Response by Schwartz et al to Letter Regarding Article, “Peripheral Artery Disease and Venous Thromboembolic Events After Acute Coronary Syndrome: Role of Lipoprotein(a) and Modification by Alirocumab: Prespecified Analysis of the ODYSSEY OUTCOMES Randomized Clinical Trial”
Authors: Gregory G. Schwartz, Michael Szarek, Vera A. Bittner, P. Gabriel Steg
Journal: Circulation (2020)

Professor Packard raises an insightful question about our recent analyses of the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) that relate the concentration of lipoprotein(a) to risk of major adverse cardiovascular events and the impact of treatment with the PCSK9 inhibitor alirocumab on that risk.Alirocumab reduced the risk of major coronary events and ischemic stroke, 1 and of major limb and venous thromboembolic events compared with placebo. 2 In both cases, treatment hazard ratios became more robust (numerically lower) as baseline lipoprotein(a) concentration increased, associated with greater absolute reduction in lipoprotein(a) with alirocumab.Professor Packard asks whether these findings might have been confounded if higher baseline lipoprotein(a) was associated with lower likelihood of protocol-specified substitution of placebo for alirocumab.If so, patients with higher baseline lipoprotein(a) may have had greater persistence of alirocumab treatment, potentially resulting in greater treatment benefit.The question arises because cholesterol in lipoprotein(a) contributes to measured low-density lipoprotein (LDL) cholesterol but is reduced by alirocumab to a lesser extent than cholesterol in LDL particles.From lowest to highest quartile of baseline lipoprotein(a), within-quartile median levels were 2.0, 12.2, 37.6, and 92.2 mg/dL for lipoprotein(a) and 83, 85, 86, and 92 mg/dL for LDL cholesterol.Assuming lipoprotein(a) contributes 30% of its mass to measured LDL cholesterol, 3 baseline lipoprotein(a) contributed approximately 1, 4, 11, and 28 mg/dL to measured baseline LDL cholesterol in the respective lipoprotein(a) quartiles.At month 4, median changes from baseline in lipoprotein(a) with alirocumab were 0, -5.0, -9.7, and -20.4 mg/dL, respectively.Of 9462 patients in the alirocumab group, 730 (7.7%) had protocol-specified substitution of placebo.As predicted by Professor Packard, the percentage of patients with placebo substitution decreased from lowest to highest quartile of baseline lipoprotein(a): 12.2%, 9.7%, 7.0%, and 1.9%.To determine whether this gradient of placebo substitution contributed to the gradient of treatment hazard ratios across baseline lipoprotein(a) quartiles, we performed sensitivity analyses that excluded the patients with placebo substitution.Treatment hazard ratios were minimally affected: in the analysis including all patients, hazard ratios (95% CIs) for major coronary or cerebrovascular events across baseline lipoprotein(a) quartiles were 0.95 (0.79-1.15), 0.85 (0.71-1.02), 0.79 (0.66-0.94), and 0.83 (0.70-0.98).In the sensitivity analysis, corresponding values were 1.00 (0.82-1.21), 0.89 (0.74-1.07), 0.80 (0.67-0.96), and 0.83 (0.71-0.98).In the analysis including all patients, treatment hazard ratios (95% CIs) for major limb and venous thromboembolic events across baseline lipoprotein(a)