Table 13.

—[Section 3.2.1] Summary of Findings: Prophylactic-Dose Heparin for VTE Prevention in Patients With Acute Hemorrhagic Stroke and Restricted Mobility^72-74

Outcomes	No. of Participants (Studies) Follow-up	Quality of the Evidence (GRADE)	Relative Effect (95% CI)	Anticipated Absolute Effects, Time Frame 30 d
				Risk With No Prophylactic Low-Dose Heparinn	Risk Difference With Prophylactic Low-Dose Heparin (UFH or LMWH) (95% CI)
Overall mortality	114 (2 studiesa) 10 d	Lowb-d due to risk of bias, imprecision	RR, 1.05 (0.46-2.36)	400 deaths per 1,000	20 more deaths per 1,000 (from 216 fewer to 544 more)
PE (fatal and nonfatal)	10,681 (8 studiese) 14-90 d	Moderatec,d,f due to imprecision	RR, 0.7 (0.47-1.03)e	16 PEs per 1,000g	5 fewer PEs per 1,000 (from 8 fewer to 0 more)
Symptomatic DVT	914 (8 studiese) 2-52 wk	Moderated,f,h due to inconsistency	RR, 0.31 (0.21-0.42)e	48 DVTs per 1,000g	33 fewer DVTs per 1,000 (from 28 fewer to 38 fewer)
Rebleeding	189 (3 studiesi) 7-10 dj	Lowc,d,k due to risk of bias, imprecision	RR, 0.24 (0.05-1.13)l	10 rebleeding events per 1,000m	8 fewer rebleeding events per 1,000 (from 9 fewer to 1 more)

See Table 1, 2, and 7-9 legends for expansion of abbreviations.

^aWe excluded Orken (2009) from this analysis given the control group received compression stockings, which is a confounding factor. Included studies: Boeer (1991) and Dickman (1988).

^bAllocation: unclear whether concealed in both studies (Boeer 1991, Dickmann 1988). Unclear whether ITT analysis in both studies. Neither of the two studies stopped early for benefit. Neither of the studies reported blinding patients.

^c95% CI includes both no effect and appreciable benefit or appreciable harm.

^dFewer than 300 events occurred, but quality was not downgraded for this.

^eIndirect data from studies of the effects of heparin on DVT and PE in patients with ischemic stroke. For PE: Turpie (1987), Cazzato (1989), Prins (1989), Sandset (1990), FISS (1995), Pambianco (1995), IST (1997), and FISS-bis (1998); for DVT: McCarthy (1977), Duke (1980), McCarthy (1986), Turpie (1987), Prins (1989), Sandset (1990), FISS (1995), and Pambianco (1995). Also see Summary of Findings Table 9 on VTE prophylaxis in patients with ischemic stroke.

^fAlthough relative risks for PE and DVT are taken from studies of patients with ischemic stroke, we judged that the indirectness is not significant enough to warrant rating down the quality of the evidence.

^gBaseline risks derived from the control arm of CLOTS (Lancet Neurol. 2010). Patients included in the trial were judged representative of the population of stroke patients with restricted mobility. Indeed, CLOTS used few exclusion criteria: patients with peripheral vascular disease, those with diabetic or sensory neuropathy in whom graduated compression stockings might cause skin damage; those with subarachnoid hemorrhage.

^hStatistical heterogeneity: P=.003; I²=74.3%.

ⁱIncluded studies: Orken (2009) (LMWH started>48 h after hemorrhage; although it compares LMWH to long compression stockings, the effect on rebleeding should be similar to that of a comparison of heparin vs no heparin); Boeer (1991) (UFH started between day 2 and 4 compared with UFH started on day 10; practical comparison of heparin to no heparin during the follow-up period of interest as outcome was assessed on day 10); and Dickman (1988) (UFH started on day 4 compared with UFH started on day 10; practical comparison of heparin to no heparin during the follow-up period of interest as outcome was assessed on day 10).

^jWe considered the time frame during which patients are exposed to heparin and consequently at risk for rebleeding.

^kAllocation: not concealed in one study (Orken 2009) and unclear whether concealed in two studies (Boeer 1991; Dickmann 1988). Unclear whether ITT analysis in the each of the three studies. None of the three studies stopped early for benefit. In Orken 2009, patients who died prior to day 7 (n=4) were excluded from the study after randomization; however, none of them had hematoma enlargement after randomization (author contact). None of the studies reported blinding patients. Only one study (Orken 2009) reported blinding assessors of bleeding outcome.

^lIndirect evidence from an observational study (Warsay 2008): very low incidence in rebleeding with no difference between heparin and no heparin: 1 of 200 vs 0 of 258.

^mObservational data on baseline risk of rebleeding: In one study, of 302 patients with ICH and a control CT scan 24 h after admission excluding a progressive hematoma, none experienced major bleeding after being started on LMWH. In a second study, of 97 patients with ICH and no clinical evidence of hemorrhage enlargement 36 h after admission, none showed a significant hemorrhage growth after being started on LMWH. We use 1% as baseline risk, which is the upper limit of the CI around the incidence derived from these two studies.

ⁿBaseline risk of mortality is derived from observational studies.