Dual Antiplatelet Therapy in Patients With Metabolic Syndrome After Mild Ischemic Stroke or Transient Ischemic Attack

Abstract

Background

Metabolic syndrome (MetS) attenuates antiplatelet agent effects. This study investigated the efficacy and safety of clopidogrel–aspirin therapy for secondary stroke prevention in patients with MetS.

Methods

Data were obtained from the INSPIRES (Intensive Statin and Antiplatelet Therapy for Acute High‐Risk Intracranial or Extracranial Atherosclerosis) trial. Patients with mild ischemic stroke or high‐risk transient ischemic attack were randomized to treatment with clopidogrel–aspirin or aspirin alone within 72 hours after symptom onset. MetS was defined according to the Adult Treatment Panel‐III. The primary efficacy outcome was new stroke, and the primary safety outcome was moderate ‐ to ‐ severe bleeding within 90‐day follow‐up. Differences between groups were estimated with Cox proportional hazards models, with hazard ratio (HR) and 95% CI presented.

Results

This study included 4715 patients, with a mean age of 63.7±9.6 years, 35.8% of women, and 75.8% of patients having MetS. After adjustment for potential confounders, patients with MetS were at higher risk of recurrent stroke (HR, 1.39 [95% CI, 1.06–1.82]; P=0.02) but not moderate ‐ to ‐ severe bleeding events (HR, 1.02 [95% CI, 0.47–2.21]; P=0.97) as compared with patients without MetS. However, MetS state did not impact the efficacy of clopidogrel–aspirin therapy for recurrent stroke (P for interaction=0.44) and the safety for moderate‐to‐severe bleeding events (P for interaction=0.54).

Conclusions

MetS was associated with higher risk of recurrent stroke at 90 days. There was no difference in the effect of clopidogrel–aspirin therapy on reducing new stroke and increasing moderate‐to‐severe bleeding events between patients with and without MetS.

Registration

URL: https://www.clinicaltrials.gov; Unique identifier: NCT03635749.

Nonstandard Abbreviations and Acronyms

CHANCE

Clopidogrel in High‐Risk Patients With Acute Nondisabling Cerebrovascular Events

DAPT

dual antiplatelet therapy

FBG

fasting blood glucose

HCPR

high on‐clopidogrel platelet reactivity

INSPIRES

Intensive Statin and Antiplatelet Therapy for Acute High‐Risk Intracranial or Extracranial Atherosclerosis

MetS

metabolic syndrome

mRS

modified Rankin Scale

NIHSS

National Institutes of Health Stroke Scale

WC

waist circumference

Clinical Perspective.

What Is New?

• Patients with metabolic syndrome were at higher risk of recurrent stroke, composite cardiovascular events, ischemic stroke, and poor functional outcome within 90 days as compared with those without metabolic syndrome.

• The efficacy of clopidogrel–aspirin therapy initiated within 72 hours for recurrent stroke within 90 days was not different between patients with and without metabolic syndrome.

What Are the Clinical Implications?

• Tightening metabolic control remains indispensable for secondary stroke prevention in patients with mild ischemic stroke or high‐risk transient ischemic attack.

• Dual antiplatelet therapy of clopidogrel combined with aspirin initiated within 72 hours after symptom onset could be applied in these high‐risk patients, regardless of metabolic syndrome state.

Patients with acute mild ischemic stroke or transient ischemic attack (TIA) are at high risk of recurrent stroke. ¹ , ² Dual antiplatelet therapy (DAPT) of clopidogrel combined with aspirin administered within 24 or 72 hours after symptom onset can reduce the risk of recurrent stroke at 90 days as compared with aspirin therapy alone. ³ , ⁴ , ⁵ Guidelines recommend that the DAPT can be administered to patients with a minor ischemic stroke within 24 hours after symptom onset. ⁶ However, there remain knowledge gaps in efficacy and potential harm of DAPT among specific subgroups of patients. ¹

The prevalence of metabolic syndrome (MetS) in patients with stroke is up to 32.5% to 47.2% according to different criteria and is substantially associated with an adverse prognosis. ⁷ , ⁸ Currently, subgroup analyses of DAPT trials have investigated the impact of specific components of MetS, such as hypertension, diabetes, dyslipidemia, on the efficacy of DAPT. ³ , ⁹ , ¹⁰ , ¹¹ The INSPIRES (Intensive Statin and Antiplatelet Therapy for Acute High‐Risk Intracranial or Extracranial Atherosclerosis; ClinicalTrials.gov identifier: NCT03635749) trial found that patients with hypertension, diabetes, or dyslipidemia may have lower benefit from DAPT in stroke prevention within 90 days. ³ , ¹¹ The Platelet‐Oriented Inhibition in New TIA and Minor Ischemic Stroke trial found that hypertension and hyperglycemia compromised the therapeutic effect of DAPT on stroke recurrence. ⁹ , ¹⁰ Furthermore, extensive studies demonstrate that all components of MetS are involved in the prothrombotic tendency through platelet hyperaggregability and hyperactivation. ¹² This raises a possibility that the efficacy of DAPT on recurrent stroke prevention may be decreased in patients with MetS compared with those without MetS. However, empirical evidence remains limited on whether MetS itself rather than its components could lower the efficacy of DAPT for stroke prevention as compared with the aspirin therapy alone. Only 1 study from subgroup analysis of the CHANCE (Clopidogrel in High‐Risk Patients With Acute Nondisabling Cerebrovascular Events) trial showed that the efficacy of DAPT on stroke recurrence prevention was not different between patients with and without MetS. ¹³ Notably, the CHANCE trial initiated DAPT within 24 hours after the onset of minor stroke or high‐risk TIA. ¹³ Whether MetS would make a difference to the efficacy of DAPT initiated beyond 24 hours remain unknown. Addressing this issue may provide more elaborate evidence to determine the applicability of DAPT in patients with stroke combined with MetS.

Using the data from the INSPIRES trial, we investigated the efficacy and safety of clopidogrel–aspirin therapy initiated within 72 hours after symptom onset in patients with MetS.

METHODS

Study Design and Participants

The data that support the findings of this study are available from the corresponding author upon reasonable request.

This study was a post hoc analysis of the INSPIRES trial. Details on the design and major results of the INSPIRES trial have been published elsewhere. ³ , ¹⁴ Briefly, the INSPIRES trial was a multicenter, double‐blind, placebo‐controlled, 2‐by‐2 factorial, randomized clinical trial that enrolled 6100 patients aged 35 to 80 years from 222 clinical centers in China during September 2018 to October 2022. Patients were enrolled if they had a mild ischemic stroke with National Institutes of Health Stroke Scale (NIHSS) score ≤5, a high‐risk TIA with ABCD ² score (risk score with age, blood pressure, clinical features, duration of TIA, and presence of diabetes) ≥4 between 24 and 72 hours after symptom onset, or an ischemic stroke with NIHSS score of 4 to 5 within 24 hours of ictus. ³ In addition, patients had to meet at least 1 of the following imaging criteria: at least 50% stenosis of a major intracranial or extracranial artery or acute new multiple infarctions of presumed large‐artery atherosclerosis origin. Patients were not eligible for the trial if they received intravenous thrombolysis, endovascular or antithrombotic therapy after onset, or dual antiplatelet or intensive statin therapy within 14 days before randomization; if they had hemorrhagic transformation or history of intracranial hemorrhage or subarachnoid hemorrhage; or if they did not provide informed consent or had other reasons that were not eligible for the trial according to the protocol. ¹⁴ Details of other reasons are presented in Table S1. Patients with dysphagia were also excluded for safety, as they would be at risk when taking the medication. All eligible participants were randomized in a 1:1 ratio to receive clopidogrel (300 mg on day 1 and 75 mg daily on days 2 through 90) plus aspirin (100–300 mg on day 1 and 100 mg daily on days 2 to 21 and then a matching aspirin placebo for days 22–90) or matching clopidogrel placebo for 90 days plus aspirin (100–300 mg on day 1 and 100 mg daily on days 2–90) within 72 hours after symptom onset. In the current study, we further excluded patients with missing data on blood pressure (BP), fasting blood glucose (FBG), triglyceride, or high‐density lipoprotein cholesterol (HDL‐C) at baseline. The INSPIRES trial was approved by the ethics committees of Beijing Tiantan Hospital (ethical approval No. KY2017‐065‐02) and all other participating centers. Patients or their representatives provided written informed consent before enrollment.

Data Collection

Baseline demographics and clinical characteristics including age, sex, smoking status, drinking status, past medical history (hypertension, diabetes, dyslipidemia, gout, chronic obstructive pulmonary disease, coronary heart disease, peripheral artery disease, ischemic stroke), family history of stroke, and medication history before randomization (antihypertensive agent, hypoglycemic agent, lipid‐lowering agent, antidepressant agent, aspirin, clopidogrel) were collected by trained local investigators using standardized questionnaires through face‐to‐face interviews.

Neurological assessments including NIHSS score, ABCD ² score, and modified Rankin Scale (mRS) score were performed by local neurologists at baseline and 90±7 days after randomization. Scores on the NIHSS ranged from 0 to 42 for patients with ischemic stroke. Higher scores indicate more severe stroke. The ABCD ² score assessed the risk of stroke on the basis of age, BP, clinical features, duration of TIA, and the presence or absence of diabetes in patients with TIA. Scores ranged from 0 to 7, with higher scores indicating greater risk. Baseline BP, height, body weight, waist circumference (WC), and heart rate were measured in the physical examination. Body mass index was calculated as body weight (kg) divided by the square of height (m).

Fasting venous blood was drawn and processed at local hospitals within 24 hours after randomization (if not, 72 hours after randomization were the final deadline) and at 90±7 days after randomization. FBG, glycosylated hemoglobin, alanine aminotransferase, aspartate aminotransferase, creatine kinase, serum creatinine, hemoglobin, and blood platelet count were assayed at local hospitals. Blood samples were transferred by cold chain to Beijing Tiantan Hospital for centralized storage. Total cholesterol, triglyceride, low‐density lipoprotein cholesterol, and HDL‐C were assayed at Beijing Tiantan Hospital. Non–HDL‐C was calculated as total cholesterol minus HDL‐C. Anemia in adults was defined as hemoglobin levels of <13 g/dL in men and <12 g/dL in women. ¹⁵ Chronic kidney disease was defined as having estimated glomerular filtration rate <60 mL/min per 1.73 m². ¹⁶ More details on data collection were presented in published study protocol. ¹⁴

MetS Assessment

According to the criterion of Adult Treatment Panel‐III, MetS was defined as the presence of ≥2 of the following metabolic risk factors based on baseline data: systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥85 mm Hg; FBG ≥6.1 mmol/L (110 mg/dL); triglyceride ≥1.70 mmol/L (150 mg/dL); HDL‐C <1.0 mmol/L (40 mg/dL) in men or <1.3 mmol/L (50 mg/dL) in women. ¹⁷ WC was not used to define MetS because 43.9% (2070/4715) of participants did not measure WC at baseline.

In addition, we redefined MetS for sensitivity analyses. First, according to the criterion of International Diabetes Federation, MetS was redefined as the presence of ≥2 of the following factors: systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥85 mm Hg or antihypertensive therapy; FBG ≥5.6 mmol/L (100 mg/dL) or hypoglycemic therapy; triglyceride ≥1.70 mmol/L (150 mg/dL) or lipid‐lowering therapy; HDL‐C <1.0 mmol/L (40 mg/dL) in men or <1.3 mmol/L (50 mg/dL) in women. ¹⁸ Second, acute neurological deficit may induce a stress response, which can cause transient elevation of BP or FBG. ¹⁹ Thus, to eliminate the influence of the stress response, MetS was redefined as the presence of ≥2 of the following factors on the basis of the medical history or medication history before randomization: self‐reported hypertension or antihypertensive therapy; self‐reported diabetes or hypoglycemic therapy; triglyceride ≥1.70 mmol/L (150 mg/dL) or self‐reported dyslipidemia or lipid‐lowering therapy; HDL‐C <1.0 mmol/L (40 mg/dL) in men or <1.3 mmol/L (50 mg/dL) in women.

Outcome Assessment

The primary efficacy outcome was new stroke events including ischemic or hemorrhagic stroke within 90 days. The secondary efficacy outcomes were a composite of cardiovascular event (stroke, myocardial infarction, or death from cardiovascular causes) within 90 days, ischemic stroke, hemorrhagic stroke, TIA, myocardial infarction, death from cardiovascular causes, and poor functional outcome with an mRS score of 2 to 6. The new stroke or TIA was classified on a 6‐level scale using the type of cardiovascular events and the mRS score: a score of 5 indicated fatal stroke (stroke with subsequent death); 4, severe stroke (stroke followed by an mRS score of 4 or 5); 3, moderate stroke (stroke followed by an mRS score of 2 or 3); 2, mild stroke (stroke followed by an mRS score of 0 or 1); 1, TIA; and 0, no stroke or TIA. ²⁰ Detailed definitions for efficacy outcomes can be found in the trial protocol. ¹⁴

The primary safety outcome was moderate ‐ to ‐ severe bleeding events defined by the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria. ²¹ The secondary safety outcomes included hepatotoxicity, muscle toxicity, all‐cause death, intracranial hemorrhage, any bleeding events, and other adverse or severe adverse events within 90 days. Hepatotoxicity was defined as an alanine aminotransferase or aspartate aminotransferase level of >3 times the upper limit of normal range. ¹⁴ Muscle toxicity was defined as a creatine kinase level of >10 times the upper limit of normal range, presence of muscle pain, myopathy, or rhabdomyolysis. ¹⁴

Patients were reviewed at their last follow‐up evaluation when they experienced a clinical event, at the end of the trial, at the time of withdrawal from the trial, or at the last visit if primary outcome data were missing. The time to the first event was used if there were multiple events of the same type. All outcome events were confirmed by an independent clinical event adjudication committee, who were blinded to the study group assignments. The committee physicians adjudicated stroke subtypes, myocardial infarction, and death on the basis of available medical records and imaging examinations.

Statistical Analysis

Continuous variables were presented as mean±SD or median (IQR). Categorical variables were presented as frequency and proportion. Baseline variables were compared between patients included in and excluded from this study, patients with different MetS state, and patients with different antiplatelet therapies. The Wilcoxon rank‐sum test was performed for continuous variables and χ ² test or Fisher's exact probability method for categorical variables. The cumulative risk of new stroke events between patients with different MetS states and between antiplatelet treatment groups were estimated by Kaplan–Meier method. Differences between MetS groups and between treatment groups in the incidence of stroke, composite cardiovascular events, TIA, myocardial infarction, death, and bleeding events were estimated by a Cox proportional hazards model, with hazard ratio (HR) and 95% CI presented. Proportional hazards assumption was assessed by testing the interaction of group by log‐transformed time in the model and was not violated in any of the Cox models (P for interaction>0.05). Differences in the proportion of poor functional outcome and the incidence of hepatotoxic effects and muscle toxic effects were estimated by generalized linear model, with relative risk and 95% CI presented. Models were adjusted for age, sex, smoking status, NIHSS on admission, history of ischemic stroke, history of TIA, history of coronary heart disease, time to randomization, antihypertensive therapy, lipid‐lowering therapy, hypoglycemic therapy, antiplatelet therapy, and in‐hospital statin therapy. The product term of antiplatelet treatment group and MetS state was included in the model to assess the interaction effect. Sensitivity analyses were performed in different MetS definitions and in all participants without excluding any individuals.

All statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc, Cary, NC). A 2‐sided P value <0.05 was considered statistically significant.

RESULTS

Baseline Characteristics

Of 6100 patients, 1385 patients were excluded because of missing data on BP (n=13), FBG (n=1143), or triglycerides or HDL‐C (n=229) at baseline (Figure 1). A total of 4715 patients were included in this study, with a mean age of 63.7±9.6 years and 35.8% of women. Most baseline characteristics were balanced between included and excluded patients except for current smoking, current drinking, previous ischemic stroke, anemia, BP, non–HDL‐C, and time to randomization after onset of symptoms (Table S2). Of the included patients, 75.8% (3573/4715) of patients had MetS. They tended to be women and had more vascular risk factors and a higher proportion of ischemic stroke than patients without MetS (Table S3). However, most baseline characteristics were well balanced between aspirin‐alone and clopidogrel–aspirin groups in all participants (Table S4) and in participants with and without MetS (Table 1).

Figure 1. Flowchart of the study.

NIHSS indicates National Institutes of Health Stroke Scale.

Table 1.

Baseline Characteristics of Different Antiplatelet Treatment Groups in Participants With and Without Metabolic Syndrome

Characteristic	Metabolic syndrome (N=3573)			No metabolic syndrome (N=1142)
	Aspirin (n=1821)	Clopidogrel–Aspirin (n=1752)	P value	Aspirin (n=538)	Clopidogrel–Aspirin (=604)	P value
Age, y, mean±SD	63.6±9.5	63.3±9.8	0.34	64.2±9.8	64.5±9.1	0.77
Female sex, n (%)	748 (41.1)	717 (40.9)	0.93	110 (20.5)	112 (18.5)	0.42
Current smoking, n (%)	514 (28.2)	483 (27.6)	0.66	214 (39.8)	242 (40.1)	0.92
Current drinking, n (%)	230 (12.6)	234 (13.4)	0.52	114 (21.2)	124 (20.5)	0.78
Medical history, n (%)
Hypertension	1293 (71.0)	1254 (71.6)	0.71	273 (50.7)	314 (52.0)	0.67
Diabetes	608 (33.4)	615 (35.1)	0.28	43 (8.0)	40 (6.6)	0.37
Dyslipidemia	87 (4.8)	75 (4.3)	0.48	14 (2.6)	11 (1.8)	0.37
Gout	11 (0.6)	6 (0.3)	0.26	2 (0.4)	3 (0.5)	1.00
Chronic obstructive pulmonary disease	13 (0.7)	11 (0.6)	0.75	7 (1.3)	5 (0.8)	0.43
Coronary heart disease	232 (12.7)	211 (12.0)	0.53	56 (10.4)	58 (9.6)	0.65
Peripheral artery disease	7 (0.4)	5 (0.3)	0.61	1 (0.2)	1 (0.2)	1.00
Ischemic stroke	592 (32.5)	549 (31.3)	0.45	149 (27.7)	158 (26.2)	0.56
Anemia, n (%)	271 (15.2)	272 (16.0)	0.56	95 (18.1)	125 (21.3)	0.19
Chronic kidney disease, n (%)	57 (3.3)	48 (2.9)	0.56	16 (3.2)	11 (2.0)	0.21
Family history of stroke, n (%)	240 (13.2)	206 (11.8)	0.20	61 (11.3)	64 (10.6)	0.69
Body mass index, kg/m2, mean±SD	25.1±3.3	24.9±3.2	0.10	23.8±3.1	23.8±3.0	0.98
Systolic blood pressure, mm Hg, mean±SD	150.5±20.2	150.0±19.6	0.55	141.8±21.6	142.8±22.1	0.42
Diastolic blood pressure, mm Hg, mean±SD	87.1±12.5	87.1±12.0	0.65	84.4±12.5	84.0±12.4	0.70
Heart rate, bpm, mean±SD	75.0±19.8	74.9±11.1	0.13	72.1±11.7	71.5±10.4	0.18
Triglyceride/HDL‐C, median (IQR)	1.5 (1.1–2.2)	1.4 (1.0–2.1)	<0.001	0.9 (0.6–1.1)	0.8 (0.6–1.1)	0.62
TC/HDL‐C	4.4 (3.7–5.1)	4.3 (3.6–5.1)	0.09	3.5 (3.1–4.2)	3.6 (3.1–4.2)	0.35
LDL‐C/HDL‐C	2.7 (2.2–3.3)	2.7 (2.1–3.3)	0.08	2.1 (1.7–2.6)	2.2 (1.8–2.7)	0.28
Non–HDL‐C/HDL‐C	3.4 (2.7–4.1)	3.3 (2.6–4.1)	0.09	2.5 (2.1–3.2)	2.6 (2.1–3.2)	0.35
Non–HDL‐C, mmol/L	3.2 (2.6–3.9)	3.2 (2.6–3.9)	0.59	3.0 (2.5–3.6)	3.0 (2.5–3.6)	0.31
Fasting blood glucose, mmol/L, mean±SD	7.5±3.4	7.6±3.4	0.42	5.2±1.4	5.2±1.3	0.39
Glycosylated hemoglobin, %, mean±SD	7.0±1.9	7.1±2.0	0.56	5.9±1.1	5.8±1.0	0.005
Blood platelet count, × 109/L, mean±SD	225.8±60.8	226.3±67.4	0.70	223.0±72.1	218.2±63.6	0.46
Alanine aminotransferase, U/L	18.0 (13.0–25.0)	17.0 (13.0–24.5)	0.09	16.0 (12.7–21.0)	16.0 (13.0–22.0)	0.47
Aspartate aminotransferase, U/L	18.0 (15.0–22.9)	18.0 (15.0–23.0)	0.59	19.0 (16.0–23.0)	19.0 (16.0–23.0)	0.63
Hemoglobin, g/dL, mean±SD	13.9±1.6	13.9±1.7	0.94	14.0±1.6	13.9±1.6	0.11
Use of agents before qualifying event, n (%)
Antihypertensive agent	970 (53.3)	940 (53.7)	0.82	173 (32.2)	198 (32.8)	0.82
Hypoglycemic agent	509 (28.0)	521 (29.7)	0.24	34 (6.3)	35 (5.8)	0.71
Lipid‐lowering agent	202 (11.1)	189 (10.8)	0.77	40 (7.4)	43 (7.1)	0.84
Antidepressant agent	10 (0.6)	5 (0.3)	0.22	2 (0.4)	2 (0.3)	1.00
Aspirin	273 (15.0)	243 (13.9)	0.34	50 (9.3)	63 (10.4)	0.52
Clopidogrel	13 (0.7)	10 (0.6)	0.59	3 (0.6)	5 (0.8)	0.58
Qualifying event, n (%)
TIA	245 (13.5)	224 (12.8)	0.64	65 (12.1)	70 (11.6)	0.16
Acute single infarction	366 (20.1)	338 (19.3)		94 (17.5)	133 (22.0)
Acute multiple infarctions	1210 (66.4)	1190 (67.9)		379 (70.4)	401 (66.4)
≥50% symptomatic stenosis, n (%)
Yes	1494 (83.7)	1416 (82.7)	0.43	419 (79.1)	468 (79.2)	0.96
No	292 (16.3)	297 (17.3)		111 (20.9)	123 (20.8)
Time to randomization after onset of symptoms, n (%)
≤24 h	239 (13.1)	238 (13.6)	0.82	67 (12.4)	86 (14.2)	0.14
>24 to ≤48 h	780 (42.8)	733 (41.8)		242 (45.0)	237 (39.3)
>48 to 72 h	802 (44.1)	781 (44.6)		229 (42.6)	281 (46.5)
NIHSS score in qualifying ischemic stroke, n (%)*
≤3	1191 (75.6)	1152 (75.4)	0.91	379 (80.1)	422 (79.0)	0.67
4 or 5	385 (24.4)	376 (24.6)		94 (19.9)	112 (21.0)
ABCD2 score in qualifying TIA, n/total n (%)†
4 or 5	187/245 (76.3)	176/224 (78.6)	0.56	58/65 (89.2)	61/70 (87.1)	0.71
>5	58/245 (23.7)	48/224 (21.4)		7/65 (10.8)	9/70 (12.9)

HDL‐C indicates high‐density lipoprotein cholesterol; LDL‐C, low‐density lipoprotein cholesterol; NIHSS, National Institutes of Health Stroke Scale; TC, total cholesterol; and TIA, transient ischemic attack.

^*Scores on the NIHSS ranged from 0 to 42 for patients with ischemic stroke, with higher scores indicating more severe stroke.

^† The ABCD² score assessed the risk of stroke on the basis of age, blood pressure, clinical features, duration of TIA, and the presence or absence of diabetes in patients with TIA. Scores ranged from 0 to 7, with higher scores indicating greater risk.

Association of MetS With Efficacy and Safety Outcomes

In patients with MetS, 8.5% of subjects (302/3573) had new stroke events, whereas the incidence of new stroke was merely 5.9% (67/1142) in patients without MetS (Figure 2A). After adjustment for potential confounders including in‐hospital antiplatelet therapy, patients with MetS were at higher risk of recurrent stroke (adjusted HR, 1.39 [95% CI, 1.06–1.82]; P=0.02), composite cardiovascular events (adjusted HR, 1.37 [95% CI, 1.05–1.79]; P=0.02), ischemic stroke (adjusted HR, 1.41 [95% CI, 1.07–1.86]; P=0.02), and poor functional outcome (adjusted relative risk, 1.27 [95% CI, 1.02–1.57]; P=0.03) as compared with patients without MetS. Nevertheless, MetS was not associated with moderate ‐ to ‐ severe bleeding events and all secondary safety outcomes (Table 2).

Figure 2. Cumulative incidence of new stroke events between different antiplatelet treatment groups in participants with and without MetS.

MetS indicates metabolic syndrome.

Table 2.

Association of Metabolic Syndrome With Efficacy and Safety Outcomes Within 90‐Day Follow‐Up

Outcome	Metabolic syndrome N/total (%)	No metabolic syndrome N/total (%)	Adjusted HR or RR (95% CI)*	P value
Primary outcome
Stroke†	302/3573 (8.5)	67/1142 (5.9)	1.39 (1.06–1.82)	0.02
Secondary outcomes
Composite cardiovascular event‡	306/3573 (8.6)	69/1142 (6.0)	1.37 (1.05–1.79)	0.02
Ischemic stroke	290/3573 (8.1)	63/1142 (5.5)	1.41 (1.07–1.86)	0.02
Hemorrhagic stroke	12/3573 (0.3)	5/1142 (0.4)	0.85 (0.29–2.46)	0.76
TIA	39/3573 (1.1)	8/1142 (0.7)	1.50 (0.69–3.24)	0.30
Myocardial infarction	1/3573 (0.03)	2/1142 (0.2)	0.17 (0.01–2.13)	0.17
Death from cardiovascular causes	19/3573 (0.5)	6/1142 (0.5)	1.15 (0.45–2.93)	0.77
Poor functional outcome§	394/3570 (11.0)	96/1141 (8.4)	1.27 (1.02–1.57)	0.03
Primary safety outcome
Moderate‐to‐severe bleeding‖	25/3573 (0.7)	9/1142 (0.8)	1.02 (0.47–2.21)	0.97
Secondary safety outcomes
Hepatotoxic effects¶	48/3573 (1.3)	15/1142 (1.3)	1.01 (0.61–1.66)	0.98
Muscle toxic effects#	0/3573 (0.0)	0/1142 (0.0)	–	–
Death from any cause	40/3573 (1.1)	9/1142 (0.8)	1.61 (0.77–3.36)	0.20
Any bleeding‖	88/3573 (2.5)	36/1142 (3.2)	0.83 (0.55–1.23)	0.34
Intracranial hemorrhage	15/3573 (0.4)	6/1142 (0.5)	0.92 (0.35–2.43)	0.87
Mild bleeding	67/3573 (1.9)	27/1142 (2.4)	0.83 (0.52–1.31)	0.42

HR indicates hazard ratio; RR, relative risk; and TIA, transient ischemic attack.

^*Relative risks were shown for poor functional outcome, hepatotoxic effects, and muscle toxic effects. Hazard ratios were shown for other outcomes. Absence of metabolic syndrome was set as reference in models. All models were adjusted for age, sex, smoking status, National Institutes of Health Stroke Scale on admission, time to randomization, in‐hospital statin therapy, and in‐hospital antiplatelet therapy.

^† Stroke included ischemic and hemorrhagic stroke.

^‡ Composite cardiovascular event included stroke, myocardial infarction, or death from cardiovascular causes.

^§ A poor functional outcome was defined as a modified Rankin scale score of 2 to 6.

^‖ Bleeding events were defined according to the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria.

^¶ Hepatotoxic effects were defined as an alanine aminotransferase or aspartate aminotransferase level that was >3 times the upper limit of the normal range.

^# Muscle toxic effects were defined as a creatine kinase level that was >10 times the upper limit of the normal range or as presence of muscle pain, myopathy, or rhabdomyolysis.

Efficacy Outcomes of Clopidogrel–Aspirin Therapy in Patients With and Without MetS

In patients with MetS, 8.0% of subjects (140/1752) had new stroke events in the clopidogrel–aspirin group and 8.9% (162/1821) had events in the aspirin group (adjusted HR, 0.88 [95% CI, 0.70–1.11]; P=0.27; Figure 2B). In patients without MetS, 5.0% (30/604) had new stroke events in the clopidogrel–aspirin group and 6.9% (37/538) had events in the aspirin group (adjusted HR, 0.71 [95% CI, 0.44–1.15]; P=0.17; Figure 2C). The efficacy of clopidogrel–aspirin therapy for recurrent stroke were not significantly different in patients with different MetS state (P for interaction=0.44). Similarly, there were no interaction effects of antiplatelet therapy by different MetS state for the risk of secondary outcomes including composite cardiovascular events (P for interaction=0.41), ischemic stroke (P for interaction=0.36), hemorrhagic stroke (P for interaction=0.66), TIA (P for interaction=0.89), and poor functional outcome (P for interaction=0.29) (Table 3). In sensitivity analyses, we found similar results after redefining MetS by use of the International Diabetes Federation criterion (Table S5) and use of medical history or medication history in the Adult Treatment Panel‐III (Table S6). Furthermore, sensitivity analysis performed in all participants without excluding any individuals also showed consistent results (Table S7).

Table 3.

Efficacy and Safety Outcomes of Dual Antiplatelet Therapy in Participants With and Without Metabolic Syndrome

Outcome	Metabolic syndrome (N=3573)				No metabolic syndrome (N=1142)				P value for interaction
	Aspirin N/Total (%)	Clopidogrel–Aspirin N/Total (%)	Adjusted HR or RR (95% CI)*	P value	Aspirin N/Total (%)	Clopidogrel–Aspirin N/Total (%)	Adjusted HR or RR (95% CI)*	P value
Primary outcome
Stroke†	162/1821 (8.9)	140/1752 (8.0)	0.88 (0.70–1.11)	0.27	37/538 (6.9)	30/604 (5.0)	0.71 (0.44–1.15)	0.17	0.44
Secondary outcomes
Composite cardiovascular event‡	163/1821 (9.0)	143/1752 (8.2)	0.89 (0.71–1.12)	0.33	38/538 (7.1)	31/604 (5.1)	0.72 (0.45–1.15)	0.17	0.41
Ischemic stroke	158/1821 (8.7)	132/1752 (7.5)	0.85 (0.67–1.07)	0.17	36/538 (6.7)	27/604 (4.5)	0.66 (0.40–1.09)	0.10	0.36
Hemorrhagic stroke	4/1821 (0.2)	8/1752 (0.5)	2.20 (0.65–7.39)	0.20	1/538 (0.2)	4/604 (0.7)	5.01 (0.48–52.05)	0.18	0.66
TIA	25/1821 (1.4)	14/1752 (0.8)	0.58 (0.30–1.12)	0.11	5/538 (0.9)	3/604 (0.5)	0.42 (0.09–2.08)	0.29	0.89
Myocardial infarction	0/1821 (0.0)	1/1752 (0.1)	–	–	1/538 (0.2)	1/604 (0.2)	1.61 (0.07–37.66)	0.77	1.00
Death from cardiovascular causes	8/1821 (0.4)	11/1752 (0.6)	1.34 (0.54–3.35)	0.53	0/538 (0.0)	6/604 (1.0)	–	–	0.99
Poor functional outcome§	206/1819 (11.3)	188/1751 (10.7)	0.92 (0.76–1.13)	0.44	52/537 (9.7)	44/604 (7.3)	0.76 (0.51–1.13)	0.18	0.29
Primary safety outcome
Moderate‐to‐severe bleeding‖	9/1821 (0.5)	16/1752 (0.9)	1.83 (0.81–4.16)	0.15	4/538 (0.7)	5/604 (0.8)	1.18 (0.31–4.47)	0.81	0.54
Secondary safety outcomes
Hepatotoxic effects¶	23/1821 (1.3)	25/1752 (1.4)	1.13 (0.64–1.99)	0.68	5/538 (0.9)	10/604 (1.7)	2.11 (0.71–6.30)	0.18	0.46
Muscle toxic effects#	0/1821 (0.0)	0/1752 (0.0)	–	–	0/538 (0.0)	0/604 (0.0)	–	–	–
Death from any cause	19/1821 (1.0)	21/1752 (1.2)	1.03 (0.55–1.93)	0.93	1/538 (0.2)	8/604 (1.3)	7.39 (0.91–59.68)	0.06	0.10
Any bleeding‖	40/1821 (2.2)	48/1752 (2.7)	1.25 (0.82–1.90)	0.30	13/538 (2.4)	23/604 (3.8)	1.61 (0.81–3.19)	0.17	0.53
Intracranial hemorrhage	6/1821 (0.3)	9/1752 (0.5)	1.54 (0.54–4.34)	0.42	2/538 (0.4)	4/604 (0.7)	2.12 (0.36–12.53)	0.41	0.86
Mild bleeding	32/1821 (1.8)	35/1752 (2.0)	1.14 (0.70–1.84)	0.60	9/538 (1.7)	18/604 (3.0)	1.81 (0.81–4.05)	0.15	0.33

HR indicates hazard ratio; RR, relative risk; and TIA, transient ischemic attack.

^*Relative risks were shown for poor functional outcome, hepatotoxic effects, and muscle toxic effects. HRs were shown for other outcomes. Aspirin treatment was set as reference in models. All models were adjusted for age, sex, smoking status, National Institutes of Health Stroke Scale on admission, history of ischemic stroke, history of transient ischemic attack, history of coronary heart disease, time to randomization, antihypertensive therapy, lipid‐lowering therapy, hypoglycemic therapy, antiplatelet therapy, and in‐hospital statin therapy.

^† Stroke included ischemic and hemorrhagic stroke.

^‡ Composite cardiovascular event included stroke, myocardial infarction, or death from cardiovascular causes.

^§ A poor functional outcome was defined as a modified Rankin scale score of 2 to 6.

^‖ Bleeding events were defined according to the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria.

^¶ Hepatotoxic effects were defined as an alanine aminotransferase or aspartate aminotransferase level that was >3 times the upper limit of the normal range.

^# Muscle toxic effects were defined as a creatine kinase level that was >10 times the upper limit of the normal range or as presence of muscle pain, myopathy, or rhabdomyolysis.

Safety Outcomes of Clopidogrel–Aspirin Therapy in Patients With and Without MetS

In patients with MetS, the rate of moderate to severe bleeding event was 0.9% (16/1752) in the clopidogrel–aspirin group and 0.5% (9/1821) in the aspirin group (adjusted HR, 1.83 [95% CI, 0.81–4.16]; P=0.15). In patients without MetS, the rate was 0.8% (5/604) in the clopidogrel–aspirin group and 0.7% (4/538) in the aspirin group (adjusted HR, 1.18 [95% CI, 0.31–4.47]; P=0.81). After adjustment for potential confounders, there were no interaction effects between antiplatelet therapy and MetS state for the risk of moderate ‐ to ‐ severe bleeding events (P for interaction=0.54) and secondary safety outcomes (P for interaction>0.05) (Table 3). Sensitivity analyses showed similar results (Tables S5–S7).

DISCUSSION

In this post hoc analysis of the INSPIRES trial, patients with MetS were at higher risk of recurrent stroke, composite cardiovascular events, ischemic stroke, and poor functional outcome as compared with patients without MetS. However, there were no substantial differences in the incidence of efficacy outcomes and safety outcomes between the 2 treatment groups by different MetS state, indicating that MetS did not affect the efficacy and safety of clopidogrel–aspirin therapy within 90 days.

The influence of MetS on aspirin therapy has been extensively investigated. MetS was strongly and uniquely associated with less effective inhibition of platelet cyclooxygenase‐1 by aspirin. ²² MetS attenuated aspirin efficacy among women partly due to aspirin resistance. ²³ Patients with MetS appear to have a lower antiplatelet response to aspirin than healthy individuals. ²⁴ However, the study focusing on the efficacy of DAPT with clopidogrel plus aspirin for secondary stroke prevention in patients with MetS remains rare. Only subgroup analysis of the CHANCE trial demonstrated that there was no difference in the effect of DAPT initiated within 24 hours on reducing new stroke events at 3 months between patients with and without MetS or diabetes. ¹³ Another meta‐analysis study demonstrated that dual antiplatelet trial arms had lowest incidence of stroke recurrence at 90 days and the effect was not affected by components of MetS after pooling 6 randomized controlled trials. ²⁵ However, secondary analyses of the Platelet‐Oriented Inhibition in New TIA and Minor Ischemic Stroke trial found that components of MetS (hypertension and hyperglycemia) compromised the therapeutic effect of DAPT on stroke recurrence within 90 days. ⁹ , ¹⁰ Our study extended the results of the CHANCE trial and supported that MetS did not affect the efficacy of DAPT at 90 days even if patients underwent the DAPT within 72 hours after symptom onset.

It is known that MetS leads to a hypercoagulant state and attenuates antiplatelet effect of aspirin through increasing platelet aggregation, platelet activity, platelet turnover, and decreasing fibrinolysis. ²⁴ , ²⁶ Similarly, patients with MetS had impaired response to clopidogrel and higher platelet reactivity when they underwent a large loading dose of clopidogrel treatment (600 mg) within 6 to 24 hours or a maintenance dose in a short period (75 mg daily for 1 month). ²⁷ , ²⁸ Mechanisms of high on‐clopidogrel platelet reactivity (HCPR) include impaired intestinal absorption, reduced production of clopidogrel active metabolite via pinpoint mutations in the cytochrome P450 2C19 gene, drug interactions, and increased baseline platelet reactivity. ²⁷ However, clinical data further show that prevalence of HCPR decreased in patients with MetS from 52.0% to 31.3% after 4‐month clopidogrel treatment (75 mg daily). ²⁷ The 4‐month prevalence of HCPR in patients with MetS (31.3%) was not significantly higher than that in patients without MetS (23.8%). ²⁷ MetS was not an independent predictor of HCPR at this stage. ²⁷ Although mechanisms remain unclear, this phenomenon may result from a low rate of persistent HCPR and late‐onset HCPR in patients with MetS. ²⁷ These findings indicate that long‐term clopidogrel treatment still works in the antiplatelet effect in patients both with and without MetS and may explain our findings that MetS did not compromise the efficacy of clopidogrel–aspirin therapy within 90 days. In addition, it cannot rule out the influence of relatively insufficient sample size due to the design of post hoc analysis of the INSPIRES trial. Insufficient sample size can lower power to detect the effect difference of DAPT between patients with and without MetS.

This study found that MetS was not associated with bleeding events, which was in line with others' findings. ²⁹ MetS can significantly alter hemostatic factors and leave patients in a prothrombotic state through endothelial dysfunction, enhanced platelet activity, and impaired fibrinolysis. ³⁰ , ³¹ Thus, patients with MetS are more likely to develop atherothrombotic cardiovascular events including myocardial infarction and ischemic stroke rather than bleeding events. ³⁰ , ³¹ In addition, this study did not find an association between MetS and death within 90 days. In contrast, a meta‐analysis study supports that MetS is associated with all‐cause death. ⁸ These inconsistent findings may be attributed to the shorter follow‐up time in the INSPIRES trial.

This study has important potential implications. We demonstrated that the presence of MetS was associated with higher risk of recurrent stroke, composite cardiovascular events, and poor functional outcome, supporting that MetS is a vital prognostic factor for patients with mild ischemic stroke or TIA. The results suggest that tightening metabolic control remains indispensable for secondary stroke prevention in this high‐risk population. Furthermore, guidelines recommend that DAPT with clopidogrel combined with aspirin should be used in patients who have a minor ischemic stroke within 24 hours after symptom onset. ⁶ However, evidence is limited on the efficacy and potential harm of DAPT among specific subgroups of patients according to metabolic state. ¹ This study showed that MetS did not affect the efficacy and safety of clopidogrel–aspirin therapy initiated within 72 hours, thus adding new evidence on the applicability of DAPT up to 72 hours in high‐risk patients, regardless of MetS state. In addition, previous studies evaluated the efficacy of DAPT in patients with a single metabolic disease but failed to address the effect of comorbidities of multiple metabolic disease on DAPT. ³ , ⁹ , ¹⁰ , ²⁵ The current study adds new information to the literature regarding the efficacy of DAPT in patients with comorbidities of multiple metabolic diseases.

Limitations

This study has some limitations. First, this study was a post hoc analysis of the INSPIRES trial. The sample size of current study was not calculated in advance and may lower the power of the statistical test. Second, randomization was not maintained as the participants in this study were selected from the INSPIRES trial. Although there was no significant difference in most baseline characteristics between antiplatelet treatment groups and potential confounders were adjusted during analyses, it cannot rule out the influence of unknown confounders. Third, the participants studied were mainly Han Chinese patients, thus it should be cautious to extrapolate our findings to White and Black patients with stroke. Finally, abdominal obesity defined by WC is one of the criteria of Adult Treatment Panel‐III. ¹⁷ We did not use abdominal obesity to define MetS due to deficiency of WC data, thus we may omit some patients who could be diagnosed as having MetS.

FUTURE DIRECTIONS

First, more studies with a larger sample size and covering other races are needed to verify these findings. Second, future studies should incorporate abdominal obesity to define MetS and evaluate the effect of MetS on the efficacy of DAPT. Third, this study evaluated efficacy outcomes within 90 days. Whether MetS would affect the longer‐term outcomes requires further investigation.

CONCLUSIONS

MetS was associated with an elevated risk of recurrent stroke within 90 days among patients with mild ischemic stroke or high‐risk TIA. The effect of clopidogrel–aspirin therapy on reducing new stroke and increasing bleeding events at 90 days was not different between patients with and without MetS. This study suggests that clopidogrel–aspirin therapy initiated within 72 hours after symptom onset could be applied in patients with mild ischemic stroke or high‐risk TIA, regardless of MetS state.

Sources of Funding

This study was supported by grants from the National Natural Science Foundation of China (No. 82425101), Noncommunicable Chronic Diseases–National Science and Technology Major Project (2023ZD0504800, 2023ZD0504801, 2023ZD0504802, 2023ZD0504803, 2023ZD0504804), Beijing Municipal Science & Technology Commission (No. Z231100004823036), Capital's Funds for Health Improvement and Research (2022‐2‐2045), National Key Technology Research and Development Program of China (2024YFC3044800, 2022YFF1501500, 2022YFF1501501, 2022YFF1501502, 2022YFF1501503, 2022YFF1501504, 2022YFF1501505). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclosures

P.M.B is Stroke Association Professor of Stroke Medicine and an emeritus National Institute for Health and Care Research Senior Investigator. He has received research grants from the British Heart Foundation and National Institute for Health and Care Research, has stock options in CoMind and DiaMedica, and received honoraria from them and Phagenesis. P.A. has received research grants from AstraZeneca (drug supply) and Novartis, and received speaking fee from Viatris and Novartis, consulting fees from Novartis and Neuraltide, and advisory board fee from Merck.

Supporting information

Tables S1–S7