Background
Objective
Methodology
Protocol
Eligibility criteria
Inclusion Criteria | Exclusion Criteria | |
---|---|---|
Study type | All controlled intervention study | • Non-English study • Unfinished studies (Before Phase III) • Reviews, editorials, letters, notes, surveys, conference abstract |
Participants | • SVD characterised by: 1. Primary and secondary valve abnormalities 2. Prior valvular procedures | Non-human subjects |
Intervention | One of NOACs | Combined therapy with VKA |
Control | Warfarin and its derivatives | Combined therapy with heparin |
Outcome | • Efficacy: SSEE, Mortality • Safety: Major bleeding | Unpublished data |
Search strategy and information sources
Study selection
Data collection process
Data items
Assessment of heterogeneity
Synthesis of results and summary measures
Risk of bias in individual studies
Risk of bias across studies
Bias | Judgement | Support |
---|---|---|
Article 1 | ||
Selection | Low | Quote: “we have randomized 18,206 patients with AF from over 1000 centers in about 40 countries. Eligible subjects were randomly assigned in a 1:1 ratio to receive either apixaban or warfarin …” |
Performance | Low | Quote: “To maintain blinding, study medications are packaged using a double-dummy design. The 2 sets of tablets each subject receives are distinguishable by color and size, but active apixaban tablets match placebo apixaban tablets and active warfarin tablets match placebo warfarin tablets to ensure blinding of the patient and investigator.” |
Detection | Low | |
Attrition | Low | The reason of exclusion of patient was clearly stated |
Reporting | Low | All pre-specified outcomes were reported as HR and 95%CI with respective number of patients |
Article 2 | ||
Selection | Low | Quote: “Subjects are randomized through an interactive voice/ Web response system (IVRS) ... Approximately 20,500 patients will be enrolled with history of AF documented on an electrical recording within the past 12 months for whom anticoagulation is planned for the duration of the trial. Subjects are randomized 1:1:1 ... Randomization is stratified by CHADS2 score 2 to 3 versus 4 to 6 and drug clearance” |
Performance | Low | Quote: “ENGAGE AF–TIMI 48 is a large, multinational, randomized (1:1:1), double-blind, double-dummy ... All subjects are dispensed 2 sets of study drug. The first set, edoxaban or matching placebo ... The second set, warfarin or matching placebo” |
Detection | Low | Quote: “INR measurements are performed using a point-of-care device supplied to each study site. The INR results generated by the point-of-care device are masked by a “code number,” which is reported by the investigators to a central IVRS … ” |
Attrition | Low | The reason of exclusion of patient was clearly stated |
Reporting | Low | All pre-specified outcomes were reported as HR and 95%CI with respective number of patients |
Article 3 | RE-LY [6] | |
Selection | Low | Quote: “The patients were randomized by a central randomization service, through an interactive voice response system (IVRS) located at the Coordinating Centre at Population Health Research Institute (PHRI) in Hamilton, Canada” |
Performance | High | Open label |
Detection | Low | Quote: “RE-LY is a phase 3, multicenter, prospective, open-label, randomized trial with blinded evaluation of all outcomes (PROBE design).” |
Attrition | Low | The reason of exclusion of patient was clearly stated |
Reporting | Low | All pre-specified outcomes were reported as HR and 95%CI with respective number of patients |
Article 4 | ROCKET-AF [7] | |
Selection | Low | Quote: “Over 14,000 patients have been randomized in the ROCKET AF trial at 1100 sites across 45 countries. Patients are allocated to 1 of 2 study regimens: rivaroxaban or warfarin.” |
Performance | Low | Quote: “A double-blind design was chosen to minimize bias in cointerventions and interpretation of clinical events. To maintain blinding in ROCKET AF, sham INR results are provided. A point-of-care coagulation testing device displays a code number that, when entered into the Interactive Voice Response System along with the subject’s study identification number, is decoded and generates either the subject’s real INR or a sham INR value, depending on the patient’s blinded treatment.” |
Detection | Low | |
Attrition | Low | The reason of exclusion of patient was clearly stated |
Reporting | Low | All pre-specified outcomes were reported as HR and 95%CI with respective number of patients |
Article 5 | Seeger et. al., 2017 [16] | |
Selection | High | The allocation of group is not randomised |
Performance | High | The patient and the physician was not blinded |
Detection | High | |
Attrition | Low | The reason of exclusion of patient was clearly stated |
Reporting | Low | All prespecified outcomes were reported as event rate with respective number of patients |
Article 6 | Geis et. al., 2018 [17] | |
Selection | High | The allocation of group is not randomised and the study have retrospective design |
Performance | High | The patient and the physician was not blinded |
Detection | High | |
Attrition | Low | The reason of exclusion of patient was clearly stated |
Reporting | Low | All prespecified outcomes were reported as event rate with respective number of patients |
Result
Study selection
Study characteristics
Trial | Targeted Drug | Target sample size | Duration/ month | |
---|---|---|---|---|
ARISTOTLE* | Intervention | Apixaban 5 mg BD | 2438 | 21.8 |
(Avezum et al., 2015) | Control | Wafarin (INR 2–3) | 2370 | |
ENGAGE AF-TIMI 48* | Intervention | Edoxaban 60 mg QD | 1869 | 33.6 |
(De Caterina et al., 2017) | Control | Warfarin (INR 2–3) | 955 | |
RE-LY | Intervention | Pradaxa 110/150 mg QD | 2646 | 36 |
(Ezekowitz et al., 2016) | Control | Warfarin (INR 2–3) | 652 | |
ROCKET AF* | Intervention | Rivaroxaban 20 mg QD | 939 | 48 |
(Breithardt et al., 2016) | Control | Warfarin (INR 2–3) | 1001 | |
Seeger et al. | Intervention | Apixaban | 141 | 1, 12 |
−2017 | Control | Phenprocoumon | 131 | |
Geis et al. | Intervention | NOAC | 154 | 6 |
−2018 | Control | Warfarin (INR 2–3) | 172 |
Trial | Included VHD | Baseline Clinical Characteristics | |||||||
---|---|---|---|---|---|---|---|---|---|
Group | Age | CHADS2 | HAS-BLED | HTN | CVA | DM | MI | ||
ARISTOTLE* | Bioprosthetic valve | / | 71 (64, 77) | 2.2 ± 1.1 | N/A | 4102 (85.3) | 905 (18.8) | 1086 (22.6) | 837 (17.4) |
(Avezum et al., 2015) | Mitral valve repair | ||||||||
Native valve disease | |||||||||
ENGAGE AF-TIMI 48* (De Caterina et al., 2017) | Bioprosthetic valve | HDER | 71.8 ± 9.4 | 2.92 ± 1.0 | 2.55 ± 0.98 | 2629 (93.1) | 668 (23.7) | 908 (32.2) | 1122 (39.8) |
Mitral valve repair | LDER | ||||||||
Native valve disease | |||||||||
RE-LY | Native valve disease | Intervention: D110 | 74 (68, 78) | 2 (1,3) | N/A | 988 (76.5) | 279 (21.6) | 298 (23.1) | 251 (19.4) |
(Ezekowitz et al., 2016) | Intervention: D150 | 74 (67, 79) | 2 (1,3) | 1051 (77.7) | 310 (22.9) | 320 (23.7) | 250 (18.5) | ||
Control | 74 (68, 79) | 2 (1,3) | N/A | 1012 (77.5) | 286 (21.9) | 316 (24.2) | 212 (16.2) | ||
ROCKET AF* | Mitral valve repair | AS | 78 (73, 82) | 3.6 ± 0.9 | 3 ± 0.9 | 197 (92) | 99 (46) | 92 (43) | 64 (30) |
(Breithardt et al., 2016) | Native valve disease | MR/AR | 74 (67, 79) | 3.5 ± 1.0 | 2.8 ± 1.0 | 1542 (89) | 829 (48) | 690 (40) | 404 (23) |
Seeger et al. | Post-TAVI | / | 81.3 ± 5.9 | 4.9 ± 1.2 (CHA2DS2VASc) | 3.1 ± 1.1 | N/A | 35 (12.9) | 32.4 (88) | 19.5 (53) |
−2017 | |||||||||
(Geis et al., 2018) | Post-TAVI | Intervention | 83.1 ± 5.3 | 4.6 ± 1.2 (CHA2DS2VASc) | 2.7 ± 0.8 | 147 (95) | 24 (16) | 47 (31) | 80 (52) |
Control | 83.0 ± 4.9 | 4.8 ± 1.3 (CHA2DS2VASc) | 2.9 ± 0.8 | 158 (92) | 25 (15) | 57 (33) | 88 (51) |
Synthesis of results
Study / Trial | With SEE | Without SEE | With Major Bleeding | Without Major Bleeding | All Cause Death | Survived | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Intervention | Control | Intervention | Control | Intervention | Control | Intervention | Control | Intervention | Control | Intervention | Control | |
ARISTOTLE | 64 | 89 | 2374 | 2281 | 99 | 119 | 2339 | 2251 | 222 | 215 | 2216 | 2155 |
ENGAGE TIMI 48 | 82 | 50 | 1787 | 905 | 99 | 89 | 1770 | 866 | 308 | 147 | 1561 | 808 |
RE-LY | 77 | 98 | 2569 | 1206 | 209 | 264 | 2437 | 1040 | 226 | 244 | 2420 | 1060 |
ROCKET AF | 38 | 50 | 901 | 951 | 253 | 240 | 686 | 761 | 100 | 112 | 839 | 889 |
Seeger | 3 | 7 | 138 | 124 | 5 | 7 | 136 | 124 | 2 | 5 | 139 | 126 |
−2017 | ||||||||||||
Geis (2018) | 4 | 2 | 150 | 170 | 11 | 11 | 143 | 161 | 12 | 11 | 142 | 161 |
Risk of bias
STUDY | Overall | Subgroup: VHD | Subgroup: TAVI | Sensitivity Test | Harbord’s modified test | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
RR | 95%CI | Weight(%) | RR | 95%CI | Weight(%) | RR | 95%CI | Weight(%) | RR | 95%CI | p-value | |
ARISTOTLE, 2015 | 0.699 | 0.510, 0.959 | 23.77 | 0.699 | 0.510, 0.959 | 26.35 | 0.661 | 0.415, 1.054 | 0.97 | |||
ENGAGE AF-TIMI 48, 2017 | 0.838 | 0.595, 1.181 | 22.99 | 0.838 | 0.595, 1.181 | 25.42 | 0.622 | 0.412, 0.939 | ||||
RE-LY, 2016 | 0.387 | 0.273, 0.548 | 22.85 | 0.387 | 0.273, 0.548 | 25.25 | 0.772 | 0.633, 0.941 | ||||
ROCKET AF, 2014 | 0.81 | 0.536, 1.224 | 20.95 | 0.81 | 0.536, 1.224 | 22.99 | 0.633 | 0.417, 0.960 | ||||
Seeger, 2017 | 0.398 | 0.105, 1.508 | 5.64 | 0.398 | 0.105, 1.508 | 54.56 | 0.685 | 0.479, 0.979 | ||||
Geis, 2018 | 2.234 | 0.415, 12.026 | 3.8 | 2.234 | 0.415, 12.026 | 45.44 | 0.636 | 0.456, 0.886 | ||||
Overall | 0.665 | 0.468, 0.945 | 100 | 0.652 | 0.457, 0.930 | 100 | 0.872 | 0.159, 4.767 | 100 | 0.664 | 0.474, 0.931 | |
Heterogeneity Measures | Value | df | p-value | Value | df | p-value | Value | df | p-value | |||
Cochran’s Q | 14.59 | 5 | 0.012 | 12.12 | 3 | 0.007 | 2.47 | 1 | 0.116 | |||
Heterogeneity Measures | Value (95%CI) | Value (95%CI) | Value (95%CI) | |||||||||
I2 (%) | 62.7 | 9.41, 84.65 | 75.27 | 31.56, 91.07 | 60.52 | 0.00, 90.80 | ||||||
H2 | 2.68 | 1.10, 6.51 | 4.04 | 1.46, 11.19 | 2.53 | 0.59, 10.87 | ||||||
tau2 (BDL) | 0.109 | 0.098 | 0.916 |
STUDY | Overall | Subgroup: VHD | Subgroup: TAVI | Sensitivity Test | Harbord’s modified test | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
RR | 95%CI | Weight(%) | RR | 95%CI | Weight(%) | RR | 95%CI | Weight(%) | RR | 95%CI | p-Value | |
ARISTOTLE, 2015 | 0.809 | 0.623, 1.049 | 19.42 | 0.809 | 0.623, 1.049 | 24.61 | 0.698 | 0.395, 1.234 | 0.585 | |||
ENGAGE AF-TIMI 48, 2017 | 0.568 | 0.432, 0.749 | 19.27 | 0.568 | 0.432, 0.749 | 24.43 | 0.756 | 0.437, 1.31 | ||||
RE-LY, 2016 | 0.39 | 0.319, 0.477 | 19.99 | 0.39 | 0.319, 0.477 | 25.27 | 0.831 | 0.592, 1.169 | ||||
ROCKET AF, 2014 | 1.124 | 0.965, 1.309 | 20.35 | 1.124 | 0.965, 1.309 | 25.69 | 0.621 | 0.422, 0.915 | ||||
Seeger, 2017 | 0.664 | 0.216, 2.039 | 8.78 | 0.664 | 0.216, 2.039 | 34.06 | 0.72 | 0.446, 1.164 | ||||
Geis, 2018 | 1.117 | 0.498, 2.503 | 12.19 | 1.117 | 0.498, 2.503 | 65.94 | 0.671 | 0.411, 1.093 | ||||
Overall | 0.714 | 0.461, 1.105 | 100 | 0.672 | 0.402, 1.122 | 100 | 0.935 | 0.486, 1.801 | 100 | 0.715 | 0.455, 1.122 | |
Heterogeneity Measures | Value | df | p-value | Value | df | p-value | Value | df | p-value | |||
Cochran’s Q | 71.36 | 5 | 0 | 74.19 | 3 | 0 | 0.055 | 1 | 0.459 | |||
Heterogeneity Measures | Value (95%CI) | Value (95%CI) | Value (95%CI) | |||||||||
I2 (%) | 91.12 | 83.43, 95.24 | 95.58 | 91.54, 97.69 | 0 | 0.00, 100.00 | ||||||
H2 | 11.26 | 6.03, 21.00 | 22.62 | 11.82, 43.30 | 1 | / | ||||||
tau2 (BDL) | 0.238 | 0.261 | 0 |
STUDY | Overall | Subgroup: VHD | Subgroup: TAVI | Sensitivity Test | Harbord’s modified test | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
RR | 95%CI | Weight(%) | RR | 95%CI | Weight(%) | RR | 95%CI | Weight(%) | RR | 95%CI | p-Value | |
ARISTOTLE, 2015 | 1.004 | 0.839, 1.200 | 21.54 | 1.004 | 0.839, 1.200 | 25.42 | 0.792 | 0.494, 1.271 | 0.674 | |||
ENGAGE AF-TIMI 48, 2017 | 1.071 | 0.894, 1.282 | 21.52 | 1.071 | 0.894, 1.282 | 25.4 | 0.779 | 0.498, 1.221 | ||||
RE-LY, 2016 | 0.456 | 0.373, 0.559 | 21.23 | 0.456 | 0.373, 0.559 | 25.05 | 1.018 | 0.910, 1.139 | ||||
ROCKET AF, 2014 | 0.952 | 0.738, 1.228 | 20.46 | 0.952 | 0.738, 1.228 | 24.14 | 0.806 | 0.515, 1.26 | ||||
Seeger, 2017 | 0.372 | 0.073, 1.883 | 4.18 | 0.372 | 0.073, 1.883 | 34.42 | 0.864 | 0.599, 1.247 | ||||
Geis, 2018 | 1.218 | 0.554, 2.681 | 11.08 | 1.218 | 0.554, 2.681 | 65.58 | 0.797 | 0.543, 1.171 | ||||
Overall | 0.835 | 0.578, 1.205 | 100 | 0.827 | 0.556, 1.229 | 100 | 0.811 | 0.244, 2.692 | 100 | 0.835 | 0.584, 1.195 | |
Heterogeneity Measures | Value | df | p-value | Value | df | p-value | Value | df | p-value | |||
Cochran’s Q | 48.87 | 5 | 0 | 46.38 | 3 | 0 | 1.65 | 1 | 0.2 | |||
Heterogeneity Measures | Value (95%CI) | Value (95%CI) | Value (95%CI) | |||||||||
I2 (%) | 87.89 | 76.10, 93.86 | 93.48 | 86.52, 96.52 | 49.35 | 0.00, 100.00 | ||||||
H2 | 8.26 | 4.18, 16.30 | 15.35 | 7.42, 31.76 | 1.97 | / | ||||||
tau2 (BDL) | 0.155 | 0.153 | 0.408 |