Heart, Lung and Circulation (2015) 24, 185–192 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2014.07.058
ORIGINAL ARTICLE
Dual Versus Single Antiplatelet Therapy in Patients Undergoing Transcatheter Aortic Valve Replacement: A Systematic Review and Meta-analysis Madan Raj Aryal, MD a, Paras Karmacharya, MD a, Anil Pandit, MD b, Fayaz Hakim, MD b, Ranjan Pathak, MD a*, Naba Raj Mainali, MD a, Anene Ukaigwe, MD a, Maryam Mahmood, MD a, Madan Badal, MD a, F. David Fortuin, MD b a
Department of Internal Medicine, Reading Health System, West Reading, Pennsylvania, USA 19611 Division of Cardiovascular Disease, Mayo Clinic College of Medicine, Phoenix, Arizona, USA 85054
b
Received 29 June 2014; accepted 11 July 2014; online published-ahead-of-print 24 July 2014
Background
Although dual antiplatelet therapy (DAPT) with clopidogrel and aspirin is a widely accepted strategy in patients undergoing transcatheter aortic valve replacement (TAVR), this approach is not evidence based. We therefore sought to systematically review the current evidence for this practice in terms of 30-day outcome looking at stroke, MI, bleeding, and death.
Methods
Relevant studies were identified through electronic literature search. Studies involving single antiplatelet therapy (SAPT) and DAPT in patients undergoing TAVR were included. Study specific risk ratios were calculated and combined using random-effects model meta-analysis.
Results
Analysis of data from 410 patients, stroke occurred in seven (3.16%) of SAPT and six (3.17%) of DAPT RR = 1.03 (95% CI, 0.36-2.96, P = 0.96). In analysis of 530 patients, MI occurred in three (1.07%) of SAPT and one (0.40%) of DAPT RR = 1.97 (95% CI, 0.29-13.29, P = 0.49), significant bleeding (major, life threatening and bleeding requiring transfusion) occurred in 20 (7.11%) of SAPT and 43 (17.27%) of DAPT RR = 0.41 (95% CI, 0.25-0.69, P = 0.0006). Number needed to harm for major or life threatening bleeding was 10. Death occurred in 15 (6.78%) of SAPT and 15 (7.94%) of DAPT (RR 0.91; 95% CI 0.46-1.79, P = 0.78).
Conclusion
Our meta-analysis suggests that at 30 days following TAVR there is no difference between post-procedural SAPT versus DAPT for the risk of stroke or MI and DAPT may have a higher bleeding risk. Adequately powered RCTs are warranted to clarify the optimal antiplatelet treatment strategy following TAVR.
Keywords
Transcatheter aortic valve replacement Single antiplatelet therapy Dual antiplatelet therapy Systematic review Meta-analysis
*Corresponding author at: Reading Health System, 6th Avenue and Spruce Street, West Reading, PA 19611, USA. Tel.: +610-988-8255; fax: +484-628-9003., Emails: [email protected], [email protected] © 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved.
186
Introduction Transcatheter aortic-valve replacement (TAVR) is a treatment option for some patients with symptomatic aortic stenosis at high-risk or inoperable for surgical valve replacement. In this patient population, TAVR has shown to be superior to medical therapy alone and non-inferior to surgical aortic valve replacement [1–10]. Although the procedure has a high success rate, infrequent but significant complications like myocardial infarction (2%) and stroke (3%) have been reported [1,4]. Recent consensus supports the use of antithrombotic therapy during and after TAVR procedures as it has been associated with higher thrombotic risk than surgical aortic valve replacement [7,8,11]. The use of clopidogrel (300 mg loading dose before TAVR followed by 75 mg/day) in addition to aspirin (75 to 100 mg/day) for a period of three to six months after TAVR is a common practice [1,9]; however, there are few studies comparing the efficacy of dual anti-platelet therapy (aspirin and clopidogrel, DAPT) versus single antiplatelet therapy (aspirin alone, SAPT) following TAVR. The risk and benefit of DAPT in TAVR patients who are typically older and frail remains an area of debate [1,4,10]. We therefore sought to systematically review the current literature for this practice in terms of 30-day outcome of thrombotic complications, bleeding events and overall mortality.
Methods Randomised controlled trials (RCTs) and observational studies assessing the use of DAPT versus SAPT in patients undergoing TAVR for aortic stenosis were considered for inclusion in our study. A protocol for this meta-analysis was prospectively devised that details the background, objectives and eligibility criteria of studies, outcomes and statistical methods. This is available for review upon request to investigators.
Study Selection The PRISMA statement for reporting systematic reviews recommended by the Cochrane Collaboration was followed for conducting this meta-analysis (Figure 1). Systematised search of MEDLINE, EMBASE, SCOPUS, Cochrane library and clinical trials.gov (inception to Jan 2014) was carried out to identify eligible studies. These databases were searched using the search terms under two broad search themes and combined using the Boolean operator ‘‘AND’’ (refer to supplementary file 1 for search strategy). For the theme ‘‘TAVR’’, we used a combination of MeSH, entry terms and text words: tavr, transcatheter aortic valve implantation, trans-catheter aortic valve* and transcatheter aortic valve*. For the theme ‘‘antiplatelet therapy’’; antithrombotic, antiplatelet, aspirin, acetylsalicylic acid, 2-(Acetyloxy) benzoic Acid, P2Y antagonist, P2Y receptor antagonist, clopidogrel, clopidogrel*, ticagrelor, brillinta, brilique, prasugrel and effient were used. No language restriction was used. Bibliographies belonging
M.R. Aryal et al.
to included papers, known reviews, and relevant articles were looked into for additional trials. To minimise data duplication as a result of multiple reporting, we compared papers from the same author. Two authors (PK and MRA) screened and retrieved reports and excluded irrelevant studies. Relevant data were extracted by two authors (PK and MRA) and checked by another (RP). Additional investigator (AP) participated in the review process when uncertainty about eligibility criteria arose. From each study we extracted and tabulated mean age, gender; type, dose and duration of antiplatelets used; severity of aortic stenosis in terms of mean aortic valve area, type of valve used (Table 1). The following inclusion criteria had to be met for studies to be included in the meta-analysis: 1) randomised clinical trials or observational studies, 2) studies done on patients undergoing TAVR, 3) patients having severe aortic stenosis (as defined by the authors), 4) studies that reported outcomes of interest, and 5) studies reporting bleeding events as a safety outcome.
Assessment of Risk of Bias The quality of included studies were independently evaluated by four reviewers (AU, MM, MRA and PK) using the guidelines provided by Cochrane Collaboration tool for assessing risk of bias [12]. Four included studies were assessed for random sequence generation, allocation concealment, blinding of participants and incomplete outcome data (Supplementary file 2).
Outcome Measures The primary efficacy endpoints for this study were the reduction in incidence of stroke (major, minor and transient ischaemic attack (TIA)), myocardial infarction (MI), and death. The safety endpoint was the rate of significant bleeding events (major, life-threatening and bleeding requiring blood transfusion) as defined by Valve academic research consortium (VARC). While abstracting data for this meta-analysis for the outcome variables, we chose to include data at 30 days post valve replacement.
Statistical Analysis All outcome comparisons and treatment effects were calculated with RevMan version 5.2 (Cochrane Collaboration, Oxford, United Kingdom). The summary risk ratio (RR) and 95% confidence intervals (CI) were estimated using a fixed effects method if I2 was 0%. To control for heterogeneity if present, random effect models were used for this metaanalysis as their assumption accounts for presence of variability among the studies. We calculated the I2 statistics to evaluate the percentage of heterogeneity among the trials. When interpreting heterogeneity, I2 values less than 30% were considered as low heterogeneity, 30 to 60% as moderate, and greater than 60% as high [13]. A P value of
ORIGINAL ARTICLE
Dual Versus Single Antiplatelet Therapy in Patients Undergoing Transcatheter Aortic Valve Replacement: A Systematic Review and Meta-analysis Madan Raj Aryal, MD a, Paras Karmacharya, MD a, Anil Pandit, MD b, Fayaz Hakim, MD b, Ranjan Pathak, MD a*, Naba Raj Mainali, MD a, Anene Ukaigwe, MD a, Maryam Mahmood, MD a, Madan Badal, MD a, F. David Fortuin, MD b a
Department of Internal Medicine, Reading Health System, West Reading, Pennsylvania, USA 19611 Division of Cardiovascular Disease, Mayo Clinic College of Medicine, Phoenix, Arizona, USA 85054
b
Received 29 June 2014; accepted 11 July 2014; online published-ahead-of-print 24 July 2014
Background
Although dual antiplatelet therapy (DAPT) with clopidogrel and aspirin is a widely accepted strategy in patients undergoing transcatheter aortic valve replacement (TAVR), this approach is not evidence based. We therefore sought to systematically review the current evidence for this practice in terms of 30-day outcome looking at stroke, MI, bleeding, and death.
Methods
Relevant studies were identified through electronic literature search. Studies involving single antiplatelet therapy (SAPT) and DAPT in patients undergoing TAVR were included. Study specific risk ratios were calculated and combined using random-effects model meta-analysis.
Results
Analysis of data from 410 patients, stroke occurred in seven (3.16%) of SAPT and six (3.17%) of DAPT RR = 1.03 (95% CI, 0.36-2.96, P = 0.96). In analysis of 530 patients, MI occurred in three (1.07%) of SAPT and one (0.40%) of DAPT RR = 1.97 (95% CI, 0.29-13.29, P = 0.49), significant bleeding (major, life threatening and bleeding requiring transfusion) occurred in 20 (7.11%) of SAPT and 43 (17.27%) of DAPT RR = 0.41 (95% CI, 0.25-0.69, P = 0.0006). Number needed to harm for major or life threatening bleeding was 10. Death occurred in 15 (6.78%) of SAPT and 15 (7.94%) of DAPT (RR 0.91; 95% CI 0.46-1.79, P = 0.78).
Conclusion
Our meta-analysis suggests that at 30 days following TAVR there is no difference between post-procedural SAPT versus DAPT for the risk of stroke or MI and DAPT may have a higher bleeding risk. Adequately powered RCTs are warranted to clarify the optimal antiplatelet treatment strategy following TAVR.
Keywords
Transcatheter aortic valve replacement Single antiplatelet therapy Dual antiplatelet therapy Systematic review Meta-analysis
*Corresponding author at: Reading Health System, 6th Avenue and Spruce Street, West Reading, PA 19611, USA. Tel.: +610-988-8255; fax: +484-628-9003., Emails: [email protected], [email protected] © 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved.
186
Introduction Transcatheter aortic-valve replacement (TAVR) is a treatment option for some patients with symptomatic aortic stenosis at high-risk or inoperable for surgical valve replacement. In this patient population, TAVR has shown to be superior to medical therapy alone and non-inferior to surgical aortic valve replacement [1–10]. Although the procedure has a high success rate, infrequent but significant complications like myocardial infarction (2%) and stroke (3%) have been reported [1,4]. Recent consensus supports the use of antithrombotic therapy during and after TAVR procedures as it has been associated with higher thrombotic risk than surgical aortic valve replacement [7,8,11]. The use of clopidogrel (300 mg loading dose before TAVR followed by 75 mg/day) in addition to aspirin (75 to 100 mg/day) for a period of three to six months after TAVR is a common practice [1,9]; however, there are few studies comparing the efficacy of dual anti-platelet therapy (aspirin and clopidogrel, DAPT) versus single antiplatelet therapy (aspirin alone, SAPT) following TAVR. The risk and benefit of DAPT in TAVR patients who are typically older and frail remains an area of debate [1,4,10]. We therefore sought to systematically review the current literature for this practice in terms of 30-day outcome of thrombotic complications, bleeding events and overall mortality.
Methods Randomised controlled trials (RCTs) and observational studies assessing the use of DAPT versus SAPT in patients undergoing TAVR for aortic stenosis were considered for inclusion in our study. A protocol for this meta-analysis was prospectively devised that details the background, objectives and eligibility criteria of studies, outcomes and statistical methods. This is available for review upon request to investigators.
Study Selection The PRISMA statement for reporting systematic reviews recommended by the Cochrane Collaboration was followed for conducting this meta-analysis (Figure 1). Systematised search of MEDLINE, EMBASE, SCOPUS, Cochrane library and clinical trials.gov (inception to Jan 2014) was carried out to identify eligible studies. These databases were searched using the search terms under two broad search themes and combined using the Boolean operator ‘‘AND’’ (refer to supplementary file 1 for search strategy). For the theme ‘‘TAVR’’, we used a combination of MeSH, entry terms and text words: tavr, transcatheter aortic valve implantation, trans-catheter aortic valve* and transcatheter aortic valve*. For the theme ‘‘antiplatelet therapy’’; antithrombotic, antiplatelet, aspirin, acetylsalicylic acid, 2-(Acetyloxy) benzoic Acid, P2Y antagonist, P2Y receptor antagonist, clopidogrel, clopidogrel*, ticagrelor, brillinta, brilique, prasugrel and effient were used. No language restriction was used. Bibliographies belonging
M.R. Aryal et al.
to included papers, known reviews, and relevant articles were looked into for additional trials. To minimise data duplication as a result of multiple reporting, we compared papers from the same author. Two authors (PK and MRA) screened and retrieved reports and excluded irrelevant studies. Relevant data were extracted by two authors (PK and MRA) and checked by another (RP). Additional investigator (AP) participated in the review process when uncertainty about eligibility criteria arose. From each study we extracted and tabulated mean age, gender; type, dose and duration of antiplatelets used; severity of aortic stenosis in terms of mean aortic valve area, type of valve used (Table 1). The following inclusion criteria had to be met for studies to be included in the meta-analysis: 1) randomised clinical trials or observational studies, 2) studies done on patients undergoing TAVR, 3) patients having severe aortic stenosis (as defined by the authors), 4) studies that reported outcomes of interest, and 5) studies reporting bleeding events as a safety outcome.
Assessment of Risk of Bias The quality of included studies were independently evaluated by four reviewers (AU, MM, MRA and PK) using the guidelines provided by Cochrane Collaboration tool for assessing risk of bias [12]. Four included studies were assessed for random sequence generation, allocation concealment, blinding of participants and incomplete outcome data (Supplementary file 2).
Outcome Measures The primary efficacy endpoints for this study were the reduction in incidence of stroke (major, minor and transient ischaemic attack (TIA)), myocardial infarction (MI), and death. The safety endpoint was the rate of significant bleeding events (major, life-threatening and bleeding requiring blood transfusion) as defined by Valve academic research consortium (VARC). While abstracting data for this meta-analysis for the outcome variables, we chose to include data at 30 days post valve replacement.
Statistical Analysis All outcome comparisons and treatment effects were calculated with RevMan version 5.2 (Cochrane Collaboration, Oxford, United Kingdom). The summary risk ratio (RR) and 95% confidence intervals (CI) were estimated using a fixed effects method if I2 was 0%. To control for heterogeneity if present, random effect models were used for this metaanalysis as their assumption accounts for presence of variability among the studies. We calculated the I2 statistics to evaluate the percentage of heterogeneity among the trials. When interpreting heterogeneity, I2 values less than 30% were considered as low heterogeneity, 30 to 60% as moderate, and greater than 60% as high [13]. A P value of
