PCSK9 Inhibitors: Economics and Policy

Hlatky MA, Kazi DS.
PCSK9 Inhibitors: Economics and Policy. J Am Coll Cardiol 2017;70:2677-2687.

The following are key points to remember from this article about the economics and policy issues regarding proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors:

  1. The authors review the framework for assessing the value provided by new medical technologies, summarize the current evidence about the cost-effectiveness of PCSK9 inhibitors, and discuss some general policy issues regarding new, costly medical technologies.
  2. Cost-effectiveness analysis is a tool to assess quantitatively the value provided by medical interventions, and assist decision making. The incremental cost-effectiveness ratio (ICER) is the summary measure of value reported by cost-effectiveness studies. ICER is calculated as: math where Cost1 is the total cost due to using intervention 1, Cost2 is the total cost due to using intervention 2, and QALY1 and QALY2 are the quality-adjusted life-years (QALYs) derived from using interventions 1 and 2, respectively.
  3. QALYs capture the two distinct dimensions of improved clinical effectiveness: increased life-years of survival and improved quality of life. The ICER is typically more sensitive to changes in its denominator (effectiveness = the number of QALYs added) than to changes in its numerator (cost = the number of dollars added).
  4. The numerator of the ICER represents the total net medical costs of using one intervention instead of an alternative, and captures both the “up-front costs” of the interventions as well as the “downstream costs” arising from subsequent adverse effects and clinical events. Rarely, an intervention may “pay for itself” if it sufficiently reduces costly downstream events (example, generic statins in high-risk coronary heart disease secondary prevention).
  5. Although there is no explicit willingness-to-pay threshold, in the United States, there is general agreement that interventions with ICERs <$50,000 per QALY provide good value, whereas interventions with ICERs >$150,000 per QALY are not cost-effective. Cost-effectiveness does not consider the cost-benefit in which survival can be converted to $150,000 per life-year added.
  6. Cost-effectiveness analysis is most often performed using a simulation model, but the highest quality data on economic outcomes are derived from randomized clinical trials (RCTs) that have adequate power and duration of follow-up, which is often not the case.
  7. Both cost-effectiveness and budget impact of new technologies are important considerations for sustainable health systems.
  8. Two PCSK9 inhibitors, evolocumab and alirocumab, have been approved for use in individuals with either atherosclerotic cardiovascular disease or familial hypercholesterolemia who have had an insufficient reduction in low-density lipoprotein cholesterol (LDL-C) levels on maximally tolerated statin therapy. The first large RCT (FOURIER) reported reductions in cardiac events of 15-20%, but with no effect on mortality over the relatively short follow-up. Using the outcome data from FOURIER, the assumption that mortality would be reduced to the same degree as other cardiovascular events, and the reported cost of $14,350 per year, Kazi and associates calculated a $450,000 per QALY added in secondary prevention. They noted the price of PCSK9 inhibitors would have to be reduced to about $4,200 or less per year to be cost-effective at a threshold of $100,000 per QALY.
  9. Gandra projected that in secondary prevention, a PCSK9 inhibitor would add $197,000 per patient in lifetime medication costs and save $56,000 per patient (a 28% offset) from averted events, yielding an ICER of $141,000/QALY relative to statin therapy alone. Other studies produced similar results. In primary prevention for patients with heterozygous familial hypercholesterolemia, greater clinical effectiveness at similar incremental costs yielded an ICER of $76,000/QALY relative to statin therapy alone. In contrast, for primary prevention in a health care system with a negotiated discount price of a PCSK9 inhibitor at $12,049 per year, and that treatment would reduce cardiovascular events by 53%, they projected that the higher lifetime drug costs of PCSK9 inhibitor therapy ($237,700 per patient) would be minimally offset by savings from prevented cardiovascular events ($5,800 per patient, or 2.4%), yielding an ICER of $349,000 per QALY. Also, in the fragmented healthcare system in the United States, health systems would have little incentive to “invest” in PCSK9 inhibitors because patients would be likely to move to other health plans before any benefits appeared.
  10. The economic evaluation of PCSK9 inhibitors was also assessed in cost-benefit framework ($150,000 per life-year added). In a secondary prevention scenario, with risk reductions in proportion to the degree of LDL-C lowering, they calculated that the “total social value” of a year of PCSK9 inhibitor therapy would be $11,600, not enough to justify paying $14,000 per year for the medication. The benefits and costs would be equal (implying an ICER of $150,000 per QALY) if the drug price were reduced to $11,600.
  11. There are two major approaches to improving the cost-effectiveness and reducing the budget impact of PCSK9 inhibitors: a) lowering the cost of the drug, and b) restricting its use to the highest-risk patients most likely to benefit. A third would be to better identify persons with statin intolerance. Reducing statin intolerance from 10% to 3% would result in 974,000 fewer individuals eligible for PCSK9 inhibitor therapy, and decrease health care spending by $10.2 billion over 5 years.


The high cost of PCSK9 inhibitors will not be readily solved. But both PCSK9 inhibitors and ezetimibe in combination with statins have provided convincing evidence to validate the ‘lower LDL is better hypothesis,’ and it appears that very low levels are safe. Angiographic and coronary ultrasound studies have demonstrated that lower LDL-C is associated with stabilization and regression of plaque. There are simple and relatively cheap solutions for lowering the societal costs of atherosclerotic cardiovascular disease, which includes maintaining the productivity of the workforce and reduced cost of retirees. Purists would require RCTs, but with available data, among those strategies for the lipid hypothesis include better risk stratification by adding a coronary calcium score to men and women above the low-risk cohort, earlier generic statin intervention with high-intensity statins, and the combination of generic statins with generic ezetimibe. Novel oral LDL-C lowering agents are in clinical trials that lower the LDL-C by 25%, which will reduce the need for PCSK9 inhibitors, particularly if given in combination with statins and ezetimibe.

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

Keywords: Atherosclerosis, Cholesterol, LDL, Coronary Disease, Cost-Benefit Analysis, Drug Costs, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Primary Prevention, Proprotein Convertases, Quality of Life, Quality-Adjusted Life Years, Risk, Risk Reduction Behavior, Secondary Prevention, Social Values, Subtilisins, Treatment Outcome

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