Table 3

Summary of GRADE evidence profile of PFO closure plus antiplatelet therapy vs anticoagulation in patients with cryptogenic stroke

Outcome
Timeframe
Study results and measurementsAbsolute effect estimates per 1000 patient-yearsCertainty in effect estimates
(quality of evidence)
Plain text summary
AnticoagulationPFO closure plus antiplatelet therapy
Ischaemic stroke
(standardised to 5 years)
OR: 0.44
(95% CrI 0.08 to 3.83)
Direct evidence in NMA from 353 patients in one study
Follow-up 5.3 years
29
per 1000
13
per 1000
Low
Due to very serious imprecision†
There may be little or no difference in ischaemic stroke
Difference: 16 fewer
(95% CrI 29 fewer* to 10 more)
Ischaemic stroke—modelling data from VTE literature
(standardised to 5 years)
OR: 0.93
(95% CI 0.31 to 2.76)
29
per 1000
27
per 1000
Low
Due to serious imprecision and serious indirectness‡
There may be little or no difference in ischaemic stroke
Difference: 2 fewer
(95% CI 20 fewer to 47 more)
Death
(standardised to 5 years)
Relative risk: 0.69
(95% CrI 0.02 to 32.36)
Direct evidence in NMA from 353 patients in one study
Follow-up 5.3 years
13
per 1000
9
per 1000
Moderate
Due to serious imprecision§
There is probably little or no difference in death
Difference: 4 fewer
(95% CrI 13 fewer* to 9 more)
Major bleeding
(standardised to 5 years)
OR: 0.26
(95% CrI 0.07 to 0.82)
Direct evidence in NMA from 353 patients in one study
Follow-up 5.3 years
27
per 1000
7
per 1000
Moderate
Due to serious imprecision¶
PFO closure plus antiplatelet therapy probably decreases major bleeding
Difference: 20 fewer
(95% CrI 27 fewer* to 2 fewer)
Major bleeding—modelling data from VTE literature
(standardised to 5 years)
OR: 0.28
(95% CI 0.13 to 0.55)
24
per 1000
7
per 1000
Moderate
Due to serious indirectness**
PFO closure plus antiplatelet therapy probably decreases major bleeding
Difference: 17 fewer
(95% CI 21 fewer to 11 fewer)
Persistent †† atrial fibrillation or flutter
(standardised to 1 year)
Relative risk: 4.84
(95% CI 1.91 to 12.26)
Based on data from 3560 patients in six studies
Follow-up 3.9 years
5
per 1000
23
per 1000
Moderate
Due to serious risk of bias§§
PFO closure plus antiplatelet therapy probably increases non-transient atrial fibrillation
Difference: 18 more per 1000 patients‡‡
(95% CI 5 more to 56 more)
Transient or paroxysmal atrial fibrillation or flutter
(standardised to 1 year)
Relative risk: 3.76
(95% CI 1.74 to 8.1)
Based on data from 3560 patients in six studies
Follow-up 3.9 years
5
per 1000
17
per 1000
Moderate
Due to serious risk of bias¶¶
PFO closure plus antiplatelet therapy probably increases transient atrial fibrillation
Difference: 12 more per 1000 patients ‡‡
(95% CI 3 more to 31 more)
Device or procedure-related adverse event
(standardised to 1 year)
Risk difference: 0.04
(95% CI 0.02 to 0.05)
Based on data from 3560 patients in six studies
Follow-up 3.9 years
0
per 1000
36
per 1000
HighPFO closure plus antiplatelet therapy increases device or procedure-related adverse events
Difference: 36 more per 1000 patients ‡‡
(95% CI 23 more to 50 more)
Transient ischaemic attack
(standardised to 5 years)
OR: 1.27
(95% CrI 0.4 to 4.52)
Direct evidence in NMA from 353 patients in one study
Follow-up 5.3 years
22
per 1000
28
per 1000
Moderate
Due to serious imprecision***
There is probably little or no difference in transient ischaemic attack
Difference: 6 more per 1000
(95% CrI 22 fewer* to 22 more)
Pulmonary embolism—modelling data from VTE literature
(standardised to 5 years)
OR: 9.09
(95% CI 3.7 to 25.0)
1
per 1000
5
per 1000
Moderate
Due to serious indirectness†††
There is probably little or no difference in pulmonary embolism
Difference: 4 more per 1000
(95% CI 1 more to 13 more)
Systemic embolism
(standardised to 5 years)
OR: 291.0
(95% CrI 0.0 to 999.0)
Direct evidence in NMA from 353 patients in one study
Follow-up 5.3 years
0
per 1000
0
per 1000
Moderate
Due to serious imprecision‡‡‡
There is probably little or no difference in systemic embolism
  • The baseline risk for PFO closure was used to estimate the absolute effect in the anticoagulation arm. The baseline risk in the PFO arm was calculated based on the median risk of the outcome in the six RCTs included. This allowed for consistency in the absolute effect estimate in the PFO closure arms in tables 2 and 3 and the anticoagulation arms in tables 3 and 4 allowing for ease in comparison.

  • *The calculated CI using risk difference, because of uncertainty in the point estimates, permits reductions greater than the point estimates in the PFO group. To avoid confusion, we have truncated to present the maximum reduction as equal to the PFO event rate.

  • †Imprecision: very serious. Wide CI. Low number of events.

  • ‡Indirectness: serious. In addition to the direct evidence from randomised trials in patients with PFO and a cryptogenic ischaemic stroke, we additionally considered external evidence from randomised trials that assessed the impact of anticoagulation vs antiplatelet therapy for the secondary prevention of venous thromboembolism. Imprecision: serious. Wide CIs, includes both appreciable benefit and harm.

  • §Imprecision: serious. Wide CIs, includes both appreciable benefit and harm. Low number of events.

  • ¶Imprecision: serious. Wide CI, included a not important benefit. Low number of events.

  • **Indirectness: serious. In addition to the direct evidence from randomised trials in patients with PFO and a cryptogenic ischaemic stroke, we additionally considered external evidence from randomised trials that assessed the impact of anticoagulation vs antiplatelet therapy for the secondary prevention of venous thromboembolism.

  • ††Defined as persistent according to the study definition or requiring a cardioversion attempt: the calculated CI using risk difference, because of uncertainty in the point estimates, permits reductions greater than the point estimates in the PFO group. To avoid confusion, we have truncated to present the maximum reduction as equal to the PFO event rate.

  • ‡‡In the first year after procedure rather than 5 years.

  • §§Risk of bias: serious. Not clearly stated how this was measured or assessed with prolonged ECG monitoring. Also, it is not clear for all events whether it was transient or persistent.

  • ¶¶Risk of bias: serious. Not clearly stated how this was measured or assessed with prolonged ECG monitoring. Also, it is not clear for all events whether it was transient or persistent.

  • ***Imprecision: serious. Wide CI, includes both appreciable benefit and harm. Low number of events.

  • NMA , network meta-analysis;  PFO,  patent foramen ovale; RCT, randomised controlled trial; VTE, venous thromboembolism.