Implementation of a Structured Guideline–Based Program for the Secondary Prevention of Ischemic Stroke in China
Background and Purpose—High rates of ischemic stroke and poor adherence to secondary prevention measures are observed in the Chinese population.
Methods—We used a national, multicenter, cluster-randomized controlled trial in which 47 hospitals were randomized to either a structured care program group (n=23) or a usual care group (n=24). The structured care program consisted of a specialist-administered, guideline-recommended pharmaceutical treatment and a lifestyle modification algorithm associated with written and Internet-accessed educational material for patients for the secondary prevention of ischemic stroke. The primary efficacy outcome was the proportion of patients who adhered to the recommended measures at 12-month postdischarge. This trial is registered with ClinicalTrial.gov (NCT00664846).
Results—At 12 months, 1287 (72.1%) patients in the Standard Medical Management in Secondary Prevention of Ischemic Stroke in China (SMART) group and 1430 (72%) patients in the usual care group had completed the 12-month follow-up (P=0.342). Compared with the usual care group, those in the SMART group showed higher adherence to statins (56% versus 33%; P=0.006) but no difference in adherence to antiplatelet (81% versus 75%; P=0.088), antihypertensive (67% versus 69%; P=0.661), or diabetes mellitus drugs (73% versus 67%; P=0.297). No significant difference in the composite end point (new-onset ischemic stroke, hemorrhagic stroke, acute coronary syndrome, and all-cause death) was observed (3.56% versus 3.59%; P=0.921).
Conclusions—The implementation of a program to improve adherence to secondary ischemic stroke prevention efforts in China is feasible, but these programs had only a limited impact on adherence and no impact on 1-year outcomes. Further development of a structured program to reduce vascular events after stroke is needed.
Stroke, a global health problem, is ranked third as a cause of disability-adjusted life-years (DALYs) according to the study of global burden of disease 2010 (GBD 2010).1 In developing countries, premature loss of life and stroke-related disability are a heavy burden with increasing economic and social costs.2 In China, the government has identified stroke as a high priority for both primary and secondary prevention and has supported the organization and publication of several national stroke guidelines to improve standards of care; however, these efforts have had an unclear impact on patient outcomes.3–5
Many studies have shown major evidence-practice gaps, including a decline in the adherence of patients to treatments after discharge from the hospital.6 A variety of structured programs, such as the Get With the Guidelines (GWTG) stroke program in the United States,7 have been shown to improve the quality of in-hospital stroke treatment. Long-term adherence to treatments is critical to ensure that secondary ischemic stroke prevention measures are maximally effective. A similar program must be implemented to improve the quality of secondary stroke prevention after hospital discharge. A cluster-randomized, guideline-based, structured care program, known as the Standard Medical Management in Secondary Prevention of Ischemic Stroke in China (SMART) study, was performed to assess the feasibility and effectiveness of structured care management and treatment to prevent recurrent ischemic stroke in China.
Methods and Patients
The details of the rationale and design of the SMART study have been published elsewhere.8 SMART was a national, multicenter, cluster-randomized controlled trial to assess the effectiveness of a guideline-based structured care program for secondary stroke prevention, as opposed to usual care, in China. For the trial, the following inclusion criteria were used: patients >18 years old; proven stroke because of cerebral infarction (according to standard clinical criteria with supporting brain imaging, either computer tomography or MRI), or transient ischemic attack; hospitalization within 30 days after the index event; clinical stability; and previous independence in their daily activities, as indicated by scores of 0 to 3 on the modified Rankin scale. The following exclusion criteria were used: radiological evidence of intracerebral hemorrhage; clear cause of stroke or transient ischemic attack unrelated to atherosclerosis (eg, cervical artery dissection or perivascular procedural stroke), although strokes resulting from cardioemboli were included; severe comorbid illness or unstable medical condition (eg, congestive cardiac failure, respiratory failure, renal failure, severe liver dysfunction, or malignancy with a likelihood of death within 2 years); significant memory or behavioral disorders requiring daily care; concurrent participation in another clinical trial; and pregnancy.
We obtained written informed consent from the participants or their legal surrogates. The study was approved by the central ethics committee at the principal study center at Peking Union Medical College Hospital and the ethics committees at the participating study sites.
We invited 48 hospitals (n=42 level-3 hospitals and n=6 level-2 hospitals) to participate in the study. The hospitals were stratified based on their size (level-2 hospitals had ≥100 inpatient beds providing acute medical care and preventative care services to populations of ≈100 000; level-3 hospitals were major tertiary referral centers in provincial capitals and major cities and location (by province). The hospitals were randomized to either the SMART program or the usual care group using a simple cluster method. However, 1 hospital (level 3) withdrew from the study before it began, leaving 23 hospitals (level-3 hospitals, n=20; level-2 hospitals, n=3) in the SMART group and 24 hospitals (level-3 hospitals, n=21; level-2 hospitals, n=3) in the usual treatment group.
All patients were evaluated and followed up by neurologists. The SMART program comprised a combination of interventions, consistent with the current guidelines for the secondary prevention of ischemic stroke: pharmaceutical treatment targeted toward specific pathological subtypes, according to Trial ORG10172 in the Acute Stroke Treatment (TOAST) criteria (ie, large-artery atherosclerosis, small-vessel occlusion, cardioembolism, stroke of other determined pathogenesis, and stroke of undetermined pathogenesis);9 lifestyle modification; and patient education (Appendix I in the online-only Data Supplement). We discussed lifestyle modification with the patients, including smoking cessation, healthy diet, and regular exercise. Patient education included an interactive education session emphasizing the importance of adhering to the SMART program: that is, accessing a unique password-protected website that outlined aspects of the prevention of ischemic stroke and using materials discussing risk-factor control through medication and lifestyle changes. The usual care group received only those interventions chosen by their attending neurologist-clinician, without the use of the algorithm or interactive education and access to the educational website. After the initial central training in the study procedures, the key responsible clinician researchers at each participating hospital were required to register each eligible patient and record their essential demographic and clinical details on special study case record forms. We collected data at baseline and on follow-up dates. We performed site monitoring to assess the clinicians’ adherence to the SMART program and review the quality of the data by examining the source medical records.
Assessment of Outcomes
The primary efficacy outcome was the proportion of the patients who adhered to the secondary ischemic stroke prevention measures according to the recommendations of the SMART program. The secondary outcome was the composite of new-onset ischemic stroke, new-onset hemorrhagic stroke, acute coronary syndrome, and all-cause death. We recorded serious adverse events during follow-up, regardless of whether the local investigator considered the adverse effects related to the treatment (definite, uncertain, or no causality), and we reported all pertinent information to the data monitoring committee.
The sample size estimation was 1771 patients per group, based on a 10% increase in the use of antiplatelet therapy in the SMART group versus a control usual care rate of 76%, assuming a 5% Type I error and a 2% allowance for variation using a 2-sided test. However, we estimated that a total of 4074 patients would be required for the study, assuming an overall dropout rate of 15% in each group.
We compared the baseline patient characteristics of the randomized groups using the t test or χ2 test, as appropriate. We calculated the adherence to each of the recommended measures for the hospital discharge and 12-month outcomes. To evaluate adherence, each measure for which a patient was eligible constituted an observation; the outcome was dichotomized as 1 (measure met) or 0 (measure not met) to indicate whether the recommended treatment was fulfilled. The percentage of adherence to each measure was defined as the total number of measures performed divided by the total number of eligible patients. To investigate the overall associations of the SMART group and the adherence to measures, a generalized estimating equations linear regression model was used to account for the interdependence of members from same center. Times to event outcomes were analyzed using Cox proportional hazards models, including the SMART program as a factor and with adjustments for covariates.
A standard value of P<0.05 was considered statistically significant. We performed all data analyses using SAS version 9.2 (SAS Institute Inc, Cary, NC).
Between April 1, 2008, and December 31, 2010, a total of 3821 patients were assigned to receive either care through the SMART program or usual care at 1 of the 47 participating hospitals. The baseline demographic and clinical characteristics demonstrated that the patients in the SMART group were slightly older (62±11 versus 60±12 years; P=0.004), had worse neurological impairments (ie, higher National Institutes of Health Stroke Scale [NIHSS] scores, 4.9±4.5 versus 4.3±4.3; P=0.001), were more likely to have a history of hypercholesterolemia (17% versus 14%; P=0.04), and were less likely to smoke (30% versus 34%; P=0.002) than the patients who received usual care (Table 1). After adjusting for age and NIHSS score, no significant difference in the proportion of medication use prescribed at discharge was observed between the 2 groups (Table 2).
Adherence to Secondary Stroke Prevention Measures
The levels of adherence to measures (antiplatelet, antihypertensive, and antidiabetic medications, and statin and warfarin use) for the secondary prevention of ischemic stroke were calculated at 6 (Table 3) and 12 months (Table 4) after the index ischemic stroke event. A significant difference in adherence to statin use between the 2 groups was observed at 12 months (SMART group: 56% versus usual treatment group: 33%; P=0.006), although there were no significant differences in adherence to other measures between the 2 groups: antiplatelet drug use (SMART group: 81% versus usual treatment group: 75%; P=0.088), antihypertensive drug use (SMART group: 67% versus usual treatment group: 69%; P=0.661), and antidiabetic drug use (SMART group: 73% versus usual treatment group: 67%; P=0.297). Of 1791 patients, the educational website recorded 1624 entries from the SMART group during the study or 0.91 per patient per annum.
There was no significant decrease in the secondary end point (new-onset ischemic stroke, intracranial hemorrhage, acute coronary syndrome, and all-cause death) in the SMART group compared with the usual care group (3.50% versus 3.59%; P=0.921; Table 5).
This pragmatic, nationwide, multicenter, cluster-randomized controlled trial presents updated information and recommends adherence to medical treatments for the prevention of secondary ischemic stroke using a program of guideline-based structured care and patient education in China. Compared with usual care, our specially designed SMART program increased patient adherence to the medical regimen of statins, although not to antiplatelet drugs, antihypertensive drugs, antidiabetic drugs, or warfarin for the treatment of cardioembolic stroke, during a 12-month follow-up period. There was no difference between the groups in the composite vascular end point of ischemic stroke, new-onset hemorrhagic stroke, acute coronary syndrome, and all-cause mortality.
Despite strong evidence supporting therapies and multiple guidelines for their use, high-risk patients often discontinue prescribed therapies after discharge from the hospital. The current status of secondary stroke prevention in China is not satisfactory. A recent study on the secondary prevention of ischemic stroke in urban China (ChinaQUEST) revealed that the use of antiplatelet drugs and lipid-lowering therapy substantially declined after hospital discharge.10 These findings indicate that physicians and patients should focus more attention on improving the quality of secondary stroke prevention after hospital discharge, which is crucial for prevention outcomes. Concerted efforts have been made to improve acute stroke management in various countries and districts. The GWTG-Stroke program has been associated with increased adherence to all 7 prespecified performance measures for in-hospital acute stroke care.7 A recent positive evaluation of the GWTG-Stroke program in Taiwan suggested that such initiatives are applicable outside the United States to improve the quality of stroke care.11 We suggest that similar programs for secondary stroke prevention be performed worldwide.
For patients with noncardioembolic ischemic stroke, antiplatelet agents are recommended to reduce the high risk of recurrent stroke and other cadiovascular events.12 Although these drugs are easy to use, inexpensive, and well tolerated, adherence to antiplatelet drugs is not optimal, as anticipated. The ChinaQUEST study demonstrated that antiplatelet use declined from 81% at the time of hospital discharge to 66% at 12 months poststroke.7 In contrast to antihypertensive therapy, in which blood pressure is monitored to achieve a treatment target, the effects of antiplatelet drugs are not visible, and patients might doubt the effectiveness of the treatment when recurrent ischemic events occur or worry about the risk of bleeding. Thus, patient education may be more critical than previously recognized to ensure good adherence to antiplatelet therapy.
In the present study, we demonstrated that patients with hypertension and those with diabetes mellitus exhibit consistent levels of adherence to antihypertensive and antidiabetic drugs. The randomized groups showed a minimal difference in use during 12 months, and this good adherence to antihypertensive drugs is consistent with the findings of a previous study.7 This adherence to medications might in part reflect the high level of awareness about the importance of hypertension as a major risk factor for stroke.13 In addition, the well-developed Chinese Hypertension Prevention and Treatment Guidelines3 and various medical and educational activities have contributed to increased public awareness of hypertension and diabetes mellitus.
In the present study, adherence to warfarin was only 28% in the SMART group and 29% in the usual care group 12 months poststroke. These figures are consistent with those obtained in a registry study in Taiwan, in which anticoagulant treatment (warfarin) was used by only 28% of patients with atrial fibrillation at the time of hospital discharge,11 and a recent German study, in which only 31% of patients with atrial fibrillation used anticoagulants.14 The main reason for the poor adherence to anticoagulant treatment is the inconvenience and complexities of regular monitoring. Strategies to improve adherence to anticoagulant treatment in China might include physician and patient education and easy access to facilities that provide international normalized ratio monitoring.
There is now strong evidence that the use of statins in the secondary prevention of ischemic stroke is beneficial.15,16 Although statin use was significantly higher in the SMART group than in the usual care group and statin use in the SMART group at 12 months after discharge was much higher than that observed in the ChinaQUEST study (56% versus 17%),10 the use of these drugs remains substantially lower than that in developed countries; statin use of 74% was observed in the Swedish Prescribed Drug Register at 12 months after stroke.6 This result indicated that patient education is effective in substantially increasing statin use in secondary ischemic stroke prevention; thus, these efforts should be strengthened in the future.
There were no significant differences in medication adherence (except statin use) and cardiovascular events compared with usual care. Several factors might account for the negative results. The primary reasons are likely the short follow-up time and small sample. Difference between SMART-based care and usual care might be more evident after long-term implementation in a larger population. In addition, the SMART program improved adherence to only 1 of the 5 drugs assessed. Improving adherence to the intervention is the first step toward reducing the likelihood of a recurring stroke. Achieving the treatment target may be the next important step. Moreover, most of the participating hospitals were large and located in urban areas (eg, level-3 hospitals), where physicians have the resources to provide high levels of medical care, potentially increasing adherence to guidelines. Although the physicians at the usual care facilities were not familiar with the SMART program, they may improve their practice through continuous medical education gained via experience. The improvement of their practice in this manner would underestimate the power of the SMART program and potentially yield negative results for the comparison of the SMART program with usual care.
With increasing use of the Internet and social media, Internet-based education likely plays an increasingly important role in medical care. However, the percentage of individuals with Internet access is only 2% among people >60 years old (which comprises the majority of patients with stroke), according to a survey performed by the China Internet Network Information Center (CNNIC) in 2009.17 Other strategies include educating caregivers to provide support and using mobile phone text messaging to send information and reminders for scheduling appointments, adhering to a medical regimen, and monitoring patient health status.
SMART is a nationwide, multicenter, cluster-randomized controlled trial that provides valuable information on the current status of secondary ischemic prevention. The results of the present study demonstrate that the SMART program is feasible and can improve adherence to statins. The results obtained from this study might provide valuable information for modifying strategies to further improve the quality of secondary stroke prevention.
The present study has several limitations. First, the drop-off rate was high, reflecting the current status of secondary stroke prevention. Patients and physicians typically pay more attention to in-hospital treatment during the acute phase of the illness than to long-term prevention after hospital discharge. Improvements to the SMART program may be necessary to reduce the observed drop-off rate, including methods for offsite follow-up such as regular telephone or text communication. Second, most stroke patients in China are treated in small, below-level-2 hospitals with limited high-quality medical resources; therefore, SMART should enroll more small hospitals to assess the effectiveness of the program. Third, there is an imbalance in the baseline characteristics, which likely reflects the cluster-randomized nature of the trial. A generalized estimating equations linear regression model was used to account for the interdependence of members from same center, and the analysis was adjusted for these imbalance characteristics. Finally, in addition to adherence to pharmacological interventions, adherence to various behavioral factors (eg, smoking cessation, healthy diet, and regular exercise) should be considered because these factors contribute to the prevention of cardiovascular events.
In conclusion, the implementation of a program to improve adherence to secondary ischemic stroke prevention efforts in China is feasible, but the current implementation had only a limited impact on adherence and no impact on 1-year outcomes. Further development of a structured program to reduce vascular events after stroke is needed.
We thank the Standard Medical Management in Secondary Prevention of Ischemic Stroke in China (SMART) investigators and centers (Appendix II in the online-only Data Supplement) for their participation in this trial. We thank all of the patients who participated in SMART study.
Sources of Funding
This study was funded by the National Key Technology Research and Development Program in the 11th 5-year plan of China.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.113.001424/-/DC1.
- Received March 10, 2013.
- Accepted November 18, 2013.
- © 2014 American Heart Association, Inc.
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