Using PCSK9 Inhibitors to Reduce Major Cardiovascular Outcomes

A class of drugs known as PCSK9 inhibitors are approved to treat rare inherited conditions known as familial hypercholesterolemias. By inhibiting the enzyme encoded by the proprotein convertase subtilisin/kexin type 9 gene, these drugs can dramatically reduce cholesterol and significantly reduce cardiovascular events in patients with these inherited conditions.

Researchers have been investigating whether these drugs can also protect other patients at high risk for a cardiovascular event, including some whose low-density lipoprotein cholesterol (LDL-C) levels are well below currently recommended thresholds resulting from optimized statin therapy.

The first strong evidence arrived in March, and the answer appears to be yes.

Data from 3 large trials—the FOURIER trial of evolocumab (Repatha/Amgen) and the SPIRE-1 and SPIRE-2 trials of a discontinued experimental product called bococizumab (Pfizer)—indicate that patients with a history of cardiovascular events benefit significantly from dramatic LDL-C reductions associated with PCSK9 use, even when they begin with “low” cholesterol.

After a federal judge banned the sale of the only other approved drug in the class, alirocumab (Praluent/Sanofi, Regeneron), when Amgen successfully claimed that the product infringed on 2 of its patents, the US Court of Appeals in early February granted a stay of the controversial decision that would have seen Praluent pulled from the market. Would-be competitors are undergoing trials, but none are close to market.


The SPIRE trials provided indirect evidence to support using a PCSK9 inhibitor in combination with statin therapy, although collective analysis of the 2 trials found that bococizumab use was not associated with significant reductions in cardiovascular events. When investigators looked only at the higher-risk patients in the SPIRE-2 trial, however, and at patients in both trials who maintained a strong response to the drug, they found that patients who used bococizumab enjoyed significantly better outcomes than statin-only controls.

The FOURIER trial, moreover, provided strong, direct evidence to support supplemental treatment in patients with a history of atherosclerotic cardiovascular disease who used statins. It showed that the addition of evolocumab to statin therapy reduced the risk of a broad composite of cardiovascular outcomes by 15% among 27,564 such patients.

Researchers looking at the risk of myocardial infarction (MI), stroke, and cardiovascular death found that evolocumab reduced the risk risk by 20% overall and that reduction grew to 25% beyond the first year of treatment.

“I believe these data should change treatment protocols for high-risk patients,” said FOURIER lead investigator Marc S. Sabatine, MD, the Lewis Dexter, MD, Chair in Cardiovascular Medicine at Brigham and Women’s Hospital in Boston. “There is simply no medical reason why you would not use a treatment that reduces major cardiovascular outcomes by 25% while producing no significant adverse events,” he said.

Current indications from the FDA and current standards of care from specialty societies advocate the use of PCSK9 inhibitors mostly for the treatment of patients with heterozygous or homozygous familial hypercholesterolemia. But insurers appear to be balking at using PCSK9 for even those conditions because of wholesale prices that, according to a Journal of the American Medical Association article by Dhruv S. Kazi, MD, top $14,000 a year.

A pair of studies presented at the American College of Cardiology’s 66th Annual Scientific Sessions by Duke University’s Ann Marie Navar, MD, PhD, found that commercial payers and Medicare are rejecting about 80% of initial requests for evolocumab coverage.

Pressure for wider coverage could mount, however, if follow-up research demonstrates a significant reduction in cardiovascular death.

“Our evolocumab trial did not find a significant reduction in cardiovascular deaths, probably because of 2 reasons,” Sabatine said. “First, our follow-up only averaged a little over 2 years. Second, the proportion of cardiovascular deaths that are due to acute myocardial infarction and acute stroke are much lower now than in the past.”

Sabatine believes that 5-year evolocumab usage data would show a significant death reduction and the elimination of roughly 1 MI, death, or stroke for every 25 patients treated. That figure, he noted, is comparable with or lower than the number needed to treat findings in the trials that justified statin therapy in patients with average cholesterol levels as well as the trials that justified intensive statin therapy.

The FOURIER trial evaluated evolocumab in patients with a history of cardiovascular disease and LDL-C of ≥70 mg/dL. Investigators supplemented the regimens of those 27,564 patients with injections of either placebo or evolocumab. (Patients chose in advance between 140 mg every 2 weeks or 420 mg every month and received either the medication or the placebo injection on the preferred timetable.)

After a median follow-up of 2.2 years, 1344 patients receiving evolocumab (9.8%) and 1563 patients receiving placebo (11.3%) experienced cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization (HR, 0.80; 95% CI, 0.73-0.88; P <.001). Patients receiving evolocumab, whose LDL-C fell from a median of 92 mg/dL at baseline to 30 mg/dL after 48 weeks of treatment, fared even better than patients receiving placebo on the secondary endpoint: a composite of cardiovascular death, MI, or stroke (HR, 0.80; 95% CI, 0.73- 0.88; P <.001).

Previous trials had shown that evolocumab and alirocumab could lower LDL-C levels by more than 50%, even in patients who were already using other medications. Other trials had shown improved outcomes when mean LDL-C levels fell from the recommended level of 100 mg/dL to 70 mg/ dL and in a subsequent trial, from 70 mg/dL to 54 mg/dL.

No previous trial, however, had demonstrated an association between subsequent reductions and further improvements to outcomes, but Sabatine and his colleagues noted in the New England Journal of Medicine (NEJM) that patients who began in the lowest quartile of LDL-C—patients whose mean levels fell from 70 mg/dL to just 22 mg/dL&mdash;saw a greater reduction in the risk of cardiovascular death, MI, or stroke (—22%) than those in the top quartile of LDL-C levels, whose mean levels fell from 126 mg/dL to 43 mg/ dL and whose risk for a cardiovascular event fell 17%. In other words, reducing LDL-C levels to just under a quarter of what has long been a “healthy” level seems to improve cardiovascular outcomes.

These findings were bolstered by the SPIRE trial findings that were also published, as a single article, in the March 24 issue of NEJM.

SPIRE-1 evaluated supplemental bococizumab in 16,817 patients with a history of cardiovascular events and LDL-C ≥70 mg/dL, while SPIRE-2 evaluated it in 10,621 patients with LDL-C ≥100 mg/dL. Most patients in both trials initially experienced large reductions in LDL-C, but the effect diminished over time in many patients, leading Pfizer to end the study early and suspend development.

The truncated data failed to show a significant reduction of cardiovascular events in either SPIRE-1 patients or in the combined study group. However, the incomplete study data showed significant benefits for the higher-risk SPIRE-2 patients, along with various subgroups of patients who had experienced and maintained the greatest LDL-C reductions.

Although the study was not exactly a success for bococizumab, it demonstrated a simple truth about LDL-C.

“Lower is better,” said lead study author Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital.

Ridker also believes the recent trials justify PCSK9 combination therapy in high-risk patients, but he doubts it will become the norm anytime soon.

“The first step is to ensure that all patients are initially on high-intensity statin therapy and are compliant with diet, exercise, and smoking cessation,” he said.

Patients who need further LDL-C reduction have options: ezetimibe, which costs about $80 a month, or a PCSK9 inhibitor.

“For now, cost issues are likely to determine that choice,” Ridker said. â—

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