MPA | Pharmacy News

By Marina Maes, Pharm.D., PGY1 pharmacy practice resident, University of Michigan Health System, Ann Arbor and Kaylyn Dougherty, Pharm.D., MHIIM, PGY1 managed care resident, University of Michigan Prescription Drug Plan, Ann Arbor 

Cardiovascular disease accounts for nearly one of every three deaths in the United States and is the leading global cause of death, representing 31 percent of all global deaths in 2013.1 Low-density lipoprotein (LDL) is a well-established modifiable risk factor for cardiovascular disease, and reduction in LDL has been associated with risk reduction in negative cardiovascular outcomes including myocardial infarction, stroke and mortality. 

In 2013, the American College of Cardiology (ACC) and American Heart Association (AHA) developed new practice guidelines for the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults.2 Prior to the development of these guidelines, the management of cholesterol and cardiovascular risk reduction was largely based on lowering LDL cholesterol to a specific target goal. In patients at highest risk, the recommended LDL goal was <70 mg/dL. However, in the updated guidelines, less emphasis was placed on targeting a specific LDL goal, and instead the focus shifted toward targeting and treating high risk patient populations. Specifically, the guidelines recommend that patients 21 years and older with clinical atherosclerotic cardiovascular disease (ASCVD) should be initiated on high-intensity statin therapy.2 The current guidelines make no recommendations for or against specific LDL cholesterol goals in this patient population. 

Although statins are the primary pharmacologic agents for secondary prevention of ASCVD, several non-statin medications are used in clinical practice for management of cholesterol and ASCVD risk reduction including, but not limited to, ezetimibe, and more recently, evolocumab and alirocumab. Ezetimibe is an oral medication that reduces absorption of cholesterol from the gut through targeting the Niemann-Pick C1-like 1 (NPC1L1) protein, while evolocumab and alirocumab are newer monoclonal antibody injectable agents targeting proprotein convertase subtilisin/kexin type 9 (PCSK9). Inhibition of PCSK9 leads to an increased availability of LDL-receptors which are essential for clearance of LDL cholesterol from the blood. 

In recent years, new data has emerged regarding the benefits of adjunct non-statin therapy. In 2015, the outcomes of the IMPROVE-IT trial were announced. This randomized, double-blind, placebo-controlled trial evaluated the effect of ezetimibe and statin therapy compared to statin therapy alone in patients following an acute coronary syndrome (ACS) event. The primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization, or nonfatal stroke was modestly lower in the combination arm compared to the statin monotherapy arm (hazard ratio 0.94, 95 percent confidence interval 0.89-0.99, p=0.016).3 Additionally, the combination arm had a lower LDL than the statin monotherapy arm (53.7 mg/dL vs. 69.5 mg/dL; p<0.001). 

In March 2017, the results of the FOURIER trial were published. This randomized, double-blind, placebo-controlled trial evaluated the addition of evolocumab to statin therapy in patients with ASCVD.4 The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina or coronary revascularization. The primary endpoint was reduced in the evolocumab arm (HR 0.85; 95 percent confidence interval 0.79 to 0.92; p<0.001).4 It is also important to note that the median LDL achieved in the evolocumab arm was 30 mg/dL. The ODYSSEY Outcomes trial is currently in progress, evaluating the effect of statin therapy with the addition of alirocumab on the occurrence of cardiovascular events in patients who have recently experienced an ACS event. Study completion is expected December 2017.5

The LDL cholesterol levels achieved in the FOURIER and IMPROVE-IT trials were lower than recommended LDL target goals of <70 mg/dL for the highest risk patient populations found in older guidelines. The patients in these trials were on background therapy with moderate-to-high intensity statins and the primary endpoints were still statistically significant. Based on this new evidence, perhaps targeting lower LDL cholesterol levels for secondary prevention in patients with ASCVD may still have a place in practice. 

In 2016, the ACC released the first expert consensus decision pathway describing the role of non-statin therapies for LDL-cholesterol lowering in the management of ASCVD risk.6 Since then, additional evidence surrounding the safety and efficacy of PCSK9 inhibitors has been published, including the FOURIER trial mentioned above. In September 2017, the Committee released revised recommendations pertaining to patients with clinical ASCVD with or without comorbidities on statin therapy for secondary prevention. They recommended consideration of ezetimibe or a PCSK9 inhibitor, such as evolocumab or alirocumab, in all patients with clinical ASCVD who do not achieve at least a 50 percent reduction in LDL cholesterol with a maximally tolerated statin. Following the initiation of the first agent, the addition of a second non-statin medication is reasonable as needed. The consideration of either ezetimibe or a PCSK9 inhibitor should also factor in patient preferences, costs and route of administration in addition to percent of LDL lowering desired. For <25 percent of additional LDL lowering, ezetimibe may be preferred, while in patients who require >25 percent additional LDL lowering, a PCSK9 inhibitor may be preferred. Additionally, they recommend considering an LDL cholesterol goal of <70 mg/dL in all patients, with or without the presence of comorbidities, diagnosed with clinical ASCVD on statin therapy for secondary prevention, though guidance is not explicit of when to use this target.6

Although these recent studies demonstrate a clear benefit in reduction of cardiovascular outcomes with the use of non-statin therapies in addition to standard of care with statins, there is much information that is still unknown. We do not know what the long-term effects are of these newer medications and we do not know what the ideal target LDL cholesterol level should be, or if there should even be a target. Furthermore, the cost of the newer PCSK9 agents are prohibitive for many patients and health plans. Additional studies and time are needed to fully assess the implications of non-statin therapies and LDL cholesterol goals. 

1. Benjamin EJ, Blaha MJ, Chiuve SE, et al; on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics – 2017 update: a report from the American Heart Association [published online ahead of print January 25, 2017]. Circulation. doi: 10.11.61/CIR.0000000000000485. 
2. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. Circulation. 2013: 01.cir.0000437738.63853.7a. 
3. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015; 372:2387-2397. 
4. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017; 376:1712-22. 
5. ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab. (2017). Retrieved from No. NCT01663402)
6. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2017 Focused Update of the 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk. JACC 2017; 70 (14) 1785-1822. 

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