Cardiovascular event reduction with PCSK9 inhibition among 1578 patients with familial hypercholesterolemia: Results...

Familial hypercholesterolemia (FH) is a dominant genetic disorder associated with elevated low-density lipoprotein cholesterol (LDL-C) and premature atherosclerotic events. Although therapeutic monoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) are indicated for LDL-C reduction among adult patients with FH, placebo-controlled outcome data among FH patients are scant.

Directly compare the efficacy of PCSK9 inhibition as compared to placebo on hard cardiovascular outcomes in FH patients enrolled in the Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE) program.

We estimated the efficacy of PCSK9 inhibition with bococizumab on future cardiovascular event rates among 1578 FH patients and 15,959 patients without FH who were selected for comparable lipid levels (on-statin levels of LDL-C >100 mg/dL or non-high-density lipoprotein cholesterol > 130 mg/dL). All patients were randomized by computer generated codes to bococizumab 150 mg subcutaneously every 2 weeks or to matching placebo in the SPIRE clinical trials program and were followed over a median period of 11.2 months for major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). Analysis is by intention to treat. The SPIRE trials are closed and registered at ClinicalTrials.gov: NCT01968954, NCT01968967, NCT02100514, NCT01968980, NCT01975376, and NCT01975389.

Compared to non-FH patients, FH patients enrolled in the SPIRE trials were on average younger (58 vs 63 years), more likely to be women (42 vs 35%), more likely to be primary prevention patients (42 vs 23%), had higher mean baseline LDL-C levels (151 vs 127 mg/dL), and lower rates of diabetes (25 vs 52%) and hypertension (59 vs 82%). FH and non-FH patients both had 55% reductions in LDL-C with bococizumab. Among FH patients, major adverse cardiovascular events occurred among 18 of 781 allocated to bococizumab and 22 of 797 allocated to placebo (hazard ratio 0.83; 95% confidence interval 0.44-1.54, P = .55). This best estimate of effect was similar in magnitude to that observed in the much larger group of patients without FH (hazard ratio 0.79, 95% confidence interval 0.64-0.97, P = .023) with no statistically significant evidence of heterogeneity between groups (P = .87). Incidence rate ratios comparing bococizumab to placebo for adverse events were similar among those with and without FH. The proportion of patients developing antidrug antibodies was higher among those with FH compared to those without FH (43% vs 36%, P < .001).

In these randomized placebo-controlled data, the subgroup of statin-treated FH patients had a similar magnitude of risk reduction for hard cardiovascular events with the PCSK9 inhibitor bococizumab as did patients without FH, with no evidence of statistical heterogeneity between groups.