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
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.
- A 59% mean reduction of LDL-c (95%CI: 58-60, P<0.00001) was seen with evolocumab treatment as compared with placebo, to a median level of 30 mg/dL (IQR: 19-46 mg/dL). Absolute reduction was 56 mg/dL (95%CI: 55-57). This LDL-c reduction was stable over time during 168 weeks study duration.
- A statistically significant 15% reduction of primary end point events was seen with evolocumab as compared to placebo treatment (3 yr Kaplan-Meier rate: 12.6% vs. 14.6%, HR: 0.85, 95%CI: 0.79-0.92, P<0.0001). The curves separated within the first year.
- A statistically significant 20% reduction in the harder key secondary end point was seen with evolocumab as compared to placebo treatment (3 yr Kaplan-Meier rate: 7.9% vs. 9.9%, HR: 0.80, 95%CI: 0.73-0.88, P<0.0001).
- Of the components of the secondary end point, MI was significantly lower with evolocumab (3 yr Kaplan-Meier rate: 4.4 vs. 6.3, HR: 0.73, 95%CI: 0.73-0.82), as was stroke (2.2 vs. 2.6, HR: 0.79, 95%CI: 0.66-0.95). CV death did not show a significant difference between treatment groups (2.5 vs. 2.4, HR: 1.05, 95%CI: 0.88-1.25). The effects on death due to acute MI or due to stroke were non-significant, but directionally consistent with other benefits, while other CV death was not.
- Fewer coronary coronary revascularisations were seen (3 yr Kaplan-Meier rate: 7.0% vs.9.2%, HR: 0.78, 95%CI: 0.71-0.86). Urgent revascularisations showed the largest effect (3.7% vs. 5.4%, HR: 0.73, 95%CI: 0.64-0.83).
- Subgroup analyses based on type of disease, baseline LDL-c, baseline statin intensity, use of ezetimibe or initial dosing regimen did not show a significant interaction between the subgroup variable and the effect of evolocumab on the primary or key secondary endpoint.
- LDL-c levels as low as 22 mg/dL were seen. Plotting achieved LDL-c level and key secondary endpoint event rate for LDL-c baseline quartiles in both treatment arms showed that the lower achieved LDL-c levels were associated with lower rates of CV death, MI or stroke.
- In data up to 1 year, a 16% relative risk reduction (RRR) of the key secondary endpoint was seen (HR: 0.84, 95%CI: 0.74-0.96, P=0.008). Data from month 12 through month 36 showed a 25% RRR (HR: 0.75, 95%CI: 0.66-0.85, P<0.00001).
- For fatal or non-fatal MI or stroke, 19% RRR was seen in the first 12 months (HR: 0.81, 95%CI: 0.70-0.93, P=0.003), and 33% RRR in months 12-36 (HR: 0.67, 95%CI: 0.59-0.77, P<0.00001).
- Rates of adverse events were similar in both treatment groups, including muscle-related events (5.0% vs. 4.8%), cataract (1.7% vs. 1.8%), new onset diabetes (8.1% vs. 7.7%) and neurocognitive events (1.6% vs. 1.5%).
- 0.3% of patients on evolocumab developed binding antibodies, and none of the patients showed neutralising antibodies.
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.
Our coverage of ACC.17 is based on the information provided during the congress.