Rationale and design of a randomized, double-blind, placebo-controlled trial of 6 versus 12 months clopidogrel therapy after implantation of a drug-eluting stent: The Intracoronary Stenting and Antithrombotic Regimen: Safety And EFficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting (ISAR-SAFE) study

doi:10.1016/j.ahj.2008.12.019

American Heart Journal

Volume 157, Issue 4, April 2009, Pages 620-624.e2

https://doi.org/10.1016/j.ahj.2008.12.019 Get rights and content

Background

Concern regarding the rate of delayed acute stent thrombosis associated with drug-eluting stent (DES) treatment has resulted in upward revision of the advised duration of dual antiplatelet therapy after DES implantation by both European and United States guideline writing committees. In fact, the corroboration of an increased rate of late thrombotic events remains outstanding, and these clinical practice guidelines are limited by an inadequate evidence base on which to ground their recommendations.

Hypothesis

We postulate that a 6-month duration of clopidogrel therapy after DES implantation is associated with a clinical outcome that is not inferior to that of a 12-month therapy.

Study design

The Intracoronary Stenting and Antithrombotic Regimen: Safety And EFficacy of Six Months Dual Antiplatelet Therapy After Drug-Eluting Stenting (ISAR-SAFE) is a multinational, double-blind, placebo-controlled, randomized trial designed to examine the effects of a 6-month duration of clopidogrel therapy after DES implantation compared to that of 12 months. Patients on clopidogrel therapy at 6 months after DES implantation will be randomized in a 1:1 fashion to discontinuation of clopidogrel versus a further 6 months of treatment. The primary end point is a composite of death, myocardial infarction, stent thrombosis, stroke, or thrombolysis in myocardial infarction major bleeding. Clinical follow-up is scheduled at 9 months postrandomization (15 months postintervention). According to power calculations based on a noninferiority design, it is estimated that 6,000 patients are required to be enrolled.

Summary

There is clinical equipoise on the issue of optimal duration of dual antiplatelet treatment after percutaneous intervention with DES. The ISAR-SAFE trial aims to assess whether discontinuation of clopidogrel 6 months after DES implantation is noninferior to routine prolongation of such therapy out to 1 year.

Section snippets

Randomized controlled trial data relating to duration of DAT after PCI in the pre-DES era

Both the PCI arm of the Clopidogrel in Unstable angina to prevent Recurrent Events (PCI-CURE)⁹ and the Clopidogrel for the Reduction of Events During Observation (CREDO)¹⁰ investigators reported a significant reduction in ischemic events (of the order of 25%-30% compared with placebo) after prolongation of poststenting DAT to 9 and 12 months, respectively. However, it should be remembered that both the main CURE trial (of which PCI-CURE was only a substudy) and CREDO study also showed a

Evidence for increased late thrombotic events with DES

Concerns regarding a possible increased risk of late thrombotic occlusion after DES implantation have been present since early in the course of DES incorporation into routine clinical practice,¹⁷ although overall the evidence seems conflicting. We previously conducted a meta-analysis of 14 trials comparing the outcomes of patients treated with sirolimus-eluting stents and bare metal stents and found no excess risk of stent thrombosis over 5 years.¹⁸ In agreement with this, 2 analyses of 4 and 8

Study design

This is a prospective, multinational, randomized, double-blind, placebo-controlled trial designed to examine the effects of a 6-month duration of clopidogrel therapy after DES implantation compared to that of a 12-month therapy. The hypothesis to be tested is that a 6-month duration is not inferior to that of a 12-month therapy (noninferiority hypothesis).

Summary

There is clinical equipoise on the issue of optimal duration of dual antiplatelet treatment after percutaneous intervention with DES. The Intracoronary Stenting and Antithrombotic Regimen: Safety And EFficacy of Six Months Dual Antiplatelet Therapy After Drug-Eluting Stenting (ISAR-SAFE) trial is a large-scale, multinational, double-blinded, placebo-controlled trial which aims to enrol 6,000 patients to assess whether restriction of clopidogrel therapy to 6 months post-DES implantation is

Acknowledgements

R.A.B. acknowledges support by a Research Fellowship in Atherothrombosis from the European Society of Cardiology.

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Comparison of Baseline Characteristics and Inhospital Outcomes of Patients and Use of Bare Metal Versus Drug-Eluting Stents During Percutaneous Coronary Intervention 2005 to 2015 at a Single Tertiary Hospital
2017, American Journal of Cardiology
With steady growth in the use of drug-eluting stents (DES), the indications for bare metal stents (BMS) have significantly changed over the last decade. This study aims to describe trends in the use of BMS and the evolution of the population receiving them over the past 10 years and determine patient characteristics associated with using BMS. Consecutive patients who underwent percutaneous coronary intervention (PCI) at the Washington Hospital Center from January 2005 through March 2015 were included. Baseline characteristics and inhospital outcomes of patients who underwent PCI with BMS versus DES were compared during 2 different time periods: from 2005 to 2010 and from 2011 to 2015. Multivariable analyses were performed for each period of time to determine independent variables associated with the choice of BMS rather than DES; 20,321 patients who underwent PCI were included in the present study. The mean age was 65.0 ± 12.5 years, 65.2% were men, and 30.4% were black. BMS use peaked in 2007 (47%) but has fallen steadily since; BMS accounted for only 10% of stents used in 2015. Presentation with acute coronary syndrome or cardiogenic shock was more common in patients receiving a BMS; this was reflected in higher rates of inhospital mortality and major bleeding among patients receiving BMS versus DES. Covariables independently associated with receiving a BMS common to both time periods included black race, Hispanic ethnicity, cardiogenic shock or acute coronary syndrome, oral anticoagulation, current smoking, increasing age, lower hematocrit, and history of chronic renal insufficiency. In conclusion, there has been a precipitous decline in the use of BMS over the last decade. Newer stent technology that promises shorter duration of dual antiplatelet therapy is likely to lead to the extinction of BMS over the next decade.
Balancing the risk of spontaneous ischemic and major bleeding events in acute coronary syndromes
2017, American Heart Journal
Evaluation of antithrombotic treatments for acute coronary syndromes (ACS) requires balancing ischemic and bleeding risks to assess net benefit. We sought to compare the relative effects of ischemic and bleeding events on mortality.
In the PLATelet inhibition and patient Outcomes (PLATO) trial, we compared spontaneous ischemic events (myocardial infarction or stroke) with spontaneous major bleeding events (PLATO major, Thrombolysis In Myocardial Infarction [TIMI] major, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries [GUSTO] severe) with respect to risk of mortality using time-dependent Cox proportional hazards models. The comparison was performed using ratio of hazard ratios for mortality increase after ischemic vs bleeding events.
A total of 822 patients (4.4%) had ≥1 spontaneous ischemic event; 485 patients (2.6%), ≥1 spontaneous PLATO major bleed, 282 (1.5%), ≥1 spontaneous TIMI major bleed; and 207 (1.1%), ≥1 spontaneous severe GUSTO bleed. In patients who had both events, bleeding occurred first in most patients. Regardless of classification, major bleeding events were associated with increased short- and long-term mortality that were not significantly different from the increase associated with spontaneous ischemic events: ratio of hazard ratios (95% CIs) for short- and long-term mortality after spontaneous ischemic vs bleeding events: 1.46 (0.98-2.19) and 0.92 (0.52-1.62) (PLATO major); 1.26 (0.80-1.96) and 1.19 (0.58-2.24) (TIMI major), 0.72 (0.47-1.10) and 0.83 (0.38-1.79) (GUSTO severe) (all P > 0.05)
In patients with ACS on dual antiplatelet therapy, spontaneous major bleeding events seem “prognostically equivalent” to spontaneous ischemic complications. This result allows quantitative comparisons between both actual and predicted bleeding and ischemic risks. Our findings help to better define net clinical benefit of antithrombotic treatments and more accurately estimate mortality after ischemic and bleeding events in patients with ACS.
Overtime evaluation of the vascular HEALing process after everolimus-eluting stent implantation by optical coherence tomography. The HEAL-EES study
2015, Cardiovascular Revascularization Medicine
Citation Excerpt :
Anyway, many trials have been performed and many other are still ongoing to test the optimal duration of DAT after stent implantation. The majority of those trials may be however penalized from the fact to newer-generation DES together with first-generation DES, likely diluting the beneficial effect of a short DAT over a long DAT [45–48]. The GLOBAL-LEADERS trial is so far the only trial which is testing a very short DAT with the use of newer-generation DES. (
Second-generation drug-eluting stent (DES) have shown a better safety and efficacy as compared to first generation DES due to an improved vascular healing process. This process has not been so far evaluated in vivo in an overtime fashion by optical coherent tomography (OCT). We sought to evaluate the vascular healing process after everolimus-eluting stent (EES) implantation at 6, 9 and 12 months, by OCT.
Consecutive 36 patients undergoing percutaneous coronary intervention with EES were randomized 1:1:1 to receive OCT imaging at 6 (group A), 9 (group B) or 12-month follow-up (group C). One patient from group C was excluded because of target lesion revascularization at 1-month, whereas 5 patients withdraw the informed consent. Finally, 30 patients were analyzed.
Neointimal thickness was not different between 3 groups (group A: 99.50 [94.06–127.79] μm, group B: 107.26 [83.48–133.59] μm, group C: 127.67 [102.51–138.49] μm; p = 0.736). Although the percentage of “uncovered struts” was significantly higher in group A as compared to the other groups (8.0% vs. 4.4% vs. 2.9%, respectively; p = 0.180), the ratio of uncovered to total struts per section < 30% was similar between 3 groups (0.3% vs. 0.3% vs. 0%, respectively; p = 1.000).
Healing process following EES implantation seems almost completed at 6-month follow-up. These data, which need to be confirmed in a larger study, may support the decision to shorten dual antiplatelet therapy.
Safety of short-term dual antiplatelet therapy after drug-eluting stents: An updated meta-analysis with direct and adjusted indirect comparison of randomized control trials
2015, International Journal of Cardiology
Citation Excerpt :
Although they concluded that this result was hypothesis generating, it supports the fact that high-risk patients would need a tailored approach to the duration of DAPT. Several other RCTs on this topic are currently being undertaken (DAPT trial [40], ISAR-SAFE [41], OPTIDUAL [42], Nobori DAPT (NCT01514227), EDUCATE (NCT01069003), DAPT-STEMI (NCT01459627), SMART-DATE (NCT01701453)). All of these trials are comparing between 6 and 12 months of DAPT against 12 to 30 months and looking at different clinical presentations and stent platforms.
Duration of dual antiplatelet therapy (DAPT) following drug-eluting stents (DES) remains controversial and is a topic of ongoing research.
Direct and adjusted indirect comparisons of all the recent randomized control trials (RCTs) were performed to evaluate the safety of short-term versus long-term DAPT following DES.
8 RCTs were identified and 7 (16,318 subjects) were included. 4 groups of 3 vs 12 months, 6 vs 12 months, 6 vs 24 months and 12 vs 24 months of DAPT were used for direct comparison. There was no significant difference in stent thrombosis, myocardial infarction (MI), stroke and revascularization, cardiovascular and all-cause mortality between the different durations in all 4 groups. Pooling trials of 3–6 months of DAPT against 12 months, we found a significant reduction in the risk of total bleeding (RR 0.61, 95% CI 0.43–0.87). Adjusted indirect comparison between 3 vs 6 months, 3 vs 24 months and 6 vs 24 month duration of DAPT showed no significant differences in risk of death or MI, or revascularization between 3 or 6 months and 24 months. However, 24 months of DAPT was associated with significantly more bleeding than 3 or 6 months.
3 to 6 months of DAPT following second generation DES and above is safe with no increased risk of thrombotic complications and mortality, and lower bleeding risk. However a tailored approach may be more appropriate for high-risk patients.
Antiplatelet therapy after drug-eluting stent implantation
2015, Journal of Cardiology
Dual antiplatelet therapy (DAPT), which is the combination of aspirin and a platelet P2Y₁₂ inhibitor, is the cornerstone of secondary prevention in ischemic heart disease requiring intracoronary stenting. Although the efficacy of DAPT in the reduction of ischemic events has been well validated, the optimal duration, and indeed combination, of therapy is yet to be established. This area continues to attract debate with new developments in stent design and antiplatelet agents, as well as evolving clinical skill levels.
Presently, clinical guidelines advocate the use of DAPT for 6–12 months following drug-eluting stent (DES) implantation, but this can vary according to clinical indication, bleeding risk, and country of practice. Concerns have arisen that unnecessary prolongation of DAPT may be associated with increased bleeding events, as well as cost. Whether these guidelines effectively cater to current stenting techniques, devices, and antiplatelet agents remains to be determined. This review analyzes contemporary issues surrounding DAPT following DES implantation, as researchers continue to seek to strike the optimal balance between bleeding and thrombotic risk.
Although reduced DAPT durations continue to show promising results in preventing ischemic events while also mitigating bleeding risk, ultimately the consideration of clinical presentation as well as medical and social history is paramount to guiding the optimal duration and cessation of DAPT.
SYNTAX score predicts major bleeding following drug-eluting stent implantation in an all-comers population
2015, Revista Espanola de Cardiologia
En estudios previos se ha descrito que la intervención coronaria aplicada a lesiones complejas presenta una correlación independiente con las hemorragias mayores. La puntuación SYNTAX es un instrumento angiográfico utilizado para evaluar el grado de complejidad de las enfermedades arteriales coronarias. El objetivo de este estudio es evaluar la capacidad de la puntuación SYNTAX para predecir hemorragias mayores tras el implante de stents liberadores de fármacos.
Se analizó a un total de 722 pacientes sometidos a implante de stents liberadores de fármacos de una población de pacientes consecutivos incluidos en el estudio entre enero de 2007 y abril de 2010. Se investigó la incidencia de hemorragias mayores y trombosis del stent durante un periodo de 2 años. La hemorragia mayor se evaluó mediante la puntuación CRUSADE y los criterios del Bleeding Academic Research Consortium. Se estratificó a los pacientes en los siguientes grupos según los criterios del ensayo SYNTAX: baja (≤ 22; n = 484), intermedia (23-32; n = 128) y alta (≥ 33; n = 110).
Se observaron hemorragias mayores en 47 pacientes (6,5%) en el periodo de estudio de 2 años, y hubo 12 episodios de trombosis del stent (1,7%). Las tasas de hemorragia mayor en los pacientes de los terciles bajo, intermedio y alto de la puntuación SYNTAX fueron del 2,9, el 7,8 y el 20,9% respectivamente (p < 0,0001). La puntuación SYNTAX mostró una hazard ratio ajustada de hemorragia mayor a los 2 años de 1,81 (intervalo de confianza del 95%, 1,27-2,57). El valor predictivo del área bajo la curva de características operativas del receptor ajustada por hemorragia mayor mejoró significativamente tras la inclusión de la puntuación CRUSADE (estadístico C, 0,890 frente a 0,812).
Aunque la puntuación SYNTAX puede predecir el riesgo de hemorragias mayores, el valor predictivo de la puntuación CRUSADE fue superior. Estas puntuaciones pueden resultar de utilidad en la toma de decisiones clínicas respecto a las estrategias de revascularización y la duración óptima del tratamiento antiagregante plaquetario doble tras implante de stents liberadores de fármacos.
Previous studies have reported that coronary intervention for complex lesions is independently correlated with major bleeding. The SYNTAX score is an angiographic tool used to grade the complexity of coronary artery diseases. The aim of this study was to assess the ability of the SYNTAX score to predict major bleeding following drug-eluting stent implantation.
We analyzed 722 patients who underwent drug-eluting stent implantation in an all-comers population between January 2007 and April 2010. The incidence of major bleeding and stent thrombosis was investigated during a 2-year period. Major bleeding was evaluated using the CRUSADE score and Bleeding Academic Research Consortium criteria. Patients were stratified into the following groups according to the SYNTAX trial: low (≤ 22; n = 484), intermediate (23–32; n = 128), and high (≥ 33; n = 110).
Major bleeding was observed in 47 patients (6.5%) during the 2-year period, and there were 12 incidents of stent thrombosis (1.7%). Major bleeding rates for patients in the low, intermediate, and high SYNTAX score tertiles were 2.9%, 7.8%, and 20.9%, respectively (P < .0001). The SYNTAX score had an adjusted hazard ratio of 1.81 (95% confidence interval, 1.27-2.57) for 2-year major bleeding. The predictive value of the adjusted area under the receiver operating characteristic curve for major bleeding significantly improved after inclusion of the CRUSADE score (C statistic, 0.890 vs 0.812).
Although the SYNTAX score can predict major bleeding risk, the predictive value of the CRUSADE score was higher. These scores may be useful in clinical decision-making on revascularization strategies and on the optimal duration of dual antiplatelet therapy following drug-eluting stent implantation.
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Background

Hypothesis

Study design

Summary

Section snippets

Randomized controlled trial data relating to duration of DAT after PCI in the pre-DES era

Evidence for increased late thrombotic events with DES

Study design

Summary

Acknowledgements

Lancet

Am J Cardiol

J Am Coll Cardiol

Lancet

J Am Coll Cardiol

J Am Coll Cardiol

Stent thrombosis late after implantation of first-generation drug-eluting stents: a cause for concern

Circulation

Duration of Antiplatelet Therapy Following Intracoronary Stenting: Are Changes Needed?

Eur Heart J Suppl

A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents

N Engl J Med

A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators

N Engl J Med

Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting : the clopidogrel aspirin stent international cooperative study (CLASSICS)

Circulation

Low-dose aspirin for the prevention of atherothrombosis

N Engl J Med

Circulation

Guidelines for percutaneous coronary interventions. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology

Eur Heart J

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

Jama

Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation

N Engl J Med