Anticoagulation in acute ischemic stroke: A systematic search

Stroke is one of the most important diseases worldwide. Several clinical scenarios demand full dose of anticoagulants primary to stroke etiology or to the treatment of comorbidity. However, controversy exists over many issues regarding anticoagulation treatment in stroke such as time for initiation, efficacy according to stroke etiology, the ideal dose of anticoagulants, and whether novel anticoagulants should be used.

Method:

Computerized search for clinical trials and randomized controlled clinical trials was done to the present date at Medline, Scielo, Embase, PsychInfo, and Cochrane Library using MeSH terms and the keywords stroke, ischemic stroke, anticoagulation, anticoagulants, heparin, low-molecular-weight heparin, warfarin, dabigatran, rivaroxaban, apixaban. The PRISMA statement was used to evaluate clinical trials.

Results:

Fourteen clinical trials were selected based on inclusion criteria. No evidence was found supporting the early use of heparin, heparinoids or low-molecular-weight heparin (LMWH) early after stroke. No consistent evidence for the use of warfarin and the newer oral anticoagulants were found. Argatroban was the only anticoagulant with significant positive results early after large-artery ischemic stroke.

Conclusion:

The ideal time for initiating anticoagulation remains undefined, requiring further investigation. Early anticoagulation for ischemic stroke is not recommended, with few exceptions, such as that of argatroban.

Keywords:
acute ischemic stroke; anticoagulation; heparin; warfarin

FISS	IST	TOAST	HAEST	TAIST	TOPAS	FISS-tris	ARGIS-1
Drug used	Nadroparin 4,100 IU (aXa), SC, 2x/daily; nadroparin 4,100 IU, once daily, or placebo	UFH 5,000 or 12,500 IU, SC, 2x/daily, with or without aspirin 300 mg	Danaparoid, IV, in bolus+ continuous infusion, dose of 0.6-0.8 IU/mL vs. placebo	Dalteparin 100 IU/kg, SC, 2x/daily, vs. aspirin 160 mg, daily	Tinzaparin 175 IU/kg or 100 IU/kg, SC, daily vs. aspirin 300 mg/day	Certoparin 3,000 IU (aXa), SC, daily or 2x/daily, 5,000 IU (aXa), 2x/daily, or 8,000 IU (aXa), 2x/daily	Nadroparin calcium 3,800 IU, SC, 2x/daily, vs. aspirin 160 mg/day	Argatroban (100 µg/kg),IV, followed by continuous infusion of 3 µg/kg/min or 1 µg/kg/min vs. placebo
Duration of anticoagulation	10 days^* * Patients remained on secondary prevention of stroke using antiplatelet therapy after anticoagulation.	14 days^* * Patients remained on secondary prevention of stroke using antiplatelet therapy after anticoagulation.	7 days	14 days	10 days^* * Patients remained on secondary prevention of stroke using antiplatelet therapy after anticoagulation.	12-16 days	10 days^* * Patients remained on secondary prevention of stroke using antiplatelet therapy after anticoagulation.	5 days
Time between onset of symptoms and anticoagulation	Within 48 hours	Within 48 hours	Within 24 hours	Within 30 hours	Within 48 hours	Within 12 hours	Within 48 hours	Within 12 hours
Number of patients involved	308	19,435	1,281	449	1,486	404	603	13,342
Short-term outcomes	No differences at functional or bleeding rates between the groups at 10 days	↓ Ischemic stroke and pulmonary embolism; ↑ Hemorrhagic stroke and extracranial bleeding at 14 days	In general, ↑ bleeding. More favorable outcomes among large-artery atherosclerosis patients at 7 days	↑ Symptomatic intracranial hemorrhaging;Dalteparin showed no benefit in prevention of recurrent stroke at 14 days	↑ Intracranial hemorrhaging, particularly at high doses within 24 hours;↓ Venous thrombotic events with high dose tinzaparin	No functional difference between groups. Clinical improvement in all groups within 14 days. Severe bleeding more frequent in highest doses	Hemorrhagic transformation and adverse events were similar across groups	Bleeding rates were similar among groups; no major bleeding; neurological scores did not differ among the groups
Long-term outcomes	Significant dose-dependent reduction in risk of death or dependency at 6 months with LMWH	Heparin showed no benefit for disability or death at 6 months ↑ Rate of patients with complete regression of symptoms using aspirin	More favorable outcomes among large-artery atherosclerosis patients at 3 months	No differences between groups for independence or death at 6 months	No differences between groups for independence at 3 or 6 months	Treatment groups were not different with respect to favorable functional outcome at 90 days	Patients with Barthel Index ≥ 85% at 6 months: 73% in use of nadroparin and 69% using aspirin	Neurological scores did not differ among the groups at 90 days

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[1] *Correspondence: Address: Rua Francisco Telles, 250, Jundiaí, SP - Brazil. Postal code: 13202-550. ivan.aprahamian@gmail.com