Editor's Note: Commentary based on Mahaffey KW, Stevens SR, White HD, et al; ROCKET AF Investigators. Ischaemic cardiac outcomes in patients with atrial fibrillation treated with vitamin K antagonism or factor Xa inhibition: results from the ROCKET AF trial. Eur Heart J 2014;35:233-41.

Background

Oral direct factor Xa inhibitors are new anticoagulants developed to overcome several limitations of warfarin; they do not require routine blood tests and have fewer drug-food and drug-drug interactions. A disadvantage of direct factor Xa inhibitors is that they do not currently have an established specific antidote to quickly reverse their anticoagulation effects. ROCKET-AF was a randomized controlled trial in patients with non-valvular atrial fibrillation (AF) comparing efficacy and safety between the direct factor Xa inhibitor rivaroxaban and warfarin. The main analysis demonstrated that rivaroxaban was non-inferior to warfarin in terms of stroke and ischemic embolism prevention.1 This prespecified secondary analysis reports the prevalence of prior myocardial infarction (MI) and the incidence of cardiovascular (CV) events in this trial.2 It is an important paper because prior analyses suggested that oral factor IIa (thrombin) inhibitors were associated with an increased rate of MI as compared to warfarin.

Methods

ROCKET-AF was a randomized, double-blind, multicenter trial comparing rivaroxaban 20 mg daily (15 mg daily if creatinine clearance 30-49 mL/min at randomization) and warfarin. The patient population was comprised of patients with non-valvular AF with CHADS2 score ≥2. This secondary analysis focused on patients with history of prior MI. CV events were defined as a composite of CV death, MI, or unstable angina (UA). The following comparisons were performed:

1. Baseline patient characteristics between patients with and without prior MI;
2. Incidence of stroke, cardiac, and bleeding outcomes between patients with and without prior MI;
3. Incidence of CV events between patients on warfarin and rivaroxaban.

Results

Among 14,624 randomized patients, 2468 (17%) had prior MI at enrollment. The main results were as follows:

1. Patients with prior MI were more likely to be male (75 vs. 57%), on aspirin (47 vs. 34%), have prior congestive heart failure (78 vs. 59%), diabetes (47 vs. 39%), hypertension (94 vs. 90%), higher mean CHADS2 score (3.64 vs. 3.43), and fewer prior strokes or transient ischemic attacks (46 vs. 54%).
2. Patients with history of prior MI had similar rates of stroke and embolic events. Patients with prior MI had more recurrent CV events and higher mortality. These patients also had higher rates of major bleeding. Patients with prior MI had higher risk for CV events (HR 1.6, 95% CI 1.2–2.2; p<0.002) after adjusting for differences in baseline characteristics.
3. Patients who received rivaroxaban had a non-significant reduction in the hazard of CV death, MI, or UA (HR 0.86, 95% CI 0.73–1.00; p=0.051 [adjusted HR 0.88, 95% CI 0.75–1.03; adjusted p=0.103]).

Conclusion

Among the ROCKET-AF trial participants with non-valvular AF, 17% had prior history of MI. These patients were more likely to experience subsequent cardiac and bleeding events. A non-significant trend towards reduction in CV events was observed in patients on rivaroxaban compared to warfarin.

Commentary/Perspective

The observation that patients with prior MI are at higher risk of recurrent CV events, including CV death and bleeding complications, is consistent with observations in other patient populations than AF.3

The trend towards reduction in CV events with rivaroxaban compared to warfarin warrants careful interpretation. First, this trend was no longer statistically significant when adjusted to other possibly confounding factors. Second, there were no statistically significant differences in the incidence of MI (HR 0.73, 95% CI 0.51-1.04; p=0.26) or unstable angina (HR 0.81, 95% CI 0.49-1.35; p=0.60); the difference in CV events (unadjusted analysis) was mainly driven by decrease in CV death, which also included endpoints other than deaths from cardiac ischemia such as stroke, systemic embolism, and arrhythmias. Third, a prior meta-analysis including ROCKET-AF showed no difference in incidence of MI when combining data from 3 studies comparing direct factor Xa inhibitors and warfarin (OR 0.97, 95% CI 0.78–1.20; p=0.77).4 The absence of a significant reduction in ischemic cardiac events with rivaroxaban compared to warfarin may be due to a lack of a true effect or insufficient power to detect a difference.

Overall, this analysis showed that patients with prior MI are at increased risk of experiencing CV events and bleeding complications. It is still not clear whether the direct factor Xa inhibitor rivaroxaban reduces non-fatal ischemic cardiac events more than warfarin.

References

1. Mahaffey KW, Stevens SR, White HD, et al; ROCKET AF Investigators. Ischaemic cardiac outcomes in patients with atrial fibrillation treated with vitamin K antagonism or factor Xa inhibition: results from the ROCKET AF trial. Eur Heart J 2014;35:233-41.
2. Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91.
3. Go AS, Mozaffarian D, Roger VL, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2013 update: a report from the American Heart Association. Circulation 2013;127:e6-e245.
4. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2013 pii: S0140-6736(13)62343-0.

Keywords: Angina, Unstable, Creatinine, Double-Blind Method, Morpholines, Random Allocation, Thiophenes, Warfarin

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