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. 2023 May 24;8(3):692–702. doi: 10.1177/23969873231174942

Ischaemic stroke despite antiplatelet therapy: Causes and outcomes

Norbert Silimon 1, Boudewijn Drop 1, Leander Clénin 1, Krassen Nedeltchev 1,2, Timo Kahles 2, Alexander A Tarnutzer 3, Mira Katan 4, Leo Bonati 4,5, Stephan Salmen 6, Sylvan Albert 7, Alexander Salerno 8, Emmanuel Carrera 9, Christian Berger 10, Nils Peters 11, Friedrich Medlin 12, Carlo Cereda 13, Manuel Bolognese 14, Georg Kägi 1,15, Susanne Renaud 16, Julien Niederhauser 17, Christophe Bonvin 18, Michael Schärer 19, Marie-Luise Mono 20, Andreas Luft 21, Biljana Rodic-Tatic 22, Urs Fischer 1,4, Simon Jung 1, Marcel Arnold 1, Thomas Meinel 1, David Seiffge 1,✉
PMCID: PMC10472957  PMID: 37622482

Abstract

Background:

Ischaemic stroke may occur despite antiplatelet therapy (APT). We aimed to investigate frequency, potential causes and outcomes in patients with ischaemic stroke despite APT.

Methods:

In this cohort study, we enrolled patients with imaging-confirmed ischaemic stroke from the Swiss Stroke Registry (01/2014-07/2022). We determined the frequency of prior APT, assessed stroke aetiology (modified TOAST classification) and determined the association of prior APT with unfavourable functional outcome (modified Rankin Scale score 3–6) and recurrent ischaemic stroke at 3 months using regression models.

Results:

Among 53,352 patients, 27,484 (51.5%) had no prior antithrombotic treatment, 17,760 (33.3%) were on APT, 7039 (13.2%) on anticoagulation and 1069 (2.0%) were on APT + anticoagulation. In patients with a history of ischaemic stroke/TIA (n = 11,948; 22.4%), 2401 (20.1%) had no prior antithrombotic therapy, 6594 (55.2%) were on APT, 2489 (20.8%) on anticoagulation and 464 (3.9%) on APT + anticoagulation. Amongst patients with ischaemic stroke despite APT, aetiology was large artery atherosclerosis in 19.8% (n = 3416), cardiac embolism in 23.6% (n = 4059), small vessel disease in 11.7% (n = 2011), other causes in 7.4% (n = 1267), more than one cause in 6.3% (n = 1078) and unknown cause in 31.3% (n = 5388). Prior APT was not independently associated with unfavourable outcome (aOR = 1.06; 95% CI: 0.98–1.14; p = 0.135) or death (aOR = 1.10; 95% CI: 0.99–1.21; p = 0.059) at 3-months but with increased odds of recurrent stroke (6.0% vs 4.3%; aOR 1.26; 95% CI: 1.11–1.44; p < 0.001).

Conclusions:

One-third of ischaemic strokes occurred despite APT and 20% of patients with a history of ischaemic stroke had no antithrombotic therapy when having stroke recurrence. Aetiology of breakthrough strokes despite APT is heterogeneous and these patients are at increased risk of recurrent stroke.

Keywords: Acute ischaemic stroke, antiplatelet therapy, anticoagulation, incidence, aetiology, stroke severity, functional outcome, recurrent stroke

Introduction

Antiplatelet therapy (APT) is the cornerstone of primary and secondary prevention of a variety of cardiovascular conditions including secondary prevention of non-cardioembolic stroke and transient ischaemic attack. 1 Aspirin, in particular, is a well-established antiplatelet agent that reduces the overall cardiovascular risk in secondary prevention of cardiovascular disease and cerebrovascular events by about a fifth to a quarter per year.2,3 However, strokes do (re-) occur despite APT with a yearly risk of around 3%–4% after the index event. In the US, approximately 185,000 (23%) of the 795,000 incident ischaemic strokes each year are recurrent strokes. 4 It is estimated that about one-third to one-half of these strokes occur while on APT. 4 Furthermore, about one-third of ischaemic strokes in patients with atrial fibrillation occurs while on oral anticoagulation (AC)5,6 and there has been a number of recent studies on ischaemic stroke despite anticoagulant therapy elucidating aetiology, risk of recurrent stroke and secondary prevention strategies.7,8

Data from a large, national stroke registry in a health care setting with universal coverage and without major barriers for acute stroke treatment and secondary prevention therapies may help to characterise this problem and provide the groundwork for future studies assessing specific diagnostic and therapeutic interventions for this vulnerable population.

The aim of this study was to explore and characterise ‘breakthrough’ ischaemic strokes occurring despite APT both in the overall population and in patients with a history of ischaemic stroke or transient ischaemic attack. We thought to assess frequency, aetiology, clinical characteristics and outcomes, including functional outcome, recurrent strokes, intracranial haemorrhage and death in patients who had ischaemic stroke despite APT using data from a large, prospective national stroke registry.

Methods

Study cohort

This study is a retrospective analysis of prospectively collected clinical data from consecutive stroke patients enrolled in the Swiss Stroke Registry (SSR) between January 2014 and July 2022. The SSR 9 is a national registry enrolling all patients with acute ischaemic or haemorrhagic stroke and transient ischaemic attack treated at one of the Swiss Stroke Units or Centres (certified according to national criteria that are in line with those of the European Stroke Organisation 10 ).

We included patients ⩾18 years of age who had an imaging-confirmed ischaemic stroke and were enrolled in the SSR. We excluded patients with missing data on prior APT. We did not include patients with transient ischaemic attacks or stroke mimics.

Ethics

Enrolment in the SSR is mandatory by Swiss law for the purpose of quality control. Patients are informed about the use of their data for research purposes. In accordance with Swiss law, patients refusing the use of their data for research, were excluded from the study. The project was approved by both the local ethics (KEK Bern 2022-01465) and the SSR steering committees and complies with the Declaration of Helsinki.

Baseline and outcome variables from the SSR

Local investigators at each SSR site collect patient data on admission and during hospitalisation using electronic case report forms, which are centrally stored in a secured database at the clinical trials unit in Basel (CH).

For the analyses, we used the following prospectively collected variables: Demographics (age, sex), event characteristics (time of symptom onset/admission), medical history (hypertension, dyslipidaemia, diabetes mellitus, atrial fibrillation, active smoking, previous ischaemic stroke, previous transient ischaemic attack, previous intracranial haemorrhage, peripheral arterial disease, coronary heart disease), baseline medical data (premorbid modified Rankin scale (mRS), National Institutes of Health Stroke Scale (NIHISS) on admission, blood pressure, blood glucose), prior antithrombotic treatment (APT and/or AC), acute treatment (intravenous thrombolysis, endovascular treatment) and aetiology (modified Trial of Org 10172 in Acute Stroke Treatment – TOAST 11 (we consolidated the TOAST subgroups ‘negative evaluation’ and ‘incomplete evaluation’ to ‘unknown causes’)).

Clinical follow-up

As part of the SSR, local investigators conduct a standardised follow-up after 3 months for all patients treated at the respective centre. During these structured telephone or in person visits information on recurrent events after discharge (recurrent ischaemic stroke, intracerebral haemorrhage, death), as well as the mRS is collected.

Primary and secondary outcomes

The primary outcome of our study was the frequency of prior antiplatelet therapy. Secondary outcomes were stroke severity at baseline (measured with the admission NIHSS), stroke aetiology, unfavourable functional outcome at 3 months (defined as mRS 3–6), death at 3 months, intracerebral haemorrhage at 3 months and recurrent ischaemic stroke at 3 months.

Statistical analysis

Patients meeting the inclusion and exclusion criteria were grouped based on their prior antithrombotic treatment (no prior antithrombotic treatment, prior APT, prior AC, prior APT + AC). Applying the appropriate statistical methods, we compared the four groups concerning baseline medical data and stroke aetiologies (modified TOAST). We reported median values with interquartile range (IQR) or mean values with standard deviation (SD) as appropriate.

To investigate the association between prior antithrombotic treatment and the outcome variables NIHSS on admission and 3-month follow-up outcomes (unfavourable functional outcome, recurrent ischaemic stroke, intracerebral haemorrhage and death), we used quantile regression and binomial logistic regression models. We performed the analysis both in the overall population and in patients with a history of ischaemic stroke or transient ischaemic attack.

In the analysis of the effect of prior antithrombotic treatment on stroke severity (NIHSS), we included age (continuous), sex (categorical), premorbid mRS (ordinal), serum glucose on admission (continuous), systolic blood pressure on admission (continuous), time between stroke onset and admission (continuous), history of ischaemic stroke, intracranial haemorrhage, hypertension, diabetes, atrial fibrillation (categorical variables) as covariates (known epidemiologic, clinical and therapeutic confounders).

For the analysis of 3 months outcomes, we included intravenous thrombolysis (categorical), endovascular treatment (categorical) and NIHSS on admission (continuous). For recurrent stroke and ICH at follow-up premorbid mRS was omitted as they are clinically unlikely to influence the outcome. However, TOAST aetiology (categorical) was included for the analysis of recurrent stroke at follow-up because stroke aetiology influences recurrence risk. We calculated adjusted odds ratios (aOR) or adjusted β-coefficients with corresponding 95% confidence intervals (95% CI). The significance level was set at 0.05 and p-values were two-tailed. Results were not corrected for multiple testing. As to our pre-defined statistical analysis plan, we excluded patients with missing data items from the multivariable analysis. As a post-hoc sensitivity analysis, we repeated the analyses after performing 85 repetitions of multiple imputation of missing variables included in the regression analysis using the STATA ‘mi impute chained’ and ‘mi estimate’ commands. The number of imputations needed for reliable results was calculated as described by von Hippel 12 to be at least 81.

Furthermore, in another post-hoc analysis, we performed the regression analysis of stroke severity and 3-months outcomes in the subgroup of patients on dual antiplatelet therapy. Therefore, we subdivided the original APT group into patients on single and dual antiplatelet therapy and compared each of the groups with the group without prior antithrombotic treatment.

All statistical analyses were performed using STATA (StataCorp. 2019. Stata Statistical Software: Release 16. College Station, TX: StataCorp LLC.).

Results

Of 55,741 patients with imaging-proven ischaemic stroke enrolled in the SSR, 152 patients were excluded because of age <18 and 2237 patients because of missing information on prior APT. Thus, the final study population consisted of 53,352 patients (Figure 1). Mean age was 72.4 years (SD ± 13.7), 42.5% were female, 18.8% had a history of ischaemic stroke, 6.2% had a history of transient ischaemic attack, median NIHSS was 3 (IQR 1–8), 32.4% received acute revascularization treatment (intravenous thrombolysis (16.5%), endovascular treatment (8.3%) or both (7.5%), see Table 1).

Figure 1.

Figure 1.

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Flow diagram of the study population.

ICH: intracerebral haemorrhage; mRS: modified Rankin scale; N: number of patients; NIHSS: National Institutes of Health Stroke Scale.

Table 1.

Baseline characteristics according to pre-stroke antithrombotic treatment.

Characteristic All
 No ATT
 APT
 AC
 APT + AC
 p
N = 53,352 N = 27,484 (51.5%) N = 17,760 (33.3%) N = 7039 (13.2%) N = 1069 (2.0%)
Age (years; mean ± SD) 72.4 ± 13.7 68.6 ± 14.8 75.7 ± 11.1 78.1 ± 10.7 75.2 ± 10.5 <0.001
Sex (female) 22,650 (42.5%) 12,152 (44.3%) 6980 (39.3%) 3196 (45.5%) 322 (30.1%) <0.001
BMI (kg/m2; median (p25, p75)) 25.4 (23.0, 28.4) 25.4 (22.9, 28.3) 25.5 (23.1, 28.4) 25.3 (22.9, 28.4) 25.8 (23.3, 29.0) 0.009
History of stroke (yes) 9794 (18.8%) 1862 (7.0%) 5372 (31.0%) 2154 (31.3%) 406 (39.0%) <0.001
History of TIA (yes) 3211 (6.2%) 648 (2.4%) 1835 (10.6%) 588 (8.6%) 140 (13.5%) <0.001
History of ICH (yes) 965 (1.9%) 474 (1.8%) 347 (2.0%) 130 (1.9%) 14 (1.3%) 0.19
History of hypertension (yes) 38,644 (74.2%) 17,254 (64.4%) 14,774 (85.2%) 5695 (82.7%) 921 (88.3%) <0.001
History of diabetes (yes) 11,348 (21.8%) 4166 (15.5%) 5156 (29.8%) 1671 (24.3%) 355 (34.0%) <0.001
History of smoking (yes) 10,750 (20.7%) 6083 (22.8%) 3568 (20.7%) 871 (12.7%) 228 (22.0%) <0.001
History of AF (yes) 12,635 (24.3%) 4032 (15.0%) 3165 (18.3%) 4831 (70.1%) 607 (58.2%) <0.001
History of CHD (yes) 9498 (18.3%) 1435 (5.4%) 5853 (33.8%) 1664 (24.2%) 546 (52.5%) <0.001
History of PAD (yes) 2901 (5.6%) 411 (1.5%) 1774 (10.3%) 492 (7.2%) 224 (21.6%) <0.001
Time onset to admission (min; mean ± SD) 635.9 ± 831.9 647.5 ± 834.2 638.7 ± 845.7 594.5 ± 792.2 564.1 ± 788.0 <0.001
Glucose on admission (mmol/l; mean ± SD) 7.2 ± 2.7 7.0 ± 2.6 7.4 ± 2.8 7.2 ± 2.4 7.3 ± 2.6 <0.001
Syst. BP on admission (mmHg; mean ± SD) 156.7 ± 28.0 157.5 ± 28.4 156.9 ± 27.3 154.0 ± 27.4 149.7 ± 28.1 <0.001
Diast. BP on admission (mmHg; mean ± SD) 85.1 ± 17.5 86.7 ± 17.5 83.0 ± 16.9 84.4 ± 18.3 81.7 ± 18.2 <0.001
NIHSS on admission (points; median (p25, p75)) 3.0 (1.0, 8.0) 3.0 (1.0, 8.0) 3.0 (1.0, 8.0) 4.0 (2.0, 11.0) 4.0 (1.0, 9.0) <0.001
Recanalisation treatment <0.001
 Only IVT 8781 (16.5%) 5104 (18.6%) 3255 (18.4%) 375 (5.3%) 47 (4.4%)
 Only EVT 4435 (8.3%) 1943 (7.1%) 1141 (6.4%) 1198 (17.1%) 153 (14.4%)
 IVT and EVT 4013 (7.5%) 2486 (9.1%) 1282 (7.2%) 221 (3.1%) 24 (2.3%)
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AC: anticoagulation; AF: atrial fibrillation; APT: antiplatelet therapy; ATT: antithrombotic therapy; BMI: body-mass-index; BP: blood pressure; CHD: coronary heart disease; diast.: diastolic; EVT: endovascular treatment; ICH: intracerebral haemorrhage; IVT: intravenous thrombolysis; N: number of patients; NIHSS: National Institutes of Health Stroke Scale; p25: 25th percentile (first quartile); p75: 75th percentile (third quartile); PAD: peripheral artery disease; SD: standard deviation; syst.: systolic; TIA: transient ischaemic attack.

Of the study population, 27,484 patients (51.5%) had no previous antithrombotic treatment, 17,760 patients (33.3%) were on APT (of those 78.6% were on aspirin, 12.5% on clopidogrel, 8.6% (n = 1534) on dual antiplatelet therapy (mostly aspirin + clopidogrel or ticagrelor); <0.3% were on prasugrel, ticagrelor or dipyridamole), 7039 patients (13.2%) had prior AC (of those 65.2% were on direct oral anticoagulation and 34.8% on vitamin K antagonists) and 1069 patients (2.0%) were on both, APT and AC (67 patients (0.1%) were treated according to the COMPASS regimen 13 (aspirin and rivaroxaban; no atrial fibrillation, but coronary heart disease or peripheral artery disease), 7380 patients (13.8%) potentially eligible for this regimen).

In the subgroup of patients with a history of ischaemic stroke or transient ischaemic attack (n = 11,948), 2401 patients (20.1%) had no prior antithrombotic therapy, 6594 patients (55.2%) were on APT, 2489 patients (20.8%) on AC and 464 patients (3.9%) on both, APT and AC. The baseline characteristics of this subgroup are summarised in Supplemental Table 1.

The distribution of prior antithrombotic treatment per year during the study period is displayed in Figure 2 (a – upper panel: all patients with ischaemic stroke, b – lower panel: patients with a history of ischaemic stroke or transient ischaemic attack).

Figure 2.

Figure 2.

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Antithrombotic therapy by case year in the overall population (a) and in patients with history of acute ischaemic stroke (AIS) or transient ischaemic attack (TIA) (b).

AC: anticoagulation; APT: antiplatelet therapy.

Over the study period, the proportion of patients on anticoagulation increases (5%) and APT decreases by approximately the same proportion (5%–6%), while the other categories remain relatively constant (p < 0.001 for trend). In the subgroup of patients with a history of ischaemic stroke and transient ischaemic attack, this effect is even more accentuated (p < 0.001 for trend).

Aetiology

Information on aetiology was available for 51,728 patients (97%). Among patients with ischaemic stroke despite prior APT, aetiology was due to large artery atherosclerosis in 3416 (19.8%), cardiac embolism in 4059 (23.6%), small vessel disease in 2011 (11.7%), other causes in 1267 (7.4%), more than one cause in 1078 (6.3%) and unknown causes in 5388 (31.3%). The aetiologies (modified TOAST classification) according to different antithrombotic pre-treatments are shown in Figure 3.

Figure 3.

Figure 3.

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Stroke aetiologies (modified TOAST) according to pre-stroke antithrombotic treatment.

AC: anticoagulation; APT: antiplatelet therapy; ATT: antithrombotic treatment; PFO: patent foramen ovale.

Stroke severity on admission

Information on admission NIHSS was available for 52,883 patients (99%). Prior antithrombotic treatment was independently associated with lower admission severity. For prior APT median NIHSS was 0.31 points lower (β = −0.31; 95% CI −0.47 to −0.15; p < 0.001), for prior AC 0.81 points lower (β = −0.81; 95% CI −1.05 to −0.58; p < 0.001) and for prior APT + AC 1.10 points lower (β = −1.10; 95% CI −1.61 to −0.59; p < 0.001) compared to patients without any prior antithrombotic treatment (Table 2).

Table 2.

Regression analysis of stroke severity and follow-up outcomes according to pre-stroke antithrombotic therapy in overall study cohort and in the subpopulation with a history of ischaemic stroke or transient ischaemic attack.

Characteristic No ATT APT p AC p APT + AC p N
Stroke severity at admission ref. β (95% CI) β (95% CI) β (95% CI)
NIHSS at admission a 1.00 −0.31 (−0.47 to −0.15) <0.001 −0.81 (−1.05 to −0.58) <0.001 −1.10 (−1.61 to −0.59) <0.001 34,483
n = 18,096 n = 11,187 n = 4574 n = 626
 History of AIS/TIA 1.00 −0.74 (−1.11 to −0.37) <0.001 −1.12 (−1.59 to −0.66) <0.001 −1.20 (−1.99 to −0.41) 0.003 7892
n = 1568 n = 4334 n = 1693 n = 297
3 month follow-up outcomes ref. aOR (95% CI) aOR (95% CI) aOR (95% CI)
Functional outcome (mRS > 3) b 1.00 1.06 (0.98–1.14) 0.135 1.28 (1.15–1.42) <0.001 1.40 (1.11–1.75) 0.003 28,464
n = 14,912 n = 9226 n = 3808 n = 518
 History of AIS/TIA 1.00 0.90 (0.75–1.07) 0.239 1.01 (0.81–1.26) 0.939 1.15 (0.81–1.63) 0.447 6424
n = 1217 n = 3562 n = 1399 n = 246
Recurrent ischaemic stroke c 1.00 1.26 (1.11–1.44) <0.001 1.54 (1.29–1.83) <0.001 1.09 (0.75–1.59) 0.650 29,503
n = 15,616 n = 9554 n = 3790 n = 543
 History of AIS/TIA 1.00 1.01 (0.79–1.30) 0.923 1.23 (0.91–1.66) 0.186 0.89 (0.53–1.51) 0.673 6671
n = 1250 n = 3749 n = 1404 n = 268
ICH d 1.00 1.27 (1.05–1.53) 0.013 0.98 (0.74–1.29) 0.867 0.79 (0.40–1.58) 0.512 29,640
n = 15,689 n = 9629 n = 3784 n = 538
 History of AIS/TIA 1.00 1.09 (0.67–1.77) 0.718 1.14 (0.63–2.03) 0.670 0.59 (0.17–2.03) 0.402 6698
n = 1247 n = 3777 n = 1410 n = 264
Deathe 1.00 1.10 (0.99–1.21) 0.059 1.60 (1.41–1.80) <0.001 1.69 (1.29–2.21) <0.001 28,524
n = 14,939 n = 9252 n = 3814 n = 519
 History of AIS/TIA 1.00 0.71 (0.57–0.88) 0.002 0.99 (0.77–1.27) 0.940 0.89 (0.57–1.39) 0.620 6442
n = 1218 n = 3577 n = 1401 n = 246
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AC: anticoagulation; AIS: acute ischaemic stroke; aOR: adjusted odds ratio; APT: antiplatelet therapy; ATT: antithrombotic therapy; ICH: intracerebral haemorrhage; mRS: modified Rankin scale; N: number of patients; NIHSS: National Institutes of Health Stroke Scale; ref.: reference; TIA: transient ischaemic attack; 95% CI: 95% confidence interval.

Adjusted beta-coefficients and odds ratios of outcome events in the respective antithrombotic therapy group as compared to no antithrombotic therapy (reference beta coefficient/odds ratio of 1.00). Comparisons of stroke severities were calculated using a quantile regression model, the comparisons of the 3-months follow-up outcomes using binomial logistic regression models. The analyses were adjusted for the following covariates.

Covariates included in all analyses: age (continuous), sex (categorical), serum glucose on admission (continuous), systolic blood pressure on admission (continuous), time between stroke onset and admission (continuous), history of ischaemic stroke, intracranial haemorrhage, hypertension, diabetes, atrial fibrillation (categorical variables).

Additional covariates for each analysis:

a

Premorbid mRS (ordinal).

b,e

Premorbid mRS (ordinal), intravenous thrombolysis (categorical), endovascular treatment (categorical), NIHSS on admission (continuous).

c

Intravenous thrombolysis (categorical), endovascular treatment (categorical), NIHSS on admission (continuous), modified TOAST aetiology (categorical).

d

Intravenous thrombolysis (categorical), endovascular treatment (categorical), NIHSS on admission (continuous).

In the subgroup of patients with a history of ischaemic stroke or transient ischaemic attack, we observed the same associations (APT: β = −0.74; 95% CI −1.11 to −0.37; p < 0.001; AC: β = −1.12; 95% CI −1.59 to −0.66; p < 0.001; APT + AC: β = −1.20; 95% CI −1.99 to −0.41; p = 0.003; Table 2).

Functional outcome at 3-months

Information on functional outcome at 3 months was available for 41,297 patients (77%). The median mRS was 2 (IQR 0–3) for the entire cohort; the median mRS was 1 (IQR 0–3) for patients without prior antithrombotic therapy, 2 (IQR 1–4) for patients on prior APT, 3 (IQR 1–5) for patients on prior AC and 2 (IQR 1–4) for patients on prior APT + AC. Overall, 14,682 patients (35.6%) had unfavourable outcome (mRS 3–6); 6101 patients (28.8%) among those had no prior antithrombotic therapy, 5380 patients (39.3%) were on prior APT, 2810 patients (50.6%) were on prior AC and 391 patients (47.1%) were on prior APT + AC.

There was no statistically significant association between unfavourable functional outcome at 3-months and prior APT compared to no antithrombotic therapy (aOR 1.06; 95% CI 0.98–1.14; p = 0.135). However, prior AC and APT + AC was associated with increased odds for unfavourable outcome (AC: aOR 1.28; 95% CI 1.15–1.42; p < 0.001; APT + AC: aOR 1.40; 95% CI 1.11–1.75; p = 0.003; Table 2).

Among patients with a history of ischaemic stroke or transient ischaemic attack, overall 3912 patients (42.2%) had an unfavourable outcome. Six hundred eighty-eight patients (38.7%) had no prior antithrombotic pre-treatment, 2060 patients (40.0%) were on prior APT, 1001 patients (50.7%) were on prior AC and 163 patients (44.4%) were on prior APT + AC. In multivariate analysis in this subgroup, there was no association between prior antithrombotic therapy and unfavourable outcome (Table 2).

Recurrent ischaemic stroke, intracerebral haemorrhage and death at 3-months

Information on recurrent stroke was available in 38,865 patients (73%), for intracerebral haemorrhage in 38,936 (73%) and on mortality in 41,744 patients (78%).

Overall, 2045 patients (5.3%) had recurrent ischaemic stroke at 3 months; 863 patients (4.3%) among those had no prior antithrombotic pre-treatment, 766 patients (6.0%) were on prior APT, 361 patients (7.3%) were on prior AC and 55 patients (7.2%) were on prior APT + AC. In multivariate analysis, prior APT (aOR 1.26; 95% CI 1.11–1.44; p < 0.001) and prior AC (aOR 1.54; 95% CI 1.26–1.83; p < 0.001) were associated with increased odds for recurrent stroke (Table 2). Among patients with a history of ischaemic stroke or transient ischaemic attack, overall 704 patients (8.1%) suffered recurrent stroke. Among those 130 patients (7.9%) had no prior antithrombotic treatment, 382 patients (7.8%) were on prior APT, 160 patients (9.0%) were on prior AC and 32 patients (9.1%) were on prior APT + AC. In multivariate analysis, we did not observe any significant association between prior antithrombotic treatment and risk of recurrent stroke in this subgroup (Table 2).

Overall, 839 patients (2.2%) had intracerebral haemorrhage at 3 months; 400 patients (2.0%) among those had no prior antithrombotic pre-treatment, 316 patients (2.4%) were on prior APT, 110 patients (2.2%) were on prior AC and 13 patients (1.7%) were on prior APT + AC. In multivariate analysis, prior APT (aOR 1.27; 95% CI 1.05–1.53; p = 0.013), but not prior AC (aOR 0.98; 95% CI 0.74–1.29; p = 0.867) was associated with increased odds for intracerebral haemorrhage. Among patients with a history of ischaemic stroke or transient ischaemic attack, overall 179 patients (2.1%) had intracerebral haemorrhage. Among those, 32 patients (2.0%) had no prior antithrombotic treatment, 104 patients (2.1%) were on prior APT, 39 patients (2.2%) were on prior AC and 4 patients (1.2%) were on prior APT + AC. After adjusting for confounders, we did not find any association between prior antithrombotic therapy and intracerebral haemorrhage at follow-up (Table 2).

Overall, at 3 months 5865 patients (14.0%) died; 2316 patients (10.8%) among those without prior antithrombotic therapy, 2032 patients (14.6%) among those on prior APT, 1333 patients (23.8%) among those on prior AC and 184 patients (21.8%) among those on prior APT + AC. In multivariate analysis, there was a statistically significant association between death and prior AC (aOR 1.60; 95% CI 1.41–1.80; p < 0.001) and prior APT + AC (aOR 1.69; 95% CI 1.29–2.21; p < 0.001) but not with prior APT (aOR 1.10; 95% CI 0.99–1.21; p = 0.059). Among patients with a history of ischaemic stroke or transient ischaemic attack, 1486 patients (16.0%) died; 309 patients (17.4%) among those had no prior antithrombotic treatment, 708 patients (13.7%) were on prior APT, 412 patients (20.8%) were on prior AC and 57 patients (15.5%) were on prior APT + AC. In multivariate analysis, we found a significant association between prior APT and decreased odds for death (aOR 0.71; 95% CI 0.57–0.88; p = 0.002; Table 2).

Sensitivity analysis via multiple imputation models

The results of the sensitivity analysis using multiple imputation of missing variables are consistent with the main analysis (Supplemental Table 2). Only in the analysis of functional outcome, the association between prior APT and unfavourable functional outcome now reached the level of significance (aOR 1.06; 95% CI 1.00–1.11; p = 0.041; Supplemental Table 2).

Post-hoc analysis of stroke severity and 3-months outcomes in patients on dual antiplatelet therapy

The results of the regression analyses are summarised in Supplemental Table 3. While the recurrence rate in the overall population is significantly elevated in both single and dual APT, in the subgroup of patients with a history of ischaemic stroke or transient ischaemic attack the odds are only elevated in patients treated with dual APT (aOR 1.76; 95% CI 1.18–2.61; p < 0.001).

Discussion

This large national stroke-registry based study yielded the following key findings: (1) A third of all incident ischaemic strokes are breakthrough strokes despite prior APT. (2) Among patients with a history of ischaemic stroke or transient ischaemic attack, one out of five patients did not have any antithrombotic therapy at the time of stroke recurrence. (3) Aetiology of ischaemic stroke despite prior APT was heterogeneous covering the entire spectrum of stroke aetiologies according to (modified) TOAST criteria. (4) At 3 months, ischaemic stroke despite prior APT was associated with increased odds for recurrent ischaemic stroke and intracerebral haemorrhage, but there was no association with unfavourable functional outcome or death.

Taken together, our study refines and expands our knowledge on breakthrough ischaemic strokes despite APT. The percentage of patients with ischaemic stroke despite APT in our national stroke registry-based study aligns with previous studies worldwide ranging between 16% and 50% from small single centre or multi-centre studies including a few 100 up to over 90,000 patients.5,14–21 However, the vast majority of these studies had been conducted in the early 2000 up to 2015 and only one study reported patients from 2018 but included only 200 patients. Therefore, our study provides the most up-to date information on the prevalence of prior APT in patients with incident ischaemic stroke in the setting of modern antithrombotic therapy including the availability of novel agents (i.e. ticagrelor, prasugrel) and secondary prevention strategies (e.g. dual antiplatelet therapy). Therefore, the observed differences are probably related to the studies being performed in different health care settings (US, Europe, Asia) and time-periods.

The finding that every fifth patient with a history of ischaemic stroke or transient ischaemic attack did not take any antithrombotic therapy at the time of recurrent stroke is alarming as these strokes might have been prevented. The percentage of patients with a history of ischaemic stroke or transient ischaemic attack without any antithrombotic treatment in our study is comparable to other studies, that is, a US Get-with-the-Guidelines multi-centre study (14.2% only previous stroke) 22 or a smaller study from China (34%). 23

Moreover, this is the largest study to report detailed information on aetiology of breakthrough strokes despite APT. While a meta-analysis including nine studies presented a pooled number of 5739 patients, 24 our study enrolled more than 17,000 patients on prior APT. Our study revealed that the aetiology of breakthrough strokes despite APT is heterogeneous and includes the entire spectrum of stroke aetiologies. Most importantly, about one-fourth of these strokes were found to be due to cardiac-embolism. Although APT has some effect in patients with atrial fibrillation 25 to prevent stroke, the optimal preventive treatment remains oral anticoagulation. 26 Furthermore, our study found that only one-third of ischaemic strokes despite APT are due to atherosclerotic disease (either large artery or small vessel disease) indicating potential treatment failure of APT while a large proportion of strokes was due to other determined or unknown causes. In theory, reasons for breakthrough stroke despite APT may include a variety of reasons beyond cardio-embolic and arteriosclerotic disease including conditions unlikely to respond to APT (e.g. endocarditis, vasculitis). Other possible factors are compliance and medication errors (drug interactions, non-label dosage). Especially adherence, 27 antiplatelet resistance28–30 and high on-treatment platelet reactivity 31 have been reported to be of great importance in breakthrough strokes despite APT.

Our data provide evidence that patients on prior APT show decreased NIHSS on admission compared to no prior antithrombotic therapy, which is in line with some smaller studies (174 of 260 patients on APT 32 and 401 of 1862 patients on aspirin 33 ) and a multicentre stroke register analysis amongst 10,433 patients (of these 1914 patients were on aspirin). 14

In contrast to our study, in other analyses (260 patients, 32 1862 patients, 33 5700 patients, 15 10,433 patients 14 ) APT was associated with better functional outcome (mRS) at discharge14,32 or at 3 months.15,33 Whereas some studies showed an unfavourable outcome at 3 months of patients on APT (234 patients 18 ) or no difference regardless of antithrombotic therapy (433 patients, 34 2048 patients 35 ). Besides the significantly larger cohort, the percentage of patients on prior APT was significantly higher in our study (except for one small study 32 ) and different studies defined outcomes differently (favourable mRS 0–1,32,33 favourable mRS 0–2,15,18,34 mRS absolute values 14 ). Finally, one US Get-with-the-Guidelines multi-centre registry with more than half a million patients found a favourable functional outcome (mRS 0–1) in patients on prior antithrombotic therapies (APT and AC) compared to no antithrombotic pre-treatment, but this was assessed at hospital discharge and not at 3 months as in our study. 22

Furthermore, one study compared the incidents of recurrent stroke and/or death at 3 or 12 months respectively, in a post hoc analysis of the NINDS rt-PA and TOAST study cohorts (1275 and 624 patients respectively) and found no difference between patients with and without prior APT. 36 Another two studies found no difference in the mortality rates at 3 months (234 patients) 18 or 12 months (4275 patients) in patients with APT compared to no antithrombotic therapy as well. While one older study found a lower 4-week mortality with prior aspirin use. 20

In our study, the odds for stroke recurrence at 3-months were higher in patients on prior APT (and AC). However, this effect was not significant in the subgroup of patients with a history of ischaemic stroke or transient ischaemic attack.

It is conceivable that the higher recurrence risk in the overall APT population might reflect a higher overall vascular risk profile compared to patients specifically with a history of ischaemic stroke or transient ischaemic attack. In addition, while in the overall population the odds for death were higher (except for APT), in those with a history of ischaemic stroke or transient ischaemic attack they were not. In fact, in patients on APT, the odds were slightly lower, in favour of a ‘protective’ effect.

These results should be taken with caution because firstly, the correction for co-variables should have controlled a portion of the differences. Secondly, the sample size of the subgroup of patients with a history of ischaemic stroke or transient ischaemic attack is relatively small compared to the effect size we would expect (and that have seen in the overall cohort). Furthermore, the proportions of patients without prior antithrombotic treatment and prior APT differ in the overall study cohort and in the subgroup (see Table 2), therefore, there is a possibility that the analysis for this subgroup might be underpowered.

The optimal therapy for breakthrough stroke despite APT is unknown. As demonstrated by our study, about one-fourth of these patients have cardio-embolic strokes and these patients should receive oral anticoagulation therapy for secondary prevention. Moreover, there was a trend towards an increased proportion of patients on anticoagulation between 2014 and 2022 that may be attributed to an increasingly extensive search for and detection of atrial fibrillation. 37

For the remaining three-fourths, there is persistent uncertainty about optimal treatment, despite available data from several studies and one meta-analysis indicating that the addition of or a switch to another APT might lower the probability of future ischaemic vascular events.38–40 Most importantly, this data originates from a period before pivotal trials on dual antiplatelet therapy and the combination of aspirin and low-dose rivaroxaban. 13 In our study only a fraction of patients were treated according to the COMPASS regimen, however, the percentage of possibly eligible patients was significantly higher (over 10%) and there might be potential in reducing cardiovascular risk in our cohort. In particular, ischaemic strokes despite APT had the highest proportion of large artery atherosclerosis aetiology (and thus probably the highest atherosclerotic burden). Therefore, these patients might be particularly interesting for therapy according to the COMPASS regimen at discharge. Finally, it is to be seen whether other add-on antithrombotic (e.g. factor XI inhibitors)41,42 and anti-inflammatory therapies (e.g. colchicine) 43 can convey additional benefits.

Our study has several limitations. First, despite the prospectively collected data, this is a retrospective analysis that introduces a certain degree of bias. Second, this is a hospital based cohort including only patients treated at certified stroke units and stroke centres. Therefore, patients treated outside this setting are not included. However, the vast majority of stroke patients in Switzerland is treated at one of these certified centres. Third, there are limitations introduced through the available variables in the SSR. Therefore, there is unfortunately no granular data on discharge medication, on change of stroke aetiology at recurrent stoke, on medication adherence and the follow-up period is fixed (3 months). Finally, the analyses in the subgroup of patients with a history of ischaemic stroke or transient ischaemic attack might be underpowered considering the expected odds ratios.

The strengths of our study are the large study sample size, prospective data collection, the availability of TOAST classification and long-term follow-up data beyond hospital discharge. Furthermore, we provide sensitivity analyses through multiple imputation models that underline the robustness of our data. Finally, our study included regional stroke units, large non-academic stroke centres and university hospitals advocating generalisability of our findings.

In conclusion, this large multi-centre study using data from a prospective national stroke registry demonstrated the important frequency of breakthrough ischaemic strokes despite APT and their clinical relevance. Most importantly, one out of five patients with a history of ischaemic stroke or transient ischaemic attack was not taking any antithrombotic therapy at the time of stroke recurrence. Furthermore, those patients with stroke despite APT were at increased risk of recurrent stroke at 3 months advocating for novel prevention strategies, which may combine patient education and novel antithrombotic treatments.

Supplemental Material

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Acknowledgments

The authors thank the patients who participated in the study.

Footnotes

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AAT reported consultant and/or speaker fees from Mitsubishi Tanabe Pharma, Medtronic, AstraZeneca and Schwabe Pharma outside the submitted work. MK received research grants from the Swiss National Science Foundation (NR 182267; NR 204977; NR 198783), the Swiss Heart Foundation; the USZ-Foundation and has received nonfinancial support from B.R.A.H.M.S. Thermofisher Scientific as well as ROCHE Diagnostics, none related to this study. MK has served on the advisory board of Medtronic, Astra Zeneca, BMS/Pfizer and Bayer. MB reported consultant fees from Astra Zeneca and Sandoz outside the submitted work. TRM reported grants from Bangerter Rhyner Foundation, Swiss Heart Foundation and Swiss National Science Foundation outside the submitted work. DJS reported grants from Bangerter Rhyner Foundation and Swiss Heart Foundation outside the study; personal fees from Bayer, Alexion and VarmX outside the submitted work. No other disclosures/conflicts of interest were reported.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical approval: The project was approved by both the local ethics (KEK Bern 2022-01465) and the SSR steering committees and complies with the Declaration of Helsinki.

Informed consent: Enrolment in the SSR is mandatory by Swiss law for the purpose of quality control. Patients are informed about the use of their data for research purposes. In accordance with Swiss law, patients refusing the use of their data for research, were excluded from the study.

Guarantor: DJS.

Contributorship: NS, TRM, DJS were involved in conceiving the study, protocol development, gaining ethical approval. NS and DJS conducted the literature research. All authors were involved in data acquisition. NS and DJS conducted analysis and interpretation of data. NS and DJS wrote the first draft of the manuscript. All authors revised the manuscript for important intellectual content and approved the final version of the manuscript.

Supplemental material: Supplemental material for this article is available online.

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Supplementary Materials

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Supplemental material, sj-docx-1-eso-10.1177_23969873231174942 for Ischaemic stroke despite antiplatelet therapy: Causes and outcomes by Norbert Silimon, Boudewijn Drop, Leander Clénin, Krassen Nedeltchev, Timo Kahles, Alexander A Tarnutzer, Mira Katan, Leo Bonati, Stephan Salmen, Sylvan Albert, Alexander Salerno, Emmanuel Carrera, Christian Berger, Nils Peters, Friedrich Medlin, Carlo Cereda, Manuel Bolognese, Georg Kägi, Susanne Renaud, Julien Niederhauser, Christophe Bonvin, Michael Schärer, Marie-Luise Mono, Andreas Luft, Biljana Rodic-Tatic, Urs Fischer, Simon Jung, Marcel Arnold, Thomas Meinel and David Seiffge in European Stroke Journal

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Supplemental material, sj-pdf-2-eso-10.1177_23969873231174942 for Ischaemic stroke despite antiplatelet therapy: Causes and outcomes by Norbert Silimon, Boudewijn Drop, Leander Clénin, Krassen Nedeltchev, Timo Kahles, Alexander A Tarnutzer, Mira Katan, Leo Bonati, Stephan Salmen, Sylvan Albert, Alexander Salerno, Emmanuel Carrera, Christian Berger, Nils Peters, Friedrich Medlin, Carlo Cereda, Manuel Bolognese, Georg Kägi, Susanne Renaud, Julien Niederhauser, Christophe Bonvin, Michael Schärer, Marie-Luise Mono, Andreas Luft, Biljana Rodic-Tatic, Urs Fischer, Simon Jung, Marcel Arnold, Thomas Meinel and David Seiffge in European Stroke Journal

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