New oral anticoagulants are not superior to warfarin in secondary prevention of stroke or transient ischemic attacks, but lower the risk of intracranial bleeding: insights from a meta-analysis and indirect treatment comparisons

Abstract

Purpose: Patients with Atrial Fibrillation (AF) and prior stroke are classified as high risk in all risk stratification schemes. A systematic review and meta-analysis was performed to compare the efficacy and safety of New Oral Anticoagulants (NOACs) to warfarin in patients with AF and previous stroke or transient ischemic attack (TIA).

Methods: Three randomized controlled trials (RCTs), including total 14527 patients, comparing NOACs (apixaban, dabigatran and rivaroxaban) with warfarin were included in the analysis. Primary efficacy endpoint was ischemic stroke, and primary safety endpoint was intracranial bleeding. Random-effects models were used to pool efficacy and safety data across RCTs. RevMan and Stata software were used for direct and indirect comparisons, respectively.

Results: In patients with AF and previous stroke or TIA, effects of NOACs were not statistically different from that of warfarin, in reduction of stroke (Odds Ratio [OR] 0.86, 95% confidence interval [CI] 0.73- 1.01), disabling and fatal stroke (OR 0.85, 95% CI 0.71-1.04), and all-cause mortality (OR 0.90, 95% CI 0.79 -1.02). Randomization to NOACs was associated with a significantly lower risk of intracranial bleeding (OR 0.42, 95% CI 0.25-0.70). There were no major differences in efficacy between apixaban, dabigatran (110 mg BID and 150 mg BID) and rivaroxaban. Major bleeding was significantly lower with apixaban and dabigatran (110 mg BID) compared with dabigatran (150 mg BID) and rivaroxaban.

Conclusion: NOACs may not be more effective than warfarin in the secondary prevention of ischemic stroke in patients with a prior history of cerebrovascular ischemia, but have a lower risk of intracranial bleeding.

Figure 1. Search strategy and study selection as per PRISMA checklist.

Figure 2. Forest plot(s) comparing NOACs and warfarin in AF patients with previous stroke or TIA, for stroke (A), disabling and fatal stroke(B), stroke and systemic embolism (C), hemorrhagic stroke (D), and all-cause mortality (E).

Figure 3. Forest plot(s) comparing NOACs and warfarin in AF patients with previous stroke or TIA, for major bleeding (A), intracranial bleeding (B), and gastrointestinal bleeding(C).

Figure 4. Forest plot comparing NOACs (including only 150 mg dabigatran) and warfarin for stroke (A) and intracranial bleeding (B).

Figure 5. Forest plot comparing NOACs (including only 110 mg dabigatran) and warfarin for stroke (A) and intracranial bleeding (B).

Figure 6. Meta-regression analysis for stroke (with following variables- mean time in therapeutic range, mean age, percentage of male population, percentage of patients with diabetes, hypertension, congestive heart failure and follow up duration).

Figure 7. Meta-regression analysis for major bleeding (with following variables- mean time in therapeutic range, mean age, percentage of male population, percentage of patients with diabetes, hypertension, congestive heart failure and follow up duration).