ISAR-TRIPLE

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Fiedler KA et al. "Duration of triple therapy in patients requiring oral anticoagulation after drug-eluting stent implantation". J Am Coll Cardiol. 2015. 65(16):1619-30.
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Clinical Question

In patients requiring oral anticoagulation (OAC) for a separate indication undergoing drug-eluting stent (DES) placement after coronary intervention, is six weeks of clopidogrel therapy (in addition to aspirin and OAC) associated with superior net clinical outcome with regard to thrombosis and bleeding compared to 6 months of clopidogrel therapy?

Bottom Line

In patients requiring oral anticoagulation (OAC) for a separate indication undergoing drug-eluting stent (DES) placement after coronary intervention, six weeks of clopidogrel therapy in addition to aspirin and OAC is not associated with improved net clinical outcomes compared to 6 months of clopidogrel therapy after 9 months. Both major bleeding risk and thrombotic risk appeared to be similar with either the shorter or longer duration of "triple therapy" over this limited period of follow-up.

Major Points

Dual-antiplatelet therapy (DAPT) with aspirin and a thienopyridine is known to be effective in preventing recurrent coronary thrombotic events, including the highly morbid and often fatal complication of in-stent thrombosis, following placement of drug-eluting stents (DES) during coronary intervention. However, the optimal duration of DAPT after DES placement is unclear. Although ACC/AHA guidelines recommend at least 12 months of dual-antiplatelet therapy following DES, recent trials such as DAPT and PEGASUS-TIMI 54 suggest that a longer duration of DAPT may be beneficial in reducing late stent thrombosis.[1] Conversely, the ISAR-SAFE trial showed that 6 months of DAPT was not associated with increased thrombotic events compared to the usual 1 year.[2]

Deciding upon the duration of DAPT following DES becomes even more complex when patients have an existing indication for oral anticoagulation (OAC), most commonly atrial fibrillation. These patients are often prescribed "triple therapy", or DAPT with OAC, which is known to be associated with a significantly increased risk of bleeding compared to DAPT alone.[3] As a result of this increased bleeding and the intuitive notion that OAC may also provide thrombotic protection against stent thrombosis, there has been interest in establishing whether shorter (or modified) durations of triple therapy can be safely prescribed after DES. The landmark WOEST trial demonstrated that the combination of OAC and clopidogrel upfront after DES was associated with lower bleeding rates with no increase in thrombotic events compared to triple therapy. Although this trial was criticized for being underpowered, the latest ACC/AHA guidelines now provide a class IIb recommendation for clopidogrel and OAC after DES placement. Despite this recommendation, triple therapy is often still utilized after DES in patients receiving OAC, and further investigation into the risks/benefits of triple therapy in this setting were warranted.

The 2015 Intracoronary Stenting and Antithrombotic Regimen-Testing of a 6-Week Versus a 6-Month Clopidogrel Treatment Regimen in Patients with Concomitant Aspirin and Oral Anticoagulant Therapy Following Drug-Eluting Stenting (ISAR-TRIPLE) trial randomized 614 patients to 6 weeks of clopidogrel therapy (in addition to OAC and aspirin) or 6 months of clopidogrel therapy (in addition to OAC aspirin) and assessed whether the shorter duration of triple therapy was associated with superior outcomes with regard to a net clinical outcome including both bleeding and thrombotic events. At 9 months, there was no significant difference in the primary endpoint with 6 weeks vs. 6 months of triple therapy. Furthermore, there were no significant differences between the groups in regards to component thrombotic or bleeding events, although a post-hoc landmark analysis starting after the 6 week group stopped clopidogrel did demonstrate a 7% absolute reduction in BARC bleeding between groups. Notably, however, the trial was underpowered to detect a difference in thrombotic events between groups and is limited by only 9 months of follow up time. Nevertheless, although ISAR-TRIPLE is strictly a negative study (as it did not establish superiority in net clinical benefit with the shorter duration of triple therapy), the fact that shortening the triple therapy course to 6 weeks resulted in no increase in thrombotic events including stent thrombosis along with a minor signal for decreased bleeding adds to the growing body of evidence suggesting that it may be reasonable to shorten the duration of triple therapy (or even defer it altogether) by using an OAC and single antiplatelet in patients recently undergoing DES placement requiring anticoagulation for a separate indication.

Guidelines

No guidelines have been published reflecting the results of this study.

Design

  • Prospective, randomized, open-label trial
  • N=614
    • 6 weeks clopidogrel (+ OAC and aspirin, n=307)
    • 6 months clopidogrel (+ OAC and aspirin, n=307)
  • Setting: 3 centers in Europe
  • Enrollment: September 2008 - December 2013
  • Duration follow-up: 9 months
  • Analysis: Intention-to-treat
  • Primary outcome: Net clinical benefit (death, MI, definite stent thrombosis, stroke, or TIMI major bleeding)

Population

Inclusion Criteria

  • Patients with an indication for OAC and DES implantation

Exclusion Criteria

  • Age ≤18 years
  • Previous stent thrombosis
  • DES implantation in LM coronary artery
  • Cardiogenic shock
  • Malignancies or other comorbid conditions with life expectancy < 1 year or that may result in protocol noncompliance
  • Planned major surgery within the next 9 months with the need to discontinue antiplatelet therapy
  • Active bleeding, bleeding diathesis, recent trauma or major surgery in the last month, history of intracranial bleeding or structural abnormalities, suspected aortic dissection
  • Known allergy or intolerance to study medications
  • Pregnancy (known, suspected, or planned)
  • Relevant hematologic deviations
  • Previous enrollment in this trial
  • Patient's inability to comply with study protocol

Baseline Characteristics

From the 6-week group.

  • Demographics: Age 74 years, female 25.4%
  • Co-morbidities: BMI 27.5, DM 27.7%, HTN 76.9%, HLD 73.9%, smoker 9.1%
  • Cardiac: MI 29.3%, CABG 23.8%, Multivessel CAD 72.0%
  • Clinical presentation: STEMI 1.0%, NSTEMI 16.3%, UA 16.0%, Stable angina 66.8%
  • Medications at Discharge: Aspirin 100%, Clopidogrel 100%, BB 86.3%, ACEi 64.2%, ARB 23.1%, CCB 22.8%, Diuretic 68.4%, Statin 85.3%
  • Anticoagulant Indication: AF 82.7%, Mechanical valve 5.5%, VTE 7.5%, Other 4.2%
  • CHADS2-Vasc Score: One 0%, Two 4.7%, Three 10.6%, Four 27.2%, Five 27.6%, Six 19.7%, Seven 6.3%, Eight 3.1%, Nine 0.8%

Interventions

  • Treatment allocation concealed randomization 1:1 to
    • 6 weeks clopidogrel (+ OAC and aspirin, n=307)
    • 6 months clopidogrel (+ OAC and aspirin, n=351)
  • Coronary angiography performed according to conventional and local standards
  • Patients received a loading dose of 300-600mg clopidogrel prior to PCI
  • During study, patients received clopidogrel 75mg daily for 6 weeks (6-week group) or 6 months (6-month group) along with aspirin 75-200mg daily and a VKA
  • Patients were assessed by telephone call or office visit at 6 weeks, 6 months, and 9 months
  • Outcome events were adjudicated and classified by an event committee whose members were unaware of the assigned treatment

Outcomes

Comparisons are 6-week vs. 6-month clopidogrel.

Primary Outcome

Net clinical benefit (death, MI, stent thrombosis, stroke, major bleeding)
30 (9.8%) vs. 27 (8.8%) [HR 1.14, 95% CI 0.68-1.91, p=0.63]

Secondary Outcomes

Cardiac death, MI, stent thrombosis, or ischemic stroke
12 (4.0%) vs. 13 (4.3%) [HR 0.93, 95% CI 0.43-2.05, p=0.87]
TIMI major bleeding
16 (5.3%) vs. 12 (4.0%) [HR 1.35, 95% CI 0.64-2.84, p=0.44]
Death
12 (4.0%) vs. 16 (5.2%) [HR 0.75, 95% CI 0.35-1.59, p=0.45]
Any BARC bleeding (landmark analysis)
48 (20.5%) vs. 70 (27.9%) [HR 0.68, 95% CI 0.47-0.98, p=0.04]

Subgroup Analysis

The lack of treatment effect in the primary outcome was consistent across all pre-specified subgroups defined by age, sex, diabetes, history of stroke, history of bleeding, hypertension, clinical presentation, indication for OAC, ejection fraction, and renal function.

Criticisms

  • Nearly two-thirds of patients underwent DES placement for chronic stable angina. It is not clear whether patients presenting with ACS are at higher risk for stent thrombosis and thus may derive benefit from triple therapy.
  • Limited duration of follow up of 9 months and relatively modest sample size limit power to detect rare outcomes such as stent thrombosis. A salutary effect of triple therapy on thrombotic outcomes with a longer duration of follow up or increased power to detect a smaller effect cannot be ruled out.
  • Open-label design allows for bias, although this is somewhat mitigated by treatment allocation concealment.

Funding

  • The study was funded in part by a grant from study sponsor Deutsches Herzzentrum Munchen.
  • Authors with multiple ties to industry.

Further Reading

  1. Levine GN et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 2016. :.
  2. Schulz-Schüpke S et al. ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting. Eur. Heart J. 2015. 36:1252-63.
  3. Lamberts M et al. Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study. Circulation 2012. 126:1185-93.