Evaluation of the efficacy of aspirin combined with low doses of clopidogrel in the treatment of symptomatic intracranial artery stenosis in the elderly

doi:10.21203/rs.3.rs-2124760/v1

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Evaluation of the efficacy of aspirin combined with low doses of clopidogrel in the treatment of symptomatic intracranial artery stenosis in the elderly

https://doi.org/10.21203/rs.3.rs-2124760/v1

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Background

Symptomatic intracranial artery stenosis (ICAS) is a significant worldwide economic and great threat to public health. Currently, little is known about the accurate status of the efficient and tolerable dose of dual antiplatelet therapy (DAPT) as the mainstay treatment for ICAS. The aim of this study is to evaluate the efficacy and safety of aspirin plus clopidogrel in small doses for the treatment of symptomatic ICAS in the elderly.

Methods

This research included 142 older adults with symptomatic ICAS who were enrolled between April 2013 and April 2018. They were split into two groups: 73 patients in the lower dose group who received 75 mg of aspirin daily and 50 mg of clopidogrel daily, and 69 patients in the usual group who received 100 mg of aspirin daily and 75 mg of clopidogrel daily.

Results

Ages of 142 patients ranged from 60 to 81, with a mean of 70.9 ± 6.4. 58 participants were with IS and 84 were with TIA. A total of 132 patients were followed up. The low-dose group had a lower recurrence risk of ischemic stroke (IS) or transient ischaemic attack (TIA) than the conventional group at 1-year and 2-year follow-up, as well as a reduced frequency of adverse events and gastrointestinal injury (P < 0.05). Furthermore, after the 1-year follow-up, patients with severe symptomatic ICAS had a greater recurrence risk of IS and TIA than patients with mild symptomatic ICAS in both groups (P > 0.05).

Conclusion

The efficacy and safety of low-dose aspirin combined with clopidogrel were significantly better than those of ordinary dose within 24 months in elderly patients with symptomatic ICAS. However, the small size of this study limits the validity of the results.

Aspirin

Clopidogrel

Elderly

Symptomatic intracranial artery stenosis

Effect

China has a higher proportion of patients with ischaemic stroke (IS) due to intracranial atherosclerotic stenosis (ICAS), now over 30% ^[1], and is characterized by a high risk of recurrence ^[2]. Furthermore, ICAS is also an independent risk factor for IS in Asian and African-American patients ^[3]. As an emerging treatment for symptomatic ICAS, percutaneous transluminal angioplasty (PTA) has only been selectively performed in a subset of patients due to insufficient evidence-based medical evidence recently ^[4]. Although dual antiplatelet therapy (DAPT) has been applied as the basis of internal medicine in patients with symptomatic ICAS, there are few studies on the dose or evaluating the efficacy and safety of DAPT in elderly patients with this disease ^[5]. After the rupture of atherosclerotic plaque, subendothelial collagen tissue was exposed, and platelets adhered to the rupture under the action of chemotaxis, adhesion and cytokines produced by inflammatory cells. After adhesion, platelets activate and release thromboxane A2 (TXA2), adenosine diphosphate (ADP), thrombin, etc., which make platelets aggregate and cross-linked with fibrin, the end product of coagulation cascade, and finally lead to thrombosis. Aspirin is a cyclooxygenase (COX) inhibitor, which plays an antiplatelet role mainly by reducing the synthesis of TXA2. Clopidogrel can selectively and irreversibly block the binding of ADP and platelet P2Y12 receptor to inhibit platelet aggregation. Therefore, the clinical data of elderly patients with symptomatic ICAS treated with aspirin combined with clopidogrel should be conducted for in-depth analysis, especially in terms of efficacy and safety.

PTA is mainly applicable to some vascular lesions with distal ischemia caused by local arterial stenosis ^[6]. The technique is to insert a balloon into the narrow trachea and expand the narrow trachea through pressure to achieve the purpose of forming. It is not only used with a soft mirror, but also can expand a certain part repeatedly after inserting a hand mirror, or other methods can be used. Commons are coronary artery, lower extremity artery, and cerebral artery balloon dilatation ^{[7, 8]}. After local anesthesia, under the guidance of dynamic radiation monitoring, the catheter reaches the stenosis through the artery, inflates and expands through the balloon at the end of the catheter, expands and blocks the blood vessels, improves the blood supply at the distal end of the artery, and needs to be inserted with stents to keep the blood vessels unobstructed if necessary ^[9]. After balloon dilatation, most patients' symptoms are relieved, but there is also the possibility of recurrence.

This manuscript mainly discusses the clinical effect and adverse reactions of low-dose DAPT in the treatment of elderly patients with symptomatic ICAS.

Study subjects

The study population was enrolled in the people's hospital in Shijiazhuang, China from April 2013 to April 2018. Patients were confirmed as affected with symptomatic ICAS. The ICAS was measured using the North American Carotid Endarterectomy Test criteria ^[10]. Inclusion criteria for the participant in the study were shown as follows: (1) age ≥ 60 years; (2) unilateral intracranial artery stenosis ≥ 50% and dominant vertebral artery (or combined contralateral vertebral artery occlusion) stenosis ≥ 50% by Computed Tomography Angiography (CTA); (3) previous stenosis-related IS or ischemic attack (TIA) episodes within the previous 12 months; (4) informed consent from the subject and family. (5) These patients can take drugs to improve their symptoms without surgery.

We excluded participants according to the following criteria: (1) contraindication or allergy to antiplatelet agents or contrast; (2) had uncontrolled severe hypertension: systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 115 mmHg; (3) had a severe vascular disease such as intracranial aneurysm and smog; (4) had a history of chronic atrial fibrillation, venous thromboembolism requiring anticoagulation; (5) had a history of intracranial hemorrhage, gastrointestinal bleeding or bladder. Finally, a total of 142 patients with symptomatic ICAS were recruited for our current study. The studies involving human participants were reviewed and approved by Shijiazhuang people's hospital of the ethics committee (20211280). The patients/participants provided their written informed consent to participate in this study.

Treatment

All patients were divided into the low-dose group (aspirin (Bayer Healthcare Ltd.) 75mg/d + clopidogrel (Shenzhen Xinlitai Pharmaceutical Co., Ltd.) 50mg/d) and the conventional group (aspirin 100mg/d + clopidogrel 75mg/d) according to the wishes of the patients and their families. Patients enrolled in the group received symptomatic treatment such as lipid-lowering, blood pressure blood sugar control, and circulation improvement according to the presence or absence of comorbidities.

Data collection

Follow-up visits were conducted by a combination of outpatient and telephone, including history taking and physical examination. The patients all underwent CTA of the head, transcranial Doppler ultrasound (TCD), and carotid ultrasound. A double-blind review by two attendings or higher imaging physicians was used. These examinations were repeated at 30 days, 3, 6, 12, and 24 months after the application of DAPT to record the recurrence of IS and TIA, calculate the target vessel stenosis rate in the two groups, and compare the efficacy and safety endpoint events in the two groups. Patients were also given health education at each follow-up stage, including smoking cessation and alcohol restriction, improved diet, and increased exercise.

Measurement of efficacy and safety

The primary efficacy endpoint was a follow-up for IS or TIA recurrence. The secondary efficacy endpoints were worsening of target vessel stenosis (≥ 10% increase in a stenosis), death from vascular causes, and other vascular events including myocardial infarction, pulmonary embolism, and lower limb atherosclerotic occlusive disease requiring hospitalization. The Composite efficacy endpoint events included both primary and secondary efficacy endpoint events. The primary safety endpoint events were gastrointestinal injury or other site bleeding requiring hospitalization and/or blood transfusion. The secondary safety endpoint events were dyspepsia, skin mucosa, and gum bleeding. Gastrointestinal injuries ranged from dyspepsia to fatal peptic ulcers, bleeding, or perforation. The Composite safety endpoint events included both primary and secondary safety endpoint events. Participants who did not experience any events or were lost to follow-up by the end of the follow-up period were treated as censored.

The severity of pre-treatment neurological impairment was assessed using the National Institutes of Health Stroke Scale (NIHSS). Moderate ICAS was unilateral intracranial or dominant vertebral artery stenosis of 50%-70% and severe ICAS was unilateral intracranial or dominant vertebral artery stenosis of 71%-99%.

Statistical analysis

Data were analyzed using SPSS 26.0 software (SPSS, Inc., Chicago, USA). We used the t-test or Wilcoxon signed-rank test to evaluate the difference in the continuous variables between the cases and controls and used the χ2 test for the categorical variables. The continuous data were expressed as mean ± standard deviation and t-tests were used for comparison. The χ2 test was used for the categorical data when comparing two groups. The cumulative incidence of endpoint events was analyzed by survival analysis (Kaplan-Meier method), and the Log-Rank test was used for comparison between survival curves. In the present study, all P values were two-sided and P < 0.05 was deemed to indicate statistical significance.

Baseline characteristics

One hundred and forty-two patients with symptomatic ICAS, including 75 males and 67 females, are chosen analytically. Their ages ranged from 60 to 81, with a mean of 70.9 ± 6.4. Among them, 58 participants were with IS and 84 were with TIA. The rate of intracranial arterial stenosis ranged from 50–99%, with a mean of 75.6 ± 15.2%. Combined risk factors included smoking in 69 cases, hypertension in 101 cases, diabetes mellitus in 45 cases, hyperlipidemia in 77 cases, and coronary heart disease in 10 cases. There was no difference in clinical baseline information between the conventional group and the low-dose group, as shown in Table 1.

Table 1

Comparison of clinical baseline information between patients in the conventional and low-dose groups.
	Conventional group (n = 69)	Low-dose group (n = 73)	χ²/t value	P value
Sex (n, %)			0.676	0.411
male	34 (49.3)	41 (56.2)
female	35 (50.7)	32 (43.8)
Age (year, mean ± SD)	69.9 ± 6.6	71.8 ± 6.3	1.739	0.084
BMI (kg²/m, mean ± SD)	27.4 ± 4.4	26.7 ± 4.2	-0.863	0.389
Smoker (n, %)	33 (47.8)	36 (49.3)	0.031	0.859
Hyperlipidemia (n, %)	32 (46.4)	45 (61.6)	3.331	0.068
Hypertension (n, %)	49 (71.0)	52 (71.2)	0.001	0.977
Diabetes (n, %)	24 (34.8)	21 (28.8)	0.593	0.441
Coronary heart disease (n, %)	5 (7.2)	5 (6.8)	0.000	1.000
Cerebral infarction (n, %)	32 (46.4)	26 (35.6)	1.700	0.192
NIHSS value (mean ± SD)	8.2 ± 2.0	7.9 ± 1.9	-0.595	0.553
Narrowing rate (%, mean ± SD)	78.0 ± 15.5	73.7 ± 14.7	-1.696	0.092
Severe ICAS (n, %)	46 (66.7)	43 (48.9)	0.914	0.339

The follow-up time ranged from 1–35 months, with a mean of 27.2 ± 8.4 months. The difference between the conventional group (27.0 ± 8.3) and the low-dose group (27.0 ± 8.3) months was not statistically significant (t = 0.291, P = 0.772). Finally, 132 cases were effectively followed up. 10 cases were lost during follow-up, including 4 cases in the conventional group and 6 cases in the low-dose group.

Evaluation of efficacy and safety

The efficacy and safety endpoint events over 24 months are shown in Table 2. The number of efficacy and safety events in the low-dose group compared with the conventional group over 24 months is shown in Table 3. The rate of composite safety endpoint events was 6.8% (5/73) in the low-dose group, which was lower than that in the conventional group at 20.3% (14/69), with a statistically significant difference (χ2 = 5.529, P = 0.019).

Table 2

Incidence of efficacy and safety endpoint events in the low-dose group versus the conventional group over 24 months (n, %).
	30 days	3 months	12 months	24 months
Efficacy
Primary endpoints	3(4.1)/2(2.9)	6(8.3)/7(10.3)	17(24.4)/16(24.1)	27(39.6)/26(40.1)
Secondary endpoints	1(1.4)/1(1.4)	4(5.5)/6(8.9)	9(12.8)/7(10.5)	16(23.1)/12(18.3)
Composite endpoints	4(5.5)/3(4.3)	10(13.8)/13(19.2)	26(36.9)/22(33.1)	38(54.5)/35(53.8)
Safety
Primary endpoints	0(0.0)/0(2.9)	0(0.0)/0(10.3)	1(1.4)/1(1.6)	1(1.4)/2(3.1)
Secondary endpoints	0(0.0)/0(0.0)	1(1.4)/1(1.5)	3(4.3)/6(9.1)	6(8.9)/12(18.7)
Composite endpoint	0(0.0)/0(0.0)	1(1.4)/1(1.5)	3(4.3)/7(10.7)	6(8.9)/14(21.6)
Note: Numerator figures are for the low-dose group, and denominator figures are for the conventional group.

Table 3

Comparison of efficacy and safety endpoint events in the low-dose group versus the conventional group at 24 months.
	Low-dose group	Conventional Group	χ² value	P value
Efficacy
Primary endpoints	27	26	0.007	0.932
Secondary endpoints	16	13	0.207	0.649
Composite endpoints	38	36	0.035	0.852
Safety
Primary endpoints	1	2	0.002	0.961
Secondary endpoints	5	12	3.741	0.053
Composite endpoint	5	14	5.529	0.019

Evaluation of gastrointestinal (GI) injuries

Finally, 15 cases had GI injuries at the end of the follow-up. There was one case of gastric bleeding in the low-dose group and one case of gastric ulcer perforation in the conventional group as the primary safety endpoint, all of which recovered after hospitalization. 7 cases of dyspepsia, 3 cases of gastric pain, 1 case of abdominal pain, 1 case of diarrhea, and 1 case of duodenal ulcer were among the 13 secondary safety endpoints, and the symptoms resolved after treatment. The cumulative incidence of GI injury was lower in the low-dose group at 5.5% (4/73) than that in the conventional group at 15.9% (11/69), and the difference was statistically significant by the Log-rank χ2 test (χ2 = 4.231, P = 0.040).

Evaluation of the efficacy of ICAS with different degrees of stenosis

The recurrence rate of IS and TIA in the severe symptomatic ICAS group was 27.4% (20/73) in the low-dose group compared with 9.6% (7/73) in the moderate symptomatic ICAS group at 24 months of follow-up, with a statistically significant difference (χ2 = 4.798, P = 0.028). The difference was statistically significant (χ2 = 6.048, P = 0.014), and the recurrence rate of IS and TIA in the conventional group with severe symptomatic ICAS was 31.9% (22/69) compared with 5.8% (4/69) in the moderate symptomatic ICAS group.

The treatment of symptomatic ICAS, which seriously affects patients’ quality of life and increases the socioeconomic burden, is a hot topic of clinical research, but the choice between pharmacological and PTA treatment modalities has been controversial. Studies have shown that PTA can partially restore neurological function and reduce mortality in patients with symptomatic ICAS ^[11], but complications related to ischemia-reperfusion, embolic dislodgement, and bleeding can increase stroke recurrence and mortality, seriously affecting the clinical prognosis of patients ^[12]. Some studies also suggested that aggressive pharmacological interventions are preferable to PTA ^[13]. To date, studies have demonstrated the benefit of DAPT for primary and secondary prevention of IS or TIA, and for patients with symptomatic ICAS, it is recommended that it should be applied early and long-term after the onset of the disease ^[14]. Given the comparable benefit of aspirin in the range of 50–325 mg/d for the prevention of IS ^[15], and the fact that studies have found the greatest benefit of DAPT for 90 days in patients with symptomatic ICAS ^[16]. In combination with the advanced age of patients, the study was developed to observe the efficacy and safety of a 90-day regimen of low-dose DAPT for the treatment of elderly patients with symptomatic ICAS. This experiment shows that the efficacy and adverse reactions of the low-dose group are better than those of the conventional dose group.

The reoccurrence rates of IS or TIA within 1 and 3 months were 4.1% and 8.3% in the low-dose group and 2.9% and 10.3% in the conventional group, respectively ^[17]. The difference between the reoccurrence rates of IS or TIA in the low-dose group and the conventional group was not statistically significant, and the reoccurrence rates at 12 and 24 months were 24.4% and 39.6% in the low-dose group and 24.1% and 40.1% in the conventional group, respectively, both of which were higher than those in a related study ^[18]. The probable explanation might relate to the fact that all of the subjects in this enrollment were elderly patients. Persoon et al. ^[19] reported that age was a risk factor for the first or recurrence of ICAS, which was considered to be related to the fact that patients of advanced age are themselves atherosclerotic and have increased combined risk factors leading to sclerosis. The secondary and composite efficacy endpoints in the low-dose group were not significantly different from those in the conventional group, and this can be assumed that the low-dose group was as effective as the conventional group in treating symptomatic ICAS.

Bleeding due to DAPT occurred most frequently in the gastrointestinal tract ^[20]. The event rate of 6.8% (5/73) was significantly lower than that of 20.3% (14/69) in the conventional group. The low-dose group was considered superior to the conventional group in terms of safety evaluation. A common adverse effect of DAPT in elderly patients is gastrointestinal injury. The incidence of gastrointestinal injury in this study was 5.9% (11/69) in the conventional group compared to 5.5% (4/73) in the low-dose group (P < 0.05), which should be associated with increased gastrointestinal toxicity due to higher doses of DAPT ^[21]. Tegos et al. ^[22] reported a linear positive correlation between the severity of ICAS and the incidence of stroke. And the recurrence rates of IS and TIA were significantly higher (P < 0.05) in patients with severe symptomatic ICAS than that in patients with moderate symptomatic ICAS in the low-dose and conventional groups in this study period at 24 months. The above results are consistent with the findings in the literature ^[23]. It is worth noting that the selection of patients and treatment modality were not randomly generated. The correlation with DAPT needs to be clarified, all of which may cause bias in the observations. In addition, the research on prevention and treatment is mainly concentrated in urban areas. To better balance medical resources, the research population including township patients should be included. However, some domestic patients with are or TIA has poor compliance with the DAPT secondary prevention ^[24].

The low-dose group of DAPT demonstrated better effective and safe than the conventional group. The results of the present study support the use of the low-dose of DAPT for the medical treatment in elderly patients with Symptomatic ICAS. In addition, the study found that the recurrence rate of is and TIA in patients with severe symptoms of ICAS is higher than that in elderly patients with moderate symptoms of ICAS in the two groups during fellow-up. Further studies need to investigate the efficacy and safety of low-dose DAPT in a long-term perspective.

Ethics approval and consent to participate

The studies and experimental protocols involving human participants were reviewed and approved by Shijiazhuang people's hospital of the ethics committee (20211280). The patients/participants provided their written informed consent to participate in this study. All methods in this study were carried out in accordance with relevant guidelines and regulations.

Consent for publication

Not applicable.

Availability of data and materials

The data support the finding of this study are available from the corresponding author upon request.

Competing interests

All authors declare that they have no competing interests.

Funding

The study was funded by the Medical Science Research Project of the Health Commission of Hebei Province, China (No. 20210352). The funding body played no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Authors contribution

ZYW and ZCS participated in the design of this study. HXS drafted and wrote the main manuscript text. BZ and SL collected clinical and demographic data. JY and JC performed the statistical analysis. HLL prepared tables 1-3. All authors critically reviewed the manuscript and agreed on this final version to be submitted to the journal.

Acknowledgments

Not applicable.

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No competing interests reported.

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Evaluation of the efficacy of aspirin combined with low doses of clopidogrel in the treatment of symptomatic intracranial artery stenosis in the elderly

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Version 1

Abstract

Background

Methods

Results

Conclusion

Introduction

Materials And Methods

Study subjects

Treatment

Data collection

Measurement of efficacy and safety

Statistical analysis

Results Analysis

Baseline characteristics

Evaluation of efficacy and safety

Evaluation of gastrointestinal (GI) injuries

Evaluation of the efficacy of ICAS with different degrees of stenosis

Discussion

Conclusions

Declarations

References

Additional Declarations

Status:

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