DAPT

Published

Mauri L, et al. "Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents". The New England Journal of Medicine. 2014. 371(23):2155-2166.
PubMed • Full text • PDF

Clinical Question

Among patients who have completed one year of dual antiplatelet therapy (DAPT) after drug-eluting stent PCI, does continued DAPT reduce stent thrombosis and death, MI, or stroke without increasing bleeding?

Bottom Line

Among patients who completed one year of dual antiplatelet therapy (DAPT) after drug-eluting stent PCI, continued DAPT (totaling 30 months) reduces the rate of stent thrombosis and death, MI, or stroke at the cost of increased bleeding.

Major Points

Drug-eluting stents are intended to have lower rates of late restenosis than bare-metal stents through inhibition of neointimal proliferation. However, drug-eluting stents are at higher risk for in-stent thrombosis because of delayed endothelialization, incomplete healing, hypersensitivity, and underlying atherosclerotic disease. This risk is greatly reduced with DAPT, typically with aspirin and a thienopyridine (eg, clopidogrel). The 2011 ACC/AHA/SCAI guidelines recommend 12 months of therapy, although the optimal duration is not known.

The DAPT study enrolled 9,961 compliant patients who tolerated 12 months of DAPT following drug-eluting stent PCI, and randomized patients to an additional 18 months of a thienopyridine or to placebo. Continuation therapy was associated with a reduction in stent thrombosis (0.4% vs. 1.4%; NNT 100) and in the composite outcome of all-cause mortality, MI, or stroke (4.3% vs. 5.9%; NNT 62), which was driven by a reduction in MI (2.1% vs. 4.1%; NNT 50). As expected, continuation therapy was associated with a modest increase in bleeding risk (2.5% vs. 1.6%; NNH 111).

Continuation therapy was unexpectedly associated with an increased rate of all-cause mortality (2.0% vs. 1.5%; P=0.05). The authors report that this was driven by non-cardiovascular death, particularly cancer-related death (0.62% vs. 0.28%; P=0.02). This may be explained in part by the observation that cancer was more frequently reported in the continued therapy arm (2.03% vs. 1.62%; P=0.14). Regardless of the explanation, this finding requires further investigation.

Given these conflicting outcomes, the optimal duration of DAPT remains unresolved. As the month 12 eligibility criteria in this trial excluded individuals with prior bleed on DAPT, the true bleeding risk for prolonged DAPT in all-comers is likely underestimated in this population. There may be a role for prolonged therapy in those at high risk for an event and low risk for bleeding, but further studies to identify these individuals is required. The subgroup analyses are suggestive of benefit in several groups including males, non-diabetics, and those receiving drug-eluting stents with sirolimus or paclitaxel.

Of note, follow-up of the PEGASUS-TIMI 54 trial found that an extended regimen of ticagrelor plus ASA as DAPT found similar risk/benefit tradeoffs as this study.

Guidelines

ACC/AHA DAPT in CAD (2016, adapted)

• The dose of ASA 81 mg recommended in DAPT (COR I, LOE B-NR)
• If stable ischemic heart disease treated with PCI:
  • If BMS, treat with DAPT, including a P2Y₁₂ inhibitor for ≥1 month (COR I, LOE A)
  • If DES, treat with DAPT, including a P2Y₁₂ inhibitor for ≥6 months (COR I, LOE B-R)
  • If BMS or DES and good tolerance of DAPT and not high bleeding risk, continuing DAPT beyond the 1 or 6 month duration may be reasonable (COR IIb, LOE A)
  • If DES and high-risk for bleeding, high risk for bleeding complication (major intracranial surgery), or significant overt bleeding, discontinuation of P2Y₁₂ after 3 mo may be reasonable (COR IIB, LOE C-LD)
• If ACS treated with PCI:
  • If BMS or DES, treat with DAPT, including a P2Y₁₂ inhibitor (clopidogrel, prasugrel, or ticagrelor) for ≥12 mo (COR I, LOE B-R)
    • Ticagrelor may be preferable to clopidogrel for maintenance P2Y₁₂ inhibitor therapy (COR IIa, LOE B-R)
    • If not at a high risk for bleeding complications and no history of stroke/TIA, it is reasonable to choose prasugrel over clopidogrel for maintenance P2Y₁₂ inhibitor therapy (COR IIa, LOE B-R)
  • If coronary stent placed, tolerance of DAPT, no bleeding complications, no elevated risk of bleeding, continuation of DAPT for >12 mo may be reasonable (COR IIb, LOE A)
  • If DES placed and on DAPT, those with high risk of bleeding (e.g., oral anticoagulants), high risk for bleeding complication (major intracranial surgery), or significant overt bleeding, discontinuation of P2Y₁₂ inhibitor therapy after 6 mo may be reasonable (COR IIb, LOE C-LD)
  • Do not give prasugrel if history of stroke/TIA (COR III/harm, LOE B-R)

Design

• Multicenter, randomized, placebo-controlled trial
• N=9,961
  • Continued therapy (n=5,020)
  • Aspirin (n=4,941)
• Setting: 452 sites in N. America, Europe, Australia, and New Zealand
• Enrollment: 2009-2011
• Follow-up: 30 months post-PCI (18 months after randomization)
• Analysis: Intention-to-treat
• Primary outcomes:
  • Stent thrombosis
  • All-cause mortality, MI, or stroke
  • Bleeding

Population

Inclusion Criteria

• At time of PCI:
  • Age >18 years
  • Undergoing PCI with stent, or had PCI with stent in prior 3 days
  • No contraindications for DAPT for the next 30 months
• At month 12 randomization:
  • Event free in prior 12 months (death, MI, stroke, repeat coronary revascularization, stent thrombosis, or moderate or severe GUSTO bleeding)
  • Compliant with medical therapy in prior 12 months

Exclusion Criteria

• At time of PCI:
  • PCI with stent diameter <2.25 mm or >4 mm
  • Pregnant
  • Planning surgery requiring >14 days of discontinuation of DAPT in next 30 months
  • Medical condition with life expectancy <3 years
  • Requiring OAC, including warfarin
  • Known hypersensitivity to an intervention medication
  • Both DES and BMS at the index event
• At month 12 randomization:
  • Pregnant
  • Switched thienopyridine type or dose in the prior 10.5 months
  • PCI or cardiac surgery in prior 10.5 months
  • Anticipated need for cessation of DAPT for >14 days in the following 21 months
  • Medical condition with life expectancy <3 years
  • On OAC, including warfarin

Baseline Characteristics

• Age 62 years; Female 25%; Weight 92 kg; BMI 31 kg/m²
• Non-White race 9%; Hispanic/Latino 3%
• N. America: 90%
• PMH: DM 31%, HTN 75%, Stroke/TIA 3%; HF 5%; PAD 6%; MI 22%; Cancer 10%
• Current or recent smoker: 25%
• Prior PCI 31%; prior CABG 11.5%
• Indication for PCI: STEMI 11%, NSTEMI 16%, UA 17%, stable angina 38%
• Any risk for stent thrombosis: 51%
• Thienopyridine at start of open-label period: Clopidogrel 65% vs. prasugrel 35%
• Drug eluting: Everolimus 47%, paclitaxel 27%, zotarolimus 13%, sirolimus 11%, multiple 2%
• PCI: 1.3 treated lesions, 1.1 treated vessels, 1.5 stents, stent length 28 mm
• Treated vessel:
  • LM 1%, LAD 41%, right 33%, Circ 23%
  • Venous graft 2.5%, arterial graft 0.5%

Interventions

• Following 12 months of open label ASA + clopidogrel/prasugrel (original trial), participants were randomized to a group:
  • Continued therapy - ASA 75-162mg daily for 18 months and clopidogrel 75mg or prasugrel 10mg for a total of 30 months of DAPT
  • Placebo - ASA 75-162 mg daily + placebo
• Following the 18 month study period, there was an additional 3-month observational period post-intervention with ASA alone for a total of 33 months of monitoring

Outcomes

Comparisons are continued therapy vs. placebo.

Primary Outcome

Stent thrombosis

0.4% vs. 1.4% (HR 0.29; 95% CI 0.17-0.48; P<0.001; NNT 100)

All-cause mortality, MI, or stroke

4.3% vs. 5.9% (HR 0.71; 95% CI 0.59-0.85; P<0.001; NNT 62)

Moderate or severe bleeding, according to GUSTO

2.5% vs. 1.6% (diff 1.0%; 95% CI 0.4% to 1.5%; 2-sided P=0.001; NNH 111)

Moderate: 1.7% vs. 1.0% (2-sided P=0.004; NNH 143)

Severe: 0.8% vs. 0.6% (2-sided P=0.15)

Secondary Outcomes

All-cause mortality

2.0% vs. 1.5% (HR 1.36; 95% CI 1.00-1.85; P=0.05; NNH 200)

Cardiac: 0.9% vs. 1.0% (P=0.98)

Vascular: 0.1% vs. 0.1% (P=0.98)

Non-CV: 1.0% vs. 0.5% (P=0.002; NNH 200)

Bleeding: 0.22% vs. 0.06% (P=0.057)

Trauma: 0.18% vs. 0.04% (P=0.07)

Cancer: 0.62% vs. 0.28% (P=0.02)

MI

2.1% vs. 4.1% (HR 0.47; 95% CI 0.37-0.61; P<0.001; NNT 50)

Stroke

0.8% vs. 0.9% (HR 0.80; 95% CI 0.51-1.25; P=0.32)

Ischemic: 0.5% vs. 0.7% (P=0.16)

Hemorrhagic: 0.3% vs. 0.2% (P=0.68)

Bleeding, according to BARC

BARC 2, 3, or 5: 5.6% vs. 2.9% (2-sided P<0.001; NNH 37)

2: 3.1% vs. 1.5% (2-sided P<0.001; NNH 62)

3: 2.6% vs. 1.5% (2-sided P<0.001; NNH 91)

5: 0.1% vs. 0.1% (2-sided P=0.38)

Additional Analyses

Cancer

Baseline: 9.8% vs. 9.5% (P=0.63)

Cancer during month 0-12: 0.40% vs. 0.51% (P=0.46)

Cancer during month 12-33: 2.03% vs. 1.62% (P=0.14)

Subgroup Analysis

Full subgroup analyses are presented in the supplementary appendix. Only subgroups with P-value for interaction <0.05 are presented here.

Stent thrombosis

Sex (P=0.04)

Male: 0.3% vs. 1.5% (HR 0.21; 95% CI 0.11-0.39)

Female: 0.6% vs. 0.8% (HR 0.73; 95% CI 0.28-1.91)

All-cause mortality, MI, or stroke

Diabetes (P=0.01)

Non-diabetic: 3.3% vs. 5.5% (HR 0.59; 95% CI 0.46-0.74)

Diabetic: 6.7% vs. 6.9% (HR 0.95; 95% CI 0.72-1.25)

Thienopyridine type (P=0.03)

Clopidogrel: 4.5% vs. 5.2% (HR 0.80; 95% CI 0.64-1.01)

Prasugrel: 4.0% vs. 7.3% (HR 0.52; 95% CI 0.38-0.71)

DES type (P=0.048)

Sirolimus: 4.2% vs. 6.8% (HR 0.54; 95% CI 0.31-0.93)

Zotarolimus: 4.0% vs. 5.3% (HR 0.76; 95% CI 0.44-1.30)

Paclitaxel: 4.5% vs. 8.4% (HR 0.52; 95% CI 0.37-0.71)

Everolimus: 4.3% vs. 4.5% (HR 0.89; 95% CI 0.67-1.18)

GUSTO moderate or severe bleeding

CABG (P=0.01)

No prior CABG: 2.5% vs. 1.3% (HR 1.90; 95% CI 1.38-2.63)

Prior CABG: 2.0% vs. 3.0% (HR 0.66; 95% CI 0.31-1.41)

Criticisms

• This trial excluded individuals who poorly tolerated DAPT in the first 12 months so it was testing 18 month continuation among those who tolerated DAPT well initially, rather than 30 months of continuous therapy among all participants
• The 12 month exclusion criteria selected for compliant patients
• Unclear if these outcomes are generalizable to those with DES types not included in this trial
• Did not randomize to thienopyridine so analyses comparing clopidogrel and prasugrel lack internal validity

Funding

Conducted under an investigational-device exemption through a public–private collaboration involving the FDA.

• Private: Abbott, Boston Scientific, Cordis, Medtronic, Bristol-Myers Squibb-Sanofi Pharmaceuticals Partnership, Eli Lilly, Daiichi Sankyo
• Public: Department of Health and Human Services