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One Month Post-PCI DAPT May Be Enough in High-Bleeding-Risk Patients, but Insufficient after ACS: MASTER-DAPT & STOPDAPT-2 ACS trials

A comment by the ESC Working Group on Thrombosis

Coronary Artery Disease (Chronic)
Cardiovascular Surgery
Acute Cardiac Care
Treatment
Coronary Intervention


Short description of the article

MASTER DAPT (Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation With an Abbreviated Versus Prolonged DAPT Regimen; NCT03023020; funded by Terumo) and STOPDAPT-2 ACS (ShorT and OPtimal Duration of Dual AntiPlatelet Therapy-2 Study for the Patients With ACS; NCT03462498; funded by Kyoto University, Graduate School of Medicine) were investigator-initiated, open-label, multicentre trials comparing the safety and efficacy of abbreviated and standard dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with stent implantation [1,2].

The MASTER DAPT study enrolled 4,579 high-bleeding risk patients who had undergone the implantation of a biodegradable-polymer sirolimus-eluting coronary stent due to chronic or acute coronary syndrome (mean age 76 years, 69% male, 36% with indications for oral anticoagulation [OAC]). The patients who had not experienced any thrombotic or bleeding events during the first month following PCI were randomly assigned to discontinue DAPT immediately (abbreviated therapy) or to continue it for at least 3 months (standard therapy). The three co-primary endpoints were (i) net adverse clinical events (NACE: all-cause death, myocardial infarction, stroke, major bleeding [Bleeding Academic Research Consortium, BARC type 2, 3 or 5), (ii) major adverse cardiac or cerebral events (MACCE: all-cause death, myocardial infarction, stroke) and (iii) major or clinically relevant nonmajor bleeding (BARC type 2, 3, 5). The incidence of NACE was comparable in the abbreviated and standard therapy groups during the 12-month follow-up (7.5% vs. 7.7%; hazard ratio [HR] 0.97; 95% confidence interval [CI] 0.78 - 1.20; P<0.001 for noninferiority in the per-protocol population). The incidence of MACCE was similar in both groups as well (6.1% vs. 5.9%; HR 1.02; 95% CI 0.80 - 1.30; P<0.001 for noninferiority in the per-protocol population). The incidence of major or clinically relevant nonmajor bleeding events was lower in the abbreviated therapy group, compared to the standard therapy group (6.5% vs. 9.4%; HR 0.68; 95% CI 0.55 - 0.84; P<0.001 for superiority in the intention-to-treat population). In the subgroup analysis, abbreviated DAPT decreased the bleeding risk only in the subgroup of patients without an OAC indication (4.6% vs. 8.1%, HR 0.55; 95% CI 0.41–0.74; P<0.001), whereas the rates of NACE and MACCE were comparable in patients treated with abbreviated and standard DAPT, regardless of OAC administration [3].

The STOPDAPT-2 ACS study enrolled 4,134 patients with acute coronary syndrome and no indication for anticoagulation, who had received a cobalt-chromium everolimus-eluting stent (mean age 67 years, 79% male). Patients with indication for OAC were excluded from the study. Patients were randomized to discontinue DAPT 1 month after the PCI (abbreviated therapy) or to continue it for 12 months (standard therapy). The incidence of NACE (composite of cardiovascular death, myocardial infarction, any stroke, definite stent thrombosis, Thrombolysis in Myocardial Infarction [TIMI] major and minor bleeding events) was comparable in the abbreviated and standard DAPT groups (3.20% vs. 2.83%; HR 1.14; 95% CI 0.80 - 1.62) during the 12-month follow-up, but did not reach the significance level for noninferiority (P=0.06). There was a trend towards higher incidence of MACCE (cardiovascular death, myocardial infarction, any stroke, definite stent thrombosis) in the abbreviated DAPT group (2.76% vs. 1.86%; HR 1.50; 95% CI 0.99-2.26). In addition, abbreviated DAPT was associated with nearly 2-fold higher risk of myocardial infarction, compared to the standard DAPT (1.59% vs. 0.85%; HR 1.91; 95% CI 1.06-3.44). The incidence of TIMI major and minor bleeding events was lower in the abbreviated DAPT group, compared to the standard DAPT group (0.46% vs. 1.17%; HR 0.46; 95% CI 0.23-0.94).

Comment by Aleksandra Gasecka, MD, PhD

The duration of DAPT following PCI with stent implantation remains an area of extensive research. The MASTER DAPT and STOPDAPT-2 ACS trials both addressed the question of the optimal DAPT duration to prevent the ischemic complications, while limiting the bleeding risk.

The MASTER DAPT showed that in patients at increased bleeding risk, abbreviated DAPT was noninferior to standard DAPT regarding NACE and MACCE, regardless of concomitant OAC treatment, and superior to standard DAPT regarding bleeding events in patients without an OAC indication. In contrast, the STOPDAPT-2 ACS failed to show the noninferiority of the abbreviated DAPT regarding the composite ischemic and bleeding endpoint among patients with ACS, with a trend towards higher rate of composite ischemic endpoint and a nearly 2-fold significant increase in the risk of myocardial infarction. Consistent with the MASTER DAPT, both major and minor bleeding events were less frequent with the abbreviated DAPT. Although the MASTER DAPT reached its primary endpoints, whereas the STOPDAPT-2 ACS did not, the results of both trials are in fact consistent, since both trials focused on entirely different populations.

The MASTER DAPT enrolled only patients at high risk of bleeding, who were excluded from most previous DAPT trials. Noteworthy, all patients were event-free during the first month of post-PCI DAPT, therefore excluding those with early in-stent restenosis or stent thrombosis. Hence, the study population comprised of patients who were not only at high risk of bleeding, but also at low risk of thrombotic events. On the other hand, patients were enrolled regardless of the clinical presentation (chronic or acute coronary syndrome), number, location, or complexity of the treated lesions, allowing to include also those with clinical or angiographic high ischaemic risk features. Based on the study results, it can be concluded that in the selected population of high-bleeding patients who were event-free during the first month after the PCI, abandoning aspirin increases the treatment safety without compromising its efficacy. Nevertheless, the results cannot be extrapolated to patients who are not at high bleeding risk or who did experience a thrombotic event during the first month post-PCI. Further, all patients were uniformly treated with a biodegradable-polymer sirolimus-eluting stent, so the results may not extend to patients receiving other stent types. Finally, the applicability of the MASTER DAPT to patients with acute coronary syndrome (ACS) remains to be established. The ACS patients comprised 48% of the study cohort, but only 11% of them were admitted due to ST-elevation myocardial infarction (STEMI). Hence, whether (the high bleeding risk) STEMI patients indeed benefit from the abbreviated DAPT, requires further investigation.

The STOPDAPT-2 ACS aimed to specifically address the question of the optimal DAPT duration in ACS patients undergoing PCI, but – in contrast to MASTER DAPT – those at high risk of bleeding were excluded from the trial. As much as 56% of the study participants were admitted with STEMI (3.2% with cardiogenic shock, 4.0% requiring mechanical circulatory support), in whom potent P2Y12 inhibitors are recommended as the default treatment strategy [4,5]. In contrast to the current guideline recommendations, 52.5% of patients were treated with clopidogrel, whereas 47.5% received reduced-dose prasugrel (3.75 mg once daily) during the first month post-ACS. After that, all patients switched to clopidogrel, and aspirin was abandoned in the abbreviated DAPT group. On one hand, the use of less potent P2Y12 inhibitors and reduced-dose prasugrel seems reasonable in the East Asian population due to the higher bleeding risk [6]. On the other hand, given the non-standard choice and dosage of the P2Y12 inhibitors, extrapolation of the results to the European population is challenging. Previously, two multicentre randomized clinical trials evaluated the efficacy and safety of monotherapy with a potent P2Y12 inhibitor after a minimum period of DAPT (1-3 months) in patients after ACS: GLOBAL LEADERS and TWILIGHT [7,8]. In the GLOBAL LEADERS trial, ticagrelor monotherapy was similar regarding ischaemic protection and bleeding compared to DAPT in 15,968 patients who underwent PCI during 2-year observation. In the TWILIGHT trial, ticagrelor monotherapy decreased the risk of bleeding without increasing the risk of ischaemic events compared to DAPT among 7,119 high-risk patients after PCI during 1-year observation. In contrast to STOPDAPT-2 ACS, where clopidogrel monotherapy failed to show non-inferiority compared to standard DAPT, ticagrelor monotherapy seemed to be the same efficient and potentially safer than standard DAPT. Thus, the use of potent P2Y12 inhibitors, either in monotherapy or as a part of DAPT, still seems to be the optimal therapeutic choice after an ACS.

Altogether, the results of MASTER DAPT and STOPDAPT-2 ACS clearly indicate that the decision regarding the DAPT choice and duration should be made based on the individual risk of thrombotic and bleeding events. However, both trials provide more questions than answers: How to treat patients at high risk of both bleeding and thrombotic events? Is clopidogrel enough in patients with STEMI? Should the treatment regimen be tailored to the stent type? Which combination of antiplatelet and antithrombotic agents is optimal after PCI in patients requiring OAC? These and other questions need to be answered to develop the DAPT strategies tailored to the individual patient’s needs.

Comment by Prof. Diana A. Gorog, MB BS, MD, PhD, FRCP, FESC

Treatment with dual antithrombotic therapy (DAPT) increases the risk of major bleeding. The studies discussed here aimed to assess the safety of shortened DAPT duration in patients at high bleeding risk (MASTER DAPT) and ACS (STOPDAPT-2 ACS) following PCI.

A reduction in bleeding is to be expected with shorter DAPT duration, so it is not surprising that this approach resulted in a lower incidence of major or clinically relevant nonmajor bleeding in MASTER DAPT. However, what is surprising, is that the occurrence of major (BARC 3-5, TIMI major or GUSTO moderate-severe) bleeding was not reduced. This begs the question: is it worth abbreviating DAPT to 1 month? While there was no reduction in major bleeding, it is noteworthy that 79% of patients in both groups were taking clopidogrel as the P2Y12 inhibitor; the magnitude of benefit in reducing major bleeding may have been greater if using a more potent P2Y12 inhibitor associated with higher bleeding risk. This study suggests that it is safe to abbreviate DAPT, certainly in low ischaemic risk patients, although less than half the enrolled patients had an ACS, and relatively few had STEMI.

In higher ischaemic risk patients with ACS, the STOPDAPT-2 ACS study showed that 1-month DAPT was inferior to 12 months’ DAPT with respect to the primary endpoint of the composite of cardiovascular and bleeding outcomes at one year, with a trend toward an increase in cardiovascular events despite a reduction in major bleeding. STOPDAPT-2 ACS notably employed intracardiac imaging (IVUS or OCT) in 97% of patients, which probably accounted for the relatively low rate of ischaemic events, that is not reflective of everyday practice. That is important, because in a “real world” setting where intracoronary imaging is not routinely employed, the rate of coronary ischemic events would be expected to be higher, and the shorter DAPT duration may expose an excess ischaemic risk. Finally, the STOP-DAPT 2 ACS trial is provocative in using clopidogrel, when current guidelines advocate the use of more potent P2Y12 inhibitors ticagrelor or prasugrel in ACS patients.

Should these trials change clinical practice? Probably not, for the majority of patients. That is because MASTER DAPT, whilst demonstrating the non-inferiority of the shorter DAPT approach, also showed that use of abbreviated DAPT did not reduce major bleeding in high bleeding risk patients, and in higher ischaemic risk patients, STOPDAPT-2 ACS did not reliably demonstrate the non-inferiority of this approach in terms of preventing major adverse cardiovascular events. Furthermore, in real life, there is a very significant overlap between high-ischaemic and high-bleeding risk patients.

Thus, the optimal duration of DAPT remains unclear. One month is not proven to be safe in preventing ischaemic events, yet 12 months may be too much in those at high-bleeding risk. Importantly, the optimal monotherapy following de-escalation remains unclear and it is possible that ticagrelor may have an important role to play here.

For now, for ACS patients undergoing PCI, 12 months of DAPT should remain the standard of care if there is no major bleeding concern, with clopidogrel reserved for those who cannot take ticagrelor or prasugrel. In high bleeding risk patients, use of clopidogrel as part of DAPT and abbreviated DAPT duration can be considered, on a case-by-case basis, supported by the current new evidence, acknowledging that this approach has not been shown to reduce major bleeding, and its effectiveness in preventing major cardiovascular events has not been reliably established.

References


  1. Valgimigli M, Frigoli E, Heg D, et al. Dual Antiplatelet Therapy after PCI in Patients at High Bleeding Risk. New England Journal of Medicine. 2021; Aug 28; [ahead of print].
  2. Presented by Dr. Hirotoshi Watanabe at the European Society of Cardiology Virtual Congress, August 30, 2021.
  3. Smits P, Frigoli E, Tijssen J, et al., on behalf of the 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; Aug 29: [ahead of print].
  4. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease. Eur Heart J 2018; 39: 213-260.
  5. Jean-Philippe Collet, Holger Thiele, Emanuele Barbato, et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2021; 42: 1289-1367.
  6. Akita K, Inohara T, Yamaji K, et al. Impact of reduced-dose prasugrel vs. standard-dose clopidogrel on in-hospital outcomes of percutaneous coronary intervention in 62 737 patients with acute coronary syndromes: a nationwide registry study in Japan. European Heart Journal-Cardiovascular Pharmacotherapy. 2020; 6: 231-238.
  7. Vranckx P, Valgimigli M, Jüni P, et al. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial. Lancet; 2018; 392: 940–949.
  8. Mehran R, Baber U, Sharma SK, et al. Ticagrelor with or without Aspirin in High-Risk Patients after PCI. N Engl J Med. 2019; 381: 2032-2042.Presented by Dr. Hirotoshi Watanabe at the European Society of Cardiology Virtual Congress, August 30, 2021.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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