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Effect of Alirocumab on Incidence of Atrial Fibrillation After Acute Coronary Syndromes: Insights from the ODYSSEY OUTCOMES Trial

Open AccessPublished:March 13, 2022DOI:https://doi.org/10.1016/j.amjmed.2022.02.016

      Abstract

      Background

      Using data from the ODYSSEY OUTCOMES trial (NCT01663402), we sought to identify factors associated with the development of incident atrial fibrillation in patients with recent acute coronary syndrome without prior atrial fibrillation and to determine whether alirocumab treatment influenced risk of incident atrial fibrillation.

      Methods

      ODYSSEY OUTCOMES compared alirocumab treatment with placebo in 18,924 patients with recent acute coronary syndrome and dyslipidemia despite high-intensity or maximum-tolerated statin therapy. The primary outcome of major adverse cardiovascular events (MACE) comprised death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischemic stroke, or unstable angina requiring hospitalization. Patients were classified as having previous atrial fibrillation (present prior to or at randomization) or no previous atrial fibrillation. A multivariable model was used to determine factors associated with incident atrial fibrillation.

      Results

      Among 18,262 participants without prior atrial fibrillation at baseline, 499 (2.7%) had incident atrial fibrillation during follow-up. Older age, history of heart failure or myocardial infarction, and higher body mass index were significantly associated with incident atrial fibrillation. Treatment with alirocumab or placebo did not influence the cumulative incidence of atrial fibrillation (hazard ratio 0.91; 95% confidence interval, 0.77-1.09). Patients with vs without a history of atrial fibrillation had a higher incidence of MACE (8.8 vs 3.7 events per 100 patient-years), without significant interaction between atrial fibrillation and randomized treatment on risk of MACE (Pinteraction = .78).

      Conclusions

      While alirocumab did not modify risk of incident atrial fibrillation after acute coronary syndrome, it did reduce the risk of MACE, regardless of prior atrial fibrillation history. History of atrial fibrillation is an independent predictor of recurrent cardiovascular events after acute coronary syndrome.

      Keywords

      Clinical Significance
      • Alirocumab treatment after acute coronary syndrome did not affect the incidence of atrial fibrillation.
      • Alirocumab reduced the risk of major adverse cardiovascular events after acute coronary syndrome, irrespective of prior atrial fibrillation.
      • A history of atrial fibrillation is an independent predictor of recurrent cardiovascular events after acute coronary syndrome.

      Introduction

      Proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors promote substantial and sustained low-density lipoprotein cholesterol lowering and reduce cardiovascular events in high-risk patients treated with statins.
      • Schwartz GG
      • Steg PG
      • Szarek M
      • et al.
      Alirocumab and cardiovascular outcomes after acute coronary syndrome.
      ,
      • Sabatine MS
      • Giugliano RP
      • Keech AC
      • et al.
      Evolocumab and clinical outcomes in patients with cardiovascular disease.
      The ODYSSEY OUTCOMES trial compared treatment with the PCSK9 inhibitor, alirocumab, with placebo in 18,924 patients with recent acute coronary syndromes and residual dyslipidemia despite high-intensity or maximum-tolerated statin therapy.
      • Schwartz GG
      • Steg PG
      • Szarek M
      • et al.
      Alirocumab and cardiovascular outcomes after acute coronary syndrome.
      Atrial fibrillation is a marker of risk in patients presenting with acute coronary syndrome. An ongoing question has been whether lipid-lowering therapies, either directly or indirectly through prevention of ischemic cardiovascular events, reduce the incidence of atrial fibrillation. Analyses of statin trials have not provided consistent evidence of benefit,
      • Fang WT
      • Li HJ
      • Zhang H
      • Jiang S
      The role of statin therapy in the prevention of atrial fibrillation: a meta-analysis of randomized controlled trials.
      and the potential effect of PCSK9 inhibition on the incidence of atrial fibrillation is unknown.
      The current analysis determined: 1) factors associated with the development of incident atrial fibrillation in acute coronary syndrome patients without prior atrial fibrillation; 2) whether alirocumab treatment influenced incident atrial fibrillation; 3) whether a history of atrial fibrillation was associated with the risk of major adverse cardiovascular events (MACE); and 4) whether there was any interaction between prior history of atrial fibrillation and the effect of alirocumab on MACE.

      Methods

      The randomized, double-blind, placebo-controlled ODYSSEY OUTCOMES trial (NCT01663402) compared the efficacy and safety of alirocumab vs placebo in 18,924 patients with recent acute coronary syndrome and elevated atherogenic lipoproteins despite high-intensity or maximum-tolerated statin treatment. Patients were randomly assigned to receive alirocumab or placebo beginning 1-12 months after acute coronary syndrome and were followed for a median of 2.8 years. The primary outcome of MACE comprised death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischemic stroke, or unstable angina requiring hospitalization.
      • Schwartz GG
      • Steg PG
      • Szarek M
      • et al.
      Alirocumab and cardiovascular outcomes after acute coronary syndrome.
      Study participants were classified as having previous atrial fibrillation (present prior to or at randomization) or no previous atrial fibrillation. In the latter category, the incidence of atrial fibrillation after randomization was determined from investigator reports of adverse events. A multivariable model was used to determine factors associated with incident atrial fibrillation. Treatment hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for the primary outcome and selected secondary outcomes.

      Results

      Overall, 662 patients (3.5%) had a history of atrial fibrillation at baseline and 18,262 (96.5%) had no history of atrial fibrillation. Patients with a history of atrial fibrillation were older than those without prior atrial fibrillation (mean [SD] age: 65.7 [9.2] vs 58.2 [9.1] years) and had a greater burden of comorbidities, including cerebrovascular disease (11.6% vs 4.7%), peripheral artery disease (7.9% vs 3.8%), hypertension (83.2% vs 63.6%), and heart failure (35.6% vs 13.8%).
      Among participants without prior atrial fibrillation at baseline, 499 (2.7%) had incident atrial fibrillation during follow-up. Older age, history of heart failure or myocardial infarction, and higher body mass index were significantly associated with incident atrial fibrillation. Among the 18,894 patients who received at least one dose of study medication, treatment with alirocumab or placebo did not influence the cumulative incidence of atrial fibrillation (HR 0.91; 95% CI, 0.77-1.09; Figure).
      Figure
      FigureCumulative incidence of incident atrial fibrillation (AF) by randomized treatment in the safety population (18,894 patients). Hazard ratio 0.91; 95% confidence interval, 0.77-1.09.
      Patients with vs without a history of atrial fibrillation had a higher incidence of MACE (8.8 vs 3.7 events per 100 patient-years), cardiovascular death (2.8 vs 0.9 events per 100 patient-years), myocardial infarction (5.8 vs 2.6 events per 100 patient-years), stroke (1.3 vs 0.5 events per 100 patient-years), all-cause death (4.0 vs 1.3 events per 100 patient-years), and hospitalization for atrial fibrillation (2.9 vs 0.6 events per 100 patient-years). There was no significant interaction between atrial fibrillation and randomized treatment on risk of MACE (Pinteraction = .78): treatment HR in patients with atrial fibrillation at baseline, 0.81 (95% CI, 0.58-1.12) vs 0.85 (95% CI, 0.78-0.93) in the subgroup without atrial fibrillation at baseline.

      Discussion

      Our findings confirm prior observations that patients with a history of atrial fibrillation have a higher risk of MACE after acute coronary syndrome.
      • Guimarães PO
      • Peterson ED
      • Stevens SR
      • et al.
      Antithrombotic treatment gap among patients with atrial fibrillation and type 2 diabetes.
      ,
      • Lopes RD
      • Elliott LE
      • White HD
      • et al.
      Antithrombotic therapy and outcomes of patients with atrial fibrillation following primary percutaneous coronary intervention: results from the APEX-AMI trial.
      Incident atrial fibrillation was associated with older age and a greater burden of cardiovascular comorbidities, but was not influenced by assignment to treatment with alirocumab or placebo despite the benefit of the former on MACE.
      As this was a post hoc analysis, our results should be taken to be exploratory. Other limitations include the absence of protocol-specified periodic electrocardiograms or ambulatory electrocardiographic studies, and the absence of systematic adjudication of incident atrial fibrillation events. Future studies with more rigorous atrial fibrillation ascertainment may be warranted.
      In conclusion, history of atrial fibrillation is an independent predictor of recurrent cardiovascular events after acute coronary syndrome. While alirocumab did not modify the risk of incident atrial fibrillation after acute coronary syndrome, it did reduce the risk of MACE, regardless of prior atrial fibrillation history.

      Acknowledgments

      Editorial support was provided by Sophie Rushton-Smith of Medlink Healthcare Communications, London, and was funded by Sanofi.

      References

        • Schwartz GG
        • Steg PG
        • Szarek M
        • et al.
        Alirocumab and cardiovascular outcomes after acute coronary syndrome.
        N Engl J Med. 2018; 379: 2097-2107
        • Sabatine MS
        • Giugliano RP
        • Keech AC
        • et al.
        Evolocumab and clinical outcomes in patients with cardiovascular disease.
        N Engl J Med. 2017; 376: 1713-1722
        • Fang WT
        • Li HJ
        • Zhang H
        • Jiang S
        The role of statin therapy in the prevention of atrial fibrillation: a meta-analysis of randomized controlled trials.
        Br J Clin Pharmacol. 2012; 74: 744-756
        • Guimarães PO
        • Peterson ED
        • Stevens SR
        • et al.
        Antithrombotic treatment gap among patients with atrial fibrillation and type 2 diabetes.
        Int J Cardiol. 2019; 289: 58-62
        • Lopes RD
        • Elliott LE
        • White HD
        • et al.
        Antithrombotic therapy and outcomes of patients with atrial fibrillation following primary percutaneous coronary intervention: results from the APEX-AMI trial.
        Eur Heart J. 2009; 30: 2019-2028