Abstract
Background:
Recent guidelines suggest that aspirin-ticagrelor may be considered for stroke prevention after mild acute ischemic stroke. However, it is unclear how commonly this dual antiplatelet therapy (DAPT) regimen is used in practice.
Methods:
We performed a cross-sectional analysis of the Get With The Guidelines-Stroke registry 2017–2023. Patients with a non-cardioembolic mild ischemic stroke (defined as NIHSS <6) who presented within 24 hours of last known well without a contraindication to DAPT were included. The primary study outcome was the proportion of patients prescribed aspirin-ticagrelor at hospital discharge; temporal patterns of prescribing aspirin-ticagrelor and aspirin-clopidogrel over time are also described. In addition to standard tests of comparison, we used multiple logistic regression to evaluate associations between patient and facility factors and aspirin-ticagrelor use reported as odds ratios (OR) with 95% confidence intervals (CI).
Results:
Among 1,018,736 patients meeting study criteria, 478,049 (46.9%) were female and median age was 68 (IQR: 59, 78) years. A total of 12,845 (1.3%) patients were discharged on aspirin-ticagrelor whereas 448,348 (44.0%) were discharged on aspirin-clopidogrel. Prescriptions for aspirin-ticagrelor and for aspirin-clopidogrel significantly increased over the study time-period. In regression analysis, coronary artery disease/prior myocardial infarction (OR: 2.6 [95% CI: 2.5–2.7]), Asian race (OR: 2.1 [95% CI: 1.9–2.2]), aspirin-clopidogrel prescription upon admission (OR: 2.0 [95% CI:1.9–2.1]), and history of stroke/TIA (OR: 1.98 [95% CI: (1.9–2.1)]), were substantially associated with aspirin-ticagrelor use whereas lacking insurance/self-pay (OR: 0.7 [95% CI: 0.6–0.8]), rural setting (OR: 0.8 [95% 0.7–0.9]), and primary stroke centers (OR: 0.3 [95% CI: 0.3–0.4]) were inversely associated with aspirin-ticagrelor. In the subgroup of 176,897 (17.4%) patients with NIHSS 4–5, 74,912 (50.8%) were discharged on aspirin-clopidogrel and 2,394 (1.4%) on aspirin-ticagrelor.
Conclusion:
Unlike aspirin-clopidogrel, aspirin-ticagrelor is infrequently administered after mild acute ischemic stroke (NIHSS <6) despite current guidelines, though the use of both DAPT regimens increased over time.
Keywords: Ischemic Stroke, Dual Antiplatelet Therapy, Secondary Stroke Prevention, Ticagrelor
Introduction
Implementing evidence-based preventative treatments into clinical practice is a well-recognized public health challenge.1 For instance, the uptake of aspirin-clopidogrel after high-risk TIA or minor acute ischemic stroke (NIHSS <4) has been sub-optimal despite strong endorsement by societal guidelines (AHA/ASA class of recommendation [COR] 1, level of evidence [LOE] A).2–4 The latest AHA/ASA guidelines also note that for patients with minor or moderate acute ischemic stroke (NIHSS <6), aspirin-ticagrelor for 30 days may be considered to reduce the risk of recurrent stroke (COR 2b, LOE B-R) based on evidence of benefit in a large randomized, placebo-controlled trial (The Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and ASA [acetylsalicylic acid] for Prevention of Stroke and Death [THALES]).5,6 Therefore for strokes with NIHSS of 4–5, guidelines currently only recommend aspirin and ticagrelor.
However, ticagrelor costs more than clopidogrel,7 requires twice daily dosing, and is associated with dyspnea in some patients while clopidogrel is not.8 Practice patterns of aspirin-ticagrelor use in minor or moderate acute ischemic stroke have not previously been well described. We therefore sought to leverage a large, heterogeneous, representative, nationwide hospital-level U.S. registry to evaluate the similarities and differences between real-world aspirin-ticagrelor use and evidence-based guidelines.5 We also explored patient- and facility-level factors associated with ticagrelor-aspirin use in minor or moderate stroke.
Methods
Data availability
The data used in this analysis cannot be shared directly with other investigators. Interested researchers may submit a proposal to the AHA-Get With The Guidelines (GWTG) committee to request access. IQVIA (Parsippany, New Jersey) serves as the data collection and coordination center.
Design
We performed a cross-sectional analysis of the GWTG-Stroke registry from 2017 to 2023. Details of the GWTG-Stroke registry, including case ascertainment and data collection methodologies, have been previously described.9,10 Each participating hospital received either human research approval to enroll cases without individual patient consent under the common rule, or a waiver of authorization and exemption from subsequent review by their institutional review board (IRB). Advarra, the IRB for the AHA, determined that this study is exempt from IRB oversight. Additionally, our current analysis was approved by the IRB of Weill Cornell Medicine with a waiver of consent granted because we only used de-identified data. Prior researchers have demonstrated that information included in GWTG-Stroke is highly reliable and accurate.11 We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines to report results.12
Population
Our primary study cohort included all adult patients with a final diagnosis of non-cardioembolic minor or moderate ischemic stroke (defined as NIHSS <6) who presented to a GWTG-Stroke hospital within 24 hours of last known well. Any patient with an indication for anticoagulation (history of atrial fibrillation, prosthetic heart valve, index stroke due to hypercoagulability, history of venous thromboembolism), anticoagulation prescription, prior intracerebral hemorrhage, and those treated with thrombolysis and/or thrombectomy on arrival were excluded from our study to align with current guidelines regarding eligibility for dual antiplatelet therapy (DAPT) after stroke.5 Patients without a NIHSS recorded, those transferred to another hospital, and those who were diagnosed with TIA rather than ischemic stroke were also excluded. Information about the presence of vascular risk factors (prior stroke/TIA, CAD/MI, diabetes, hypertension, hyperlipidemia, heart failure, smoking, migraine, and dementia) was collected from the registry.
We conducted secondary analyses on the subgroup of patients with moderate ischemic stroke (NIHSS 4–5) as opposed to minor stroke (NIHSS <4) because the former were not included in the two pivotal trials demonstrating efficacy of aspirin-clopidogrel compared to aspirin alone (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke [POINT]13 and Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack [CHANCE]14), but were included in the randomized controlled trial demonstrating efficacy of aspirin-ticagrelor (THALES) as compared to aspirin monotherapy.6,15
Outcome
The primary study outcome was the proportion of minor or moderate ischemic stroke patients prescribed aspirin-ticagrelor at the time of hospital discharge. The secondary outcome was the change in aspirin-ticagrelor prescriptions at discharge over time. We also explored patient-level and hospital-level factors associated with being prescribed aspirin-ticagrelor at hospital discharge.
Analysis
We used standard descriptive statistics to report demographic, clinical, and facility-level characteristics. To evaluate temporal patterns of aspirin-ticagrelor and aspirin-clopidogrel use we used Chi-square for trend and report annual percent change. Both joinpoint and segmented models were used to identify a natural change point in the administration of aspirin-ticagrelor during the study period. In secondary analyses, we separately excluded patients whose index stroke was due to large artery atherosclerosis disease and those who were prescribed DAPT before their index stroke since their reason for treatment might have been unrelated to stroke severity.
To identify factors associated with prescriptions for aspirin-ticagrelor, we compared patients discharged on aspirin-ticagrelor to all others (discharged on aspirin monotherapy, discharged on no antiplatelet therapy, discharged on aspirin-clopidogrel, or discharged on other regimens). Pearson’s Chi-squared test was used for categorical variables, and Student’s t-test or the Wilcoxon rank sum test was used for continuous or ordinal variables, as appropriate based on data distribution. Using multiple logistic regression, we evaluated the relationships between patient and facility factors and aspirin-ticagrelor use, with associations reported as odds ratios (OR) with 95% confidence intervals (CI) among the subset of cases without any missing variables (complete cases). Regression analysis was not planned in the subgroup of patients with NIHSS 4–5 due to anticipated small sample size. No missing values were imputed in our analyses. The threshold of statistical significance was α=0.05. Analyses were performed with R version (4.3.2) by C.Z. The AHA Precision Medicine Platform (https://precision.heart.org) was used for data analysis.
Results
Baseline Characteristics
We identified a total of 1,018,736 ischemic stroke patients with NIHSS score of 0–5 who met all study eligibility criteria (Fig. 1).
Fig. 1.
Flowchart showing study inclusion/exclusion criteria.
As shown in Table 1, 478,049 (47%) patients were female and median age was 68 (IQR: 59, 78) years. At the time of admission, 605,439 (59.43%) patients were not on any antiplatelet agents; only 4,248 (0.42%) patients were prescribed aspirin-ticagrelor at the time of admission. At discharge, 461,172 (45.6%) patients with NIHSS 0–5 were prescribed DAPT, including 12,845 (1.3%) patients who were prescribed aspirin-ticagrelor. Among patients on aspirin-ticagrelor, 10,451 (1.2%) had an NIHSS 0–3 whereas 2,394 (1.4%) had an NIHSS 4–5.
Table 1.
Baseline Characteristics of ischemic stroke patients with an NIHSS 0–5 (N=1,018,736).
| Characteristic | |
|---|---|
| Demographics | |
| Median Age (IQR) | 68 (59, 78) |
| Female Sex, N(%) | 478,049 (47%) |
| Race and ethnicity, N(%) | |
| White | 659,555 (65%) |
| Asian | 33,866 (3.3%) |
| Black | 190,067 (19%) |
| Hispanic | 90,304 (8.9%) |
| Other | 44,944 (4.4%) |
| Insurance Type, N(%) | |
| Medicaid | 118,242 (14%) |
| Medicare | 342,034 (40%) |
| Private | 343,727 (40%) |
| Self pay/uninsured | 48,597 (5.6%) |
| Other | 166,136 (16.3%) |
| Vascular Risk Factors | |
| Stroke/TIA, N(%) | 289,611 (28.4%) |
| Coronary Artery Disease/Myocardial Infarction N(%) | 178,157 (18%) |
| Diabetes, N(%) | 381,114 (38%) |
| Hypertension, N(%) | 764,672 (76%) |
| Hyperlipidemia, N(%) | 498,219 (50%) |
| Heart Failure, N(%) | 53,881 (5.4%) |
| Smoking, N(%) | 222,925 (22%) |
| Migraine, N(%) | 34,680 (3.4%) |
| Dementia, N(%) | 20,469 (2.0%) |
| Clinical Features | |
| NIHSS 0–3 (minor) | 841,839 (83%) |
| NIHSS 4–5 (moderate) | 176,897 (17%) |
| Admission Medications | |
| Aspirin-clopidogrel, N(%) | 76,848 (7.5%) |
| Aspirin-ticagrelor, N(%) | 4,248 (0.4%) |
| Aspirin monotherapy, N(%) | 292,659 (29%) |
| Clopidogrel monotherapy, N(%) | 38,587 (3.8%) |
| Ticagrelor monotherapy, N(%) | 830 (0.08%) |
| Other antiplatelet regimen, N(%) | 125 (0.01%) |
| Discharge Medications | |
| Aspirin-clopidogrel, N(%) | 448,348 (44%) |
| Aspirin-ticagrelor, N(%) | 12,845 (1.5%) |
| Aspirin monotherapy, N(%) | 404,234 (39.7%) |
| Clopidogrel monotherapy, N(%) | 70,142 (6.9) |
| Ticagrelor monotherapy, N(%) | 631 (0.06%) |
| Other antiplatelet regimen, N(%) | 82,806 (8.1%) |
| Region | |
| Midwest, N(%) | 209,584 (21%) |
| Northeast, N(%) | 203,754 (20%) |
| South, N(%) | 430,428 (42%) |
| West, N(%) | 174,970 (17%) |
| Hospital Setting | |
| Primary Stroke Center, N(%) | 406,987 (40%) |
| Comprehensive Stroke Center, N(%) | 222,288 (22%) |
| Rural, N(%) | 50,210 (5.3%) |
| Academic Hospital, N(%) | 457,305 (53%) |
Temporal Trends
Among patients with NIHSS 0–5, discharge prescriptions for aspirin-ticagrelor increased over time from in 0.3% in 2017 to 2.4% in 2023 (P<0.001; Fig. 2). Discharge prescriptions for aspirin-clopidogrel also increased over time from 27% in 2017 to 57% in 2023 (P<0.001; Fig. 2). In secondary analyses excluding patients with stroke due to large artery atherosclerosis (n=131,667 [12.9%]) and those previously prescribed DAPT (n=76,848 [7.5%]), the temporal trends of increased aspirin-ticagrelor and aspirin-clopidogrel use persisted (P< 0.001). Over the study period, the annual percent change for aspirin-ticagrelor prescription was 35.9% (95% CI, 27.9–44.4%), while the annual percent change for aspirin-clopidogrel was 12.3% (95% CI, 8.8–15.9%). We identified a change point in the use of aspirin-ticagrelor in 2021, with the annual rate of increase slowing after 2021 compared to before, corresponding to the publication of the THALES trial in 2021. Comparing aspirin-ticagrelor use before 2021 (2017 to 2020) to after 2021 (2021–2023), the year THALES was published,6 3,653 (0.7%) versus 9,192 (2.0%) patients were discharged on aspirin-ticagrelor (p<0.001).
Fig. 2. Trend in dual antiplatelet therapies in minor to moderate ischemic stroke (NIHSS 0–5).
Among patients with NIHSS 0–5 (N=1,018,736), discharge prescriptions for aspirin-ticagrelor increased from in 0.3% in 2017 to 2.4% in 2023 (P<0.001) and discharge prescriptions for aspirin-clopidogrel increased from 27% in 2017 to 57% in 2023 (P<0.001).
Factors associated with aspirin-ticagrelor use
As shown in Table 2, when compared to all other included patients with NIHSS 0–5, those discharged on aspirin-ticagrelor were more frequently male, Asian, insured, and had more vascular risk factors. When compared to patients discharged on aspirin-clopidogrel, those discharged on aspirin-ticagrelor were similarly more frequently male, Asian, insured, and had more vascular risk factors. Presenting to a comprehensive stroke center, an academic center, and one in a non-rural location were also associated with being discharged on aspirin-ticagrelor.
Table 2.
Factors associated with aspirin-ticagrelor use (N=1,018,736).
| Characteristic | All Others (N=1,005,891) | Aspirin-ticagrelor (N=12,845) | P-value (Aspirin-ticagrelor vs. all others) | Aspirin-clopidogrel (N=448,348) | P-value (Aspirin-ticagrelor vs. Aspirin-clopidogrel) |
|---|---|---|---|---|---|
| Demographics | |||||
| Mean Age (IQR) | 67.7 (13.7) | 67.6 (12.2) | 0.4 | 67.8 (12.9) | 0.03 |
| Female Sex | 472,422 (47%) | 5,627 (44%) | <0.001 | 201,057 (45%) | 0.02 |
| Race and ethnicity | |||||
| – White | 651,469 (65%) | 8,086 (63%) | <0.001 | 294,953 (66%) | <0.001 |
| – Asian | 33,077 (3.3%) | 789 (6.1%) | 14,793 (3.3%) | ||
| – Black | 187,870 (19%) | 2,197 (17%) | 81,251 (18%) | ||
| – Hispanic | 89,247 (8.9%) | 1,057 (8.2%) | 37,960 (8.5%) | ||
| – Other | 44,228 (4.4%) | 716 (5.6%) | 19,391(4.3%) | ||
| Insurance | |||||
| – Medicaid | 116,459 (14%) | 1,783 (15%) | <0.001 | 52,147 (13%) | <0.001 |
| – Medicare | 337,079 (40%) | 4,955 (42%) | 160,284 (41%) | ||
| – Private | 339,067 (40%) | 4,660 (39%) | 155,152 (40%) | ||
| – Self-pay/uninsured | 48,279 (5.7%) | 318 (2.7%) | 20,160 (5.2%) | ||
| – Other | 165,007 (16.4) | 1,129 (8.8) | 60,605 (13.5%) | ||
| Vascular Risk Factors | |||||
| Stroke/TIA | 282,698 (28.1) | 6913 (53.8) | <0.00001 | 148,258 (33.1%) | <0.001 |
| Coronary artery disease | 172,727 (17%) | 5,430 (42%) | <0.001 | 94,790 (21%) | <0.001 |
| Diabetes | 374,270 (38%) | 6,844 (53%) | <0.001 | 183,142 (41%) | <0.001 |
| Hypertension | 753,692 (76%) | 10,980 (86%) | <0.001 | 350,933 (79%) | <0.001 |
| Dyslipidemia | 489,430 (49%) | 8,789 (69%) | <0.001 | 242,863 (54%) | <0.001 |
| Smoking | 220,300 (22%) | 2,625 (20%) | <0.001 | 98,998 (22%) | <0.001 |
| Heart failure | 52,622 (5.3%) | 1,259 (9.8%) | <0.001 | 25,117 (5.6%) | <0.001 |
| Obesity | 313,728 (32%) | 5,313 (41%) | <0.001 | 152,978 (34%) | <0.001 |
| Migraine | 34,223 (3.4%) | 457 (3.6%) | 0.5 | 15,075 (3.4%) | 0.3 |
| Dementia | 20,148 (2.0%) | 321 (2.5%) | <0.001 | 8,986 (2.0%) | <0.001 |
| Clinical factors | |||||
| NIHSS 0–3 (minor) | 831,388 (83%) | 10,451 (81%) | <0.001 | 373,436 (83.3%) | <0.00001 |
| NIHSS 4–5 (moderate) | 174,503 (17%) | 2,394 (19%) | 74,912 (16.7%) | ||
| Hospital Data | |||||
| Primary Stroke Center | 403,859 (40%) | 3,128 (24%) | <0.001 | 175,680 (39%) | <0.001 |
| Comprehensive Stroke Center | 217,342 (22%) | 4,946 (39%) | <0.001 | 99,078 (22%) | <0.001 |
| Rural location | 49,799 (5.3%) | 411 (3.5%) | <0.001 | 22,553 (5.4%) | <0.001 |
| Academic | 450,565 (53%) | 6,740 (59%) | <0.001 | 205,910 (55%) | <0.001 |
Table 3 shows the results of our multivariable regression analysis with discharge on aspirin-ticagrelor as the dependent variable. We included 682,749 complete cases; the proportion of aspirin-ticagrelor use (n=7,655) was similar among complete cases (1.1%) as in the full study cohort (1.3%). We included sex, race and ethnicity, study year, insurance type, stroke severity (minor [NIHSS 0–3] versus moderate [NIHSS 4–5]), vascular risk factors (prior stroke/TIA, CAD/MI, diabetes, hypertension, hyperlipidemia, heart failure, smoking, migraine, dementia), stroke center status (primary or comprehensive), hospital teaching status, and rurality in our model. History of stroke/TIA (OR: 2.0 [95% CI: 1.9–2.1]), coronary artery disease/prior myocardial infarction (OR: 2.6 [95% CI: 2.5–2.7]), and Asian race (OR: 2.1 [95% CI: 1.9–2.2]) were associated with aspirin-ticagrelor use. Being on aspirin-clopidogrel at admission was also associated with aspirin-ticagrelor at discharge (OR: 2.0 [95% CI: 1.9–2.1]). Lacking insurance/self-pay (OR: 0.7 [95% CI: 0.6–0.8]), rural hospital setting (OR: 0.8 [95% 0.7–0.9]), and primary stroke centers (OR: 0.3 [95%CI: 0.3–0.4]) were inversely associated with aspirin-ticagrelor use.
Table 3.
Multivariable regression model to explore factors associated with aspirin-ticagrelor use in minor to moderate stroke patients (N=682,749).
| Characteristic | Odds Ratio (95% CI) |
|---|---|
| Demographics | |
| Female Sex | 0.98 (0.94–1.03) |
| Black | 0.89 (0.84–0.94) |
| Asian | 2.05 (1.88–2.24) |
| Other | 1.31 (1.20–1.44) |
| Hispanic | 0.90 (0.83–0.98) |
| Private Insurance | 1.16 (1.11–1.22) |
| Medicaid | 1.01 (0.94–1.07) |
| Self pay/uninsured | 0.72 (0.63–0.82) |
| Other insurance | 1.03 (0.82–1.30) |
| Clinical Features and Vascular risk Factors | |
| Stroke severity | 1.01 (0.96–1.06) |
| Prior Stroke/TIA | 1.98 (1.90–2.07) |
| Coronary artery disease/prior myocardial infarction | 2.62 (2.50–2.74) |
| Diabetes Mellitus | 1.30 (1.24–1.36) |
| Hypertension | 1.14 (1.07–1.21) |
| Hyperlipidemia | 1.34 (1.28–1.41) |
| Smoking | 0.95 (0.91–1.00) |
| Heart Failure | 1.04 (0.97–1.11) |
| Obesity | 1.32 (1.26–1.38) |
| Dementia | 0.74 (0.65–0.85) |
| Aspirin-clopidogrel on admission | 1.98 (1.88–2.08) |
| Other | |
| Stroke center status | 0.33 (0.31–0.35) |
| Teaching status | 1.03 (0.99–1.08) |
| Rurality | 0.75 (0.66–0.85) |
| Study Year | 1.38 (1.36–1.39) |
Subgroup of NIHSS 4–5
In the subgroup of patients with NIHSS 4–5 (moderate acute ischemic stroke) who constituted 176,897 (17.4%) of the study cohort, 74,912 (50.8%) were discharged on aspirin-clopidogrel and 2,394 (1.4%) were discharged on aspirin-ticagrelor.
Trends for both aspirin-clopidogrel and aspirin-ticagrelor use increased over time (P< 0.001 for both [Fig. 3]). In 2017, 0.3% of patients with NIHSS 4–5 were discharged on aspirin-ticagrelor whereas 2.5% were discharged on aspirin-ticagrelor in 2023. Similarly, aspirin-clopidogrel was prescribed at discharge to 27% of patients with NIHSS 4–5 whereas in 2023 aspirin-clopidogrel was prescribed in 55%. Over the study period in the subgroup of patients with NIHSS 4–5, annual percent change for aspirin-ticagrelor prescription among patients with an NIHSS 4–5 was 35.6% (95% CI, 24.2–48.1%); the annual percent change for aspirin-clopidogrel was 11.5% (95% CI, 8.5–14.5%).
Fig. 3. Trend in dual antiplatelet therapies in the subgroup of moderate ischemic stroke (NIHSS 4–5).
Among patients with NIHSS 4–5 (N=176,897), discharge prescriptions for aspirin-ticagrelor increased from in 0.3% in 2017 to 2.5% in 2023 (P<0.001) and discharge prescriptions for aspirin-clopidogrel increased from 27% in 2017 to 55% in 2023 (P<0.001).
Factors associated with being prescribed aspirin-ticagrelor in the subgroup of stroke patients with moderate symptoms (NIHSS 4–5) were younger age, Asian race, not having a self-pay/uninsured insurance status, presence of vascular risk factors, and treatment at a comprehensive stroke center, academic center, or non-rural location in unadjusted analyses (Table 4).
Table 4.
Factors associated with aspirin-ticagrelor use in the subgroup of moderate (NIHSS 4–5) ischemic stroke (N=176,897).
| Characteristic | All others with NIHSS 4–5 (N=174,503) | Aspirin-ticagrelor Use with NIHSS 4–5 (N=2,394) | P-value |
|---|---|---|---|
| Demographics | |||
| Median Age (IQR) | 68 (59, 78) | 68 (59, 76) | <0.001 |
| Female Sex | 83,720 (48.0%) | 1,122 (46.9%) | 0.3 |
| Race and ethnicity | |||
| – White | 106,375 (60.9%) | 1,396 (58.3%) | <0.001 |
| – Asian | 5,929 (3.4%) | 144 (6.0%) | |
| – Black | 38,325 (22%) | 514 (21.5%) | |
| – Hispanic | 15,828 (9.1%) | 198 (8.3%) | |
| – Other | 8,046 (4.6%) | 142 (5.9%) | |
| Insurance | |||
| – Medicaid | 25,116 (14.4%) | 384 (16%) | <0.001 |
| – Medicare | 60,621 (34.7%) | 945 (39.5%) | |
| – Private | 51,237 (29.3%) | 806 (33.7%) | |
| – Self-pay/uninsured | 8,866 (5.1%) | 66 (2.8%) | |
| – Other | 28,753 (16.5%) | 193 (8.1%) | |
| Vascular Risk Factors | |||
| Stroke/TIA | 58,055 (33.3%) | 1,412 (59.0%) | <0.001 |
| Coronary artery disease | 31,279 (17.9%) | 966 (40.4%) | <0.001 |
| Diabetes | 70,748 (40.5%) | 1,324 (55.3%) | <0.001 |
| Hypertension | 134,031 (76.8%) | 2,088 (87.2%) | <0.001 |
| Dyslipidemia | 84,318 (48.3%) | 1,644 (68.7%) | <0.001 |
| Smoking | 42,526 (24.4%) | 549 (22.9%) | 0.055 |
| Heart failure | 10,912 (6.3%) | 241 (10.1%) | <0.001 |
| Obesity | 52,094 (29.8%) | 1,022 (42.7%) | <0.001 |
| Migraine | 4,772 (2.8%) | 82 (3.4%) | 0.050 |
| Dementia | 5,199 (3.0%) | 77 (3.2%) | 0.6 |
| Hospital Characteristics | |||
| Primary Stroke Center | 66,451 (38.1%) | 515 (21.5%) | <0.001 |
| Comprehensive Stroke Center | 41,624 (23.8%) | 985 (41.1%) | <0.001 |
| Rural location | 9,184 (5.3%) | 71 (3.0%) | <0.001 |
| Academic | 82,627 (47.3%) | 1,336 (55.8%) | <0.001 |
Discussion
We found that aspirin-ticagrelor was infrequently administered after mild ischemic stroke, including those with NIHSS 4–5, in a large US-based registry despite current guidelines.5 Although there was a gradual increase in its administration from 2017 through 2023, even in the later epoch of our study, nearly half of identified mild stroke patients were not prescribed any dual antiplatelet therapy.
We identified several factors associated with receiving a prescription for aspirin-ticagrelor. Our finding that vascular risk factors, particularly prior stroke/TIA and coronary artery disease, and prior aspirin-clopidogrel prescription were associated with aspirin-ticagrelor use, suggests that prescribers preferentially choose this regimen in patients thought to be at high risk of stroke recurrence, or in patients with additional indications such as coronary stents. Asian race being associated with aspirin-ticagrelor use likely reflects application of findings from a Chinese trial (CHANCE-2) wherein, among patients with CYP2C19 loss of function alleles, the risk of stroke at 90 days was modestly lower in those treated with aspirin-ticagrelor versus with aspirin-clopidogrel.16 However, whether aspirin-ticagrelor was prescribed based on the results of CYP2C19 testing in our cohort is uncertain since information regarding this testing is not available in our dataset. Because there are no clinical practice guidelines regarding CYP2C19 testing after TIA/minor stroke in the US, we suspect testing rates in our cohort were low.5,17 We also do not know if any platelet function assays were used to inform choice of antiplatelet therapy in our cohort. Given the cost of ticagrelor in the US, it is not surprising that we found that patients who lack insurance are unlikely to be prescribed this medication.
Our finding that rates of aspirin-clopidogrel administration have increased over time for patients with minor or moderate ischemic stroke even though patients with NIHSS 4–5 were not included in the CHANCE or POINT trials is consistent with prior work demonstrating a divergence between narrow clinical trial inclusion/exclusion criteria and actual practice in the use of short-term DAPT.2,3,18 Recently, a large study called the Intensive Statin and Antiplatelet Therapy for Acute High-Risk Intracranial or Extracranial Atherosclerosis (INSPIRES) demonstrated the efficacy of aspirin-clopidogrel within 72 hours of symptom onset in patients with NIHSS 0–5, expanding patients in whom this regimen may be warranted.19 The results of this recent study are unlikely to have impacted our observational data because it was published in 2023, but it does support the practice we observed of increasing use of aspirin-clopidogrel over time for minor or moderate stroke patients. The change point after which increasing aspirin-ticagrelor use slowed that we identified in 2021 is difficult to interpret and does not clearly relate to the publication of CHANCE-2 in 2021 or THALES in 2020.6,16
Our study has several limitations. While we found that rural hospital location and primary stroke center status were inversely associated with aspirin-ticagrelor prescription, we did not explore more detailed hospital-specific practice patterns of aspirin-ticagrelor prescription because of the relatively few patients discharged on this regimen. A prior study using GWTG-Stroke data found that hospitals that were more likely to prescribe DAPT for minor strokes were also more likely to do so for non-minor strokes.3 We also did not evaluate high-risk TIA (defined as ABCD2 score ≥4) patients in this study due to both limitations of the registry database and the known challenges of accurately diagnosing TIA.20 Whether patterns of aspirin-ticagrelor use among high-risk TIA patients are similar to those in ischemic stroke is uncertain. Similarly, though we conducted a subgroup analysis excluding patients with large artery atherosclerotic disease, we do not know how purported stroke mechanism may have impacted aspirin-ticagrelor prescription practices.21 Finally, we do not know if some patients were placed on aspirin-ticagrelor during their index stroke hospitalization and then were switched to a single antiplatelet agent or another regimen prior to discharge; information in this registry is only available for medications prescribed at the time of discharge.
Conclusion
Unlike aspirin-clopidogrel, aspirin-ticagrelor is infrequently administered after minor or moderate ischemic stroke (NIHSS <6) despite evidence-based guidelines. Though prescriptions for both dual antiplatelet regimens have increased over time, overall, we found that nearly half of identified ischemic stroke patients with NIHSS <6 were not discharged on DAPT.
Disclosures
Dr. Xian reports research grants from the NIA (R01AG062770 and R01AG066672).
Sponsorship Statement
The Get With The Guidelines®-Stroke (GWTG-Stroke) program is provided by the American Heart Association. GWTG-Stroke is sponsored, in part, by Novartis, Novo Nordisk, AstraZeneca, Bayer and HCA Healthcare.
Footnotes
CRediT authorship contribution statement
Ava L. Liberman: Writing – review & editing, Writing – original draft, Project administration, Investigation, Formal analysis, Conceptualization. Cenai Zhang: Data curation. Sara K. Rostanski: Investigation. Hooman Kamel: Conceptualization. Babak B. Navi: Conceptualization. Natalie T. Cheng: Investigation. Radhika Sundararajan: Investigation. Steven R. Messe: Investigation. Gregg C. Fonarow: Investigation. Shyam Prabhakaran: Investigation. Ying Xian: Investigation.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data used in this analysis cannot be shared directly with other investigators. Interested researchers may submit a proposal to the AHA-Get With The Guidelines (GWTG) committee to request access. IQVIA (Parsippany, New Jersey) serves as the data collection and coordination center.