ACC.17: Discontinued PCSK9 inhibitor benefits high-risk patients in trial

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An analysis of two randomized trials found that taking bococizumab had no benefits with regards to reducing the risk of major adverse cardiovascular events in lower cardiovascular risk patients.

However, the injectable medication had a significant benefit for patients deemed at high cardiovascular risk.

Lead researcher Paul M. Ridker, MD, of Brigham and Women’s Hospital in Boston, presented the results in a late-breaking clinical trial session at the ACC scientific session on March 17 in Washington, DC. The findings were simultaneously published online in The New England Journal of Medicine.

Pfizer funded the study. In November, Pfizer announced that the company would stop developing bococizumab, which is a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor.

The FDA has approved two PCSK9 inhibitors: alirocumab (Praluent, Regeneron Pharmaceuticals and Sanofi Aventis) and evolocumab (Repatha, Amgen).

Pfizer initiated these two cardiovascular outcomes trials, known as SPIRE-1 and SPIRE-2, in October 2013 to evaluate the safety and efficacy of bococizumab in patients with cardiovascular disease or those considered high risk for a first vascular event.

Patients in both trials were required to take high-dose statins for at least the previous four weeks before enrolling. If they could not tolerate high-dose statins, they could take lower doses.

Patients in the SPIRE-1 trial were required to have low-density lipoprotein (LDL) cholesterol level of at least 70 mg/dL and a non-high-density lipoprotein (HDL) cholesterol level of at least 100 mg/dL. Meanwhile, the SPIRE-2 trial required patients to have an LDL cholesterol level of at least 100 mg/dL and a non-HDL cholesterol level of at least 130 mg/dL.

The researchers followed the patients for incident cardiovascular events until Nov. 1, 2016 and for adverse events through the last patient visit. The analysis included all cardiovascular events that occurred by Nov. 1, 2016, and were adjudicated and confirmed by Feb. 20, 2017.

A total of 16,187 patients enrolled in SPIRE-1 and 10,621 patients enrolled in SPIRE-2. At baseline, the mean LDL cholesterol level was 94 mg/dL in SPIRE-1 and 134 mg/dL in SPIRE-2. The mean age in the combined trials was 63 years old, and 30 percent of patients were women. The median follow-up times were 7 months in SPIRE-1 and 12 months in SPIRE-2.

At 14 weeks, patients in the bococizumab group had a mean 56.0 percent reduction in LDL cholesterol and patients in the placebo group had a mean 2.9 percent increase in LDL cholesterol. In addition, 28 percent of patients in the bococizumab group had an LDL cholesterol level of 25 mg/dL or less at 14 weeks. Patients in the bococizumab group had a mean 41.8 percent reduction in LDL cholesterol at 52 weeks and a mean 38.3 percent reduction at 104 weeks.

When combining the two studies, the primary endpoint occurred in 352 patients in the bococizumab group and 397 patients in the placebo group. The primary end point consisted of nonfatal MIs, nonfatal strokes, hospitalizations for unstable angina requiring urgent revascularization or cardiovascular deaths.

In SPIRE-1, the primary endpoint occurred in 173 patients each in the bococizumab group and the placebo group in SPIRE-1. In SPIRE-2, the primary endpoint occurred in 179 patients in the bococizumab group and in 224 patients in the placebo group in SPIRE-2.

The rates of serious adverse events were 19.5 per 100 patient-years in the bococizumab group and 19.7 per 100 patient-years in the placebo group. The rates of adverse events that led to drug discontinuation were 6.3 per 100 patient-years and 4.2 per 100 patient-years, respectively.

“These results support the general idea that further reduction in LDL, beyond what you can achieve with a statin, further lowers cardiovascular event rates,” Ridker said in a news release. “The findings add to what we know about PCSK9 inhibitors, and it is encouraging that we found a statistically significant reduction in events among the highest-risk patients who had the highest LDL levels.”