Stroke peril due to altered lipid profiles and resistance to acetylsalicylic acid: A meta-analysis

INTRODUCTION

Resistance to antiplatelet therapy in stroke patients poses an alarming challenge in the area of neurovascular diseases. Almost a century ago, aspirin, i.e. acetylsalicylic acid (ASA), was introduced as an analgesic and antipyretic agent. A non-selective cyclooxygenase (COX) inhibitor, aspirin impedes platelet accretion and is used in the prevention of blood clots in Transient Ischaemic Attack and ischaemic stroke (IS).^[1,2] Aspirin is a commonly recommended drug to diminish the progression of IS in a clinical setup. Stroke is the third leading cause of death worldwide and has been recognised as a major health problem. In high-income nations, there is a 42% reduction in stroke incidence and a significant increase in stroke incidence in low- to middle-income countries.^[3]

Despite the use of antiplatelet drugs, the incidence of thrombotic events has led to the concept of ‘antiplatelet resistance’.^[4] ‘Aspirin resistance’ along with ‘failure of antiplatelet drug’, ‘unresponsive antiplatelets’ and ‘injudicious efficacy’ are some abbreviations used to describe this condition. ASA inhibition of platelet aggregation occurs due to interaction with thromboxane A2 in platelets, triggered by the inhibition of COX-1. Thromboxane A2 leads to platelet aggregation that may contribute towards clot formation and the probable peril of heart attack or stroke.^[4]

The development of methods to evaluate how platelets support blood clotting and to monitor platelet function in people taking aspirin makes it more likely that weak responses or ‘aspirin resistance’ will be classified as a laboratory finding rather than a true clinical condition. Many studies have reported that individuals with diminished or completely unresponsive antiplatelet response to ASA may encounter higher risks of cardiovascular events. Cardiovascular risks are higher in patients with ASA resistance relative to those who are sensitive to ASA therapy.^[5,6] In addition, a high prevalence of aspirin resistance (28.0–65.0%) was seen among post-stroke aspirin users.^[7]

The connotation between high blood lipid content and increased platelet activity is not new. A retrospective clinical study reported that hyperlipidaemia enhances the chance of ASA dysfunction even in patients having the first episode of IS.^[8] Elevated blood lipid levels may independently predict aspirin resistance in stroke survivors receiving aspirin treatment, according to existing research.^[9] A weak association between hyperlipidaemia, ischaemic heart disease and the prevalence of ASA resistance measured by the platelet function analyzer (PFA)-100 analyser has been reported in patients on usual doses (100–300 mg/day) of aspirin after first-ever IS.^[10]

Despite all facts, aspirin is still the standard first-line antiplatelet therapy for the prevention of primary as well as secondary stroke. Aspirin use results in a 13–25% reduction in stroke recurrence.^[11] The guidelines of the American Heart Association and American Stroke Association suggest moderate use of aspirin in the primary prevention of stroke in high-risk categories.^[12] The processes that lead to aspirin resistance likely extend beyond aspirin itself and may affect other medications that prevent platelet aggregation (e.g., clopidogrel).^[13,14]

It has been seen that despite being on antiplatelet drugs like aspirin, there is thrombus formation, nonetheless. Several pharmacogenetic and pharmacodynamic properties may lead to aspirin resistance in stroke patients.^[15,16] Some observational studies suggest that an altered blood lipid profile may cause aspirin resistance. Therefore, this meta-analysis was commenced to explore the connotation of blood lipid profile with aspirin unresponsiveness in neurovascular patients with/at high risk of IS. As the burden of stroke is assumed to rise greatly in the next decade, it is essential to characterise drug resistance factors for stroke. It will benefit stroke patients by adapting better preventive strategies to diminish stroke risk and developing novel, specific drugs as treatment guidelines.

MATERIALS AND METHODS

This cumulative review was performed on published guidelines from the Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analyses.^[17]

Risk of bias

The quality assessment was done for all included studies in our meta-analysis by three independent authors (AKS, GV and PD). Publications bias was evaluated using Funnel plots illustrated in Figure 1 (a: total cholesterol [TC]; b: triglyceride [TG]; c: High-density lipoprotein [HDL]; d: low-density lipoprotein [LDL]) and Egger’s test, and Begg’s test was also estimated [Table 1], where P < 0.05 was considered as statistically significant.

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Figure 1:

(a) Funnel plot representing the publication bias analysis of total cholesterol. (b) Funnel plot representing the publication bias analysis of triglyceride. (c) Funnel plot representing the publication bias analysis of high-density lipoprotein. (d) Funnel plot representing the publication bias analysis of low-density lipoprotein. SMD: Standard mean difference

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Table 1: Summary of the observed results, Egger’s test and Begg’s test estimated for study bias.

S. No	Lipid profile	No of Studies	No of subjects		SMD	95% CI	P-value	Heterogenicity (I2) (%)	Egger’s test (P-value)	Begg’s test (P-value)
			AR	AS
1	TC	6	181	577	0.04	−0.13–0.21	0.64	0	0.682	0.573
2	Triglycerides	5	142	480	0.83	−0.30–1.95	<0.001	96	0.275	0.091
3	HDL	5	141	403	−0.09	−0.28–0.11	0.39	0	0.309	1.000
4	LDL	5	208	755	−1.11	−7.12–4.90	0.72	47	0.314	0.138
5	TG (removing large effect size)	4	105	421	0.08	−0.19–0.35	0.55	29	--	--

TC: Total cholesterol, TG: Triglycerides, HDL: High density lipid, LDL: Low density lipid, AR: Aspirin resistance, AS: Aspirin sensitive, SMD: Standard mean difference, CI: Confidence interval, P<0.001 was statistically significant

RESULTS

For TC, six studies consisting of 181 aspirin-resistant and 577 aspirin-sensitive subjects were included in this meta-analysis. No significant difference (standard mean difference [SMD] = 0.04, 95% CI: −0.13–0.21, P = 0.64) was observed between the groups [Figure 2]. For TGs, a total of 6 studies consisting of 142 aspirin-resistant and 480 aspirin-sensitive subjects were included. Our findings indicated a significant association of elevated TG levels in aspirin resistance groups compared to non-resistance groups (SMD = 0.83, 95% CI: 0.30–1.95, P < 0.001). However, meta-influence suggested no significant association when a large effect size study was excluded (SMD = 0.08, 95% CI: −0.19–0.35, P = 0.23), as shown in Figure 3a-c. For HDL, a total of 5 studies consisting of 141 aspirin-resistant and 403 aspirin-sensitive subjects were assessed in this meta-analysis. No significant difference (SMD = −0.09, 95% CI: −0.28–0.11, P = 0.56) was observed between the groups [Figure 4]. For low-density lipoprotein (LDL), a total of 8 studies, including 208 aspirin-resistant studies and 755 aspirin-sensitive subjects, were selected. No significant difference (SMD = 1.11, 95% CI: −7.12–4.90, P = 0.07) was observed between the groups [Figure 5].

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Figure 2:

The non-significant association was observed between high cholesterol level and aspirin resistance groups as compared to non-resistance (Standard mean difference = 0.04, 95% Confidence interval [CI]: −0.13–0.21, P = 0.64). SD: Standard deviation

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Figure 3:

(a) A significantly high-triglyceride level was observed in the Aspirin resistance groups as compared to non-resistance (Standard mean difference [SMD] = 0.83, 95% Confidence interval [CI]: 0.30–1.95, P < 0.001). (b) Significantly high triglyceride level was observed in the Aspirin resistance groups as compared to non-resistance (SMD= 0.08, 95% CI: −0.19–0.35, P = 0.23). (c) Sensitivity analysis representing no significant association for triglycerides.

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Figure 4:

The non-significant low high-density lipoprotein level was observed in Aspirin resistance groups as compared to non-resistance (Standard mean difference= −0.09, 95% Confidence interval [CI]: −0.28–0.11, P = 0.56).

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Figure 5:

No significant difference was observed in low-density lipoprotein level between aspirin resistance and the aspirin sensitive group (Standard mean difference = 1.11, 95% Confidence interval [CI]: −7.12–4.90, P = 0.07).

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DISCUSSION

This meta-analysis explores the connotation of blood lipid profile with aspirin resistance in stroke patients with clinical non-responsiveness to aspirin therapy and elevated risk of IS. The blood lipid profile was found to be associated with the platelet response to aspirin therapy following the first IS. Antiplatelet resistance is extremely variable for different drugs, i.e. 3–85% for aspirin and 28–44% for clopidogrel.^[18]

Platelet resistance has been frequently related to a higher risk of vascular incidents such as stroke and coronary artery disease. Although individualisation of antiplatelet therapy might be beneficial to achieve optimum platelet inhibition, there are numerous issues that impede the translation of platelet function measures to standard clinical practice. Currently, there are no laboratory tests that can measure optimal platelet responsiveness. Overall, their results show weak correlation with each other and exhibit high intra-assay variability.

Findings of the present meta-analysis have a significant relation between the elevated TG levels in aspirin resistance groups as compared to non-resistance (SMD= 0.83, 95% CI: 0.30–1.95, P < 0.001). However, sensitivity analysis [Figure 3c] proposed no substantial connotation when a large effect size was excluded (SMD= 0.08, 95% CI: −0.19– 0.35, P = 0.23). A study revealed that blood TG levels are the only biomarker associated with platelet response to aspirin therapy after the first IS. It was significantly higher in patients with aspirin resistance compared with aspirin responders (237 ± 11 vs. 174 ± 13 mg/dL, P < 0.01).^[9] The findings from this study are in concordance with our study results. Another study reported that an elevated level of TGs was also linked to low platelet reactivity. This correlation was shown in univariate analysis and remained high in patients with documented coronary disease after multivariate analysis.^[19] The relationship between the lipid profile and platelet reactivity may vary in patients with different vascular diseases.^[20] In addition, the differing association between TG levels and ASA resistance could be attributed to the significantly greater inter- and intra-individual variability of TG levels compared to the variability observed in TC, LDL cholesterol or HDL cholesterol.^[9]

Elevated lipids and higher platelet reactivity are not novel concepts.^[9] The development of hyperlipidaemia is a crucial peril aspect for ASA resistance and stroke.^[9] The prevalence of hyperlipidaemia in the ASA-resistant patients in a related study was 65%, compared to 26% of the average ASA responders. It was found that there is a small correlation with ASA resistance and conventional lipid biomarkers.^[9] Patients with aspirin resistance showed a higher TC/HDL ratio and elevated lipoprotein levels compared to aspirin-sensitive individuals. However, two other clinical studies reported no association between aspirin resistance and elevated TGs.^[19,21]

Existing studies have illustrated that the intrinsic microthrombotic mechanism of aspirin resistance is communal in lacunar than embolic strokes.^[21] The findings of another study aligned with this report, showing a higher incidence of lacunar stroke among 1^st-time stroke patients using aspirin. However, biological aspirin resistance was not assessed, preventing the exclusion of the possibility of a standardised diagnosis of aspirin resistance.^[22] Existing reports recommended that relapse can occur in subjects without biological aspirin resistance.^[23]

Based on findings from a meta-analysis examining nine trials, 941 patients (1.19%) in the aspirin group experienced non-fatal stroke compared to 979 patients (1.26%) in the control group. The analysis revealed that aspirin administration for primary cardiovascular prevention did not significantly reduce non-fatal stroke incidence (odds ratio: 0.94; 95% CI: 0.85–1.04). Statistical heterogeneity assessment yielded a P = 0.38, with an I² value of 16.2%, Q statistic of 8.53 and 8° of freedom.^[24] An eleven-trial meta-analysis investigating aspirin’s role in primary stroke prevention among people without cardiovascular disease found that stroke events affected 1277 individuals (1.61%) receiving aspirin and 1297 individuals (1.67%) in control groups. The data demonstrated that prophylactic aspirin use did not yield a statistically meaningful reduction in overall stroke occurrence (odds ratio: 0.95; 95% CI: 0.88–1.03). The heterogeneity assessment showed minimal variation between studies with a P = 0.47, an I² value of 2.4%, Q statistic of 9.67 and degrees of freedom = 10.^[24]

It has been suggested by many recent studies that hypertriglyceridaemia influences aspirin resistance. They have also assumed that aspirin may exert antiplatelet properties through alternative non-COX pathways.^[25-27] Other data suggest that aspirin resistance has a significant connotation with poor metabolic control.^[25] It is not only due to a single metabolic abnormality but a constellation of multiple metabolic disorders.^[9] The key catabolic pathway for TG metabolism is linked with lipoprotein lipase, an enzyme that is expressed on the endothelial surface.^[26] A high TG level may cause platelets to be rigid, reducing the fluidity of membrane lipids. The synthesis of COX products, aspirin is not able to inhibit COX pathway completely.

Coronary artery disease and stroke have some common risk factors and similar pathophysiology. Data and evidence from the literature should be judiciously examined before indiscriminate application. The comparative role of platelet activation in stroke pathophysiology and coronary artery disease may not be similar. For example, in less than half of the ISs, atherosclerotic plaque breakup with resulting platelet accumulation and thrombus formation is a causative process. The aetiology of acute coronary syndromes differs significantly from stroke, with plaque rupture accounting for approximately 90% of coronary events. In addition, the risk profile for treatment adjustments based on platelet function assessments shows important distinctions between cerebrovascular and coronary conditions. Notably, stroke patients face an elevated risk of intracranial haemorrhage from antiplatelet therapy compared to those with coronary artery disease, necessitating different safety considerations when managing these respective conditions.^[27] It is important to assess the effectiveness and safety of ‘platelet function test-guided antiplatelet therapy’ independently in patients with IS before any concrete guidelines for this population can be made.

CONCLUSION

This meta-analysis found no consistent association between lipid parameters and aspirin resistance in ischemic stroke patients. Although elevated triglycerides initially appeared linked to resistance, the association was not sustained after sensitivity analysis. These findings suggest lipid profiles alone are insufficient to predict aspirin resistance, which likely involves multifactorial influences. Further robust, standardized studies are warranted to clarify this relationship and support individualized antiplatelet therapy.