Bleeding Risks with Triple Antithrombotic Therapy

Antithrombotic therapies, defined broadly as pharmacologic agents aimed at inhibiting components of either the coagulation or platelet aggregation cascades, have served for decades as therapeutic cornerstones in the management of many cardiovascular conditions including acute coronary syndromes (ACS) and acute myocardial infarction (AMI), atrial fibrillation (AF), venous thrombosis and thromboembolism (VTE), in the setting of prosthetic heart valves and following percutaneous coronary intervention (PCI). However as the number of available oral antiplatelet and anticoagulant agents continues to grow, so too does the uncertainty regarding optimal combination therapy in the growing pool of patients with overlapping clinical indications necessitating multiple antithrombotic agents. The following summary highlights key clinical considerations related to the conjunctive use of oral anticoagulant therapy and oral dual antiplatelet therapy (DAPT), often referred to simply as "triple therapy."1-2

Figure 1: Bleeding Risks with Triple Antithrombotic TherapyWhile most anticoagulated patients in the United States are treated with warfarin, oral anticoagulation either with the direct thrombin inhibitor dabigatran or the direct factor Xa inhibitor, rivaroxaban is gaining popularity. Similarly, DAPT most often comprises aspirin plus the thienopyridine, clopidogrel bisulfate. Other approved oral antiplatelet agents also being used in combination with aspirin include the more potent thienopyridine, prasugrel and the cylcopentyl triazalopyrimidine platelet inhibitor, ticagrelor. As noted above, numerous clinical syndromes warrant long-term treatment with either oral anticoagulation or DAPT or both. One of the most common clinical scenarios requiring the use of triple anticoagulant therapy is the occurrence of atrial fibrillation in patients undergoing PCI or sustaining ACS/AMI. It has been estimated that 5-7% of patients undergoing PCI in the United States either have atrial fibrillation or another compelling indication for oral anticoagulation, thus amounting to approximately 50,000 patients requiring triple therapy annually for this cluster of indications, alone.1-3,6-11 As it is beyond the scope of this article to address the numerous permutations of indication and choice of triple therapy, many of which have not been studied in any significant fashion, the focus shall remain on the attendant risks of warfarin plus aspirin/clopidogrel, especially as it relates to the aforementioned AF/PCI patient subset. Currently triple therapy is regarded as a Class IIb/Level of Evidence C recommendation in the American College of Cardiology/American Heart Association/European Society of Cardiology guidelines for the management of atrial fibrillation.1-2

When patients requiring chronic anticoagulation undergo PCI with stent placement, common choices for combined anticoagulant/antiplatelet therapy include warfarin plus DAPT, DAPT alone (foregoing anticoagulation for the period of DAPT), warfarin plus clopidogrel monotherapy or warfarin plus aspirin monotherapy. Whereas modulation of serum coagulation factors mainly impacts thrombus formation associated with AF and venous stasis, antiplatelet therapy primarily decreases atherothrombotic events in arterial beds where shear-force platelet activation is believed to play a role. This is clearly borne out by the respective bodies of literature evaluating the thrombotic/thromboembolic risk reduction afforded by aspirin, DAPT or warfarin (compared variably against placebo or one another) in AF as well similar comparisons in the early coronary stenting experience. Thus there is a strong scientific argument to be made for triple therapy in patients with competing thrombotic risks in multiple vascular beds or structures. Indeed, in a contemporary U.S. registry-based experience, it was noted that the majority of warfarin-anticoagulated patients undergoing hospitalization for ACS and requiring PCI with coronary stent placement (n=1,247) were discharged on triple therapy (60%).3 Available data suggest however that this approach clearly increases the risk of major bleeding. One report suggested a nearly 5% rate of major bleeding on triple therapy with approximately 50%, 6-month mortality in the patients who bled.4 A Danish AMI registry found a stepwise increase in bleeding risk assessed over a 16 month follow-up period, with intensification of the antithrombotic regimen, ranging from 2.6% with aspirin monotherapy to 12% on triple therapy and 12.3% with clopidogrel/warfarin (Figure 1).5 Meta-analysis data estimate the risk of major bleeding on triple therapy to be 2.2% at one month, increasing to as much as 12% at one year.6 While the exact magnitude of bleeding risk for any given population may be variable, the mortality hazard associated with large bleeds remains within a consistent range across studies. In stented patients, especially those undergoing PCI in the context of ACS or AMI, major bleeding is associated with a several-fold increase in one-year mortality.7-8 In a recent pooled analysis of the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) and Catheterization and Urgent Intervention Triage Strategy (ACUITY) trials, TIMI major bleeding was the single most predictive factor for long-term mortality (hazard ratio = 4.45) exceeding even those risks associated with myocardial infarction or stent thrombosis.9 In this unfortunate subset of patients, the threat posed by bleeding is not only linked to the actual blood loss and the ensuing ischemic, hemodynamic and/or vascular sequelae but also to the almost inevitable interruption or cessation of antiplatelet therapy. Additionally, some investigators have found an independent cardiovascular risk associated with transfusion therapy which persists even after propensity adjustment.

Given the obvious conflict raised by the prospect of triple therapy, vis-a-vis more complete ischemic/ thromboembolic protection in the face of significantly increased bleeding risk and perhaps bleeding-related mortality, current efforts are focused on more precise quantification of bleeding risk, standardization of bleeding definitions and development of concrete strategies to contain bleeding risk. Factors known to independently increase the risk of bleeding on oral anticoagulant therapy (independent of concomitant antiplatelet therapy) include moderate to severe renal dysfunction, advanced age, diabetes mellitus, left ventricular dysfunction, intensity of anticoagulation and duration of therapy.9-11 Risk scoring systems such as HAS-BLED (Hypertension, Abnormal renal and hepatic function, Stroke, Bleeding, Labile INRs, Elderly, Drugs and alcohol) may potentially be applicable to the patient population being discussed. Many of the same factors as those mentioned above are also linked to post PCI bleeding.9-11 Additional risk factors in the post-PCI population include female gender, large-bore arterial access, concomitant performance of right heart catheterization, prolonged arterial sheath dwell time, ACS or AMI presentation, administration of parenteral platelet glycoprotein inhibitors and femoral (vs. radial) arterial access for catheterization. Differences between studies with respect to presentation acuity, procedural technique, bleeding definitions, follow-up period and event adjudication have hindered efforts however, to unify these observations into a single schema for quantification of aggregate bleeding risk associated with various combinations of risk factors, particularly in the setting of triple therapy. A recent publication from the Bleeding Academic Research Consortium (BARC)12 has proposed a standardized format for classifying bleeding in cardiovascular clinical trials into the following categories:

Type 0: No bleeding

Type 1: Bleeding that is not actionable

Type 2: Overt, actionable bleeding or bleeding requiring medical evaluation or intervention or hospitalization, not fitting into Types 3-5

Type 3: Major non CABG-related bleeding
Type 3a - Overt bleeding with hemoglobin drop of 3 to <5 g/dL or any overt bleeding requiring transfusion
Type 3b - Overt bleeding with hemoglobin drop of ≥5 g/dL, cardiac tamponade, bleeding requiring surgical intervention or bleeding requiring vasoactive agents
Type 3c - Intracranial / Intraspinal hemorrhage or intraocular bleed compromising vision

Type 4: CABG-related bleeding with reoperation for the purpose of controlling bleeding, perioperative intracranial bleeding, transfusion of ≥5 units blood within 48 hours, chest tube output ≥ 2L within 24 hours

Type 5: Fatal bleeding
Type 5a - Probable fatal bleed without autopsy or imaging confirmation
Type 5b - Definite fatal bleed with overt bleeding or autopsy/imaging confirmation

Perhaps most importantly, a number of recent observations have lent insight into optimizing the balance of safety and efficacy for those patients deemed appropriate for triple therapy. As mentioned above, most observations regarding triple therapy are only applicable to the combination of aspirin/clopidogrel/warfarin. One may presume that the substitution of more potent antiplatelet agents such as prasugrel or ticagrelor for clopidogrel would further increase the risk of bleeding and should therefore be avoided if at all possible until clinical data are available. Similarly triple therapy combinations where novel anticoagulant compounds are substituted for warfarin largely represent unapproved or unproven therapeutic realms. One notable exception is the investigational use of rivaroxaban in a reduced twice-daily dose (reduced as compared with the dose approved for nonvalvular AF thromboprohylaxis) in conjunction with DAPT, post-ACS. In the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction (ATLAS ACS 2–TIMI 51) study, rivaroxaban 2.5 mg twice daily significantly reduced the occurrence of the primary efficacy end point (death from cardiovascularcauses, myocardial infarction, or stroke), cardiovascular mortality and all-cause mortality as compared with placebo with a modest increase in major bleeding but no increase in fatal bleeding. For the current iteration of triple therapy (aspirin/clopidogrel/warfarin), tight control of INR in the 2.0-2.5 range has been shown to reduce bleeding as has limiting the total duration of triple therapy. To this end, one may carefully weigh the merits of PCI vs. medical management in the setting of stable coronary disease, give consideration to PTCA alone without stent implantation or use bare metal stents with the intention of limiting DAPT to 1 month post-PCI. Recent data with certain second-generation drug-eluting stents also indicate that it may be safe to truncate DAPT at 3 months, rather than the 12 months currently endorsed by practice guidelines. Adoption of a radial access approach in patients destined for triple therapy may reduce access site bleeding as compared with the femoral approach currently employed in the in vast majority of PCIs in the U.S. Concomitant use of a proton pump inhibitors post-PCI may reduce GI bleeding on triple therapy, recognizing that controversy yet remains regarding the impact of certain PPIs (primarily omeprazole and esomeprazole) on the hepatic biotransformation of clopidogrel at the level of the cytochrome P450 2C19 isoenzyme. Finally, in patients judged to be at sufficiently low risk of AF-related thromboembolism, interruption of anticoagulation for the duration of DAPT may be also considered as a means for limiting bleeding while preserving some measure of overall antithrombotic benefit. Deliberate selection of DAPT in lieu of oral anticoagulation for reduction of stroke in AF currently holds a Class IIb/LOE B recommendation in the 2011 ACCF/AHA/HRS Focused Update on the Management of Patients with Atrial Fibrillation and is reserved for patients deemed unsuitable for oral anticoagulation.1-2,10-11


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Keywords: Acute Coronary Syndrome, Anticoagulants, Atrial Fibrillation, Cytochrome P-450 Enzyme System, Myocardial Infarction, Percutaneous Coronary Intervention, Platelet Aggregation, Proton Pump Inhibitors, Risk Factors, Stents, Stroke, Thromboembolism, United States

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