Antiplatelet Therapy Following TAVI
Antiplatelet Therapy Following TAVI
We searched PubMed, Medline, EMBASE and the Current Controlled Trials for English-language studies on the antithrombotic treatment following TAVI published between 1 January 2002 and April 2014. We chose 2002 as the lower boundary of the search given that the first human case description of TAVI was published in that year.
The following key words were used: 'transcatheter aortic valve implantation', 'percutaneous aortic valve', 'transfemoral aortic valve implantation', 'transapical aortic valve implantation', 'percutaneous aortic valve implantation', 'endovascular aortic valve implantation', 'Core Valve', 'Edwards Sapien valve', 'JenaValve', 'heart valve prosthesis implantation', 'transcatheter aortic valve replacement', 'trans subclavian aortic valve implantation', 'platelet aggregation inhibitors', 'antiplatelet', 'dual antiplatelet therapy', 'clopidogrel', 'aspirin', 'acetylsalicylic acid', 'single antiplatelet therapy', 'thienopyridine'. Additionally, we manually searched the abstracts of the following conferences: Transcatheter Cardiovascular Therapeutics, European Society of Cardiology and American Heart Association. Moreover, we reviewed the references of reviews and identified studies for additional articles.
Studies were included if they complied with the following requirements: inclusion of patients with aortic stenosis treated with TAVI, clear description of postprocedural antithrombotic treatment including one group treated with single antiplatelet therapy (SAT) and another treated with DAPT, and minimum follow-up of 1 month. Studies were excluded if only one antithrombotic treatment was considered or when the treatment groups merely included DAPT versus SAT in combination with VKA treatment. Study selection was done by two independent reviewers (MH and RD).
Of the 191 potentially eligible studies, 180 were excluded at the title/abstract level. The remaining 11 studies were subjected to a more detailed review using the predefined inclusion and exclusion criteria. An additional six studies were excluded for the following reasons: DAPT was compared with SAT combined with VKA in TAVI patients with known atrial fibrillation (AF; n=3), ischaemic and bleeding events were only reported in patients treated with DAPT (n=2), bleeding events were the only reported outcome (n=1) and exclusion of 30-day events from the analysis (n=1; see figure 1).
(Enlarge Image)
Figure 1.
Flow diagram of studies included in this meta-analysis. DAPT, dual antiplatelet therapy; VKA, vitamin K antagonist; SAT, single antiplatelet therapy.
In total, four studies were identified with a total of 640 patients, including two randomised controlled trials (RCTs). The principal investigator of each trial was approached and all consented to collaborate in a patient level pooled analysis. They provided the requested data, and vouched for the correctness of the data. Institution review board (IRB) approval was obtained by three studies and informed consent was obtained in all studies. Poliacikova et al did not request IRB approval considering that this was a retrospective analysis of prospective gathered data from the National British Cardiovascular Interventions Society TAVI database for which informed consent was previously obtained. For the current patient pooled analysis we obtained approval from the medical ethical committee of the Academic Medical Center, Amsterdam, The Netherlands.
We included patient-level data from four studies comparing single versus DAPT following TAVI. In all of these studies, clinical endpoints included all-cause mortality, acute coronary syndrome (ACS), stroke, life-threatening and major bleeding as defined by the Valve Academic Research Consortium (VARC) criteria.
The recently published SAT-TAVI study is a RCT comparing 81 mg ASA lifelong with DAPT (75 mg clopidogrel and 81 mg ASA) for 6 months in 120 patients. Patients randomised to DAPT were provided a preloading dose of 300 mg clopidogrel 1 day preprocedural.
In the RCT by Ussia et al, 79 patients were randomised to 100 mg ASA lifelong or 3 months DAPT (75 mg clopidogrel and 100 mg ASA). Patients randomised to DAPT were provided a preloading dose of 300 mg clopidogrel 1 day preprocedural.
Durand et al compared two antiplatelet regimens in 292 patients enrolled in three centres participating in the FRANCE 2 TAVI registry. In two centres the adopted antiplatelet treatment included SAT 1 day preprocedural and the third centre adopted DAPT as the standard treatment. In the DAPT group, a loading dose of 300 mg clopidogrel was provided 1 day preprocedural when treated transfemoral. In the transapical cases no loading dose of clopidogrel was administered but clopidogrel 75 mg was started 1 day postprocedural in combination with ASA 75 mg lifelong.
Lastly, Poliacikova et al prospectively compared two antiplatelet regimens in a patient registry treated between December 2007 and June 2012. Before May 2010 the hospital policy included DAPT for 6 months, including preloading with ASA 300 mg and clopidogrel 300 mg 2–6 h preprocedural, followed by 6 months 75 mg of both ASA and clopidogrel. After May 2010, the policy changed to only ASA lifelong. For the current analysis additional data on patients treated between May 2010 and March 2014 were provided (N=343).
The data requested for each study patient included the following at baseline: date of inclusion, age, gender, body mass index, diabetes mellitus, AF, renal disease, prior cerebrovascular event, peripheral artery disease, prior myocardial infarction (MI), prior coronary artery bypass grafting, prior percutaneous coronary intervention, left ventricular ejection fraction (LVEF), New York Heart Association functional classification, aortic valve peak gradient (mm Hg), aortic valve area (cm), European System for Cardiac Operative Risk Evaluation score, Society of Thoracic Surgeons (STS) score (%); antithrombotic treatment: loading dose, maintenance dose, treatment duration; procedural characteristics: date TAVI, approach (transfemoral, transapical, subclavian, transaortic), valve type, valve size, device success and during follow-up: 30-day occurrence of all-cause mortality (all-cause or cardiovascular death), acute coronary syndrome (ACS), cerebrovascular event, cerebrovascular event classification (major/minor or transient ischaemic attack) and bleeding (life-threatening or disabling, major or minor bleeding). Data were checked for consistency against the original publications.
The primary endpoint was defined as the net adverse clinical and cerebral events (NACE) at 1 month, a composite of all-cause mortality, ACS, stroke (major and minor), life-threatening and disabling bleeding or major bleeding as defined by VARC criteria. Moreover, the individual endpoints of the composite were compared between patients treated with ASA and DAPT.
Continuous variables are presented as either mean±SD or median with IQRs and compared with the unpaired Student's t test if they followed a normal distribution, and with the independent Mann–Whitney U test when they did not. Categorical variables are expressed as frequency (percentages) and were compared using Pearson's χ test.
For the non-randomised studies we applied propensity score matching to account for differences in baseline characteristics between patients treated with ASA or DAPT. In each observational study separately, a multivariable logistical regression model was used to estimate propensity scores, with the two groups (ie, DAPT vs ASA) as dependent variable and potential confounders as covariates. In the study by Durand et al, we included prior MI, age, peripheral artery disease and LVEF, and in the study by Poliacikova et al, we included New York Heart Association functional classification and valve type in the multivariable logistical regression models. For variables STS and EuroSCORE, there were some missing data, but were both not predictive for antiplatelet treatment and therefore not included in the propensity model. The propensity matched cohort was established by matching each individual case treated with DAPT in random order to the patient from the control group with the closest propensity score. The difference between the propensity scores of the patients treated with DAPT and their matched counterparts could be no more than 0.25 times the SD of the propensity for DAPT. The propensity score derivation and matching process were performed in each dataset separately. The degree of balance in covariates between patients with ASA and DAPT after matching was assessed by calculating the standardised difference and assessment of global imbalance.
Matched patients in the two cohorts were pooled with the patient data of the RCTs for further analysis. The OR with 95% CI was estimated for each individual study with logistical regression for the RCTs and the adapted Mantel–Haenszel method for the matched cohorts. Considering that both unmatched and matched studies were included, a pooled OR of NACE and individual endpoints was obtained by adaption of the Mantel–Haenszel method. In this method the unmatched studies and the matched pairs within the matched studies are treated as strata. Forest plots for each endpoint were generated by inserting the calculated ORs in Review manager using the generic inverse variance methods.
Heterogeneity between studies was assessed by visually comparing ORs for each study with the overall estimate and by calculating an I value for every outcome. A statistical significance for hypothesis testing was set at a p value <0.05. All statistical analyses were performed using SPSS software (V.20.0; SPSS, Chicago, Illinois, USA), R (R Foundation for Statistical Computing, Vienna, Austria) and Review Manager software (V.5.2; The Nordic Cochrane Centre, Copenhagen, Denmark).
Methods
Data Sources and Study Selection
We searched PubMed, Medline, EMBASE and the Current Controlled Trials for English-language studies on the antithrombotic treatment following TAVI published between 1 January 2002 and April 2014. We chose 2002 as the lower boundary of the search given that the first human case description of TAVI was published in that year.
The following key words were used: 'transcatheter aortic valve implantation', 'percutaneous aortic valve', 'transfemoral aortic valve implantation', 'transapical aortic valve implantation', 'percutaneous aortic valve implantation', 'endovascular aortic valve implantation', 'Core Valve', 'Edwards Sapien valve', 'JenaValve', 'heart valve prosthesis implantation', 'transcatheter aortic valve replacement', 'trans subclavian aortic valve implantation', 'platelet aggregation inhibitors', 'antiplatelet', 'dual antiplatelet therapy', 'clopidogrel', 'aspirin', 'acetylsalicylic acid', 'single antiplatelet therapy', 'thienopyridine'. Additionally, we manually searched the abstracts of the following conferences: Transcatheter Cardiovascular Therapeutics, European Society of Cardiology and American Heart Association. Moreover, we reviewed the references of reviews and identified studies for additional articles.
Studies were included if they complied with the following requirements: inclusion of patients with aortic stenosis treated with TAVI, clear description of postprocedural antithrombotic treatment including one group treated with single antiplatelet therapy (SAT) and another treated with DAPT, and minimum follow-up of 1 month. Studies were excluded if only one antithrombotic treatment was considered or when the treatment groups merely included DAPT versus SAT in combination with VKA treatment. Study selection was done by two independent reviewers (MH and RD).
Of the 191 potentially eligible studies, 180 were excluded at the title/abstract level. The remaining 11 studies were subjected to a more detailed review using the predefined inclusion and exclusion criteria. An additional six studies were excluded for the following reasons: DAPT was compared with SAT combined with VKA in TAVI patients with known atrial fibrillation (AF; n=3), ischaemic and bleeding events were only reported in patients treated with DAPT (n=2), bleeding events were the only reported outcome (n=1) and exclusion of 30-day events from the analysis (n=1; see figure 1).
(Enlarge Image)
Figure 1.
Flow diagram of studies included in this meta-analysis. DAPT, dual antiplatelet therapy; VKA, vitamin K antagonist; SAT, single antiplatelet therapy.
In total, four studies were identified with a total of 640 patients, including two randomised controlled trials (RCTs). The principal investigator of each trial was approached and all consented to collaborate in a patient level pooled analysis. They provided the requested data, and vouched for the correctness of the data. Institution review board (IRB) approval was obtained by three studies and informed consent was obtained in all studies. Poliacikova et al did not request IRB approval considering that this was a retrospective analysis of prospective gathered data from the National British Cardiovascular Interventions Society TAVI database for which informed consent was previously obtained. For the current patient pooled analysis we obtained approval from the medical ethical committee of the Academic Medical Center, Amsterdam, The Netherlands.
Study Population
We included patient-level data from four studies comparing single versus DAPT following TAVI. In all of these studies, clinical endpoints included all-cause mortality, acute coronary syndrome (ACS), stroke, life-threatening and major bleeding as defined by the Valve Academic Research Consortium (VARC) criteria.
The recently published SAT-TAVI study is a RCT comparing 81 mg ASA lifelong with DAPT (75 mg clopidogrel and 81 mg ASA) for 6 months in 120 patients. Patients randomised to DAPT were provided a preloading dose of 300 mg clopidogrel 1 day preprocedural.
In the RCT by Ussia et al, 79 patients were randomised to 100 mg ASA lifelong or 3 months DAPT (75 mg clopidogrel and 100 mg ASA). Patients randomised to DAPT were provided a preloading dose of 300 mg clopidogrel 1 day preprocedural.
Durand et al compared two antiplatelet regimens in 292 patients enrolled in three centres participating in the FRANCE 2 TAVI registry. In two centres the adopted antiplatelet treatment included SAT 1 day preprocedural and the third centre adopted DAPT as the standard treatment. In the DAPT group, a loading dose of 300 mg clopidogrel was provided 1 day preprocedural when treated transfemoral. In the transapical cases no loading dose of clopidogrel was administered but clopidogrel 75 mg was started 1 day postprocedural in combination with ASA 75 mg lifelong.
Lastly, Poliacikova et al prospectively compared two antiplatelet regimens in a patient registry treated between December 2007 and June 2012. Before May 2010 the hospital policy included DAPT for 6 months, including preloading with ASA 300 mg and clopidogrel 300 mg 2–6 h preprocedural, followed by 6 months 75 mg of both ASA and clopidogrel. After May 2010, the policy changed to only ASA lifelong. For the current analysis additional data on patients treated between May 2010 and March 2014 were provided (N=343).
Data Collection
The data requested for each study patient included the following at baseline: date of inclusion, age, gender, body mass index, diabetes mellitus, AF, renal disease, prior cerebrovascular event, peripheral artery disease, prior myocardial infarction (MI), prior coronary artery bypass grafting, prior percutaneous coronary intervention, left ventricular ejection fraction (LVEF), New York Heart Association functional classification, aortic valve peak gradient (mm Hg), aortic valve area (cm), European System for Cardiac Operative Risk Evaluation score, Society of Thoracic Surgeons (STS) score (%); antithrombotic treatment: loading dose, maintenance dose, treatment duration; procedural characteristics: date TAVI, approach (transfemoral, transapical, subclavian, transaortic), valve type, valve size, device success and during follow-up: 30-day occurrence of all-cause mortality (all-cause or cardiovascular death), acute coronary syndrome (ACS), cerebrovascular event, cerebrovascular event classification (major/minor or transient ischaemic attack) and bleeding (life-threatening or disabling, major or minor bleeding). Data were checked for consistency against the original publications.
Definition of Outcomes
The primary endpoint was defined as the net adverse clinical and cerebral events (NACE) at 1 month, a composite of all-cause mortality, ACS, stroke (major and minor), life-threatening and disabling bleeding or major bleeding as defined by VARC criteria. Moreover, the individual endpoints of the composite were compared between patients treated with ASA and DAPT.
Statistical Analysis
Continuous variables are presented as either mean±SD or median with IQRs and compared with the unpaired Student's t test if they followed a normal distribution, and with the independent Mann–Whitney U test when they did not. Categorical variables are expressed as frequency (percentages) and were compared using Pearson's χ test.
For the non-randomised studies we applied propensity score matching to account for differences in baseline characteristics between patients treated with ASA or DAPT. In each observational study separately, a multivariable logistical regression model was used to estimate propensity scores, with the two groups (ie, DAPT vs ASA) as dependent variable and potential confounders as covariates. In the study by Durand et al, we included prior MI, age, peripheral artery disease and LVEF, and in the study by Poliacikova et al, we included New York Heart Association functional classification and valve type in the multivariable logistical regression models. For variables STS and EuroSCORE, there were some missing data, but were both not predictive for antiplatelet treatment and therefore not included in the propensity model. The propensity matched cohort was established by matching each individual case treated with DAPT in random order to the patient from the control group with the closest propensity score. The difference between the propensity scores of the patients treated with DAPT and their matched counterparts could be no more than 0.25 times the SD of the propensity for DAPT. The propensity score derivation and matching process were performed in each dataset separately. The degree of balance in covariates between patients with ASA and DAPT after matching was assessed by calculating the standardised difference and assessment of global imbalance.
Matched patients in the two cohorts were pooled with the patient data of the RCTs for further analysis. The OR with 95% CI was estimated for each individual study with logistical regression for the RCTs and the adapted Mantel–Haenszel method for the matched cohorts. Considering that both unmatched and matched studies were included, a pooled OR of NACE and individual endpoints was obtained by adaption of the Mantel–Haenszel method. In this method the unmatched studies and the matched pairs within the matched studies are treated as strata. Forest plots for each endpoint were generated by inserting the calculated ORs in Review manager using the generic inverse variance methods.
Heterogeneity between studies was assessed by visually comparing ORs for each study with the overall estimate and by calculating an I value for every outcome. A statistical significance for hypothesis testing was set at a p value <0.05. All statistical analyses were performed using SPSS software (V.20.0; SPSS, Chicago, Illinois, USA), R (R Foundation for Statistical Computing, Vienna, Austria) and Review Manager software (V.5.2; The Nordic Cochrane Centre, Copenhagen, Denmark).
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