Study to explore shortest-ever duration of triple therapy after PCI

Roisin Colleran and Adnan Kastrati

The COBRA REDUCE trial is exploring the safety and efficacy of prescribing dual antiplatelet therapy (DAPT) for just two weeks in high bleeding risk patients who are already receiving oral anticoagulation and who have undergone percutaneous coronary intervention (PCI) with the Cobra PzF stent (Celonova). This represents the shortest duration of triple therapy that has been studied in a randomised controlled trial. Roisin Colleran and Adnan Kastrati review the rationale and aims of the trial.

In patients undergoing PCI, DAPT has proven to be more effective and safer than anticoagulation for prevention of ischaemic events, with fewer haemorrhagic complications.1 However, a significant proportion of patients who undergo PCI also have an indication for oral anticoagulation and in such patients, the optimal antithrombotic regimen remains unknown. Neither American nor European guidelines for clinical practice give strong recommendations regarding the optimal strategy or duration of antithrombotic therapy in these patients.2,3

Atrial fibrillation is the most common indication for oral anticoagulation in patients who undergo PCI. In patients with the condition, oral anticoagulation is more effective than is DAPT for prevention of systemic thromboembolic events.4 In patients with atrial fibrillation and stable coronary artery disease, the addition of antiplatelet monotherapy (aspirin or clopidogrel) to oral anticoagulation significantly increases the risk of bleeding compared with oral anticoagulation alone.5 Nonetheless, patients with atrial fibrillation who undergo PCI often have a period of treatment with triple therapy comprising oral anticoagulation in addition to DAPT—a strategy associated with increased bleeding risk.

While a number of studies have investigated the optimal antithrombotic strategy in such patients, the majority of these have focused on safety endpoints. It comes as no surprise that a reduction in the number, dose, or duration of triple therapy reduces bleeding events.6–9 However, maintaining efficacy is also important and the effect of such measures on ischaemic events is not clear. The PIONEER AF-PCI trial, for example, compared treatment with low-dose rivaroxaban and a P2Y12 inhibitor for 12 months (dual therapy) vs. very low dose rivaroxaban and DAPT for one, six or 12 months vs. a vitamin K antagonist and DAPT for one, six or 12 months. Although “clinically significant bleeding” was lower in the dual therapy group, ischaemic event rates were numerically highest in this group.7 The RE-DUAL PCI trial compared dual therapy with dabigatran 110mg or 150mg with a P2Y12 inhibitor (clopidogrel or ticagrelor) vs. triple therapy with a vitamin K antagonist and aspirin and a P2Y12 inhibitor (clopidogrel or ticagrelor).8 While bleeding was significantly lower in the lower dose dual therapy group, stent thrombosis and myocardial infarction were both numerically higher. As neither study was powered to show a statistically significant difference with respect to ischaemic events between treatment groups, results are inconclusive in this respect. In contrast, the ISAR TRIPLE trial—which compared six weeks vs. six months of triple therapy in patients taking a vitamin K antagonist who underwent PCI—is the only study to date to give equal weight to safety and efficacy.6,9 The primary endpoint, “net clinical outcomes”, was a composite of ischaemic and bleeding events and was not different between treatment groups.

Following the same principle, the ongoing COBRA REDUCE trial is being conducted by the ISAResearch group and aims to determine whether treatment with the Cobra PzF stent and two weeks of DAPT has higher safety and non-inferior outcomes for thromboembolic events compared with conventional therapy in patients taking oral anticoagulation. This is the shortest duration of triple therapy to be investigated in a randomised study to date and is based on the expectation that the Cobra PzF stent may be particularly suited for implantation in patients who are not candidates for prolonged duration DAPT. The Cobra PzF stent is a balloon-expandable cobalt-chromium alloy stent that is treated with a nano-thin layer of Polyzene-F—an inorganic polymer with high biocompatibility —and represents an alternative approach to reduce neointimal formation after stent implantation. The hypothesised advantage of the stent is that the anti-inflammatory properties and rapid endothelialisation promoted by its Polyzene-F coating result in reduced thrombogenicity and enhanced antirestenotic efficacy in comparison with untreated bare metal stents. Preclinical studies have shown that the Cobra PzF stent is non-thrombogenic and is associated with rapid tissue healing after PCI.

Enrolment of 996 patients is planned at 45 centres across the USA and Europe. Patients undergoing PCI in the setting of stable or unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI) who require long-term oral anticoagulation therapy are randomly allocated (1:1) to treatment with the Cobra PzF stent plus 14 days of DAPT or another FDA-approved drug-eluting stent—Xience, Promus, Synergy, or Resolute (Abbott, Boston Scientific, Medtronic, respectively)—plus three to six months months DAPT, stratified by the use of coumadin derivatives or novel oral anticoagulants and centre. The co-primary outcomes measures are BARC ≥ 2 bleeding after hospital discharge or after 14 days, whichever is earlier (superiority hypothesis) and the combined incidence of all-cause death, myocardial infarction, definite or probable stent thrombosis, and ischaemic stroke at six months (non-inferiority hypothesis).

Roisin Colleran and Adnan Kastrati are both at Deutsches Herzzentrum München, Technische Universität München, Munich, Germany


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  2. Levine et al. J Am Coll Cardiol 2016. Epub.
  3. Valgimigli et al. 2017 Eur Heart J 2017. Epub.
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  5. Lamberts et al. Circulation 2014; 129: 1577–85.
  6. Dewilde et al. Lancet 2013; 381: 1107–15.
  7. Gibson et al. N Engl J Med 2016; 375: 2423–34.
  8. Cannon et al. N Engl J Med 2017; 377: 1513–24.
  9. Fiedler et al. J Am Coll Cardiol 2015; 65: 1619-29.
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