Abstract
Background:
In select patients with minor ischemic stroke, dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel is recommended if initiated early and continued for 21 to 90 days. Dual antiplatelet therapy use, in a broader population, has shown to increase the risk of bleeding without an increased antithrombotic benefit. An ongoing area of uncertainty is whether DAPT would benefit the nonminor stroke population when continued for 21 to 90 days.?s
Objective:
To describe the effects of DAPT after a nonminor stroke.
Methods:
This single-center, retrospective cohort study included patients initiated on antiplatelet therapy started within 1 week of symptom onset for a nonminor ischemic stroke from January 2013 to January 2020. Patients with any bleeding disorder or National Institutes of Health Stroke Scale score <4 were excluded. The primary endpoint was major bleeding at 3 months. Secondary endpoints included recurrent stroke and minor bleeding.
Results:
A total of 158 patients met criteria for inclusion. Ninety (57%) received DAPT, and 68 (43%) received single antiplatelet therapy (SAPT). The primary endpoint occurred in 3 patients in the DAPT group and 1 patient in the SAPT group (P = 0.463). Minor bleeding occurred in 1 patient receiving DAPT and 2 patients receiving SAPT (P = 0.402). There were 10 patients in the DAPT group and 5 patients in the SAPT group who experienced recurrent stroke or transient ischemic attack (P = 0.429). Limitations of this study include the retrospective single-center study design.
Conclusion:
There was a comparable risk of bleeding and recurrent stroke between DAPT and SAPT in patients admitted with an acute nonminor stroke.
Keywords: dual antiplatelet therapy, stroke, aspirin, clopidogrel, bleeding, recurrence
Background
Stroke is the leading cause of disability among adults and the fifth leading cause of death in the United States, behind cardiovascular disease, cancer, COVID-19, and unintentional injuries. 1 Ischemic stroke accounts for approximately 87% of all strokes, and the risk of recurrent stroke can be as high as 15% in the 90 days after a minor ischemic stroke or a transient ischemic attack (TIA). 2 Antiplatelet therapy for early secondary prevention is the mainstay of therapy in noncardioembolic ischemic stroke. 3 Single antiplatelet therapy (SAPT) with aspirin is recommended in most patients within 24 to 48 hours after symptom onset. 4 In patients with a minor noncardioembolic ischemic stroke or high-risk TIA, dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel should be used if initiated early and continued for 21 to 90 days.3,4 These recommendations are primarily driven by reductions in recurrent stroke when DAPT was used short term (21-90 days) in patients with high-risk TIA or minor stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤3).5,6 These data are in contrast to previous studies that demonstrated that DAPT use, in a broader patient population for a longer duration, increased the risk of bleeding without antithrombotic benefit.7-9 It is uncertain whether short-term use of DAPT would benefit the nonminor stroke population without an excess risk of hemorrhage when continued for only 21 to 90 days. These patients, with nonminor stroke, have a higher risk of bleeding and an increased likelihood of worse clinical outcomes than those with minor stroke.10,11 This study was conducted to assess the efficacy and safety of short-term DAPT in a nonminor stroke population defined as an NIHSS score ≥4.
Methods
This retrospective analysis was conducted at a 505-bed community teaching hospital in the southeastern United State between January 2013 and January 2020. The study protocol was approved by the institutional review board. All patients who presented with an acute noncardioembolic ischemic stroke were screened for inclusion. Patients were included if they had an NIHSS of ≥4 and received at least one antiplatelet agent started within 1 week of symptom onset. Patients with a diagnosis of hemorrhage, bleeding disorder, modified Rankin scale score >2, clear indication for anticoagulation, or pregnancy or breastfeeding were excluded. The primary outcome was a major bleeding event within 90 days defined by the Global Use of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) criteria for severe or moderate bleeding. Secondary outcomes included recurrent stroke or TIA within 1 year, minor bleeding event within 3 months defined by the GUSTO criteria as bleeding that does not meet major bleeding criteria, other cardiovascular events, readmissions within 30 days, and readmissions within 90 days.
Patients were placed into either an SAPT group or a DAPT group based on the prescribed antiplatelet(s). Categorical variables were represented with descriptive statistics. Due to the descriptive nature of the primary outcome, a power analysis was not performed. Statistical analysis included descriptive statistics and χ2 tests for primary and secondary outcomes. All statistical analyses were performed using IBM SPSS Statistics for Windows, Version 27.0 (Armonk, New York).
Results
A total of 887 patients had a diagnosis of acute ischemic stroke within the specified time frame. Seven hundred twenty-nine patients were excluded, with the most common reasons being an NIHSS score <4, an indication for anticoagulation, or ischemic stroke being ruled out. One hundred fifty-eight patients were included in the analysis. Of these, 90 patients were in the DAPT group and 68 patients were in the SAPT group.
The baseline characteristics of the patient population are summarized in Table 1. The mean age was 66.9 years in the DAPT group and 63.8 years in the SAPT group, and >50% of patients were men. The mean NIHSS score was 8.6 in the DAPT group and 8.4 in the SAPT group. More patients in the DAPT group had a previous history of stroke or TIA (33.3% vs 14.7%) and a higher occurrence of hypertension (84.4% vs 64.7%), previous myocardial infarction (MI) (11.1% vs 4.4%), and diabetes (36.7% vs 26.5%). All patients in the DAPT group received the combination of aspirin and clopidogrel. In the SAPT group, 62 (91%) patients received aspirin and 6 (9%) patients received clopidogrel.
Table 1.
Baseline Characteristics.
| Characteristics | DAPT (n = 90) | Monotherapy (n = 68) |
|---|---|---|
| Age, y, mean (SD) | 66.9 (12.5) | 63.8 (15.9) |
| Sex (female), n (%) | 44 (48.9) | 30 (44) |
| Height, in, mean (SD) | 67.2 (4.4) | 67.2 (4.1) |
| Weight, kg, mean (SD) | 81.5 (21.0) | 81.7 (22.3) |
| BMI, kg/m2, mean (SD) | 27.9 (6.6) | 28 (6.8) |
| NIHSS score, mean (SD) | 8.6 (5.0) | 8.4 (4.7) |
| Admission SBP, mm Hg, mean (SD) | 167.4 (27.5) | 162.5 (32.9) |
| Admission hemoglobin, mean (SD) | 13.3 (1.6) | 13.8 (2.0) |
| Medical history, n (%) | ||
| Stroke/TIA | 30 (33.3) | 10 (14.7) |
| Hypertension | 76 (84.4) | 44 (64.7) |
| Myocardial infarction | 10 (11.1) | 3 (4.4) |
| Diabetes mellitus | 33 (36.7) | 18 (26.5) |
Abbreviations: BMI, body mass index; DAPT, dual antiplatelet therapy; NIHSS, National Institutes of Health Stroke Scale; SBP, systolic blood pressure; TIA, transient ischemic attack.
Table 2.
Outcomes.
| Endpoint | DAPT (n = 90) | Monotherapy (n = 68) | P value |
|---|---|---|---|
| Major bleed, n (%) | 3 (3.3) | 1 (1.5) | 0.463 |
| Minor bleed, n (%) | 1 (1.1) | 2 (2.9) | 0.402 |
| Recurrent stroke/TIA within 1 y, n (%) | 10 (11.1) | 5 (7.4) | 0.429 |
| Readmission within 30 d, n (%) | 14 (15.6) | 9 (13.2) | 0.689 |
| Readmission within 90 d, n (%) | 26 (28.9) | 16 (23.5) | 0.566 |
| Cardiovascular events, n (%) | |||
| Myocardial infarction | 2 (2.2) | 3 (4.4) | 0.442 |
| Revascularization | 0 (0) | 1 (1.5) | 0.250 |
Abbreviations: DAPT, dual antiplatelet therapy; TIA, transient ischemic attack.
The primary outcome of major bleeding occurred in 3 (3.3%) patients receiving DAPT and 1 (1.5%) patient receiving SAPT (P = 0.463). Each of these patients developed an intracranial hemorrhage. Minor bleeding occurred in 1 (1.1%) patient receiving DAPT and 2 (2.9%) patients receiving SAPT (P = 0.402). Of the patients who experienced a minor bleed, 2 patients developed hematuria, whereas 1 patient developed hemorrhagic stercoral ulcers. All bleeding events in the SAPT group occurred in patients receiving aspirin. Recurrent stroke or TIA occurred in 10 (11.1%) patients in the DAPT group and 5 (7.4%) patients in the SAPT group (P = 0.429). All recurrent events in the SAPT group occurred in patients receiving aspirin. In the DAPT group, 14 (15.6%) patients were readmitted within 30 days versus 9 (13.2%) patients in the SAPT group (P = 0.689). Rates of readmission within 90 days occurred in 26 (28%) patients in the DAPT group versus 16 (23.5%) patients in the SAPT group (P = 0.586). Rates of other cardiovascular events were similar between groups.
Of the 90 patients in the DAPT group, 68 (75.6%) patients had a duration of therapy that could be identified within the electronic health record. Of these 68 patients, 13 (19.1%) were continued to the time of review without being discontinued. The median duration of therapy for the remaining 55 patients was 6 months, with an interquartile range of 2 to 20 months. Six (8.8%) patients discontinued DAPT therapy within 30 days of their stroke, and 3 of these patients (5.5%) discontinued therapy on day 21. Other indications for DAPT were not collected.
Discussion
This study demonstrated a comparable risk of both major and minor bleeding when DAPT was compared with SAPT in a nonminor stroke population. Overall, there were only 4 major bleeds and 3 minor bleeds. This finding is consistent with studies that assessed the use of DAPT for a short, defined period in patients with an acute minor stroke or TIA.5,6 In the Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) study, there was no difference in severe bleeding, and the overall incidence was low (0.2%) at 90 days when DAPT was continued for only 21 days. 6 Conversely, the Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA (POINT) study did demonstrate an increased risk of major hemorrhage when DAPT therapy was continued for 90 days (0.9% vs 0.4%, P = 0.2). 5 The addition of clopidogrel to aspirin therapy would be expected to increase bleeding and has been demonstrated in large clinical trials.8,9 Therefore, long-term use is not recommended.3,4
This study showed a nonsignificant increase in the incidence of recurrent stroke or TIA in the DAPT group with 10 events compared with 5 events in the SAPT group. This could potentially be explained by the fact that the patients receiving DAPT were at an increased risk for stroke given higher rates of hypertension, diabetes, MI, stroke, or TIA at baseline. This finding contrasts with the benefit previously seen with short-term DAPT in patients with an acute minor stroke or TIA. The CHANCE study showed an absolute difference of 3.5% in the reduction of ischemic stroke at 90 days when DAPT was continued for 21 days, whereas POINT showed an absolute difference of 1.7% when DAPT was continued for 90 days.5,6
Other observational studies examining DAPT in acute nonminor stroke have had varied results. Lee et al 12 examined the role of DAPT in an observational study that included 15 430 patients with mild-to-moderate stroke (NIHSS score ≤10) within 24 hours of symptom onset. The primary efficacy outcome was a 3-month composite of stroke, MI, and all-cause mortality. Bleeding was not assessed. Dual antiplatelet therapy decreased the incidence of the primary outcome versus SAPT (15.5% vs 16.7%, P = 0.03) at 90 days.
Similarly, Kim et al 13 conducted a multicenter stroke registry database study in 4461 patients with acute, nonminor stroke (NIHSS 4-15). The primary outcome measure was a composite of stroke, MI, and all-cause mortality at 90 days. Bleeding was not assessed. There was no difference between DAPT and SAPT for the primary outcome (20.9% vs 22.9%, P = 0.13) at 90 days.
This study demonstrates that DAPT is being used in real-world clinical practice in a nonminor population and for a longer duration than is currently recommended.3,4 The median duration of therapy was 6 months, and 13 patients were continued on DAPT long term. This highlights the need for future randomized clinical trials to explore an optimal DAPT strategy including duration of therapy in patients with acute, nonminor stroke.
Limitations of this study include the retrospective single-center study design that limited the number of patients available for the cohort, and data collection relied solely on existing documentation in the electronic medical record. In addition, the observational nature of this study only allows for the conclusion that there is no apparent association between DAPT use and increased risk of bleeding in an acute, nonminor stroke population. Further studies are needed to validate these observations.
Conclusion
Patients treated with DAPT following nonminor stroke were found to have similar rates of major and minor bleeding, recurrent stroke or TIA within 1 year, and readmissions at 30 and 90 days compared with patients treated with SAPT. Dual antiplatelet therapy was infrequently discontinued within 90 days.
Footnotes
Author Contributions: JD: contributed to conception and design; contributed to acquisition, analysis, and interpretation; drafted manuscript; critically revised manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy.
SB: contributed to conception and design; contributed to interpretation; critically revised the manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy.
KG: contributed to conception and design; contributed to interpretation; critically revised the manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy.
NAP: contributed to conception and design; contributed to analysis and interpretation; critically revised the manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy.
JAS: contributed to conception and design; contributed to analysis and interpretation; drafted the manuscript; critically revised the manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy.
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iDs: Sarah Blackwell 
https://orcid.org/0000-0001-6664-5213
Nathan A. Pinner https://orcid.org/0000-0003-1938-5951
Jessica A. Starr https://orcid.org/0000-0003-2704-4372
References
- 1.Murphy SL, Kochanek KD, Xu JQ, Arias E.Mortality in the United States, 2020 (NCHS Data Brief, No 427). National Center for Health Statistics; 2021. [PubMed] [Google Scholar]
- 2.Amarenco P, Lavallee PC, Labreuche J, et al. One-year risk of stroke after transient ischemic attack or minor stroke. N Engl J Med. 2016;374(16):1533-1542. doi: 10.1056/NEJMoa1412981 [DOI] [PubMed] [Google Scholar]
- 3.Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 guideline for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline from the American Heart Association/American Stroke Association. Stroke. 2021;52(7):e364-e467. doi: 10.1161/STR.0000000000000375 [DOI] [PubMed] [Google Scholar]
- 4.Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019;50(12):e344-e418. doi: 10.1161/STR.0000000000000211 [DOI] [PubMed] [Google Scholar]
- 5.Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med. 2018;379(3):215-225. doi: 10.1056/NEJMoa1800410 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369(1):11-19. doi: 10.1056/NEJMoa1215340 [DOI] [PubMed] [Google Scholar]
- 7.Benavente OR, Hart RG, McClure LA, et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012;367(9):817-825. doi: 10.1056/NEJMoa1204133 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354(16):1706-1717. doi: 10.1056/NEJMoa060989 [DOI] [PubMed] [Google Scholar]
- 9.Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364(9431):331-337. doi: 10.1016/s0140-6736(04)16721-4 [DOI] [PubMed] [Google Scholar]
- 10.Hilkens NA, Algra A, Diener HC, et al. Predicting major bleeding in patients with noncardioembolic stroke on antiplatelets: S2TOP-BLEED. Neurology. 2017;89(9):936-943. doi: 10.1212/WNL.0000000000004289 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Abdul-Rahim AH, Fulton RL, Sucharew H, et al. National institutes of health stroke scale item profiles as predictor of patient outcome: external validation on independent trial data. Stroke. 2015;46(2):395-400. doi: 10.1161/STROKEAHA.114.006837 [DOI] [PubMed] [Google Scholar]
- 12.Lee HL, Kim JT, Lee JS, et al. Comparative effectiveness of dual antiplatelet therapy with aspirin and clopidogrel versus aspirin monotherapy in mild-to-moderate acute ischemic stroke according to the risk of recurrent stroke: an analysis of 15 000 patients from a nationwide, multicenter registry. Circ Cardiovasc Qual Outcomes. 2020;13(11):e006474. doi: 10.1161/CIRCOUTCOMES.119.006474 [DOI] [PubMed] [Google Scholar]
- 13.Kim JT, Park MS, Choi KH, et al. Comparative effectiveness of dual antiplatelet therapy with aspirin and clopidogrel versus aspirin monotherapy in acute, nonminor stroke: a nationwide, multicenter registry-based study. Stroke. 2019;50(11):3147-3155. doi: 10.1161/STROKEAHA.119.026044 [DOI] [PubMed] [Google Scholar]