Table 2.
GRADE evaluation of the certainty of evidence
| Certainty assessment | № of patients | Effect | Certainty | Importance | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| № of studies | Study design | Risk of bias | Inconsistency | Indirectness | Imprecision | Other considerations | Haloperidol | Placebo | Relative (96.7%/98% CI)* | Absolute (96.7%/98% CI)* | ||
| All-cause mortality (follow-up: range 28 days to 90 days) | ||||||||||||
| 5 | Randomised trials | Not seriousa | Not serious | Not serious | Seriousb | Nonec | 272/789 (34.5%) | 295/764 (38.6%) | RR 0.89 (0.87 to 1.03) | 42 fewer per 1.000 (from 50 fewer to 8 more) |
⨁⨁⨁◯ Moderate |
Critical |
| SAE/SAR (highest proportion) (follow-up: range 3 days to 90 days) | ||||||||||||
| 5 | Randomised trials | Not seriousa | Seriousd | Not serious | Seriousj | Nonec | 311/789 (39.4%) | 331/764 (43.3%) | RR 0.94 (0.81 to 1.10) | 26 fewer per 1.000 (from 82 fewer to 43 more) |
⨁⨁◯◯ Low |
Critical |
| SAEs/SARs (cumulated events) (follow-up: range 3 days to 90 days) | ||||||||||||
| 5 | Randomised trials | Not seriousa | Seriousd,e | Not serious | Very seriousf | Nonec | 426/789 (54.0%) | 440/764 (57.6%) |
RR 0.97 (0.85 to 1.11) |
17 fewer per 1.000 (from 86 fewer to 63 more) |
⨁◯◯◯ Very low |
Critical |
| Days alive without delirium or coma (follow-up: 14 days) | ||||||||||||
| 3 | Randomised trials | Not seriousg | Not serious | Not serious | Not serioush | Missing data have the potential to change evaluationc | 7.2 | 6.8 | – | MD 0.33 days more (0.31 fewer to 0.97 more) |
⨁⨁⨁◯ Moderate |
Important |
| Delirium severity | ||||||||||||
| 0 | Randomised trials | – | Not estimable | – | Important | |||||||
| Cognitive function | ||||||||||||
| 0 | Randomised trials | – | Not estimable | – | Critical | |||||||
| Health-related quality of life | ||||||||||||
| 0 | Randomised trials | – | Not estimable | – | Critical | |||||||
| QTc prolongation (follow-up: range 3 days to 90 days) | ||||||||||||
| 3 | Randomised trials | Not serious | Not serious | Not serious | Very seriousi | Nonec | 28/709 (3.9%) | 18/683 (2.6%) | RR 1.47§ (0.78 to 2.76) | 12 more per 1.000 (from 5 fewer to 43 more) |
⨁⨁◯◯ Low |
Important |
CI, confidence interval; MD, mean difference; RR, risk ratio
*TSA-adjusted 96.7% CI for primary outcomes and TSA-adjusted 98% CI for secondary outcomes
§95% CI
a3 of 5 trials were at overall low risk of bias. Trials with high risk of bias had small sample size and did not have much influence on the pooled effect estimate
bTSA showed that we did not have sufficient information to confirm or reject a 20% RRR. The cumulative z-curve did not cross monitoring boundaries. The accrued information size was between 50 and 100% of required information size, and therefore downgraded 1 level
c3 trials comparing haloperidol with placebo were identified in trial registers. These trials were terminated or had status unknown and trial results were not available. These unpublished trials were not considered as serious publication bias
dTrials did not adhere to ICH-GCP. Some trials reported SAEs others reported SARs
eI2 was 87% (P < 0.01) for cumulated SAEs. Inconsistencies in number of events, but overlapping CIs
fThe accrued information size was < 50% of the required information size estimated by TSA. No TSA monitoring boundaries were crossed. Therefore, we downgraded with 2 levels for imprecision
g3 of 4 trials were at low risk of bias and included the majority of patients
hTSA showed that the cumulative z-curve crossed the futility area with 80% of the required information size
iAccrued information was < 5% of the required information size. Downgraded 2 levels
jTSA reached futility for a RRR of 20%, but CI was wide and did include a potential 20% RRR but also a potential 10% RRI, indicating uncertainty. Downgraded 1 level