Physicians' Academy for Cardiovascular Education

Consistent long-term LDL-c reduction by PCSK9 inhibitor translates into CV benefit in high-risk patients already on statins

Primary Results of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) Trial

Presented at ACC.17 by Marc Steven Sabatine

Mar. 16, 2017 - news

Background

The FOURIER trial was a randomised, double-blind, placebo-controlled trial of the PCSK9 inhibitor evolocumab, a fully human anti-PCSK9 monoclonal antibody, in 27564 high-risk, stable patients with established CV disease on high or moderate intensity statin therapy, with or without ezetimibe.

Phase 2 and phase 3 study data showed that evolocumab was safe and well-tolerated. Previous exploratory data suggested a reduction of CV events upon about 60% LDL-lowering with evolocumab, but the long-term effect remained to be studied.

In the FOURIER study, patients had LDL-c >70 mg/dL (median: 92 mg/dL, IQR: 80-109) and non-HDL-c >100 mg/dL at baseline. Median follow-up was 26 months (IQR: 22-30). 2907 patients experienced a primary endpoint (CV death, MI, stroke, hospitalisation for unstable angina, or coronary revascularisation) and 1829 experienced a key secondary endpoint (CV death, MI or stroke). 69% of participants were on high-intensity statin, 30% on moderate-intensity statin, and 5% used ezetimibe.

Main results

Conclusion

These data of the FOURIER trial show that treatment with evolocumab showed consistent lowering throughout the trial duration, to a median achieved LDL-c of 30 mg/dL. A reduction of CV events was seen with the PCSK9 inhibitor as compared with placebo, in high-risk patients already on statin therapy. The benefit was consistent across subgroups.

It takes time for the LDL-c reduction to translate into clinical benefit. The event curves separated in the first year, and continued to spread during the course of the trial. After the first year, a 25% reduction in CV death, MI or stroke was seen.

The HRs of year 2 data for major coronary events, stroke, urgent coronary revascularisation and major vascular events are similar to those reported in the meta-analysis of year 2 of the Cholesterol Treatment Trialists Collaboration (CTTC). The long-term benefits seen in this trial are consistent with the benefit seen with statins per mmol/L lowering of LDL-c.

Evolocumab was safe and well tolerated, without development of neutralising antibodies.

In the discussion of the trial data in the press conference, Valentine Fuster was positive about the event reduction, although the absolute event reduction is a modest 2%. But, he pointed out that he was very positive about the diverging curves. Considering the costs of this treatment, many experts point out that it is now important to identify those patient groups that will most benefit from treatment with evolocumab. The current American guidelines do not focus on specific LDL-c goals, but on dosing regimens. Based on new scientific insights, the guidelines might need to be reconsidered.

An open label extension study involving about 6000 patients will be conducted, which will give more long-term data on safety. A question was raised about possible cross-reactivity of antibodies developed across various PCSK9 monoclonal antibodies. These antibodies are very specific, and the risk of cross-reactivity is extremely low. A Pfizer database currently holds 150 people who switched to another PCSK9 antibody, and only 1 person has shown cross-reactivity.

Disclosures

Our coverage of ACC.17 is based on the information provided during the congress.

This study was published today in the NEJM