Principal Findings:

The primary outcome, major adverse cardiac events (MACE), for alirocumab vs. placebo, was 9.5% vs. 11.1%, hazard ratio (HR) 0.85, 95% confidence interval 0.78-0.93, p < 0.001.

• Coronary heart disease (CHD) death: 2.2% vs. 2.3%, p = 0.38
• MI: 6.6% vs. 7.6%, p = 0.006
• Ischemic stroke: 1.2% vs. 1.6%, p = 0.01
• Unstable angina: 0.4% vs. 0.6%, p = 0.02

Secondary outcomes (for alirocumab vs. placebo):

• Death/MI/ischemic stroke: 10.3% vs. 11.9%, p = 0.0003
• All-cause mortality: 3.5% vs. 4.1%, p = 0.026
• Ischemia-driven coronary revascularization: 7.7% vs. 8.8%, p = 0.009
• ALT >3 x ULN: 2.3% vs. 2.4%
• CK >10 x ULN: 0.5% vs. 0.5%
• Neutralizing antidrug antibodies: 42 vs. 6
• New-onset diabetes: 9.6% vs. 10.1%
• LDL-C at 4 months: 40 mg/dl vs. 93 mg/dl
• LDL-C at 48 months: 66 mg/dl vs. 103 mg/dl

On-treatment analysis, LDL-C reduction in alirocumab vs. placebo at 4 months (37.6 mg/dl vs. 93.3 mg/dl, 62.7% reduction), at 48 months (53.3 vs. 101.4 mg/dl, 54.7% reduction).

Patients with baseline LDL-C ≥100 mg/dl appeared to derive the highest benefit: MACE: 11.5% vs. 14.9%, HR 0.76; CHD death: 2.5% vs. 3.4%, cardiovascular death: 2.9% vs.4.2%, all-cause mortality: 4.1% vs. 5.7%, although the p-value for interaction based on baseline LDL-C levels was not significant.

Economic analysis: At an incremental cost-effectiveness ratio threshold of $100,000/quality-adjusted life-year (QALY), a treatment cost of up to $6,319 would be considered cost-effective. For patients with LDL-C ≥100 mg/dl, this value was $13,357, and for those with LDL <100 mg/dl, it was $2,083. For an incremental cost-effectiveness ratio of $50,000/QALY, the corresponding values were $3,293, $6,910, and $1,139 for all patients, LDL ≥100 mg/dl and LDL mg/dl <100, respectively. Incremental cost-effectiveness ratio (ICER) analyses were also performed using patient-level data directly from the trial. Using an annual treatment cost of $5,850, the base case ICER was $92,200 per QALY gained ($41,800/QALY if baseline LDL ≥100 mg/dl, $299,9400 if LDL <100 mg/dl).

Total events: Total nonfatal MI (first and subsequent) for alirocumab vs. placebo, was 2,186 vs. 2,513 events, HR 0.87, 95% CI 0.82-0.93, p < 0.0001.

Lipoprotein (a) [Lp(a)] reduction: Higher Lp(a) levels were associated with female gender, non-White race, and lower prevalence of diabetes and smoking. MACE rates were higher with increasing Lp(a) levels, mostly driven by a higher risk of MACE and CHD death/nonfatal MI. Median level was 21.2 mg/dl. Relative risk reduction was similar across Lp(a) quartiles. In contrast, absolute risk reduction for MACE was greater at higher baseline Lp(a) levels exceeding 2% in the upper two quartiles (p for interaction = 0.0011 across Lp(a) quartiles. Compared with baseline, Lp(a) levels decreased by 0, 5.1, 9.8, and 20.2 mg/dl across the four quartiles of baseline Lp(a) levels. After adjusting for baseline Lp(a), baseline LDL-C and change from baseline to 4 months in LDL-C, alirocumab significantly reduced MACE compared with placebo (HR 0.994, 95% CI 0.99-0.999, p = 0.0081). Proportion of MACE events reduced by alirocumab increased from 4% to 11% to 27% for Lp(a) levels at the 25th, 50th, and 75th percentiles, respectively.

Alirocumab-induced reductions in Lp(a) (median -5.0 [-13.6, 0] mg/dl) and corrected LDL-C (median -51.3 [-67.1, -34.0] mg/dl) independently predicted lower risk of total cardiovascular events. Each 5 mg/dl reduction in Lp(a) predicted a 2.5% relative reduction in cardiovascular events.

Role of high-sensitivity C-reactive protein (hsCRP) in lipoprotein a [Lp(a)]-associated risk reduction: In 10,323 patients with baseline hsCRP <2 mg/L, the cardiovascular event rate in the placebo group increased modestly in the highest baseline Lp(a) quartile. Overall treatment hazard ratio (HR) was 0.91 without trend across Lp(a) quartiles. In contrast, in 7,967 patients with baseline hsCRP ≥2 mg/L, the cardiovascular event rate with placebo increased monotonically across baseline Lp(a) quartiles (p for trend < 0.0001). Overall treatment HR was 0.82 and decreased monotonically across Lp(a) quartiles (p for trend = 0.0003).

Effect on stroke: Alirocumab reduced the risk of any stroke (HR, 0.72; 95% CI, 0.57-0.91) and ischemic stroke (HR, 0.73; 95% CI, 0.57-0.93) without increasing hemorrhagic stroke (HR, 0.83; 95% CI, 0.42-1.65). Results were independent of baseline LDL-C or history of cerebrovascular disease.

Total hospitalizations: Approximately 40% of patients experienced at least one hospitalization during the study, while approximately 1% of patients died before experiencing a hospitalization. With 16,629 total hospitalizations and 726 deaths, 331 fewer hospitalizations, and 58 fewer deaths were observed with alirocumab compared with placebo, translating to 15.6 total hospitalizations or deaths avoided with alirocumab per 1,000 patient-years of assigned treatment.

Peripheral artery disease (PAD) and venous thromboembolic (VTE) events: In the placebo group, risk of incident PAD events (critical limb ischemia, limb revascularization, or ischemic amputation) was related to baseline quartile of lipoprotein(a) (p_trend = 0.0021), but not to baseline quartile of LDL-C_corrected (p_trend = 0.06). There was similarly an association of incident VTE events (deep vein thrombosis or pulmonary embolism) with baseline quartile of lipoprotein(a) (p_trend = 0.06), but not LDL-C_corrected (p_trend = 0.85). Alirocumab reduced risk of PAD events (HR 0.69, 95% CI 0.54-0.89, p = 0.004), with nonsignificantly fewer VTE events (HR 0.67, 95% CI 0.44-1.01, p = 0.06).

Age-based analysis: Mean age, 59 years; 26.9% ≥65 years; 5.3% ≥75 years; 0.2% ≥85 years. LDL-C lowering with alirocumab independent of age. Primary composite endpoint for alirocumab vs. placebo for age ≥65 years: 12.9% vs. 16.8% (HR 0.78); age <65 years: 8.8% vs. 9.7% (HR 0.89; p for interaction = 0.19). Due to higher event rates in older patients, absolute benefit was higher with increasing age. Adverse events were similar for alirocumab vs. placebo for age <65 years vs. ≥65 years.

Role of apolipoprotein B (apoB): Median apoB at baseline was 79 mg/dL. In proportional hazards analysis in the placebo group, MACE incidence increased across increasing baseline apoB strata. At month 4 of treatment, the median apoB level was 39 mg/dL in the alirocumab group and 80 mg/dL in the placebo group. Patients in the highest baseline apoB stratum had the largest absolute change in apoB, −56 mg/dL compared with −41 mg/dL in the middle baseline stratum and −27 mg/dL in the lowest baseline stratum. Event rates for MACE for alirocumab vs. placebo based on baseline level of apoB: <75 mg/dL: 2.9 vs. 3.2/100 patient-years (PY); 75−<90: 3.5 vs. 4.0/100 PY; ≥90: 4.4 vs. 5.5/100 PY (p for trend < 0.001). In the alirocumab group, the incidence of MACE after month 4 decreased monotonically across apoB strata. Achieved apoB was predictive of MACE after adjustment for achieved LDL-C or non–HDL-C but not vice versa.

Very low achieved LDL-C: 7.7% of patients achieved two consecutive LDL-C levels <15 mg/dl in the alirocumab arm and had blinded substitution with placebo thereafter. On propensity analysis, MACE rates in this group vs. placebo: 2.3 vs. 3.2 events per 100 PY (p = 0.047); all-cause mortality: 0.7% vs. 1.2% (p = 0.06); MI: 1.5% vs. 2.1% (p = 0.11).