaloids found in its extract.4 Mitragynine,

the dominant alkaloid, may exert selective μ-opioid receptor activity, especially when used in moderation.5 Proponents of kratom argue that it is useful in patients who are withdrawing from licit or illicit narcotic use. Those against the use of kratom believe that because its action is basically opioid in nature, nothing is gained.

There are no clinical trials in humans to determine either the safety or efficacy of kratom. However, a growing body of laboratory data shows some very intriguing actions of the extract. One study demonstrated both adrenergic and serotonergic actions, as well as actual opioid antagonistic functions.6 These activities are seen as promising means to ease withdrawal from narcotic dependence.

In the absence of human clinical trials based in the United States, we are forced to depend largely on pharmacokinetic data and foreign trials. One case report highlights the differing actions of kratom based on total daily dose.7 In this report, a man in his early 40s was using escalating doses of prescribed hydromorphone for a chronic pain condition. Due

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ALTERNATIVE MEDS UPDATE to a sudden change in his personal life, he was forced to abruptly cease use of this potent drug.

To manage his intense symptoms of withdrawal, he began ingesting a kratom tea 4 times a day. The tea greatly alleviated his physical pain without the typical sedation from prescription medication.7 In a survey in Malaysia, researchers sought to determine the demographics and substance use habits of self-treated kratom users.8 Nearly 77% of participants reported histories of prior drug use, often heroin. At the time of the survey, more than 45% of subjects were still using at least 1 other psychoactive substance. A majority of participants reported greater productivity, better appetites, and a reduction in heroin withdrawal symptoms after beginning kratom use.8

Safety, interactions, side effects The safety of this product is definitely in question. Due to its known opioid action, addiction and overdose are easily possible. In August 2016, the DEA published a notice of intent to classify this compound as a schedule I drug.9 Due to a huge public response, however, a formal retraction of that intent was published in October 2016, pending further review.9 Regardless of regulation, kratom should be considered an opioid compound and, as such, possess all of the potential side effects and interactions of the class. Until such studies are conducted that more clearly show safety and efficacy for specific uses, there is no indication for this compound.

pain or intense withdrawal from other opiates report using 15 to 20 g or more per day. The type of product and the amount used dictate cost, with an average cost per ounce of about $30.

Summary

Kratom powder is a commonly used form in the United States.

Kratom’s legal future is uncertain, pending further review from the DEA and FDA. A public comment period closed on December 1.

How supplied, dose, cost

With the abundance of approved medications at the disposal of healthcare providers, the use of an unproven and potentially dangerous product such as kratom is not justified. However, providers must be aware of the growing use of this compound in the United States and, when opioid use is either ongoing or newly initiated, screen for use of this product. n References 1. Rech MA, Donahey E, Dziedzic JMC, Oh L, Greenhalgh E. New drugs of abuse. Pharmacotherapy. 2015;35:189-197.

2. Assanangkornchai S, Muekthong A, Sam-Angsri N, Pattanasattayawong U. The use of Mitragynine speciosa (“Krathom”), an addictive plant, in Thailand. Subst Use Misuse. 2007;42:2145-2157.

3. Raffa RB, ed. Kratom and Other Mitragynines: The Chemistry and Pharmacology of Opioids from a Non-Opium Source. Boca Raton, FL: CRC Press; 2014.

4. León F, Habib E, Adkins JE, Furr EB, McCurdy CR, Cutler SJ. Phytochemical characterization of the leaves of Mitragyna speciosa grown in the USA. Nat Prod Commun.

2009;4:907-910.

5. Adkins JE, Boyer EW, McCurdy CR. Mitragyna speciosa, a psychoactive tree from Southeast Asia with opioid activity.

Curr Top Med Chem. 2011;11:1165-1175.

6. Suhaimi FW, Yusoff NH, Hassan R, et al. Neurobiology of Kratom and its main alkaloid mitragynine. Brain Res Bull.

2016 Sep;126(Pt 1):29-40.

7. Boyer EW, Babu KM, Adkins JE, McCurdy CR, Halpern JH. Self-treatment of opioid withdrawal using kratom (Mitragynia speciosa korth). Addiction. 2008;103:1048-1050.

8. Vicknasingam B, Narayanan S, Beng GT, Mansor SM. The informal use of ketum (Mitragyna speciosa) for opioid withdrawal in the northern states of peninsular Malaysia and implications for drug substitution therapy. Int J Drug Policy.

2010. 21: 283-288.

9. US Drug Enforcement Administration. Federal Register.

Withdrawal of notice of intent to temporarily place mitragynine and 7-hydroxymitragynine into schedule I. https://www. federalregister.gov/d/2016-24659. Published October 13, 2016.

© THINKSTOCK

Kratom is widely available in the United States either online or in most ‘head shops.’ It is available in a variety of forms including extract, powder, or capsule. Due to the lack of any quality control, there is no way to establish a ‘recommended dose.’

Also, the concentration of the active ingredient, mitragynine, varies widely based on the form of the product. Extracts tend to be more concentrated, while powders and capsules are weaker.

Those who report sporadic use for anxiety or other episodic concerns may only use 1 to 2 g at a time, whereas daily users managing chronic 72 THE CLINICAL ADVISOR • JANUARY 2017 • www.ClinicalAdvisor.com

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