Dual Antiplatelet Therapy Beyond 90 Days in Symptomatic Intracranial Stenosis in the SAMMPRIS Trial

Abstract

Background

The safety and efficacy of dual antiplatelet use for symptomatic intracranial atherosclerosis beyond 90 days is unknown. Data from SAMMPRIS was used to determine if dual antiplatelet therapy (DAPT) beyond 90 days impacted the risk of ischemic stroke and hemorrhage.

Methods

This post hoc exploratory analysis from SAMMPRIS included patients who did not have a primary endpoint within 90 days after enrollment (n=397). Patients in both the aggressive medical management (AMM) and percutaneous transluminal angioplasty and stenting (PTAS) arms were included. Baseline features and outcomes during follow-up were compared between patients who remained on DAPT beyond 90 days (on clopidogrel) and patients who discontinued clopidogrel and remained on aspirin alone at 90 days (off clopidogrel) using Fisher’s exact tests.

Results

The stroke rate was numerically lower in the group on clopidogrel vs off clopidogrel among both the AMM alone arm (6.0% versus 10.8%, P=0.31) and the PTAS arm (8.7% versus 9.8%; P=0.82), but the difference was not significant. The major hemorrhage rates were numerically higher in the group on clopidogrel vs. off clopidogrel group among both the AMM alone arm (4.0% versus 2.5%; P=0.67) and the PTAS arm (10.9% versus 3.5%; P=0.08), but were not significant.

Conclusion

This exploratory analysis suggests that prolonged DAPT use may lower the risk of stroke in medically treated patients with intracranial stenosis but may increase the risk of major hemorrhage.

Background

Intracranial atherosclerotic stenosis (ICAS) is one of the most common stroke etiologies worldwide⁽¹⁾ and is associated with a high risk of recurrent stroke^{(1, 2)}. A few trials have studied various antithrombotic regimens for secondary stroke prevention in patients with symptomatic ICAS. The Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial showed that aspirin was safer and equally as effective as warfarin⁽²⁾ over a mean duration of 1.8 years. The CLAIR study showed that the combination of aspirin and clopidogrel initiated within 7 days of symptom onset for a total of 7 days was superior to aspirin alone for reducing microembolic signals on transcranial Doppler (TCD) in patients with intracranial stenosis⁽³⁾. Studies of patients with heterogeneous causes of TIA or minor stroke suggest that combining aspirin with clopidogrel is superior to aspirin alone for stroke prevention if prescribed for 21–90 days but is associated with a higher risk of major hemorrhage^{(4, 5)}.

The Stenting and Aggressive Medical Management for Prevention of Recurrent stroke in Intracranial Stenosis (SAMMPRIS) trial compared ischemic and hemorrhagic outcomes in patients randomized to aggressive medical management (AMM) plus percutaneous transluminal angioplasty and stenting (PTAS) versus AMM alone^(6,7). In this post-hoc analysis of the SAMMPRIS data, we sought to determine the impact of extending dual antiplatelet therapy (DAPT) beyond 90 days on the risk of recurrent ischemic stroke and major hemorrhage.

Methods

SAMMPRIS was a National Institute of Health (NIH)-funded, randomized, controlled, multicenter trial⁽⁸⁾. The study protocol was approved by the institutional review board at participating sites and all patients gave written informed consent to participate. The protocol required aspirin 325 mg per day for the duration of the trial and clopidogrel 75 mg per day for 90 days only, unless another non-neurological indication (e.g. cardiac stent) required prolonged use of clopidogrel. Patients were considered “on clopidogrel” if they required the use of clopidogrel in addition to aspirin beyond 90 days due to non-neurological indications. Patients were considered “off clopidogrel” if they discontinued use of clopidogrel at 90 days after enrollment of SAMMPRIS and remained only on aspirin.

The primary outcome in SAMMPRIS was any stroke or death within 30 days after enrollment or any ischemic stroke in the territory of the qualifying artery beyond 30 days. One of the safety outcomes was any major hemorrhage, which was defined as intracranial or systemic hemorrhage requiring hospitalization, blood transfusion or surgery.

We used T-tests (for normally continuous variables) and chi-square test (for binary variables) to compare baseline characteristics in patients on vs. off clopidogrel after 90 days in the medical and stenting groups separately. We compared the overall rates of the primary outcome and major hemorrhage using the logrank test. The analysis was conducted using SAS (version 9.3). An alpha level of 0.05 was used as the level of statistical significance. All reported P values are two-sided and have not been adjusted for multiple testing.

Results

Data on 397 patients who did not have a primary endpoint within 90 days after enrollment were included in these analyses. In the AMM alone arm, 50 patients were on clopidogrel and 158 patients were off clopidogrel after 90 days of enrollment. In the PTAS arm, 46 patients were on clopidogrel and 143 patients were off clopidogrel after 90 days. There was no difference in the percentage of patients on clopidogrel beyond 90 days in both groups (50/208 (24%) in the AMM alone arm versus 46/189 (24%) in the PTAS arm, P=0.94). Baseline factors that were different between those on vs. off clopidogrel in the AMM alone and PTAS arms combined were: age, history of diabetes, history of hyperlipidemia and history of coronary artery disease (CAD) (Table 1). Patients in the on clopidogrel group were older (mean age 62.0 (SD 11.5)) than the off clopidogrel group (mean age 58.9 (SD 11.2) (P=0.02). The on clopidogrel group also had higher rates of diabetes (58.3% versus 38.2%, P=<0.01), hyperlipidemia (96.8% versus 86.0%, P=<0.01), and CAD (37.5% versus 19.3%, P=<0.01) than the off clopidogrel group.

Table 1:

Baseline Characteristics of patients on and off clopidogrel after 90 days in both the AMM and PTAS arms

	On Clopidogrel (N=96)	Off Clopidogrel (N=301)	p-value
Age, mean (SD)	62.0 (11.5)	58.9 (11.2)	0.02†
Female, n (%)	38 (39.6%)	111 (36.9%)	0.63‡
Race, n (%)			0.09‡
Black	16 (16.7%)	80 (26.6%)
White	76 (79.2%)	203 (67.4%)
Other	4 (4.2%)	18 (5.9%)
History of hypertension, n (%)	84 (87.5%)	271 (90.0%)	0.48‡
History of diabetes, n (%)	56 (58.3%)	115 (38.2%)	<0.01‡
History of hyperlipidemia, n (%)	93 (96.8%)	259 (86.0%)	<0.01‡
Smoking, n (%)			0.17‡
Never	34 (35.4%)	103 (34.3%)
Previously	40 (41.6%)	100 (33.3%)
Currently	22 (22.9%)	97 (32.3%)
History of coronary artery disease, n (%)	36 (37.5%)	58 (19.3%)	<0.01‡
History of stroke (prior to the qualifying event), n (%)	27 (28.1%)	70 (23.2%)	0.30‡
Qualifying event, n (%)			0.73‡
Stroke	61 (63.5%)	197 (65.4%)
Transient ischemic attack	35 (36.4%)	104 (34.5%)
Symptomatic artery, n (%)			0.29‡
Intracranial carotid artery	22 (22.9%)	57 (18.9%)
Middle cerebral artery	36 (37.5%)	143 (47.5%)
Vertebral artery	12 (12.5%)	40 (13.3%)
Basilar artery	26 (27.1%)	61 (20.3%)

^†T-test

^‡Chi-square

In the AMM alone arm, the percent of patients who had a primary endpoint in the on clopidogrel group was lower than in the off clopidogrel group but this difference was not statistically significant (6% versus 10.8%, P=0.31) (Table 2). Additionally, in the AMM alone arm, the percent of patients who had a major hemorrhage in the on clopidogrel group was higher than in the off clopidogrel group but this difference was not statistically significant (4.0% versus 2.5%; P=0.67). In the PTAS arm, the percent of patients who had a primary endpoint after 90 days was similar in the on clopidogrel vs. off clopidogrel groups (8.7% versus 9.8%; P=0.82), but the percent with a major hemorrhage after 90 days was numerically higher in the on clopidogrel group vs. off clopidogrel group however this was not statistically significant (10.9% versus 3.5%; P=0.08).

Table 2:

Summary of the included patients in each group, duration of follow up and outcomes:

			On Clopidogrel	95% CI On Clopidogrel	Off Clopidogrel	95% CI Off Clopidogrel	p-value
		Aggressive Medical Management alone arm
No. Patients			50		158
Duration of follow-up in months, median (IQR)			36		33
Primary endpoint,* n (%)			3 (6.0%)	1.3–16.5	17 (10.8%)	6.4–16.7	0.31†
Major hemorrhage, n (%)			2 (4.0%)	0.5–13.7	4 (2.5%)	0.7–6.4	0.67†
		Percutaneous Transluminal Angioplasty and Stenting arm
No. Patients			46		143
Duration of follow-up in months, median (IQR)			34		36
Primary endpoint,* n (%)			4 (8.7%)	2.4–20.8	14 (9.8%)	5.5–15.9	0.82†
Major hemorrhage, n (%)			5 (10.9%)	3.6–23.6	5 (3.5%)	1.1–8.0	0.08†

^*ischemic stroke in the territory or any stroke or death within 30 days after revascularization during follow-up

^†logrank test

Discussion

This analysis of SAMMPRIS patients showed a numerically lower risk of the primary endpoint in patients on vs off clopidogrel in the AMM alone arm beyond 90 days after enrollment. Although the percent of patients who had a primary endpoint beyond 90 days in the on clopidogrel group (6.0%) was 44% lower than the off clopidogrel group (10.8%), this difference was not statistically significant possibly because of the low power of this exploratory post-hoc analysis. Patients who were on clopidogrel beyond 90 days were more likely to be older and have a higher burden of vascular risk factors at baseline, which is not surprising given that only patients with CAD and peripheral vascular disease were permitted to take clopidogrel beyond 90 days in SAMMPRIS. Since patients who were on clopidogrel were significantly older and had more vascular risk factors compared to those off of clopidogrel, they would be expected to have more vascular events. Yet there was a tendency toward a lower rate of the primary end point in the on clopidogrel group (albeit not statistically significant). We postulate that this could be from a protective effect of prolonged DAPT.

However, this is partially offset by the increased risk of bleeding. The off clopidogrel group in the AMM arm had a 37.5% lower relative risk of a major hemorrhage than the on clopidogrel group beyond 90 days (4.0% on group vs 2.5% off group), but this difference was also not statistically significant perhaps because of low power. Of note, in the PTAS arm, despite the small sample size, the percentage of patients with major hemorrhage in the on clopidogrel group was almost statistically higher (p=0.08) than in the off clopidogrel group beyond 90 days.

Despite the increased risk of major hemorrhage with prolonged use of DAPT, almost half of US stroke neurologists and interventionists who responded to a survey conducted after the SAMMPRIS results were published reported that they recommended indefinite use of dual antiplatelet therapy in patients with ICAS⁽⁹⁾. This may be because SAMMPRIS showed that ICAS subjects treated medically are still at high risk of recurrent stroke beyond 90 days, with the rate of the primary endpoint at 1 year more than double the rate at 90 days and far exceeding the 1-year rate of major hemorrhage⁽¹⁰⁾. This is in distinction to subjects with TIA or minor stroke from heterogeneous causes in whom the risk of ischemic stroke drops substantially after 30 days and is similar in subjects on aspirin alone or DAPT beyond 30 days^{(4, 5)}.

Our study has limitations as it was a post-hoc analysis, was underpowered because of the small number of patients in the on clopidogrel group, and patients were not randomized to on versus off clopidogrel beyond 90 days. However, the lack of randomization in this case very likely resulted in the on clopidogrel patients being a higher risk group, yet they had a lower observed risk of the primary endpoint in the AMM alone arm. These results lead to the hypothesis that prolonged DAPT in patients with ICAS treated medically is associated with a lower risk of ischemic stroke than limited duration DAPT followed by aspirin alone that will far offset the increased risk of major hemorrhage. Testing of this hypothesis will require an adequately powered randomized trial.