Dual Antiplatelet Therapy - DAPT

Feb 16, 2018
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Harvard Clinical Research Institute
Date Presented:
08/30/2016
Date Published:
02/22/2017
Date Updated:
02/16/2018
Original Posted Date:
11/18/2014
References

Contribution To Literature:

The DAPT study showed that longer duration of DAPT following PCI results in lower stent thrombosis and recurrent MIs, but higher bleeding and all-cause mortality compared with a 12-month duration.

Description:

Current guidelines recommend that dual antiplatelet therapy (DAPT) with aspirin and an ADP receptor antagonist be continued for a minimum of 12 months following drug-eluting stent (DES) percutaneous coronary intervention (PCI). The optimal duration, however, remains unclear. This trial sought to investigate if 30 months of DAPT was superior to 12 months in patients undergoing DES and bare-metal stent (BMS) PCI.

Study Design

  • Placebo-controlled
  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Age >18 years
  • PCI with stent deployment within the past 24 hours
  • No known contraindication to DAPT for at least 30 months after enrollment and stent implantation
  • At 12 months, patient free from death, MI, stroke, repeat coronary revascularization, major bleeding, and stent thrombosis, and compliant with DAPT following stent implantation

    Number of screened applicants: 25,682
    Number of enrollees: 9,961
    Duration of follow-up: 30 months following initial screening
    Mean patient age: 61.7 years
    Percentage female: 25%

Exclusions:

At initial screening:

  • Index procedure stent placement with stent diameter <2.25 mm or >4.0 mm
  • Pregnant women
  • Planned surgery necessitating discontinuation of DAPT within the 30 months following enrollment
  • Current medical condition with a life expectancy of <3 years
  • Subjects on warfarin or similar anticoagulant therapy
  • Subjects with hypersensitivity or allergies to one of the drugs or components
  • Subject treated with both DES and BMS during the index procedure

At 12 months: 

  • Pregnant women
  • Subject switched thienopyridine type or dose within 6 months prior to randomization
  • PCI or cardiac surgery between 6 weeks post-index procedure and randomization
  • Planned surgery necessitating discontinuation of antiplatelet therapy within 21 months
  • Current medical condition with a life expectancy of <3 years
  • Subjects on warfarin or similar anticoagulant therapy

Primary Endpoints:

  • MACCE at 18 months following enrollment (30 months from index procedure)
  • Stent thrombosis at 18 months (30 months from index procedure)
  • Moderate or severe GUSTO bleeding at 18 months (30 months from index procedure)

Secondary Endpoints:

  • All-cause mortality

Drug/Procedures Used:

Patients were enrolled 72 hours after stent placement and were given open-label aspirin and thienopyridine for 12 months, per current practice norms. At 12 months, patients without an ischemic or bleeding complication and with documented compliance, were randomized in a 1:1 fashion to receive an additional 18 months of DAPT or matching placebo. Stratification was performed based on DES versus bare-metal stents (BMS), hospital, clopidogrel versus prasugrel, and risk factors for stent thrombosis.

Principal Findings:

DES PCI: A total of 9,961 patients were randomized at 452 sites in 11 countries: 5,020 to prolonged DAPT and 4,941 to placebo. Baseline characteristics were fairly similar between the two arms. Approximately 30% had diabetes mellitus, 25% were smokers and 6% had peripheral arterial disease. Indication for PCI was stable angina in 38%, ST-segment elevation myocardial infarction (STEMI) in 10% and NSTE-acute coronary syndrome (NSTE-ACS) in 32%. Approximately two thirds of the patients received clopidogrel, whereas the rest received prasugrel. Stents implanted during index PCI was everolimus-eluting stent (EES) in 47%, paclitaxel-eluting stent (PES) in 27%, zotarolimus-eluting stent (ZES) in 13%, sirolimus-eluting stent (SES) in 11%, and multiple in the others. The mean number of lesions treated was 1.1, with about 1.5 stents/patient. The vessel treated was left anterior descending in 41% and right coronary artery in 32%.

The primary endpoint of major adverse cardiac and cerebrovascular events (MACCE) was significantly lower in the continued DAPT arm compared with placebo (4.3% vs. 5.9%, hazard ratio 0.71, 95% confidence interval 0.59-0.85, p < 0.001). There were reductions in all MI (2.1% vs. 4.1%, p < 0.001) and stent thrombosis (0.4% vs. 1.4%, p < 0.001), but all-cause mortality was higher (2.0% vs. 1.5%, p = 0.05), driven mostly by an increase in noncardiovascular deaths (1% vs. 0.5%, p = 0.002), including cancer-related death (0.62% vs. 0.28%, p = 0.02) and bleeding-related death (0.22% vs. 0.06%, p = 0.06). GUSTO moderate and severe bleeding was also higher with DAPT (2.5% vs. 1.6%, p = 0.001), as was BARC 2, 3, or 5 bleeding (5.6% vs. 2.9%, p < 0.001).

BMS PCI: A total of 1,580 patients were randomized; 842 to prolonged DAPT and 845 to placebo. Indication for PCI was STEMI in 38% and NSTEMI in 21%. Clopidogrel was prescribed on discharge at 88% of patients, and prasugrel in the rest. The primary endpoint of MACCE was similar in the continued DAPT arm compared with placebo (4.0% vs. 4.7%, HR 0.92, 95% CI 0.57-1.47, p = 0.72; p for interaction = 0.32). There were no differences in all-cause mortality (1% vs. 1.2%, p = 0.83), MI (2.7% vs. 3.1%, p = 0.74), stroke (0.7% vs. 0.6%, p = 0.74), or stent thrombosis (0.5% vs. 1.1%, p = 0.24; p for interaction = 0.42). GUSTO moderate and severe bleeding was also higher with DAPT (2.0% vs. 0.9%, p = 0.07), as was BARC 2, 3, or 5 bleeding (4.6% vs. 1.8%, p = 0.002).

EES PCI: The primary MACCE endpoint was similar for prolonged DAPT vs. placebo (4.3% vs. 4.5%, HR 0.89, 95% CI 0.67-1.19, p = 0.42). Stent thrombosis (0.3% vs. 0.7%, p = 0.04) and MI (2.1% vs. 3.2%, p = 0.01) were lower, whereas moderate and severe bleeding (2.5% vs. 1.3%, p = 0.01) and mortality (2.2% vs. 1.1%, p = 0.02) were higher.

Matched propensity analysis of DES vs. BMS: MACCE events were lower in DES at 33 months compared with BMS (11.4% vs. 13.4%, p < 0.0001), as was stent thrombosis (1.7% vs. 2.6%, p < 0.0001). No differences were observed in all-cause mortality (4.2% vs. 5.1%, p = 0.16) or MI (7.2% vs. 8.1%, p = 0.27). The highest hazard for stent thrombosis for BMS was within the first 12 months (while on open-label DAPT) (0.7% vs. 1.7% within first 12 months vs. 1.7% vs. 2.6% within 33 months of index PCI). Differences between DES and BMS were most pronounced for EES vs. BMS. Bleeding risk was not different between DES and BMS (4.0% vs. 3.7%, p = 0.32).

Cause-specific mortality: Increased mortality signal led to second blinded CEC review, with particular focus on bleeding and cancer. Mortality for DAPT vs. placebo: 1.9% vs. 1.5%, p = 0.07; cardiovascular mortality: 1.0% vs. 1.0%, p = 0.97; noncardiovascular mortality: 0.9% vs. 0.5%, p = 0.01; bleeding-related death: 0.3% vs. 0.2%, p = 0.36; cancer-related death: 0.6% vs. 0.3%, p = 0.02; cancer incidence: 2.0% vs. 1.6%, p = 0.12. On longer follow-up to 33 months, mortality remained higher: 2.2% vs. 1.8%, p = 0.05, again due to higher noncardiovascular mortality: 1% vs. 0.7%, p = 0.02.

DAPT score: Based on the relative risks of ischemia (stent thrombosis and MI) and bleeding (GUSTO moderate or severe) between 12 and 30 months, a prediction score (DAPT score) was created. Final variables were age, prior PCI or MI, stent diameter <3 mm, chronic heart failure or left ventricular ejection fraction <30%, MI at presentation, PES, smoking and diabetes (range for score: 3-8). Patients with lower scores (<2) had a lower ischemic risk and a higher bleeding risk, while patients with higher scores (≥2) had a higher ischemic risk and a lower bleeding risk.

  • For DAPT <2: stent thrombosis or MI: 1.7% vs. 2.3%, p = 0.07; bleeding: 3% vs. 1.4%, p < 0.001
  • For DAPT ≥2: stent thrombosis or MI: 2.7% vs. 5.7%, p < 0.001; bleeding: 1.8% vs. 1.4%, p = 0.26

Interaction with optimal medical therapy (OMT): Comparing prolonged DAPT to placebo, rates of MACCE were 4.2% vs. 5.0% among patients on OMT (HR 0.82, CI 0.66-1.02, p = 0.077) and 4.5% vs. 7.0% among those off OMT (HR 0.63, CI 0.49-0.82, p < 0.001; p for interaction = 0.25). Patients on OMT had lower rates of MI (2.7% vs. 3.7%, p = 0.003), MACCE (4.6% vs. 5.7%, p = 0.007), and bleeding (1.6% vs. 2.5%, p < 0.001), but not stent thrombosis (0.8% vs. 1.0%, p = 0.17) in comparison with patients off OMT.

MI risk: Discontinuing thienopyridine after either 12 or 30 months was associated with an early increase in MI risk. The majority of MIs (~75%) occurring after thienopyridine discontinuation were not related to stent thrombosis. MI risk was noted in patients with both low and high DAPT scores.

Interpretation:

The results of the DAPT trial indicate that prolonged duration of DAPT up to 30 months following index PCI with a DES results in lower stent thrombosis and recurrent MIs compared with a 12-month duration of DAPT, although bleeding and all-cause mortality were higher with prolonged therapy. The BMS subset shows a less impressive treatment effect, although the p-value for interaction between DES versus BMS was not significant. Similarly, the EES subset showed no difference for the primary endpoint with prolonged therapy. Both stent thrombosis and spontaneous MIs were reduced in DES patients, but not in BMS patients. The mechanism of benefit is unclear, since a non-stent thrombosis-related MI reduction would be expected to be observed equally in DES and BMS patients. In the propensity-matched analysis, the highest difference between DES and BMS for stent thrombosis and MACCE appeared to be within the first year (while on open-label DAPT). The DAPT score may be a useful tool for individualizing decisions regarding dual antiplatelet duration in patients post-PCI, but will need further validation. 

Following concerns regarding late and very late stent thrombosis with first-generation DES, American College of Cardiology (ACC)/American Heart Association (AHA) guidelines recommended a minimum duration of 12 months of DAPT following DES PCI. However, the optimal duration remains unknown and trials have sought to study both sides of the duration spectrum. On the one hand, trials such as PRODIGY, RESET, and OPTIMIZE sought to assess shorter durations (3-6 months) of DAPT with at least 50% second-generation DES use in mostly stable patients. On the other hand, trials such as DES-LATE and EXCELLENT sought to assess if prolonged DAPT treatment would be superior to 12 months.

The DAPT trial is the largest trial on this topic to date, and suggests that although there may be an ischemic benefit with prolonged DAPT therapy, there is a price to pay in terms of bleeding risk. The excess in mortality is concerning, and appears to be predominantly due to cancer-related mortality. It is unclear if this is a chance finding or a true biological effect. Moreover, these results only apply to patients who have not had an ischemic or bleeding event within the first year, and were also fully compliant with DAPT therapy, thus somewhat limiting the generalizability of this trial. Patients in this trial received contemporary stents, although nearly a quarter received PES, which are inferior to EES and ZES. The magnitude of benefit appeared to be highest in the PES patients, and lower in patients receiving EES. It is unclear to what extent this trial will immediately impact clinical practice. Further follow-up and data from other ongoing trials are awaited.

References:

Stefanescu Schmidt AC, Kereiakes DJ, Cutlip DE, et al., on behalf of the DAPT Investigators. Myocardial Infarction Risk After Discontinuation of Thienopyridine Therapy in the Randomized DAPT Study (Dual Antiplatelet Therapy). Circulation 2017;135:1720-32.

Resor CD, Nathan A, Kereiakes DJ, et al., on behalf of the Dual Antiplatelet Therapy Study Investigators. Impact of Optimal Medical Therapy in the Dual Antiplatelet Therapy Study. Circulation 2016;134:989-98.

Presented by Dr. Charles Resor at the European Society of Cardiology Congress, Rome, Italy, August 30, 2016.

Presented by Dr. Robert W. Yeh at the American Heart Association Scientific Sessions, Orlando, FL, November 10, 2015.

Hermiller JB, Krucoff MW, Kereiakes DJ, et al., on behalf of the Dual Antiplatelet Therapy (DAPT) Study Investigators. Benefits and risks of extended dual antiplatelet therapy after everolimus-eluting stents. JACC Cardiovasc Interv 2016;9:138-47.

Presented by Dr. Laura Mauri at the European Society of Cardiology Congress, London, September 1, 2015.

Mauri L, Kereiakes DJ, Yeh RW, et al., on behalf of the DAPT Study Investigators. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155-66.

Presented by Dr. Laura Mauri at the American Heart Association Scientific Sessions, Chicago, IL, November 16, 2014.

Presented by Dr. Dean J. Kereiakes at the American Heart Association Scientific Sessions, Chicago, IL, November 18, 2014.

Keywords: Myocardial Infarction, Acute Coronary Syndrome, Stroke, Angina, Stable, Drug-Eluting Stents, Peripheral Arterial Disease, Risk Factors, Ticlopidine, Piperazines, American Heart Association, Sirolimus, Aspirin, Purinergic P2Y Receptor Antagonists, Stents, Percutaneous Coronary Intervention, Paclitaxel, Thrombosis, Coronary Vessels, Diabetes Mellitus, Transcatheter Cardiovascular Therapeutics, AHA Annual Scientific Sessions, ESC Congress, AHA Annual Scientific Sessions


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