Triple antithrombotic therapy with aspirin, clopidogrel, and warfarin is used in about 5% of patients after coronary stent implantation, mostly due to atrial fibrillation and left ventricular thrombosis.1 This antithrombotic combination has a higher risk of bleeding than dual antiplatelet therapy or warfarin. The third-generation P2Y12 inhibitor, prasugrel, has been shown to be more effective that clopidogrel in patients with acute coronary syndromes undergoing angioplasty; however, this drug increased bleeding.2 A higher risk of bleeding has recently been reported when prasugrel, rather than clopidogrel, was used in patients with coronary stents and an indication for warfarin,3 although with no fatal cases. We report 2 cases of fatal bleeding in patients undergoing primary angioplasty due to an ST-elevation myocardial infarction, with subsequent initiation of warfarin.
The first case was a 58-year-old male smoker weighing 85kg who was hypertensive and dyslipidemic and who presented with an anterior ST-elevation myocardial infarction and severe left ventricular dysfunction. Creatinine, hemoglobin, and platelet count on admission were normal. Dual antiplatelet therapy using aspirin and prasugrel was started on admission. Bivalirudin was used during angioplasty, with bailout abciximab and balloon counterpulsation due to no-reflow and no ST-resolution after stent implantation in the left anterior descending artery. On postadmission day 9, revascularization was completed by stenting of a severely narrowed left circumflex artery. During rehabilitation, a left ventricular thrombus was detected on echocardiography and warfarin was added to dual antiplatelet therapy. Four months later, the patient was admitted due to progressive loss of consciousness: a left temporoparietal intraparenchymal hemorrhage was detected on computed tomography scan. The international normalized ratio (INR) was 3.49 (previous values were a maximum of 2.5-3.0). Hemoglobin and platelet count were normal. The patient died despite immediate neurosurgery. Autopsy revealed bleeding from a small arteriovenous malformation.
The second case was a 68-year-old man weighing 96kg, who was hypertensive and diabetic and who had no history of heart disease or bleeding. He was admitted with an anterior ST-elevation myocardial infarction and severe left ventricular dysfunction. His INR on admission was 1.15. His proximal left anterior descending artery was treated with stenting. Dual antiplatelet therapy was started with aspirin and prasugrel. In the following days, the patient's hemodynamics improved slowly, cardiac rhythm was atrial fibrillation with frequent episodes of ventricular tachycardia: anticoagulation was started with enoxaparin and then with warfarin. On postadmission day 13, the patient had rectal bleeding with a hemoglobin drop to 8.3g/dL (1U fresh frozen plasma transfused). Colonoscopy showed abundant hematic material, without the possibility of identifying the bleeding source due to patient instability. Warfarin and prasugrel were withdrawn and vitamin K was administered. Twenty-four hours later, the patient had a new episode of melena with hemodynamic deterioration. Colonoscopy showed a bleeding ulcer in the transverse colon, which was treated using a clip. A further 2h later, the patient had cardiac arrest due to ventricular fibrillation followed by asystole and unsuccessful fluid and cardio-pulmonary resuscitation with exitus.
Upon admission, both patients were at low estimated risk of bleeding: they were relatively young, male, and had normal body weight and no previous bleeding or stroke. ST-elevation myocardial infarction and diabetes were preferential indications to use prasugrel rather than clopidogrel.4 Finally, the patients’ risk of stent thrombosis was higher than average due to severe left ventricular dysfunction. However, later in their clinical course, both patients developed an indication for warfarin. In the patient with intracranial hemorrhage, this complication occurred 3.5 months after the initiation of warfarin and was attributed to an undiagnosed arteriovenous malformation. An additional causative factor for the fatal episode was a higher than optimal INR value at the time of hemorrhage, although previous values were within the guideline-recommended range. In the patient with enteric bleeding, severe hypotension subsequent to massive bleeding in the context of severe left ventricular dysfunction might also have been a causative factor for stent thrombosis, but the same mechanism is more likely to have caused severe myocardial ischemia with ventricular fibrillation.
With regard to anticoagulation, expert recommendations1 suggest a target INR of 2.0 to 2.5 in the case of triple antithrombotic therapy. Low-dose dabigatran or rivaroxaban, which have been shown to have similar efficacy to warfarin but a lower risk of bleeding, might be possibilities to explore. With regard to the antiplatelet component of the combination, withdrawing aspirin from triple therapy has been associated with less bleeding,5 and this strategy should be tested for efficacy in larger numbers of patients. For patients already on warfarin at the time of stenting, clopidogrel is the only P2Y12 inhibitor empirically recommended by current guidelines. When starting oral anticoagulant therapy in patients like ours, who develop an indication for warfarin after stent implantation and the initiation of dual antiplatelet therapy with either prasugrel or ticagrelor, it seems to be prudent to downgrade the potency of P2Y12 inhibition to clopidogrel. Alternative strategies, such as reducing the dosage of prasugrel to 5mg o.d. should be specifically investigated.
CONFLICTS OF INTERESTDr Savonitto reports having received consultancy or speaker fees from Eli Lilly, Daiichi Sankyo, AstraZeneca, Correvio, The Medicines Company, and research grants from Eli Lilly, Correvio and Novartis. Drs Ferri and Corrada have no potential conflict of interest to declare.