Double Antithrombotic Therapy Best for PCI Patients With AF

June 27, 2019

In patients with atrial fibrillation undergoing percutaneous coronary intervention (PCI) or with an acute coronary syndrome (ACS), an antithrombotic regimen of double therapy with a non-vitamin K antagonist oral anticoagulant (NOAC) plus a P2Y12 inhibitor antiplatelet agent such as clopidogrel (Plavix, Bristol-Myers Squibb) is the preferred treatment option, a new network meta-analysis suggests.

The analysis of four randomized trials comparing different combinations of anticoagulants and antiplatelet drugs found that the NOAC/P2Y12 inhibitor combination was associated with fewer bleeding complications — including intracranial hemorrhage — without a significant difference in ischemic events compared with regimens including a vitamin K antagonist anticoagulant (such as warfarin) and dual antiplatelet therapy (DAPT; aspirin plus a P2Y12 inhibitor).

"In this setting of AF patients with ACS or undergoing PCI, less does seem to be more to get closer to the sweet spot for the maximum reduction in ischemic events at minimal bleeding risk," lead author, Renato Lopes, MD, PhD, Duke Clinical Research Institute, Durham, North Carolina, told Medscape Medical News.

"The vitamin K antagonist anticoagulant plus DAPT regimen should generally be avoided," he added.

The analysis was published online June 19 in JAMA Cardiology.

Lopes explained that patients with AF undergoing PCI for acute coronary syndromes pose a challenge for clinicians in terms of antithrombotic therapy. Oral anticoagulants are indicated for patients with AF for stroke prevention, and patients undergoing PCI are normally treated with dual antiplatelet therapy to reduce the risk of recurrent atherothrombotic events and stent thrombosis. 

"Trying to find the best combination of agents to maximize antithrombotic effect with minimal bleeding is difficult," he said.  

"Until a few years ago, there were no good randomized trials on this, but recently several such trials have been conducted with different combinations. But they have not been large enough individually for certainty around efficacy endpoints," he noted.

In 2018, the outcomes of these trials were combined in a meta-analysis that concluded that omitting aspirin resulted in fewer major bleeds while preserving efficacy compared with a vitamin K antagonist or NOAC with DAPT.

"While the findings of this analysis are important, the sample size of approximately 5000 patients did not permit assessment of differences in less frequent but important complications such as stent thrombosis. Moreover, it also remains unclear whether different classes of anticoagulants (vitamin K antagonists or NOACs) affect safety and efficacy in this high-risk population,” the authors write.

To address these issues, they performed the current Bayesian network meta-analysis that allowed for simultaneous comparisons of multiple antithrombotic strategies. "This approach presents the largest evidence base to date — with a total of 10,000 patients — to inform antithrombotic decisions in this high-risk group of patients," Lopes noted.

"For the main endpoint — major bleeding, including intracranial hemorrhage, — we found that the double therapy of a NOAC and a P2Y12 inhibitor had the lowest risk, and in terms of ischemic events, there were no major differences between any of the combinations," Lopes said. "So from these results I think we can say that this double therapy should be the general preferred combination for these patients."

Lopes reported that the worst combination was a vitamin K antagonist anticoagulant plus DAPT. "This triple therapy combination had the highest risk of bleeding and no additional anti-ischemic benefit, so should be avoided for most patients," he cautioned.

All patients took aspirin for the first few days after PCI. "The question the trials were addressing was whether aspirin could be dropped after the initial high-risk period — and the answer appears to be a definite yes," Lopes said. "So I think we can use aspirin for the in-hospital stay after PCI, but this can be stopped then when the patient is discharged."

These data also show that warfarin is best replaced with a NOAC for most patients, Lopes says. "Warfarin is being used less and less now. It is a complicated drug needing monitoring, and [it] causes increased bleeding compared to NOACs, including ICH, especially in the elderly. And this is the population who get AF."

He notes that by adopting the double therapy of a NOAC and a P2Y12 inhibitor, two mainstays of cardiovascular therapy are being made redundant.

"Warfarin is being replaced by a NOAC, and aspirin can be dropped altogether after the first few days," he said. "Our results show that when patients are already on an anticoagulant they don’t need two antiplatelet agents as well, and aspirin is the best one to drop to reduce bleeding risk."

For the analysis, the researchers included data from four randomized studies (WOEST, PIONEER AF-PCI, RE-DUAL PCI, and AUGUSTUS) in a total of 10,026 patients. The overall prevalence of ACS varied from 28% to 61%, and most patients were at high risk.

Results showed that the NOAC/P2Y12 inhibitor combination had the lowest rate of major bleeding.

Table. Thrombolysis in Myocardial Infarction (TIMI) Major Bleeding

Treatment

Odds Ratio (95% Confidence Interval)

VKA + DAPT  

Reference

VKA + P2Y12 inhibitor

0.58 (0.31 - 1.08)

NOAC + DAPT

0.70 (0.38 - 1.23)

NOAC + P2Y12 inhibitor 

0.49 (0.30 - 0.82)

 

There was no difference in ischemic events between the various combinations.

Table. Trial-defined Primary Major Adverse Cardiac Events

Treatment

Odds Ratio (95% Confidence Interval)

VKA + DAPT  

Reference

VKA + P2Y12 inhibitor

0.96 (0.60 - 1.46)

NOAC + DAPT

0.94 (0.60 - 1.15)

NOAC + P2Y12 inhibitor 

1.02 (0.71 - 1.97)

 

The authors note that although the sample size was sufficient to draw firm conclusions on the overall populations for the primary safety and efficacy outcomes, it may still be insufficient to ascertain more modest effects on rare but serious events, such as stent thrombosis.

They add that most patients used clopidogrel as the P2Y12 inhibitor, and it is not known whether the use of other more potent P2Y12 inhibitors (ticagrelor and prasugrel) would have the same effects on safety and efficacy in combination with oral anticoagulant therapy.

They suggest that an individual patient-level data analysis could further explore which patients would benefit most from a given treatment combination, and whether adjustments need to be made by sex, race/ethnicity, age, clinical presentation (ACS and stable coronary artery disease), thromboembolic risk, bleeding risk, stent placement, stent type, and other procedural characteristics.

Support for this study was provided by Duke Clinical Research Institute. Lopes reported grants and personal fees from Bristol-Myers Squibb and Pfizer and personal fees from Boehringer Ingelheim and Bayer AG during the conduct of the study and grants from Amgen Inc, GlaxoSmithKline, Medtronic PLC, and sanofi-aventis outside the submitted work.

JAMA Cardiol. Published online June 19, 2019. Abstract 

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