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Different levels of blood pressure, different benefit from dual antiplatelet therapy in minor stroke or TIA patients

The study aimed to evaluate whether the benefits of dual antiplatelet therapy would be influenced by blood pressure (BP) levels, among acute minor stroke or transient ischemic attack (TIA). In CHANCE (Clopidogrel in High-Risk Patients with Acute Nondisabling cerebrovascular Events) trail, Patients were stratified by systolic BP (SBP) and diastolic BP (DBP) level measured on admission, respectively, using the supine position BP within 24 hours after symptoms onset. The primary efficacy outcome was stroke recurrence, bleeding was the safety outcome. Patients with SBP ≥ 140 mmHg, dual antiplatelet treatment could reduce the risk of stroke recurrence significantly (HR 0.654, 95% CI 0.529–0.793, p < 0.001) than mono antiplatelet therapy. And patients with DBP ≥ 90 mmHg, clopidogrel-aspirin significantly reduced the risk of recurrent stroke (HR 0.588, 95% CI 0.463–0.746, p < 0.001), compared with aspirin alone. However, in patients with SBP < 140 mmHg or DBP < 90 mmHg, no significant difference was observed between clopidogrel plus aspirin and aspirin alone. there was no difference in bleeding episodes by treatment assignment across categories of SBP or DBP. Patients with SBP ≥ 140 mmHg or DBP ≥ 90 mmHg after minor stroke or TIA got more benefits from dual antiplatelet therapy. Bleeding risk from dual antiplatelet treatment did not increase among patients with higher BP level on admission.

Minor ischemic stroke and transient ischemic attack (TIA) patients are at high risk of recurrent stroke from 12% to 20% during the first 3 months after the index stroke or TIA [1][2][3] . The Clopidogrel in High-risk patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial found that dual antiplatelet therapy (clopidogrel plus aspirin) within 24 hours after symptom onset could reduce the risk of subsequent stroke by 32.0%, as compared with aspirin alone 4 . Besides dual antiplatelet therapy, antihypertensive therapy is also an effective intervention for prevention of recurrent stroke in minor stroke patients 5,6 . As we know, the Secondary Prevention of Small Subcortical Strokes (SPS3) trial support that in patients with recent lacunar stroke, the use of a systolic-blood-pressure (SBP) target of less than 130 mm Hg is likely to be beneficial 7 . However, no studies had focused on whether these 2 intervention strategies have interaction on stroke outcomes.
In this subgroup analysis of the Clopidogrel in High-Risk Patients with Acute Nondisabling cerebrovascular Events (CHANCE) trail, we aimed to investigate whether there was interaction between BP (SBP and DBP) level and antiplatelet therapy on stroke recurrence among patients with minor stroke and high-risk TIA.  Fig. 1). In addition, among patients with DBP ≥ 90 mmHg, dual antiplatelet therapy also significantly reduced the occurrence of new stroke (8.0 versus 13.3%, crude HR 0.588, 95% CI, 0.463-0.746, p < 0.001), and combined vascular events (8.2 versus 13.6%, crude HR 0.585, 95% CI, 0.462-0.741, p < 0.001) compared with mono antiplatelet treatment (Table 3 and Fig. 2).
However, in patients with SBP < 140 mmHg or DBP < 90 mmHg, no significant difference was observed in the occurrence rate of recurrent stroke, and combined vascular events between clopidogrel -aspirin and aspirin alone (Figs 1 and 2).
After adjusting for gender, age, BMI, current or previous smoking and drinking, medical history (TIA or ischemic stroke, hypertension, hypercholesterolemia, diabetes mellitus), qualifying event (TIA or minor stroke), and secondary medication (anti-hypertension, anti-diabetes and lowering-lipid), the multivariable Cox proportional hazards models showed the similar results (Tables 2 and 3).
In addition, there was no significant difference of bleeding event rate between dual and mono antiplatelet treatment, either in SBP or DBP subgroup (

Discussion
In this post-hoc analysis of the CHANCE trial, we found that patients with SBP ≥ 140 mmHg or DBP ≥ 90 mmHg got more benefits from dual antiplatelet therapy on stroke recurrence and CVD than patients with SBP < 140 mmHg or DBP < 90 mmHg. And clopidogrel plus aspirin did not increase the risk of bleeding in patients with SBP ≥ 140 mmHg or DBP ≥ 90 mmHg. Why the BP level could affect the efficacy of dual antiplatelet therapy on patients with minor stroke or TIA? The precise underlying mechanism remains unclear. Because baseline BP was measured within 24 hours after stroke onset, we considered that the protection mechanism 8-10 of stress-induced hypertension after stroke may amplify the efficacy of dual antiplatelet therapy, especially for those with large artery stenosis in cerebral or carotid arteries. Previous studies 11,12 indicated that dual antiplatelet therapy with clopidogrel and aspirin was more effective than aspirin alone in reducing microembolic signals in patients with ischemic stroke or TIA due to extracranial or intracranial arterial stenosis. And patients with multiple stenosis of cerebral arteries need higher BP level to maintain the cerebral perfusion [13][14][15] . The synergistic effect between high BP and dual antiplatelet may contribute to the current finding.
Elevated BP upon admission was common in patients with acute ischemic stroke, which was considered to play an important role in maintain the cerebral circulation and cerebral perfusion of ischemic tissue 16,17 . However, several previous studies also demonstrated that increased BP in acute phase may be detrimental to the brain edema and hemorrhage transformation [18][19][20] . So the relationship between early elevation in BP and prognosis remains controversial, some reports suggested that initially high blood pressure was associated with a poor prognosis [21][22][23] , while other study suggested that elevated BP contributed to a more favorable prognosis 8 or did not affect the prognosis 24 . The previous study demonstrated that elevated BP was significantly associated with a past history of hypertension, which was consisted with our study (See Table 1) 17 . As we all known, hypertension is one of the most important risk factor for atherosclerosis and stroke 25 , so patients with past history of hypertension maybe combine more serious atherosclerosis than normotensive patients, and need higher BP level to maintain the cerebral perfusion of ischemic tissue. We suspect that synergies between the hypertension and dual antiplatelet may improve the prognosis.
In the present study, clopidogrel plus aspirin did not seem to increase the greater bleeding risk in patients with elevated BP on admission than patients with SBP < 140 mmHg or DBP < 90 mmHg. Although the exact mechanism underlying the conflicting results was not clear, and the possible explanation for the difference as follow. First, compared with previous studies including patients with more severe stroke, the patients in our trail at a relative low risk for bleeding or hemorrhage transformation. Second, in our trail, dual antiplatelet treatment was administered for just 21days, followed by clopidogrel alone for a total of 90 days. Dual antiplatelet therapy in short term did not increase the risk of bleeding.
Our study has some limitations. Firstly, not all patients had imaging data in CHANCE trail 26 , we could not get the information about extracranial or intracranial arterial stenosis of all the patients, so the above assumption cannot be validated in the study. Further investigation is needed to investigate the synergistic effect between BP and dual antiplatelet therapy in ischemic stroke patients with symptomatic extracranial or intracranial arterial stenosis. Secondly, the incidence of bleeding events was lower in CHANCE trail, which may reduce the statistical power. So the future study need to further manifested the relationship between very high BP after ischemic stroke and bleeding risk, among patients who received dual antiplatelet treatment. Third, this study was a post-hoc analysis, which may increase the type I error, so our result need to be confirmed by other studies.
In conclusion, we found an interesting phenomenon, which may give some implications for clinical practice. That is, minor stroke or TIA patients with SBP ≥ 140 mmHg or DBP ≥ 90 mmHg, maybe more suitable for dual antiplatelet therapy. With respect to safety outcome, bleeding risk of dual antiplatelet therapy did not seem to increase with elevated BP.

Methods
Study population. CHANCE was a randomized, double-blind, placebo-controlled clinical trial at 114 clinical centers in China as reported elsewhere 4,27 . In brief, patients ≥ 40 years with acute minor stroke (NIH Stroke Scale < [NIHSS] 28 ≤3) or high-risk TIA (ABCD 2 ≥4) within 24 hours of symptoms ictus were randomly assigned to either dual antiplatelet treatment (clopidogrel at an initial dose of 300 mg, followed by 75 mg per day for 90days, plus aspirin at a dose of 75 mg per day for the first 21 days) or mono antiplatelet treatment (aspirin at a dose of 75 mg per day for 90 days). The CHANCE protocol was approved by ethics committees of Beijing Tiantan Hospital and all other study centers. All participants or their legal proxies provided written informed consent.

Blood Pressure Measurement and Group Assignment. At admission, within 24 hours after symptoms
ictus, three BP readings separated by at least two minutes in the supine position were recorded by doctors or trained nurses. Measurement of BP was according to a protocol for BP measurement in the clinic or office recommended by the American Heart Association 29 , and the average of the three readings as the BP on admission.
In this subgroup analysis, we tested the efficacy and safety of dual antiplatelet therapy in patients stratified by the BP level on admission: SBP ( ≥140 mmHg or < 140 mmHg),and DBP ( ≥90 mmHg or < 90 mmHg), respectively.
Outcomes assessment. The efficacy outcomes 4 were stroke recurrence (ischemic stroke or hemorrhage stroke), and combined vascular events (ischemic stroke, hemorrhagic stroke, myocardial infarction, or vascular death) during 90 days of follow-up. The safety outcome was any bleeding, according to the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) definition 30 . Moreover, the follow-up at 90-day was done by face to face. All of the efficacy and safety outcomes were confirmed by the central adjudication committee which was blinded to the study group assignments. For each group stratified by BP level, the differences between dual and mono antiplatelet therapy in the rates of stroke recurrence, combined vascular events, and bleeding during the 90 days follow up were evaluated by using crude and multivariable Cox proportional hazards models. Two-tailed p value less than 0.05 indicated statistical significance. Abbreviations: CVD = combined vascular events (ischemic stroke, hemorrhagic stroke, myocardial infarction, or vascular death); DBP = diastolic blood pressure.