Prolonging Dual-Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study - PRODIGY

Description:

Current guidelines recommend that dual antiplatelet therapy (DAPT) with aspirin and a thienopyridine be continued for a minimum of 12 months following drug-eluting stent (DES) percutaneous coronary intervention (PCI). This recommendation comes from data from numerous observational studies suggesting that early DAPT discontinuation is associated with an increased risk of stent thrombosis. However, randomized controlled data to support this recommendation are lacking. Accordingly, the PRODIGY investigators sought to study if 24 months of DAPT is superior to 6 months of DAPT in all-comers undergoing PCI with both DES and bare-metal stents (BMS).

Contribution to the Literature: The PRODIGY trial showed that shorter duration of DAPT may be associated with similar CV outcomes and lower bleeding at 24 months, especially in stable CAD patients.

Study Design

  • Blinded
  • Parallel
  • Placebo Controlled
  • Randomized
  • Stratified

Patient Populations:

  • Age ≥18 years
  • Indication for PCI with intent to treat
  • Reference vessel diameter ≥2.25 mm
  • Number of screened applicants: 2,789
  • Number of enrollees: 1,970
  • Duration of follow-up: 2 years
  • Mean patient age: 68
  • Percentage female: 23%
  • Ejection fraction: 52.5%

Exclusions:

  • Known allergy to aspirin or clopidogrel
  • Planned major surgery within 24 months
  • Major surgery within 15 days
  • History of bleeding diathesis
  • Previous stroke in the last 6 months
  • Concomitant oral anticoagulation
  • Life expectancy <24 months
  • Pregnancy 

Primary Endpoints:

  • Death/MI/ stroke

Secondary Endpoints:

  • All-cause mortality
  • Death/MI
  • Stent thrombosis
  • Type II, III, or V BARC defined bleeding

Drug/Procedures Used:

Patients were randomized in a 1:1:1:1 balanced randomization to receive either Xience V (everolimus-eluting stent [EES]), Taxus (paclitaxel-eluting stent [PES]), Endeavor (zotarolimus-eluting stent [ZES]), or BMS, and then further randomized 30 days thereafter to either a short duration of DAPT (≤6 months) or prolonged duration (24 months). Duration <6 months was acceptable in patients with stable coronary artery disease (CAD) undergoing BMS PCI. Stratification was by center, ST-segment elevation myocardial infarction (STEMI), and diabetes mellitus status. All patients received aspirin (160-325 mg orally or 500 mg intravenously as a loading dose and then 80-160 mg orally indefinitely) and clopidogrel (300 or 600 mg orally as a loading dose) and then 75 mg/day for the treatment duration.

Concomitant Medications:

Statins (92%), beta-blockers (84%), and proton pump inhibitors (37%)

Principal Findings:

A total of 2,013 patients were randomized to the four stents, of which 1,970 were then randomized to short DAPT (n = 983) or prolonged DAPT (n = 987) after 1 month. Baseline characteristics were fairly similar between the two arms. About 25% had diabetes mellitus, 4% had history of prior stroke, 26% had prior myocardial infarction (MI), and 18% had undergone prior PCI. Presentation was STEMI in 33%, non-STEMI in 23%, and unstable angina in about 19% of the patients (acute coronary syndrome total 75%).

Multivessel CAD was noted in 66%; 38% underwent multivessel PCI. Left anterior descending artery PCI was performed in 53% of the patients, and left main trunk in 6%. The mean number of treated lesions was 1.5, with a total stent length of about 30 mm per patient. Per randomization, 75% were treated with DES (50% with so-called “second-generation DES”) and 25% with BMS. About 83.1% were on DAPT at 6 months in the short DAPT arm (all discontinuations were in BMS patients) and 98.8% in the prolonged DAPT arm; at 2 years, the respective numbers were 0.3% and 94.7% (p < 0.0001 for all time points). Approximately 97.5% of patients in the short DAPT arm were still on aspirin at 2 years.

The primary endpoint of death/MI/cerebrovascular accident (CVA) was similar between the short duration and prolonged duration arms over 720 days of follow-up (10.0% vs. 10.1%, hazard ratio [HR] 0.98, 95% confidence interval [CI] 0.74-1.29; p = 0.91). Individual endpoints including all-cause mortality (6.6% vs. 6.6%, p = 0.98), death or MI (9.6% vs. 8.9%, p = 0.62), cardiovascular (CV) death (3.8% vs. 3.7%, p = 0.98), and CVA (1.4% vs. 2.1%, p = 0.17) were all similar between the two arms. On landmark analysis at 6 months, no difference was noted between the two arms for the primary endpoint (6.4% vs. 7.2%, p = 0.53). Definite late (0.4% vs. 0.8%, p = 0.53) and very late (0.3% vs. 0%, p = 0.65) stent thrombosis rates were also similar. None of the prespecified subgroups including diabetes, DES versus BMS, single- versus multi-vessel PCI, age, or gender demonstrated any difference.

The key safety endpoint of bleeding (defined as Bleeding Academic Research Consortium [BARC] type II, III, or V) was significantly lower in the short-duration DAPT arm (3.5% vs. 7.4%, HR 0.46, 95% CI 0.1-0.69, p = 0.00018). Thrombolysis In Myocardial Infarction (TIMI) major bleeding (0.6% vs. 1.6%, p = 0.04) and red blood cell transfusions (1.3% vs. 2.6%, p = 0.04) were also lower with short-duration DAPT.

Impact of clinical presentation: The primary endpoint was not different between the prolonged duration and short duration arms in patients presenting with acute coronary syndrome (ACS) (11.1% vs. 11.7%, p = 0.67) or stable CAD (7.5% vs. 4.8%, p = 0.21). However, BARC bleeding was significantly higher in stable CAD patients with prolonged therapy (8.2% vs. 1.6%, p = 0.0002), compared with ACS patients (7.1% vs. 4.1%, p = 0.015) (p for interaction = 0.024).

Patients with peripheral arterial disease (PAD): Patients with PAD had a higher risk of death and ischemic events (HR 2.80, 95% CI 2.05-3.83; p < 0.001). There was evidence of significant effect modification by PAD (p for interaction = 0.01), such that major adverse cardiac event rates were significantly reduced in patients with prolonged DAPT compared with short-term DAPT (16.1% vs. 27.3%, HR 0.54, 95% CI 0.31-0.95, p = 0.03) in patients with PAD, but not in those without PAD (9.3% vs. 7.4%, p = 0.15). Death was also reduced in PAD patients (10.2% vs. 21.1%, p = 0.02). Similarly, definite or probable stent thrombosis was lower in patients with PAD with prolonged DAPT (HR 0.07, 95% CI 0-0.12, p = 0.01). BARC 2,3,5 bleeding was similar with prolonged and short-term DAPT (5.2% vs. 6.9%, p = 0.62), but higher in patients without PAD (p for interaction = 0.04).

Effect of sex: Prolonged DAPT did not reduce the primary endpoint in men (adjusted hazard ratio, 1.08; 95% confidence interval, 0.77-1.52; p = 0.66) and women (adjusted hazard ratio, 1.01; 95% confidence interval, 0.59-1.75; p = 0.96) (interaction, p = 0.79). Bleeding rates were also similar for men and women.

Interpretation:

The results of this landmark trial indicate that short duration of DAPT (≤6 months) is similar to prolonged duration of DAPT (24 months) following PCI with either DES or BMS for ischemic endpoints; all bleeding is significantly reduced. This was true for most subgroups studied, including ACS patients. In fact, in stable CAD patients (although these constituted a small subset), bleeding risk was nearly 5-fold higher with prolonged therapy compared with a shorter treatment duration, suggesting that shorter durations may be preferable in stable CAD patients undergoing PCI, particularly in those with a high bleeding risk profile. The major exception was in patients with PAD, where prolonged DAPT did reduce ischemic events, including mortality, without increasing bleeding event rates.

This trial formed part of the evidence base that resulted in a revision of the most updated 2016 American College of Cardiology/American Heart Association recommendations to 6 months of DAPT for low-risk patients undergoing PCI for stable CAD.

References:

Franzone A, Piccolo R, Gargiulo G, et al. Prolonged vs Short Duration of Dual Antiplatelet Therapy After Percutaneous Coronary Intervention in Patients With or Without Peripheral Arterial Disease: A Subgroup Analysis of the PRODIGY Randomized Clinical Trial. JAMA Cardiol 2016;Aug 30:[Epub ahead of print].

Editorial Comment: Bonaca MP. Antithrombotic Therapy in Patients With Peripheral Artery Disease. JAMA Cardiol 2016;Aug 30:[Epub ahead of print].

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

Gargiulo G, Ariotti S, Santucci A, et al. Impact of Sex on 2-Year Clinical Outcomes in Patients Treated With 6-Month or 24-Month Dual-Antiplatelet Therapy Duration: A Pre-Specified Analysis From the PRODIGY Trial. JACC Cardiovasc Interv 2016;Aug 17:[Epub ahead of print].

Valgimigli M, Campo G, Monti M, et al., on behalf of the PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY (PRODIGY) Investigators. Short- Versus Long-Term Duration of Dual Antiplatelet Therapy After Coronary Stenting: A Randomized Multicentre Trial. Circulation 2012;Mar 21:[Epub ahead of print].

Presented by Dr. Marco Valgimigli at the European Society of Cardiology Congress, Paris, France, August 2011.

Costa F, Vranckx P, Leonardi S, et al. Impact of clinical presentation on ischaemic and bleeding outcomes in patients receiving 6- or 24-month duration of dual-antiplatelet therapy after stent implantation: a pre-specified analysis from the PRODIGY (Prolonging Dual-Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia) trial. Eur Heart J 2015;Feb 25:[Epub ahead of print].

Clinical Topics: Acute Coronary Syndromes, Invasive Cardiovascular Angiography and Intervention, Stable Ischemic Heart Disease, Vascular Medicine, Interventions and ACS, Interventions and Coronary Artery Disease, Interventions and Vascular Medicine, Chronic Angina

Keywords: Coronary Artery Disease, Myocardial Infarction, Acute Coronary Syndrome, Stroke, Erythrocyte Transfusion, Platelet Aggregation Inhibitors, Coronary Restenosis, Drug-Eluting Stents, Risk Factors, Ticlopidine, Sirolimus, Angioplasty, Balloon, Coronary, Purinergic P2Y Receptor Antagonists, Paclitaxel, Taxus, Thrombosis, Peripheral Arterial Disease, ESC Congress


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