Victor J. Del Brutto, MD
Large artery atherosclerosis (LAA) is responsible for a fourth of all ischemic strokes and is the mechanism of cerebral ischemia with the highest risk of recurrence. Current evidence supports that aggressive platelet anti-aggregation is beneficial in the acute phase due to the high thrombogenicity caused by plaque rupture, while the use of statins and strict vascular risk factors control is more relevant chronically to assure plaque stability and to stop arterial disease progression. Current guidelines recommend long-term antiplatelet monotherapy for secondary stroke prevention. However, high-risk clinical settings such as coexistence of coronary artery disease, stroke recurrence despite taking one antiplatelet agent, high-degree stenosis, or presence of micorembolic signals on transcranial Doppler often lead physicians to prescribe dual antiplatelet therapy (DAPT) beyond the acute phase.
The current study used a large multicenter prospective stroke registry from Korea to compare the effectiveness of DAPT with clopidogrel plus aspirin versus aspirin monotherapy in preventing vascular events and death in patients who had an ischemic stroke or TIA attributed to LAA. At one-year follow up, combination therapy was associated with lower risk of having the composite outcome of any stroke, myocardial infarction, or all-cause death. Of notice, DAPT did not reduce the risk of stroke recurrence when compared to aspirin alone, thus results were mainly attributable to overall mortality reduction (Figure 4).
Figure 4. Kaplan-Meier curves for primary outcome (A), stroke recurrence (B), and all-cause death (C) after stabilized inverse probability of treatment weighting in intention-to-treat, per-protocol, and as-treated populations. A indicates aspirin; and C+A, clopidogrel plus aspirin.
A similar rate of stroke recurrence between the two treatment groups could be explained by greater prevalence of vascular risk factors on patients treated with DAPT, thus showing a relative benefit of aggressive antiplatelet treatment in high-risk patients. On the other hand, physicians’ hesitance to use DAPT in patients with multiple comorbidities and lower life expectancy could explain the higher mortality seen in patients treated with aspirin alone. The authors used propensity scores and stabilized inverse probability of treatment weighting to balance for such differences. However, lack of randomization and other study design limitations preclude definitive conclusions.
Interestingly, Kaplan-Meier curves showed a steady benefit of DAPT through one year of follow up. This observation challenges the results achieved by the CHANCE and POINT trials in which DAPT value was mainly seen in the first few weeks after an index event and then vanished primarily due to the increased risk of bleeding complications. These trials, however, did not focus on patients with LAA exclusively. In contrast, the SPS3 and MATCH trials failed to show DAPT effectiveness when used beyond the acute phase, but nevertheless, these studies were weighted to patients with small vessel disease rather than LAA.
It is therefore suggested that long-term DAPT might be beneficial in patients with LAA and high-risk profile. A randomized controlled trial evaluating this hypothesis seems reasonable. Other antiplatelet agents with different pharmacological profiles such as cilostazol and ticagrelor are currently under study, and results will improve our understanding in how to prevent stroke recurrence among patients with LAA.
I can not agree more with Dr. Brutto’s excellent and insightful interpretation.