Objective

To compare the cost-effectiveness of apixaban vs warfarin for secondary stroke prevention in patients with atrial fibrillation (AF).

Methods

Using standard methods, we created a Markov decision model based on the estimated cost of apixaban and data from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial and other trials of warfarin therapy for AF. We quantified the cost and quality-adjusted life expectancy resulting from apixaban 5 mg twice daily compared with those from warfarin therapy targeted to an international normalized ratio of 2-3. Our base case population was a cohort of 70-year-old patients with no contraindication to anticoagulation and a history of stroke or TIA from nonvalvular AF.

Results

Warfarin therapy resulted in a quality-adjusted life expectancy of 3.91 years at a cost of $378,500. In comparison, treatment with apixaban led to a quality-adjusted life expectancy of 4.19 years at a cost of $381,700. Therefore, apixaban provided a gain of 0.28 quality-adjusted life-years (QALYs) at an additional cost of $3,200, resulting in an incremental cost-effectiveness ratio of $11,400 per QALY. Our findings were robust in univariate sensitivity analyses varying model inputs across plausible ranges. In Monte Carlo analysis, apixaban was cost-effective in 62% of simulations using a threshold of $50,000 per QALY and 81% of simulations using a threshold of $100,000 per QALY.

Conclusions

Apixaban appears to be cost-effective relative to warfarin for secondary stroke prevention in patients with AF, assuming that it is introduced at a price similar to that of dabigatran.

The aims of this article are to review the evidence regarding the use of non-vitamin K oral anticoagulants (NOACs) for secondary stroke prevention as compared to vitamin K antagonists in patients with atrial fibrillation (AF) and in patients with embolic strokes of uncertain source (ESUS), and when to initiate or resume anticoagulation after an ischaemic stroke or intracranial haemorrhage. Four large trials compared NOACs with warfarin in patients with AF. In our meta-analyses, the rate of all stroke or systemic embolism (SE) was 4.94% with NOACs vs. 5.73% with warfarin. Among the patients with AF and previous transient ischaemic attack or ischaemic stroke, the rate of haemorrhagic stroke was halved with a NOAC vs. warfarin, and the rate of major bleeding was 5.7% with a NOAC vs. 6.4% with warfarin. There was no significant difference in mortality. In a trial comparing apixaban with aspirin in patients with AF, the rate of stroke or SE was 2.4% at 1 year with apixaban vs. 9.2% at 1 year with aspirin and the rates of major bleeding were 4.1% with apixaban vs. 2.9% with aspirin. Data from registries confirmed the results from the randomized trials. Initiation or resumption of anticoagulation after ischaemic stroke or cerebral haemorrhage depends on the size and severity of stroke and the risk of recurrent bleeding. Two large trials tested the hypothesis that NOACs are more effective than 100 mg aspirin in patients with ESUS. Neither trial showed a significant benefit of the NOAC over aspirin. In the meta-analysis, the rate all stroke or SE was 4.94% with NOACs vs. 5.73% with warfarin and the rate of haemorrhagic stroke was halved with a NOAC. The four NOACs had broadly similar efficacy for the major outcomes in secondary stroke prevention.

Background Atrial fibrillation/flutter (AF) after transient ischemic attack (TIA) has not been well studied. We compared the likelihood of new AF diagnosis after ischemic stroke versus TIA. Methods and Results The POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) trial enrolled adults within 12 hours of minor ischemic stroke or high-risk TIA. Our exposure was index event type (ischemic stroke versus TIA). The primary analysis used the original trial definition of TIA (resolution of symptoms/signs). In secondary analyses, TIA cases with infarction on neuroimaging were reclassified as strokes. Our primary outcome was a new AF diagnosis, ascertained from adverse event and treatment interruption/discontinuation reports. We calculated C-statistics for variables associated with newly diagnosed AF. We used Kaplan-Meier survival statistics and Cox models adjusted for demographics and vascular risk factors. Excluding 49 subjects with baseline AF, 2746 patients had index stroke and 2086 patients had index TIA. During the 90-day follow-up, 106 patients had newly diagnosed AF. Cumulative risks of AF were 2.7% (95% CI, 2.1%-3.4%) after stroke and 2.0% (95% CI, 1.5%-2.7%) after TIA (P=0.15). After reclassifying index events by neuroimaging, cumulative AF risk was higher after stroke (2.7%; 95% CI, 2.2%-3.4%) than TIA (1.8%; 95% CI, 1.3%-2.5%) (P=0.04). Index event type had negligible predictive utility (C-statistic, 0.54). Conclusions Among patients with cerebral ischemia, the distinction between TIA versus minor stroke did not stratify the risk of subsequent AF diagnosis, implying that patients with TIA should undergo similar heart-rhythm monitoring strategies as patients with ischemic stroke.

Background and purpose

Randomized trials demonstrated the benefit of dual antiplatelet therapy in patients with minor ischemic stroke or high-risk transient ischemic attack. We sought to determine whether the presence of carotid stenosis was associated with increased risk of ischemic stroke and whether the addition of clopidogrel to aspirin was associated with more benefit in patients with versus without carotid stenosis.

Methods

This is a post-hoc analysis of the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) that randomized patients with minor ischemic stroke or high-risk transient ischemic attack within 12 hours from last known normal to receive either clopidogrel plus aspirin or aspirin alone. The primary predictor was the presence of ≥50% stenosis in either cervical internal carotid artery. The primary outcome was ischemic stroke. We built Cox regression models to determine the association between carotid stenosis and ischemic stroke and whether the effect of clopidogrel was modified by ≥50% carotid stenosis.

Results

Among 4881 patients enrolled POINT, 3941 patients met the inclusion criteria. In adjusted models, ≥50% carotid stenosis was associated with ischemic stroke risk (hazard ratio, 2.45 [95% CI, 1.68-3.57], P<0.001). The effect of clopidogrel (versus placebo) on ischemic stroke risk was not significantly different in patients with <50% carotid stenosis (adjusted hazard ratio, 0.68 [95% CI, 0.50-0.93], P=0.014) versus those with ≥50% carotid stenosis (adjusted hazard ratio, 0.88 [95% CI, 0.45-1.72], P=0.703), P value for interaction=0.573.

Conclusions

The presence of carotid stenosis was associated with increased risk of ischemic stroke during follow-up. The effect of added clopidogrel was not significantly different in patients with versus without carotid stenosis. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03354429.

Background and Purpose- While combination aspirin and clopidogrel reduces recurrent stroke compared with aspirin alone in patients with transient ischemic attack (TIA) or minor stroke, the effect on disability is uncertain. Methods- The POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) randomized patients with TIA or minor stroke (National Institutes of Health Stroke Scale score ≤3) within 12 hours of onset to dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel versus aspirin alone. The primary outcome measure was a composite of stroke, myocardial infarction, or vascular death. We performed a post hoc exploratory analysis to examine the effect of treatment on overall disability (defined as modified Rankin Scale score >1) at 90 days, as well as disability ascribed by the local investigator to index or recurrent stroke. We also evaluated predictors of disability. Results- At 90 days, 188 of 1964 (9.6%) of patients enrolled with TIA and 471 of 2586 (18.2%) of those enrolled with stroke were disabled. Overall disability was similar between patients assigned DAPT versus aspirin alone (14.7% versus 14.3%; odds ratio, 0.97 [95% CI, 0.82-1.14]; P=0.69). However, there were numerically fewer patients with disability in conjunction with a primary outcome event in the DAPT arm (3.0% versus 4.0%; odds ratio, 0.73 [95% CI, 0.53-1.01]; P=0.06) and significantly fewer patients in the DAPT arm with disability attributed by the investigators to either the index event or recurrent stroke (5.9% versus 7.4%; odds ratio, 0.78 [95% CI, 0.62-0.99]; P=0.04). Notably, disability attributed to the index event accounted for the majority of this difference (4.5% versus 6.0%; odds ratio, 0.74 [95% CI, 0.57-0.96]; P=0.02). In multivariate analysis, age, subsequent ischemic stroke, serious adverse events, and major bleeding were significantly associated with disability in TIA; for those with stroke, female sex, hypertension, or diabetes mellitus, National Institutes of Health Stroke Scale score, recurrent ischemic stroke, subsequent myocardial infarction, and serious adverse events were associated with disability. Conclusions- In addition to reducing recurrent stroke in patients with acute minor stroke and TIA, DAPT might reduce stroke-related disability. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00991029.

Background

Combination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during the first 3 months after a minor ischemic stroke or transient ischemic attack (TIA). A trial of combination antiplatelet therapy in a Chinese population has shown a reduction in the risk of recurrent stroke. We tested this combination in an international population.

Methods

In a randomized trial, we assigned patients with minor ischemic stroke or high-risk TIA to receive either clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day, plus aspirin (at a dose of 50 to 325 mg per day) or the same range of doses of aspirin alone. The dose of aspirin in each group was selected by the site investigator. The primary efficacy outcome in a time-to-event analysis was the risk of a composite of major ischemic events, which was defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event, at 90 days.

Results

A total of 4881 patients were enrolled at 269 international sites. The trial was halted after 84% of the anticipated number of patients had been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemic events occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P=0.02), with most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P=0.02).

Conclusions

In patients with minor ischemic stroke or high-risk TIA, those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone. (Funded by the National Institute of Neurological Disorders and Stroke; POINT ClinicalTrials.gov number, NCT00991029 .).

Background

The aim of this study was to determine the effect of smoking status on subsequent stroke risk in patients with minor ischemic stroke or TIA and to determine whether smoking modifies the effect of clopidogrel-based DAPT on subsequent stroke risk.

Methods

This was a post-hoc analysis of the Platelet Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial, which had a 90-day follow-up period. We used multivariable Cox regression and subgroup interaction analysis to determine the effect of smoking on the risk of subsequent ischemic stroke and major hemorrhage, respectively.

Results

Data from 4877 participants enrolled in the POINT trial were analyzed. Among these, 1004 were current smokers and 3873 were non-smokers at the time of index event. Smoking was associated with a non-significant trend toward an increased risk of subsequent ischemic stroke during follow up (adjusted HR, 1.31 (95% CI, 0.97-1.78), p = 0.076). The effect of clopidogrel on ischemic stroke did not differ between non-smokers (HR, 0.74 (95% CI, 0.56-0.98), p = 0.03) and smokers (HR, 0.63 (95% CI, 0.37-1.05), p = 0.078), p for interaction = 0.572. Similarly, the effect of clopidogrel on major hemorrhage did not differ between non-smokers (hazard ratio, 1.67 (95% CI, 0.40-7.00), p = 0.481) and smokers (HR, 2.59 (95% CI, 1.08-6.21), p = 0.032), p for interaction = 0.613.

Conclusions

In this post-hoc analysis of the POINT trial we found that the effect of clopidogrel on reducing subsequent ischemic stroke as well as risk of major hemorrhage did not depend on smoking status, indicating that smokers benefit to a similar degree from DAPT as non-smokers.

Background and purpose

SOCRATES (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes), comparing ticagrelor with aspirin in patients with acute cerebral ischemia, found a nonsignificant 11% relative risk reduction for stroke, myocardial infarction, or death (P=0.07). Aspirin intake before randomization could enhance the effect of ticagrelor by conferring dual antiplatelet effect during a high-risk period for subsequent stroke. Therefore, we explored the efficacy and safety of ticagrelor versus aspirin in the patients who received any aspirin the week before randomization.

Methods

A prespecified subgroup analysis in SOCRATES (n=13 199), randomizing patients with acute ischemic stroke (National Institutes of Health Stroke Scale score of ≤5) or transient ischemic attack (ABCD² score of ≥4) to 90-day treatment with ticagrelor or aspirin. Patients in the prior-aspirin group had received any aspirin within the week before randomization. Primary end point was time to stroke, myocardial infarction, or death. Safety end point was PLATO (Study of Platelet Inhibition and Patient Outcomes) major bleeding.

Results

The 4232 patients in the prior-aspirin group were older, had more vascular risk factors, and vascular disease than the other patients. In the prior-aspirin group, the primary end point occurred in 138/2130 (6.5%) of patients on ticagrelor and in 177/2102 (8.3%) on aspirin (hazard ratio, 0.76; 95% confidence interval, 0.61-0.95; P=0.02); in patients with no prior-aspirin usage an event occurred in 304/4459 (6.9%) and 320/4508 (7.1%) on ticagrelor and aspirin, respectively (hazard ratio, 0.96; 95% confidence interval, 0.82-1.12; P=0.59). The treatment-by-prior-aspirin interaction was not statistically significant (P=0.10). In the prior-aspirin group, major bleeding occurred in 0.7% and 0.4% of patients on ticagrelor and aspirin, respectively (hazard ratio, 1.58; 95% confidence interval, 0.68-3.65; P=0.28).

Conclusions

In this secondary analysis from SOCRATES, fewer primary end points occurred on ticagrelor treatment than on aspirin in patients receiving aspirin before randomization, but there was no significant treatment-by-prior-aspirin interaction. A new study will investigate the benefit-risk of combining ticagrelor and aspirin in patients with acute cerebral ischemia (URL: https://www.clinicaltrials.gov. Unique identifier: NCT03354429).

Clinical trial registration

URL: https://www.clinicaltrials.gov. Unique identifier: NCT01994720.

Background We sought to determine recurrent stroke predictors among patients with embolic strokes of undetermined source (ESUS). Methods and Results We applied Cox proportional hazards models to identify clinical features associated with recurrent stroke among participants enrolled in RE-SPECT ESUS (Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source) trial, an international clinical trial evaluating dabigatran versus aspirin for patients with ESUS. During a median follow-up of 19 months, 384 of 5390 participants had recurrent stroke (annual rate, 4.5%). Multivariable models revealed that stroke or transient ischemic attack before the index event (hazard ratio [HR], 2.27 [95% CI, 1.83-2.82]), creatinine clearance <50 mL/min (HR, 1.69 [95% CI, 1.23-2.32]), male sex (HR, 1.60 [95% CI, 1.27-2.02]), and CHA₂DS₂-VASc ≥4 (HR, 1.55 [95% CI, 1.15-2.08] and HR, 1.66 [95% CI, 1.21-2.26] for scores of 4 and ≥5, respectively) versus CHA₂DS₂-VASc of 2 to 3, were independent predictors for recurrent stroke. Conclusions In RE-SPECT ESUS trial, expected risk factors previously linked to other common stroke causes were associated with stroke recurrence. These data help define high-risk groups for subsequent stroke that may be useful for clinicians and for researchers designing trials among patients with ESUS. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02239120.

Background and purpose

Clopidogrel is an antiplatelet drug that is metabolized to its active form by the CYP2C19 enzyme. The CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) found a significant interaction between loss-of-function allele status for the CYP2C19 gene and the effect of dual antiplatelet therapy with aspirin and clopidogrel on the rate of early recurrent stroke following acute transient ischemic attack/minor stroke. The POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke Trial), similar in design to CHANCE but performed largely in North America and Europe, demonstrated a reduction in early recurrent stroke with dual antiplatelet therapy compared with aspirin alone. This substudy was done to evaluate a potential interaction between loss-of-function CYP2C19 alleles and outcome by treatment group in POINT.

Methods

Of the 269 sites in 10 countries that enrolled patients in POINT, 134 sites participated in this substudy. DNA samples were genotyped for CYP2C19 *2, *3, and *17 alleles and classified as being carriers or noncarriers of loss-of-function alleles. Major ischemia consisted of ischemic stroke, myocardial infarction, or ischemic vascular death.

Results

Nine hundred thirty-two patients provided analyzable DNA. The rates of major ischemia were 6.7% for the aspirin group versus 2.3% for the dual antiplatelet therapy group (hazard ratio, 0.33 [95% CI, 0.09-1.21]; P=0.09) among carriers of loss-of-function allele. The rates of major ischemia were 5.6% for the aspirin group versus 3.7% for the dual antiplatelet therapy group (hazard ratio, 0.65 [95% CI, 0.32-1.34]; P=0.25) among noncarriers. There was no significant interaction by genotype for major ischemia (P=0.36) or stroke (P=0.33).

Conclusions

This substudy of POINT found no significant interaction with CYP2C19 loss-of-function carrier status and outcome by treatment group. Failure to confirm the findings from the CHANCE trial may be because the loss-of-function alleles tested are not clinically important in this context or because the 2 trials had differences in racial/ethnic composition. Additionally, differences between the 2 trials might be due to chance as our statistical power was limited to 50%. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00991029.