Introduction

Long-term treatment with cilostazol, a phosphodiesterase 3 inhibitor, coupled with aspirin or clopidogrel was shown to halve the risk of recurrent ischemic stroke and have a similar risk of severe or life-threatening bleeding compared to aspirin or clopidogrel alone in patients at high risk for recurrent noncardioembolic ischemic stroke in a randomized, controlled trial, the Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com) [1]. Cilostazol is known to have a lower risk of bleeding than the other antiplatelet agents [2, 3], and the result of the safety outcome was within the expectations of the trial investigators. In contrast, the strong efficacy of the dual antiplatelet therapy (DAPT) with half the risk of recurrent ischemic stroke exceeded our assumptions to some extent. The possible clinical conditions causing such clear efficacy need clarification.

The post-stroke blood pressure (BP) level is predictive of recurrent stroke risk [4,5,6,7]. Several guidelines recommend intensive BP lowering for chronic stroke to prevent recurrent stroke [8,9,10]. Appropriate risk-factor modification would strengthen the preventive power of antithrombotic pharmacotherapy. Thus, BP control might have affected the main results of CSPS.com.

The primary research objective of the present sub-study was to determine the associations of long-term BP after stroke as a time-dependent covariate with the risk of subsequent ischemic events, including recurrent ischemic stroke, in the CSPS.com cohort. The secondary objective was to clarify the associations of follow-up BP level with the therapeutic superiority of cilostazol-based DAPT to monotherapy

Methods

Study design and setting

CSPS.com was a multicenter, randomized, open-label, parallel-group trial, involving participants from 292 sites across Japan registered from December 2013 through March 2017. The trial protocol, statistical analysis plan, design, and main and major post hoc results of CSPS.com have been reported previously [1, 11,12,13,14,15]. CSPS.com was registered in ClinicalTrials.gov NCT01995370 and the University Hospital Medical Information Network clinical trial registry in Japan UMIN 000012180 and approved by the ethics committee at each participating site. All patients gave written, informed consent before randomization. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.

Participants

Eligible patients were between 20 and 85 years of age who had a non-cardioembolic ischemic stroke identified on magnetic resonance imaging between 8 and 180 days before the start of the protocol treatment and were taking either aspirin or clopidogrel alone as antiplatelet therapy when providing informed consent. The patients were required to meet at least one of the following three criteria indicating a high risk for stroke recurrence: (a) ≥ 50% stenosis of a major intracranial artery; (b) ≥ 50% stenosis of an extracranial artery; and (c) two or more of the following risk factors (age ≥ 65 years, hypertension, diabetes mellitus, chronic kidney disease, peripheral arterial disease, history of ischemic stroke other than the qualifying one for this trial, history of ischemic heart disease, and current smoking). Additional information regarding the inclusion and exclusion criteria is provided elsewhere [1, 11]. For example, patients with emboligenic heart disease were excluded from the study. In this sub-study, patients with consistent BP data at baseline and at least once during the follow-up period were included.

Patients were randomly assigned in a 1:1 ratio to receive either monotherapy with aspirin (81 or 100 mg) or clopidogrel (50 or 75 mg) once daily or dual therapy with cilostazol (100 mg, twice daily, the recommended dose for stroke prevention in Japan) and either aspirin (81 or 100 mg) or clopidogrel (50 or 75 mg), once daily. Trial medication was continued for half a year or longer, for a maximum of 3.5 years. Changes in these three antiplatelet medications were not permitted after informed consent was obtained. Systolic and diastolic BPs (SBP, DBP) were measured in a sitting position at follow-up visits 1, 3, and 6 months later and every 6 months thereafter.

Outcomes

The primary efficacy outcome was the first recurrence of ischemic stroke. The secondary efficacy outcome was the first occurrence of a composite of stroke, myocardial infarction, and vascular death. The safety outcome was the first occurrence of severe or life-threatening bleeding as defined in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries classification [16]. These events have been defined elsewhere [1, 11].

Statistical analysis

Continuous data are reported as medians (interquartile range) or means ± standard deviation, and categorical data are presented as numbers (%). In principle, all BP data were treated as time-dependent covariates. The variables “percent change” and “difference” were derived as the ratio of BP values to baseline BP value and the difference from baseline at each time point, respectively. Note that these variables are still time-dependent covariates.

For example, consider a patient with a baseline BP value of 140 mmHg and follow-up BP values of 150, 140, and 130 mmHg. In the “raw value” analysis, the follow-up values of 150, 140, and 130 mmHg are directly used, with the baseline value of 140 mmHg serving as a fixed (time-independent) adjustment variable. In the “difference” analysis, the changes from the baseline are calculated as 10, 0, and −10 mmHg, respectively. For the “percent change” analysis, the converted values are computed as follows: (150/140)*100, (140/140)*100 and (130/140)*100, yielding percentages of 107%, 100%, and 93% respectively.

A Cox proportional hazards model was used to calculate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of the percent changes, differences, and raw values of BP. For the analysis of raw values, follow-up BP values were treated as time-dependent covariates, while baseline BP value was included as time-independent covariate. HRs are represented as per 10% for percent change and per 10 mmHg for difference and raw value. Multivariable adjustment was performed using sex, age, and variables that were proven to affect the outcomes of CSPS.com, including assigned treatment, antiplatelet agents at randomization, intracranial artery stenosis, and the timing of starting trial treatment [11,12,13,14]. The preventive effect of dual therapy relative to monotherapy on outcomes considering its interaction with BP levels was visualized using a generalized additive model. In brief, the hazard function was estimated through a generalized additive model of Poisson regression, which allows for flexible modeling of complex nonlinear relationships, and calculated aHR and 95% CI values were plotted against BP. All statistical analyses were performed using R version 4.2.0 (R Core Team 2022). Fitting the generalized additive model was done with pammtools and mgcv R packages.

Results

Of the total 1879 randomized patients, 222 were excluded from the present study due to lack of sufficient and consistent data on BP (or unclear description between the timing of events onset and that of follow-up BP measurement), and 1657 were finally studied; 790 were assigned to dual therapy and 867 to monotherapy (Fig. 1). Table 1 shows the patients’ baseline characteristics. Overall, average BP was 139.0 ± 19.7/79.0 ± 13.4 mmHg at baseline and 136.1 ± 12.6/77.0 ± 9.2 mmHg at mean follow-up. The median duration of follow-up was 1.5 years overall (interquartile range 1.0–2.3 years), resulting in 2700.9 person-years of follow-up. Ischemic stroke occurred in 74 patients, the composite of stroke, myocardial infarction, and vascular death occurred in 92 patients, and severe or life-threatening bleeding occurred in 18 patients. All severe or life-threatening bleeding events were symptomatic intracranial hemorrhages. Figure 2 shows BP levels at each visit. The median number of BP measurements per patient was 5 (interquartile range: 4–7).

Fig. 1
figure 1

Trial profile

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Table 1 Patients’ baseline characteristics and blood pressure levels
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Fig. 2
figure 2

Blood pressure at each visit

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Primary outcome of ischemic stroke

Table 2 shows the associations of BP-derived variables with recurrent ischemic stroke. When BP was treated as a time-dependent covariate, the aHR of a 10% SBP increase from baseline was 1.19 (95% CI: 1.03–1.36), and that of a 10 mmHg SBP increase from baseline was 1.14 (1.03–1.28). With the baseline SBP as a fixed (time-independent) covariate, the aHR of SBP was 1.14 (1.00–1.31) per 10 mmHg. On the other hand, no DBP-derived variables showed significant associations with the outcome.

Table 2 Associations of variables derived from blood pressure with outcomes
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Table 3 shows the associations of SBP-derived variables with recurrent ischemic stroke in subgroups by assigned antiplatelet therapy and those by the antiplatelet agent at randomization. Similar numerical data with those in the overall patients were obtained in all subgroups, with significant associations of the percent change and the difference in SBP in the monotherapy subgroup and the clopidogrel subgroup. Note that the event rate was somewhat higher in patients taking clopidogrel (50/973) than those taking aspirin (24/684). The difference was probably because the physicians preferred clopidogrel to aspirin for patients with history of ischemic stroke and those with intra-/extracranial artery stenosis, that showed clearly higher risk of recurrent ischemic stroke [1, 12].

Table 3 Associations of variables derived from systolic blood pressure with ischemic stroke
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Fig. 3A shows the aHR of dual therapy relative to monotherapy plotted against SBP. The estimated aHR curve for the outcome showed the benefit of dual therapy over a wide SBP range from ≈120 mmHg to ≈165 mmHg uniformly, with the greatest risk reduction when SBP was ≈150 mmHg.

Fig. 3
figure 3

Hazard ratio curve of the dual therapy group versus the monotherapy group. A Ischemic stroke, B a composite of stroke, myocardial infarction, and vascular death. Adjusted by sex, age, assigned treatment, antiplatelet agents at randomization, intracranial artery stenosis, and the time of starting trial treatment

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Other outcomes

The aHR for the secondary outcome of composite events of a 10% and a 10 mmHg SBP increase from baseline was 1.18 (1.04–1.34) and 1.15 (1.04–1.26), respectively (Table 2). With the baseline SBP as a fixed covariate, the aHR of SBP was 1.15 (1.01–1.30). No DBP-derived variables showed significant associations with the outcome. The estimated aHR curve for the outcome showed the benefit of dual therapy relative to monotherapy over a wide SBP range from ≈120 mmHg to ≈160 mmHg uniformly (Fig. 3B).

No SBP-derived or DBP-derived variables showed significant associations with the safety outcome of severe or life-threatening bleeding (Table 2).

Discussion

This was a sub-analysis of the randomized CSPS.com trial to determine the effects of follow-up BP parameters as a time-dependent covariate on recurrent stroke risk. The first major finding of this study was that both ischemic stroke and composite cardiovascular events increased significantly as the variables derived from SBP increased, but not as the DBP-derived variables increased. The second major finding was that the benefit of dual therapy was uniformly observed over a wide SBP range, with the greatest risk reduction when SBP was ≈150 mmHg.

Cilostazol inhibits phosphodiesterase activity and suppresses cyclic adenosine monophosphate (cAMP) degradation, increases intracellular cAMP concentrations, activates the cAMP-dependent protein kinase A, and inhibits platelet aggregation [2, 3, 17]. Both cilostazol monotherapy and cilostazol-based long-term DAPT were recommended as the first-line antiplatelet agents for secondary stroke prevention in Japan [10] and several Asian countries based on the results of CSPS2 and CSPS.com [1, 18]. Cilostazol monotherapy was weakly recommended for stroke or transient ischemic attack attributable to moderate to severe intracranial artery stenosis in the United States of America [19]. Cilostazol has pleiotropic effects other than inhibiting platelet aggregation, such as a vasodilatory effect on smooth muscle cells via the increase in intracellular cAMP concentrations [20]. The vasodilation may cause mild BP lowering; a 2 to 4 mmHg lower SBP level was observed during cilostazol-based DAPT than during monotherapy throughout the follow-up period in the overall CSPS.com cohort [1].

Lower percent changes, differences, and raw values of SBP were associated with lower risks of ischemic stroke. This “the lower, the better” phenomenon in stroke survivors was common to the results of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) [4, 7], but different from those of the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study, where the risk was higher for patients with SBP < 120 mmHg [21]. Since patients within 120 days after stroke were enrolled in PRoFESS and those within 5 years were enrolled in PROGRESS, failure of cerebral autoregulation during subacute stroke might have affected the results more in PRoFESS. In addition, the Secondary Prevention of Small Subcortical Strokes (SPS3) and Recurrent Stroke Prevention Clinical Outcome (RESPECT) trials showed a significant risk reduction of intracerebral hemorrhage in patients with a target SBP < 130 mm Hg or < 120 mmHg compared with a higher target but did not show the significant reduction of ischemic stroke [22,23,24]. A reason for the differences in results between these trials and ours is that in our study, SBP was treated as a time-dependent covariate, and our findings were not confined to a specific SBP range, such as around 130 mmHg. Additionally, the discrepancies may be due to the fact that patients’ SBP data were treated consecutively in our study, without grouping patients based on a specific SBP value. Another possible explanation was the higher percentage of patients assigned to dual therapy in the lower mean SBP population, since dual therapy excessively lowered SBP by 2 to 4 mmHg.

In contrast, the DBP-derived variables were not associated with the outcome. The J-shaped relationship between DBP and adverse cardiovascular outcomes including stroke with DBP nadir around 70–80 mmHg has been repeatedly reported [25,26,27,28,29,30]. The J-shaped curve might be due to the positive association of low DBP and evident or subclinical myocardial damage [31] and due to the high frequency of isolated systolic hypertension with an increased pulse pressure in the low DBP cohort [30, 32]. However, the presence of a J-shaped relationship between DBP and the risk of stroke alone was somewhat unclear [25, 26, 31], presumably partly due to differences in mechanisms between cerebral and coronary autoregulation [33].

The benefit of dual therapy was observed over a wide SBP range. This suggests a simple message: the positive results of promising trial treatments can be more clearly identified when the vascular risk factors of the participants are appropriately controlled. Patients with good BP management might also be mindful of their general health condition and modify risk factors other than hypertension, and thus the impact of dual therapy might be clearer in such patients.

Visit-to-visit SBP variability was reported to be firmly associated with stroke outcomes and subsequent events [34,35,36]. Since the number of visits in the present patients was small (median 5), the association between BP variability and outcomes was not examined.

The strength of this study was that BP was treated as a time-dependent covariate and evaluated over time. For example, summarizing a patient’s BP values into a single statistic, e.g., mean BP, and treating it as a time-independent covariate would be equivalent to assuming that the patient’s BP is constant at the mean BP level throughout the follow-up period. However, this may miss the more detailed relationship between BP and events. The present method takes into account the fact that a patient’s BP is not constant and can change during the follow-up period, allowing for a more detailed and relevant assessment.

The limitations of the present study include the post hoc nature of the analysis, meaning that the associations identified might not necessarily imply causality. Severe stroke could cause both subsequent events and higher BP values. Second, visits for BP measurement were not frequent for patients developing events early after enrollment. Third, the present sample size seemed to be small for appropriate subgroup analyses, although numerical results indicated a tendency for a positive association between SBP and subsequent ischemic stroke regardless of assigned antiplatelet therapy and the antiplatelet agent at randomization. Fourth, the number of severe or life-threatening bleeding events (intracranial hemorrhage) was too small to perform meaningful statistical analysis. Hemorrhagic stroke generally shows a stronger association with follow-up BP than ischemic stroke [7, 37, 38].

Perspective of Asia

In Asia, cilostazol is widely used for secondary stroke prevention. DAPT including cilostazol decreased the risk of recurrent ischemic stroke compared to aspirin or clopidogrel monotherapy in patients with lacunar stroke and those with intracranial arterial stenosis [15, 39]; both of these pathologies are common to Asian population. BP lowering after stroke is an optimal strategy to strengthen the power of cilostazol-based DAPT in Asian stroke patients.

Conclusion

The present sub-study renewed our understanding of the importance of intensive BP lowering for secondary stroke prevention and also suggested the necessity of appropriate BP control for success in stroke clinical trials.