TABLE 1.
Summary of Study Characteristics
| First Author Year | Study Design | N | Study Period | Age at Fontan (y) | Age at Study Inclusion | Follow-Up (y) | Fontan Type | Study Drug |
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| Al-Jazairi et al20 2019 | Retrospective | 423 | 1985–2010 | 3.0 (IQR: 2.0) | Following Fontan | 13.6 (IQR: 8.7) | AP (n = 7) LT (n = 307) ECC (n = 107) Other (n = 2) |
Aspirin (n = 22) Warfarin (n = 385) None (n = 24) |
| Attard et al21 2021 | Retrospective | 121 | 1975–2020 | 4.8 (range 3.6–6.6) | 20.8 (range 15.5–28.1) (at least 5 y after Fontan procedure) | 16.2 (range 11.3–22.70) | AP (n = 12) LT (n = 28) ECC (n = 78) Unknown (n = 3) |
Aspirin (n = 54) Warfarin (n = 67) |
| Barker et al22 2005 | Retrospective | 402 | 1975–1998 | 2.2 | Following Fontan | 3.5 | LT (n = 306) ECC (n = 15) Other (n = 81) |
Aspirin (n = 277) Warfarin (n = 39) None (n = 36) Unknown (n = 50) |
| Cheung et al23 2005 | Retrospective | 85 | 1980–2002 | 6.2 ± 4.8 | Following Fontan | 6.6 ± 3.8 | AP (n = 51) LT (n = 19) ECC (n = 15) |
Aspirin (n = 8) Warfarin (n = 46) None (n = 31) |
| d’Udekem et al24 2007 | Retrospective | 215 | 1980–2000 | 4.4 (IQR: 3.0–7.0) | Following Fontan | 12 ± 6 | AP (n = 152) LT (n = 105) ECC (n = 48) (305 patients that underwent a Fontan procedure in the intervention period) |
Aspirin (n = 18) Warfarin (n = 176) None (n = 21) |
| Egbe et al25 2016 | Retrospective | 278 | 1994–2004 | 15 ± 6 | 31 ± 9 | 7.3 ± 1.2 | AP (n = 225) LT (n = 37) ECC (n = 16) |
Aspirin (N=181) Warfarin (n = 88) NOAC (n = 3) None (n = 6) |
| Faircloth et al26 2017 | Retrospective | 89 | 1997–2014 | 3 (IQR: 1.88–3.88) (event) 3.5 (IQR: 3–4.5) (no event) | Following Fontan | 8.3 (IQR: 6.8–11.4) | AP (n = 0) LT (n = 19) ECC (n = 70) |
Not specified |
| Haas et al27 2000 | Retrospective | 45 | 1990–1997 | 4 | Following Fontan | 5.3 | ECC (n = 45) | Aspirin (n = 38) Warfarin (n = 7) |
| Iyengar et al28 2016 | Retrospective | 475 | 1997–2010 | 4.4 (IQR: 3.5–5.6) (<1 y)/5.2 (IQR: 4.4–6.2) (>1 y) | Following Fontan | 7 (IQR: 4.7–9.7) | ECC (n = 475) | At <1 y Aspirin (n = 52) Warfarin (n = 410) None (n = 10) At >1 y Aspirin (n = 157) Warfarin (n = 301) None (n = 17) |
| Kaulitz et al29 2005 | Retrospective | 142 | 1988–2002 | 5.5 | Following Fontan | 7.6 | LT (n = 121) ECC (n = 21) |
Aspirin (n = 86) Warfarin (n = 11) None (n = 45) |
| Kawamatsu et al30 2021 | Retrospective | 139 | 2015–2018 | 13 ± 10 | 27 ± 7 | 7.9 ± 5.3 | AP (n = 9) LT (n = 48) ECC (n = 81) Unknown (n = 1) |
Antiplatelet (n = 43) Warfarin (n = 54) NOAC (n = 37) None (n = 5) |
| Lin et al31 2016 | Retrospective | 57 | 1992–2014 | 5.4 (IQR: 3.1–6.8) | 17.3 (IQR: 11.1–20.8) | 8.1 (IQR: 3.25–12.9) | AP (n = 35) LT (n = 17) ECC (n = 2) Other (n = 3) |
Not specified |
| Rationale for the Study Drug | Atrial Arrhythmiasa | Thromboembolic Event Rates (per 100 Patient-y) | Types of Thromboembolic Eventsb | Major Bleeding Event Rates (per 100 Patient-y) |
|---|---|---|---|---|
|
| ||||
| Not mentioned | 109/423 (26%) | Aspirin: 0.6, Warfarin: 0.8, NOAC: NA, None: NA | Not mentioned | Aspirin: 0.4, Warfarin: 0.3, NOAC: NA, None: NA |
| Not mentioned | Not mentioned | Aspirin: 0.5, Warfarin: 0.3, NOAC: NA, None: NA | 7 ischemic strokes, 2 PEs, 4 intracardiac thrombi | Aspirin: NA, Warfarin: NA, NOAC: NA, None: NA |
| Not mentioned | Not mentioned | Aspirin: 0.1, Warfarin: 0.0, NOAC: NA, None: 1.4 | Not mentioned | Aspirin: NA, Warfarin: NA, NOAC: NA, None: NA |
| Not mentioned | 8/77 (10%) with symptomatic cardiac arrhythmias | Aspirin: 0.0, Warfarin: 0.8, NOAC: NA, None: 0.8 | 2 strokes, 1 thrombus in blind ending PA stump, 1 unclear (2 were on warfarin, 1 had IART/PLE) | Aspirin: 0.0, Warfarin: 0.0, NOAC: NA, None: 0.0 |
| Not mentioned | 62/257 (24%) | Aspirin: 0.0, Warfarin: 0.7, NOAC: NA, None: 0.0 | 9 PEs, 1 stroke, 2 TIAs, 1 renal infarct (all were on warfarin at the time of the event) | Aspirin: NA, Warfarin: NA, NOAC: NA, None: NA |
| Not mentioned | 100% | Aspirin: 4.4, Warfarin: 2.2, NOAC: NA, None: 43.2 | 33 Fontan conduits/RA, 32 PEs, 14 intracardiac thrombi, 15 ischemic strokes, 2 renal infarctions, 1 splenic infarction | Aspirin: NA, Warfarin: NA, NOAC: NA, None: NA |
| Not mentioned | 30/89 (34%) | Aspirin: 1.9, Warfarin: 2.0, NOAC: NA, None: NA | 2 deep vein thromboses, 1 innominate vein/SVC, 1 PE, 3 Fontan conduits/RA, 1 single ventricle (2 were on warfarin) | Aspirin: NA, Warfarin: NA, NOAC: NA, None: NA |
| Absence of sinus rhythm or suboptimal hemodynamics (not further specified) | 6/45 (13%) had transient supraventricular tachycardia in the early postoperative phase | Aspirin: 0.0, Warfarin: 0.0, NOAC: NA, None: NA | - | Aspirin:, Warfarin:, NOAC:, None: |
| Center preference | Not mentioned | Aspirin: 0.4, Warfarin: 1.2, NOAC: NA, None: 2.4 | 6 strokes, 2 TIAs, 3 watershed infarcts, 17 Fontan conduit thromboses, 5 PEs, 1 renal embolism | Aspirin: 0.1, Warfarin: 0.5, NOAC: NA, None: 0.0 |
| Based on surgical method, preoperative parameters and early post-operative functional result (not further specified) |
18/142 (13%) | Aspirin: 0.2, Warfarin: 0.0, NOAC: NA, None: 2.4 | 2 strokes, 8 systemic venous thrombi (8 were on heparin, 1 on warfarin, 1 had no TE prophylaxis) | Aspirin: 0.0, Warfarin: 0.0, NOAC: NA, None: 0.0 |
| Not specified | 29/139 (21%) | Aspirin: 0.7, Warfarin: 1.7, NOAC: 0.0, None: 4.3 | Not specified | Aspirin: 0.7, Warfarin: 2.0, NOAC: 0.6, None: 0.0 |
| Aspirin (n = 13) Warfarin (n = 36) None (n = 8) | 100% | Aspirin: 3.8, Warfarin: 1.0, NOAC: NA, None: 7.7 | 12 strokes | Aspirin: NA, Warfarin: NA, NOAC: NA, None: NA |
| First Author Year | Study Design | N | Study Period | Age at Fontan (y) | Age at Study Inclusion | Follow-Up (y) | Fontan Type | Study Drug |
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| Mahnke et al32 2005 | Retrospective | 132 | 1976–2001 | Not mentioned | Following Fontan | 7.6 | AP (n = 40) LT (n = 74) ECC (n = 18) |
Aspirin (n = 87) Warfarin (n = 28) None (n = 17) |
| Manlhiot et al33 2012 | Retrospective | 162 | 2000–2009 | 3.4 | Following Fontan | 2.3 | LT (n = 35) ECC (n = 124) Other (n = 3) |
Aspirin (n = 26) Warfarin (n = 126) None (n = 10) |
| McCrindle et al34 2021 | RCT | 112 | 2016–2020 | 4.0 ± 1.6 | Following Fontan | 1 | Not reported | Aspirin (n = 34) NOAC (n = 78) NOAC were used in prophylactic doses |
| Monagle et al35 2011 | RCT | 111 | 1998–2003 | 4.8 | Following Fontan | 2 | ECC (n = 95) LT (n = 16) |
Aspirin (n = 57) Warfarin (n = 54) |
| Potter et al36 2013 | Retrospective | 210 | 1973–1991 | 8.5 | Following Fontan | 14.5 | AP (n = 102) LT (n = 81) ECC (n = 4) Other (n = 23) |
Aspirin (n = 51) Warfarin (n = 54) None (n = 105) |
| Seipelt et al37 2002 | Retrospective | 101 | 1986–1998 | 7.3 | Following Fontan | 5.7 | AP (n = 40) LT (n = 61) |
Aspirin (n = 14) Warfarin (n = 26) None (n = 45) |
| Small et al38 2018 | Retrospective | 52 | 2004–2017 | 8.2 (median) | 25.9 (range 16.2–39.4) | 2.8 | AP (n = 52) | Aspirin (n = 13) Warfarin (n = 13) None (n = 2) Other (n = 5) |
| Takawira et al39 2008 | Retrospective | 13 | 1997–2002 | 4.9 | Following Fontan | 5.2 | ECC | Aspirin (n = 10) Warfarin (n = 2) None (n = 1) |
| Yang et al40 2019 | Retrospective | 74 | 2014–2019 | 1.4±0.9 y | 32 ± 10 | 1.2 (median) | AP (n = 26) TCPC (n = 48) |
NOAC (n = 74) |
| Rationale for the Study Drug | Atrial Arrhythmiasa | Thromboembolic Event Rates (per 100 Patient-y) | Types of Thromboembolic Eventsb | Major Bleeding Event Rates (per 100 Patient-y) |
|---|---|---|---|---|
|
| ||||
| Prior PE, prosthetic valve or physician preference caused by ECC | 17/132 (13%) | Aspirin: 0.3, Warfarin: 0.0, NOAC: NA, None: 0.6 | 3 strokes (none had atrial arrhythmias) | Aspirin: 0.0, Warfarin: 0.0, NOAC: NA, None: 0.0 |
| Not mentioned | Not mentioned | Aspirin: 12.9, Warfarin: 4.5, NOAC: NA, None: 21.7 | Not mentioned | Aspirin: 0.0, Warfarin: 0.3, NOAC: NA, None: 0.0 |
| Randomization to Aspirin vs Rivaroxaban | Not mentioned | Aspirin: 8.8, Warfarin: NA, NOAC: 2.6, None: NA | 1 PE, 1 stroke, 2 venous thromboses | Aspirin: 0.0, Warfarin: NA, NOAC: 1.3, None: NA |
| Randomization to Aspirin vs Warfarin | Not mentioned (patients with a recognized indication for anticoagulation were a priori excluded) | Aspirin: 10.5, Warfarin: 12.0, NOAC: NA, None: NA | 20 within the Fontan connection, 4 PEs, 7 other venous sites (7 patients had thromboses identified in multiple locations) | Aspirin: 0.9, Warfarin: 0.9, NOAC: NA, None: NA |
| Not mentioned | Not mentioned | Aspirin: 0.6, Warfarin: 0.8, NOAC: NA, None: 2.2 | 25 RA, 3 PA, 2 SVC, 3 pulmonary venous atrium, 7 with missing information | Aspirin: NA, Warfarin: NA, NOAC: NA, None: NA |
| Before 1995 all patients received no treatment or Aspirin, after 1995 all received Warfarin | 18/85 (21%) | Aspirin: 1.6, Warfarin: 1.1, NOAC: NA, None: 4.2 | 2 Strokes, 2 SVC/PA thrombus (1 of which was followed by fatal PE), 1 PE, 1 innominate vein thrombus (with chylothorax), 4 RA thrombus, 3 residual PA trunk | Aspirin: 0.0, Warfarin: 0.0, NOAC: NA, None: 0.0 |
| Inconsistent (atrial arrhythmia was the cause to choose warfarin or aspirin) | 100% (none had a history of thromboembolic events at the beginning of the study period) | Aspirin: 16.5, Warfarin: 2.8, NOAC: NA, None: NA | Not mentioned | Aspirin: 2.7, Warfarin: 8.5, NOAC: NA, None: NA |
| Not mentioned | 0/13 (0%) | Aspirin: 0.0, Warfarin: 0.0, NOAC: NA, None: 0.0 | - | Aspirin: NA, Warfarin: NA, NOAC: NA, None: NA |
| Not mentioned | 52/74 (70%) | Aspirin: 6.0, Warfarin: 1.5, NOAC: 2.9, None: NA | 2 PEs, 1 stroke | Aspirin: 0.0, Warfarin: 0.8, NOAC: 2.9, None: NA |
a
The denominator might be different from the number of subjects included in the meta-analysis depending on the way the data is reported in the individual studies.
b
Acute treatment strategies for thromboembolic events have not been reported universally. Heparin has been used in several reported cases for the acute management of thromboembolic events.
AP = atriopulmonary; ECC = extracardiac conduit; LT = lateral tunnel; NA = not applicable/assessed; NOAC = nonvitamin K oral anticoagulant; PA = pulmonary artery; PE = pulmonary embolism; RA = right atrium; TCPC = total cavopulmonary connection; TIA = transient ischemic attack.