Aspirin for Stroke Prevention in Elderly Patients With Vascular Risk Factors
Japanese Primary Prevention Project
Background and Purpose—The effect of aspirin in primary prevention of stroke is controversial among clinical trials conducted in Western countries, and no data are available for Asian populations with a high risk of intracranial hemorrhage. The objective of this study was to evaluate the effect of aspirin on the risk of stroke and intracranial hemorrhage in the Japanese Primary Prevention Project (JPPP).
Methods—A total of 14 464 patients (age, 60–85 years) with hypertension, dyslipidemia, and diabetes mellitus participated and were randomized into 2 treatment groups: 100 mg of aspirin or no aspirin. The median follow-up period was 5.02 years.
Results—The cumulative rate of fatal or nonfatal stroke was similar for the aspirin (2.068%; 95% confidence interval [CI], 1.750–2.443) and no aspirin (2.299%; 95% CI, 1.963–2.692) groups at 5 years; the estimated hazard ratio was 0.927 (95% CI, 0.741–1.160; P=0.509). Aspirin nonsignificantly reduced the risk of ischemic stroke or transient ischemic attack (hazard ratio, 0.783; 95% CI, 0.606–1.012; P=0.061) and nonsignificantly increased the risk of intracranial hemorrhage (hazard ratio, 1.463; 95% CI; 0.956–2.237; P=0.078). A Cox regression adjusted by the risk factors for all stroke, which were age >70 years, smoking, and diabetes mellitus, supported the above result.
Conclusions—Aspirin did not show any net benefit for the primary prevention of stroke in elderly Japanese patients with risk factors for stroke, whereas age >70 years, smoking, and diabetes mellitus were risk factors for stroke regardless of aspirin treatment.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00225849.
Antiplatelet drugs are used for the secondary prevention of stroke because antiplatelet therapy has been proven to have a larger benefit than risk in this setting.1 For this purpose, aspirin is the most widely used antiplatelet drug worldwide, not only because of low cost but also because of huge experiences, equal efficacy in men and women, young and old patients, and diabetics and nondiabetics with predictive benefit/risk profile, and no dependency on (currently recognized) genetic underpinnings for efficacy.2,3 On the contrary, large clinical trials conducted in Western countries have reported conflicting results regarding the efficacy of aspirin for the primary prevention of stroke,4–7 and no evidence is available regarding the effect of aspirin in Asian populations, which have a higher risk of intracranial hemorrhage (ICH) than white populations.8,9 The Japanese Primary Prevention Project (JPPP) was an investigator-driven, nationwide, multicenter, open-label, randomized, parallel-group trial of aspirin for the primary prevention of vascular events, including stroke that was conducted in 14 464 Japanese patients who were >60 years old and had at least one major vascular risk factor.10 Patients were randomized to receive either 100 mg of aspirin or no aspirin and were followed for ≤6.5 years. The primary outcome was a composite of nonfatal myocardial infarction (MI), nonfatal stroke, and vascular death. The secondary outcomes included individual end points. The last follow-up examination was performed in May 2012, and the median follow-up period was 5.02 years.
JPPP was the first large randomized controlled trial of aspirin in an Asian population, which accounts for >60% of the world’s population, and was thus expected to make a great contribution to public health worldwide. The main results of the JPPP have recently been presented and published.10 Aspirin did not significantly reduce the composite primary outcome. Regarding the secondary outcomes, aspirin significantly reduced nonfatal MI and transient ischemic attack (TIA) but did not reduce nonfatal stroke and significantly increased extracranial hemorrhage.10
The objective of this study was to evaluate the effects of aspirin on ischemic stroke and ICH for the primary prevention of stroke in more detail using an exploratory post hoc analysis of the patients who participated in the JPPP.
The details of the study design have been published previously.11 The JPPP was an investigator-driven, nationwide, multicenter cooperative, randomized, open-label, parallel-group clinical trial. Patients were recruited by their primary care physicians at 1007 clinics across Japan between March 2005 and June 2007. The inclusion and exclusion criteria have been described elsewhere.11 Patients between the ages of 60 and 85 years and who had hypertension, dyslipidemia, and diabetes mellitus were included. All of these risk factors were diagnosed according to Japanese guideline criteria: systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg for hypertension; total cholesterol ≥220 mg/dL, low-density lipoprotein cholesterol ≥140 mg/dL, high-density lipoprotein cholesterol ≤40 mg/dL, or triglyceride ≥150 mg/dL for dyslipidemia; and fasting plasma glucose ≥126 mg/dL, any blood glucose ≥200 mg/dL in the 75-g glucose tolerance test, or hemoglobin A1c ≥6.5% for diabetes mellitus.10 Patients with history of coronary artery disease, cerebrovascular disease, including TIA, atherosclerotic disease requiring surgery or intervention, or atrial fibrillation, were excluded. Patients with history of peptic ulcer or bleeding disorder were also excluded. Furthermore, patients with allergy or hypersensitivity to aspirin and those who were receiving other antiplatelet drugs or anticoagulants were also excluded.
Written informed consent was obtained from all the patients. The study was conducted according to the Declaration of Helsinki and Ethical Guidelines for Clinical Studies and was approved by the institutional review board of each participating center.
After a baseline evaluation, the patients were randomized 1:1 to receive either a 100-mg tablet of enteric-coated aspirin or no aspirin, in addition to any ongoing medication. The randomization was stratified according to the 3 risk factors, and 7 strata were used to account for all possible combinations. The minimization method was applied to balance sex and age within each stratum. Pseudorandom numbers were generated using the Mersenne Twister method with a seed of 4989. The study statistician generated the random allocation sequence using a central computerized system, and study physicians were informed of the treatment assignments via the study website or by fax. At baseline and at each annual study assessment, the following variables were evaluated in the clinic: disease outcomes, adverse events, adherence with treatment, blood pressure, serum lipids, blood glucose, smoking status, and body weight. Follow-up of the last recruited patient was completed in May 2012. Risk factor control was continued throughout the follow-up period according to the Japanese therapeutic guidelines.10,11
The primary outcome was a composite of death from cardiovascular causes (MI, stroke, and other cardiovascular causes), nonfatal stroke (ischemic or hemorrhagic, including undefined cerebrovascular events), and nonfatal MI. Secondary end points were a composite of the same events as the primary end point plus TIA, angina pectoris, and atherosclerotic disease requiring surgery or intervention. Other secondary end points were death from cardiovascular disease, death from noncardiovascular causes, nonfatal stroke (ischemic or hemorrhagic), nonfatal MI, TIA, angina pectoris, atherosclerotic disease requiring surgery or intervention, and serious extracranial hemorrhage requiring transfusion or hospitalization. Study end points were assessed centrally and biannually by an expert, multidisciplinary event adjudication committee that was blinded to the treatment assignments according to the Prospective Randomized Open Blinded End Point (PROBE) trial design.
Apart from the primary and secondary end points described earlier, we evaluated the effects of aspirin on fatal or nonfatal stroke, ischemic stroke plus TIA, ischemic stroke, and ICH using exploratory Cox regression analyses in this stroke substudy. The distribution of time-to-events was estimated using the Kaplan–Meier method in each study group. Intergroup differences in the events were accessed using the stratified log-rank test with stratification for risk factors and a 2-sided significance level of α=0.05. Hazard ratios (HRs) were calculated using the Cox proportional hazards model, and the 95% confidence intervals (CIs) were determined. Adjustments for factors used in the allocation of patients to the study groups were incorporated as needed. We also calculated the risk score for all stroke events using the Cox regression hazard model. Then, we performed a subgroup analysis on the effects of aspirin on risk of stroke and TIA by classifying the patients into high-risk and low-risk groups after scoring each risk factor based on the results of the Cox regression analysis.
The details of cerebrovascular events are shown in Table 2. Fatal or nonfatal strokes occurred in 128 patients in both the aspirin and no aspirin groups. Significantly fewer patients experienced TIA before any stroke in the aspirin group than in the no aspirin group, as has already been reported.10 The cumulative rates of any stroke or TIA in both groups are shown in Figure 1A. No significant difference in the rate of any stroke or TIA at 5 years was observed between the 2 groups (2.068% in the aspirin group and 2.299% in the no aspirin group; adjusted HR, 0.927; 95% CI, 0.741–1.160; P=0.509). Figure 1B shows the cumulative rates of any stroke in both groups. Furthermore, no significant difference in the rate of any stroke at 5 years was observed between the 2 groups (1.809% in the aspirin group and 1.828% in the no aspirin group; adjusted HR, 1.011; 95% CI, 0.791–1.291; P=0.932). Figure 1C shows the cumulative rates of ischemic stroke at 5 years in both groups. Fewer ischemic strokes occurred in the aspirin group than in the no aspirin group, but the difference was not significant (1.199% in the aspirin group and 1.451% in the no aspirin group; adjusted HR, 0.842; 95% CI, 0.631–1.123; P=0.240).
The details of ICH are shown in Table 2. Cerebral hemorrhage occurred more frequently in the aspirin group (28 patients) than in the no aspirin group (15 patients), whereas the rates of subarachnoid hemorrhage (10 and 8 patients, respectively) and subdural hematoma (13 and 12 patients, respectively) were comparable between the 2 groups. The cumulative rate of ICH at 5 years was nonsignificantly higher in the aspirin group than in the no aspirin group (0.748% in the aspirin group and 0.511% in the no aspirin group; adjusted HR, 1.463; 95% CI, 0.956–2.237; P=0.078; Figure 1D).
The factors affecting stroke and TIA were evaluated using a Cox regression analysis in all patients recruited (Table 3). Aspirin was not one of the factors affecting cerebrovascular events. Age ≥70 years, smoking, and diabetes mellitus were independent risk factors for cerebrovascular events. According to the estimated parameters, the risk score was calculated as a total of 2 for age ≥70 years, 1 for smoking, and 1 for diabetes mellitus. A score of 0 or 1 was classified as low risk, and a score of 2 or more was classified as high risk. The cumulative rate of cerebrovascular events at 5 years was not different between the aspirin group and the no aspirin group not only for the low-risk patients (1.154% in the aspirin group and 1.390% in the no aspirin group; HR, 0.839; 95% CI, 0.529–1.330%; P=0.4538), but also for the high-risk patients (2.722% in the aspirin group and 2.961% in the no aspirin group; HR, 0.955; 95% CI, 0.739–1.234; P=0.7246; Figure 2).
Clinical trials in Western countries have reported conflicting results regarding the efficacy of aspirin for primary stroke prevention.4–6 According to a meta-analysis reported by the Antithrombotic Trialists’ Collaboration,7 aspirin did not reduce the risk of stroke for primary prevention because the risk ratio of stroke for aspirin versus a control was 0.95 (95% CI, 0.85–1.06). In this meta-analysis, aspirin nonsignificantly reduced the risk of ischemic stroke (rate ratio for aspirin versus control, 0.86; 95% CI, 0.74–1.00) but nonsignificantly increased the risk of hemorrhagic stroke (rate ratio, 1.32; 95% CI, 1.00–1.75).7 Results of our study were similar to these results. Therefore, the generalization of these results to the Japanese elderly population with risk factors for stroke seems reasonable, and aspirin can be concluded not to reduce the risk of stroke because the nonsignificant reduction of ischemic stroke is offset by the nonsignificant increase in hemorrhagic stroke. The presently ongoing Study to Assess the Efficacy and Safety of Enteric-Coated Acetylsalicylic Acid in Patients at Moderate Risk of Cardiovascular Disease (ARRIVE),12 A Study of Cardiovascular Events in Diabetes (ASCEND),13 Aspirin in Reducing Events in the Elderly (ASPREE),14 and International Standard Randomised Controlled Trial Number (ISRCTN)15 trials, in which the majority of recruited patients are from Western populations, may provide additional information regarding ethnic differences in the efficacy and safety of aspirin for the primary prevention of stroke.
Aspirin should be used for patients in whom a net clinical benefit, which is estimated by the total incidence of major ischemic and hemorrhagic events, can be expected.16–19 The rate of ischemic stroke is higher in Japan than in the United States and is comparable to that in Western Europe, whereas the rate of hemorrhagic stroke is higher than that in the populations of both the United States and Western Europe.8,20,21 Therefore, we suspected that the risk-benefit profile of aspirin for primary stroke prevention might be different between Japanese and Western populations. In reality, the rate of ischemic stroke was lower in the JPPP population than in the Antithrombotic Trialists' Collaboration (ATT) population for primary prevention (0.26%/y versus 1.04%/y), whereas the rate of hemorrhagic stroke was higher in the JPPP population than in the ATT population (0.08%/y versus 0.03%/y).7 However, the results of our subanalysis of stroke in the JPPP were similar to the results of the meta-analysis reported by ATT regarding the net relative benefit for primary stroke prevention.7
The cumulative rate of ICH at 5 years was 0.748% in the aspirin group and 0.511% in the no aspirin group. In JPPP population, the rate of hypertension was high, which was 85%, although the blood pressure was well controlled as a whole because the mean systolic blood pressure was 137 mm Hg and the mean diastolic blood pressure was 78 mm Hg at baseline. According to the results of Hisayama study,22 incidence of cerebral hemorrhage was 1.2/1000 person-year in persons with high normal blood pressure (130–139/85–89 mm Hg). The estimated numbers in 7000 people at 5 years in one group of JPPP are calculated to be 42, which is comparable to 38 in the aspirin group and <23 in the no aspirin group. However, the data in Hisayama study was relatively old because they included 32-year-old data, when the incidence of cerebral hemorrhage was high. In Japan, the incidence of cerebral hemorrhage is gradually declining along with the progress of blood pressure management. According to recent stroke registries in Japan, percentage of hemorrhagic stroke is ≈25% of all strokes, which is still higher than the percentage in Western countries.20–22 In Hisayama study described earlier, the percentage of cerebral hemorrhage was 22% to 30% in people with high normal to grade 1 hypertension.22 In JPPP, the percentage of cerebral hemorrhage was 30% in the aspirin group and 23% in the no aspirin group. Taking together these data into consideration, the rate of ICH in JPPP population seems to be reasonable.
The relatively low rate of ischemic stroke may be attributable to well-controlled risk factors, as demonstrated in the baseline data.11,18 However, despite the sufficient management of risk factors, hemorrhagic stroke was more common in the JPPP population than in the ATT population.7 Among ICH, cerebral hemorrhage was more common in the aspirin group than in the no aspirin group, whereas subarachnoid hemorrhage and subdural hematoma were comparable between the 2 groups. The strongest risk factor for cerebral hemorrhage is widely recognized to be hypertension.19–25 In the Secondary Prevention of Small Subcortical Strokes (SPS3) trial,26 the rate of hemorrhagic stroke was significantly reduced by a systolic blood pressure target of <130 mm Hg, compared with a systolic blood pressure target of 130 to 149 mm Hg in patients receiving aspirin alone or aspirin plus clopidogrel. In the Bleeding With Antithrombotic Therapy (BAT) study,27 which was an observational cohort study in patients receiving antithrombotic drugs for cerebrovascular or cardiovascular diseases, the optimal cutoff blood pressure level to predict ICH was 130/81 mm Hg. Based on these results, the Guidelines of the Japanese Society of Hypertension 2014 recommended a target blood pressure of <130/80 mm Hg for stroke patients receiving antithrombotics.28 Also, in the Japanese Guidelines for the Management of Stroke 2015, a blood pressure <130/80 mm Hg is recommended for patients receiving antithrombotics.29 However, there is no recommendation for blood pressure control in patients receiving antiplatelet drugs for primary stroke prevention because there is no convincing evidence in this population. A stricter control of blood pressure, compared with the conventional blood pressure control level, may be required to reduce the risk of cerebral hemorrhage in patients treated with aspirin for the primary prevention of strokes, especially among populations with a high risk of ICH, such as Japanese or other Asian populations. We plan to perform a blood pressure subanalysis of the JPPP data, which may include a study to analyze the effects of blood pressure levels on ischemic and hemorrhagic events in detail.
A Cox regression analysis to calculate the risk score for all the patients recruited in the JPPP showed that the risk factors for cerebrovascular events were age >70 years, smoking, and diabetes mellitus. Hypertension and dyslipidemia were common in both groups, which might have masked their significance as risk factors. The present results suggest that smoking cessation and the management of diabetes mellitus are important as modifiable risk factors to reduce the residual risk of cerebrovascular events, regardless of treatment with aspirin in elderly Japanese patients with vascular risk factors.
In limitation of this study, this was not a double-blind study but was a PROBE study. We think that there was no problem in selection bias. Because patients who were eligible at screening to meet inclusion but not exclusion criteria were recruited consecutively at each clinic, the study statistician generated random allocation sequence using a central computerized system, and study physicians were informed of treatment assignments via the study website as previously described. Baseline characteristics, which were reported in detail previously, were balanced between the 2 groups for patient demographics and disease risk factors. Additionally, adjudication of end points was performed centrally by an expert committee blinded to treatment assignment.
As described in the main analysis paper of JPPP, we used modified intention-to-treat analysis.10 We stated there in detail what kind of patients were included for this analysis. As for crossover to aspirin, we did not apply rank preserving structural failure time models to assume a difference from the case of 100% adherence. Because accuracy of information on adherence to aspirin was not sufficient to apply the models. Self-reported adherence to study medication at every year is shown in Table I in the online-only Data Supplement.
The number of patients lost to follow-up was 791 in the aspirin group and 753 in the no aspirin group as reported previously.10 It is likely that some strokes occurred among participants lost to follow-up. However, the potential effect of under-ascertainment is likely to be small as discussed previously.10
Dose of aspirin we used was 100 mg in JPPP. One might argue the possibility that other doses could have a different behavior. However, clinical evidence suggested that the magnitude of the benefit of aspirin is similar for doses from 50 to 1500 mg.30 In contrast, toxicity does vary by dose; principal toxicity of aspirin is gastrointestinal hemorrhage, and higher doses of aspirin are associated with greater risk. Therefore, lower doses of aspirin (≤325 mg) are recommended for long-term prevention of vascular events.30
JPPP was a collaborative study mainly not by vascular neurologists but by general physicians, and vascular imaging was not required for the diagnosis of stroke. Therefore, it was difficult to classify atherothrombotic stroke and lacunar stroke. However, there has been no clear evidence for the difference in the efficacy of antiplatelet therapy between atherothrombotic stroke and lacunar stroke to date. In reality, the American Heart Association/American Stroke Association Guidelines for stroke prevention in patients with stroke and TIA recommend antiplatelet therapy in noncardioembolic ischemic stroke, including not only atherothrombotic stroke but also lacunar stroke.30
In conclusion, aspirin did not have any net benefit for the primary prevention of strokes in elderly Japanese patients with risk factors.
This study was presented in part before Late Breaking Science of the International Stroke Conference 2015 on February 12 in Nashville.
We thank Dr Peter Rothwell, Professor of Clinical Neurology, University of Oxford, for helpful advice and criticism in editing the article.
Sources of Funding
JPPP was supported by the funds from the Japanese Ministry of Health, Labor, and Welfare, and the Wacksman Foundation of Japan.
Dr Uchiyama received grant support and personal fees from Bayer, Boehringer Ingelheim, Daiichi Sankyo, Otsuka, and Sanofi Aventis. Dr Ishizuka was a former employee of Sanofi-Aventis and reported no other disclosure. Dr Shimada received personal fees from Bayer, Daiichi Sankyo, Dainihon Sumitomo, MSD, Novartis, Omron, and Takeda. Dr Teramoto received grant support and personal fees from Amgen, Aska, Astellas, Bayer, Daiichi Sankyo, Kissei, Kobayashi, MSD, and Pfizer. DrYamazaki received grant support from AstraZeneka, Daiichi Sankyo, Dainihon Sumitomo, Kowa, Kyowa Hakko Kirin, MSD, Mitsubishi Tanabe, Pfizer, and Takeda and other fees from Astra Zeneka, Daiichi Sankyo, Dainihon Sumitomo, Kowa, Merk sharp & Dohme, Tanabe Mitsubishi, Mochida, Novartis, Sanofi-Aventis, Shionogi, Pfizer, and Takeda. Dr Oikawa received personal fees from Daiichi Sankyo, MSD, Astellas, Mochida, Takeda, Bayer, and Kyowa Hakko Kirin. Dr Murata received personal fees from Daiichi Sankyo, Sanofi-Aventis, and Pfizer. Dr Yokoyama received personal fees from Bayer. Dr Minematsu received grant support from Lundbeck and personal fees from Tanabe Mitsubishi, Kyowa Hakko Kirin, Sanofi-Aventis, Otsuka, Bayer, Astellas, Daiichi Sankyo, Astra Zeneka, Boehringer Ingelheim, Pfizer, Stryker, Medicos Hirata, MSD, and Sawai. Dr Matsumoto received personal fees from Astellas, Eizai, Otsuka, Takeda, Daiichi Sankyo, Novartis, Bayer, Pfizer, BMS, Sanofi-Aventis, Boehringer Ingelheim, Mochida, MSD, and Tsumura. Dr Ikeda received fees for medical advice from Astra Zeneka, Bayer, Daiichi Sankyo, Glaxo Smith Kline, and Sanofi-Aventis. The other authors report no conflicts.
The main paper of the Japanese Primary Prevention Project was presented at the American Heart Association Scientific Sessions, November 2014, Chicago, IL, and simultaneously published in JAMA November 2014. The results of this subanalysis were presented in part at the International Stroke Conference, February 2015, Nashville, TN.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.115.012461/-/DC1.
- Received December 16, 2015.
- Revision received March 16, 2016.
- Accepted March 29, 2016.
- © 2016 American Heart Association, Inc.
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