MASTER DAPT clinical trial review

MASTER DAPT clinical trial review

Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation With an Abbreviated Versus Prolonged DAPT Regimen (MASTER DAPT) trial assessed an abbreviated duration of dual antiplatelet therapy in patients at high risk for bleeding after implantation of a drug eluting coronary stent [1]. Randomization was done one month after implantation of biodegradable-polymer sirolimus-eluting coronary stent in those at high bleeding risk. Abbreviated therapy group discontinued dual antiplatelet therapy immediately and continued on single antiplatelet therapy. Standard therapy group continued dual antiplatelet therapy for at least two additional months.

There were three ranked primary outcomes. One was net adverse clinical events, a composite of death from any cause, myocardial infarction, stroke or major bleeding. Second was major adverse cardiac or cerebral events, a composite of death from any cause, myocardial infarction or stroke. Third was major or clinically relevant nonmajor bleeding. Cumulative incidences were assessed at 335 days. First two ranked primary outcomes were evaluated for noninferiority in the per-protocol population. The third outcome was assessed for superiority in the intention-to-treat population [1].

In the per-protocol group of 4434 patients, net adverse clinical events occurred in 165 patients in the abbreviated therapy group and in 172 patients in standard therapy group. Major adverse cardiac or cerebral event occurred in 133 patients in abbreviated therapy group and in 132 patients of standard therapy group. Both these met the criteria for noninferiority. There were 4579 patients in the intention-to treat population. 148 patients in the abbreviated therapy group and 211 patients in the standard therapy group had major or clinically relevant nonmajor bleeding. This met the criteria for superiority with P<0.001 [1]. So the abbreviated therapy had lower bleeding with similar MACE and NACE compared to standard therapy.

The median duration of DAPT was 34 days in the abbreviated group and 193 days in the standard therapy group, in this clinical trial. Choice of P2Y₁₂ inhibitor for DAPT and the type of monotherapy after the discontinuation of DAPT were at the discretion of the investigator. Clopidogrel was the most frequently used P2Y₁₂ inhibitor in the standard therapy group and was the most frequently used monotherapy in the abbreviated therapy group at the time of randomization and thereafter.

MASTER DAPT trial was an investigator initiated open label randomized trial. Patients with or without oral anticoagulant therapy after coronary stenting were included. There was stratification of randomization by concomitant indication for oral anticoagulation. Net adverse clinical outcomes and major adverse cardiac and cerebral events did not differ with abbreviated antiplatelet therapy in patients with high bleeding risk with or without indication for oral anticoagulation. Lower bleeding rates were noted in those without an indication for oral anticoagulation. It was driven mainly by a reduction in Bleeding Academic Research Consortium 2 bleedings [2].

In this context, an earlier metanalysis had shown that double antithrombotic therapy, particularly if consisting of a non-vitamin K oral anticoagulant (NOAC) instead of vitamin K antagonist and P2Y₁₂ inhibitor is associated with a reduction in bleeding. This included major and intracranial hemorrhages. The benefit was counterbalanced by a higher risk of cardiac, mainly stent related, but not cerebrovascular ischemic events [3]. That analysis included 10,234 patients in four trials, in which 5496 were on dual antithrombotic therapy while 4738 were on triple antithrombotic therapy.

2020 European Society of Cardiology (ESC)/European Association for Cardio-Thoracic Surgery (EACTS) guidelines for atrial fibrillation (AF) recommends abbreviated periods of triple antithrombotic therapy in those with coronary stents [4]. When the risk of stent thrombosis is low and risk of bleeding deemed high, they suggest stopping aspirin within a week and continuing NOAC with P2Y₁₂ inhibitor (clopidogrel preferred) for up to 12 months in patients undergoing uncomplicated percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS). Triple therapy up to 1 month may be considered if the thrombotic risk outweighs the bleeding risk.

The corresponding duration of dual antithrombotic therapy with NOAC and clopidogrel in PCI for chronic coronary syndrome is 6 months. Aspirin is stopped within one week if the bleeding risk is more than the thrombotic risk. Just as in case of ACS, when the risk of stent thrombosis is deemed higher than the bleeding risk, triple antithrombotic therapy may be considered for up to 1 month [4]. It may be noted that the duration of DAPT recommended in the 2020 ECS/EATCS guidelines for those at high bleeding risk and AF was lower than the time of randomization in MASTER-DAPT trial (less than 1 week vs 1 month). But ultra short period of DAPT may be associated with higher stent related ischemic events [3].

References

1. Valgimigli M, Frigoli E, Heg D, Tijssen J, Jüni P, Vranckx P, Ozaki Y, Morice MC, Chevalier B, Onuma Y, Windecker S, Tonino PAL, Roffi M, Lesiak M, Mahfoud F, Bartunek J, Hildick-Smith D, Colombo A, Stanković G, Iñiguez A, Schultz C, Kornowski R, Ong PJL, Alasnag M, Rodriguez AE, Moschovitis A, Laanmets P, Donahue M, Leonardi S, Smits PC; MASTER DAPT Investigators. Dual Antiplatelet Therapy after PCI in Patients at High Bleeding Risk. N Engl J Med. 2021 Oct 28;385(18):1643-1655. doi: 10.1056/NEJMoa2108749. Epub 2021 Aug 28. PMID: 34449185.
2. Smits PC, Frigoli E, Tijssen J, Jüni P, Vranckx P, Ozaki Y, Morice MC, Chevalier B, Onuma Y, Windecker S, Tonino PAL, Roffi M, Lesiak M, Mahfoud F, Bartunek J, Hildick-Smith D, Colombo A, Stankovic G, Iñiguez A, Schultz C, Kornowski R, Ong PJL, Alasnag M, Rodriguez AE, Moschovitis A, Laanmets P, Heg D, Valgimigli M; MASTER DAPT Investigators. Abbreviated Antiplatelet Therapy in Patients at High Bleeding Risk With or Without Oral Anticoagulant Therapy After Coronary Stenting: An Open-Label, Randomized, Controlled Trial. Circulation. 2021 Oct 12;144(15):1196-1211. doi: 10.1161/CIRCULATIONAHA.121.056680. Epub 2021 Aug 29. PMID: 34455849; PMCID: PMC8500374.
3. Gargiulo G, Goette A, Tijssen J, Eckardt L, Lewalter T, Vranckx P, Valgimigli M. Safety and efficacy outcomes of double vs. triple antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention: a systematic review and meta-analysis of non-vitamin K antagonist oral anticoagulant-based randomized clinical trials. Eur Heart J. 2019 Dec 7;40(46):3757-3767. doi: 10.1093/eurheartj/ehz732. PMID: 31651946.
4. Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, Boriani G, Castella M, Dan GA, Dilaveris PE, Fauchier L, Filippatos G, Kalman JM, La Meir M, Lane DA, Lebeau JP, Lettino M, Lip GYH, Pinto FJ, Thomas GN, Valgimigli M, Van Gelder IC, Van Putte BP, Watkins CL; ESC Scientific Document Group. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J. 2021 Feb 1;42(5):373-498. doi: 10.1093/eurheartj/ehaa612. Erratum in: Eur Heart J. 2021 Feb 1;42(5):507. Erratum in: Eur Heart J. 2021 Feb 1;42(5):546-547. Erratum in: Eur Heart J. 2021 Oct 21;42(40):4194. PMID: 32860505.