Utilization of and Adherence to Guideline-Recommended Lipid-Lowering Therapy After Acute Coronary Syndrome

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 66, NO. 2, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER INC.

http://dx.doi.org/10.1016/j.jacc.2015.05.030

REVIEW TOPIC OF THE WEEK

Utilization of and Adherence to Guideline-Recommended Lipid-Lowering Therapy After Acute Coronary Syndrome Opportunities for Improvement Benjamin J. Hirsh, MD,* Nathaniel R. Smilowitz, MD,y Robert S. Rosenson, MD,* Valentin Fuster, MD, PHD,* Laurence S. Sperling, MDz

ABSTRACT In addition to aggressive lifestyle and nonlipid risk factor modification, statin therapy improves cardiovascular disease outcomes following acute coronary syndromes. Despite established benefits of treatment, contemporary registries reveal substantial underutilization of and nonadherence to statin therapy for secondary prevention. In randomized controlled trials investigating statin therapy, including moderate-intensity statin plus ezetimibe therapy, rates of nonadherence are reported in up to 40% of subjects. Durable strategies to address gaps in lipid lowering for secondary prevention are essential to maximize reduction in cardiovascular disease risk. (J Am Coll Cardiol 2015;66:184–92) © 2015 by the American College of Cardiology Foundation.

L

ipid lowering with 3-hydroxy-3-methyl-glu-

that statin therapy reduces cardiovascular disease

taryl-CoA reductase inhibitor (statin) therapy

(CVD) events by 25% to 40% and that these benefits

is essential for secondary prevention after

accrue within the first 6 months after ACS (3,4).

acute coronary syndromes (ACS) in combination

Consequently, high-intensity statin therapy before

with an antiplatelet agent, beta-blocker, angio-

hospital discharge after ACS is a Class I, Level of Evi-

tensin-converting enzyme inhibitor, or angiotensin

dence: A guideline-recommendation, irrespective of

receptor antagonist, and intensive lifestyle and

baseline LDL-C level (5).

risk factor modifications, including weight reduction

Despite these established benefits, contemporary

in overweight individuals, smoking cessation, and

registries reveal substantial underutilization of and

aerobic exercise. Statin therapy lowers concentra-

nonadherence to statin prescriptions for secondary

tions of low-density lipoprotein-cholesterol (LDL-C)

prevention after ACS. In RCTs investigating the

and other apolipoprotein-B–containing lipoproteins,

efficacy of statin therapy on CVD outcomes after

reduces arterial inflammation, stabilizes the lipid

ACS, including the recently reported IMPROVE-

core, and promotes regression of atherosclerosis

IT

(1,2). Randomized clinical trials (RCTs) have shown

Efficacy International Trial), up to 40% of patients

(IMProved

Reduction

of

Outcomes:

From the *Cardiovascular Institute, Mount Sinai Medical Center, Icahn School of Medicine at Mount Sinai, New York, New York; yDivision of Cardiology, Department of Medicine, New York University School of Medicine, New York, New York; and the zDivision of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia. Dr. Rosenson has received institutional grants from Amgen, AstraZeneca, and Sanofi; has received consulting fees from Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, GlaxoSmithKline, Novartis, Regeneron, and Sanofi; and has received royalties from UpToDate, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. P. K. Shah, MD, served as the Guest Editor for this paper. Listen to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster. Manuscript received April 6, 2015; revised manuscript received May 15, 2015, accepted May 25, 2015.

Vytorin

Hirsh et al.

JACC VOL. 66, NO. 2, 2015 JULY 14, 2015:184–92

discontinued the study medication prematurely (6).

admission were prescribed the high-intensity

ABBREVIATIONS

Clinical practice registries demonstrate even higher

dose at discharge.

AND ACRONYMS

nonadherence rates. Other clinical trials and registries

Other registries have reported similar

following

findings. In the United States and Europe,

discontinuation of statin therapy after ACS (2,7).

23% to 38% of patients hospitalized for MI are

Suboptimal pharmacologic LDL-C lowering after ACS

prescribed maximal-intensity statin therapy

can be attributed to statin underutilization (Table 1)

at discharge (11–13). An observational study of

and to medication nonadherence (Tables 2 and 3).

6,748 patients at 31 U.S. hospitals enrolled in

have

reported

185

Lipid Lowering After ACS

higher

mortality

rates

ACS = acute coronary syndrome(s)

CVD = cardiovascular disease FDC = fixed-dose combination therapy

LDL-C = low-density-

both the PREMIER (Prospective Registry

lipoprotein cholesterol

UNDERUTILIZATION OF

Evaluating Myocardial Infarction: Events and

STATIN THERAPY AFTER ACS:

MI = myocardial infarction

Recovery) and the TRIUMPH (Translational

CONTEMPORARY EVIDENCE

RCT = randomized controlled

Research Investigating Underlying disparities

trial

in acute Myocardial infarction Patients’ Health status) In a recent issue of the Journal, Maddox et al. (8)

registries (11) found that although 88% of patients

used the National Cardiovascular Data Registry’s

were prescribed a statin at discharge after ACS,

PINNACLE (Practice Innovation and Clinical Excel-

only 1 in 3 were prescribed a statin at goal dose. The

lence) database to assess the effect of the 2013

TRIUMPH registry defined the goal dose as achieving

American College of Cardiology/American Heart As-

>75% of maximal statin potency (approximately a

sociation cholesterol guidelines (5) on current car-

50% to 60% reduction in LDL-C), which included:

diovascular practice in the United States. In the

atorvastatin 40 to 80 mg, lovastatin 80 mg, pravas-

cohort of 1,174,545 patients age 18 years or older,

tatin 80 mg, rosuvastatin 20 to 40 mg, or simvastatin

1,029,633 (91.2%) were eligible for statins on the

80 mg daily.

basis of known atherosclerotic CVD. Among patients

These failures to prescribe statins or to maximize

with atherosclerotic CVD, 506,009 (49.9%) received

statin intensity suggest a lack of knowledge regarding

statin therapy only; 200,789 (20.0%) received both

the benefits of high-dose statin therapy over moder-

statin

ate- or low-dose statin therapy (14), as demonstrated

and

nonstatin

therapies;

28,887

(2.9%)

received nonstatin therapy only; and 285,211 (27.9%)

in clinical trials of ACS patients (3,15). For example, the

patients did not receive any lipid-lowering medica-

most important predictor of change to a high-intensity

tion. These findings suggest that a large number of

statin was the dosage the patient received before the

patients lack optimized lipid management. Similar

ACS event (10), suggesting a continued treatment

findings were reported in a recent analysis of sec-

focus on LDL-C levels, lack of knowledge regarding the

ondary prevention in patients with a history of

benefits of high-intensity statins, or clinical inertia.

myocardial infarction (MI) from the large National

Underutilization of high-intensity statin diminished

Health

(9).

progressively in the year after the ACS event. Frag-

Although statin use in the United States increased

mented care in inpatient and ambulatory settings and

over the past decade from 36% in 1999 to nearly 73%

poor communication between community-care pro-

in 2012 (p ¼ 0.04), opportunities exist to improve

viders and specialists may limit provider attention to

risk reduction and lipid lowering for the 27% of pa-

starting statin therapy or dose optimization. To

tients who are not currently taking statin therapy

improve decision-making and statin utilization for

after ACS.

older patients with multiple comorbidities on several

and

Nutrition

Examination

Survey

The statin dose prescribed after ACS is also a

medications, physicians may need alternative guide-

concern. A separate publication in the Journal

lines that address concerns for possible medication

examined a sample of Medicare beneficiaries who

interactions with statins (16). Nurse-managed pro-

were prescribed a statin at discharge following a

tocols may provide another useful approach in

hospitalization for ACS from 2007 to 2009 (10). Only

improving outpatient implementation of guideline-

27.0% of prescriptions filled were for a high-intensity

directed measures and promoting adherence of pa-

statin, which increased to only 35% within 365 days

tients with multiple medical comorbidities (17).

from the discharge date. Among patients not taking

Shorter hospitalizations for acute MI over the

statins before admission, 23.1% were prescribed a

past decade permit less time for dose titration

high-intensity statin at discharge. Only 9.4% of

before discharge. Moreover, current performance

patients treated with a low- to moderate-intensity

measures credit providers for any dose of guideline-

statin before admission were prescribed a high-

recommended medication, even a low/moderate-

intensity statin at discharge. In contrast, 80.7% of

intensity statin (11). Although specific reasons for

patients treated with a high-intensity statin before

statin nonprescription, such as prior intolerance, may

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Lipid Lowering After ACS

T A B L E 1 Underutilization of Statin Therapy for Secondary Prevention

Statin Prescribed

First Author (Ref. #)

Registry

Years

N

Rosenson et al. (10)

CMS

2006–2010

8,762 1,029,633

Inclusion Criteria

27%*

Medicare beneficiaries 65–74 yrs of age who filled a statin prescription after a CHD event

72%†

Adults with confirmed ASCVD

Maddox et al. (8)

PINNACLE

2008–2012

Arnold et al. (11)

TRIUMPH

2005–2008

Arnold et al. (12)

PREMIER þ TRIUMPH

2003–2008

Javed et al. (13)

GWTG

2005–2009

Ho et al. (32)

KPCO CAD Registry

2000–2005

15,767

86%†

Patients in CAD registry with prior MI, PCI, or CABG

Ho et al. (51)

PREMIER

2003–2004

2,498

80%†

Adults hospitalized with ACS, discharged alive

4,271

91%†/23%‡

Adults hospitalized with ACS, discharged alive, no contraindications to statin

6,748

88%§/33%k

Adults hospitalized with ACS, discharged alive

65,396

89%†/38%*

Adults hospitalized with ACS, prescribed lipid-lowering therapy at discharge

*Intensive lipid-lowering therapy with atorvastatin 40 or 80 mg, rosuvastatin 20 or 40 mg, simvastatin 80 mg, or statin of any dose þ ezetimibe þ any statin therapy. †Any statin therapy. ‡Maximally potent statin (rosuvastatin 20 to 40 mg or atorvastatin 80 mg) at hospital discharge. §Any statin therapy at hospital discharge. kStatin at $75% of the target dose at hospital discharge. ACS ¼ acute coronary syndrome(s), ASCVD ¼ atherosclerotic cardiovascular disease; CABG ¼ coronary artery bypass graft; CAD ¼ coronary artery disease; CHD ¼ congenital heart disease; CMS ¼ Centers for Medicare and Medicaid Services; GWTG ¼ Get With The Guidelines; KPCO ¼ Kaiser-Permanente of Colorado; MI ¼ myocardial infarction; PCI ¼ percutaneous coronary intervention; PINNACLE ¼ Practice Innovation And Clinical Excellence; PREMIER ¼ Prospective Registry Evaluating Myocardial Infarction: Events and Recovery; TRIUMPH ¼ Translational Research Investigating Underlying disparities in acute Myocardial infarction Patients’ Health status.

account for some treatment gaps in quality of care

atorvastatin dose due to laboratory abnormalities or

metrics at discharge, further studies are required to

side effects; the remainder stopped due to patient or

understand and address deficiencies. Continued

physician preference (14). In-depth focus on the

monitoring of practice patterns will facilitate health

rationale for premature study drug discontinuation

care delivery of optimal therapies for secondary pre-

in clinical trials, commonly ascribed to patient or

vention (18).

physician preference, may inform explanations for statin discontinuation in routine clinical practice. In

NONADHERENCE TO STATIN THERAPY FOR

large, real-world registries of patients with CHD,

SECONDARY PREVENTION

adherence to statin therapy is even lower than in

IMPROVE-IT is the first clinical outcomes trial to

In addition to statin underutilization, nonadherence

clinical trials and can reach 50% at 1 year (Table 3). show that statin therapy plus a nonstatin LDL-C–

to lipid-lowering therapy for secondary prevention

lowering treatment reduces CVD in patients who

remains an important obstacle to CVD event reduc-

are at high risk of recurrent CVD events. Even in

tion (Central Illustration).

this well-designed trial, 42% of subjects prematurely

Adherence refers to the extent to which a pa-

discontinued the study therapy, likely reducing

tient’s medication-taking practice coincides with

the treatment effect in both arms and leading to

prescribed medical recommendations (20). Although

underestimation of the observed benefit. The ave-

many patient characteristics can affect statin effi-

rage annualized rate of statin discontinuation in

cacy, nonadherence is among the most important

IMPROVE-IT is similar to that in other large RCTs

determinants of outcome. Rasmussen et al. (21)

of statin therapy for secondary prevention (Table 2).

demonstrated that increasing levels of statin ad-

The highest annual rates of statin discontinuation

herence are inversely associated with LDL-C and

were reported in the A to Z (Aggrastat to Zocor) (19)

mortality after ACS. Only 50% to 60% of patients

and PROVE IT-TIMI 22 (Pravastatin or Atorvastatin

remain adherent within 1 year of initiation, de-

Evaluation and Infection Therapy–Thrombolysis In

clining to 30% to 40% at 2 years (22,23). Non-

Myocardial Infarction 22) (14) trials, with >30% of

adherence is multifactorial and is influenced by

patients discontinuing therapy over the course of

demographic and socioeconomic factors, lifestyle

follow-up. In the majority (55%) of cases in the A to

habits, time since last provider visit, adverse effects

Z trial, the study statin was discontinued due to

of therapy, and complex medication regimens (24).

physician or patient preference, with adverse expe-

Nonadherence affects all guideline-directed medical

riences or events accounting for 28% of premature

therapy, including LDL-C–lowering therapy. A mul-

discontinuation (19). In the PROVE IT-TIMI 22 study,

timodality, systems-based, incentive approach may

only

be necessary to overcome these barriers.

5.3%

of

patients

discontinued

the

study

Hirsh et al.

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Lipid Lowering After ACS

T A B L E 2 Rates of Statin Discontinuation in RCTs With Statins Including Patients With Prior ACS

Study (Ref. #)

Year

N

Discontinuation of Statin Therapy

Statin Studied

Follow-Up Duration

Average Annual % Discontinuation

IMPROVE-IT (6)

2014

18,144

Simvastatin

42%

72 months*

7.0%

SEARCH (52)

2010

12,064

Simvastatin

27%

80 months†

4.1%

14%

58 months*

2.9%

IDEAL (53)

2005

8,888

Atorvastatin

TNT (54)

2005

10,001

Atorvastatin

A to Z (19)

2004

4,497

Simvastatin

34%

PROVE IT-TIMI 22 (14)

2004

4,162

Atorvastatin

HPS (55)

2002

20,536

Simvastatin

LIPID (56)

1998

9,014

CARE (57)

1996

4S (58)

1994

7%‡

59 months*

1%‡

24 months*

17.2%

30%

24 months†

15.2%

18%

60 months†

3.6%

Pravastatin

19%

73 months†

3.1%

4,159

Pravastatin

6%

60 months*

1.2%

4,444

Simvastatin

10%

65 months*

1.9%

*Median. †Mean. ‡Discontinuation due to treatment-related adverse events only. All-cause discontinuation was not reported. 4S ¼ Scandinavian Simvastatin Survival Study; ACS ¼ acute coronary syndrome(s); A to Z ¼ Aggrastat to Zocor; CARE ¼ Cholesterol and Recurrent Events; HPS ¼ Heart Protection Study; IDEAL ¼ Incremental Decrease in End Points Through Aggressive Lipid Lowering; IMPROVE-IT ¼ IMProved Reduction of Outcomes: Vytorin Efficacy International Trial; LIPID ¼ Long-Term Intervention with Pravastatin in Ischaemic Disease; PROVE IT-TIMI 22 ¼ Pravastatin or Atorvastatin Evaluation and Infection Therapy– Thrombolysis In Myocardial Infarction 22; RCT ¼ randomized controlled trial; SEARCH ¼ Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine; TNT ¼ Treating to New Targets.

MEASURING ADHERENCE

such as diaries. Questioning of patients during provider visits or through questionnaires can be sus-

Providers are currently not adept at recognizing

ceptible to misrepresentation and tend to over-

nonadherence (25). In qualitative studies, providers

estimate adherence (25,26). Pill counts, another

did not inquire about adherence in one-third of pa-

common approach to assess medication adherence,

tients with poor blood pressure control (26,27), sug-

appear to be simple and objective. However, patients

gesting a need for broader recognition of the

can switch medicines between bottles and may have

importance of nonadherence to outcomes, which will

an insufficient or excess quantity of pills that can

be increasingly linked to provider payment, posing

influence accuracy (26,27). Despite these biases,

both new challenges and opportunities. Measuring

poorer adherence, as measured by these methods, has

nonadherence is challenging, requiring integration of

been associated with adverse CVD events (24,27).

health services at multiple levels. Currently, adher-

Electronic monitoring devices and event monitors

ence is inferred on the basis of pill counts, blister

that record the timing and opening of bottles pro-

packs, and patient questionnaires or self-reports,

vide more reliable data on adherence dynamics over

T A B L E 3 Adherence to Statin Therapy for Secondary Prevention of CAD in Registry Databases

First Author (Ref. #)

Registry

Years

N

Statin Adherence

Ho et al. (51)

PREMIER

2003–2004

2,498

78.5%*

Ho et al. (32)

KPCO

2000–2005

13,596

74%†

Muntner et al. (23)

CMS Chronic Condition Data Warehouse

2007–2009

2,695

63.8%‡

53.6%†

Inclusion Criteria

Follow-Up (Yrs)

Adults hospitalized with ACS, discharged alive, no contraindications to statin

1

Patients in Kaiser CAD registry with prior MI, PCI, or CABG Medicare beneficiaries with CHD-related hospitalization, filled prescriptions for antihypertensive, initiation of statin therapy within 90 days of hospital discharge

4.1 1

Yang et al. (59)

Medicare Part D Enrollees

2005–2006

962,877

Medicare Part D enrollees with diabetes

0.5

Foody et al. (60)

PharmMetrics Patient Centric Database

2003–2005

11,331

50%§

Statin naïve adults with a prior cardiac event and $1 prescription for atorvastatin or simvastatin

0.75

Ye et al. (61)

MedStat MarketScan Commercial Claims and Encounters Database þ Medicare Supplemental and Coordination of Benefit Database

2000–2002

5,548

61.4%k

Patients who initiated statin treatment within 6 months of hospitalization for cardiovascular disease

1

*Interview with medication review. †Proportion of days covered $80%. ‡Proportion of days covered $50%. §Continuation without >60-day gap. kMedication possession ratio $80%. Abbreviations as in Table 1.

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Lipid Lowering After ACS

C ENT RAL I LLU ST RATI ON Lipid Lowering After ACS: Opportunities at Multiple Levels of Health Care Delivery to Address Challenges in Provider Utilization of and Patient Adherence to Statin Therapy After ACS

HEALTH SYSTEM FACTORS Challenges

Solutions

Challenges

• Limited access to medical care

• Education/media campaign

• Failure to prescribe statin therapy

• Multiple providers

• Coordination of care

• Failure to maximally intensify statins

• High copayments and insurance coverage • High drug costs • Clinical inertia

PATIENT FACTORS

PROVIDER BEHAVIOR

• Reduce or eliminate copayments • Pill burden reduction with fixed dose combination therapy (polypill)

• Failure to reintroduce statins • Time constraints

Solutions

Challenges

• Provider education • Clinical decision support tools (EMR prescribing alerts) • Adherence to guidelines

• Patient education

• Co-morbid conditions • Depression (particularly post-ACS)

• Participation in quality improvement programs

• Cognitive impairment • Caregiver involvement • Adverse reactions and intolerance to statins

• Dosing strategies for patients with presumed statin intolerance

• Automated pill counters

• Discharge counseling

• Lack of patient education

• Team-based approach

• Pharmacy refill tracking/reminders

Solutions

• Demographics, socioeconomics

• Polypharmacy • Drug-drug interactions • White coat adherence

• Re-challenge with statin in patients with a history of myalgia

• Smartphone reminder applications • Pill burden reduction with fixed dose combination therapy (polypill) • Once-daily medication dosing • Patient outreach programs • Caregiver participation • Cardiac rehabilitation

Optimal Statin Use After Acute Coronary Syndrome

Hirsh, B.J. et al. J Am Coll Cardiol. 2015; 66(2):184–92.

ACS ¼ acute coronary syndrome(s); EMR ¼ electronic medical record.

time and, therefore, greater insight into patients’

measurements and implementation of interventions

medication-taking behavior (28). Electronic medica-

to improve adherence will require strong clinical care

tion packaging devices are also being tested to

partnerships between multiple providers, pharma-

improve monitoring of adherence. Although these

cies, caregivers, and patients.

methods are used widely in research settings, there is limited data supporting their validity in routine

SOCIODEMOGRAPHICS AND

clinical practice, and variability in the quality of

HEALTH SYSTEMS

studies testing these devices complicates assessments of their efficacy (29). Other direct measures of

Lower-income earners, black or Hispanic women,

adherence, including measurements of medication

those without access to a caregiver, and patients with

levels or metabolites, were effective in improving

higher copayments are more likely to discontinue

blood pressure control for patients with resistant

statin treatment after MI (33). Several interventions

hypertension (30); however, these methods are

may improve adherence for these vulnerable pa-

currently too inconvenient and costly for routine

tients.

practice (24).

instructional checklists, educational drug fact pam-

Health

literacy

interventions,

including

Clinical support tools may also be used to facilitate

phlets, and national campaigns promoting disease

assessment of adherence. Other measures strongly

awareness, have illustrated the benefits of treatment.

associated with nonadherence include physiological

Providing information in the patient’s native lan-

markers, such as visit-to-visit variability in LDL-C

guage may lessen the burden of poor health literacy.

(31). More recently, electronic pharmacy refill data

Policy changes designed to overcome barriers to

have been utilized to monitor adherence; patients

care, such as elimination of out-of-pocket costs, the

with prescriptions filled $80% of the time are cate-

use of generic rather than brand-name medications,

gorized as adherent (32). This approach is gaining

and full coverage for preventative medications after

momentum, but requires that patients obtain pre-

MI, are cost-neutral with respect to overall health

scriptions within a closed pharmacy system. Reliable

care spending and have demonstrated improved

Hirsh et al.

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Lipid Lowering After ACS

adherence (34,35). Other health system barriers to

RECOGNIZING TEMPORAL PATTERNS

optimal secondary prevention include access to pro-

IN ADHERENCE

vider appointments, continuity of care, prescription of limited numbers of medication refills, and pro-

Patient adherence is greatest in the 5 days before and

viders’ competing priorities for patients with multiple

after an appointment with a provider, and diminishes

medical comorbidities (18). Other patient-level bar-

significantly thereafter; this is termed “white coat

riers to care include belief systems, varying expecta-

adherence” (41). Adherence can be improved by

tions

of

applying individualized surveillance through inter-

with

ventions including electronic medical prescription-

of

noticeable

treatment, benefits

forgetfulness, of

taking

and

lack

medications

filling records and use of reminder trigger systems.

apparent side effects (36). At an initial patient encounter, providers should

Currently, over 90% of the U.S. population owns a

gather data on drug insurance coverage, social

mobile phone, and recent efforts have demonstrated

support, and the role of the caregiver. The pro-

successful utilization of text messaging to understand

vider should assess the risk for medication non-

and improve adherence (42). Future trials that in-

adherence, evaluate reasons for forgetfulness (when

corporate this technology in the study design are

applicable), and consider the expectation of the

likely to improve adherence.

treatment outcome most valued by the patient.

The transition from the inpatient to the outpatient

Because physician time constraints can make such

setting is another crucial time period to monitor and

conversations impractical, team-based approaches

ensure adherence. A multimodal approach has been

may be necessary. In addition to outpatient nurse-

effective. Ho et al. (43) randomized 253 patients dis-

management protocols, pharmacy outreach pro-

charged after ACS from 4 centers to either a multi-

grams are effective in providing further education

faceted intervention to improve adherence or usual

on medications, monitoring, and reinforcing adher-

care. The intervention arm, combining education and

ence (31,37).

counseling at discharge with post-discharge communication with pharmacists and automated voice

LIFESTYLE AND COMORBID CONDITIONS

messages, demonstrated a 15.4% increase in adherence (89.3% vs. 72.9%; p ¼ 0.003) over the year

Obesity, smoking, alcohol consumption, and the

following discharge. Another approach improved

presence of medical comorbidities are associated with

early adherence by programming an electronic med-

nonadherence to statin therapy in secondary pre-

ical record–linked automated phone call reminder to

vention (32). Providers, family caregivers, and health

patients who did not fill a statin prescription 1 to 2

care systems must facilitate and support behavioral

weeks post-discharge (44).

changes. Cardiac rehabilitation is an underutilized intervention that demonstrates a significant effect on

ADVERSE EFFECTS OF

morbidity and mortality after MI, percutaneous cor-

LIPID-LOWERING THERAPY

onary intervention, or coronary artery bypass graft (38). In addition to improved health benefits through

Statin intolerance and concerns regarding adverse

enhanced physical activity and nutritional coun-

effects of statin therapy contribute to nonadherence.

seling, participants demonstrate >30% improvement

Many patients may be reluctant to begin statin ther-

in adherence to statin therapy (39).

apy due to concern for developing adverse events. In

Depression is an underappreciated predictor of statin

nonadherence

in

outpatients

with

RCTs, statin therapy causes only a slight increase in

CVD.

side effects compared with placebo. Statin intoler-

Recognition of the signs and symptoms of depression

ance ranges from approximately 1% to 10% in RCTs, to

and routine screening can provide important cli-

as high as 10% to 25% in observational studies (33,45).

nical information to physicians at both initial and

Myalgia, the most common reason for discontinua-

subsequent visits (40). Psychosocial support and

tion, occurs with similar frequency in both placebo

behavioral tools can be valuable for integrating

and treatment arms (45,46). In a recent systematic

medication adherence into daily life. Adherence may

analysis on myalgia prevalence reported by 26 statin

be improved by communication with open-ended

clinical trials, Ganga et al. (45) found an average

questions and shared decision-making. Likewise,

incidence of 12.7% in patients treated with statins

adherence to cardiovascular medications has been

compared with 12.4% in the placebo group (p ¼ 0.06),

linked to faith in the provider, suggesting that the

suggesting that both patients and physicians over-

quality of the patient-provider relationship may be an

estimate the frequency of statin-associated myalgia.

important determinant (24).

However, clinical trials included in this analysis did

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Lipid Lowering After ACS

not use a standard definition for statin-associated

adherence and outcomes in secondary prevention of

myalgia, and only 1 trial specifically queried patients

CVD.

regarding muscle problems.

In the UMPIRE (Effects of a Fixed Dose Combina-

Until large clinical trials incorporate uniform defi-

tion Strategy on Adherence and Risk Factors in Pa-

nitions and standardized assessment of myalgias,

tients with or at High Risk of CVD) trial (49), use of a

the incidence and prevalence of statin-induced my-

pill combining simvastatin with aspirin, lisinopril,

algias remains uncertain. Furthermore, pre-statin

and atenolol demonstrated a substantial improve-

assessments of myopathy, myalgias, and other

ment in self-reported adherence compared with usual

constitutional symptoms, such as fatigue, should be

care (86% in the FDC arm vs. 65% in the usual-care

performed to ensure that symptoms present at base-

arm; p < 0.001). Among patients nonadherent

line are not erroneously attributed to statin therapy.

before study enrollment, a marked improvement in

Notwithstanding these controversies, simple strate-

adherence was noted (77.2% in the FDC arm vs. 23.1%

gies to overcome intolerance to statins have been

in the standard-care arm; p < 0.01).

successful. Rechallenging with the same or a different

Most recently, the FOCUS (Fixed-Dose COmbina-

statin, reduced dosing, or alternate-day dosing have

tion Drug for Secondary Prevention PROJECT) trial

proven effective for 92.2% of patients who were

(50) tested adherence to the polypill versus its 3

initially intolerant of statins (46).

individual components (simvastatin 40 mg, aspirin

Misperceptions regarding the long-term safety

100 mg, and ramipril 2.5, 5, or 10 mg) in a randomly

and risk-benefit ratio of lipid lowering may also

selected population of 695 patients from 4 countries

contribute to nonadherence. Although statins can

following acute MI as part of phase 2 testing. After

increase the incidence of diabetes mellitus (1 addi-

9 months of follow-up, the polypill group demon-

tional case per 500 patients treated with intensive vs.

strated improved adherence compared with the

moderate-intensity statin therapy), existing data

group receiving 3 separate medications (50.8%

suggests that the CVD benefits outweigh this risk (47).

compared with 41%; p ¼ 0.019) without an increase

Patient counseling on

and pre-

in adverse effects, demonstrating the potential

emptively addressing concerns regarding adverse ef-

utility of this strategy in secondary prevention.

fects are important measures to improve adherence.

Notably, the study was not designed to assess

these

benefits

clinical outcomes.

PILL BURDEN AND FIXED-DOSE COMBINATION THERAPY

From a global health perspective, the polypill’s potential to improve CVD event reduction in secondary prevention is appealing for patients in

Guideline-recommended therapy for patients after

Western nations due to reduced complexity of

ACS specifies the use of multiple agents, including a

treatment, convenience, and ease of distribution. In

statin, aspirin, and often an (angiotensin-converting

lower-income countries, where CVD is projected to

enzyme) inhibitor and beta-blocker. Although cost

constitute the leading cause of death by 2030, its

may affect adherence, in the MI-FREEE (Post-

potential to deliver medications at lower cost is

Myocardial Infarction Free Rx Event and Economic

particularly appealing (20). Detractors express con-

Evaluation) trial (48), elimination of copayments

cerns regarding efficacy and the possibility that side

resulted in only a 4% to 6% improvement in adher-

effects from 1 component could lead to discontin-

ence. Overall rates of adherence to prescribed treat-

uation of treatment and loss of benefit from all

ment were <50% (even in the group with full

drugs in the formulation. Therefore, caution is

coverage) at a median follow-up of 394 days. There-

warranted, and larger clinical outcomes trials are

fore, other factors, including pill burden, may have a

needed.

greater effect on nonadherence than cost. Adherence to medication is inversely related to the number of pills and doses required per day (21).

CONCLUSIONS AND OUTLOOK: THE PRESENT AND FUTURE

Reduction of pill burden has demonstrated improvement in adherence, particularly in patients at high

Despite great advances in optimizing medical man-

risk for CVD (20,49). Fixed-dose combination therapy

agement

(FDC), or the polypill, contains medications that

achieving

address multiple CVD risk factors and is gaining mo-

Within the optimal conditions of recent clinical trials,

mentum for its potential to facilitate application of

patients continue to demonstrate high rates of non-

guideline-recommended therapy (20). The polypill is

adherence after ACS. Multiple large database regis-

now under investigation as a measure to improve

tries report even greater rates of nonadherence and

after

ACS,

fundamental

cardiovascular

risk

challenges

reduction

to

remain.

Hirsh et al.

JACC VOL. 66, NO. 2, 2015 JULY 14, 2015:184–92

Lipid Lowering After ACS

underutilization of high-intensity statin therapy.

pressure

These failures have an enormous effect on achieving

Although a well-designed clinical outcomes trial

medication

use

in

high-risk

patients.

improved outcomes.

supports combination therapy with a statin plus

Guidelines, enhanced quality metrics, coordina-

ezetimibe to reduce CVD events in ACS patients,

tion of care, and outpatient outreach programs offer

increasing provider awareness of guideline-driven

mechanisms to improve implementation of system-

high-intensity statin utilization and patient adher-

based approaches to optimal prescribing. Strategies

ence to all forms of therapy may be more important

that incorporate strong clinical care partnerships

ways to improve clinical outcomes.

to address nonadherence to smoking cessation, hypertension control, exercise programs, and lipid

REPRINT

management will result in improved outcomes after

Dr. Laurence S. Sperling, Department of Medicine,

REQUESTS

AND

CORRESPONDENCE:

ACS. The polypill is a strategy that offers a viable,

Division of Cardiology, Emory University, 1365 Clifton

simple, and highly effective intervention to over-

Road, Northeast, Building A, Suite 2200, Atlanta,

come nonadherence to antiplatelet, lipid, and blood

Georgia 30322. E-mail: [email protected].

REFERENCES 1. Tawakol A, Fayad ZA, Mogg R, et al. Intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation: results of a multicenter fluorodeoxyglucose-positron emission tomography/computed tomography feasibility study. J Am Coll Cardiol 2013;62:909–17. 2. Puri R, Libby P, Nissen SE, et al. Long-term effects of maximally intensive statin therapy on changes in coronary atheroma composition: insights from SATURN. Eur Heart J Cardiovasc Imaging 2014;15:380–8. 3. Lee KH, Jeong MH, Kim HM, et al. Benefit of early statin therapy in patients with acute myocardial infarction who have extremely low low-density lipoprotein cholesterol. J Am Coll Cardiol 2011;58:1664–71. 4. Berent R, Berent T, Karkutli E, et al. Influence of high-dose highly efficient statins on short-term mortality in patients undergoing percutaneous coronary intervention with stenting for acute coronary syndromes. Am J Cardiol 2014;114: 1128–9.

National Health and Nutrition Examination Surveys (NHANES), 1999–2012. J Am Heart Assoc 2015;4:e001709.

outpatients: the American College of Cardiology and National Cardiovascular Data Registry’s PINNACLE (Practice Innovation And Clinical

10. Rosenson RS, Kent ST, Brown TM, et al. Un-

Excellence) program. J Am Coll Cardiol 2010;56: 8–14.

derutilization of high-intensity statin therapy after hospitalization for coronary heart disease. J Am Coll Cardiol 2015;65:270–7. 11. Arnold SV, Spertus JA, Masoudi FA, et al. Beyond medication prescription as performance measures: optimal secondary prevention medication dosing after acute myocardial infarction. J Am Coll Cardiol 2013;62:1791–801. 12. Arnold SV, Kosiborod M, Tang F, et al. Patterns of statin initiation, intensification, and maximization among patients hospitalized with an acute myocardial infarction. Circulation 2014;129: 1303–9. 13. Javed U, Deedwania PC, Bhatt DL, et al. Use of intensive lipid-lowering therapy in patients hospitalized with acute coronary syndrome: an analysis of 65,396 hospitalizations from 344 hospitals participating in Get With The Guidelines (GWTG).

5. Stone NJ, Robinson JG, Lichtenstein AH, et al.

Am Heart J 2011;161:418–24.e1–3.

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;63:2889–934.

14. Cannon CP, Braunwald E, McCabe CH, et al.,

6. Cannon CP, Blazing MA, Giugliano RP, et al., for the IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387–97. 7. Navarese EP, Kowalewski M, Andreotti F, et al. Meta-analysis of time-related benefits of statin therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Am J Cardiol 2014;113:1753–64.

for the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350: 1495–504. 15. Leeper NJ, Ardehali R, deGoma EM, et al. Statin use in patients with extremely low low-

19. de Lemos JA, Blazing MA, Wiviott SD, et al., for the A to Z Investigators. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004;292:1307–16. 20. Sanz G, Fuster V. Prevention: polypills for cardiovascular prevention: a step forward? Nat Rev Cardiol 2013;10:683–4. 21. Rasmussen JN, Chong A, Alter DA. Relationship between adherence to evidence-based pharmacotherapy and long-term mortality after acute myocardial infarction. JAMA 2007;297:177–86. 22. Lauffenburger JC, Robinson JG, Oramasionwu C, et al. Racial/ethnic and gender gaps in the use of and adherence to evidence-based preventive therapies among elderly Medicare part D beneficiaries after acute myocardial infarction. Circulation 2014;129:754–63. 23. Muntner P, Yun H, Sharma P, et al. Ability of low antihypertensive medication adherence to predict statin discontinuation and low statin adherence in patients initiating treatment after a coronary event. Am J Cardiol 2014;114:826–31. 24. Ho PM, Bryson CL, Rumsfeld JS. Medication adherence: its importance in cardiovascular outcomes. Circulation 2009;119:3028–35.

density lipoprotein levels is associated with improved survival. Circulation 2007;116:613–8.

25. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353:487–97.

16. Fried TR, Tinetti ME, Iannone L. Primary care clinicians’ experiences with treatment decision making for older persons with multiple conditions. Arch Intern Med 2011;171:75–80.

26. Cutler DM, Everett W. Thinking outside the pillbox—medication adherence as a priority for health care reform. N Engl J Med 2010;362:1553–5.

8. Maddox TM, Borden WB, Tang F, et al. Implications of the 2013 ACC/AHA cholesterol guidelines for adults in contemporary cardiovascular practice: insights from the NCDR PINNACLE registry. J Am Coll Cardiol 2014;64:2183–92.

17. Shaw RJ, McDuffie JR, Hendrix CC, et al. Effects of nurse-managed protocols in the outpatient management of adults with chronic

9. Shah NS, Huffman MD, Ning H, et al. Trends in myocardial infarction secondary prevention: The

18. Chan PS, Oetgen WJ, Buchanan D, et al. Cardiac performance measure compliance in

conditions: a systematic review and meta-analysis. Ann Intern Med 2014;161:113–21.

27. Zimolzak AJ, Spettell CM, Fernandes J, et al. Early detection of poor adherers to statins: applying individualized surveillance to pay for performance. PLoS One 2013;8:e79611. 28. Sutton S, Kinmonth AL, Hardeman W, et al. Does electronic monitoring influence adherence to medication? Randomized controlled trial of measurement reactivity. Ann Behav Med 2014;48:293–9.

191

192

Hirsh et al.

JACC VOL. 66, NO. 2, 2015 JULY 14, 2015:184–92

Lipid Lowering After ACS

29. Checchi KD, Huybrechts KF, Avorn J, et al. Electronic medication packaging devices and medication adherence: a systematic review. JAMA 2014;312:1237–47.

study of the dynamics of statin use. Arch Intern Med 2007;167:847–52.

30. Brinker S, Pandey A, Ayers C, et al. Therapeutic drug monitoring facilitates blood pressure control in resistant hypertension. J Am Coll Cardiol 2014; 63:834–5.

cardiovascular preventive treatment (INTERACT trial). PLoS One 2014;9:e114268.

31. Mann DM, Glazer NL, Winter M, et al. A pilot study identifying statin nonadherence with visitto-visit variability of low-density lipoprotein cholesterol. Am J Cardiol 2013;111:1437–42. 32. Ho PM, Magid DJ, Shetterly SM, et al. Medication nonadherence is associated with a broad range of adverse outcomes in patients with coronary artery disease. Am Heart J 2008;155:772–9.

42. Wald DS, Bestwick JP, Raiman L, et al. Randomised trial of text messaging on adherence to

43. Ho PM, Lambert-Kerzner A, Carey EP, et al. Multifaceted intervention to improve medication adherence and secondary prevention measures after acute coronary syndrome hospital discharge: a randomized clinical trial. JAMA Intern Med 2014; 174:186–93. 44. Derose SF, Green K, Marrett E, et al. Automated outreach to increase primary adherence to cholesterol-lowering medications. JAMA Intern Med 2013;173:38–43.

33. Wei MY, Ito MK, Cohen JD, et al. Predictors of statin adherence, switching, and discontinuation in the USAGE survey: understanding the use of sta-

45. Ganga HV, Slim HB, Thompson PD. A systematic review of statin-induced muscle problems in clinical

tins in America and gaps in patient education. J Clin Lipidol 2013;7:472–83.

46. Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med 2013;158:526–34.

34. Choudhry NK, Fischer MA, Avorn JL, et al. The impact of reducing cardiovascular medication copayments on health spending and resource utilization. J Am Coll Cardiol 2012;60:1817–24. 35. Gagne JJ, Choudhry NK, Kesselheim AS, et al. Comparative effectiveness of generic and brandname statins on patient outcomes: a cohort study. Ann Intern Med 2014;161:400–7. 36. Vawter L, Tong X, Gemilyan M, et al. Barriers to antihypertensive medication adherence among adults–United States, 2005. J Clin Hypertens (Greenwich) 2008;10:922–9. 37. Schnipper JL, Kirwin JL, Cotugno MC, et al. Role of pharmacist counseling in preventing adverse drug events after hospitalization. Arch Intern Med 2006;166:565–71. 38. Sandesara PB, Lambert CT, Gordon NF, et al. Cardiac rehabilitation and risk reduction: time to “rebrand and reinvigorate.” J Am Coll Cardiol 2015;65:389–95. 39. Shah ND, Dunlay SM, Ting HH, et al. Longterm medication adherence after myocardial infarction: experience of a community. Am J Med 2009;122:961.e7–13. 40. Gehi A, Haas D, Pipkin S, et al. Depression and medication adherence in outpatients with coronary heart disease: findings from the Heart and Soul Study. Arch Intern Med 2005;165:2508–13. 41. Brookhart MA, Patrick AR, Schneeweiss S, et al. Physician follow-up and provider continuity are associated with long-term medication adherence: a

trials. Am Heart J 2014;168:6–15.

47. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a metaanalysis. JAMA 2011;305:2556–64. 48. Choudhry NK, Avorn J, Glynn RJ, et al., for the Post-Myocardial Infarction Free Rx Event and Economic Evaluation (MI FREEE) Trial. Full coverage for preventive medications after myocardial infarction. N Engl J Med 2011;365:2088–97. 49. Thom S, Poulter N, Field J, et al., for the UMPIRE Collaborative Group. Effects of a fixeddose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial. JAMA 2013;310: 918–29. 50. Castellano JM, Sanz G, Peñalvo JL, et al. A polypill strategy to improve adherence: results from the FOCUS project. J Am Coll Cardiol 2014; 64:2071–80. 51. Ho PM, Spertus JA, Masoudi FA, et al. Impact of medication therapy discontinuation on mortality after myocardial infarction. Arch Intern Med 2006;166:1842–7. 52. Meade T, Sleight P, Collins R, et al., for the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet 2010;376: 1658–69.

53. Pedersen TR, Faergeman O, Kastelein JJ, et al., for the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 2005;294:2437–45. 54. LaRosa JC, Grundy SM, Waters DD, et al., for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425–35. 55. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22. 56. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349–57. 57. Sacks FM, Pfeffer MA, Moye LA, et al., for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335:1001–9. 58. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–9. 59. Yang Y, Thumula V, Pace PF, et al. Predictors of medication nonadherence among patients with diabetes in Medicare Part D programs: a retrospective cohort study. Clin Ther 2009;31:2178–88, discussion 2150–1. 60. Foody JM, Joyce AT, Rudolph AE, et al. Persistence of atorvastatin and simvastatin among patients with and without prior cardiovascular diseases: a US managed care study. Curr Med Res Opin 2008;24:1987–2000. 61. Ye X, Gross CR, Schommer J, et al. Association between copayment and adherence to statin treatment initiated after coronary heart disease hospitalization: a longitudinal, retrospective, cohort study. Clin Ther 2007;29:2748–57.

KEY WORDS adherence, ezetimibe, low-density lipoprotein cholesterol, secondary prevention, statin therapy