Reviewed by Dr. Neil Keshvani
Arrieta A, et al. JAMA Cardiol. 2017 Dec 1;2(12):1369-1374

Innovative new medications such as monoclonal antibodies have the power to profoundly impact patient’s lives. However, due to their skyrocketing price, physicians need a framework to judge if a certain patient will receive a benefit that is worthy of the costs. One such class of medications, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), have been shown to significantly reduce LDL levels. The FOURIER trial1 recently compared major adverse cardiovascular events and LDL levels in patients receiving statins with evolocumab versus patients only on statins. This trial showed a significant reduction in LDL levels and lower rates of nonfatal MI, stroke, and revascularization without a significant change in mortality between the two groups. However, despite this benefit, the cost of evolocumab ($14,300 per year) has limited its clinical use.

In this study, the authors analyzed the cost effectiveness of evolocumab using a Markov model, which is a statistical tool used in probabilistic forecasting, applied to a hypothetical cohort of 1000 patients similar to the FOURIER population. The authors used the risk reductions in cardiovascular events observed in the FOURIER trial and projected the cardiovascular risks beyond the study length using the Framingham risk functions. The model does not account for a mortality benefit, per the FOURIER trial.

Cost effectiveness is analyzed using the quality-adjusted-life-year (QALY), where a QALY of 1 indicates one year of perfect health. The incremental cost-effectiveness ratio (ICER) is then used to summarize the cost-effectiveness of a health care intervention. The ICER is calculated by taking the difference in cost between two possible interventions and dividing by their effect. Typical cut-off values for societally acceptable prices are $50,000 to $100,000 per QALY. The study investigators also calculate the return on investment from the perspective of a private insurance company, which essentially compares the health savings from reduced events and gains from additional years of premiums paid to the cost of the medication.

In 1000 hypothetical patients resembling the FOURIER trial population, adding evolocumab to statins yielded an ICER of $337,729 per QALY. From the perspective of an insurer, for every dollar spent on evolocumab, the insurer would lose $1.86, representing a negative return on investment. This suggests that evolocumab is priced almost three times higher than the accepted societal cost-effectiveness threshold of $100,000 per QALY. Thus, a 62% price reduction to an annual cost of $5,459 would be required to reduce the ICER to this threshold.

This cost-effectiveness analysis of evolocumab joins two other recently published analyses that delve into the same question. Kazi2 reported an ICER of $450,000 per QALY, while Fonarow3 estimated between $286,600 per QALY and $413,000 per QALY. This highlights the challenge in modeling cost-effectiveness; the assumptions made by the models heavily influence the results. In this study by Arrieta, adding coronary revascularization as a cardiovascular event to the model reduced the ICER to $257,119 per QALY. These values are all dependent on the data from one trial, and further studies with longer follow-up time to assess mortality end points will be required to more accurately estimate the cost-effectiveness of PCSK9 inhibitors.

Effective therapies that are not cost-effective exacerbate healthcare inequalities, as the therapies are only available to patients who can afford them. All of the currently published models show that a reduction in annual drug costs is required to bring the cost-effectiveness of PCSK9i therapy into societally acceptable ranges. The current pricing of PCSK9 inhibitors coupled with the available data do not support widespread use until there are more impactful clinical outcomes associated with therapy, such as a mortality benefit, or a reduction in cost.

1. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017 May 4;376(18):1713-1722.
2. 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(7):743-753.
3. Fonarow GC, Keech AC, Pedersen TR, et al. Cost-effectiveness of evolocumab therapy for reducing cardiovascular events in patients with atherosclerotic cardiovascular disease. JAMA Cardiol. 2017 Oct 1;2(10):1069-1078.