Could NOACs Have a Role for Secondary Prevention After STEMI?
Even with the increase in bleeding when added to antiplatelet therapy, there could be a net benefit, a meta-analysis suggests.
Adding a non-vitamin K antagonist oral anticoagulant (NOAC) to antiplatelet therapy to prevent recurrent events after ACS appears to do more good than harm in the subset of patients with STEMI, although the net clinical effect goes in the other direction for those with NSTE ACS, a meta-analysis suggests.
In the overall cohort of patients with ACS, using a NOAC plus antiplatelet therapy was associated with a lower risk of the composite endpoint of cardiovascular death, MI, and stroke compared with using antiplatelet therapy alone (OR 0.85; 95% CI 0.77-0.93), according to lead author Mauro Chiarito, MD (Humanitas University, Pieve Emanuele-Milan, Italy), and colleagues.
That finding was consistent in patients with STEMI (OR 0.76; 95% CI 0.66-0.88), but not in those with NSTE ACS (OR 0.92; 95% CI 0.78-1.09), the investigators report in a study published online February 7, 2018, ahead of print in JAMA Cardiology.
The risk of major bleeding was higher with the addition of a NOAC (OR 3.17; 95% CI 2.27-4.42), a finding seen regardless of ACS type.
Senior author Giulio Stefanini, MD, PhD (Humanitas University), told TCTMD that this is the first time it has been shown that the effect of adding NOACs to post-ACS regimens differs by ACS type.
The results “support the fact that the addition of a [NOAC] may be useful in patients at higher thrombotic risk, meaning STEMI patients, since in this patient population . . . it emerges that the number needed to treat is way lower than the number needed to harm, while in non-ST-elevation acute coronary syndromes the number needed to treat and the number needed to harm are more or less equivalent,” Stefanini said.
In the STEMI subset, the number needed to treat was 63 and the number needed to harm was 96. Corresponding values in the NSTE ACS group were 130 and 137.
Stefanini cautioned, however, that the results should only be considered hypothesis-generating.
Unmet Need Despite Recent Progress
Over the past 3 decades, there have been major advances in the treatment of ACS, but the risk of recurrent events remains high, underscoring the continuing need for better options. One method is intensifying the antithrombotic regimen by adding a NOAC to standard antiplatelet therapy. A handful of trials have tested this approach—mostly by adding a NOAC to dual antiplatelet therapy—with results showing reductions in ischemic risk coupled with increases in bleeding.
Chiarito, Stefanini, and colleagues pooled results from six recent phase II or III trials—APPRAISE, APPRAISE 2, APPRAISE J, ATLAS ACS-TIMI 46, ATLAS ACS 2-TIMI 51, and REDEEM—to evaluate the overall safety and efficacy of the approach and to explore differences by ACS type. The 29,667 total patients were nearly evenly split between the STEMI and NSTE ACS subgroups. The NOACs used in the trials were apixaban (Eliquis; Bristol-Myers Squibb), rivaroxaban (Xarelto; Bayer/Janssen), and dabigatran (Pradaxa; Boehringer Ingelheim).
Adding a NOAC was associated with a nonsignificantly lower risk of cardiovascular death (OR 0.86; 95% CI 0.73-1.01) and a significantly lower risk of MI (OR 0.83; 95% CI 0.74-0.95), with no difference for stroke (OR 0.81; 95% CI 0.54-1.20). That pattern was consistent in the STEMI subset, but in NSTE ACS patients, use of a NOAC was not tied to any apparent benefits.
“The rationale for using [NOACs] in patients with ACS without an indication for oral anticoagulation, especially for those with STEMI, is linked to the pivotal role of thrombin in this clinical setting,” the authors explain. “After an acute MI, high thrombin levels are traceable for at least 6 months and thrombin generation is inversely correlated with recurrent cardiovascular events. Therefore, the higher thrombotic burden and coagulation cascade activation during and after STEMI compared with NSTE ACS could help to explain, at least in part, our findings.”
However, there are other possible explanations for the discrepancy between STEMI and NSTE ACS, including differences in clinical characteristics and in therapeutic strategies. “The relative effect of these features on [NOAC] treatment effects should be further investigated in future studies,” Chiarito and colleagues write.
Risk Stratification Could be Useful
Future research also should explore whether certain patients do better than others with the combination of a NOAC and antiplatelet therapy, Stefanini said.
“Our evidence supports the concept that risk stratification after ACS may allow us to identify a group of patients at higher thrombotic risk which benefit from an intensification of antithrombotic therapy with the addition of a [NOAC] on top of antiplatelet therapy,” he said, speculating that distinctions can probably be made within the STEMI subset according to baseline characteristics.
“Certainly, the identification of patients at lower bleeding risk may help us to identify a subgroup of patients among those with STEMI that might benefit the most,” Stefanini said. He pointed to the PRECISE-DAPT score as one tool that might be used for risk stratification.
Stefanini said a strategy of adding a NOAC to antiplatelet therapy for post-ACS secondary prevention has not taken hold in everyday practice yet because the benefits observed in trials so far have been offset by bleeding risks. The findings from this meta-analysis, he added, could be used to design future trials focusing on patients with STEMI, in whom the risk/benefit ratio may be more favorable.
Chiarito M, Cao D, Cannata F, et al. Direct oral anticoagulants in addition to antiplatelet therapy for secondary prevention after acute coronary syndromes: a systematic review and meta-analysis. JAMA Cardiol. 2018;Epub ahead of print.
- The study was partially funded through an institutional grant from Humanitas Research Hospital.
- Stefanini reports receiving a research grant from Boston Scientific and speaker/consulting fees from B. Braun, Biosensors, Boston Scientific, and Edwards Lifesciences.
- Chiarito reports no relevant conflicts of interest.