The influence of mean arterial pressure on the efficacy and safety of dual antiplatelet therapy in minor stroke or transient ischemic attack patients

Abstract

Mean arterial pressure (MAP) is the strongest predictor of stroke. The combination of clopidogrel and aspirin within 24 hours after onset has been suggested by the Clopidogrel in High‐Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) study to be superior to aspirin alone. However, it is not clear whether poststroke blood pressure has an influence on the efficacy and safety of dual antiplatelet treatment. We have performed a post hoc analysis from the CHANCE trial. Patients were stratified into three groups based on MAP levels. Among patients with MAP <102 mm Hg, there was no significant difference in stroke recurrence between the clopidogrel‐aspirin group and the aspirin group (7.7% vs 7.5%; hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.73‐1.45). However, compared to aspirin treatment, the clopidogrel‐aspirin dual treatment was more effective at reducing the risk of stroke in patients with MAP ≥113 mm Hg (6.9% vs 12.3%, HR, 0.55; 95% CI, 0.39‐0.78) or 102‐113 mm Hg (9.5% vs 14.9%, HR, 0.62; 95% CI, 0.48‐0.81). There was a significant interaction between MAP and antiplatelet therapy as it relates to stroke recurrence (P for interaction = 0.037), and a similar result was found for combined vascular events (P for interaction = 0.027). In conclusion, dual antiplatelet therapy may be more effective at reducing combined vascular events in patients with higher MAP after minor stroke or transient ischemic attack.

1. INTRODUCTION

Minor stroke and transient ischemic attack (TIA) are considered high‐risk nondisabling ischemic cerebrovascular events, which have a high recurrence rate during the first 3 months after the event.1, 2 The combination of a loading dose of clopidogrel and aspirin (300 mg of clopidogrel and 75‐300 mg aspirin) within 24 hours after onset was suggested by the CHANCE study to be superior to aspirin alone.3, 4, 5 It is known that blood pressure often rises within the first 24 hours after stroke or TIA onset.6, 7, 8, 9 However, it is not clear whether poststroke blood pressure has an influence on the efficacy and safety of dual antiplatelet treatment. Mean arterial pressure (MAP) is the strongest predictor of stroke and is important for maintaining cerebral perfusion and cerebral blood flow velocity.10, 11, 12 In this study, we investigated whether the acute stage MAP level influences the efficacy and safety of dual antiplatelet therapy in patients with minor stroke or high‐risk TIA. To perform this analysis, we used the CHANCE (Clopidogrel in High‐Risk Patients with Acute Nondisabling Cerebrovascular Events) trial data.

2. MATERIALS AND METHODS

2.1. Subjects

Patients included in this study were from the CHANCE trial, which was a randomized, double‐blind, placebo‐controlled clinical trial conducted at 114 centers. These patients were of Chinese descent and had an acute minor stroke or high‐risk TIA. Details of the CHANCE trial have been published previously.13 Briefly, patients who had been seen within 24 hours after minor stroke (National Institute of Health Stroke Scale [NIHSS] ≤ 3) or patients with high‐risk TIA (ABCD2 ≥ 4) onset were randomly given either combination therapy with clopidogrel‐aspirin or aspirin alone.

The CHANCE protocol was approved by the ethics committees of Beijing Tiantan Hospital and all other study centers. All participants or their legal proxies provided written informed consent.

2.2. MAP measurement

Blood pressure measurements, including systolic blood pressure (SBP) and diastolic blood pressure (DBP), were collected three times in the supine position by doctors or trained nurses at admission. The average of the three readings was defined as the blood pressure on admission. MAP was calculated as SBP/3 + 2DBP/3.14 Patients were divided into three groups according to MAP levels (MAP < 102 mm Hg, 102 ≤ MAP < 113, and MAP ≥ 113).

2.3. Efficacy and safety outcomes

The primary efficacy outcome was a new stroke event (ischemic or hemorrhagic) during the 90‐day follow‐up period. The secondary efficacy outcome was the presence of combined vascular events (CVE) within 90 days, including ischemic stroke, hemorrhagic stroke, myocardial infarction, or vascular death. Safety outcomes indicated whether any bleeding events occurred within the 3‐month follow‐up. Bleeding events were defined according to the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria as follows: Severe bleeding was defined as fatal or intracranial hemorrhage or other hemorrhage‐causing hemodynamic compromise that required blood or fluid replacement, inotropic support, or surgical intervention; moderate bleeding was defined as bleeding that required transfusion of blood but did not lead to hemodynamic compromise requiring intervention. All reported efficacy and safety outcome events were verified by a central adjudication committee who were blinded to the study group assignments through review of all clinical and imaging information.

2.4. Statistical analysis

Continuous variables were reported as the mean ± SD, and categorical variables were reported as percentages. Baseline variables were compared using the chi‐square test for categorical variables and the ANOVA test for continuous variables. The interaction of MAP levels with antiplatelet therapy on stroke outcomes was assessed using crude and multivariable Cox proportional hazards models. Kaplan‐Meier analysis was used to calculate the cumulative incidence for each group. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc, Cary, NC). All tests were 2‐sided, and P < 0.05 was considered statistically significant.

3. RESULTS

3.1. Patient characteristics

A total of 5165 minor stroke and TIA patients were enrolled in this subgroup analysis after excluding five patients without a MAP value. The baseline characteristics of the clopidogrel‐aspirin group and the aspirin alone group (stratified by MAP tertile) are presented in Table 1. In the MAP <102 mm Hg group, the baseline variables were balanced between the clopidogrel‐aspirin group and the aspirin group. In the 102 ≤ MAP < 113 mm Hg group, there was a higher proportion of patients with hypertension in the clopidogrel‐aspirin treatment group when compared with the aspirin group. In the MAP ≥113 mm Hg group, a lower incidence of myocardial infarction was found in the clopidogrel‐aspirin group.

Table 1.

Baseline characteristics of clopidogrel‐aspirin group and aspirin group stratified by MAP levels

	MAP < 102 mm Hg			102 ≤ MAP < 113 mm Hg			MAP ≥ 113 mm Hg
	Clopidogrel‐Aspirin	Aspirin	P value	Clopidogrel‐Aspirin	Aspirin	P value	Clopidogrel‐Aspirin	Aspirin	P value
	(n = 856)	(n = 843)		(n = 735)	(n = 738)		(n = 990)	(n = 1003)
Age, mean ± SD	63.3 ± 10.9	64.1 ± 10.3	0.10	63.2 ± 10.6	62.8 ± 10.6	0.52	61.6 ± 10.8	61.3 ± 10.8	0.54
Female‐no. (%)	279 (32.6)	300 (35.6)	0.19	236 (32.1)	246 (33.3)	0.62	336 (33.9)	351 (35.0)	0.62
BMI, mean ± SD	24.3 ± 3.0	24.3 ± 2.9	0.96	24.7 ± 3.0	24.7 ± 2.9	0.76	25.0 ± 3.0	24.8 ± 3.2	0.10
Medical history‐no. (%)
TIA OR Ischemic stroke	217 (25.4)	214 (25.4)	0.99	165 (22.5)	161 (21.8)	0.77	213 (21.5)	203 (20.2)	0.48
Myocardial infarction	19 (2.2)	23 (2.7)	0.5	19 (2.6)	11 (1.5)	0.14	5 (0.5)	19 (1.9)	0.01
Hypertension	462 (54.0)	442 (52.4)	0.52	515 (70.1)	479 (64.9)	0.03	738 (74.6)	761 (75.9)	0.49
Diabetes mellitus	212 (24.8)	208 (24.7)	0.96	170 (23.1)	150 (20.3)	0.19	167 (16.9)	185 (18.4)	0.36
Hypercholesterolemia	108 (12.6)	110 (13.1)	0.79	79 (10.8)	82 (11.1)	0.82	103 (10.4)	91 (9.1)	0.32
Current or previous smoking‐no. (%)	372 (43.5)	365 (43.3)	0.95	308 (41.9)	323 (43.8)	0.47	435 (43.9)	416 (41.5)	0.27
Current or previous drinking‐ no. (%)	238 (27.8)	238 (28.2)	0.84	224 (30.5)	234 (31.7)	0.61	341 (34.4)	325 (32.4)	0.33
Qualifying event‐no. (%)
TIA	275 (32.1)	276 (32.7)	0.79	211 (28.7)	223 (30.2)	0.53	230 (23.2)	229 (22.8)	0.83
Minor stroke	581 (67.9)	567 (67.3)		524 (71.3)	515 (69.8)		760 (76.8)	774 (77.2)
Secondary prevention
Anti‐hypertension	219 (25.9)	211 (25.3)	0.77	259 (35.5)	238 (32.4)	0.22	449 (45.5)	437 (43.7)	0.41
Lowering‐lipid	364 (43.1)	327 (39.2)	0.11	304 (41.6)	309 (42.1)	0.86	426 (43.2)	439 (43.9)	0.75

MAP, mean artery pressure; TIA, transient ischemic attack;

3.2. The effect of antiplatelet therapy on MAP levels

Among patients with 102 ≤ MAP < 113 mm Hg, the clopidogrel‐aspirin group had a lower risk of stroke recurrence (6.9% vs 12.3%, crude hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.39‐0.78) and CVE (7.2% vs 12.5%, crude HR 0.57, 95% CI 0.40‐0.79), compared with the aspirin alone group (Table 2, Figures 1, and 2). Among patients with MAP ≥113 mm Hg, clopidogrel plus aspirin treatment reduced the incidence of recurrent stroke (9.5% vs 14.9%, crude HR 0.62, 95% CI 0.48‐0.81) and CVE (9.6% vs 15.2%, crude HR 0.62, 95% CI 0.48‐0.80) when compared with aspirin treatment alone (Table 2, Figures 1, and 2). After adjusting for age, gender, body mass index (BMI), medical history of TIA or ischemic stroke, myocardial infarction, hypertension, diabetes mellitus, hypercholesterolemia, smoking, drinking, qualifying events, and the secondary prevention (anti‐hypertension and lowering‐lipid), the benefits of clopidogrel‐aspirin dual treatment were still present in patients with 102 ≤ MAP ˂ 113 mm Hg and MAP ≥113 mm Hg (Table 2). However, in the MAP <102 mm Hg group, there was no significant difference in the risk of stroke recurrence (crude HR 1.03, 95% CI 0.73‐1.45) or CVE (crude HR 1.05, 95% CI 0.74‐1.48) between patients with clopidogrel‐aspirin treatment vs aspirin treatment (Table 2, Figures 1, and 2). The P value for the interaction effect of MAP levels with antiplatelet therapy was significant for the recurrent stroke variable (P = 0.037) and CVE (P = 0.027) (Table 2).

Table 2.

Effects of clopidogrel‐aspirin and aspirin therapy on outcomes by MAP levels

Outcome	MAP mm Hg	Clopidogrel‐Aspirin	Aspirin	Crude		Adjusted
		Event rate (%)	Event rate (%)	Hazard ratio (95% CI)	Interaction (P value)	Hazard ratio (95% CI)	Interaction (P value)
Stroke	<102	66/856 (7.7)	63/843 (7.5)	1.03 (0.73‐1.45)	0.042	1.05 (0.74‐1.49)	0.037
	102‐113	51/735 (6.9)	91/738 (12.3)	0.55 (0.39‐0.78)		0.54 (0.38‐0.76)
	≥113	94/990 (9.5)	149/1003 (14.9)	0.62 (0.48‐0.81)		0.62 (0.48‐0.80)
CVE	<102	67/856 (7.8)	63/843 (7.5)	1.05 (0.74‐1.48)	0.030	1.07 (0.76‐1.51)	0.027
	102‐113	53/735 (7.2)	92/738 (12.5)	0.57 (0.40‐0.79)		0.56 (0.40‐0.78)
	≥113	95/990 (9.6)	152/1003 (15.2)	0.62 (0.48‐0.80)		0.61 (0.47‐0.79)
Bleeding	<102	25/856 (2.9)	16/843 (1.9)	1.51 (0.81‐2.83)	0.584	1.74 (0.92‐3.29)	0.503
	102‐113	11/735 (1.5)	6/738 (0.8)	1.75 (0.65‐4.72)		1.61 (0.59‐4.40)
	≥113	24/990 (2.4)	19/1003 (1.9)	1.22 (0.67‐2.23)		1.23 (0.67‐2.25)

CVE, combined vascular events; MAP, mean artery pressure.

Figure 1.

Kaplan‐Meier curves demonstrate the time to stroke outcomes in patients with MAP <102 mm Hg (A), 102 ≤ MAP ˂ 113 mm Hg (B), or MAP ≥113 mm Hg (C), treated with clopidogrel‐aspirin or aspirin alone. Among patients with 102 ≤ MAP < 113 mm Hg and MAP ≥113 mm Hg, the clopidogrel‐aspirin group had a lower risk of stroke compared with the aspirin alone group. No significant difference in stroke incidence was observed in patients with MAP <102 mm Hg

Figure 2.

Kaplan‐Meier curves demonstrate the time to CVE outcomes in patients with MAP <102 mm Hg (A), 102 ≤ MAP < 113 mm Hg (B), or MAP ≥113 mm Hg (C), treated with clopidogrel‐aspirin or aspirin alone. Among patients with 102 ≤ MAP < 113 mm Hg and MAP ≥113 mm Hg, the clopidogrel‐aspirin group had a lower risk of CVE compared with the aspirin alone group. There was no statistically significant difference in patients with MAP <102 mm Hg treated with clopidogrel‐aspirin vs aspirin alone

In this study, across different MAP levels, there was no significant difference in the incidence of bleeding events between patients with clopidogrel‐aspirin treatment and aspirin alone (Table 2 and Figure 3). In addition, we analyzed the rates of every type of bleeding event in dual and mono antiplatelet treatment groups at different MAP levels (Table S1).

Figure 3.

Kaplan‐Meier curves demonstrate the time to bleeding outcomes in patients with MAP <102 mm Hg (A), 102 ≤ MAP < 113 mm Hg (B), or MAP ≥113 mm Hg (C), treated with clopidogrel‐aspirin or aspirin alone. No significant difference in the incidence of any bleeding events was observed between patients with clopidogrel‐aspirin and aspirin treatment. CVE, combined vascular events; MAP, mean artery pressure

4. DISCUSSION

In this post hoc analysis of the CHANCE trial, there was no benefit of dual antiplatelet treatment in patients with MAP <102 mm Hg. However, the combination of clopidogrel and aspirin was superior to aspirin alone for reducing the risk of stroke recurrence and CVE among patients with MAP ≥113 mm Hg or 102‐113 mm Hg. Notably, there was no change in the number of bleeding events observed in patients treated with clopidogrel‐aspirin vs aspirin alone, even in patients with high poststroke BP (MAP ≥ 113).

The above findings were consistent with our previous study,15 which showed that patients with SBP ≥140 mm Hg or DBP ≥90 mm Hg after minor stroke or TIA could get additional benefits from dual antiplatelet therapy. However, our previous study did not find the interaction between SBP (DBP) and antiplatelet treatment on recurrent stroke or CVE. In this study, there was a significant interaction between MAP and antiplatelet treatment on recurrent stroke (P = 0.037) or CVE (P = 0.027), which is an important finding. We hypothesize that cerebral perfusion is more likely to be associated with MAP compared to SBP or DBP only.16

High blood pressure levels are observed in a large proportion of ischemic stroke patients during the acute phase.17 It has been speculated that elevated blood pressure during the acute phase of ischemic stroke might be advantageous, as it may improve cerebral perfusion of the ischemic tissue. Conversely, elevated blood pressure might also be detrimental, as it can exacerbate edema and hemorrhagic transformation of the ischemic tissue.18 The MAP parameter used in this study is a major determinant of cerebral perfusion.16 Patients with higher MAP during the acute phase were therefore presumed to have increased risk of bleeding. However, our observations do not support this presumption. In the supplemental material, we further divided the data and analyzed whether the type of bleeding was affected by MAP levels. We found no significant difference between clopidogrel‐aspirin and aspirin alone treatments as it relates to the incidence of symptomatic cerebral hemorrhage across different MAP levels. There are several possible explanations for our findings. First, in the CHANCE trial, the bleeding rate was low, which could result in insufficient statistical power. Second, all patients in the CHANCE trial were enrolled in China, where the rate of intracranial atherosclerosis is higher than in western populations.19 Therefore, we suspected that patients with intracranial arterial stenosis may need a higher MAP to maintain the brain perfusion, which may offset the risk of bleeding. However, since there were few participants who had image data in the CHANCE trial,20 we could not verify this hypothesis. Therefore, more studies are needed to further explore the relationship between MAP, dual antiplatelet treatment, and bleeding events.

Previous work has suggested that high blood pressure on admission was associated with medical history of hypertension, diabetes mellitus, atrial fibrillation, and kidney disease.21 Therefore, patients with high blood pressure on admission often had more than one combined risk factor, so the risk of stroke recurrence and CVE is increased. In those patients, there may be additional benefits to dual antiplatelet treatment. In the primary analysis of the CHANCE trial, dual antiplatelet treatment was more effective than aspirin alone in patients with baseline systolic BP ≥140 mm Hg but was not significantly different in patients with lower BP values.3 This is consistent with the conclusions of this study. The subanalysis of the CAPRIE study also supported the hypothesis that clopidogrel had amplified benefits among patients with more risk factors, such as diabetes mellitus, and hyperlipidemia.22, 23, 24 However, there were only small differences in the baseline characteristics of patients treated with dual and mono antiplatelets in our study, and we adjusted for these variables in the multivariate analysis. We considered that it was not the baseline risk factors but other variables that result in the interaction between blood pressure and dual antiplatelet treatment as it relates to stroke recurrence and CVE. This is an interesting finding; however, the precise underlying mechanism remains unclear. MAP is a major determinant of cerebral perfusion, and higher MAP may represent the epiphenomenon of an underlying status of impaired cerebral hemodynamics, which is an independent risk factor and predictor of poor stroke outcome and stroke recurrence.25, 26 The impairment of emboli clearance may be one potential mechanism. Accordingly, patients with higher MAP may represent high‐risk subgroups who may benefit from the more aggressive antiplatelet regimen. We hypothesize that if the cerebral blood flow velocity was slow (MAP is an indirect parameter to represent cerebral blood flow velocity27), the microemboli is likely to aggregate as a new embolic to block small vessels. Previous studies28, 29, 30 have shown that microembolic signal could predict recurrent cerebral ischemic events in acute stroke patients. The CARESS31 and CLAIR32 trials found that combination therapy with clopidogrel and aspirin could significantly reduce the number of microemboli when compared with aspirin treatment alone. However, the effect of cerebral blood flow velocity on the microembolic aggregation was not taken into account in these two trials. We suggest that cerebral blood flow velocity (physical mechanism) may have a synergistic effect with dual antiplatelet therapy on the incidence of recurrent stroke and CVE.

This study has some limitations. First, the incidence of bleeding events was low, which lead to insufficient statistical power. Second, few patients had image data,20 so we could not understand the relationship between MAP, intracranial arterial stenosis, and outcomes. Furthermore, a larger sample study was needed to explore those complicated relationships. Third, BP was only measured at admission, and it would have been useful if subsequent BP levels were obtained. Fourth, the present study was a post hoc analysis of the CHANCE trial, and the results of the study needed large‐scale research to further confirm. Fifth, there were no details about the etiology of stroke and TIA in patients enrolled in this subgroup analysis.

In summary, the current subgroup analysis of the CHANCE trial revealed that the baseline MAP level may predict the effect of dual or mono antiplatelet treatment on stroke recurrent and combined vascular events. There was no interaction between MAP, different antiplatelet therapy, and bleeding events.

CONFLICT OF INTEREST

None.

AUTHOR CONTRIBUTIONS

Draft writing: YM. Study conception and design: FHD, and YJW. Acquisition of laboratory data: YM and YL. Acquisition of clinical data: YM and YL. Data analysis and interpretation: JX. Study supervision: YLW, FHD and YJW.

Supporting information

 

Ma Y, Liu Y, Xu J, Wang Y, Du F, Wang Y. The influence of mean arterial pressure on the efficacy and safety of dual antiplatelet therapy in minor stroke or transient ischemic attack patients. J Clin Hypertens. 2019;21:598–604. 10.1111/jch.13527