Acute coronary syndrome (ACS) is a leading cause of mortality. For early stages of ACS prognosis improved, however, at later follow-up, cardiovascular events continue to occur in up to 20% of these cases. Pharmacological agents targeting platelet aggregation or thrombin formation, further ameliorated clinical outcome, but also resulted in increased bleeding complications. The risk-benefit profile of a therapy for ACS is therefore not easily determined. Furthermore, in ACS trials, risk-benefit and net clinical outcome analyses often mingle fatal or irreversible events with survivable or reversible events, which vary considerably in their clinical impact.
An alternative approach to interpret risk-benefit data is to limit the analysis to fatal or irreversible efficacy events (non-bleeding cardiovascular death, myocardial infarction, and ischemic stroke), relative to fatal or irreversible safety events, such as fatal and intracranial bleeding.
The previously published ATLAS ACS 2-TIMI 51 trial demonstrated a survival benefit, but no difference in net clinical outcome for ACS patients receiving a low-dose (2.5 mg orally twice per day) of rivaroxaban (a factor Xa inhibitor) on top of the standard-of-care therapy.
In addition to conventional analysis, this can assist with the decision whether a treatment should be used or not
When limiting analyzed outcomes exclusively to fatal or irreversible events, a recent sub-analysis of this same study presented evidence that low dose of Rivaroxaban was associated with 115 (95% confidence interval [CI]: 18 to 212) fewer fatal or irreversible ischemic events (663 for placebo vs. 548 for therapy) and 10 (95% CI: 11 to 32) additional fatal or irreversible seriously harmful events (33 vs. 23 for placebo) per 10,000 patient-years of exposure. When the analysis was limited to non-bleeding cardiovascular death, 95 events would be prevented per 10,000 patient-years of exposure in the Rivaroxaban group.
Therefore, through limiting the analysis to events with similar clinical impact, low-dose of Rivaroxaban therapy was associated with a net reduction in fatal or irreversible events.
In response to this study, Nikolsky et al. pointed out that only 61% (9,435) of the initial 15,526 patients from the main ATLAS trial were part of this sub-analysis. These were patients randomized to the effective lower dosage of rivaroxaban. However, Nikolsky et al. considered this study valuable supplementary information, which in addition to conventional analysis, can assist with the decision whether a treatment should be used or not. However, several limitations, among others the bias in patient selection and a wide confidence interval for the prevention of fatal or irreversible events, were named. Furthermore, limitations based on time to-first-event were listed both by Nikolsky et al. and an additional comment by Ye et al. The latter comment also cautioned that the safety effects of the rivaroxaban could be underestimated due to exclusion criteria of gastrointestinal bleeding in the presented study.
Original study: J Am Coll Cardiol. 2018 Jul 10;72(2):129-136.
Nikolsky et al. , J Am Coll Cardiol. 2018 Jul 10;72(2):137-140.
Ye et al., J Am Coll Cardiol. 2018 Nov 6;72(19):2411-2412.
Author: Frederike Schmitz