Simulation of Lipid-Lowering Therapy Intensification in a Population with Atherosclerotic Cardiovascular Disease: A Case for Improved Guideline Adherence

Widespread adherence to the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease Risk in Adults remains a challenge at both the patient and physician level.1 With regard to non-statin therapies, although guidance for consideration of these agents was established in the guideline – namely, a less than anticipated reduction of low-density lipoprotein cholesterol (LDL-C) with statin therapy – there was a knowledge gap regarding which particular nonstatin agents may be the most efficacious.

Since the publication of this guideline, two pivotal trials, the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) and the Further Cardiovascular Outcomes Research With PCSK9 Inhibition With Elevated Risk (FOURIER) trial, have served to bridge this gap.2,3 In IMPROVE-IT, 10 mg/day of ezetimibe added to moderate-dose simvastatin resulted in a 24% reduction in LDL-C levels (from 70 to 54 mg/dL) and a 6% relative reduction in the primary combined end point among high risk individuals with recent acute coronary syndrome. In FOURIER, the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab added to background statin therapy resulted in a 59% reduction in LDL-C levels (from 92 to 30 mg/dL) and a 20% relative reduction in the combined endpoint of stroke, myocardial infarction, or cardiovascular death in individuals with established atherosclerotic cardiovascular disease (ASCVD). In summary, both trials showed an outcomes benefit from further lowering of LDL-C with non-statin agents added to background statin therapy.

In response to these data, and in keeping with the treatment thresholds in both IMPROVE-IT and FOURIER, the 2016 ACC Expert Consensus Decision Pathway (ECDP) document supported the implementation of non-statin therapies among those individuals with clinical ASCVD on maximally tolerated statin who failed to achieve a ≥50% reduction in LDL-C concentration or an LDL-C ≤70 mg/dL or ≤100 mg/dL, depending on the presence or absence of comorbidities.4 Moreover, whereas the cost-effectiveness of ezetimibe added on to high-intensity statin therapy is generally well established,5,6 the cost of PCSK9 inhibitor therapy remains one of the predominant barriers to its use with a list price of ~$14,000 per year.7 Evolocumab and alirocumab are approved by the Food and Drug Administration (FDA) for use as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia (HeFH) and/or clinical ASCVD who require additional lowering of LDL-C. Evolocumab is also approved for use in patients with homozygous familial hypercholesterolemia (HoFH).

With this background in mind, Dr. Christopher Cannon and colleagues sought to define the current landscape of lipid-lowering therapy among a North American cohort with established ASCVD in a recent JAMA Cardiology publication.8 Utilizing simulation modeling to extrapolate patient-level data from a cohort of 105,269 individuals, they also sought to answer the question of how many patients would require PCSK9 inhibitor therapy to achieve guideline directed lipid targets. Their first important finding was that only 53% of individuals with ASCVD received a statin at baseline, with only 15% receiving high-intensity therapy. Accordingly, only 25% of patients achieved LDL-C levels <70 mg/dL. After simulating a variety of lipid-lowering therapy intensification schemes, all of which utilized statin therapy before non-statin therapy, the authors found that 69% of patients could achieve LDL-C levels of <70 mg/dL with statin initiation or uptitration alone. Add-on ezetimibe could theoretically increase this percentage to 86%, and if the remaining 14% received PCSK9 inhibitors, then more than 99% of the ASCVD population could achieve an LDL-C target of <70 mg/dL.

The simulation model was constructed on the assumption an LDL-C level of 70 mg/dL would be used as the clinical reference point to guide initiation of PCSK9 inhibitor therapy, which is compatible with the FOURIER entry criteria. Despite a major limitation of assuming perfect adherence to lipid-lowering therapies (statin and non-statin alike), the estimates generated by the simulation model were generally in keeping with data published by the United States Department of Veterans Affairs (VA) study suggesting that approximately 10% of ASCVD patients would theoretically be eligible for PCSK9 inhibition following intensification of statin therapy or addition of ezetimbe as indicated.9

In the accompanying editorial, Dr. Sidney Smith points out several thought-provoking questions that this study raises, the foremost of which is: what criteria should be used in the determination of which patients should be treated with these agents?10 The authors themselves note a fair amount of variability in the percentage of patients needing PCSK9 inhibitor therapy depending on the defined threshold for initiation. For example, an increase in an LDL-C initiation threshold from 70 mg/dL to 80 mg/dL corresponded with a decline in PCSK9 inhibitor use from 14% to 8%. Alternatively, an initiation threshold defined by the inability to achieve ≥50% reduction in LDL-C on high-intensity statin therapy yielded a corresponding increase in PCSK9 inhibitor use to 21% of the population. Accordingly, subsequent iterations of the guidelines (currently targeted for publication in 2018) should seek to firmly define the threshold for consideration of nonstatin therapy, so that models such as those created by Cannon et. al can generate the most accurate prospectus of "demand" for PCSK9 inhibitor use. Furthermore, updated guidelines can define the optimal method for LDL-C estimation, since more precise modern algorithms for LDL-C estimation are now available.11 An update of the 2016 ACC ECDP on the use of non-statin therapies is expected to be published before the end of 2017.

Preventive cardiology in general and lipid-lowering therapies in particular are entering an incredibly exciting phase wherein the intersection of novel therapies and "big-data" analytics (as exemplified by the authors simulation model) can be leveraged to determine the most thoughtful and cost-effective ways to ensure these treatments render the maximal benefit to society. The authors are to be congratulated on conducting a study that lends important insights. The first, and perhaps most encouraging, of these insights is that an LDL-C target of <70 mg/dL in the majority of our secondary prevention population is an achievable goal utilizing oral therapies (statin and ezetimibe) which are inexpensive and have widespread familiarity among most providers.

The second insight is that if targeted efforts to achieve the former are successful, then the number of patients who will require PCSK9 inhibitor therapy will be more modest, mitigating the economic burden of these agents. However, as pointed out in Dr. Smith's editorial, the VA study estimated that the cost of evolocumab for the treatment of patients with LDL-C above 70 mg/dL, even after accounting for those adherent to maximal statin and add-on ezetimbe therapy, would still be on the order of $1 billion per year.9 Look to future cost-effectiveness analyses powered by additional data from ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) and possibly long-term follow-up of FOURIER to further illuminate the true cost-effectiveness of these agents.

Putting Dr. Cannon et al.'s findings into context, however, the looming question then turns back to the age-old issue of ensuring that clinicians and patients, through a so-called "shared accountability," do their part in improving adherence to evidence-based therapy. From the clinician perspective, the cornerstone of these efforts lies within patient education and translating the science behind some of these trials into relatable terms that can enact changes in patient behavior. And while matching our day to day clinical practice to an idealized Monte Carlo simulation, devoid of nonadherence, persistent intolerance, and patient preferences, is an unrealistic target, these data should certainly motivate us to do better.


  1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889-934.
  2. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;72:2387-97.
  3. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
  4. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 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. J Am Coll Cardiol 2016;68:92-125.
  5. Almalki ZS, Guo JJ, Alahmari A, Alotaibi N, Thaibah H. Cost-effectiveness of simvastatin plus ezetimibe for cardiovascular prevention in patients with a history of acute coronary syndrome: analysis of the IMPROVE-IT Trial. Heart Lung Circ 2017. [Epub ahead of print]
  6. Pokharel Y, Chinnakondepalli K, Vilain K, et al. Impact of ezetimibe on the rate of cardiovascular-related hospitalizations and associated costs among patients with a recent acute coronary syndrome: results from the IMPROVE-IT Trial (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circ Cardiovasc Qual Outcomes 2017;10.
  7. Kazi DS, Moran AE, Coxson PG, et al. Cost-effectiveness of PCSK9 inhibitor therapy in patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease. JAMA 2016;316:743-53.
  8. Cannon CP, Khan I, Klimchak AC, Reynolds MR, Sanchez RJ, Sasiela WJ. Simulation of lipid-lowering therapy intensification in a population with atherosclerotic cardiovascular disease. JAMA Cardiol 2017. [Epub ahead of print]
  9. Virani SS, Akeroyd JM, Nambi V, et al. Estimation of eligibility for proprotein convertase subtilisin/kexin type 9 inhibitors and associated costs based on the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk): insights from the Department of Veterans Affairs. Circulation 2017;135:2572-4.
  10. Smith SC, Jr. Defining potential use of nonstatin therapies to lower blood cholesterol levels. JAMA Cardiol 2017. [Epub ahead of print]
  11. Martin SS, Blaha MJ, Elshazly MB, et al. Comparision of a novel method vs the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile. JAMA 2013;310:2061-8.

Clinical Topics: Acute Coronary Syndromes, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins

Keywords: Cholesterol, LDL, Simvastatin, Hyperlipoproteinemia Type II, Primary Prevention, Secondary Prevention, Acute Coronary Syndrome, Comorbidity, Antibodies, Monoclonal, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Atherosclerosis, Myocardial Infarction, Stroke, Outcome Assessment (Health Care), Proprotein Convertases, Dyslipidemias

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