Dual Antiplatelet Therapy Versus Aspirin in Patients With Stroke or Transient Ischemic Attack

Meta-Analysis of Randomized Controlled Trials

Kirtipal Bhatia, MD; Vardhmaan Jain, MD; Devika Aggarwal, MD; Muthiah Vaduganathan, MD, MPH; Sameer Arora, MD, MPH; Zeeshan Hussain, MD; Guneesh Uberoi, MD; Alfonso Tafur, MD, MSc; Cen Zhang, MD; Mark Ricciardi, MD; Arman Qamar, MD, MPH

Disclosures

Stroke. 2021;52(6):e217-e223. 

In This Article

Results

Study Population

The initial literature search retrieved 8211 citations. After title, abstract, and full-text review, 4 randomized controlled trials with a total of 21,459 patients were included in this study-level meta-analysis (Figure I in the Data Supplement).[9–12] The design and characteristics of patients enrolled in these trials are described in the Table. The studies excluded patients if they had a presumed cardioembolic stroke, received thrombolytics, were planned for endovascular therapy, or had underlying indications for anticoagulation. Three trials compared the combination of clopidogrel to aspirin versus aspirin monotherapy, whereas the THALES study compared the combination of ticagrelor with aspirin versus aspirin alone. All included patients had mild to moderate noncardioembolic ischemic stroke (National Institutes of Health Stroke Scale score 0–5) or TIA, and the duration of DAPT ranged between 21 and 90 days. Duration of follow-up ranged from 30 to 90 days. Patients' mean age was 62 to 68 years and 3% to 47% of participants were female. Most patients had hypertension (50.1%–77.3%). Current or previous smoking history (26%–43%), prior stroke or TIA (21%–23%), and diabetes (10%–28%) were the other common comorbidities.

Outcomes

In comparison to aspirin monotherapy, patients treated with DAPT had a lower risk of recurrent stroke (RR, 0.76 [95% CI, 0.68–0.83]; P<0.001; I2=0%; [Figure 1A]). However, patients receiving DAPT had a higher risk of major bleeding (RR, 2.22 [95% CI, 1.14–4.34], P=0.02, I2=46.5%; [Figure 1B]). Similar magnitudes of relative risk reduction were obtained when outcomes were pooled using prespecified hazard ratios (Figure IIA and IIB in the Data Supplement). Among the secondary outcomes assessed, patients on DAPT had a lower risk of MACE (RR, 0.76 [95% CI, 0.69–0.84], P<0.001, I2=0%; [Figure 2A]) and recurrent ischemic events (RR, 0.74 [95% CI, 0.67–0.82], P<0.001, I2=0%; [Figure 2B]) during the follow-up period. There was no difference in the risk of hemorrhagic stroke (RR, 1.82 [95% CI, 0.83–3.98], P=0.13, I2 =14.7%; [Figure 2C]) or all-cause death (RR, 1.30 [95% CI, 0.90–1.89], P=0.13; I2=14.7%; [Figure 2D]). For patients receiving DAPT with clopidogrel and aspirin, the number needed to treat to prevent an additional ischemic stroke ranged from 21 to 58, compared with patients taking aspirin alone. The number needed to harm ranged from 40 in the FASTER trial (Fast Assessment of Stroke and Transient Ischemic Attack to Prevent Early Recurrence) to 186 in the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) for major bleeding. In the CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events), patients receiving DAPT experienced lower bleeding events compared to patients treated with aspirin. DAPT using ticagrelor resulted in a number needed to treat of 78 to prevent an additional ischemic stroke and a number needed to harm of 221 for major bleeding. Thus, in terms of absolute risk, in all trials, the absolute benefits of DAPT appear to be greater than the significantly elevated bleeding risk.

Figure 1.

Pooled risk-ratios and 95% confidence intervals.
A, Recurrent ischemic or hemorrhagic stroke. B, Major bleeding. CHANCE indicates Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events; DAPT, dual antiplatelet therapy; FASTER, Fast Assessment of Stroke and Transient Ischemic Attack to Prevent Early Recurrence; POINT, Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke; RR, risk ratio; and THALES, Acute Stroke or Transient Ischaemic Attack Treated With Ticagrelor and Aspirin for Prevention of Stroke and Death.

Figure 2.

Pooled risk-ratios and 95% confidence intervals.
A, Major adverse cardiovascular events. B, Recurrent ischemic stroke. C, Hemorrhagic stroke. D, All-cause death. H2 and I2 values are measures for quantifying heterogeneity in a metanalysis. CHANCE indicates Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events; DAPT, dual antiplatelet therapy; FASTER, Fast Assessment of Stroke and Transient Ischemic Attack to Prevent Early Recurrence; POINT, Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke; RR, risk ratio; and THALES, Acute Stroke or Transient Ischaemic Attack Treated With Ticagrelor and Aspirin for Prevention of Stroke and Death.

The degree of heterogeneity between the studies was low to moderate (I2=0–46.5). Mixed-effects meta-regression models demonstrated a nonsignificant positive correlation with the increasing duration of DAPT and risk of major bleeding (Figure III in the Data Supplement). However, this meta-regression analysis is limited by the low number of trials included in this study. Visual analysis of the funnel plots suggested no publication bias (Online Supplement Figure IVA and IVB); however, Egger test was not performed due to lack of sufficient trials. All studies were judged to have a low risk of bias (Figure V in the Data Supplement).

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