REVIEW URRENT C OPINION
Improving lipid control following myocardial infarction Jyoti Ankam, David I. Feldman, Michael J. Blaha, and Seth S. Martin
Purpose of review Following a myocardial infarction, lipid-lowering therapy is an established intervention to reduce the risk of recurrent cardiovascular events. Prior studies show a need to improve clinical practice in this area. Here, we review the latest research and perspectives on improving postmyocardial infarction lipid control. Recent findings Dyslipidemia and myocardial infarction remain leading causes of global disability and premature mortality throughout the world. The processes of care in lipid control involve multiple patient-level, provider-level, and healthcare system-level factors. They can be challenging to coordinate. Recent studies show suboptimal use of early high-intensity statin therapy and overall lipid control following myocardial infarction. Encouragingly, lipid control has improved over the last decade. Implementation science has identified checklists as an effective tool. At the top of the checklist for reducing atherogenic lipids and recurrent event risk postmyocardial infarction is early high-intensity statin therapy. Smoking cessation and participation in cardiac rehabilitation are also priorities, as are lifestyle counseling, promotion of medication adherence, ongoing lipid surveillance, and medication management. Summary Optimizing lipid control could further enhance clinical outcomes after myocardial infarction. Keywords cholesterol, lipids, lipoproteins, myocardial infarction, secondary prevention
INTRODUCTION Following myocardial infarction (MI), residual atherosclerotic cardiovascular disease (CVD) risk persists as an unresolved challenge [1–3]. Although such risk relates to multiple risk factors [2], suboptimal lipid control is a major component of modifiable risk. Residual long-term elevation of atherogenic lipids is thought to promote the formation of new plaque and deleterious changes in preexisting plaques. Consequently, patients with poorly controlled lipids are exposed to increased risk of recurrent atherosclerotic cardiovascular disease events and death secondary to plaque rupture and thrombosis of vulnerable plaques. Lipid-lowering therapy is a key component of a comprehensive evidence-based approach to combating such risk [4 ,5–8]. In this article, we aim to update readers on advances in the literature on post-MI lipid control. We identify recent trends, highlight areas of uncertainty, and offer our perspective on how to improve implementation of lipid management in post-MI survivors. &
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GLOBAL BURDEN OF MYOCARDIAL INFARCTION MI is one of the leading causes of global disability and premature mortality. It is a dominant component of the current worldwide burden of CVD. Of the approximate 17.3 million (30%) global deaths attributable to CVD in 2008, an estimated 7.3 million were due to coronary heart disease (CHD) [9]. In the United States alone, an estimated 15.4 million people at least 20 years old have CHD; 7.6 million of this number have had an MI [10 ]. It is projected that this year 620 000 Americans will have a new MI (defined as first hospitalized MI or CHD death), and 295 000 will have a recurrent MI. &
Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, Maryland, USA Correspondence to Seth S. Martin, MD, Johns Hopkins Hospital, 1800 Orleans Street, Zayed 7125, Baltimore, MD 21287, USA. Tel: +1 410 614 1132; fax: +1 443 287 3180; e-mail: [email protected] Curr Opin Cardiol 2014, 29:454–466 DOI:10.1097/HCO.0000000000000093 Volume 29 Number 5 September 2014
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KEY POINTS MI is one of the leading causes of morbidity and premature mortality globally. Lipid control following MI has improved over the last decade but remains suboptimal. Suboptimal use of lipid-lowering therapies after MI exposes patients to residual cardiovascular risk. Improving lipid goal attainment rates by administering in-hospital and discharge high-intensity statins can reduce recurrent major adverse cardiovascular events and death. Other top priorities on the lipid control checklist are cardiac rehabilitation, lifestyle counseling, promotion of medication adherence, lipid surveillance, and therapeutic adjustment.
The American Heart Association predicts that every 44 s an American will experience an MI and 15% of those who do will not survive that event. The average number of years of life lost to an MI is 17.2. Survivors of MI have a 1.5 to 15 times higher chance of illness and death compared with the general population. Within 1 year after MI, 19% of men and 26% of women at least 45 years old will die. These data underscore the importance of optimizing post-MI care.
LATEST OBSERVATIONAL STUDIES SUPPORTING LIPID CONTROL POSTMYOCARDIAL INFARCTION Recent evidence reinforces the benefit of early statin administration and long-term persistence with such therapy. A retrospective cohort study of 36 842 patients diagnosed with MI from 1999 to 2008 in Spain (ARIAM Registry) showed that early statin administration in the first 24 h of MI was associated with significantly lower mortality [adjusted odds ratio (OR) 0.518, 95% confidence interval (CI) 0.447–0.601]. Long-term statin persistence was further related to lower mortality (adjusted OR 0.597, 95% CI 0.449–0.798) [11]. A recent meta-analysis of 14 randomized controlled trials involving 3146 MI patients undergoing percutaneous coronary intervention showed that early administration of statin therapy and long-term persistence were cardio-protective [12]. There was a 56% relative reduction in periprocedural MI (OR 0.44, 95% CI 0.35–0.56; P < 0.00001) in those who were administered a high-intensity statin prior to percutaneous coronary intervention (n ¼ 1591), suggesting a rapid onset of benefit with such therapy.
A post-hoc analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study examined the impact of ‘structured care’ titrating atorvastatin to lipid goal (starting dose 20 mg/day, uptitrated to 80 mg/day at 6-week intervals if low-density lipoprotein cholesterol (LDL-C) goal < 100 mg/dl not reached) vs. ‘usual care.’ The study population was made up of 1600 elderly (mean age 70) and young patients (mean age 50) with established CHD [13]. Although ‘structured care’ improved CVD outcomes in both the age groups, the absolute and relative risk reductions were greater in the elderly vs. younger patients [16.5% (P < 0.0001) vs. 8.5% (P ¼ 0.0001) and 60% (P < 0.0001) vs. 42% (P ¼ 0.0001), respectively]. This is an intriguing finding that requires further study, particularly given the Cholesterol Treatment Trialists found no heterogeneity by age in the relative CVD benefit of statin therapy [14]. The advantage of combining lipid-lowering therapy with other agents has been suggested by the results of recent studies. An exploratory analysis of the landmark GISSI Prevention Trial, involving 14 704 MI patients drawn from 117 hospitals in Italy, suggested that combining statins with omega-3 polyunsaturated fatty acids was associated with lower death or reinfarction rates compared with statin monotherapy (5.1 vs. 6.8 per 100 personyears, respectively) [15]. A retrospective observational study of 27 919 high-risk CHD patients on statin therapy evaluated LDL-C control over time in those treated with an ongoing statin monotherapy regimen (50.9%) vs. uptitration of the statin regimen (39.5%) vs. switching to an ezetimibe–simvastatin combination (9.6%). The relative LDL-C concentration at follow-up compared with baseline and attainment of LDL-C < 100 and more than 70 mg/dl (2.59 and 1.81 mmol/l, respectively) were significantly more favorable in the switch group (24.0%, 81.2%, and 35.2%, respectively) as compared with the uptitrated group (9.6%, 68.0%, and 18.4%, respectively) or the initial statin monotherapy group (4.9%, 72.2%, and 23.4%, respectively) [16]. A substudy of the Acute Coronary Syndrome Israeli Surveys of 8982 acute coronary syndrome patients addressed the question of combination lipid-lowering therapy vs. statin monotherapy. The researchers observed significantly better 30-day outcomes in those treated with the combination of a fibrate (mainly bezafibrate) and statin compared with those on statin monotherapy. The incidence of major adverse cardiac events (3.2% vs. 6.0%; P ¼ 0.01) and rehospitalization (15.6% vs. 19.8%; P ¼ 0.03) was lower in the combination group [17].
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Prevention
An analysis of 2258 women from the Nurses’ Health Study and 1840 men from the Health Professionals Follow-Up Study assessed the association of diet quality (measured by Alternative Healthy Eating Index 2010) with clinical outcomes in MI survivors. In adjusted analyses, improved diet quality was associated with 24–40% lower cardiovascular and all-cause mortality [18]. The importance of diet quality cannot be overemphasized, although smoking cessation is a fundamental priority in smokers. Enhancing levels of physical activity is also a core element of comprehensive post-MI care. Each of these elements should be addressed by ensuring participation in cardiac rehabilitation. Early comprehensive short-term cardiac rehabilitation was evaluated in an offshoot of the OMEGA study comprising 3560 post-MI patients. The investigators compared those attending and not attending such programmes. Total mortality (OR 0.46, 95% CI 0.27–0.77) and major cardiac adverse events (OR 0.53, 95% CI 0.38–0.75) were significantly lower in the rehabilitation group [19].
LATEST RANDOMIZED TRIALS ADDRESSING LIPID CONTROL FOLLOWING MYOCARDIAL INFARCTION Older landmark trials laid a foundation for lipidlowering therapy with statins and nonstatins postMI (Table 1). For many years, evidence has supported the superiority of statins in lowering lipids to goal levels. On the basis of multiple lines of evidence, it has been the prevailing view that nonstatin therapy should be added only when statin and lifestyle therapy are exhausted, and lipid levels not controlled. The most recent lipid trials [20–22] focused on raising high-density lipoprotein cholesterol (HDL-C) in patients with well-controlled atherogenic lipids. Unfortunately, the HDL-C raising strategy has not proven efficacious for reasons that have been examined elsewhere [20] and the clinical trial enterprise has met major recruitment challenges of late [23].
HOW ARE WE DOING IN LIPID CONTROL FOLLOWING MYOCARDIAL INFARCTION? Are we adequately controlling lipids in post-MI patients? Moreover, how adequate is ‘adequate’? The answers to these questions depend on where one is in the world, what guideline one follows, and measurement techniques (Table 2). Although now controversial in the United States [24,25], lowering LDL-C after acute MI to goal levels of less than 100 or less than 70 mg/dl (2.59 and 1.81 mmol/l, 456
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respectively) remains the standard of care elsewhere in the world [26,27 ,28 ]. We recently showed that US patients suffering MI in 2005–2008, who were not at LDL-C goal at baseline, met the less than 100 mg/dl goal in followup about two-thirds of the time [29 ]. This was a major improvement in comparison to studies from the prior decade. A 2013 analysis of the National Health and Nutrition Examination Surveys 1999– 2008 studying 18 656 high-risk US individuals showed a favorable trend in the proportions of CHD populations achieving LDL-C less than 100 and >> Risk IIa – Benefit >> Risk IIb – Benefit Risk III – No benefit/ harm. LOE (level of evidence): A – Multiple populations evaluated (multiple RCTs/ meta-analysis). B – Limited populations evaluated (single RCT/ non-RCT). C – Very limited populations evaluated (consensus opinion of experts, small case studies, registries or standard of care).
Minimum 30 min of aerobic Minimum 30 min of exercise (3–4 times/week; moderate-intensity ideally daily); rhythmic resistphysical activity on ance exercise of 10–15 most, if not all, days repetitions (Class I, LOE A); of the week (150 increase daily activities min/week), can be (Class I, LOE B); High risk done in shorter bouts pts: institutional cardiac of 10min and built rehab (Class I, LOE B) then up over time. Refer nonsupervised home exercise patients to a struc(Class IIa, LOE C) tured cardiac rehab program and/or exercise physiologist/ qualified fitness personnel
Reduce SFA intake to < 7% 200 g/day (2–3 servings) Moderate-energy foods, Limit SFA to < 7% and < 6 g/day of salt, reduce SFA Limit calories from SFA to intake to 7% of total caltFA to < 1% of calvegetables, fruits, of fruits and vegetables, of total calories, choles5–6%; reduce % calories ories, increase intake of n-3 whole-grains, PUFA and ories, consume 1 g/ terol to < 200 mg per day, < 5 g/day of salt, 30– from tFA; DASH, USDA, PUFA, limit cholesterol intake day EPA þ DHA and MUFA (n-3 FA) from and tFA to < 1% of energy 45 g/day of fiber from AHA diets (fruits, vegto 300 mg/day and fat > 2 g/day ALA whole grains, < 10% cal- fish, avoid tFA, limit (Class I, LOE B) etables, whole grains, (canola/soybean oils, intake to 25% of total calories from SFA, < 1% cal- SFA to 30 g/day, cholesterol eat mainly plantfish), moderate amounts NHLBI Grade A) based foods (fruits, < 200 mg/day (CR, of alcohol (men: 2 and vegetables, pulses, MQE); DASH, Mediterwomen: 1 glass/day); whole - grains), lean ranean, Portfolio patemphasis on Mediterrameat, fish and poultry terns (SR, HQE) nean diet
Diet
Non-pharmacologic Therapies (Lifestyle Modification)
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Prevention
Patient System
-Age -Race -Gender
-Dedicated funding to secondary prevention service
-Health-related beliefs
-Delivery system characteristics
-Literacy -Attitudes -Presence of co-morbidities
• Health policies • Resources • Administrative complexity • Provider availability and accessibility
-Insurance status
Provider -Prescribing patterns -Referral to cardiac rehabilitation -Provider communication • Patient education • Patient counseling
FIGURE 1. Processes of care in lipid control following myocardial infarction.
statin at discharge and make the patient an active part of the decision-making process. Third, to reduce copayment, offer the option of lower-cost generic statins. In particular, at least in the United States, atorvastatin 80 mg is now generic. Fourth, use medication reminder tools (e.g., pillbox and electronic reminder device). Fifth, encourage patient participation in cardiac rehabilitation programs [29 ]. From a system level, in order to overcome confusing discordances in guidelines (Table 2), we encourage the collaborative efforts of guideline developers around the world to develop international consensus guidelines that provide explicit evidence-based recommendations for the management of post-MI patients [39 ]. This would make it easier for healthcare systems to implement Health Information Technology (HIT) strategies (e.g., electronic health records and database monitoring) to standardize and improve post-MI follow-up lipid testing, drug initiation or titration or add-on or adherence, and referrals to cardiac rehabilitation centers [40]. Cutting-edge implementation science has identified the power of the checklist in promoting the consistent delivery of high-quality care [39 ]. &&
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STATINS: PRIORITIZE EARLY HIGHINTENSITY THERAPY AND LONG-TERM ADHERENCE We want to emphasize the importance of early statin prescription. Across the world, there is a near unanimous agreement on initiating statins in the acute phase of MI (ideally within 24 h) (Table 2) [11,41]. Overwhelming evidence exists in support of prescribing a high-intensity statin (Table 1) [4 ,5]. &
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Atorvastatin 80 mg daily, in particular, has been studied in the setting of MI [5]. Prioritizing early intensive statin therapy lowers the immediate risk of major cardiovascular events and also serves as a long-term investment in risk reduction. Statins are now recognized to act by mechanisms beyond lipid profile modification [42,43]. A broad range of ‘pleiotropic’ or nonlipid-mediated effects [atheroma plaque stabilization, anti-inflammatory, angiogenic, antithrombosis, antiarrhythmic, antioxidative, antiproliferative, C-reactive protein (CRP)-lowering, antibacterial, and immunomodulatory effects] have been identified. Although not fully understood, plaque-stabilizing properties through reduction of inflammation and improvement of endothelial function appear to play a significant role [44,45]. Promoting long-term adherence to statins is essential. In general, statins are well tolerated. However, concerns may arise related to myopathy, increased fatigue, elevated liver enzymes, worsening hyperglycemia, and incident diabetes [46]. Patientfocused interventions discussing reasons for prescription, benefits and potential adverse effects of statins, reinforcing the importance of regular follow-up, giving hand-outs about the disease condition and the treatment, and reaching out through e-mail, telephone, or mail to assess medication-taking behavior may be helpful. Healthcare delivery-focused interventions include easing the process of filling or refilling prescriptions, modifying treatment regimen by adding other lipid-lowering therapies (nonstatin drugs and therapeutic lifestyle changes), and expanding communication links between physicians, pharmacists, and other members of the care team [29 ,47]. &&
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ACS (NSTE-ACS, MI and STEMI < 48 h); 1060
Chinese ACS trial NCT02077257
MI, hypercholesterolemia; 18 141 MI; 1600
ACS; 13 000
Atherosclerotic CVD [including prior MI (> 4 weeks)]; 30 000
Recent ACS (< 52 weeks), 18 000 Clinically evident CVD at high risk for recurrent events, dyslipidemia; 22 500
Unstable/chronic CHD (including MI); 874
CAD (prior PCI, MI, or CABG); 90
IMPROVE-IT NCT00202878
OPTIMISE NCT01632878
SOLID-TIMI 52 NCT01000727
REVEAL NCT01252953
ODYSSEY NCT01663402
FOURIER NCT01764633
CORDIOPREV NCT00924937
TRiCH NCT02047942
Beyond statins
AMI; 140
Condition; Sample size
INTENSIFY NCT01923077
Statin trials
Ongoing trial/study
0268-4705 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins Center-based cardiac rehabilitation vs. home-based training with telemonitoring guidance
Low-fat diet (28% fat: 12% MUFA; 8% PUFA; 8% SAT) vs. Mediterranean Diet (34% fat: 22% MUFA; 6% PUFA; 7% SAT)
Evolocumab (AMG 145, PCSK9 inhibitor) þ effective statin (A20/equivalent) Ezetimibe vs. placebo þ effective statin
Alirocumab SAR236553 (REGN727, PCSK9 inhibitor) vs. placebo
Anacetrapib (CETP inhibitor) vs. placebo
Darapladib 160 mg (Lp-PLA2 inhibitor) vs. placebo
Omega-3 fatty acid esters þ standard treatment
Ezetimibe/Simvastatin 10/40 mg vs. Simvastatin 40 daily
Rosuvastatin 20 mg vs. 10 mg daily
Early Rosuvastatin (80 mg loading dose after randomization followed by 40 mg daily)
Intervention
Table 3. A review of ongoing statin and nonstatin clinical studies in the post-MI setting
Randomized, single-blind, multicenter
III
–
III
Randomized, multicenter, double-blinded, placebocontrolled
Randomized, double-blind, single-center, parallel study
III
Randomized, multicenter, double-blinded, placebocontrolled
III
III
Randomized, multicenter, double-blinded, placebocontrolled Randomized, multicenter, double-blinded, placebocontrolled
–
III
IV
II
Phase
Prospective, multicenter observational cohort
Randomized, multicenter, double-blind
Randomized, open label, multicenter
Randomized, open label, single-center
Design
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(Continued )
Exercise tolerance from baseline to 12 weeks and 1 year
MACE and lipid levels
MACE
MACE
Major coronary events [coronary death, myocardial infarction (MI) or coronary revascularization]
MACE, major coronary events and all-cause mortality
Recurrent nonfatal MI, sudden death or new congestive heart failure
MACE, major coronary events, stroke and CV death
LDL-C lowering efficacy and safety, lipid goal attainment
LV function and coronary plaque
Endpoint
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ACS, acute coronary syndrome; ACTonHEART, Randomized Controlled Clinical Trial of Acceptance and Commitment Therapy in Cardiac Patients; AMI, acute myocardial infarction; CABG, coronary artery bypass graft; CAD, coronary artery disease; CARDIOPREV, CORonary Diet Intervention With Olive Oil and Cardiovascular PREVention; CETP, cholesteryl ester transfer protein; CHD, coronary heart disease; CR, cardiac rehabilitation; CVD, cardiovascular disease; FOURIER, Further cardiovascular OUtcomes Research with pcsk9 Inhibition in subjects with Elevated Risk; IHD, ischemic heart disease; IMPROVE-IT, IMProved Reduction of Outcomes: Vytorin Efficacy International Trial; INTENSIFY, Early Intensive Treatment With Statins Improves Left Ventricular Function in Patients With Acute Myocardial Infarction; Lp-PLA2, lipoprotein-associated phospholipase 2; LV, left ventricular; MACE, major adverse cardiovascular event; MI, myocardial infarction; MUFA, monounsaturated fatty acid; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; ODYSSEY, A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Effect of Alirocumab (SAR236553/REGN727) on the Occurrence of Cardiovascular Events in Patients Who Have Recently Experienced an Acute Coronary Syndrome; OPTIMISE, Omacor Plus standard Therapies In post Myocardial Infarction Subjects Evaluation; PCI, percutaneous coronary intervention; PCSK9, proprotein convertase subtilisin/kexin type; PREMIER, Plaque Regression and Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen; PUFA, polyunsaturated fatty acid; REVEAL, Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification; SAT, saturated fatty acid; SOLID-TIMI, Stabilization of pLaques usIng Darapladib-Thrombolysis in Myocardial Infarction; STEMI, ST-elevation myocardial infarction; TRiCH, TeleRehabilitation in Coronary Heart disease.
Coronary plaque and endothelial progenitor cells III Randomized, multicenter, singleblind ACS patients undergoing PCI; 30 PREMIER NCT01004406
Atorvastatin 80 mg þ LDL – apheresis vs. guideline statin monotherapy
Modifiable risk factors (LDL-C, BP, BMI) and improvement of psychological well being – Randomized, single-blind, single-center Current IHD patients with CR referral; 160 ACTonHEART NCT01909102
Acceptance and Commitment Therapy vs. usual care
Condition; Sample size Ongoing trial/study
Table 3 (Continued)
Intervention
Design
Phase
Endpoint
Prevention
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Nonstatin lipid-lowering agents Nonstatin drugs are in an unresolved position in the US guidelines [4 ,25] (Tables 1 and 2). However, throughout most of the world, guidelines remain explicit that in post-MI patients with residually high levels of LDL-C and other atherogenic markers a high-intensity statin and lifestyle improvements may not suffice [27 ,28 ,48]. Additional, nonstatin therapy merits strong consideration as an ‘add on’ in the management of patients not achieving lipid goals [45]. &
&
&
Lifestyle modification A heart-healthy diet and physical activity are core components of post-MI lipid control. A Mediterranean style dietary pattern is one excellent choice. This is characterized by fresh fruits, green vegetables, whole grains, oily fish, extra-virgin olive oil, and low-fat or fat-free dairy. Other staples of the diet include poultry over red and processed meat, modest amounts of nuts, seeds and dry beans, herbs and spices in lieu of salt, and a moderate amount of red wine (mainly with meals) [18,49]. In smokers, as noted previously, complete cessation of smoking is fundamental in post-MI management. This is recognized in clinical practice guidelines internationally. The European Society of Cardiology guidelines recommend the provision of cessation advice and assistance (Class I. Level of evidence A, Strong GRADE) [48]. They advocate the 5 A’s as a smoking cessation strategy: Ask, Advise, Assess, Assist, and Arrange. The European Society of Cardiology guidelines also recommend avoiding exposure to passive smoke (Class I, LOE B, Strong GRADE). The early posthospital period is a vulnerable transition in which patients may feel uneasy about returning to activity. Medically supervised, exercisebased outpatient cardiac rehabilitation improves clinical outcomes and is an underutilized resource in recuperating MI patients [50]. When referring patients to rehab centers, issues such as accessibility, relevance, social (culturally sensitive, gender specific), economic (health insurance reimbursement), and psychological (stress management) needs should be addressed. A home-based rehab program advocating walking or working around the house may run parallel with the center-based program to further increase functional capacity and survival. Over the long term, maintenance of regular physical activity is essential. Moderate-to-intensive aerobic activity for 30–60 min at least 5 days/week (150 min/week) is desirable. Volume 29 Number 5 September 2014
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EMERGING THERAPIES Several trials and observational studies using statins and novel lipid-lowering drugs are currently underway, as summarized in Table 3 [44,45].
CONCLUSION For optimal lipid control, early high-intensity statin therapy is a top priority, in association with smoking cessation, cardiac rehabilitation, lifestyle counseling, promotion of medication adherence, ongoing lipid surveillance, and appropriate titration of medications. If patients, physicians, and healthcare systems focus attention on these factors, then continued improvements in lipid control and outcomes after MI will follow. Acknowledgements We did not receive any specific funding for this article. Dr Martin is supported by the Pollin Cardiovascular Prevention Fellowship, Marie-Jose´e and Henry R. Kravis endowed fellowship, and an NIH training grant (T32HL07024). Conflicts of interest Dr Martin is listed as a co-inventor on a pending patent filed by Johns Hopkins University for a method of lowdensity lipoprotein cholesterol estimation.
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Therapeutic practice patterns related to statin potency and ezetimibe/simvastatin combination therapies in lowering LDL-C in patients with high-risk cardiovascular disease. J Clin Lipidol 2014; 8:107–116. 17. Tenenbaum A, Medvedofsky D, Fisman EZ, et al. Cardiovascular events in patients received combined fibrate/statin treatment versus statin monotherapy: acute coronary syndrome Israeli Surveys data. PLoS One 2012; 7:e35298. 18. Li S, Chiuve SE, Flint A, et al. Better diet quality and decreased mortality among myocardial infarction survivors. JAMA Intern Med 2013; 173:1808–1818. 19. Rauch B, Riemer T, Schwaab B, et al. Short-term comprehensive cardiac rehabilitation after AMI is associated with reduced 1-year mortality: results from the OMEGA study. Eur J Prev Cardiol 2013; Apr 4. [Epub ahead of print] 20. Toth PP, Barter PJ, Rosenson RS, et al. High-density lipoproteins: a consensus statement from the National Lipid Association. J Clin Lipidol 2013; 7:484–525. 21. HPS2-THRIVE Investigators. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, prespecified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013; 34:1279–1291. 22. AIM-HIGH Investigators. Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011; 365:2255–2267. 23. Martin SS, Ou FS, Newby LK, et al. Patient- and trial-specific barriers to participation in cardiovascular randomized clinical trials. J Am Coll Cardiol 2013; 61:762–769. 24. Martin SS, Blumenthal RS. Concepts and controversies: the 2013 American College of Cardiology/American Heart Association risk assessment and cholesterol treatment guidelines. Ann Intern Med 2014; 160:356–358. 25. Martin SS, Abd TT, Jones SR, et al. 2013 American cholesterol treatment guideline: what was done well and what could be done better. J Am Coll Cardiol 2014; 63:2674–2678. 26. Ton VK, Martin SS, Blumenthal RS, Blaha MJ. Comparing the new European cardiovascular disease prevention guideline with prior American Heart Association guidelines: an editorial review. Clin Cardiol 2013; 36:E1–6. 27. Anderson TJ, Gregoire J, Hegele RA, et al. Are the ACC/AHA guidelines on & the treatment of blood cholesterol a game changer? A perspective from the Canadian Cardiovascular Society Dyslipidemia Panel. Can J Cardiol 2014; 30:377–380. This is the Canadian reaction to the new US lipid guidelines. 28. Ray KK, Kastelein JJ, Matthijs Boekholdt S, et al. The ACC/AHA 2013 & guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: the good the bad and the uncertain: a comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011. Eur Heart J 2014; 35:960–968. This is the European reaction to the new US lipid guidelines. 29. Martin SS, Gosch K, Kulkarni KR, et al. Modifiable factors associated with && failure to attain low-density lipoprotein cholesterol goal at 6 months after acute myocardial infarction. Am Heart J 2013; 165:26–33. This study identifies key modifiable factors warranting prioritization when implementing lipid control therapies post-MI and formed the primary motivation for the present review article. 30. Tattersall MC, Gangnon RE, Karmali KN, et al. Trends in low-density lipoprotein cholesterol goal achievement in high risk United States adults: longitudinal findings from the 1999–2008 National Health and Nutrition Examination Surveys. PLoS One 2013; 8:e59309.
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Prevention 31. Hambraeus K, Lindhagen L, Tyden P, et al. Target-attainment rates of lowdensity lipoprotein cholesterol using lipid-lowering drugs one year after acute myocardial infarction in Sweden. Am J Cardiol 2014; 113:17–22. 32. Martin SS, Blaha MJ, Elshazly MB, et al. Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications. J Am Coll Cardiol 2013; 62:732–739. 33. Martin SS, Blaha MJ, Toth PP, et al. Very large database of lipids: rationale and design. Clin Cardiol 2013; 36:641–648. 34. Martin SS, Blaha MJ, Elshazly MB, et al. Comparison of a novel method vs the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile. JAMA 2013; 310:2061–2068. 35. Elshazly MB, Martin SS, Blaha MJ, et al. Nonhigh-density lipoprotein cholesterol, guideline targets, and population percentiles for secondary prevention in 1.3 million adults: the VLDL-2 study (very large database of lipids). J Am Coll Cardiol 2013; 62:1960–1965. 36. Desai NR, Choudhry NK. Impediments to adherence to post myocardial infarction medications. Curr Cardiol Rep 2013; 15:322. 37. Wei MY, Ito MK, Cohen JD, et al. Predictors of statin adherence, switching, and discontinuation in the USAGE survey: understanding the use of statins in America and gaps in patient education. J Clin Lipidol 2013; 7:472–483. 38. Arnold SV, Kosiborod M, Tang F, et al. Patterns of statin initiation, intensifica& tion, and maximization among patients hospitalized with an acute myocardial infarction. Circulation 2014; 129:1303–1309. This study illuminates suboptimal statin intensification and maximization post-MI and significant variability across 24 US hospitals. 39. Pronovost PJ. Enhancing physicians’ use of clinical guidelines. JAMA 2013; && 310:2501–2502. This is a practical guide to optimal guideline implementation from a leader in implementation science and pioneer of the checklists approach.
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40. Aspry KE, Furman R, Karalis DG, et al. Effect of health information technology interventions on lipid management in clinical practice: a systematic review of randomized controlled trials. J Clin Lipidol 2013; 7:546–560. 41. Angeli F, Reboldi G, Mazzotta G, et al. Statins in acute coronary syndrome: very early initiation and benefits. Ther Adv Cardiovasc Dis 2012; 6:163–174. 42. Blaha MJ, Martin SS. How do statins work?: changing paradigms with implications for statin allocation. J Am Coll Cardiol 2013; 62:2392–2394. 43. Yousuf O, Mohanty BD, Martin SS, et al. High-sensitivity C-reactive protein and cardiovascular disease: a resolute belief or an elusive link? J Am Coll Cardiol 2013; 62:397–408. 44. Berman JP, Farkouh ME, Rosenson RS. Emerging anti-inflammatory drugs for atherosclerosis. Expert Opin Emerg Drugs 2013; 18:193–205. 45. Laufs U, Weintraub WS, Packard CJ. Beyond statins: what to expect from add-on lipid regulating therapy? Eur Heart J 2013; 34:2660–2665. 46. Mancini GB, Tashakkor AY, Baker S, et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Working Group Consensus update. Can J Cardiol 2013; 29:1553–1568. 47. Maningat P, Gordon BR, Breslow JL. How do we improve patient compliance and adherence to long-term statin therapy? Curr Atheroscler Rep 2013; 15:291. 48. Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013; 34:2949–3003. 49. Estruch R, Ros E. Eat a healthy diet and drink wisely to postpone dying if you survived a myocardial infarction?: yes, but randomized clinical trials are needed. JAMA Intern Med 2013; 173:1819–1820. 50. Leon AS. Cardiac rehabilitation and secondary prevention after acute MI. In: Essential cardiology. New York: Springer; 2013. pp. 495-503.
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Improving lipid control following myocardial infarction Jyoti Ankam, David I. Feldman, Michael J. Blaha, and Seth S. Martin
Purpose of review Following a myocardial infarction, lipid-lowering therapy is an established intervention to reduce the risk of recurrent cardiovascular events. Prior studies show a need to improve clinical practice in this area. Here, we review the latest research and perspectives on improving postmyocardial infarction lipid control. Recent findings Dyslipidemia and myocardial infarction remain leading causes of global disability and premature mortality throughout the world. The processes of care in lipid control involve multiple patient-level, provider-level, and healthcare system-level factors. They can be challenging to coordinate. Recent studies show suboptimal use of early high-intensity statin therapy and overall lipid control following myocardial infarction. Encouragingly, lipid control has improved over the last decade. Implementation science has identified checklists as an effective tool. At the top of the checklist for reducing atherogenic lipids and recurrent event risk postmyocardial infarction is early high-intensity statin therapy. Smoking cessation and participation in cardiac rehabilitation are also priorities, as are lifestyle counseling, promotion of medication adherence, ongoing lipid surveillance, and medication management. Summary Optimizing lipid control could further enhance clinical outcomes after myocardial infarction. Keywords cholesterol, lipids, lipoproteins, myocardial infarction, secondary prevention
INTRODUCTION Following myocardial infarction (MI), residual atherosclerotic cardiovascular disease (CVD) risk persists as an unresolved challenge [1–3]. Although such risk relates to multiple risk factors [2], suboptimal lipid control is a major component of modifiable risk. Residual long-term elevation of atherogenic lipids is thought to promote the formation of new plaque and deleterious changes in preexisting plaques. Consequently, patients with poorly controlled lipids are exposed to increased risk of recurrent atherosclerotic cardiovascular disease events and death secondary to plaque rupture and thrombosis of vulnerable plaques. Lipid-lowering therapy is a key component of a comprehensive evidence-based approach to combating such risk [4 ,5–8]. In this article, we aim to update readers on advances in the literature on post-MI lipid control. We identify recent trends, highlight areas of uncertainty, and offer our perspective on how to improve implementation of lipid management in post-MI survivors. &
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GLOBAL BURDEN OF MYOCARDIAL INFARCTION MI is one of the leading causes of global disability and premature mortality. It is a dominant component of the current worldwide burden of CVD. Of the approximate 17.3 million (30%) global deaths attributable to CVD in 2008, an estimated 7.3 million were due to coronary heart disease (CHD) [9]. In the United States alone, an estimated 15.4 million people at least 20 years old have CHD; 7.6 million of this number have had an MI [10 ]. It is projected that this year 620 000 Americans will have a new MI (defined as first hospitalized MI or CHD death), and 295 000 will have a recurrent MI. &
Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, Maryland, USA Correspondence to Seth S. Martin, MD, Johns Hopkins Hospital, 1800 Orleans Street, Zayed 7125, Baltimore, MD 21287, USA. Tel: +1 410 614 1132; fax: +1 443 287 3180; e-mail: [email protected] Curr Opin Cardiol 2014, 29:454–466 DOI:10.1097/HCO.0000000000000093 Volume 29 Number 5 September 2014
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Li pid control postmyocardial infarction Ankam et al.
KEY POINTS MI is one of the leading causes of morbidity and premature mortality globally. Lipid control following MI has improved over the last decade but remains suboptimal. Suboptimal use of lipid-lowering therapies after MI exposes patients to residual cardiovascular risk. Improving lipid goal attainment rates by administering in-hospital and discharge high-intensity statins can reduce recurrent major adverse cardiovascular events and death. Other top priorities on the lipid control checklist are cardiac rehabilitation, lifestyle counseling, promotion of medication adherence, lipid surveillance, and therapeutic adjustment.
The American Heart Association predicts that every 44 s an American will experience an MI and 15% of those who do will not survive that event. The average number of years of life lost to an MI is 17.2. Survivors of MI have a 1.5 to 15 times higher chance of illness and death compared with the general population. Within 1 year after MI, 19% of men and 26% of women at least 45 years old will die. These data underscore the importance of optimizing post-MI care.
LATEST OBSERVATIONAL STUDIES SUPPORTING LIPID CONTROL POSTMYOCARDIAL INFARCTION Recent evidence reinforces the benefit of early statin administration and long-term persistence with such therapy. A retrospective cohort study of 36 842 patients diagnosed with MI from 1999 to 2008 in Spain (ARIAM Registry) showed that early statin administration in the first 24 h of MI was associated with significantly lower mortality [adjusted odds ratio (OR) 0.518, 95% confidence interval (CI) 0.447–0.601]. Long-term statin persistence was further related to lower mortality (adjusted OR 0.597, 95% CI 0.449–0.798) [11]. A recent meta-analysis of 14 randomized controlled trials involving 3146 MI patients undergoing percutaneous coronary intervention showed that early administration of statin therapy and long-term persistence were cardio-protective [12]. There was a 56% relative reduction in periprocedural MI (OR 0.44, 95% CI 0.35–0.56; P < 0.00001) in those who were administered a high-intensity statin prior to percutaneous coronary intervention (n ¼ 1591), suggesting a rapid onset of benefit with such therapy.
A post-hoc analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study examined the impact of ‘structured care’ titrating atorvastatin to lipid goal (starting dose 20 mg/day, uptitrated to 80 mg/day at 6-week intervals if low-density lipoprotein cholesterol (LDL-C) goal < 100 mg/dl not reached) vs. ‘usual care.’ The study population was made up of 1600 elderly (mean age 70) and young patients (mean age 50) with established CHD [13]. Although ‘structured care’ improved CVD outcomes in both the age groups, the absolute and relative risk reductions were greater in the elderly vs. younger patients [16.5% (P < 0.0001) vs. 8.5% (P ¼ 0.0001) and 60% (P < 0.0001) vs. 42% (P ¼ 0.0001), respectively]. This is an intriguing finding that requires further study, particularly given the Cholesterol Treatment Trialists found no heterogeneity by age in the relative CVD benefit of statin therapy [14]. The advantage of combining lipid-lowering therapy with other agents has been suggested by the results of recent studies. An exploratory analysis of the landmark GISSI Prevention Trial, involving 14 704 MI patients drawn from 117 hospitals in Italy, suggested that combining statins with omega-3 polyunsaturated fatty acids was associated with lower death or reinfarction rates compared with statin monotherapy (5.1 vs. 6.8 per 100 personyears, respectively) [15]. A retrospective observational study of 27 919 high-risk CHD patients on statin therapy evaluated LDL-C control over time in those treated with an ongoing statin monotherapy regimen (50.9%) vs. uptitration of the statin regimen (39.5%) vs. switching to an ezetimibe–simvastatin combination (9.6%). The relative LDL-C concentration at follow-up compared with baseline and attainment of LDL-C < 100 and more than 70 mg/dl (2.59 and 1.81 mmol/l, respectively) were significantly more favorable in the switch group (24.0%, 81.2%, and 35.2%, respectively) as compared with the uptitrated group (9.6%, 68.0%, and 18.4%, respectively) or the initial statin monotherapy group (4.9%, 72.2%, and 23.4%, respectively) [16]. A substudy of the Acute Coronary Syndrome Israeli Surveys of 8982 acute coronary syndrome patients addressed the question of combination lipid-lowering therapy vs. statin monotherapy. The researchers observed significantly better 30-day outcomes in those treated with the combination of a fibrate (mainly bezafibrate) and statin compared with those on statin monotherapy. The incidence of major adverse cardiac events (3.2% vs. 6.0%; P ¼ 0.01) and rehospitalization (15.6% vs. 19.8%; P ¼ 0.03) was lower in the combination group [17].
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An analysis of 2258 women from the Nurses’ Health Study and 1840 men from the Health Professionals Follow-Up Study assessed the association of diet quality (measured by Alternative Healthy Eating Index 2010) with clinical outcomes in MI survivors. In adjusted analyses, improved diet quality was associated with 24–40% lower cardiovascular and all-cause mortality [18]. The importance of diet quality cannot be overemphasized, although smoking cessation is a fundamental priority in smokers. Enhancing levels of physical activity is also a core element of comprehensive post-MI care. Each of these elements should be addressed by ensuring participation in cardiac rehabilitation. Early comprehensive short-term cardiac rehabilitation was evaluated in an offshoot of the OMEGA study comprising 3560 post-MI patients. The investigators compared those attending and not attending such programmes. Total mortality (OR 0.46, 95% CI 0.27–0.77) and major cardiac adverse events (OR 0.53, 95% CI 0.38–0.75) were significantly lower in the rehabilitation group [19].
LATEST RANDOMIZED TRIALS ADDRESSING LIPID CONTROL FOLLOWING MYOCARDIAL INFARCTION Older landmark trials laid a foundation for lipidlowering therapy with statins and nonstatins postMI (Table 1). For many years, evidence has supported the superiority of statins in lowering lipids to goal levels. On the basis of multiple lines of evidence, it has been the prevailing view that nonstatin therapy should be added only when statin and lifestyle therapy are exhausted, and lipid levels not controlled. The most recent lipid trials [20–22] focused on raising high-density lipoprotein cholesterol (HDL-C) in patients with well-controlled atherogenic lipids. Unfortunately, the HDL-C raising strategy has not proven efficacious for reasons that have been examined elsewhere [20] and the clinical trial enterprise has met major recruitment challenges of late [23].
HOW ARE WE DOING IN LIPID CONTROL FOLLOWING MYOCARDIAL INFARCTION? Are we adequately controlling lipids in post-MI patients? Moreover, how adequate is ‘adequate’? The answers to these questions depend on where one is in the world, what guideline one follows, and measurement techniques (Table 2). Although now controversial in the United States [24,25], lowering LDL-C after acute MI to goal levels of less than 100 or less than 70 mg/dl (2.59 and 1.81 mmol/l, 456
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respectively) remains the standard of care elsewhere in the world [26,27 ,28 ]. We recently showed that US patients suffering MI in 2005–2008, who were not at LDL-C goal at baseline, met the less than 100 mg/dl goal in followup about two-thirds of the time [29 ]. This was a major improvement in comparison to studies from the prior decade. A 2013 analysis of the National Health and Nutrition Examination Surveys 1999– 2008 studying 18 656 high-risk US individuals showed a favorable trend in the proportions of CHD populations achieving LDL-C less than 100 and >> Risk IIa – Benefit >> Risk IIb – Benefit Risk III – No benefit/ harm. LOE (level of evidence): A – Multiple populations evaluated (multiple RCTs/ meta-analysis). B – Limited populations evaluated (single RCT/ non-RCT). C – Very limited populations evaluated (consensus opinion of experts, small case studies, registries or standard of care).
Minimum 30 min of aerobic Minimum 30 min of exercise (3–4 times/week; moderate-intensity ideally daily); rhythmic resistphysical activity on ance exercise of 10–15 most, if not all, days repetitions (Class I, LOE A); of the week (150 increase daily activities min/week), can be (Class I, LOE B); High risk done in shorter bouts pts: institutional cardiac of 10min and built rehab (Class I, LOE B) then up over time. Refer nonsupervised home exercise patients to a struc(Class IIa, LOE C) tured cardiac rehab program and/or exercise physiologist/ qualified fitness personnel
Reduce SFA intake to < 7% 200 g/day (2–3 servings) Moderate-energy foods, Limit SFA to < 7% and < 6 g/day of salt, reduce SFA Limit calories from SFA to intake to 7% of total caltFA to < 1% of calvegetables, fruits, of fruits and vegetables, of total calories, choles5–6%; reduce % calories ories, increase intake of n-3 whole-grains, PUFA and ories, consume 1 g/ terol to < 200 mg per day, < 5 g/day of salt, 30– from tFA; DASH, USDA, PUFA, limit cholesterol intake day EPA þ DHA and MUFA (n-3 FA) from and tFA to < 1% of energy 45 g/day of fiber from AHA diets (fruits, vegto 300 mg/day and fat > 2 g/day ALA whole grains, < 10% cal- fish, avoid tFA, limit (Class I, LOE B) etables, whole grains, (canola/soybean oils, intake to 25% of total calories from SFA, < 1% cal- SFA to 30 g/day, cholesterol eat mainly plantfish), moderate amounts NHLBI Grade A) based foods (fruits, < 200 mg/day (CR, of alcohol (men: 2 and vegetables, pulses, MQE); DASH, Mediterwomen: 1 glass/day); whole - grains), lean ranean, Portfolio patemphasis on Mediterrameat, fish and poultry terns (SR, HQE) nean diet
Diet
Non-pharmacologic Therapies (Lifestyle Modification)
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Prevention
Patient System
-Age -Race -Gender
-Dedicated funding to secondary prevention service
-Health-related beliefs
-Delivery system characteristics
-Literacy -Attitudes -Presence of co-morbidities
• Health policies • Resources • Administrative complexity • Provider availability and accessibility
-Insurance status
Provider -Prescribing patterns -Referral to cardiac rehabilitation -Provider communication • Patient education • Patient counseling
FIGURE 1. Processes of care in lipid control following myocardial infarction.
statin at discharge and make the patient an active part of the decision-making process. Third, to reduce copayment, offer the option of lower-cost generic statins. In particular, at least in the United States, atorvastatin 80 mg is now generic. Fourth, use medication reminder tools (e.g., pillbox and electronic reminder device). Fifth, encourage patient participation in cardiac rehabilitation programs [29 ]. From a system level, in order to overcome confusing discordances in guidelines (Table 2), we encourage the collaborative efforts of guideline developers around the world to develop international consensus guidelines that provide explicit evidence-based recommendations for the management of post-MI patients [39 ]. This would make it easier for healthcare systems to implement Health Information Technology (HIT) strategies (e.g., electronic health records and database monitoring) to standardize and improve post-MI follow-up lipid testing, drug initiation or titration or add-on or adherence, and referrals to cardiac rehabilitation centers [40]. Cutting-edge implementation science has identified the power of the checklist in promoting the consistent delivery of high-quality care [39 ]. &&
&&
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STATINS: PRIORITIZE EARLY HIGHINTENSITY THERAPY AND LONG-TERM ADHERENCE We want to emphasize the importance of early statin prescription. Across the world, there is a near unanimous agreement on initiating statins in the acute phase of MI (ideally within 24 h) (Table 2) [11,41]. Overwhelming evidence exists in support of prescribing a high-intensity statin (Table 1) [4 ,5]. &
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Atorvastatin 80 mg daily, in particular, has been studied in the setting of MI [5]. Prioritizing early intensive statin therapy lowers the immediate risk of major cardiovascular events and also serves as a long-term investment in risk reduction. Statins are now recognized to act by mechanisms beyond lipid profile modification [42,43]. A broad range of ‘pleiotropic’ or nonlipid-mediated effects [atheroma plaque stabilization, anti-inflammatory, angiogenic, antithrombosis, antiarrhythmic, antioxidative, antiproliferative, C-reactive protein (CRP)-lowering, antibacterial, and immunomodulatory effects] have been identified. Although not fully understood, plaque-stabilizing properties through reduction of inflammation and improvement of endothelial function appear to play a significant role [44,45]. Promoting long-term adherence to statins is essential. In general, statins are well tolerated. However, concerns may arise related to myopathy, increased fatigue, elevated liver enzymes, worsening hyperglycemia, and incident diabetes [46]. Patientfocused interventions discussing reasons for prescription, benefits and potential adverse effects of statins, reinforcing the importance of regular follow-up, giving hand-outs about the disease condition and the treatment, and reaching out through e-mail, telephone, or mail to assess medication-taking behavior may be helpful. Healthcare delivery-focused interventions include easing the process of filling or refilling prescriptions, modifying treatment regimen by adding other lipid-lowering therapies (nonstatin drugs and therapeutic lifestyle changes), and expanding communication links between physicians, pharmacists, and other members of the care team [29 ,47]. &&
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ACS (NSTE-ACS, MI and STEMI < 48 h); 1060
Chinese ACS trial NCT02077257
MI, hypercholesterolemia; 18 141 MI; 1600
ACS; 13 000
Atherosclerotic CVD [including prior MI (> 4 weeks)]; 30 000
Recent ACS (< 52 weeks), 18 000 Clinically evident CVD at high risk for recurrent events, dyslipidemia; 22 500
Unstable/chronic CHD (including MI); 874
CAD (prior PCI, MI, or CABG); 90
IMPROVE-IT NCT00202878
OPTIMISE NCT01632878
SOLID-TIMI 52 NCT01000727
REVEAL NCT01252953
ODYSSEY NCT01663402
FOURIER NCT01764633
CORDIOPREV NCT00924937
TRiCH NCT02047942
Beyond statins
AMI; 140
Condition; Sample size
INTENSIFY NCT01923077
Statin trials
Ongoing trial/study
0268-4705 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins Center-based cardiac rehabilitation vs. home-based training with telemonitoring guidance
Low-fat diet (28% fat: 12% MUFA; 8% PUFA; 8% SAT) vs. Mediterranean Diet (34% fat: 22% MUFA; 6% PUFA; 7% SAT)
Evolocumab (AMG 145, PCSK9 inhibitor) þ effective statin (A20/equivalent) Ezetimibe vs. placebo þ effective statin
Alirocumab SAR236553 (REGN727, PCSK9 inhibitor) vs. placebo
Anacetrapib (CETP inhibitor) vs. placebo
Darapladib 160 mg (Lp-PLA2 inhibitor) vs. placebo
Omega-3 fatty acid esters þ standard treatment
Ezetimibe/Simvastatin 10/40 mg vs. Simvastatin 40 daily
Rosuvastatin 20 mg vs. 10 mg daily
Early Rosuvastatin (80 mg loading dose after randomization followed by 40 mg daily)
Intervention
Table 3. A review of ongoing statin and nonstatin clinical studies in the post-MI setting
Randomized, single-blind, multicenter
III
–
III
Randomized, multicenter, double-blinded, placebocontrolled
Randomized, double-blind, single-center, parallel study
III
Randomized, multicenter, double-blinded, placebocontrolled
III
III
Randomized, multicenter, double-blinded, placebocontrolled Randomized, multicenter, double-blinded, placebocontrolled
–
III
IV
II
Phase
Prospective, multicenter observational cohort
Randomized, multicenter, double-blind
Randomized, open label, multicenter
Randomized, open label, single-center
Design
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(Continued )
Exercise tolerance from baseline to 12 weeks and 1 year
MACE and lipid levels
MACE
MACE
Major coronary events [coronary death, myocardial infarction (MI) or coronary revascularization]
MACE, major coronary events and all-cause mortality
Recurrent nonfatal MI, sudden death or new congestive heart failure
MACE, major coronary events, stroke and CV death
LDL-C lowering efficacy and safety, lipid goal attainment
LV function and coronary plaque
Endpoint
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ACS, acute coronary syndrome; ACTonHEART, Randomized Controlled Clinical Trial of Acceptance and Commitment Therapy in Cardiac Patients; AMI, acute myocardial infarction; CABG, coronary artery bypass graft; CAD, coronary artery disease; CARDIOPREV, CORonary Diet Intervention With Olive Oil and Cardiovascular PREVention; CETP, cholesteryl ester transfer protein; CHD, coronary heart disease; CR, cardiac rehabilitation; CVD, cardiovascular disease; FOURIER, Further cardiovascular OUtcomes Research with pcsk9 Inhibition in subjects with Elevated Risk; IHD, ischemic heart disease; IMPROVE-IT, IMProved Reduction of Outcomes: Vytorin Efficacy International Trial; INTENSIFY, Early Intensive Treatment With Statins Improves Left Ventricular Function in Patients With Acute Myocardial Infarction; Lp-PLA2, lipoprotein-associated phospholipase 2; LV, left ventricular; MACE, major adverse cardiovascular event; MI, myocardial infarction; MUFA, monounsaturated fatty acid; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; ODYSSEY, A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Effect of Alirocumab (SAR236553/REGN727) on the Occurrence of Cardiovascular Events in Patients Who Have Recently Experienced an Acute Coronary Syndrome; OPTIMISE, Omacor Plus standard Therapies In post Myocardial Infarction Subjects Evaluation; PCI, percutaneous coronary intervention; PCSK9, proprotein convertase subtilisin/kexin type; PREMIER, Plaque Regression and Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen; PUFA, polyunsaturated fatty acid; REVEAL, Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification; SAT, saturated fatty acid; SOLID-TIMI, Stabilization of pLaques usIng Darapladib-Thrombolysis in Myocardial Infarction; STEMI, ST-elevation myocardial infarction; TRiCH, TeleRehabilitation in Coronary Heart disease.
Coronary plaque and endothelial progenitor cells III Randomized, multicenter, singleblind ACS patients undergoing PCI; 30 PREMIER NCT01004406
Atorvastatin 80 mg þ LDL – apheresis vs. guideline statin monotherapy
Modifiable risk factors (LDL-C, BP, BMI) and improvement of psychological well being – Randomized, single-blind, single-center Current IHD patients with CR referral; 160 ACTonHEART NCT01909102
Acceptance and Commitment Therapy vs. usual care
Condition; Sample size Ongoing trial/study
Table 3 (Continued)
Intervention
Design
Phase
Endpoint
Prevention
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Nonstatin lipid-lowering agents Nonstatin drugs are in an unresolved position in the US guidelines [4 ,25] (Tables 1 and 2). However, throughout most of the world, guidelines remain explicit that in post-MI patients with residually high levels of LDL-C and other atherogenic markers a high-intensity statin and lifestyle improvements may not suffice [27 ,28 ,48]. Additional, nonstatin therapy merits strong consideration as an ‘add on’ in the management of patients not achieving lipid goals [45]. &
&
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Lifestyle modification A heart-healthy diet and physical activity are core components of post-MI lipid control. A Mediterranean style dietary pattern is one excellent choice. This is characterized by fresh fruits, green vegetables, whole grains, oily fish, extra-virgin olive oil, and low-fat or fat-free dairy. Other staples of the diet include poultry over red and processed meat, modest amounts of nuts, seeds and dry beans, herbs and spices in lieu of salt, and a moderate amount of red wine (mainly with meals) [18,49]. In smokers, as noted previously, complete cessation of smoking is fundamental in post-MI management. This is recognized in clinical practice guidelines internationally. The European Society of Cardiology guidelines recommend the provision of cessation advice and assistance (Class I. Level of evidence A, Strong GRADE) [48]. They advocate the 5 A’s as a smoking cessation strategy: Ask, Advise, Assess, Assist, and Arrange. The European Society of Cardiology guidelines also recommend avoiding exposure to passive smoke (Class I, LOE B, Strong GRADE). The early posthospital period is a vulnerable transition in which patients may feel uneasy about returning to activity. Medically supervised, exercisebased outpatient cardiac rehabilitation improves clinical outcomes and is an underutilized resource in recuperating MI patients [50]. When referring patients to rehab centers, issues such as accessibility, relevance, social (culturally sensitive, gender specific), economic (health insurance reimbursement), and psychological (stress management) needs should be addressed. A home-based rehab program advocating walking or working around the house may run parallel with the center-based program to further increase functional capacity and survival. Over the long term, maintenance of regular physical activity is essential. Moderate-to-intensive aerobic activity for 30–60 min at least 5 days/week (150 min/week) is desirable. Volume 29 Number 5 September 2014
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Li pid control postmyocardial infarction Ankam et al.
EMERGING THERAPIES Several trials and observational studies using statins and novel lipid-lowering drugs are currently underway, as summarized in Table 3 [44,45].
CONCLUSION For optimal lipid control, early high-intensity statin therapy is a top priority, in association with smoking cessation, cardiac rehabilitation, lifestyle counseling, promotion of medication adherence, ongoing lipid surveillance, and appropriate titration of medications. If patients, physicians, and healthcare systems focus attention on these factors, then continued improvements in lipid control and outcomes after MI will follow. Acknowledgements We did not receive any specific funding for this article. Dr Martin is supported by the Pollin Cardiovascular Prevention Fellowship, Marie-Jose´e and Henry R. Kravis endowed fellowship, and an NIH training grant (T32HL07024). Conflicts of interest Dr Martin is listed as a co-inventor on a pending patent filed by Johns Hopkins University for a method of lowdensity lipoprotein cholesterol estimation.
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