Bloqueadores de glucoproteína plaquetaria IIb/IIIa durante la intervención coronaria percutánea y como tratamiento médico inicial de los síndromes coronarios agudos sin elevación del segmento ST
Resumen
Antecedentes
Durante la intervención coronaria percutánea, y en los síndromes coronarios agudos sin elevación del segmento ST, el riesgo de obstrucción de vasos aguda por la trombosis es elevado. Los bloqueadores de glucoproteína IIb/IIIa inhiben significativamente la agregación plaquetaria y pueden prevenir la mortalidad y el infarto de miocardio. Ésta es una actualización de una revisión Cochrane publicada por primera vez en 2001 y actualizada previamente en 2007 y 2010.
Objetivos
Evaluar la eficacia y la seguridad de los bloqueadores de glucoproteína IIb/IIIa administrados durante la intervención coronaria percutánea, y como tratamiento médico inicial en pacientes con síndromes coronarios agudos sin elevación del segmento ST.
Métodos de búsqueda
Se actualizaron las búsquedas en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL) en The Cochrane Library (número 12, 2012), MEDLINE (OVID, 1946 hasta enero, semana 1, 2013) y en EMBASE (OVID, 1947 hasta semana 1, 2013) el 11 enero 2013.
Criterios de selección
Ensayos controlados aleatorios que compararon los bloqueadores de IIb/IIIa por vía intravenosa con placebo o tratamiento habitual.
Obtención y análisis de los datos
Dos autores seleccionaron de forma independiente los estudios para su inclusión, evaluaron la calidad de los ensayos y extrajeron los datos. Se obtuvo información sobre la hemorragia grave como efecto adverso a partir de los ensayos. Se usaron los odds ratios (OR) y los intervalos de confianza (IC) del 95% para las medidas del efecto.
Resultados principales
Se incluyeron 60 ensayos con 66 689 pacientes. Durante la intervención coronaria percutánea (48 ensayos con 33 513 participantes), los bloqueadores de la glucoproteína IIb/IIIa redujeron la mortalidad por cualquier causa a 30 días (OR 0,79; IC del 95%: 0,64 a 0,97), pero no a seis meses (OR 0,90; IC del 95%: 0,77 a 1,05). La mortalidad por cualquier causa o el infarto de miocardio se redujo a los 30 días (OR 0,66; IC del 95%: 0,60 a 0,72) y a los seis meses (OR 0,75; IC del 95%: 0,64 a 0,86); sin embargo, aumentó la hemorragia grave (OR 1,39; IC del 95%: 1,21 a 1,61; aumento del riesgo absoluto 8,0 por 1000). Los resultados de eficacia fueron homogéneos para cada variable principal de evaluación, según la afección clínica de los pacientes, pero fueron menos marcados para los pacientes que recibieron tratamiento previo con clopidogrel, especialmente en los pacientes sin síndrome coronario agudo.
Como tratamiento médico inicial de los síndromes coronarios agudos sin elevación del segmento ST (12 ensayos con 33 176 participantes), los bloqueadores IIb/IIIa no redujeron la mortalidad a los 30 días (OR 0,90; IC del 95%: 0,79 a 1,02) o a los seis meses (OR 1,00; IC del 95%: 0,87 a 1,15), pero redujeron levemente la muerte o el infarto de miocardio a 30 días (OR 0,91; IC del 95%: 0,85 a 0,98) y a los seis meses (OR 0,88; IC del 95%: 0,81 a 0,96), aunque aumentaron la hemorragia grave (OR 1,29; IC del 95%: 1,14 a 1,45; aumento del riesgo absoluto 1,4 por 1000).
Conclusiones de los autores
Cuando se administran durante la intervención coronaria percutánea, los bloqueadores de glucoproteína IIb/IIIa por vía intravenosa reducen el riesgo de la muerte por cualquier causa a 30 días pero no a seis meses, y reducen el riesgo de muerte o infarto de miocardio a 30 días y a seis meses, con el inconveniente de que aumentan el riesgo de hemorragia grave. Los efectos de eficacia son homogéneos, pero son menos marcados en los pacientes que recibieron tratamiento previo con clopidogrel y parecieron ser efectivos sólo en los pacientes con síndrome coronario agudo. Cuando se administra como tratamiento médico inicial en los pacientes con síndromes coronarios agudos sin elevación del segmento ST, estos agentes no reducen la mortalidad, pero reducen levemente el riesgo de muerte o infarto de miocardio.
Resumen en términos sencillos
Bloqueadores de glucoproteína plaquetaria IIb/IIIa durante la intervención coronaria percutánea y como tratamiento médico inicial de los síndromes coronarios agudos
Durante las dos últimas décadas, los médicos han buscado la mejor modalidad de tratamiento para la prevención de la formación de coágulos en las arterias coronarias de pacientes con cardiopatía coronaria. Esta revisión resume los resultados de 60 estudios que usaron una clase potente de fármacos antiplaquetarios intravenosos, los bloqueadores de glucoproteína IIb/IIIa, en 66 689 participantes. Este tratamiento se evaluó en dos afecciones diferentes: en los pacientes sometidos a angioplastia coronaria (inserción de un balón pequeño desinflado en la arteria para luego expandirlo y así abrir el vaso) con o sin la colocación de un stent (un manguito o tubo metálico delgado expandible para abrir la arteria); y como tratamiento inicial de los pacientes hospitalizados por angina inestable e infarto agudo de miocardio sin elevación del segmento ST (dolor torácico coronario prolongado con o sin infarto de miocardio pequeño). Las pruebas están actualizadas a enero de 2013, y la calidad general del cúmulo de pruebas fue buena.
En términos generales, la administración de estos fármacos durante la angioplastia coronaria con o sin la colocación de un stent redujo el riesgo de muerte a 30 días y el riesgo de la muerte o infarto de miocardio a 30 días y a seis meses. Los resultados fueron similares para los pacientes estables e inestables con arteriopatía coronaria, pero se observaron comparativamente menos beneficios para los pacientes que recibieron tratamiento previo con clopidogrel, un nuevo fármaco antiplaquetario oral. Por otro lado, estos fármacos sólo redujeron ligeramente el riesgo de muerte o infarto de miocardio cuando se administraron como tratamiento médico inicial en los pacientes con angina inestable o infarto de miocardio sin elevación del segmento ST. Los beneficios de los bloqueadores de glucoproteína IIb/IIIa deben sopesarse con el riesgo elevado de hemorragia.
Authors' conclusions
Background
Description of the condition
Cardiovascular diseases were the direct cause of more than four million deaths in Europe around the year 2000 (1.9 million in the European Union), accounting for 43% of all deaths at all ages in men and 55% in women. Coronary artery disease (CAD) accounts for half of this mortality burden and depends mostly on the occurrence of acute coronary syndromes (ACS) (ESC Guidelines CV Prevention 2012).
According to the current European and American guidelines, most patients with an ACS should be referred for coronary angiography, as they recommend percutaneous coronary intervention (PCI) as the preferred treatment option for both patients with ST‐segment elevation myocardial infarction (STEMI), and patients with non‐ST elevation ACS (NSTEACS) at moderate to high risk of ischaemic events (ACCF/AHA Guideline NSTEACS 2013; ESC Guidelines NSTEACS 2011). In addition, PCI is the preferred revascularisation technique for patients with stable CAD. As a consequence, the number of PCI procedures is rapidly increasing (ACCF/AHA Guideline revascularization 2012; ESC Guidelines revascularization 2010).
The mechanism of PCI using balloon angioplasty, with or without stent implantation, includes profound vessel injury and plaque rupture, all of which triggers an immediate activation of the coagulation cascade, and adhesion, activation and aggregation of platelets (ACCF/AHA Guideline revascularization 2012; ESC Guidelines revascularization 2010). Pre‐treatment with aspirin, ticlopidine and heparin has been shown to reduce by 70% the risk of acute vessel occlusion and of myocardial infarction in these patients (ATC 2002). Bivalirudin, a new anticoagulant drug that is a direct thrombin inhibitor, has also been shown to have similar efficacy to unfractionated heparin with less bleeding (ACUITY 2006; HORIZONS‐AMI 2008). When a stent is implanted, the addition of clopidogrel instead of ticlopidine, before the procedure and during follow‐up, has also been shown to be of benefit (PCI‐CURE 2001). Thus, treatment with aspirin, clopidogrel and heparin or bivalirudin has been the standard antithrombotic treatment for this procedure (ACCF/AHA Guideline NSTEACS 2013; ESC Guidelines NSTEACS 2011). Recently, new P2Y12 receptor antagonists, like prasugrel and ticagrelor, have been demonstrated to provide quicker, greater and more consistent inhibition of platelet activation than clopidogrel (Patrono 2011), and to decrease the incidence of ischaemic events in patients with ACS submitted for PCI (PLATO 2009; TRITON TIMI‐38 2007).
The pathophysiology of non‐ST segment elevation ACS (NSTEACS), i.e. unstable angina and non‐ST segment elevation myocardial infarction, involves the rupture or erosion of an atherosclerotic coronary plaque (Falk 1995), activation of the coagulation cascade, and adhesion, activation and platelet aggregation. Treatment with aspirin and fractionated or unfractionated heparin has been shown to reduce the risk of cardiac events by 50% in patients with this syndrome (ATC 2002; Mehta 2003). The addition of clopidogrel has also been shown to decrease further the risk of vascular events by 20% in these patients (CURE 2001). Finally, fondaparinux, a new anticoagulant, has been shown to have similar efficacy with less bleeding effects than heparin (OASIS‐5 2006). Thus, the current standard antithrombotic treatment for patients with NSTEACS is the administration of aspirin and clopidogrel with heparin or fondaparinux as recommended in current clinical guidelines (ACCF/AHA Guideline NSTEACS 2013; ESC Guidelines NSTEACS 2011). Also, ticagrelor has been shown to be more effective than clopidogrel in reducing ischaemic events in patients with ACS treated invasively or conservatively (PLATO 2009), while prasugrel has been shown to be effective in patients with NSTEACS treated invasively (TRITON TIMI‐38 2007).
Description of the intervention
The glycoprotein IIb/IIIa integrin present in platelets mediates the final common pathway in platelet aggregation, spawning the development of glycoprotein IIb/IIIa receptor blockers (Phillips 1988). Intravenous glycoprotein IIb/IIIa inhibitors rapidly block up to 80% of the glycoprotein IIb/IIIa platelet receptors and inhibit fibrinogen‐mediated platelet aggregation (Gurbel 2005; Patrono 2011).
The three glycoprotein IIb/IIIa receptor inhibitors approved for clinical use are intravenous agents belonging to different classes: abciximab is a monoclonal antibody fragment; eptifibatide is a cyclic peptide; and tirofiban is a peptidomimetic molecule. All of them have a short half‐life and are eliminated by the kidney, which is the reason why they are only indicated in patients without severe renal impairment (glomerular filtration rate < 30) . Glycoprotein IIb/IIIa receptor inhibitors have been shown to be effective in reducing ischaemic events in patients undergoing PCI (ACCF/AHA Guideline revascularization 2012; ESC Guidelines revascularization 2010), while tirofiban, lamifiban and eptifibatide have been tested as initial medical treatment in patients with NSTEACS (ACCF/AHA Guideline NSTEACS 2013; ESC Guidelines NSTEACS 2011). Current guidelines give a class IIa recommendation to these drugs for their administration during PCI with a level of evidence B (data derived from a single randomised clinical trial or large non‐randomised studies) (ACCF/AHA Guideline NSTEACS 2013; ACCF/AHA Guideline revascularization 2012; ESC Guidelines NSTEACS 2011; ESC Guidelines revascularization 2010).
How the intervention might work
In patients submitted for PCI and also in patients presenting with a NSTEACS, intravenous glycoprotein IIb/IIIa blockade induces strong platelet inhibition (Gurbel 2005; Patrono 2011) and may prevent mural and intraluminal thrombus formation. This effect can prevent acute coronary occlusion and embolisation of plaque thrombi to the distal microvasculature resulting in acute myocardial infarction and death.
Why it is important to do this review
In spite of their known effects in preventing myocardial infarction, some doubts remain as to the efficacy of these drugs in decreasing mortality, the homogeneity of their effects in different subgroups of patients or PCI techniques used, and their additional benefit when patients are pre‐treated with clopidogrel (NICE 2010). In addition, since glycoprotein IIb/IIIa receptor blockers induce profound platelet inhibition, the risk of bleeding complications is increased, particularly when administered concomitantly with other antiplatelet drugs and with high‐dose heparin treatment (Quinn 2002). Thus, safety is an important issue in the management of patients with these drugs, especially during PCI.
This is an update of a Cochrane review first published in the year 2001, and previously updated in 2007 and in 2010. In the last update, the main conclusion was that when administered during PCI, intravenous IIb/IIIa blockers reduce the risk of all‐cause death and of death or myocardial infarction at 30 days and at six months, but increase the risk of severe bleeding. In contrast, when administered as initial medical treatment in patients with NSTEACS, these drugs do not reduce all‐cause mortality, slightly reduce the risk of death or myocardial infarction, and increase the risk of severe bleeding.
In the last three years, several studies have been performed with these drugs in the setting of PCI or in patients presenting with NSTEACS (ASSIST 2009; Bhattacharya 2010; INSTANT 2012; ITTI 2012; Yan 2009), while information on other small studies has become available (DANTE 2004; De Luca 2005; De Luca 2008; Gasior 2003; Kim 2005; Kurowski 2005; Prati 2005). In addition, higher doses of clopidogrel as a loading dose (i.e. 600 mg) to achieve a more rapid and potent antiplatelet effect are being used, and new anticoagulant drugs (i.e. bivalirudin and fondaparinux, OASIS‐5 2006) have been incorporated in the usual medical treatment of patients with ACS and patients referred for PCI (ACCF/AHA Guideline NSTEACS 2013; ESC Guidelines NSTEACS 2011). Since the efficacy of intravenous IIb/IIIa blockers and risk of bleeding could be different with higher doses of clopidogrel, and in the presence of these new drugs, an update of this systematic review is justifiable.
Objectives
The aim of this systematic review was to assess the efficacy and safety effects of glycoprotein IIb/IIIa blockers given in addition to standard medical treatment when administered:
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during PCI;
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as the initial medical treatment of patients with NSTEACS ('upstream treatment').
The first indication relates to a procedure rather than a health problem, where the studied treatment is administered a few minutes prior to PCI. The second indication relates to a clinical condition that includes a wide range of patient groups at different risk, where the studied treatment is administered at admission in patients with or without coronary angiography and PCI during hospitalisation. Both questions are addressed in the same review to better understand the efficacy of IIb/IIIa antagonists in patients undergoing PCI, including in patients with stable ischaemic heart disease and in patients with acute coronary syndromes with or without ST‐segment elevation. The standard medical treatment considered was aspirin and ticlopidine or clopidogrel, plus heparin or bivalirudin during PCI; and aspirin with or without clopidogrel, and heparin or fondaparinux in the initial medical treatment of patients with NSTEACS.
Methods
Criteria for considering studies for this review
Types of studies
We sought to identify all randomised controlled clinical trials, with or without blinding, studying intravenous glycoprotein IIb/IIIa blockers and in which at least one of the pre‐defined primary outcomes was measured. Specifically, we analysed trials performed when IIb/IIIa blockers were administered during PCI in patients with or without an ACS, and trials performed in patients with NSTEACS treated from admission with glycoprotein IIb/IIIa antagonists as the initial medical management.
We did not consider trials:
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on oral glycoprotein IIb/IIIa blockers, since clinical research has indicated that their administration is associated with increased mortality, and they are not available for clinical use;
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performed in patients with ST‐segment elevation acute myocardial infarction (STEMI) treated with thrombolytics or with facilitated or rescue PCI after thrombolytic treatment;
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comparing two different glycoprotein IIb/IIIa blockers;
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comparing the timing of the glycoprotein IIb/IIIa blockers administration (i.e. pre‐hospital administration versus hospital administration or administration in the emergency room versus in the catheterisation laboratory); or
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comparing the route of administration (i.e. intracoronary versus intravenous).
Types of participants
The following participants were considered for each of the two types of studies that we considered in this review:
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Studies that randomised adults (18 years and older), male or female, with or without an acute coronary syndrome, who underwent elective or urgent PCI, with or without stent implantation.
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Studies that included adult patients with NSTEACS in whom glycoprotein IIb/IIIa antagonists were administered at the time of hospital admission as part of the initial medical management.
For both indications there were no exclusion criteria regarding patients' comorbidities, the presence of renal dysfunction or the risk of bleeding.
Types of interventions
Intravenous glycoprotein IIb/IIIa blockers administered as a bolus followed by 12 to 96 hours infusion, at any dose, on top of usual care (aspirin and ticlopidine or clopidogrel, and heparin or bivalirudin).
Comparators
A control group with or without placebo, on top of usual care (aspirin and ticlopidine or clopidogrel, and heparin or bivalirudin).
For every major endpoint, two subgroup analyses have been performed in the PCI group:
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glycoprotein IIb/IIIa blockers compared with placebo (double‐blind studies) on top of usual care;
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glycoprotein IIb/IIIa blockers compared with usual care (not blinded studies).
Types of outcome measures
Primary outcomes
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All‐cause mortality at 30 days and at six months.
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All‐cause death or non‐fatal myocardial infarction at 30 days and at six months.
All‐cause mortality was chosen instead of cardiovascular mortality or fatal myocardial infarction because although most deaths occurring early after an ACS or a PCI procedure are due to fatal myocardial infarction, total mortality does not depend on physician interpretation of the cause. In addition, in all of the reviewed studies total mortality was considered.
The combined endpoint of all‐cause death or myocardial infarction was chosen because most deaths occurring early after a NSTEACS or a PCI procedure are due to an acute coronary occlusion leading to a myocardial infarction.
Because definitions of myocardial infarction may vary among studies, especially in those performed during PCI, when the data were obtainable we used as a definition of post‐procedural myocardial infarction an elevation more than three times the upper limit of normal of the biomarker of necrosis used (creatine kinase‐MB fraction (CK‐MB) or cardiac troponins) occurring within 48 hours of the procedure. Spontaneous or non‐post‐procedural myocardial infarction was defined in the presence of signs or symptoms of ischaemia not related to or appearing more than 48 hours after a PCI procedure and with elevation more than two times the upper limit of normal of the biomarker used to assess of necrosis.
Secondary outcomes
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Need for an urgent revascularisation procedure at 30 days and at six months for patients who underwent PCI.
Urgent revascularisation was chosen as a secondary endpoint as this is a consequence of refractory ischaemia and because its indication is often clinician‐driven and, in consequence, not entirely objective.
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All‐cause death, non‐fatal myocardial infarction or urgent coronary revascularisation at 30 days and at six months.
All of the components of this combined endpoint share the same pathophysiology (i.e. acute vessel occlusion) also as a secondary endpoint.
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Safety: severe bleeding at 30 days.
This was the most important safety outcome that was appropriately described in all studies. To decrease definition variability (Steinhubl 2007) and wherever reported, the Thrombolysis In Myocardial Infarction (TIMI) classification was used to define severe bleeding (Bovill 1991); the investigators' definition was used otherwise.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (2012, Issue 12), MEDLINE OVID (1946 to January Week 1 2013) and EMBASE Classic + EMBASE OVID (1947 to 2013 Week 01) on 11 January 2013. We checked and revised search strategies for the updates. See Appendix 1; Appendix 2; Appendix 3 and Appendix 4 for details of the search strategies. We loaded all records into Reference Manager and removed duplicates (see Acknowledgements).
Searching other resources
We carried out handsearches (to January 2013) of abstracts from conferences published in Circulation (American Heart Association Annual Meeting), Journal of the American College of Cardiology (American College of Cardiology Foundation Annual Congress), European Heart Journal (European Society of Cardiology Annual Congress) and online at Theheart.org, TIMI.org. We also searched Clinicaltrials.org. We also examined the references sections of reviews and meta‐analysis addressing glycoprotein IIb/IIIa inhibitors.
No language restrictions were applied to the search. English, French and Spanish language papers were read by the authors. The Cochrane Heart Group helped us by translating two Chinese articles (see Acknowledgements). All published studies could be retrieved from the bibliographic search.
Data collection and analysis
Selection of studies
Two authors screened and independently extracted results. A paper was rejected only when both review authors agreed that the article did not meet the inclusion criteria. Two review authors scored each manuscript independently using a pre‐designed in/out form. Each manuscript was scored 1 (definitely 'in', i.e. the study met the inclusion criteria); 2 (maybe 'in', i.e. small sample size or difficult to determine the type of control or of diagnosis); or 3 (definitely 'out', i.e. definitely did not meet the inclusion criteria). All manuscripts which scored at least one '1' or one '2' were analysed in common by both review authors.
Data extraction and management
Two authors independently extracted data from original reports of trial results and resolved differences by discussion. We abstracted data on characteristics of participants (age, sex, presence of diabetes, prior myocardial infarction, ACS and type), interventions (PCI and type, stent and type, pre‐treatment with clopidogrel), outcomes, trial quality characteristics (i.e. sequence generation, allocation concealment, blinding, incomplete outcome report, incomplete data addressing, selective reporting and other) onto this form. In addition, we collected data on potential confounding factors including participants' baseline risk and characteristics, trial duration, intensity of intervention (dosing and duration of treatment), type and dose of concomitant medication used and revascularisation procedures including stent implantation.
Assessment of risk of bias in included studies
Two authors independently assessed risk of bias in the included studies using The Cochrane Collaboration's 'Risk of bias' tool (Higgins 2011). We created a 'Risk of bias' table for each study by adding the degree of bias for the primary and secondary endpoints according to sequence generation, allocation concealment, blinding, incomplete outcome report, incomplete data addressing, selective reporting and other.
In addition, we further analysed the risk of bias by including two tables with the summary assessment of the risk of bias for major and minor endpoints (across key domains) within and across studies. We selected allocation concealment and blinding as the key domains for this analysis.
Only the effect of the intravenous route of administration (i.e. bolus plus infusion) was examined and compared with placebo/control with usual care (i.e. aspirin, ticlopidine/clopidogrel and heparin). To prevent attrition bias, we analysed all patients allocated to active treatment in this group regardless of whether they received it or not (i.e. intention‐to‐treat analysis). We used intention‐to‐treat data in the pooled analyses of this review as it was possible to obtain them from the publications of all the studies.
Data synthesis
We calculated pooled odds ratio (OR) of the individual and combined endpoints. Fixed‐effect meta‐analyses are presented unless a Chi2 test for heterogeneity was statistically significant at a 5% level, in which case random‐effects meta‐analyses are presented. We calculated risk differences after pooling together the studies for each meta‐analysis.
Subgroup analysis and investigation of heterogeneity
In the analysis of the effects of glycoprotein IIb/IIIa blockers administered during PCI, we performed six separate subgroup analyses:
1. According to the clinical condition of the patients:
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Stable coronary artery disease in which PCI was performed as an elective procedure
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NSTEACS
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Primary PCI in patients with STEMI
2.The technique used:
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Balloon angioplasty alone
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PCI with stent implantation
3. Pre‐treatment with clopidogrel
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Patients with ACS
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Patients without ACS
For all subgroup analyses we selected studies in which at least two‐thirds of patients had the focused condition or procedure. For the analysis of patients pre‐treated with clopidogrel and according to the known dose‐related onset of action of this drug (Hochholzer 2005), we selected only trials in which patients were receiving chronic clopidogrel treatment (five days or more), and trials in which a loading dose of 300 mg was administered at least six hours before the procedure or 600 mg at least two hours before the procedure.
We assessed heterogeneity of studies by clinical judgement according to differences in type of patients enrolled, study quality, interventions and outcome. We also evaluated funnel plots for every major endpoint.
Sensitivity analysis
In the PCI meta‐analysis, we made two different analyses in the overall group according to the presence or absence of a high risk of bias for the primary endpoint of the review. Group 1 were studies at low to intermediate risk of bias (i.e. comparison with placebo, double‐blind and with adequate allocation concealment); and Group 2 were studies at high risk of bias (i.e. comparison with usual care, without placebo and not blinded). We made a sensitivity analysis by comparing the results for each group and for the two groups together.
Results
Description of studies
Results of the search
The search strategy was designed to be very sensitive and yielded 4106 documents from the original and the 2007, 2010 and 2013 updates of the review. We screened all references from relevant reviews and meta‐analyses (see Additional references) for studies possibly missed by our search strategy. In total 184 articles were retrieved for further examination; 20 of these were from the current update. One hundred and two references to 92 studies were excluded (see Characteristics of excluded studies). Thirteen new RCTs were identified from the current update. The previous version of the review included 48 RCTs so that in total 60 trials (66,689 participants) were included in the review. Of these, 48 trials (33,513 participants) were on glycoprotein IIb/IIIa blockers administered during PCI, and 12 trials (33,176 participants) tested these drugs as initial medical treatment in patients with NSTEACS (Figure 1).
Study flow diagram.
Included studies
The three glycoprotein IIb/IIIa receptor inhibitors approved for clinical use are intravenous agents that belong to different classes: abciximab is a monoclonal antibody fragment; eptifibatide is a cyclic peptide; and tirofiban is a peptidomimetic molecule.
Most of the studies were multicentre, international studies and were performed mostly in North America and Europe, Canada, the Netherlands, France, Belgium, Germany, Spain, Poland and Italy. An important number were also performed in south American countries, Australia, New Zealand and the Czech Republic. Only eight studies were performed in low to middle‐income countries (ASIAD 2005; Bhattacharya 2010; Chen 2000; Fu 2008; ITTI 2012; Kim 2005; Shen 2008; Yan 2009).
During percutaneous coronary intervention
These studies were performed in stable or unstable coronary patients undergoing elective or urgent PCI with or without stent implantation, and IIb/IIIa blockers were administered during the procedure. In all the studies performed during elective PCI, randomisation was performed when the exact coronary anatomy was known and inclusion criteria required the presence of one or more > 70% stenosis in a coronary segment amenable to PCI.
Most of the studies excluded patients with renal dysfunction, since this condition is associated with excess dosing, and those at high risk of bleeding.
PCI was the condition studied in 48 studies with 33,513 patients. Forty‐four studies reported outcomes at 30 days while 34 studies reported outcomes at 6 to 12 months.
Among the 48 studies and according to the clinical condition of the patients, there were 18 studies in patients with stable CAD, seven studies in patients with NSTEACS and 11 studies performed during primary PCI in patients with ST‐segment elevation myocardial infarction (STEMI); the other 12 studies were performed in a mixed population. According to the technique used, there were 11 studies performed during balloon angioplasty (10 of them performed before year 2000), 33 during PCI with stent implantation and four with mixed techniques. Finally, 17 studies including 8925 patients were performed in patients pre‐treated with clopidogrel, three in patients with NSTEACS (ISAR‐REACT 2 2006; Kurowski 2005; Yan 2009), six in patients with STEMI (ASSIST 2009; BRAVE‐3 2009; Fu 2008; ITTI 2012; On‐TIME 2004; Shen 2008) and eight in patients with stable CAD (3T/2R 2009; Claeys 2005; Cuisset 2008; INSTANT 2012; ISAR‐REACT 2004; ISAR‐SWEET 2004; ISAR‐SMART‐2 2004; OPTIMIZE‐IT 2009; TOPSTAR 2002).
All patients included in trials with stent implantation received heparin, aspirin and ticlopidine or clopidogrel during and after the procedure except for the ERASER 1999 study in which ticlopidine was left to the investigator's discretion. In only two studies (CLEAR PLATELETS‐2 2009; OPTIMIZE‐IT 2009) a drug‐eluting stent was used in most of the patients. Abciximab was used in 28 trials, tirofiban in 13 and eptifibatide in seven. The doses varied among studies.
As initial medical treatment of patients with non‐ST segment elevation acute coronary syndromes
These studies were performed in patients with a recent (< 24 hours) chest pain at rest associated with ischaemic changes in the admission ECG (ST‐segment depression > 0.5 mm or transient elevation > 1 mm, > 1 mm T‐wave inversion) or CK‐MB or troponin elevation above the upper limits of normality in each participant institution. Most of these trials were performed in patients managed conservatively. All of the studies excluded patients with moderate to severe renal dysfunction and those at high risk of bleeding
Twelve studies with 33,176 patients concerned glycoprotein IIb/IIIa use as initial medical treatment in patients with NSTEACS. All these studies presented 30‐day follow‐up results and six presented six months follow‐up. Abciximab was used in one study, eptifibatide in three, tirofiban in five and lamifiban in three. No subgroup analyses were performed since all of the studies included patients with the same global condition.
PRISM 1998 differed from the other trials in that the glycoprotein IIb/IIIa blocker was given without heparin. PRISM Plus 1998 and PARAGON A 1998 also included an arm with glycoprotein IIb/IIIa blocker without heparin. Seven studies were performed following a conservative management while only three (ELISA‐2 2006; PRACTICE 2007; PRISM Plus 1998) were performed on an invasive basis with most of the patients scheduled for early coronary angiography.
Variability
The potential sources of heterogeneity among the studies may include the variability in patient characteristics. In the PCI group the mean age ranged from 59 years to 70 years with a median of 61 years, while in the group of studies on initial medical treatment of NSTEACS the mean age ranged from 60 to 65 years. Considering all studies, the proportion of males ranged from 61% to 95%, and the proportion of patients with prior myocardial infarction, which was described in most studies, ranged from 10% to 67% (see Characteristics of included studies table).
In the PCI analysis, 12 trials were performed in patients with STEMI, 11 of them during primary PCI. The frequency of this diagnosis was of 0% in 26 other studies and ranged from 3% to 41% in the other 11 trials. A specific analysis of those 11 trials has been performed.
In the analysis of glycoprotein IIb/IIIa blockers administered as initial medical treatment in patients with NSTEACS, the prevalence of positive markers of myocardial necrosis ranged from 14% to 100%. Thirty‐two to 80% of patients had ST‐segment depression at enrolment. Nine studies were performed following a conservative management with less than 14% of patients having in‐hospital PCI. In the other three studies, coronary angiography was performed in 60% to 90% of patients, and PCI from 31% to 61% of patients during drug infusion which was administered for 24 to 72 hours after enrolment.
The daily doses of aspirin ranged in the studies from 50 mg to 500 mg and those of heparin were typically aimed at maintaining an activated clotting time of > 200 seconds or an activated partial thromboplastin time between 50 and 85 seconds, or twice that of laboratory control. Only in one study (Schulman 1996) was aspirin not allowed in the treatment group but administered in the placebo group.
Some studies had arms of active treatment with lower heparin doses (EPILOG 1997) or no heparin at all (PARAGON A 1998; PRISM Plus 1998; PRISM 1998). All patients from these studies were included in the present update since a prior meta‐analysis performed with individual patient data reported similar results by including or excluding those patients (Boersma 2002). Patients from the control groups of all studies received heparin.
Dosing
Where trials had intervention arms with varying doses of glycoprotein IIb/IIIa inhibitor drugs, data from such intervention arms were pooled. In the EPIC 1994 study, one intervention arm had glycoprotein IIb/IIIa blocker administered as a bolus alone, i.e. with no subsequent perfusion; the results of that arm were not included.
Endpoints
All studies followed more than 95% of patients at 30 days and more than 90% at six months. In general the methodological quality of the 60 selected RCTs was good, but differed in PCI and non‐PCI studies. Ten of the 49 PCI trials were considered to be at high risk of bias (Table 1). However, these 10 studies with 3863 participants represented only 11.5% of the total and have been studied separately in this review for each major endpoint. In contrast, among studies on IIb/IIIa blockers administered as initial medical treatment in patients with NSTEACS, only one small study was considered to have a high risk of bias (Table 2)
| Study | N | 30‐day mortality | 6‐month mortality | 30‐day death or MI | 6‐month death or MI | Major bleeding | Within study |
| EPIC 1994 | 2099 | Low | Low | Low | Low | Low | Low |
| Simoons 1994 | 60 | Low | NA | Low | NA | Low | Low |
| IMPACT 1995 | 150 | Low | NA | Low | NA | Unclear | Low |
| Kereiakes 1996 | 93 | Low | NA | Low | NA | Low | Low |
| RESTORE 1997 | 2141 | Low | Low | Low | Low | Low | Low |
| IMPACT‐II 1997 | 4010 | Low | NA | Low | NA | Low | Low |
| EPILOG 1997 | 2792 | Low | Low | Low | Low | Low | Low |
| CAPTURE 1997 | 1265 | Low | Low | Low | Low | Low | Low |
| EPISTENT 1998 | 2399 | Low | Low | Low | Low | Low | Low |
| RAPPORT 1998 | 483 | Low | Low | Low | Low | Low | Low |
| ERASER 1999 | 215 | Low | Low | Low | Low | Low | Low |
| Galassi 1999 | 106 | High | NA | High | NA | High | High |
| Chen 2000 | 42 | Unclear | NA | Unclear | NA | Unclear | Unclear |
| ESPRIT 2000 | 2064 | Low | Low | Low | Low | Low | Low |
| ISAR‐2 2000 | 401 | Unclear | NA | High | NA | High | High |
| PRIDE 2001 | 127 | Unclear | NA | Unclear | NA | Unclear | Unclear |
| ADMIRAL 2001 | 300 | Low | Low | Unclear | Unclear | Unclear | Unclear |
| Tamburino 2002 | 107 | High | High | High | High | High | High |
| TOPSTAR 2002 | 96 | Low | Low | Unclear | Unclear | Unclear | Unclear |
| Juergens 2002 | 894 | Low | Low | Low | Unclear | Unclear | Unclear |
| CADILLAC 2002 | 2082 | Low | Low | High | High | High | High |
| ACE 2003 | 400 | High | High | High | High | High | High |
| Gasior 2003 | 41 | Unclear | Unclear | Unclear | Unclear | Unclear | Unclear |
| ADVANCE 2004 | 202 | Low | Low | Unclear | Unclear | Unclear | Unclear |
| DANTE 2004 | 96 | Low | Low | Low | Low | Unclear | Low |
| ISAR SMART‐2 2004 | 502 | NA | Low | NA | Low | Low | Low |
| ISAR‐REACT 2004 | 2159 | Low | Low | Low | Low | Low | Low |
| ISAR‐SWEET 2004 | 701 | Low | Low | Low | Low | Low | Low |
| Claeys 2005 | 200 | Unclear | Unclear | High | High | High | High |
| ASIAD 2005 | 254 | Low | Low | Unclear | Unclear | Unclear | Unclear |
| De Luca 2005 | 122 | NA | Unclear | NA | Unclear | NA | Unclear |
| Kurowski 2005 | 50 | Low | Low | Unclear | Unclear | NA | Unclear |
| Prati 2005 | 140 | NA | NA | Unclear | NA | NA | Unclear |
| ISAR‐REACT 2 2006 | 2022 | Low | Low | Low | Low | Low | Low |
| FU 2008 | 150 | NA | Unclear | NA | Unclear | Unclear | Unclear |
| Cuisset 2008 | 149 | Low | NA | High | NA | High | High |
| Shen 2008 | 172 | Unclear | Unclear | High | High | High | High |
| On‐TIME 2 2008 | 984 | Low | NA | Low | NA | Low | Low |
| De Luca 2008 | 132 | Low | Low | Low | Low | Low | Low |
| OPTIMIZE‐IT 2009 | 46 | Low | Low | High | High | High | High |
| JEPPORT 2009 | 973 | Low | NA | Low | NA | Low | Low |
| CLEAR PLATELETS‐2 2009 | 200 | Low | Low | High | High | High | High |
| BRAVE‐3 2009 | 800 | Low | NA | Low | NA | Low | Low |
| 3T/2R 2009 | 263 | Low | NA | Low | NA | Low | Low |
| ASSIST 2009 | 400 | Low | Low | Low | Low | Low | Low |
| Yan 2009 | 240 | Low | Low | Low | Low | Unclear | Low |
| INSTANT 2012 | 91 | NA | Low | NA | Unclear | Unclear | Unclear |
| ITTI 2012 | 100 | NA | Low | NA | Unclear | Unclear | Unclear |
| ACROSS STUDIES | 33,474 | Low | Low | Unclear | Unclear | Unclear |
Allocation concealment and blinding were the 2 selected key domains.
Bias for each endpoint: NA: Not applicable; Low: Plausible bias unlikely to seriously alter the results; Unclear: Plausible bias that raises some doubt about the results; High: Plausible bias that seriously weakens confidence in the results.
Bias within a study: Low: Low risk of bias for all key domains; Unclear: Unclear risk of bias for one or more key domains; High: High risk of bias for one or more key domains.
Bias across studies: Low: Most information is from studies at low risk of bias; Unclear: Most information is from studies at low or unclear risk of bias; High: The proportion of information from studies at high risk of bias is sufficient to affect the interpretation of the results.
| Study | N | 30‐day mortality | 6‐month mortality | 30‐day death or MI | 6‐month death or MI | Major bleeding | Within study |
| CANADIAN 1996 | 365 | Low | NA | Low | NA | Low | Low |
| Schulman 1996 | 227 | Low | NA | Low | NA | Low | Low |
| PURSUIT 1998 | 10,948 | Low | Low | Low | Low | Low | Low |
| PRISM 1998 | 3232 | Low | NA | Low | NA | Low | Low |
| PARAGON A 1998 | 2282 | Low | Low | Low | Low | Low | Low |
| PRISM Plus 1998 | 1915 | Low | Low | Low | Low | Low | Low |
| GUSTO‐IV 2001 | 7800 | Low | NA | Low | NA | Low | Low |
| PARAGON B 2002 | 5225 | Low | NA | Low | NA | Low | Low |
| Kim 2005 | 160 | Low | Low | Unclear | Unclear | Unclear | Unclear |
| ELISA‐2 2006 | 328 | Low | NA | High | NA | High | High |
| PRACTICE 2007 | 393 | Low | Low | Low | Low | Low | Low |
| Bhattacharya 2010 | 301 | Unclear | NA | Unclear | NA | Unclear | Unclear |
| ACROSS STUDIES | 33,176 | Low | Low | Low | Low | Low |
Allocation concealment and blinding were the 2 selected key domains.
Bias for each endpoint: NA: Not applicable; Low: Plausible bias unlikely to seriously alter the results; Unclear: Plausible bias that raises some doubt about the results; High: Plausible bias that seriously weakens confidence in the results.
Bias within a study: Low: Low risk of bias for all key domains; Unclear: Unclear risk of bias for one or more key domains; High: High risk of bias for one or more key domains.
Bias across studies: Low: Most information is from studies at low risk of bias; Unclear: Most information is from studies at low or unclear risk of bias; High: The proportion of information from studies at high risk of bias is sufficient to affect the interpretation of the results.
We pooled three studies describing endpoints occurring within follow‐up periods shorter than 30 days (i.e. in‐hospital, seven‐day, etc.) with 30‐day follow‐up studies (ERASER 1999; Kereiakes 1996; Simoons 1994) due to the fact that most adverse events occur within the first week after the procedure. Also, one study (ADVANCE 2004) that only reported events at six months was also included in the 30‐day follow‐up analysis in order not to miss important information, on the basis that > 80% of mortality and myocardial infarction and > 95% of severe bleeding occurred during the first 30 days. Finally, we pooled three studies (ISAR‐REACT 2004; ISAR‐REACT 2 2006; ISAR‐SMART‐2 2004) that reported one‐year follow‐up alone with the six‐month follow‐up analysis for the same reason.
The definition of primary and secondary outcomes varied among studies. However, it was possible to obtain or calculate the number of cases with the primary and secondary endpoints of this review in most studies. Myocardial infarction was part of the composite effectiveness endpoint of all trials, but the applied myocardial infarction definition was different, especially regarding the increased levels of the MB fraction of creatine kinase required in studies performed before the year 2005 and of troponin levels thereafter. This point was especially important regarding the definition of post‐PCI myocardial infarction. Because of this, and when data were obtainable, we used as a definition of post‐procedural myocardial infarction an elevation more than three times the upper limit of normal of the biomarker of necrosis used (creatinine kinase‐MB fraction (CK‐MB) or cardiac troponins).
The secondary endpoint 'major bleeding' was assessed by the Thrombolysis In Myocardial Infarction (TIMI) classification when described (bleeding was classified as major if it involved intracranial haemorrhage or cardiac tamponade or if it was associated with a decrease in haemoglobin concentration of more than 50 g/L regardless of whether or not a bleeding site had been identified (Bovill 1991). Otherwise, we used the 'major' bleeding described in each study. When no description of major bleeding existed at all, we selected intracranial haemorrhages and need for transfusion as 'major' bleeding.
In some instances, it was not specified whether the nature of PCI during follow‐up was urgent or not. In such cases, we considered overall revascularisations.
Excluded studies
Most of the excluded studies were not RCTs, did not compare a IIb/IIIa blocker with placebo or control, did not report clinical events or were performed in conditions other than during PCI or as initial medical treatment of patients with NSTEACS (Figure 1; see Characteristics of excluded studies).
Risk of bias in included studies
It is important to note that most of the trials excluded patients at high risk of bleeding and patients with renal failure. In addition, the mean age of the studied population was lower (61 years) than what it is usually observed in clinical practice (CRUSADE 2006; GRACE 2007).
Allocation
Reporting of adequate sequence generation was obtained in 70% of the studies and adequate allocation concealment in 54% of them. Only in 10% of the studies was the allocation concealment inadequate (or considered to be at high risk of bias (Higgins 2011) (Figure 2; Figure 3).
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Blinding
Patients and clinicians were adequately blinded to treatment (Higgins 2011) in most of the trials. Some studies were performed on an open‐label basis while in others (Claeys 2005; ISAR‐2 2000) the treatment strategy precluded blinding of the used drugs. Overall, for the primary endpoint of the review, blinding of patients and investigators was adequate in 55% of the studies, unclear in 15% and inadequate in 30% of them. For the secondary endpoints, blinding was adequate in 50%, unclear in 15% and inadequate in 35% (Figure 2; Figure 3).
Regarding allocation concealment and blinding as the two major key domains, the risk of bias across PCI studies was low for mortality and unclear for death or myocardial infarction, and for major bleeding (Table 1). In studies performed with the use of IIb/IIIa blockers as initial medical treatment in patients with NSTEACS, the risk of bias across studies was low for every major endpoint (Table 2).
Incomplete outcome data
Outcome data for the primary endpoint was adequately addressed (Higgins 2011) in 85% of the studies and for the secondary endpoints in 80% of them (Figure 2; Figure 3)
Selective reporting
Eighty‐five per cent of the studies were free of suggestion of selective outcome reporting (Higgins 2011) (Figure 2).
Other potential sources of bias
Almost all studies were industry funded, enhancing the risk of bias (Als‐Nielsen 2003; Higgins 2011). In fact, only 30% of them were apparently free of other problems that could put them at a risk of bias. We considered 50% of the studies to have an unclear risk of other sources of bias and 20% were at high risk because of the relationship between investigators and industry, premature stopping of the study or other reasons (Figure 2; Figure 3).
Effects of interventions
1. Glycoprotein IIb/IIIa blockers during percutaneous coronary intervention (PCI)
Primary endpoints
Of the 48 PCI trials with 33,513 participants, data from 43 trials with 31,744 patients (95%) were available on 30‐day mortality, and 44 trials with 31,880 participants on 30‐day mortality or myocardial infarction. Twenty‐eight of these trials with 27,205 patients (86%) were blinded studies with a placebo group and considered to be at low risk of bias. Six‐month data on mortality and on mortality or myocardial infarction were available from 33 trials with 24,845 patients (74%), of which 20 trials (20,329 patients) were blinded and at low risk of bias (Table 2).
All‐cause mortality
Mortality occurred in 0.92% of patients in the treatment group versus 1.33% in controls at 30 days, and in 2.44% and 2.94% respectively at six months. Treatment with intravenous glycoprotein IIb/IIIa blockers was associated with a significant reduction in the odds of mortality at 30 days (odds ratio (OR) 0.79, 95% confidence interval (CI) 0.64 to 0.97). The results were homogeneous (I2 = 0%) and similar for blinded (0.78, 95% CI 0.61 to 1.00) and unblinded studies (0.81, 95% CI 0.54 to 1.21); Analysis 1.1 and Figure 4. The absolute risk reduction (ARR) per thousand treated patients was of 4.0 and the number needed to treat (NNT) to save a life was 249. The results were also similar for all the different subgroups that were considered according to the clinical condition of the patients (Analysis 2.1; Analysis 3.1; Analysis 4.1) and the technique used (Analysis 5.1; Analysis 6.1), although they were less marked for patients pre‐treated with clopidogrel (OR 0.83, 95% CI 0.57 to 1.20; Analysis 7.1; Table 3).
Funnel plot of comparison: 1 During PCI (all patients), outcome: 1.1 30‐day mortality.
| Intervention | 30‐day mortality | 6‐month mortality | 30‐day death or non‐fatal MI | 6‐month death or non‐fatal MI |
| OR (95% CI) | OR (95% CI) | OR (95% CI) | OR (95% CI) | |
| 1. During PCI (all patients) | 0.79 (0.64 to 0.97) | 0.90 (0.77 to 1.05) | 0.66 (0.60 to 0.72) | 0.75 (0.64 to 0.86) |
| 1.1. Subgroup analysis by patient's condition | ||||
| Patients with stable CAD | 0.71 (0.34 to 1.46) | 0.88 (0.63 to 1.22) | 0.68 (0.55 to 0.84) | 0.77 (0.64 to 0.92) |
| Patients with NSTEACS | 0.77 (0.46 to 1.28) | 1.01 (0.74 to 1.38) | 0.68 (0.56 to 0.83) | 0.77 (0.65 to 0.92) |
| Primary PCI in patients with STEMI | 0.88 (0.64 to 1.21) | 0.88 (0.68 to 1.15) | 0.78 (0.61 to 1.00) | 0.77 (0.51 to 1.16) |
| 1.2. Subgroup analysis by technique | ||||
| Balloon angioplasty | 0.79 (0.55 to 1.14) | 1.06 (0.75 to 1.50) | 0.65 (0.56 to 0.75) | 0.78 (0.65 to 0.94) |
| PCI with stent placement | 0.78 (0.58 to 1.04) | 0.87 (0.71 to 1.07) | 0.67 (0.59 to 0.76) | 0.72 (0.60 to 0.87) |
| 1.3. Subgroup analysis by pre‐treatment with clopidogrel | 0.83 (0.57 to 1.20) | 0.95 (0.75 to 1.21) | 0.81 (0.67 to 0.98) | 0.87 (0.66 to 1.14) |
| Patients with ACS | 0.84 (0.56 to 1.25) | 0.97 (0.72 to 1.31) | 0.77 (0.61 to 0.96) | 0.77 (0.46 to 1.27) |
| Patients without ACS | 0.78 (0.29 to 2.09) | 0.92 (0.63 to 1.35) | 0.91 (0.65 to 1.28) | 0.94 (0.73 to 1.21) |
| 2. As initial medical treatment of NSTEACS | 0.90 (0.79 to 1.02) | 1.00 (0.87 to 1.15) | 0.91 (0.85 to 0.98) | 0.88 (0.81 to 0.96) |
| MI, myocardial infarction; PCI, percutaneous coronary intervention; CAD, coronary artery disease; NSTEACS, non‐ST segment elevation acute coronary syndrome; STEMI, ST‐segment elevation acute myocardial infarction; ACS, acute coronary syndromes; OR, odds ratio; CI, confidence interval | ||||
However, at six months treatment with glycoprotein IIb/IIIa inhibitors was not associated with a reduction of mortality in the overall group (OR 0.90, 95% CI 0.77 to 1.05, I2 = 0%; Analysis 1.2; Figure 5) and in each subgroup; Table 3).
Funnel plot of comparison: 1 During PCI (all patients), outcome: 1.2 6‐month mortality.
All‐cause death or myocardial infarction
The rate of death or myocardial infarction at 30 days and six months was of 5.05% versus 7.44% and 7.45% versus 10.05% in the treatment and control groups respectively. Glycoprotein IIb/IIIa blockers were associated with a significant decrease in the odds of death or myocardial infarction at 30 days (OR 0.66, 95% CI 0.60 to 0.72, P < 0.00001; I2 = 22%) without significant differences between blinded and unblinded studies (Analysis 1.3; Figure 6). The ARR per thousand treated patients was of 23.9 and the NNT was 42. The results were similar in all subgroups but were less marked in patients pre‐treated with clopidogrel (OR 0.81, 95% CI 0.67 to 0.98), especially in patients without ACS (OR 0.91, 95% CI 0.65 to 1.28; Analysis 7.3; Table 3).
Funnel plot of comparison: 1 During PCI (all patients), outcome: 1.3 30‐day mortality or myocardial infarction.
The results at six months showed marked heterogeneity (I2 = 47%) but were similar to those obtained at 30 days (OR 0.75, 95% CI 0.64 to 0.86, P < 0.0001; Analysis 1.4). The ARR per thousand treated patients was of 26.0 and the NNT was 39. Again, the results were similar in all the subgroups of patients considered in the review but were less marked for patients pre‐treated with clopidogrel (OR 0.87, 95% CI 0.66 to 1.14; Analysis 7.4; Table 3).
Secondary endpoints
Data on urgent coronary revascularisation and the combined endpoint of death, myocardial infarction or urgent revascularisation at 30 days were available from 42 trials with 31,555 patients (94% of patients included in the overall review) and from 32 trials with 21,548 patients (64% of patients included in the overall review) at six months.
Urgent revascularisation
Urgent coronary revascularisation was performed in 2.04% of patients in the treatment group versus 3.44% in controls at 30 days, and in 12.54% and 15.31% respectively at six months. Treatment with intravenous glycoprotein IIb/IIIa blockers was associated with a reduction in the risk of urgent revascularisation at 30 days (OR 0.62, 95% CI 0.54 to 0.71, P < 0.00001; I2 = 18%) (Analysis 1.5) and at six months (OR 0.85, 95% CI 0.79 to 0.93, P < 0.0001; I2 = 9%) (Analysis 1.6). At 30 days, the results were less marked for patients with stable coronary artery disease (CAD) (OR 0.84, 95% CI 0.54 to 1.32) and for those pre‐treated with clopidogrel (OR 0.89, 95% CI 0.62 to 1.28), especially in patients without ACS; while at six months, the results were similar in all subgroups (Table 4).
| Intervention | 30‐day urgent revasc | 6‐month revasc | 30‐day death, MI or revasc | 6‐month death, MI or revasc |
| OR (95% CI) | OR (95% CI) | OR (95% CI) | OR (95% CI) | |
| 1. During PCI (all patients) | 0.62 (0.54 to 0.71) | 0.85 (0.79 to 0.93) | 0.65 (0.57 to 0.75) | 0.80 (0.73 to 0.88) |
| 1.1. Subgroup analysis by patient's condition | ||||
| Patients with stable CAD | 0.84 (0.54 to 1.32) | 0.93 (0.81 to 1.08) | 0.74 (0.60 to 0.91) | 0.87 (0.77 to 0.98) |
| Patients with NSTEACS | 0.68 (0.52 to 0.89) | 0.91 (0.79 to 1.05) | 0.69 (0.58 to 0.81) | 0.85 (0.76 to 0.96) |
| Primary PCI in patients with STEMI | 0.61 (0.45 to 0.83) | 0.75 (0.63 to 0.90) | 0.69 (0.49 to 0.98) | 0.84 (0.73 to 0.97) |
| 1.2. Subgroup analysis by technique | ||||
| Balloon angioplasty | 0.58 (0.49 to 0.70) | 0.81 (0.60 to 1.10) | 0.63 (0.51 to 0.76) | 0.84 (0.75 to 0.94) |
| PCI with stent placement | 0.75 (0.58 to 0.98) | 0.87 (0.78 to 0.97) | 0.69 (0.57 to 0.84) | 0.78 [0.69 to 0.89) |
| 1.3. Subgroup analysis by pre‐treatment with clopidogrel | 0.89 (0.62 to 1.28) | 0.87 (0.76 to 0.98) | 0.88 (0.65 to 1.20) | 0.88 (0.79 to 0.98) |
| Patients with ACS | 0.82 (0.54 to 1.24) | 0.77 (0.64 to 0.94) | 0.80 (0.50 to 1.26) | 0.81 (0.69 to 0.95) |
| Patients without ACS | 1.17 (0.54 to 2.53) | 0.94 (0.80 to 1.11) | 1.08 (0.76 to 1.52) | 0.94 (0.81 to 1.10) |
| revasc, revascularisation; MI, myocardial infarction; PCI, percutaneous coronary intervention; CAD, coronary artery disease; NSTEACS, non‐ST segment elevation acute coronary syndrome; STEMI, ST‐segment elevation myocardial infarction; ACS, acute coronary syndromes; OR, odds ratio; CI, confidence interval | ||||
Death, myocardial infarction or urgent revascularisation
The combined endpoint of death, myocardial infarction or urgent revascularisation at 30 days and six months was 6.70% versus 9.71% and 19.01% versus 23.22% in the treatment and control groups respectively. IIb/IIIa blockers were also associated with a lower risk of death, myocardial infarction or urgent revascularisation both at 30 days (OR 0.65, 95% CI 0.57 to 0.75) (Analysis 1.7) and at six months (OR 0.80, 95% CI 0.73 to 0.88) (Analysis 1.8), although the analysis showed a marked heterogeneity of the results both at 30 days (I2 = 40%) and at six months (I2 = 35%). Again, the global results were similar to those obtained in all subgroups but were less marked for the subgroup of patients pre‐treated with clopidogrel (30‐day OR 0.88, 95% CI 0.65 to 1.20; six‐month OR 0.88, 95% CI 0.79 to 0.98), especially in patients without ACS (Table 4).
Safety
Data were available from 40 trials with 31,430 patients (94% of patients included in the overall review). Major bleeding occurred in 3.03% of patients in the treatment group versus 2.23% in controls. Treatment with intravenous glycoprotein IIb/IIIa blockers was associated with an increased risk of severe bleeding (OR 1.39, 95% CI 1.21 to 1.61; P < 0.0001; I2 = 12%; Analysis 1.9). The absolute risk increase per thousand treated patients over 30 days was 8.0 and the number needed to harm (NNH) was 125. The results were homogeneous in blinded and in unblinded studies (Analysis 7.9), and in all subgroups (Table 5).
| Intervention | 30‐day major bleeding (OR, 95% CI) |
| 1. PCI (all patients) | 1.39 (1.21 to 1.61) |
| 1.1. Subgroup analysis by patient's condition | |
| Patients with stable CAD | 1.83 (1.10 to 3.03) |
| Patients with NSTEACS | 1.41 (1.03 to 1.93) |
| Primary PCI in patients with STEMI | 1.54 (1.12 to 2.11) |
| 1.2. Subgroup analysis by technique | |
| Balloon angioplasty | 1.38 (1.02 to 1.86) |
| PCI with stent placement | 1.38 (1.05 to 1.82) |
| 1.3. Subgroup analysis by pre‐treatment with clopidogrel | 1.30 (0.93 to 1.83) |
| Patients with ACS | 1.27 (0.87 to 1.86) |
| Patients without ACS | 1.41 (0.67 to 2.97) |
| 2. As initial medical treatment of patients with NSTEACS | 1.29 (1.14 to 1.45) |
| d, day; PCI, percutaneous coronary intervention; NSTEACS, non‐ST elevation acute coronary syndrome; STEMI, ST elevation myocardial infarction; CAD, coronary artery disease; OR, odds ratio; CI, confidence interval | |
2. Glycoprotein IIb/IIIa blockers as initial medical treatment in patients with non‐ST segment elevation acute coronary syndromes
Primary endpoints
Data from 12 trials with 31,490 patients (94% of patients included in this meta‐analysis) were available on 30‐day mortality and myocardial infarction, while data from only six trials but with 19,396 patients (58% of patients included in the overall review) were available on six‐month mortality and myocardial infarction.
Mortality occurred in 3.32% of patients in the treatment group versus 3.62% in controls at 30 days, and in 6.26% and 6.23% respectively at six months. Death or myocardial infarction occurred in 10.50% and 11.89% at 30 days, and 13.25% and 14.53% at six months respectively.
Treatment with intravenous glycoprotein IIb/IIIa blockers was not associated with a reduction in the odds of all‐cause mortality at 30 days (OR 0.90, 95% CI 0.79 to 1.02; I2 = 9%; Analysis 8.1) or at six months (OR 1.00, 95% CI 0.87 to 1.15; I2 = 0%; Analysis 8.2). However, these agents reduced the risk of all‐cause mortality or myocardial infarction both at 30 days (OR 0.91, 95% CI 0.85 to 0.98; I2 = 28%; Analysis 8.3) and at six months (OR 0.88, 95% CI 0.81 to 0.96; I2 = 0%; Analysis 8.4). The ARR per thousand treated patients was 13.9 at 30 days and 12.7 at six months, and the corresponding NNTs were of 75 and 79 respectively.
Safety
Data were available from 12 trials with 31,099 patients (93.7% of patients included in the overall review). Treatment with intravenous glycoprotein IIb/IIIa blockers was associated with an increase in the incidence of major bleeding at 30 days (OR 1.29, 95% CI 1.14 to 1.45, P < 0.0001; I2 = 24%; Analysis 8.5). Major bleeding occurred in 3.76% and in 3.56% of patients in the treatment and control groups, respectively.
Discussion
Glycoprotein IIb/IIIa blockers during percutaneous coronary intervention (PCI)
This systematic review has identified that glycoprotein IIb/IIIa blockers may be safe and effective when administered during PCI with or without stent implantation. This is based on data from 48 trials including over 33,000 patients. Overall, the administration of IIb/IIIa blockers as a bolus immediately before the intervention followed by a 12 to 24‐hour infusion is beneficial. Although associated with an increased risk of severe bleeding (8.0 per 1000), this hazard may be considered to be offset by the reduction of 30‐day mortality (4.0 patients per 1000 treated), mortality or non‐fatal myocardial infarction (23.9 patients per 1000) and urgent revascularisation (14 patients per 1000 treated). The early benefit of glycoprotein IIb/IIIa blockers on mortality seems to be lost at six months, although the lower number of included studies and enrolled patients with six‐month follow‐up may account for these different results. The short antiplatelet effects of these intravenous drugs may also account for this apparent decrease in efficacy at six months, although the initial benefit on mortality or myocardial infarction is maintained at six months.
Most of the beneficial effects of these drugs were in the prevention of peri‐procedural myocardial infarction, a condition whose definition has varied over the years and between studies partially because troponins have only been included in their diagnosis in studies performed after the year 2005. In addition, their diagnosis is especially difficult in patients presenting with a myocardial infarction. Therefore, no study applied the current third universal definition of a post‐procedural myocardial infarction in which an elevation more than five times the upper limit of normal or a 20% increase from a previously abnormal level is required (Universal definition MI 2012). Although we tried to limit the variability of the definition by using a uniform criteria of an elevation of more than three times the upper limit of normal of the biomarker of necrosis used when the data were obtainable, the variability of the myocardial infarction definition could explain the heterogeneity observed in the analysis of this endpoint.
The beneficial effect of these drugs is homogeneous in different subgroups of patients according to their clinical condition (i.e. stable coronary artery disease (CAD), non‐ST segment elevation acute coronary syndromes (NSTEACS) or ST‐segment elevation myocardial infarction (STEMI)) and the technique used (i.e. balloon angioplasty or PCI with stent), although 30‐day and six‐month mortality was only reduced when administered in procedures with stent implantation. The use of drug‐eluting stents has been reported to be associated with a higher risk of thrombosis. Since no study on IIb/IIIa blockers has been performed specifically in patients with drug‐eluting stents, and since in only four of the 24 reviewed studies (BRAVE‐3 2009; CLEAR PLATELETS‐2 2009; ISAR‐REACT 2 2006; OPTIMIZE‐IT 2009) a drug‐eluting stent was used in more than 40% of the cases, the results of this meta‐analysis only apply to patients in which a bare metal stent was implanted.
The administration of clopidogrel before PCI in addition to aspirin and heparin, and during the first year following PCI, has been shown to reduce the risk of acute coronary occlusion and of mortality, myocardial infarction or recurrent ischaemia (PCI‐CURE 2001), and is currently the standard medical treatment for patients subjected to this procedure (ACCF/AHA Guideline NSTEACS 2013; ESC Guidelines NSTEACS 2011). In recent years, the administration of clopidogrel in addition to aspirin and heparin has also been shown to be of benefit as initial medical treatment of patients with NSTEACS (ACCF/AHA Guideline NSTEACS 2013; CURE 2001; ESC Guidelines NSTEACS 2011; PCI‐CURE 2001). Controversy currently exists about the effectiveness of glycoprotein IIb/IIIa blockers in patients submitted for PCI on long‐term clopidogrel treatment or in patients pre‐treated with a loading dose from the time of hospital admission or at least two to six hours before PCI. The results of this systematic review show that IIb/IIIa blockers are less efficacious in decreasing major and minor events in patients pre‐treated with clopidogrel, and suggest that they retain a beneficial effect only in patients with ACS. These results are in agreement with the higher risk of thromboembolic events in patients with ACS compared with patients with stable CAD. On the other hand, the risk of severe bleeding is not enhanced in patients pre‐treated with clopidogrel.
Glycoprotein IIb/IIIa blockers as initial medical treatment in patients with non‐ST segment elevation acute coronary syndromes
This systematic review also identified that glycoprotein IIb/IIIa antagonists are safe but much less effective when administered as an initial medical treatment to patients with NSTEACS than in patients undergoing PCI. This conclusion is based on data from over 33,000 patients. Overall, the administration of intravenous glycoprotein IIb/IIIa blockers as an initial bolus followed by a continuous infusion for 24 to 72 hours resulted in a modest benefit at 30 days (13.9 deaths or myocardial infarctions prevented per 1000 patients treated) and at six months. This benefit was obtained in spite of a very acceptable excess of severe bleeding (2 per 1000). However, the treatment provided no significant benefit on all‐cause mortality at 30 days or six months.
These results contrast with those mentioned above in the overall population submitted for PCI, and also in the subgroup of patients with NSTEACS that underwent PCI. It is worth noting that except for two studies (PRACTICE 2007; PRISM 1998) the beneficial effect obtained was higher in trials with a high use rate of PCI procedures than in trials with a low frequency of these procedures. In addition, in two trials (PRISM Plus 1998; PURSUIT 1998) patients that underwent PCI 24 to 72 hours after admission obtained greater benefit from glycoprotein IIb/IIIa antagonists after PCI than before the procedure, and in one trial (PARAGON B 2002) a benefit was observed only among patients that underwent PCI during drug infusion. These results strongly suggest the existence of a positive interaction between PCI and the effect of glycoprotein IIb/IIIa blockers. In fact, in previous meta‐analysis using individual data, a more marked effect of the intervention was observed among patients that underwent PCI during the administration of IIb/IIIa antagonists that among patients that did not undergo PCI (Boersma 1999; Boersma 2002). Finally, because the overall treatment effect of glycoprotein IIb/IIIa inhibitors when administered as initial medical management of patients with NSTEACS is small and these drugs are expensive, the best cost‐effectiveness ratio may be obtained when they are administered in high‐risk patients scheduled for early PCI. In this sense, one trial has shown similar effects but excess bleeding when administering one of these drugs (eptifibatide) since hospital admission (upstream treatment) rather than during early PCI (downstream treatment) (EARLY‐ACS 2009).
Characteristics and limitations of the review
Heterogeneity of studies was statistically important only in 19 of the 96 analyses performed, all of them related to PCI and 11 regarding secondary endpoints. Such heterogeneity is likely to be due to the subjective nature of urgent revascularisation, and the inclusion of small studies. Differences in patients' characteristics such as age, gender, history of myocardial infarction and proportion of patients with acute coronary syndromes, although important, did not result in significant statistical heterogeneity. It is unlikely that other factors such as drug dosages or important concomitant treatments may have affected homogeneity, particularly heparin and aspirin.
We did not perform a cost‐effectiveness analysis since this was out of the scope of our review. Some of the analysed studies performed a retrospective analysis on cost‐effectiveness, most of them with data from a specific country and applying the results of the overall study. It is of note that this kind of analysis is difficult to perform in multicentre trials in which participating countries have major differences in local practices and public health policies and economies.
It should be noted that the studied population may not be representative of all patients undergoing PCI or with NSTEACS. In the group of patients treated during PCI the mean age of patients was lower than what it is usually observed in clinical practice, as well as the proportion of other co‐morbidities (CRUSADE 2006; GRACE 2007). However, the subgroup analysis performed on these patients showed similar results to those obtained in the global analysis, and in those obtained for patients with or without stable CAD. In the group of patients with NSTEACS treated medically, the inclusion was limited to patients with ST‐segment changes during the admission ECG or with positive biological markers of myocardial necrosis. These features are present in three‐quarters of patients and are known to select high‐risk patients. In fact, in most centres patients with these characteristics are submitted for coronary angiography within 48 hours as currently recommended (ACCF/AHA Guideline NSTEACS 2013; ESC Guidelines NSTEACS 2011). In addition, some studies have shown a significant differential treatment effect when glycoprotein IIb/IIIa blockers have been administered in patients with positive or negative troponin levels at admission (Boersma 2002). On the other hand, all of these randomised controlled trials excluded patients with significant renal impairment, cerebrovascular disease and also any patient with a moderate to high risk of bleeding complications. For these reasons, the generalisability of the findings of this review is limited to a moderate to high‐risk population with a low risk of bleeding complications.
Study flow diagram.
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Funnel plot of comparison: 1 During PCI (all patients), outcome: 1.1 30‐day mortality.
Funnel plot of comparison: 1 During PCI (all patients), outcome: 1.2 6‐month mortality.
Funnel plot of comparison: 1 During PCI (all patients), outcome: 1.3 30‐day mortality or myocardial infarction.
Comparison 1 During PCI (all patients), Outcome 1 30‐day mortality.
Comparison 1 During PCI (all patients), Outcome 2 6‐month mortality.
Comparison 1 During PCI (all patients), Outcome 3 30‐day mortality or myocardial infarction.
Comparison 1 During PCI (all patients), Outcome 4 6‐month mortality or myocardial infarction.
Comparison 1 During PCI (all patients), Outcome 5 30‐day urgent revascularisation.
Comparison 1 During PCI (all patients), Outcome 6 6‐month urgent revascularisation.
Comparison 1 During PCI (all patients), Outcome 7 30‐day mortality, myocardial infarction or urgent revascularisation.
Comparison 1 During PCI (all patients), Outcome 8 6‐month mortality, myocardial infarction or urgent revascularisation.
Comparison 1 During PCI (all patients), Outcome 9 30‐day major bleeding.
Comparison 2 Subgroup of PCI in patients with stable CAD, Outcome 1 30‐day mortality.
Comparison 2 Subgroup of PCI in patients with stable CAD, Outcome 2 6‐month mortality.
Comparison 2 Subgroup of PCI in patients with stable CAD, Outcome 3 30‐day mortality or myocardial infarction.
Comparison 2 Subgroup of PCI in patients with stable CAD, Outcome 4 6‐month mortality or myocardial infarction.
Comparison 2 Subgroup of PCI in patients with stable CAD, Outcome 5 30‐day urgent revascularisation.
Comparison 2 Subgroup of PCI in patients with stable CAD, Outcome 6 6‐month urgent revascularisation.
Comparison 2 Subgroup of PCI in patients with stable CAD, Outcome 7 30‐day mortality, myocardial infarction or urgent revascularisation.
Comparison 2 Subgroup of PCI in patients with stable CAD, Outcome 8 6‐month mortality, myocardial infarction or urgent revascularisation.
Comparison 2 Subgroup of PCI in patients with stable CAD, Outcome 9 30‐day major bleeding.
Comparison 3 Subgroup of PCI in patients with NSTEACS, Outcome 1 30‐day mortality.
Comparison 3 Subgroup of PCI in patients with NSTEACS, Outcome 2 6‐month mortality.
Comparison 3 Subgroup of PCI in patients with NSTEACS, Outcome 3 30‐day mortality or myocardial infarction.
Comparison 3 Subgroup of PCI in patients with NSTEACS, Outcome 4 6‐month mortality or myocardial infarction.
Comparison 3 Subgroup of PCI in patients with NSTEACS, Outcome 5 30‐day urgent revascularisation.
Comparison 3 Subgroup of PCI in patients with NSTEACS, Outcome 6 6‐month urgent revascularisation.
Comparison 3 Subgroup of PCI in patients with NSTEACS, Outcome 7 30‐day mortality, myocardial infarction or urgent revascularisation.
Comparison 3 Subgroup of PCI in patients with NSTEACS, Outcome 8 6‐month mortality, myocardial infarction or urgent revascularisation.
Comparison 3 Subgroup of PCI in patients with NSTEACS, Outcome 9 30‐day major bleeding.
Comparison 4 Subgroup of primary PCI in patients with STEMI, Outcome 1 30‐day mortality.
Comparison 4 Subgroup of primary PCI in patients with STEMI, Outcome 2 6‐month mortality.
Comparison 4 Subgroup of primary PCI in patients with STEMI, Outcome 3 30‐day mortality or myocardial infarction.
Comparison 4 Subgroup of primary PCI in patients with STEMI, Outcome 4 6‐month mortality or myocardial infarction.
Comparison 4 Subgroup of primary PCI in patients with STEMI, Outcome 5 30‐day urgent revascularisation.
Comparison 4 Subgroup of primary PCI in patients with STEMI, Outcome 6 6‐month urgent revascularisation.
Comparison 4 Subgroup of primary PCI in patients with STEMI, Outcome 7 30‐day mortality, myocardial infarction or urgent revascularisation.
Comparison 4 Subgroup of primary PCI in patients with STEMI, Outcome 8 6‐month mortality, myocardial infarction or urgent revascularisation.
Comparison 4 Subgroup of primary PCI in patients with STEMI, Outcome 9 30‐day major bleeding.
Comparison 5 Subgroup of balloon angioplasty, Outcome 1 30‐day mortality.
Comparison 5 Subgroup of balloon angioplasty, Outcome 2 6‐month mortality.
Comparison 5 Subgroup of balloon angioplasty, Outcome 3 30‐day mortality or myocardial infarction.
Comparison 5 Subgroup of balloon angioplasty, Outcome 4 6‐month mortality or myocardial infarction.
Comparison 5 Subgroup of balloon angioplasty, Outcome 5 30‐day urgent revascularisation.
Comparison 5 Subgroup of balloon angioplasty, Outcome 6 6‐month urgent revascularisation.
Comparison 5 Subgroup of balloon angioplasty, Outcome 7 30‐day mortality, myocardial infarction or urgent revascularisation.
Comparison 5 Subgroup of balloon angioplasty, Outcome 8 6‐month mortality, myocardial infarction or urgent revascularisation.
Comparison 5 Subgroup of balloon angioplasty, Outcome 9 30‐day major bleeding.
Comparison 6 Subgroup of stent implantation, Outcome 1 30‐day mortality.
Comparison 6 Subgroup of stent implantation, Outcome 2 6‐month mortality.
Comparison 6 Subgroup of stent implantation, Outcome 3 30‐day mortality or myocardial infarction.
Comparison 6 Subgroup of stent implantation, Outcome 4 6‐month mortality or myocardial infarction.
Comparison 6 Subgroup of stent implantation, Outcome 5 30‐day urgent revascularisation.
Comparison 6 Subgroup of stent implantation, Outcome 6 6‐month urgent revascularisation.
Comparison 6 Subgroup of stent implantation, Outcome 7 30‐day mortality, myocardial infarction or urgent revascularisation.
Comparison 6 Subgroup of stent implantation, Outcome 8 6‐month mortality, myocardial infarction or urgent revascularisation.
Comparison 6 Subgroup of stent implantation, Outcome 9 30‐day major bleeding.
Comparison 7 Subgroup of PCI in patients pre‐treated with clopidogrel, Outcome 1 30‐day mortality.
Comparison 7 Subgroup of PCI in patients pre‐treated with clopidogrel, Outcome 2 6‐month mortality.
Comparison 7 Subgroup of PCI in patients pre‐treated with clopidogrel, Outcome 3 30‐day mortality or myocardial infarction.
Comparison 7 Subgroup of PCI in patients pre‐treated with clopidogrel, Outcome 4 6‐month mortality or myocardial infarction.
Comparison 7 Subgroup of PCI in patients pre‐treated with clopidogrel, Outcome 5 30‐day urgent revascularisation.
Comparison 7 Subgroup of PCI in patients pre‐treated with clopidogrel, Outcome 6 6‐month urgent revascularisation.
Comparison 7 Subgroup of PCI in patients pre‐treated with clopidogrel, Outcome 7 30‐day mortality, myocardial infarction or urgent revascularisation.
Comparison 7 Subgroup of PCI in patients pre‐treated with clopidogrel, Outcome 8 6‐month mortality, myocardial infarction or urgent revascularisation.
Comparison 7 Subgroup of PCI in patients pre‐treated with clopidogrel, Outcome 9 30‐day major bleeding.
Comparison 8 As initial medical treatment in patients with NSTEACS, Outcome 1 30‐day mortality.
Comparison 8 As initial medical treatment in patients with NSTEACS, Outcome 2 6‐month mortality.
Comparison 8 As initial medical treatment in patients with NSTEACS, Outcome 3 30‐day mortality or myocardial infarction.
Comparison 8 As initial medical treatment in patients with NSTEACS, Outcome 4 6‐month mortality or myocardial infarction.
Comparison 8 As initial medical treatment in patients with NSTEACS, Outcome 5 30‐day major bleeding.
| Study | N | 30‐day mortality | 6‐month mortality | 30‐day death or MI | 6‐month death or MI | Major bleeding | Within study |
| EPIC 1994 | 2099 | Low | Low | Low | Low | Low | Low |
| Simoons 1994 | 60 | Low | NA | Low | NA | Low | Low |
| IMPACT 1995 | 150 | Low | NA | Low | NA | Unclear | Low |
| Kereiakes 1996 | 93 | Low | NA | Low | NA | Low | Low |
| RESTORE 1997 | 2141 | Low | Low | Low | Low | Low | Low |
| IMPACT‐II 1997 | 4010 | Low | NA | Low | NA | Low | Low |
| EPILOG 1997 | 2792 | Low | Low | Low | Low | Low | Low |
| CAPTURE 1997 | 1265 | Low | Low | Low | Low | Low | Low |
| EPISTENT 1998 | 2399 | Low | Low | Low | Low | Low | Low |
| RAPPORT 1998 | 483 | Low | Low | Low | Low | Low | Low |
| ERASER 1999 | 215 | Low | Low | Low | Low | Low | Low |
| Galassi 1999 | 106 | High | NA | High | NA | High | High |
| Chen 2000 | 42 | Unclear | NA | Unclear | NA | Unclear | Unclear |
| ESPRIT 2000 | 2064 | Low | Low | Low | Low | Low | Low |
| ISAR‐2 2000 | 401 | Unclear | NA | High | NA | High | High |
| PRIDE 2001 | 127 | Unclear | NA | Unclear | NA | Unclear | Unclear |
| ADMIRAL 2001 | 300 | Low | Low | Unclear | Unclear | Unclear | Unclear |
| Tamburino 2002 | 107 | High | High | High | High | High | High |
| TOPSTAR 2002 | 96 | Low | Low | Unclear | Unclear | Unclear | Unclear |
| Juergens 2002 | 894 | Low | Low | Low | Unclear | Unclear | Unclear |
| CADILLAC 2002 | 2082 | Low | Low | High | High | High | High |
| ACE 2003 | 400 | High | High | High | High | High | High |
| Gasior 2003 | 41 | Unclear | Unclear | Unclear | Unclear | Unclear | Unclear |
| ADVANCE 2004 | 202 | Low | Low | Unclear | Unclear | Unclear | Unclear |
| DANTE 2004 | 96 | Low | Low | Low | Low | Unclear | Low |
| ISAR SMART‐2 2004 | 502 | NA | Low | NA | Low | Low | Low |
| ISAR‐REACT 2004 | 2159 | Low | Low | Low | Low | Low | Low |
| ISAR‐SWEET 2004 | 701 | Low | Low | Low | Low | Low | Low |
| Claeys 2005 | 200 | Unclear | Unclear | High | High | High | High |
| ASIAD 2005 | 254 | Low | Low | Unclear | Unclear | Unclear | Unclear |
| De Luca 2005 | 122 | NA | Unclear | NA | Unclear | NA | Unclear |
| Kurowski 2005 | 50 | Low | Low | Unclear | Unclear | NA | Unclear |
| Prati 2005 | 140 | NA | NA | Unclear | NA | NA | Unclear |
| ISAR‐REACT 2 2006 | 2022 | Low | Low | Low | Low | Low | Low |
| FU 2008 | 150 | NA | Unclear | NA | Unclear | Unclear | Unclear |
| Cuisset 2008 | 149 | Low | NA | High | NA | High | High |
| Shen 2008 | 172 | Unclear | Unclear | High | High | High | High |
| On‐TIME 2 2008 | 984 | Low | NA | Low | NA | Low | Low |
| De Luca 2008 | 132 | Low | Low | Low | Low | Low | Low |
| OPTIMIZE‐IT 2009 | 46 | Low | Low | High | High | High | High |
| JEPPORT 2009 | 973 | Low | NA | Low | NA | Low | Low |
| CLEAR PLATELETS‐2 2009 | 200 | Low | Low | High | High | High | High |
| BRAVE‐3 2009 | 800 | Low | NA | Low | NA | Low | Low |
| 3T/2R 2009 | 263 | Low | NA | Low | NA | Low | Low |
| ASSIST 2009 | 400 | Low | Low | Low | Low | Low | Low |
| Yan 2009 | 240 | Low | Low | Low | Low | Unclear | Low |
| INSTANT 2012 | 91 | NA | Low | NA | Unclear | Unclear | Unclear |
| ITTI 2012 | 100 | NA | Low | NA | Unclear | Unclear | Unclear |
| ACROSS STUDIES | 33,474 | Low | Low | Unclear | Unclear | Unclear | |
| Allocation concealment and blinding were the 2 selected key domains. Bias for each endpoint: NA: Not applicable; Low: Plausible bias unlikely to seriously alter the results; Unclear: Plausible bias that raises some doubt about the results; High: Plausible bias that seriously weakens confidence in the results. Bias within a study: Low: Low risk of bias for all key domains; Unclear: Unclear risk of bias for one or more key domains; High: High risk of bias for one or more key domains. Bias across studies: Low: Most information is from studies at low risk of bias; Unclear: Most information is from studies at low or unclear risk of bias; High: The proportion of information from studies at high risk of bias is sufficient to affect the interpretation of the results. | |||||||
| Study | N | 30‐day mortality | 6‐month mortality | 30‐day death or MI | 6‐month death or MI | Major bleeding | Within study |
| CANADIAN 1996 | 365 | Low | NA | Low | NA | Low | Low |
| Schulman 1996 | 227 | Low | NA | Low | NA | Low | Low |
| PURSUIT 1998 | 10,948 | Low | Low | Low | Low | Low | Low |
| PRISM 1998 | 3232 | Low | NA | Low | NA | Low | Low |
| PARAGON A 1998 | 2282 | Low | Low | Low | Low | Low | Low |
| PRISM Plus 1998 | 1915 | Low | Low | Low | Low | Low | Low |
| GUSTO‐IV 2001 | 7800 | Low | NA | Low | NA | Low | Low |
| PARAGON B 2002 | 5225 | Low | NA | Low | NA | Low | Low |
| Kim 2005 | 160 | Low | Low | Unclear | Unclear | Unclear | Unclear |
| ELISA‐2 2006 | 328 | Low | NA | High | NA | High | High |
| PRACTICE 2007 | 393 | Low | Low | Low | Low | Low | Low |
| Bhattacharya 2010 | 301 | Unclear | NA | Unclear | NA | Unclear | Unclear |
| ACROSS STUDIES | 33,176 | Low | Low | Low | Low | Low | |
| Allocation concealment and blinding were the 2 selected key domains. Bias for each endpoint: NA: Not applicable; Low: Plausible bias unlikely to seriously alter the results; Unclear: Plausible bias that raises some doubt about the results; High: Plausible bias that seriously weakens confidence in the results. Bias within a study: Low: Low risk of bias for all key domains; Unclear: Unclear risk of bias for one or more key domains; High: High risk of bias for one or more key domains. Bias across studies: Low: Most information is from studies at low risk of bias; Unclear: Most information is from studies at low or unclear risk of bias; High: The proportion of information from studies at high risk of bias is sufficient to affect the interpretation of the results. | |||||||
| Intervention | 30‐day mortality | 6‐month mortality | 30‐day death or non‐fatal MI | 6‐month death or non‐fatal MI |
| OR (95% CI) | OR (95% CI) | OR (95% CI) | OR (95% CI) | |
| 1. During PCI (all patients) | 0.79 (0.64 to 0.97) | 0.90 (0.77 to 1.05) | 0.66 (0.60 to 0.72) | 0.75 (0.64 to 0.86) |
| 1.1. Subgroup analysis by patient's condition | ||||
| Patients with stable CAD | 0.71 (0.34 to 1.46) | 0.88 (0.63 to 1.22) | 0.68 (0.55 to 0.84) | 0.77 (0.64 to 0.92) |
| Patients with NSTEACS | 0.77 (0.46 to 1.28) | 1.01 (0.74 to 1.38) | 0.68 (0.56 to 0.83) | 0.77 (0.65 to 0.92) |
| Primary PCI in patients with STEMI | 0.88 (0.64 to 1.21) | 0.88 (0.68 to 1.15) | 0.78 (0.61 to 1.00) | 0.77 (0.51 to 1.16) |
| 1.2. Subgroup analysis by technique | ||||
| Balloon angioplasty | 0.79 (0.55 to 1.14) | 1.06 (0.75 to 1.50) | 0.65 (0.56 to 0.75) | 0.78 (0.65 to 0.94) |
| PCI with stent placement | 0.78 (0.58 to 1.04) | 0.87 (0.71 to 1.07) | 0.67 (0.59 to 0.76) | 0.72 (0.60 to 0.87) |
| 1.3. Subgroup analysis by pre‐treatment with clopidogrel | 0.83 (0.57 to 1.20) | 0.95 (0.75 to 1.21) | 0.81 (0.67 to 0.98) | 0.87 (0.66 to 1.14) |
| Patients with ACS | 0.84 (0.56 to 1.25) | 0.97 (0.72 to 1.31) | 0.77 (0.61 to 0.96) | 0.77 (0.46 to 1.27) |
| Patients without ACS | 0.78 (0.29 to 2.09) | 0.92 (0.63 to 1.35) | 0.91 (0.65 to 1.28) | 0.94 (0.73 to 1.21) |
| 2. As initial medical treatment of NSTEACS | 0.90 (0.79 to 1.02) | 1.00 (0.87 to 1.15) | 0.91 (0.85 to 0.98) | 0.88 (0.81 to 0.96) |
| MI, myocardial infarction; PCI, percutaneous coronary intervention; CAD, coronary artery disease; NSTEACS, non‐ST segment elevation acute coronary syndrome; STEMI, ST‐segment elevation acute myocardial infarction; ACS, acute coronary syndromes; OR, odds ratio; CI, confidence interval | ||||
| Intervention | 30‐day urgent revasc | 6‐month revasc | 30‐day death, MI or revasc | 6‐month death, MI or revasc |
| OR (95% CI) | OR (95% CI) | OR (95% CI) | OR (95% CI) | |
| 1. During PCI (all patients) | 0.62 (0.54 to 0.71) | 0.85 (0.79 to 0.93) | 0.65 (0.57 to 0.75) | 0.80 (0.73 to 0.88) |
| 1.1. Subgroup analysis by patient's condition | ||||
| Patients with stable CAD | 0.84 (0.54 to 1.32) | 0.93 (0.81 to 1.08) | 0.74 (0.60 to 0.91) | 0.87 (0.77 to 0.98) |
| Patients with NSTEACS | 0.68 (0.52 to 0.89) | 0.91 (0.79 to 1.05) | 0.69 (0.58 to 0.81) | 0.85 (0.76 to 0.96) |
| Primary PCI in patients with STEMI | 0.61 (0.45 to 0.83) | 0.75 (0.63 to 0.90) | 0.69 (0.49 to 0.98) | 0.84 (0.73 to 0.97) |
| 1.2. Subgroup analysis by technique | ||||
| Balloon angioplasty | 0.58 (0.49 to 0.70) | 0.81 (0.60 to 1.10) | 0.63 (0.51 to 0.76) | 0.84 (0.75 to 0.94) |
| PCI with stent placement | 0.75 (0.58 to 0.98) | 0.87 (0.78 to 0.97) | 0.69 (0.57 to 0.84) | 0.78 [0.69 to 0.89) |
| 1.3. Subgroup analysis by pre‐treatment with clopidogrel | 0.89 (0.62 to 1.28) | 0.87 (0.76 to 0.98) | 0.88 (0.65 to 1.20) | 0.88 (0.79 to 0.98) |
| Patients with ACS | 0.82 (0.54 to 1.24) | 0.77 (0.64 to 0.94) | 0.80 (0.50 to 1.26) | 0.81 (0.69 to 0.95) |
| Patients without ACS | 1.17 (0.54 to 2.53) | 0.94 (0.80 to 1.11) | 1.08 (0.76 to 1.52) | 0.94 (0.81 to 1.10) |
| revasc, revascularisation; MI, myocardial infarction; PCI, percutaneous coronary intervention; CAD, coronary artery disease; NSTEACS, non‐ST segment elevation acute coronary syndrome; STEMI, ST‐segment elevation myocardial infarction; ACS, acute coronary syndromes; OR, odds ratio; CI, confidence interval | ||||
| Intervention | 30‐day major bleeding (OR, 95% CI) |
| 1. PCI (all patients) | 1.39 (1.21 to 1.61) |
| 1.1. Subgroup analysis by patient's condition | |
| Patients with stable CAD | 1.83 (1.10 to 3.03) |
| Patients with NSTEACS | 1.41 (1.03 to 1.93) |
| Primary PCI in patients with STEMI | 1.54 (1.12 to 2.11) |
| 1.2. Subgroup analysis by technique | |
| Balloon angioplasty | 1.38 (1.02 to 1.86) |
| PCI with stent placement | 1.38 (1.05 to 1.82) |
| 1.3. Subgroup analysis by pre‐treatment with clopidogrel | 1.30 (0.93 to 1.83) |
| Patients with ACS | 1.27 (0.87 to 1.86) |
| Patients without ACS | 1.41 (0.67 to 2.97) |
| 2. As initial medical treatment of patients with NSTEACS | 1.29 (1.14 to 1.45) |
| d, day; PCI, percutaneous coronary intervention; NSTEACS, non‐ST elevation acute coronary syndrome; STEMI, ST elevation myocardial infarction; CAD, coronary artery disease; OR, odds ratio; CI, confidence interval | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 30‐day mortality Show forest plot | 43 | 31744 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.64, 0.97] |
| 1.1 Blinded studies with a placebo group | 28 | 27205 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.78 [0.61, 1.00] |
| 1.2 Non‐blinded studies and without placebo | 15 | 4539 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.54, 1.21] |
| 2 6‐month mortality Show forest plot | 34 | 24431 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.77, 1.05] |
| 2.1 Blinded studies with a placebo group | 20 | 20329 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.76, 1.08] |
| 2.2 Non‐blinded studies and without placebo | 14 | 4102 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.65, 1.23] |
| 3 30‐day mortality or myocardial infarction Show forest plot | 44 | 31880 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.66 [0.60, 0.72] |
| 3.1 Blinded studies with a placebo group | 28 | 27205 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.66 [0.60, 0.73] |
| 3.2 Non‐blinded studies and without placebo | 16 | 4675 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.64 [0.48, 0.85] |
| 4 6‐month mortality or myocardial infarction Show forest plot | 33 | 24845 | Odds Ratio (M‐H, Random, 95% CI) | 0.75 [0.64, 0.86] |
| 4.1 Blinded studies with a placebo group | 20 | 20329 | Odds Ratio (M‐H, Random, 95% CI) | 0.72 [0.62, 0.84] |
| 4.2 Non‐blinded studies and without placebo | 14 | 4516 | Odds Ratio (M‐H, Random, 95% CI) | 0.82 [0.57, 1.18] |
| 5 30‐day urgent revascularisation Show forest plot | 42 | 31555 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.62 [0.54, 0.71] |
| 6 6‐month urgent revascularisation Show forest plot | 32 | 21548 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.85 [0.79, 0.93] |
| 7 30‐day mortality, myocardial infarction or urgent revascularisation Show forest plot | 41 | 31433 | Odds Ratio (M‐H, Random, 95% CI) | 0.65 [0.57, 0.75] |
| 8 6‐month mortality, myocardial infarction or urgent revascularisation Show forest plot | 33 | 22432 | Odds Ratio (M‐H, Random, 95% CI) | 0.80 [0.73, 0.88] |
| 9 30‐day major bleeding Show forest plot | 40 | 31430 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.39 [1.21, 1.61] |
| 9.1 Blinded studies with a placebo group | 27 | 27037 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.38 [1.19, 1.60] |
| 9.2 Non‐blinded studies and without placebo | 13 | 4393 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.53 [0.99, 2.37] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 30‐day mortality Show forest plot | 15 | 6419 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.71 [0.34, 1.46] |
| 2 6‐month mortality Show forest plot | 12 | 6323 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.63, 1.22] |
| 3 30‐day mortality or myocardial infarction Show forest plot | 15 | 6419 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.68 [0.55, 0.84] |
| 4 6‐month mortality or myocardial infarction Show forest plot | 12 | 6326 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.64, 0.92] |
| 5 30‐day urgent revascularisation Show forest plot | 14 | 6156 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.84 [0.54, 1.32] |
| 6 6‐month urgent revascularisation Show forest plot | 12 | 6326 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.81, 1.08] |
| 7 30‐day mortality, myocardial infarction or urgent revascularisation Show forest plot | 14 | 6156 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.74 [0.60, 0.91] |
| 8 6‐month mortality, myocardial infarction or urgent revascularisation Show forest plot | 12 | 6326 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.77, 0.98] |
| 9 30‐day major bleeding Show forest plot | 16 | 6510 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.83 [1.10, 3.03] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 30‐day mortality Show forest plot | 6 | 5778 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.46, 1.28] |
| 2 6‐month mortality Show forest plot | 5 | 5716 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.74, 1.38] |
| 3 30‐day mortality or myocardial infarction Show forest plot | 7 | 5914 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.68 [0.56, 0.83] |
| 4 6‐month mortality or myocardial infarction Show forest plot | 5 | 5716 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.65, 0.92] |
| 5 30‐day urgent revascularisation Show forest plot | 5 | 5728 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.68 [0.52, 0.89] |
| 6 6‐month urgent revascularisation Show forest plot | 5 | 5716 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.79, 1.05] |
| 7 30‐day mortality, myocardial infarction or urgent revascularisation Show forest plot | 5 | 5728 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.69 [0.58, 0.81] |
| 8 6‐month mortality, myocardial infarction or urgent revascularisation Show forest plot | 5 | 5716 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.85 [0.76, 0.96] |
| 9 30‐day major bleeding Show forest plot | 5 | 5728 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.41 [1.03, 1.93] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 30‐day mortality Show forest plot | 9 | 6525 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.64, 1.21] |
| 2 6‐month mortality Show forest plot | 9 | 4887 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.68, 1.15] |
| 3 30‐day mortality or myocardial infarction Show forest plot | 9 | 6525 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.78 [0.61, 1.00] |
| 4 6‐month mortality or myocardial infarction Show forest plot | 9 | 4887 | Odds Ratio (M‐H, Random, 95% CI) | 0.77 [0.51, 1.16] |
| 5 30‐day urgent revascularisation Show forest plot | 9 | 6527 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.61 [0.45, 0.83] |
| 6 6‐month urgent revascularisation Show forest plot | 9 | 4889 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.63, 0.90] |
| 7 30‐day mortality, myocardial infarction or urgent revascularisation Show forest plot | 9 | 6527 | Odds Ratio (M‐H, Random, 95% CI) | 0.69 [0.49, 0.98] |
| 8 6‐month mortality, myocardial infarction or urgent revascularisation Show forest plot | 9 | 5677 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.84 [0.73, 0.97] |
| 9 30‐day major bleeding Show forest plot | 10 | 6675 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.54 [1.12, 2.11] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 30‐day mortality Show forest plot | 11 | 13378 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.55, 1.14] |
| 2 6‐month mortality Show forest plot | 4 | 5291 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.06 [0.75, 1.50] |
| 3 30‐day mortality or myocardial infarction Show forest plot | 11 | 13378 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.65 [0.56, 0.75] |
| 4 6‐month mortality or myocardial infarction Show forest plot | 4 | 5291 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.78 [0.65, 0.94] |
| 5 30‐day urgent revascularisation Show forest plot | 11 | 13378 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.58 [0.49, 0.70] |
| 6 6‐month urgent revascularisation Show forest plot | 4 | 5291 | Odds Ratio (M‐H, Random, 95% CI) | 0.81 [0.60, 1.10] |
| 7 30‐day mortality, myocardial infarction or urgent revascularisation Show forest plot | 11 | 13378 | Odds Ratio (M‐H, Random, 95% CI) | 0.63 [0.51, 0.76] |
| 8 6‐month mortality, myocardial infarction or urgent revascularisation Show forest plot | 5 | 6229 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.84 [0.75, 0.94] |
| 9 30‐day major bleeding Show forest plot | 10 | 13285 | Odds Ratio (M‐H, Random, 95% CI) | 1.38 [1.02, 1.86] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 30‐day mortality Show forest plot | 28 | 15827 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.78 [0.58, 1.04] |
| 2 6‐month mortality Show forest plot | 25 | 13754 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.71, 1.07] |
| 3 30‐day mortality or myocardial infarction Show forest plot | 29 | 15963 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.67 [0.59, 0.76] |
| 4 6‐month mortality or myocardial infarction Show forest plot | 25 | 13757 | Odds Ratio (M‐H, Random, 95% CI) | 0.72 [0.60, 0.87] |
| 5 30‐day urgent revascularisation Show forest plot | 26 | 15516 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.58, 0.98] |
| 6 6‐month urgent revascularisation Show forest plot | 24 | 13663 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.78, 0.97] |
| 7 30‐day mortality, myocardial infarction or urgent revascularisation Show forest plot | 26 | 15516 | Odds Ratio (M‐H, Random, 95% CI) | 0.69 [0.57, 0.84] |
| 8 6‐month mortality, myocardial infarction or urgent revascularisation Show forest plot | 25 | 13758 | Odds Ratio (M‐H, Random, 95% CI) | 0.78 [0.69, 0.89] |
| 9 30‐day major bleeding Show forest plot | 27 | 15643 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.38 [1.05, 1.82] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 30‐day mortality Show forest plot | 13 | 8048 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.83 [0.57, 1.20] |
| 1.1 Patients with ACS | 7 | 4634 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.84 [0.56, 1.25] |
| 1.2 Patients without ACS | 6 | 3414 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.78 [0.29, 2.09] |
| 2 6‐month mortality Show forest plot | 14 | 7526 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.75, 1.21] |
| 2.1 Patients with ACS | 8 | 3934 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.97 [0.72, 1.31] |
| 2.2 Patients without ACS | 6 | 3592 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.92 [0.63, 1.35] |
| 3 30‐day mortality or myocardial infarction Show forest plot | 13 | 8048 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.67, 0.98] |
| 3.1 Patients with ACS | 7 | 4634 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.61, 0.96] |
| 3.2 Patients without ACS | 6 | 3414 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.65, 1.28] |
| 4 6‐month mortality or myocardial infarction Show forest plot | 14 | 7529 | Odds Ratio (M‐H, Random, 95% CI) | 0.87 [0.66, 1.14] |
| 4.1 Patients with ACS | 8 | 3934 | Odds Ratio (M‐H, Random, 95% CI) | 0.77 [0.46, 1.27] |
| 4.2 Patients without ACS | 6 | 3595 | Odds Ratio (M‐H, Random, 95% CI) | 0.94 [0.73, 1.21] |
| 5 30‐day urgent revascularisation Show forest plot | 11 | 7737 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.62, 1.28] |
| 5.1 Patients with ACS | 6 | 4586 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.82 [0.54, 1.24] |
| 5.2 Patients without ACS | 5 | 3151 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.17 [0.54, 2.53] |
| 6 6‐month urgent revascularisation Show forest plot | 13 | 7435 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.76, 0.98] |
| 6.1 Patients with ACS | 8 | 3936 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.64, 0.94] |
| 6.2 Patients without ACS | 5 | 3499 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.80, 1.11] |
| 7 30‐day mortality, myocardial infarction or urgent revascularisation Show forest plot | 11 | 7737 | Odds Ratio (M‐H, Random, 95% CI) | 0.88 [0.65, 1.20] |
| 7.1 Patients with ACS | 6 | 4586 | Odds Ratio (M‐H, Random, 95% CI) | 0.80 [0.50, 1.26] |
| 7.2 Patients without ACS | 5 | 3151 | Odds Ratio (M‐H, Random, 95% CI) | 1.08 [0.76, 1.52] |
| 8 6‐month mortality, myocardial infarction or urgent revascularisation Show forest plot | 13 | 7381 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.79, 0.98] |
| 8.1 Patients with ACS | 7 | 3786 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.69, 0.95] |
| 8.2 Patients without ACS | 6 | 3595 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.81, 1.10] |
| 9 30‐day major bleeding Show forest plot | 14 | 8239 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.30 [0.93, 1.83] |
| 9.1 Patients with ACS | 7 | 4734 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.27 [0.87, 1.86] |
| 9.2 Patients without ACS | 7 | 3505 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.41 [0.67, 2.97] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 30‐day mortality Show forest plot | 12 | 31490 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.79, 1.02] |
| 2 6‐month mortality Show forest plot | 5 | 14171 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.87, 1.15] |
| 3 30‐day mortality or myocardial infarction Show forest plot | 12 | 31490 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.85, 0.98] |
| 4 6‐month mortality or myocardial infarction Show forest plot | 6 | 19396 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.81, 0.96] |
| 5 30‐day major bleeding Show forest plot | 12 | 31099 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.29 [1.14, 1.45] |
