Introduction
Methods
PICO-statement
Eligibility criteria
Information sources & search strategy
Selection process
Data collection & data items
Study risk of bias assessment
Effect measures for outcomes
Methods of data synthesis and statistical analysis
Results
Study selection
Study characteristics
Author | Year of publication | Study design | Type of Comparison | Number of participants per group | Adult / pediatric patients | Type of ECMO | Indication for ECMO | Male sex | Mean age ± SD (years) | aPTT aim (s) |
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Hamzah [63] | 2022 (under review) | Multi center, retrospective | Heparin vs. Bivalirudin | Total: 225 Hep.: 150 Biv.: 75 | pediatric | VV-ECMO: 36 VA-ECMO: 141 eCPR: 48 | eCPR: 48 CPB weaning: 115 Not reported: 62 | Hep.: 74 Biv.: 38 | Hep.: 8 (1, 36) Biv.: 7 (2, 37) (months, median, IQR) | Not reported |
Pieri [58] | 2021 | Single center, retrospective | Heparin vs. Bivalirudin | Total: 125 Hep.: 26 Biv.: 99 | All adult patients | VV-ECMO only | ARDS only | Total: 93 | Not reported | Hep.: 55–60 Biv.:55–60 |
Sheridan [9] | 2021 | Single center, retrospective | Heparin vs. Bivalirudin | Total: 150 Hep.: 50 Biv.: 100 | All adult patients | VV-ECMO: 52 VA-ECMO: 88 | CS: 58 Resp. fail.: 59 PE: 10 CPB weaning: 11 Others:12 | Total: 106 Hep.: 32 Biv.: 74 | Total: 53 ± 14.5 Hep.: 53 ± 14 Biv.: 54 ± 15 | Hep.: < 95 and anti-FXa 0.3–0.7 IU/mL Biv.:45–75 |
Machado [54] | 2021 | Single center, retrospective | Heparin vs. Bivalirudin | Total: 32 Hep.: 14 Biv.: 18 | All pediatric patients | VA-ECMO: 30 VV-ECMO: 1 Hybrid: 1 | Not reported | Total: 12 Hep.: 9 Biv.: 7 | Hep.: 39.8 ± 76.1 Biv.: 36 ± 58.8 (months) | Not reported (individual goals) |
Seelhammer [62] | 2021 | Single center, retrospective | Heparin vs. Bivalirudin | Total: 422 Hep.: 288 Biv.: 134 | Adult: 333 Pediatric: 89 | VA-ECMO: 358 VV-ECMO: 64 | Post cardiotomy: 162 CS: 100 Resp. fail.: 86 eCPR: 69 Transplant: 5 | Total: 265 Hep.: 183 Biv.: 82 | Not reported | Hep.: 60–90 Biv.: 60–80 |
Schill [63] | 2021 | Single center, retrospective | Heparin vs. Bivalirudin vs. switched | Total: 54 Hep.: 34 Biv.: 14 Switched: 8 | All pediatric patients | VA-ECMO: 38 VV-ECMO: 18 | Post cardiotomy: 20 Resp. fail.: 19 CS: 17 | Not reported | Hep.: 16.3 (4.8, 143.7) Biv.: 5.5 (3.7, 79.6) (months, median,IQR) | Hep.: anti-FXa 0.3–0.7 IU/mL Biv.: 60–95 |
Kaushik [52] | 2021 | Single center, retrospective | Heparin vs. Bivalirudin vs. switched | Total: 39 Hep.: 27 Biv.: 8 Switched: 4 | All pediatric patients | VA-ECMO:34 VV-ECMO: 4 Hybrid: 1 | Resp. Fail.: 12 CS: 11 eCPR: 6 | Total: 20 Hep.: 15 Biv.: 3 | Hep.: 4.0 (0.5, 92.0) Biv.: 0.6 (0.0, 80.0) (months, median, IQR) | Hep.: 60–90 Biv.: 60–90 |
Rivosecchi [60] | 2021 | Single center, retrospective | Heparin vs. Bivalirudin | Total: 295 Hep.: 162 Biv.: 133 | All adult patients | VV-ECMO only | Resp. fail.: 145 Pre/post-transplant: 108 Post cardiotomy: 20 Others: 22 | Total: 146 Hep.: 95 Biv.: 81 | Hep.: 49 (36,61) Biv.: 49 (36,61) (median, IQR) | Hep.: anti-FXa 0.25–0.35 IU/mL Biv.: 60–75 |
Fisser [10] | 2021 | Single center, retrospective | Heparin vs. Argatroban | Total: 117 Hep.: 78 Arg.: 39 | All adult patients | VV-ECMO only | ARDS only | Total: 80 Hep.: 51 Arg.: 29 | Hep.: 56 (48,63) Arg.: 55 (46,61) (median, IQR) | Hep.: 45–55 Arg.:45–55 |
Cho [50] | 2021 | Single center, retrospective | Heparin vs. Argatroban | Total: 35 Hep.: 24 Arg.: 11 | All adult patients | VA-ECMO: 10 VV-ECMO: 21 Hybrid: 4 | Not reported | Total: 22 Hep.: 15 Arg.: 7 | Total: 46 ± 17 Hep.: 45 ± 16 Arg.: 49 ± 20 | Hep.: 40–60 or 60–80 (high dose) Arg.:43–85 |
Hamzah [11] | 2020 | Single center, retrospective | Heparin vs. Bivalirudin | Total: 32 Hep.: 16 Biv.: 16 | All pediatric patients | VA-ECMO: 29 VV-ECMO: 3 | Post cardiotomy:13 Others: not reported | Total: 14 Hep.: 8 Biv.: 6 | Total: 12 (0–212) Hep.: 59 (0, 212) Biv.: 31 (0–99) (months, median, IQR) | Hep.: 60–80 Biv.: 58–78 or 50–70 (open chest) |
Kaseer [51] | 2020 | Single center, retrospective | Heparin vs. Bivalirudin | Total: 52 Hep.: 33 Biv.: 19 | All adult patients | VA-ECMO: 28 VV-ECMO: 24 | CS:15 ARDS:24 Transplant: 17 Others:1 | Total: 37 Hep.: 25 Biv.: 12 | Total: 55 (18, 83) Hep.: 53 (21, 83) Biv.: 56 (18, 71) (median, IQR) | Hep.: 50–70 or 40–60 Biv.: 60–90 or 50–70 |
Macielak [55] | 2019 | Single center, retrospective | Heparin vs. Bivalirudin vs. switched | Total: 153 Hep.: 100 Biv.: 10 Switched: 43 | All adult patients | VA-ECMO: 134 Other types not reported | Salvage: 61% CS: 46% ARDS:29% Resp. fail.: 29% CPB weaning: 23% Others: 12% | Total: 127 | Total: 52.8 ± 14.2 Hep.: 51.4 ± 14.0 Biv.: 57.9 ± 13.8 | Hep.: 72–95 Biv.: 60–80 |
Berei [49] | 2018 | Single center, retrospective | Heparin vs. Bivalirudin | Total: 72 Hep.: 28 Biv.: 44 | All adult patients | VA-ECMO: 66 VV-ECMO: 6 | CS: 51 Sepsis: 11 Resp. fail.: 4 Others: 6 | Total: 47 Hep.: 18 Biv.: 29 | Hep.: 55.9 ± 13.1 Biv.: 55.2 ± 15.2 | Hep.: 45–65 or 65–90 Biv.: 45–65 or 65–90 |
Menk [56] | 2017 | Single center, retrospective | Heparin vs. Argatroban | Total: 78 Hep.: 39 Arg.: 39 | All adult patients | VV-ECMO: 43 pECLA: 24 Hybrid: 11 | ARDS only | Total: 54 Hep.: 27 Arg.: 27 | Hep.: 48 (35,64) Arg.: 47 (36,60) (median, IQR) | Hep.: 50–75 Arg.:50–75 |
Ljajikj [53] | 2017 | Single center, retrospective | Heparin vs. Bivalirudin | Total: 20 Hep.: 10 Biv.: 10 (after PS-Matching) | All adult patients | VA-ECMO only | support pre, during and after LVAD implantation only | Total: 17 Hep.: 9 Biv.: 8 | Hep.: 52.5 ± 9.7 Biv.: 48.2 ± 14.1 | Not reported |
Pieri [57] | 2013 | Single center, retrospective | Heparin vs. Bivalirudin | Total: 20 Hep.: 10 Biv.: 10 | All adult patients | VA-ECMO: 10 VV-ECMO: 10 | Not reported | Total: 16 Hep.: 9 Biv.: 7 | Hep.: 54 ± 12.7 Biv.: 59.5 ± 14.4 | Hep.: 45–60 Biv.: 45–60 |
Ranucci [59] | 2011 | Single center, retrospective | Heparin vs. Bivalirudin | Total: 21 Hep.: 8 Biv.: 13 | Adult: 12 Pediatric: 9 | VVA-ECMO: 21 | Post cardiotomy only | Not reported | Hep.: 13.9 ± 19 Biv.: 36.5 ± 29 | Hep.: 50–80 Biv.: 50–80 |
Risk of bias assessment
Results of individual studies and data syntheses for primary and secondary outcomes
In-hospital mortality
Research topic: Direct thrombin inhibitors compared with heparin for extracorporeal membrane oxygenation therapy | ||||||
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Patients: Adult and pediatric patients Setting: In-hospital extracorporeal membrane oxygenation therapy Intervention: Direct thrombin inhibitors Comparison: Unfractionated heparin | ||||||
Outcomes | Illustrative comparative risksb (95% CI) | Relative effect (95% CI) | No of Participants (studies) | Quality of the evidence (GRADE) | Comments | |
Assumed riska | Corresponding risk | |||||
unfractionated heparin | Direct thrombin inhibitors | |||||
Mortality | 474 per 1000 | 393 per 1000 (346 to 450) | RR 0.83 (0.73 to 0.95) | 1777 (17) | ⊕ ⊝ ⊝ ⊝ very low due to lack of RCTs, risk of bias, publication bias | |
Major bleeding events | 501 per 1000 | 336 per 1000 (251 to 456) | RR 0.67 (0.5 to 0.91) | 1355 (16) | ⊕ ⊝ ⊝ ⊝ very low due to lack of RCTs, risk of bias, publication bias | |
Minor bleeding events | 287 per 1000 | 247 per 1000 (195 to 316) | RR 0.86 (0.68 to 1.10) | 632 (8) | ⊕ ⊝ ⊝ ⊝ very low due to lack of RCTs, risk of bias, imprecision | |
Pump-related thrombosis | 233 per 1000 | 163 per 1000 (121 to 217) | RR 0.7 (0.52 to 0.93) | 1361 (13) | ⊕ ⊝ ⊝ ⊝ very low due to lack of RCTs, risk of bias, imprecision, publication bias | |
Patient-related thrombosis | 200 per 1000 | 162 per 1000 (118 to 220) | RR 0.81 (0.59 to 1.10) | 1447 (15) | ⊕ ⊝ ⊝ ⊝ very low due to lack of RCTs, risk of bias, inconsistency, publication bias | |
length of ECMO therapy (hours and days) | See comment | The SMD in length of ECMO therapy in the intervention groups was 0.12 higher (-0.03 lower to 0.27 higher) | 1274 (12) | ⊕ ⊝ ⊝ ⊝ very low due to lack of RCTs, risk of bias, imprecision, publication bias | Mean for control group not estimable as different measures were used for outcome assessment | |
length of hospital stay (days) | The mean time to anticoagulation goal ranged across control groups from 5 to 47 days | The SMD in length of hospital stay in the intervention groups was 0.19 higher (-0.30 lower to 0.69 higher) | 467 (4) | ⊕ ⊝ ⊝ ⊝ very low due to lack of RCTs, risk of bias, imprecision, publication bias | ||
time to anticoagulation goal (hours) | The mean time to anticoagulation goal ranged across control groups from 9 to 32 h | The SMD in time to anticoagulation goal in the intervention groups was 0.2 lower (-0.73 lower to 0.34 higher) | 324 (4) | ⊕ ⊝ ⊝ ⊝ very low due to lack of RCTs, risk of bias, imprecision, publication bias | ||
Percentage of time within therapeutic range (percentage) | The mean percentage of time within therapeutic range ranged across control groups from 11 to 31 percent | The SMD of percentage of time within therapeutic range in the intervention groups was 0.54 higher (0.14 to 0.94 higher) | 491 (5) | ⊕ ⊝ ⊝ ⊝ very low due to lack of RCTs, risk of bias, publication bias |