Rate of HIT
Monitoring of levels
In the heparin group, there were fewer recurrent ischemic strokes at 14 days (2.9% vs. 3.8%, 2p = 0.005). This was offset by an increase in hemorrhagic strokes (1.2% vs. 0.4%, 2p < 0.00001), resulting in a nonsignificant difference in death or nonfatal recurrent stroke at 14 days. The 12,500 IU dose of UFH was associated with more bleeding, more hemorrhagic strokes, and more deaths at 14 days. At 6 months the percentage dead or dependent was identical in both groups (62.9%).
Conflicting data were obtained from a randomized, placebo-controlled trial of 418 patients in which UFH was started within 3 hours of onset of symptoms as treatment for acute nonlacunar hemispheric cerebral infarction.9 Patients were randomized to receive intravenous UFH or saline. In the heparin group, there were more independent patients as judged by a modified Rankin Scale (mRS) score of 0-2 (38.9% vs. 28.6%, p = 0.025). The incidence of symptomatic ICH (sICH) was greater in the heparin group (6.2% vs. 1.4%, p = 0.008) but no difference was found in rates of mortality or systemic hemorrhage between groups. This suggested a net benefit from UFH in this context, even after accounting for the increased frequency of sICH.
The Trial of Org 10172 in Acute Stroke Treatment (TOAST) was a randomized, double-blind, placebo-controlled trial of danaparoid in 1281 patients within 24 hours of onset of acute ischemic stroke.10 A three-stage dosage regime was used to achieve plasma anti-factor Xa activity of 0.8 unit/mL. Favorable outcome was defined as the combination of a Glasgow Outcome Scale (GOS) score of 1 or 2 and a modified Barthel Index (BI) score of 12 or greater (on a scale of 0-20) at 3 months or 7 days. Very favorable outcome required the combination of a GOS score of 1 and a Barthel Index (BI) score of 19 or 20 at 3 months or 7 days.
The primary analysis showed no significant difference in the rate of favorable outcome at 3 months between the groups. Secondary analysis of 7-day outcomes found 59.2% of the heparinoid group compared to 54.3% of the placebo group with favorable outcome (p = 0.07) and 33.9% compared to 27.8% having a very favorable outcome (p = 0.01). Strokes due to large artery atherosclerosis (LAA) had significantly higher rates of favorable and very favorable outcome at 3 months among subjects who received the heparinoid (p = 0.04). No treatment effect was noted in other stroke subtypes. Although rates of neurological deterioration within the first 7 days were similar in both groups, more major bleeding events occurred within 10 days in the danaparoid group (33 events vs. 11 events, p < 0.005).
One meta-analysis examined the safety and efficacy of LMWH and heparinoids in 11 randomized trials of 3048 patients with acute ischemic stroke.11 It reported a reduction in the incidence of deep venous thrombosis (DVT) (odds ratio (OR) 0.27,
95% CI 0.08-0.96) and symptomatic pulmonary embolism (PE) (OR 0.34, 95% CI 0.17-0.69), but an increase in major extracranial hemorrhage when compared to placebo (OR 2.17, 95% CI 1.10-4.28). Nonsignificant reductions in combined death and disability, as well as increases in case fatality and sICH were also observed. The authors concluded that insufficient evidence existed to support the routine use of LMWH in the management of patients with ischemic stroke.
The Cochrane Collaborators also reviewed acute anticoagulant therapy in 22 trials involving 23,547 patients.12 Selection criteria were randomized trials comparing early anticoagulant therapy (started within 2 weeks of stroke onset) with control in patients with acute presumed or confirmed ischemic stroke. The anticoagulants included were UFH, LMWH, heparinoids, oral anticoagulants, and thrombin inhibitors. They found that, although anticoagulant therapy was associated with about 9 fewer recurrent ischemic strokes per 1000 patients treated, it was also associated with a similar sized 9 per 1000 patients increase in sICH. Similarly, anticoagulants prevented about 4 PEs per 1000, but this benefit was offset by an extra 9 major extracranial hemorrhages. They concluded that immediate anticoagulant therapy in patients with acute ischemic stroke is not associated with a net short- or long-term benefit.
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