Randomized comparison of 6- versus 24-month clopidogrel therapy after balancing anti-intimal hyperplasia stent potency in all-comer patients undergoing percutaneous coronary intervention: Design and rationale for the PROlonging Dual-antiplatelet treatment after Grading stent-induced Intimal hyperplasia study (PRODIGY)

doi:10.1016/j.ahj.2010.07.034

American Heart Journal

Volume 160, Issue 5, November 2010, Pages 804-811

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Background

The optimal duration of clopidogrel therapy after coronary stenting is debated because of the scarcity of randomized controlled trials and inconsistencies arising from registry data. Although prolonged clopidogrel therapy after bare metal stenting is regarded as an effective secondary prevention measure, the safety profile of drug-eluting stents itself has been questioned in patients not receiving ≥12 months of dual-antiplatelet therapy.

Hypothesis

Twenty-four months of clopidogrel therapy after coronary stenting reduces the composite of death, myocardial infarction, or stroke compared with 6 months of treatment.

Study design

PRODIGY is an unblinded, multicenter, 4-by-2 randomized trial. All-comer patients with indication to coronary stenting are randomly treated—balancing randomization—with bare metal stent (no active late loss inhibition), Endeavor Sprint zotarolimus-eluting stent (Medtronic, Santa Rosa, CA) (mild late loss inhibition), Taxus paclitaxel-eluting stent (Boston Scientific, Natick, MA) (moderate late loss inhibition), or Xience V everolimus-eluting stent (Abbott Vascular, Santa Clara, CA) (high late loss inhibition). At 30 days, patients in each stent group are randomly allocated to receive 24 or up to 6 months of clopidogrel therapy―primary end point randomization. With 1,700 individuals, this study will have >80% power to detect a 40% difference in the primary end point after sample size augmentation of 5% and a background event rate of 8%.

Summary

The PRODIGY trial aims to assess whether 24 months of clopidogrel therapy improves cardiovascular outcomes after coronary intervention in a broad all-comer patient population receiving a balanced mixture of stents with various anti-intimal hyperplasia potency.

Section snippets

Bare metal stents and duration of dual-antiplatelet treatment

The coronary implantation of bare metal stents (BMSs) prevents the acute recoil and postinjury arterial shrinkage (constrictive remodeling) associated with balloon angioplasty. Yet, it also replaces atherosclerotic coronary disease with the iatrogenic condition of in-stent neointimal hyperplasia that may frequently result in in-stent restenosis (ISR). As vascular healing rapidly occurs after implantation, a regimen of dual-antiplatelet therapy for 30 days is generally recommended after BMS to

Drug-eluting stents and duration of dual-antiplatelet treatment

Considerable effort has gone into the development of stents with an active coating to inhibit ISR—the drug-eluting stent (DES).⁷

The eluted drugs are selected to be able to inhibit the complex cascade of events that lead to neointimal formation after stent implantation. The inflammatory and proliferative mechanisms of the general tissue-healing response are crucial targets for therapeutic approaches aimed at reducing neointimal proliferation. As a consequence, inhibition of neointimal

Study design and population

PROlonging Dual-antiplatelet treatment after Grading stent-induced Intimal hyperplasia study (PRODIGY) is a 4-by-2, randomized, multicenter, clinical trial designed to evaluate the efficacy and safety of prolonging duration of clopidogrel therapy up to 24 months in all-comer patients receiving a balanced mixture of stents with various anti-intimal hyperplasia potency.

Patients undergoing elective, urgent, or emergent PCI with intended stent implantation are randomly assigned in a 1:1:1:1 fashion

Randomization

Allocation of study treatment is performed by the treating physician immediately after eligibility criteria are met and subsequently at 30 days after intervention via sealed envelopes. Both randomization procedures are achieved with computer-generated random sequence produced in the coordinating center with a random block size.

Treatment protocol and follow-up procedures

All patients receive aspirin (160-325 mg orally or 500 mg intravenously as a loading dose and then 80-160 mg orally indefinitely) and clopidogrel as follows: 300 or 600 mg orally as a loading dose to be given preferably before PCI but not later than at the time the patient leaves the catheterization laboratory and then 75 mg/d for the treatment duration provided by the randomization scheme, that is, either 6 months in the SHORT arm—in patients randomized to the BMS-SHORT arm for stable CAD,

Follow-up

Patients return for study visits at 30 days, then every 6 months up to 2 years, then annually until 5 years after the index procedure, and finally after 10 years (last study visit). During follow-up visits, patients will be examined, will be assessed for adverse events, and will undergo 12-lead electrocardiogram (ECG) recordings. At all follow-up time points, patients will be questioned on their compliance with the study medication. Any interruption or termination, as well as the reason for

Study end points

The primary objective of this study is to assess whether 24-month dual-antiplatelet treatment with aspirin and clopidogrel after coronary stenting, evaluated from the 30-day landmark time point, is associated to a lower cumulative incidence of all-cause death, nonfatal MI, or stroke within 24 months after index coronary intervention compared with 6-month dual anti-platelt therapy (DAT) duration after DES or ≥1-month DAT duration after BMS implantation.

Secondary end points include each component

Statistical considerations

In the CREDO trial, a benefit of long-term clopidogrel between day 29 and 1 year was observed in terms of a 32% decrease in the composite of death or MI (from 4.4% to 3.0%).4, 5 The composite of death, MI, or stroke was reduced by 37% in the clopidogrel arm (5.2% to 3.3%), with Kaplan-Meier curves starting to progressively diverge at 6 months in a time-dependent manner toward the end of follow-up.4, 5 The CREDO trial was carried out in the BMS era, and the difference in duration of

Study distinctive features

The dual-antiplatelet therapy (DAPT) study is a prospective, multicenter, randomized, double-blind trial to assess the effectiveness and safety of 12 versus 30 months. The superiority of long-term DAPT is hypothesized both on death, MI, or stroke and on stent thrombosis. Eligible patients are those treated with DESs who are free from MI, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting. The Intracoronary Stenting and Antithrombotic

Study organization

The PRODIGY trial is being conducted at 3 investigative sites in Italy. The study is an investigator-driven clinical trial entirely supported by a research grant from the University of Ferrara, and no extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents. Data are being coordinated and analyzed by the Academic Research Unit of Medical Trial

Disclosures

Conflict of interests: none.

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Cited by (56)

Involvement of stromal cell-derived factor-1α (SDF-1α), stem cell factor (SCF), fractalkine (FKN) and VEGF in TSG protection against intimal hyperplasia in rat balloon injury
2019, Biomedicine and Pharmacotherapy
Intimal hyperplasia is the major therapeutic concern after percutaneous coronary intervention. The aim of this study is to investigate effects of 2,3,4′,5-tetrahydroxystilbene-2-O-β-D glucoside (TSG) on intimal hyperplasia and the underling mechanisms through attenuating the expressions of stromal cell-derived factor-1α (SDF-1α)/CXCR4, stem cell factor (SCF)/c-kit and fractalkine (FKN)/CX3CR1, and through promoting re-endothelialization with vascular endothelial growth factor (VEGF).
Rats were operated with carotid artery balloon injury. The treatment groups were gavaged with 50 and 100 mg/kg/d of TSG. After 10 days of treatment, carotid artery pathological changes were evaluated by histology. Serum levels of SDF-1α, SCF, FKN and VEGF were detected by enzyme linked immunosorbent assay. The protein expressions of the receptors c-kit, CXCR4, CX3CR1, as well as CD34 and proliferating cell nuclear antigen (PCNA) were detected by immunochemistry.
TSG dose-dependently inhibited balloon injury-induced intimal hyperplasia, as evidenced by reducing neointima area (NIA), neointima area/media area (NIA/MA), neointima area/internal elastic area (NIA/IELA), and by decreasing the protein expression of PCNA. TSG reduced serum levels of SDF-1α, SCF and FKN, and it also decreased the expressions of the corresponding receptors c-kit, CXCR4, CX3CR1 in neointima. Importantly, the level of VEGF in peripheral blood and the expression of CD34 in vascular walls were increased to promote re-endothelialization.
This study clearly demonstrated that TSG was effective in inhibiting intimal hyperplasia, and this effect was mediated, at least in part, through the SCF/c-kit, SDF-1α/CXCR4 and FKN/CX3CR1 axes. Importantly, TSG could increase VEGF and CD34 to promote endothelial repair.
A systematic review of the efficacy of aspirin monotherapy versus other antiplatelet therapy regimens in peripheral arterial disease
2018, Journal of Vascular Surgery
Citation Excerpt :
Patients in the long-term DAPT group also had significantly higher baseline rates of hyperlipidemia (86.0% vs 95.0%; P = .006), CAD (58.7% vs 88.1%; P < .0001), and prior MI (20.1% vs 49.7%; P < .0001), which limits the quality and implications of these data. A subgroup analysis36 of the Synergy Between Stent and Drugs to Avoid Ischemic Recurrences After Percutaneous Coronary Intervention (PRODIGY) trial50,51 studied the effects of long-term (24 months) vs short-term (6 months) clopidogrel and aspirin DAPT after PCI treatment (with bare-metal stents or drug-eluting stents) in patients with comorbid PAD. At 24 months of follow-up, rates of MACCEs (death, MI, or ischemic stroke; 16.1% vs 27.3%; P = .03), MACEs (cardiac death, MI, or ischemic stroke; 12.1% vs 22.3%; P = .04), and definite or probable stent thrombosis (0.0% vs 6.0%; P = .01) were significantly decreased in patients treated with long-term DAPT.
Dual antiplatelet therapy (DAPT) usually refers to the administration of aspirin plus a platelet P2Y₁₂ receptor blocker. This combination is commonly prescribed after revascularization procedures in patients with peripheral arterial disease (PAD) to prevent failure of the intervention. However, there is not a consensus among peripheral vascular specialists regarding whether the optimal treatment regimen for their patients is mono antiplatelet therapy (MAPT) or DAPT. Furthermore, there is no consensus regarding the optimal duration of DAPT. This study was undertaken to systematically and critically review the evidence for the use of DAPT after revascularization in PAD, hypothesizing that longer durations of DAPT will result in decreased rates of major adverse cardiac events, major adverse limb events, and mortality, without a significant increase in severe bleeding episodes compared with MAPT or shorter durations of DAPT.
A systematic search strategy encompassing DAPT and PAD was deployed in two databases. Studies including arterial bypasses using venous or prosthetic conduits, endovascular procedures, diagnostic angiography of lower extremity arteries, and patients with high risk factors were included.
We included 14 studies, 10 of which were randomized controlled trials (RCTs). The overall risk of bias for the RCTs ranged from low to moderate, whereas nonrandomized studies had moderate to high risk of bias. The results of this review suggest that use of DAPT in patients with PAD reduces rates of major adverse cardiac events (risk ratio [RR], 0.79; 95% confidence interval [CI], 0.68-0.91; P = .002), major adverse cardiac and cerebrovascular events, and mortality (RR, 0.57; 95% CI, 0.45-0.72; P < .00,001) compared with those of patients treated with MAPT. Lower extremity-specific end points, such as major adverse limb events and target lesion revascularization (RR, 0.70; 95% CI, 0.49-1.01; P = .06) were also decreased in the DAPT cohort. Rates of moderate bleeding, however, were increased in those treated with DAPT, whereas rates of major bleeding (RR, 0.98; 95% CI, 0.68-1.41; P = .92) remained similar in both treatment groups. The effects of DAPT duration on outcomes of revascularization in patients with PAD have yet to be studied in an RCT.
DAPT appears to be beneficial for preventing complications after revascularization in PAD, including thrombotic failure of the intervention. However, the durations of DAPT use in these studies are heterogeneous, suggesting that additional data are needed to determine the optimal use of DAPT in PAD patients.
Effect of over-2-year dual antiplatelet therapy on the rate of major adverse cardiac and cerebral events for everolimus-eluting stent implantation: The landmark analysis from Tokyo-MD PCI registry
2017, Journal of Cardiology
Long-term dual antiplatelet therapy (DAPT) for patients treated with coronary stents has been reported to be effective. However the effectiveness of long-term DAPT for everolimus-eluting stent (EES) implanted patients has been controversial. We assessed the major adverse cardiac and cerebral events (MACCE: a composite of death, myocardial infarction, or cerebral arterial disease) in patients free from MACCE during the first 2 years after EES implantation.
A total of 1918 patients who underwent successful percutaneous coronary intervention (PCI) with EES at 22 centers in Japan in 2010–2011 were enrolled, and 742 patients were free from MACCE for 2 years. We divided these MACCE-free patients into two groups: those who received DAPT for >2 years (Over-2-Year DAPT: n = 591), and those who received DAPT for ≤2 years (Under-2-Year DAPT: n = 151). We performed the landmark analysis that began at 2 years and evaluated at 3 years after PCI about the occurrence of MACCE, major bleeding, stent thrombosis, and restenosis between these groups, both with and without baseline adjustment by propensity score matching (n = 145 in both groups).
Fifty MACCE cases were reported (Over-2-Year DAPT, 38; Under-2-Year DAPT, 12), with no significant differences between the 2 groups (log-rank test, p = 0.19). Even after baseline adjustment, there were no differences in MACCE occurrence (Over-2-Year DAPT, 8; Under-2-Year DAPT, 11, p = 0.19); 15 cases of major bleeding, 5 of restenosis, and 2 of stent thrombosis were observed after 2-years’ follow-up, with no statistical differences between the groups, although the event numbers were too low for comparison.
Continuing DAPT for >2 years did not prevent MACCE in patients free from MACCE during initial 2 years after EES implantation. Few events of major bleeding, stent thrombosis, and restenosis were observed, with no statistical differences.
Role of stent type and of duration of dual antiplatelet therapy in patients with chronic kidney disease undergoing percutaneous coronary interventions. Is bare metal stent implantation still a justifiable choice? A post-hoc analysis of the all comer PRODIGY trial
2016, International Journal of Cardiology
Chronic kidney disease (CKD) is a powerful predictor of major cardiovascular events and stent thrombosis (ST) in patients undergoing percutaneous coronary interventions (PCI). No randomized data are available to compare, and guide the selection of type of stent between bare metal (BMS) or drug eluting stent (DES) in this population.
We performed a post-hoc analysis of the PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY (PRODIGY) trial, in which stable or unstable patients with coronary artery disease undergoing PCI were randomized 1:1:1:1 to receive BMS, paclitaxel- (PES), zotarolimus- (ZES-S), or everolimus- (EES) eluting stent. A total of 2003 patients were randomized, and 22 patients were excluded for missing serum creatinine leading to a final population of 1981 patients. Primary outcome was definite or probable ST. We also assessed MACE (myocardial infarction, stroke, or death), and all-cause death, as secondary outcome.
CKD, defined with estimated glomerular filtration rate < 60 ml/min/1.73 m², was found in 373 patients (18.8%). The incidence of ST at 2 years was 5.1% in CKD and 2.1% in non-CKD patients (HR 2.57, 95% confidence interval (CI) 1.46 to 4.52, p < 0.001). At multivariable regression we found that patients randomized to EES or ZES-S, but not PES, had lower risk of ST at two years as compared with BMS: adjusted HR = 0.288, 95% CI [0.107–0.778, p = 0.014] and HR = 0.394, 95% CI [0.164–0.947, p = 0.037] respectively. The number of patients needed to be treated to prevent 1 ST with an EES vs BMS was 20 in CKD and 50 in patients without CKD. EES patients had the lowest incident MACE events 26.4% as compared to BMS 35.1%, ZES-S 33.0%, or PES 35.7% patients, p = 0.551. All-cause death was lowest in ZES-S group 10.6% as compared to BMS 18.1%, PES 25.5% and EES 14.9%, p = 0.040. We found no significant interaction between DAPT duration (6 vs 24 months) and stent type on primary outcome, P_INT = 0.47 for BMS, P_INT = 0.57 for PES, P_INT = 0.41 for ZES-S and P_INT = 0.28 for EES.
In an all-comer population of patients with stable and unstable CAD, CKD at baseline was associated with a double risk of ST and MACE. CKD patients receiving EES had less than half risk of ST 2 years after PCI as compared with BMS and PES. Our analysis suggests that 2nd generation limus-based stent should be favored over paclitaxel-based DES or BMS to reduce ST and MACE in CKD patients.
Dual Antiplatelet Therapy Duration: A Review of Current Available Evidence
2016, Clinical Therapeutics
Citation Excerpt :
Prespecified exclusion criteria were: (1) duplicated data, and (2) ongoing trials without final results. A total of 10 RCTs have been conducted to date pertaining to the duration of antiplatelet therapy after PCI stenting during the acute (ST-elevation MI) or nonacute (non–ST-elevation acute coronary syndromes [NSTEACS]-stable angina) setting.11–21 Of note, all of these trials used clopidogrel as the additional antiplatelet factor, and no data on the newer agents (ie, prasugrel and ticagrelor) were available.
Multiple regimens of antiplatelet and anticoagulation therapy have been used in the past in patients undergoing percutaneous coronary intervention (PCI). Later trials of PCI stenting demonstrated the efficacy of dual-antiplatelet therapy (DAPT) in reducing stent- and non–stent-related thrombotic events in this specific population. Nonetheless, the required duration of DAPT has not yet been elucidated. In this article we sought to identify various randomized clinical trials (RCTs), pooled analyses, meta-analyses, and data pertaining to the optimal duration of DAPT and attempt some recommendations based on patients’ clinical and procedural profiles.
We performed an extensive search using MEDLINE, Scopus, Cochrane Library, and Internet sources for abstracts, manuscripts, and conference reports without any language or date restrictions. In our review we included all available evidence from RCTs, meta-analyses, observational studies, and abstracts pertaining to our topic. Search results that were deemed irrelevant or that would not serve the goal or topic of our review were excluded.
Our search yielded 10 RCTs directly comparing different durations of DAPT, 3 meta-analyses amassing the evidence resulting from randomized data, and numerous observational studies that served the aim of our review. The observational studies included in the manuscript are directly related to instances in which RCTs could not be performed or introduce important concepts related to the duration of DAPT.
There is no conclusive evidence that determines the mandatory DAPT duration after PCI. In addition, there are distinct patient populations that need specific treatment regimens, such as diabetic patients or those on long-term oral anticoagulation. Therefore, clinical judgement and meticulous examination of all pertaining risk factors are required for each individual. These factors include those related to a patient’s characteristics, treatment procedures, lesion complexity, and stent type. Currently ongoing studies are anticipated to further elucidate and integrate our understanding with regard to DAPT.
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
2016, JACC: Cardiovascular Interventions
The aim of this study was to assess the impact of sex on 2-year outcomes after percutaneous coronary intervention (PCI) in patients randomly allocated to 24-month versus 6-month dual-antiplatelet therapy (DAPT).
The optimal duration of DAPT after PCI is highly debated. Whether sex per se should drive decision making on DAPT duration remains unclear.
The primary efficacy endpoint of PRODIGY (Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study) was the composite of death, myocardial infarction, or cerebrovascular accident at 24-month follow-up. The key safety endpoint was type 2, 3, or 5 bleeding according to the Bleeding Academic Research Consortium criteria.
Women (n = 459 [23.3%]) were older and more likely to have hypertension, lower creatinine clearance, and acute coronary syndrome but had a lower severity of coronary artery disease. After adjustment, prolonged DAPT, compared with 6-month treatment, did not reduce the primary endpoint in both men (adjusted hazard ratio: 1.080; 95% confidence interval: 0.766 to 1.522; p = 0.661) and women (adjusted hazard ratio: 1.013; 95% confidence interval: 0.588 to 1.748; p = 0.962) (interaction p = 0.785). No sex disparity was identified across multiple secondary ischemic endpoints, including overall or cardiovascular mortality, myocardial infarction, and stent thrombosis. There was also no clear sex-related effect on clinically relevant bleeding, including Bleeding Academic Research Consortium type 3 or 5, TIMI (Thrombolysis in Myocardial Infarction), and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) scales.
The present findings suggest that men and women undergoing PCI have similar adjusted 2-year ischemic and bleeding outcomes, despite being characterized by different clinical presentation. Sex failed to emerge as a treatment modifier with respect to DAPT duration, suggesting that decision making on DAPT duration in female patients should weigh ischemic versus bleeding risks.

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Background

Hypothesis

Study design

Summary

Section snippets

Bare metal stents and duration of dual-antiplatelet treatment

Drug-eluting stents and duration of dual-antiplatelet treatment

Study design and population

Randomization

Treatment protocol and follow-up procedures

Follow-up

Study end points

Statistical considerations

Study distinctive features

Study organization

Disclosures

Lancet

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Am J Cardiol

Am J Cardiol

Should dual antiplatelet therapy after drug-eluting stents be continued for more than 1 year? Dual antiplatelet therapy after drug-eluting stents should be continued for more than one year and preferably indefinitely

Circ Cardiovasc Interv

Should dual antiplatelet therapy after drug-eluting stents be continued for more than 1 year? Dual antiplatelet therapy after drug-eluting stents should not be continued for more than 1 year and preferably indefinitely

Circ Cardiovasc Interv

Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial

Jama

Risk reduction with long-term clopidogrel following percutaneous coronary intervention

Eur Heart J