Putting the FOURIER Findings in Perspective
By Kevin C Maki, PhD
Background and Methods
Earlier this year the results from the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial were published in the New England Journal of Medicine1 in conjunction with their presentation at the American College of Cardiology Scientific Sessions. For the trial, 27,564 patients with atherosclerotic cardiovascular disease (ASCVD) and low-density lipoprotein cholesterol (LDL-C) at least 70 mg/dL while on statin therapy were randomly assigned to receive 140 mg of evolocumab or placebo by subcutaneous injection every 2 weeks. Evolocumab is a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor that lowers LDL-C and cholesterol carried by other apolipoprotein B-containing lipoproteins by reducing the rate at which hepatic LDL receptors are catabolized.
The primary and key secondary composite outcomes were:
- Primary: cardiovascular (CV) death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization;
- Key secondary: CV death, myocardial infarction, stroke.
The median baseline LDL-C level was 92 mg/dL, which was reduced by an average of 59% compared to placebo at 48 weeks to a median value of 30 mg/dL. Levels of non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B, were also reduced by 52% and 49%, respectively.
The primary outcome was reduced by 15% (95% confidence interval [CI] 8 to 21%) and the key secondary endpoint was reduced by 20% (95% CI 12 to 27%) with evolocumab vs. placebo over an average follow-up period of 2.2 years. In the placebo group, the primary and key secondary outcomes occurred in 11.3% and 7.4% of subjects, respectively. Efficacy results were consistent across subgroups, including men and women and quartiles of baseline LDL-C. The effect appeared to grow over time. Beyond 12 months, the reduction in the key secondary outcome with evolocumab was 25%, compared to 16% during the first 12 months. Other than injection site reactions (2.1% vs. 1.6%), no significant differences in adverse events were present between treatment groups.
The results from FOURIER bolster the case for the view that “lower is better” when it comes to LDL-C and related atherogenic lipoprotein variables such as non-HDL-C and apolipoprotein B. The trial had a shorter follow-up time (2.2 years) than most statin trials, which have averaged roughly 5 years of treatment. The event rate in FOURIER was relatively high (about 3-5% per year in the placebo group).
The reduction in LDL-C from a median baseline level of 92 to an on-treatment level of 30 mg/dL is a reduction of about 62 mg/dL (1.6 mmol/L). The results from the Cholesterol Treatment Trialists’ (CTT) analysis of data from statin trials2,3 would predict a reduction in risk of roughly 33% over five years for major vascular events [1 – (0.78^1.6) = 0.328], assuming a hazard ratio of 0.78 per 1.0 mmol/L reduction in LDL-C. However, the follow-up period was shorter than 5 years, so we have to look at the CTT analysis for shorter timeframes for comparison. The definition of major vascular event in the CTT analysis included the combined outcome of major coronary event, non-fatal or fatal stroke, or coronary revascularization. This outcome has elements of both the primary and key secondary outcomes in FOURIER. For simplicity, I will focus on the key secondary outcome in FOURIER of CV death, myocardial infarction or stroke for comparison to the CTT results with statin therapy.
During years 0-1, the hazard ratio in the CTT analysis was 0.90 per mmol/L of LDL-C reduction.2 The corresponding hazard ratios for years 1-2 and 2-3 were 0.78 and 0.74, respectively.2 I will use 0.78 in my calculations for simplicity, since this corresponds to the overall result from the CTT analysis. For the first year, the predicted risk reduction in FOURIER based on the CTT values would be 15.5% [1 – (0.90^1.6) = 0.155]. This corresponds very closely to the 16% reduction in the key secondary outcome during the first 12 months. Beyond 12 months, the effect in FOURIER was a 25% reduction in risk. This is slightly below the predicted 32.8% reduction predicted by the CTT relationship, but certainly not far enough below the predicted value to conclude that the relationship is not similar.
In his presentation at the American College of Cardiology meeting, the Principal Investigator, Dr. Marc Sabatine, compared the results from year 2 of follow-up in FOURIER and the CTT analysis for the outcomes of major coronary events and stroke.3 They were very similar, as you can see by examining the hazard ratios and 95% CIs, which are shown below:
- Major coronary events
- CTT: 0.78 (0.70 to 0.86)
- FOURIER: 0.80 (0.71 to 0.90)
- CTT: 0.77 (0.66 to 0.91)
- FOURIER: 0.77 (0.63 to 0.94)
Thus, once the relatively short follow-up period is taken into account, the results from FOURIER are consistent with those from the CTT analysis, and are generally supportive of a linear relationship between LDL-C reduction and lower CV event risk, extending to lower levels than had previously been studied in large CV outcomes trials.
The findings from FOURIER are consistent with those from a pooled analysis of 10 trials in the development program for another PCSK9 inhibitor, alirocumab.4 In that analysis, a 39 mg/dL reduction in LDL-C (roughly 1 mmol/L) was associated with a hazard ratio of 0.76 (95% CI 0.63 to 0.91) compared with control for major adverse CV events. Similar results were obtained for non-HDL-C and apolipoprotein B reductions. When expressed per 50% reduction from baseline, the relative risk reductions for LDL-C, non-HDL-C and apolipoprotein B were 29%, 29% and 32%, respectively.
The results from FOURIER have generated confusion because the risk reduction reported was less than some had expected. The CV benefits of LDL-C reduction take some time to become fully apparent. Thus, after taking into account the comparatively short follow-up period of 2.2 years, it is clear that the FOURIER results are aligned with previous results from statin trials, as represented by the CTT analysis, as well as the findings from the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), in which the small incremental reduction of about 0.4 mmol/L in LDL-C when ezetimibe was added to statin therapy translated into additional CV event risk reduction of 7-10%.5 Accordingly, the FOURIER results further strengthen the evidence that reducing LDL-C (and related variables such as non-HDL-C and apolipoprotein B) will reduce CV event risk in high-risk patients.
Additional evidence is expected to become available in 2018 from a trial with the other PCSK9 inhibitor currently cleared by the Food and Drug Administration, ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab. Assuming that the results from that trial confirm those from FOURIER, the debate will continue to focus not on who might benefit from therapy, but rather for whom PCSK9 inhibitor therapy is justified, given the cost of approximately $14,000 per year.
1. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713-1722.
2. The Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267-1278.
3. The Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670-1681.
4. Ray KK, Ginsberg HN, Davidson MH, et al. Reductions in atherogenic lipids and major cardiovascular events: a pooled analysis of 10 ODYSSEY trials comparing alirocumab with control. 2016;134:1931-1943.
5. 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.