Abstract
Background
The potential benefit of long-term dual antiplatelet therapy (DAPT) for secondary prevention of atherothrombotic events is unclear. Data from different randomized controlled trials (RCT) using different agents in different subgroups showed inconsistent results.
Methods
We performed a systematic review and meta-analysis from RCTs that tested different prolonged durations of DAPT for secondary prevention. Long term DAPT arm was defined as those receiving DAPT for more than 12 months. Long-term aspirin arm was defined as those receiving either aspirin alone long term or DAPT for less than 12 months.
Results
The use of long term DAPT was associated with a significant decrease in composite of death, myocardial infarction (MI) and stroke (6.08% vs. 6.71%; odds ratio OR = 0.86 [0.78–0.94]; P = 0.001). This reduction of death, MI and stroke was mainly noticed in patients with prior MI or stroke, but not with PAD or multiple risk factors. The reduction was seen with post PCI patients with prasugrel and only in those with prior MI with clopidogrel and ticagrelor. Long-term use of DAPT was associated with significant increase in major bleeding (1.47% vs. 0.88%; OR = 1.65 [1.23–2.21]; P = 0.001).
Conclusion
Long-term use of DAPT for secondary prevention is associated with lower risk of death, MI and stroke beneficial especially in patients with prior MI and stroke, but it is associated with increased risk of bleeding. Prolonging DAPT requires careful assessment of the trade-off between ischemic and bleeding complications and should probably be reserved for patients with higher risk for atherothrombotic events.
1
Introduction
Atherosclerotic vascular disease including coronary artery disease, cerebrovascular disease, and peripheral arterial disease are the leading cause of death and disability in the world . Platelets activation plays a key rule in the pathobiology of thrombotic ischemic events . Aspirin monotherapy reduces the risk of ischemic events both among patients who present with an acute coronary syndrome and in secondary prevention for patients with atherosclerotic vascular disease . The addition of a P2Y12 receptor antagonist to aspirin has been shown to reduce further the risk of ischemic events in patients with symptomatic atherosclerotic vascular disease .
Multiple studies compared long-term dual antiplatelet therapy (DAPT) to ASA or short DAPT. Findings of these studies assessing the effect of extended duration dual antiplatelet therapy varied. As while the Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events (CHARISMA) trial showed reduction in no difference in both cardiac and non cardiac death , similarly other studies [ITALIC (Is There A LIfe for DES after discontinuation of Clopidogrel), PRODIGY (PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY) and DES LATE (optimal duration of clopidogrel therapy with DES to reduce Late coronary Arterial Thrombotic Event)] showed similar trends in regard to all cause and cardiac death . However the Dual Antiplatelet Therapy Study (DAPT Study) showed no difference in cardiac death and higher incidence on non-cardiac death . The results of DAPT were not consistent with those of PEGASUS-TIMI 54 trial (the Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction) that showed a lower incidence of cardiac death with no difference in death from other causes . Using meta-analysis to pool data from multiple RCTs provides a more precise assessment of the effects of treatment, and also increases the number of patients within clinical subgroups of interest, often providing adequate statistical power to evaluate outcomes in these subgroups . While multiple meta-analyses were published comparing different durations of dual antiplatelets, all these meta-analysis included RCT where both arms have no long term DAPT beyond 12 months after percutaneous intervention or MI and some of them only looked at patients after drug-eluting stent (DES) implantation . Therefore none of these meta-analyses is able to address the issue of using long term DAPT in the secondary prevention of death, myocardial infarction (MI) and/or stroke in patients with atherosclerotic diseases.
Our current meta-analysis compares the rule of long-term DAPT vs. long term ASA in the secondary prevention of atherothrombotic events in patients with atherosclerotic diseases.
2
Methods
Relevant studies were identified through electronic searches of MEDLINE and the Cochrane Central Register of Controlled Trials databases from 01/01/1997 to 05/10/2015. The start date was defined as 01/01/1997 as the FDA approved the use of first P2Y12 inhibitor “clopidogrel” in 1997.
The search strategy used the terms “dual antiplatelet therapy,” “DAPT”, “Long-Term” “prevention”, “coronary artery disease” or “peripheral vascular disease,” “stroke.” “clopidogrel”, “Plavix”, “prasugrel”, “Effient”, “ticagrelor”, “Brilinta”, “thienopyridine”, “DAPT”, “death”, “mortality”, “survival”, “randomized controlled trial”, “random”, “random allocation”, “double-blind”, and “single-blind”. Searches were restricted to trials of human participants with full text published in English. In addition, we searched bibliographies of relevant studies, reviews, editorials, letters, and meeting abstracts. The analysis was restricted to include only prospective RCTs or pre-specified sub-analyses from RCTs that included an arm with randomized patients to long-term DAPT; and reported both safety and efficacy outcomes. All included studies reported each of the following efficacy outcomes: composite of death/MI/stroke, all cause death, cardiac death, MI, stroke as well as safety data including a minimum of minor or moderate bleeding and major bleeding. Also each of the included study has a long term arm of DAPT that extends beyond 12 months after MI or PCI if the patient has coronary artery disease (CAD).
The quality of the identified studies was assessed with respect to control for confounders, measurement of exposure, completeness of follow-up, and blinding. We followed a scoring system based on a checklist derived from recommended criteria recommended by the QUOROM (The Quality of Reporting of Meta-analyses) and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to assess the quality of the trials used in this meta-analysis .
Three reviewers (ZF, AM and SM) independently extracted data from the list of included studies. Extracted data included authorship, study period, publication year, study design, study region, baseline characteristics of patients, sample size, clinical events, and duration of follow-up. The following outcomes were extracted: composite of death/MI and stroke (primary end point), all-cause death, cardiac death, MI and stroke [cerebrovascular accident (CVA)] for efficacy outcomes and minor/moderate and major bleeding for safety outcomes.
A random effects model meta-analysis following the DerSimonian-Laird method was used to determine relative risks for the ASA alone and long DAPT groups for each endpoint . This method treats study affiliation as a random effect and considers both the within-study variance and the between-study variance. Heterogeneity (inconsistency of results among studies) was assessed using the DerSimonian-Laird I2 statistic, which calculates the proportion of between-study variability that cannot be attributed to sampling variation . All meta-analyses were conducted with R statistical software for Windows with the package meta (R Foundation for Statistical Computing, Vienna, Austria).
2
Methods
Relevant studies were identified through electronic searches of MEDLINE and the Cochrane Central Register of Controlled Trials databases from 01/01/1997 to 05/10/2015. The start date was defined as 01/01/1997 as the FDA approved the use of first P2Y12 inhibitor “clopidogrel” in 1997.
The search strategy used the terms “dual antiplatelet therapy,” “DAPT”, “Long-Term” “prevention”, “coronary artery disease” or “peripheral vascular disease,” “stroke.” “clopidogrel”, “Plavix”, “prasugrel”, “Effient”, “ticagrelor”, “Brilinta”, “thienopyridine”, “DAPT”, “death”, “mortality”, “survival”, “randomized controlled trial”, “random”, “random allocation”, “double-blind”, and “single-blind”. Searches were restricted to trials of human participants with full text published in English. In addition, we searched bibliographies of relevant studies, reviews, editorials, letters, and meeting abstracts. The analysis was restricted to include only prospective RCTs or pre-specified sub-analyses from RCTs that included an arm with randomized patients to long-term DAPT; and reported both safety and efficacy outcomes. All included studies reported each of the following efficacy outcomes: composite of death/MI/stroke, all cause death, cardiac death, MI, stroke as well as safety data including a minimum of minor or moderate bleeding and major bleeding. Also each of the included study has a long term arm of DAPT that extends beyond 12 months after MI or PCI if the patient has coronary artery disease (CAD).
The quality of the identified studies was assessed with respect to control for confounders, measurement of exposure, completeness of follow-up, and blinding. We followed a scoring system based on a checklist derived from recommended criteria recommended by the QUOROM (The Quality of Reporting of Meta-analyses) and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to assess the quality of the trials used in this meta-analysis .
Three reviewers (ZF, AM and SM) independently extracted data from the list of included studies. Extracted data included authorship, study period, publication year, study design, study region, baseline characteristics of patients, sample size, clinical events, and duration of follow-up. The following outcomes were extracted: composite of death/MI and stroke (primary end point), all-cause death, cardiac death, MI and stroke [cerebrovascular accident (CVA)] for efficacy outcomes and minor/moderate and major bleeding for safety outcomes.
A random effects model meta-analysis following the DerSimonian-Laird method was used to determine relative risks for the ASA alone and long DAPT groups for each endpoint . This method treats study affiliation as a random effect and considers both the within-study variance and the between-study variance. Heterogeneity (inconsistency of results among studies) was assessed using the DerSimonian-Laird I2 statistic, which calculates the proportion of between-study variability that cannot be attributed to sampling variation . All meta-analyses were conducted with R statistical software for Windows with the package meta (R Foundation for Statistical Computing, Vienna, Austria).
3
Results
Our systematic literature search identified 2456 articles, of which 6 met the inclusion criteria for this analysis ( Fig. 1 ). These 6 RCT included a total of 55,563 patients . The populations included in these trials were distributed as follows: one trial of patients at high risk of atherothrombotic events , and five trials of patients with coronary artery disease after percutaneous coronary intervention and or acute coronary syndrome . Dual antiplatelet therapy in all trials consisted of aspirin and P2Y12 inhibitor . Four trials used clopidogrel exclusively as the P2Y12 inhibitor used , one trial included clopidogrel and prasugrel , while one trial used ticagrelor as the P2Y12 inhibitor . Supplemental Table 1 shows characteristics of each of these RCT, while Supplemental Table 2 shows the patients’ characteristics of the meta-analysis cohort.
3.1
Efficacy
The use of long term DAPT was associated with a significant decrease in the primary outcome consist of a composite of death, MI and stroke (6.08% vs. 6.71%; odds ratio OR = 0.86 [0.78–0.94]; P = 0.001; Fig. 2 ). The use of long term DAPT was not associated with any differences in all-cause death (4.13% vs. 4.05%; OR = 1.02 [0.85–1.22]; P = 0.83), cardiac death (2.26% vs. 2.27%; OR = 0.96 [0.85–1.08]; P = 0.46) or stroke (1.35% vs. 1.61%; OR = 0.85 [0.71–1.02]; p = 0.07). However the use of long term DAPT was associated with a significant decrease in the incidence of MI (2.77% vs. 3.16%; OR = 0.75 [0.58–0.96]; P = 0.03). Fig. 3 shows the impact of the long term DAPT use on the individual efficacy outcomes.
