Triple therapy in hospitalized patients: Facts and controversies

Dual antiplatelet therapy (DAPT) (aspirin plus a thienopyridine: clopidogrel or prasugrel) has become the standard treatment for patients with acute coronary syndromes (ACS) and after coronary stent placement (Table 1). Anticoagulant therapy with warfarin is indicated for stroke prevention in atrial fibrillation (AF), profound left ventricular dysfunction, and after mechanical heart valve replacement, as well as for treatment of deep venous thrombosis and pulmonary embolism (Table 2). It is estimated that 41% of the U.S. population over age 40 years is on some form of antiplatelet therapy,6 and 2.5 million patients, mostly elderly, are on long‐term warfarin therapy.7 More specifically, 5% of patients undergoing percutaneous coronary interventions (PCIs) also have an indication for warfarin.8 With widespread use of drug‐eluting stents (DES), the need for a longer duration of DAPT, and the increased age and complexity of hospitalized patients, the safety and challenges of triple therapy (combined DAPT and warfarin) have become more important to the practice of hospital medicine. Triple therapy may increase hospitalization rates, as the risk of major bleeding is four to five times higher than with DAPT.911 In contrast, DAPT is much less effective than warfarin alone in preventing embolic events in AF,12 and warfarin alone or in combination with aspirin (ASA) is inadequate therapy to prevent stent thrombosis. Even fewer data exist on the efficacy and safety of triple therapy in patients with mechanical valves or left ventricular dysfunction.

Hospitalists commonly care for patients on triple therapy; certain indications are appropriate and supported from the available literature while others lack evidence. Knowledge of existing practice guidelines and of supporting research studies leads to optimal management of these complicated patients, and minimizes excessive morbidity from bleeding complications or thromboembolic events such as strokes and stent thrombosis.

In the first part of this article, we present the evidence that supports current recommendations for DAPT or warfarin in specific medical conditions. We also address controversies and unanswered questions. The second part of this review focuses on the available data and provides guidance on the optimal care of patients on triple therapy.

Dual Antiplatelet Therapy Following Acute Coronary Syndromes

Table 3 summarizes key randomized trials of DAPT versus ASA alone in several clinical scenarios. The addition of clopidogrel to ASA in patients with nonST‐elevation ACS reduced the risk of adverse ischemic outcomes in the clopidogrel in unstable angina to prevent recurrent events (CURE) trial,15 as well as in its substudy, the PCI‐CURE (patients with ACS who have undergone stenting).17 In the main CURE study, the study groups diverged within the first 30 days after randomization and the benefit of DAPT persisted throughout the 12 months of the study period. DAPT is also superior to ASA in patients with ST‐elevation myocardial infarction (MI) (CLARITYTIMI 28 and COMMIT trials).13, 14 On the basis of these findings, DAPT has become the standard of care for patients with ACS. The American College of Cardiology (ACC)/American Heart Association (AHA)3 and the European Society of Cardiology18 recommend ASA treatment indefinitely for patients with ACS whether or not they underwent PCI. Clopidogrel is recommended for at least 12 months following ACS, especially for patients who receive a coronary stent.

Despite the proven efficacy of DAPT in ACS, about 15% of patients die or experience reinfarction within 30 days of diagnosis.19 The continued risk for thrombotic events could be due to delayed onset of platelet inhibition and to patient heterogeneity in responsiveness to therapy with ASA and/or clopidogrel.20 Consequently, the optimum dose for clopidogrel and ASA following ACS is uncertain. The CURRENT‐OASIS 7 trial evaluated the efficacy and safety of high‐dose clopidogrel (600‐mg loading dose, 150 mg once daily for 7 days, followed by 75 mg/d) versus standard‐dose clopidogrel (300‐mg loading dose, followed by 75 mg/d) and ASA (75‐100 mg versus 300‐325 mg/d) in patients with ACS who were treated medically, with or without stenting.21 In the overall study population as well as in patients who did not receive stenting, there was no significant difference in the combined rate of death from cardiovascular causes, MI, and stroke between patients receiving the high‐dose and the standard‐dose clopidogrel (4.2% vs 4.4%; P = .37) and high‐dose versus low‐dose ASA (4.2% vs 4.4%; P = .47). There were no significant differences in bleeding complications between the two clopidogrel treatment arms or between the high‐dose and low‐dose ASA groups.

The ACC/AHA guidelines recommend ASA, 75‐162 mg/d indefinitely after medical therapy without stenting (class I, level of evidence: A)3 and clopidogrel 75 mg/d for at least 1 month (class IA) and optimally for 1 year (class IB). Clopidogrel monotherapy is appropriate for patients with ACS who are unable to tolerate ASA due to either hypersensitivity or recent significant gastrointestinal bleeding.

As is the case after coronary stenting, interruption of DAPT soon after ACS may subject patients to high recurrence of cardiovascular events, although few data are available to support this observation. Interruption of DAPT due to bleeding complications or surgical procedures more than 1 month after ACS may be reasonable for a patient who did not receive a stent. Clinicians should restart DAPT after the surgical procedure once the bleeding risk becomes acceptable.

Dual Antiplatelet Therapy Following Coronary Stenting

Warfarin After Acute Coronary Syndromes

Warfarin with different international normalized ratio (INR) goals alone or in combination with ASA has been evaluated after ACS. In an early trial, patients with recent (mean interval 27 days) MI were treated with warfarin alone versus placebo.41 Warfarin conferred a relative risk reduction in mortality of 24% (95% CI, 4‐44%; P = .027) at the expense of major bleeding rates of 0.6%/y. In the ASPECT trial,42 moderate to high intensity anticoagulation after MI resulted in a 53% and 40% reduction in the relative risk of reinfarction (annual incidence 2.3% versus 5.1%) and cerebrovascular events (annual incidence 0.7% versus 1.2%), respectively. In the WARIS II43 and ASPECT‐244 trials, moderate intensity warfarin (INR 2.0‐2.5) in combination with low‐dose ASA, compared with ASA alone, reduced the composite occurrence of death or nonfatal reinfarction, as well as recurrent coronary occlusion after ST‐segment elevation MI. High‐intensity warfarin therapy alone (INR 3.0‐4.0 for ASPECT, 2.8‐4.2 for WARISII) reduced ischemic vascular events compared with ASA alone. Not unexpectedly, major bleeding episodes were more common among patients receiving warfarin.

No randomized trials have compared DAPT with warfarin plus ASA for patients with ACS who did not receive stents. The ACC/AHA guidelines recommend warfarin for secondary prevention following ACS (class IIb). High‐intensity warfarin alone (INR 2.5‐3.5) or moderate intensity (INR 2.0‐2.5) with low‐dose ASA (75‐81 mg/d) may be reasonable for patients at high ischemic and low bleeding risk who are intolerant of clopidogrel (level of evidence: B). Fixed dose warfarin is not recommended by the ACC/AHA primarily on the basis of the Coumadin Aspirin Reinfarction Study (CARS) results. This study of patients following MI was discontinued prematurely because of a lack of incremental benefit of reduced‐dose ASA (80 mg/d) combined with either 1 or 3 mg of warfarin daily when compared with 160 mg/d of ASA alone.

Triple Therapy for PCI and Atrial Fibrillation

AF is the most frequent indication (70%) for long‐term therapy with warfarin in patients scheduled for stent placement.10 Clinical trials have shown that warfarin alone is superior to ASA, clopidogrel, or DAPT for prevention of stroke in patients with AF.45, 46 Although warfarin is indispensable in these settings, DAPT is similarly necessary after stent implantation. As triple therapy increases the risk of bleeding, the management of patients with AF and who have received stents remains controversial. This situation is particularly problematic among patients who have received DES and may benefit from extended DAPT. No randomized trials exist to clarify the optimal treatment in these patients; and the feasibility of such studies is questionable. Small, mostly retrospective, studies (Table 4) provide limited guidance on this issue; most studies focus on bleeding events rather than the cardiovascular efficacy of triple therapy. Because of these limitations, cardiovascular societies give IIb recommendation for either triple therapy or the combination of warfarin and clopidogrel in this setting and the level of evidence is C.1, 59, 60

In the largest study to date, Nguyen et al.58 evaluated 800 patients who underwent stenting for ACS and were discharged on warfarin plus single antiplatelet agent or triple therapy as part of the GRACE registry. At 6 months, triple therapy conferred a significant reduction in stroke (0.7% versus 3.4%, P = .02) but not in death or MI. There were no differences in in‐hospital major bleeding events between the two groups (5.9% versus 4.6%; P = .46). Similarly, Sarafoff et al.53 reported no significant differences in the combined endpoint (death, MI, stent thrombosis or stroke) or bleeding complications among patients who received triple therapy or DAPT at 2 years of follow‐up. In contrast, Ruiz‐Nodar et al.52 showed that triple therapy, compared with DAPT, at discharge reduced the incidence of death (17.8% versus 27.8%; adjusted HR = 3.43; 95% CI, 1.617.54; P = .002) and major adverse cardiac events (26.5% versus 38.7%; adjusted HR = 4.9; 95% CI, 2.1711.1; P = .01), without a substantial increase in major bleeding events.

The value of combination antiplatelet therapy to prevent stent thrombosis in these patients is clearer in the study reported by Karjalainen et al.10 This case‐control study of 239 patients receiving warfarin at baseline who underwent PCI evaluated a primary endpoint of death, MI, target‐vessel revascularization, or stent thrombosis and a secondary endpoint of major bleeding and stroke to 12 months of follow‐up. Forty‐eight percent of patients received triple therapy, whereas 15.5% were discharged on DAPT. The remaining patients received warfarin plus a single antiplatelet agent. Stent thrombosis occurred more frequently among patients receiving warfarin plus ASA (15.2%) than among those receiving triple therapy (1.9%). As expected, stroke was more frequent in patients treated with DAPT (8.8%) than among those receiving triple therapy (2.8%). Major bleeding was similar between groups. Therapy with warfarin was an independent predictor of both major bleeding and major cardiac events at 1 year. This observation illustrates that the outcome of PCI in patients on chronic warfarin therapy is unsatisfactory irrespective of the antithrombotic combinations used, highlighting the need for better strategies to treat these patients.

Choice of Therapy and Management of Patients Eligible for Triple Therapy

Current guidelines for PCI do not provide guidance for patients with an indication for triple therapy due to a paucity of published evidence. Several ongoing prospective trials aim to address the management of these patients (AFCAS, ISAR‐TRIPLE). Pending further study, clinicians should consider the embolic risk (CHADS2 score), target INR, type of stent, bleeding risk, and duration of treatment when determining the appropriate antiplatelet/anticoagulant combinations. The CHADS2 score (Table 2) stratifies the risk for stroke among patients with AF,4 while the Outpatient Bleeding Risk Index (OBRI) allows estimation of bleeding risk.12, 61 The OBRI considers age > 65 years, prior stroke, prior gastrointestinal bleeding, and any of four comorbidities (recent MI, anemia, diabetes, or renal insufficiency) in order to stratify patients into three risk groups.61 Patients with three to four risk factors have a high risk of bleeding (23% at 3 months and 48% at 12 months) whereas patients with no risk factors have only a 3% risk of bleeding at 12 months. Unfortunately, advanced age and prior stroke appear in both OBRI and CHADS.

For patients with AF who are at high risk for embolic stroke (>3% per year), we recommend triple therapy for the shortest time possible, followed by warfarin and ASA indefinitely. In case of BMS, it is acceptable to shorten triple therapy duration to 1 month. The optimal duration of triple therapy for patients with DES is uncertain; recommended durations range from 3 months to 1 year.62 If the potential consequences of stent thrombosis are high due to a large amount of myocardium at risk, an extended period of triple therapy might be justified. For patients whose stroke risk is lower (CHADS2 score of 0‐1), the risk for bleeding likely outweighs any benefit from stroke prevention. In this instance, it is reasonable to use DAPT with ASA and clopidogrel for 1 month after BMS and 12 months after DES, followed by ASA, with or without warfarin, indefinitely. In a recently published study, patients with AF and a CHADS2 score of 1 had a yearly stroke risk of 1.25% while taking DAPT63; the risk of major bleeding for triple therapy is 6.1% per year.64

For patients who have a high bleeding risk, BMS are the preferred stent type as the duration of triple therapy might be limited to 4 weeks. To our knowledge, no randomized study has evaluated the outcome of patients with BMS compared with DES who also have an indication for warfarin. Because studies have suggested that clopidogrel is more effective than aspirin in preventing stent thrombosis and in reducing death or MI after coronary stenting,40, 65 warfarin and single antiplatelet therapy with clopidogrel might be a reasonable treatment option in patients with high bleeding risk. The WOEST study (NCT00769938), currently recruiting participants, is the first randomized study specifically designed to test this hypothesis.

Since gastrointestinal bleeding accounts for approximately 30‐40% of hemorrhagic events in patients on combined ASA and anticoagulant therapy, an expert consensus document recommended concomitant treatment with proton pump inhibitors (PPIs) to reduce this risk.66 In contrast, the 2009 Focused Updates of the ACC/AHA/SCAI Guidelines did not recommend the use of PPIs with DAPT in the setting of ACS.2 This is because of studies that show inhibition of platelet activation,67 and potential clinical harm,68 when clopidogrel is combined with certain PPIs that inhibit the CYP2C19 enzyme. However, to date there are no convincing randomized clinical trial data documenting an important clinical drug‐drug interaction. The U.S. Food and Drug Administration (FDA) advises that physicians avoid the use of clopidogrel in patients with impaired CYP2C19 function due to known genetic variation or due to concomitant use of drugs that inhibit CYP2C19 activity. More specifically, the FDA recommends avoiding the use of omeprazole and esomeprazole in patients taking clopidogrel.69

In particular, elderly patients have an increased risk of bleeding while receiving triple therapy. In a study of patients over age 65, 2.5% were hospitalized for bleeding in the first year after PCI, and the use of triple therapy was the strongest predictor of bleeding (more than threefold increase).70 One in five patients suffered death or MI at 1 year after hospitalization for bleeding.70 The basis for poor outcomes after hospitalization for bleeding in this population is multifactorial and may be due to the location of bleeding, associated hypercoagulable state, potential adverse impact of blood transfusion, withdrawal of warfarin therapy in patients with AF and PCI, and the premature discontinuation of DAPT. The use of nonsteroidal anti‐inflammatory drugs (NSAIDs) is common among the elderly and conferred a doubling of bleeding risk.70 Limiting the use of NSAID, the use of low‐dose ASA beyond 30 days after stent implantation, greater use of BMS, and maintaining INR at the lowest possible level (INR of 22.5) will reduce the risk for bleeding.57, 71

New Anticoagulants

Due to the high risk for bleeding with warfarin and the challenges inherent in INR monitoring, researchers have developed several novel anticoagulants whose advantages include fixed daily dosing and no need for monitoring. Dabigatran is a direct oral thrombin inhibitor that is already licensed in Europe and Canada for thromboprophylaxis after hip or knee surgery. It has also been studied in patients with AF. In the RE‐LY trial, patients with AF who received dabigatran 110 mg daily had rates of stroke and systemic embolism that were similar to those with warfarin, as well as lower rates of major hemorrhage.72 The randomized ReDEEM trial, reported at the AHA 2009 Scientific Sessions, was aimed at finding a dosage of dabigatran that achieves a good balance between clinical effectiveness and bleeding risk when combined with aspirin and clopidogrel after acute MI. Dosages ranging from 50 mg twice daily to 150 mg twice daily were all associated with 6‐month rates of bleeding lower than 2%. Hospitalists should view these encouraging results cautiously until the publication of ReDEEM trial results in a peer‐reviewed journal.

A variety of oral Xa antagonists are also being evaluated in patients with AF or ACS. These trials offer insight into triple therapy regimens that include ASA, clopidogrel, and an Xa antagonist. In a recent study of the oral Xa antagonist rivaroxaban, investigators stratified 3491 subjects with ACS according to whether they received concomitant ASA alone or ASA and clopidogrel.73 Subjects receiving ASA plus rivaroxaban had a modest increase in bleeding. Triple therapy, however, increased the composite bleeding rate from 3.5% in the DAPT group to approximately 6‐15% (low‐dose or high‐dose rivaroxaban, respectively). Rivaroxaban is currently under review by the FDA.

These novel agents might eventually replace warfarin for many or most indications for anticoagulation. It is imperative that future research compare the efficacy and risk of bleeding between triple therapy using these new agents and triple therapy with warfarin.

Conclusions

The management of patients on long‐term anticoagulation who require DAPT because of ACS or coronary stenting is challenging. DAPT may safely substitute for warfarin only for patients at low risk for a thromboembolic event (ie, low‐risk AF with low CHADS2 score). Clinicians should not interrupt warfarin in patients at higher risk (ie, intermediate to high‐risk AF, mechanical valves, or recent venous thromboembolism), even in the presence of DAPT. In these patients, triple therapy is the optimal approach following coronary stenting (and possibly during the initial period after ACS without stenting). As this approach confers a fivefold increase in bleeding complications compared with DAPT, careful monitoring of the INR, the addition of PPIs, and the exclusion of elderly patients who are at the highest risk for bleeding complications74 is recommended. The preferred duration of triple therapy after BMS in patients who require long‐term anticoagulation is 1 month, whereas the optimal duration after ACS or DES remains unresolved.