Quality Plus Aspirin
Argelia Long
The authors concluded that combined clopidogrel and aspirin reduced the likelihood of major cardiovascular events associated with acute coronary syndrome or percutaneous coronary intervention compared with monotherapy, but increased the likelihood of major bleeding. Although the review had limitations, in particular the restriction to published studies in English, in most respects it was well conducted and the conclusions appeared reliable.
MEDLINE (from 1966), Cochrane Central Register of Controlled Trials, DARE, Cochrane Database of Systematic Reviews and the ACP Journal Club were searched to August 2006. The reference lists of potentially relevant articles were also checked. The search was limited to studies in English.
Randomised controlled trials (RCTs) comparing combined clopidogrel and aspirin therapy with aspirin or clopidogrel monotherapy were eligible for inclusion. Required outcomes were efficacy and safety. Primary review outcomes for efficacy were major coronary events (a composite of death, stroke or myocardial infarction). The primary safety outcome was major bleeding (for example, substantially disabling bleeding that was causing a drop in haemoglobin of at least five grams per decilitre or the transfusion of over two units of blood). Secondary efficacy outcomes were fatal or non-fatal myocardial infarction, all-cause mortality and ischaemic stroke. Studies with surrogate outcomes (for example, platelet aggregation) were excluded.
Patients in the included studies had acute coronary syndrome with or without ST-segment elevation, had undergone percutaneous coronary intervention or had other disorders (for example, recent ischaemic stroke or transient ischaemic attack, established vascular disease, multiple athero-thrombotic risk factors). Patients' mean age ranged from 57.2 to 66.5 years. Most were male (mean 70 per cent). Mean/median duration of follow up ranged from 28 days to 18 months.
Two reviewers independently assessed study validity using the Jadad scale (measures adequacy of randomisation, blinding, and management of withdrawals and dropouts). Disagreements were resolved by consensus
Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated from the number of events in each group, using intention to treat analysis. Numbers needed to treat (NNT) or harm were also calculated. Studies were subgrouped by patient diagnosis (acute coronary syndrome, percutaneous coronary intervention or other) and by duration of follow up. Two reviewers independently extracted data using a standardised protocol. Disagreements were resolved by consensus.
Where three or more studies in one subgroup reported the same outcome, a meta-analysis examining pooled ORs with 95% CIs was performed using both fixed- and random-effects models. Results from random-effects models were used in interpretation of findings. Heterogeneity was assessed by visual scan of the forest plot and with the Q statistic. Subgroup analyses were conducted by duration of follow-up.
Combined clopidogrel and aspirin reduced the likelihood of major cardiovascular events associated with acute coronary syndrome or percutaneous coronary intervention compared with monotherapy, but increased the likelihood of major bleeding.
The objectives and inclusion criteria of the review were clear and relevant sources were searched. However, it did not appear that specific efforts were made to retrieve unpublished studies and the search was limited by language, so the review is prone to publication and language biases. Steps were taken to minimise the risk of bias and error by having more than one reviewer involved in data extraction and validity assessment, but it was unclear whether this also applied to study selection. Although most of the characteristics of the included studies were reported in adequate detail, very little information was provided about the results of the validity assessment. The sub-grouping of studies by patient diagnosis and the statistical techniques used to pool studies and assess for heterogeneity appeared appropriate. However, where statistically significant heterogeneity was detected it was not explored further. Publication bias was not assessed. Although the review had limitations, in particular the restriction to published studies in English, in most respects it was well conducted and the authors' conclusions appeared reliable.
Practice: The authors stated that the benefits of dual therapy outweighed the risks for patients with acute coronary syndrome or percutaneous coronary intervention, but not for other patient subgroups. However, the risk-benefit balance was uncertain beyond the immediate acute-care phase, as the bleeding risk appeared to increase over time.
Bowry A D, Brookhart M A, Choudhry N K. Meta-analysis of the efficacy and safety of clopidogrel plus aspirin as compared to antiplatelet monotherapy for the prevention of vascular events. American Journal of Cardiology 2008; 101 (7): 960-966. [PubMed: 18359315]
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.
The review investigated the effect of aspirin combined with warfarin in patients recovering from acute coronary syndromes. The review concluded that at an international normalised ratio of 2-3 the combination of aspirin and warfarin is superior to aspirin alone in reducing the risk of major adverse events, although it significantly increases the risk of major bleeding. The conclusion appears reliable.
To determine the effect of aspirin plus warfarin (A+W) compared with aspirin alone for the secondary prevention of major adverse events (MAEs) in patients recovering from acute coronary syndromes (ACS).
Randomised controlled trials (RCTs) with no significant imbalances in major baseline characteristics among study groups, using intention-to-treat analysis and with a follow-up of greater than 80%, were eligible for inclusion. The follow-up period ranged from 3 months to 5 years.
Studies of A+W compared with aspirin alone, administered for the prevention of MAEs, were eligible for inclusion. The dose of aspirin ranged from 75 to 325 mg/day. The dose of warfarin was not reported.
Patients recovering from ACS were eligible for inclusion. The participants were patients admitted to hospital for unstable angina, unspecified acute myocardial infarction (MI), or ST-elevation or non-ST-elevation MI. The age of the patients was not reported. The average international normalised ratio (INR) in the warfarin arm ranged from less than 1.5 to 3.
The outcomes of interest were the combined rate of MAE (defined as all-cause death, nonfatal MI or nonfatal thromboembolic stroke) and the rate of major bleeding (MB) (defined as intracranial haemorrhages, bleeds requiring transfusion, or a drop in haemoglobin of at least 2 g/dL).
The authors stated that the validity of the trials was assessed according to the grading outlined in the Cochrane Handbook, with A, B and C indicating a low, moderate or high probability of bias, respectively.
Both fixed-effect and random-effects models were used to calculate the summary ORs with 95% confidence intervals (CIs) for binary outcomes. The number-needed-to-treat (NNT) to prevent one MAE and the number-needed-to-harm (NNH) by causing one MB were also calculated. Publication bias was assessed using a funnel plot and Egger's test.
Heterogeneity amongst the studies was assessed using the Cochran Q statistic and the I-squared measure. A sensitivity analysis was used to assess the contribution of each study to the pooled estimates by excluding trials one at a time, starting from those with the lowest quality score. The statistical analyses were performed for all studies and also for studies with target or measured INRs of between 2 and 3.
Thirteen of the 14 studies were of a good quality and had greater than 97% follow-up. No study was excluded because of a follow-up of less than 80%. In the sensitivity analysis, the exclusion of any trial did not significantly alter the overall results. Significant heterogeneity was found when data were pooled for MAEs irrespective of INR (P=0.001), but when the analysis was restricted to the studies with an INR of 2-3 there was no significant heterogeneity.
In patients recovering from ACS at INR of 2-3, a combination of A+W is superior to aspirin alone in preventing MAEs, although it doubles the risk of MB. Whether this combined regimen is also superior to a double antiplatelet strategy or to newer evolving treatments warrants further investigation.
The review question and inclusion criteria were clear and the search was reasonable, but the authors did not adequately describe how they selected the studies. Study quality was assessed, but only some components of the assessment were reported and the authors did not state how they performed the quality assessment; the potential for reviewer error or bias could not, therefore, be assessed. There was significant heterogeneity in the overall analysis of all studies, although the authors discussed the possible reasons for this heterogeneity and addressed the issue by restricting the analyses to studies with INRs of between 2 and 3. Overall, the authors' conclusion appears to be supported by the evidence presented.
Practice: The authors stated that there is compelling evidence on the support of aspirin combined with intermediate-intensity oral anticoagulations for the prevention of MAEs in patients with ACS, particularly those at high risk of recurrent cardiovascular and cerebrovascular events who are willing to face the logistic hurdles and the predictable and uncommon risk of bleeding inherent to this treatment strategy.
Research: The authors stated that a head-to-head comparison of aspirin combined with properly-dosed oral anticoagulants with a double antiplatelet regimen, or a triple-armed study comparing these two strategies with aspirin alone during the first 9 to 12 months after ACS, is warranted.
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