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From the Stroke Center and Department of Neurology (B.O., J.L.S.), UCLA School of Medicine, Los Angeles, CA; Division of Biostatistics and Epidemiology (H.B.), Weill Medical College of Cornell University, New York, NY; Department of Biostatistics (L.E.C.), School of Public Health, the University of North Carolina at Chapel Hill; Department of Neurology (A.N.), Washington University School of Medicine, St. Louis, MO; Department of Neurology (J.M.), McGill University, Montreal, Canada; and the Departments of Neurology (J.F.T.) and Medicine (Endocrinology/ Metabolism) (J.R.C.), Wake Forest University School of Medicine, Winston-Salem, NC.
Address correspondence and reprint requests to Dr. Bruce Ovbiagele, Stroke Center and Department of Neurology, University of California at Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095; e-mail: Ovibes{at}mednet.ucla.edu
| Abstract. |
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Methods: The authors abstracted data from the Vitamin Intervention for Stroke Prevention (VISP) study database from the United States and Canada to incorporate into algorithms for initiating statin therapy according to the National Cholesterol Education Program (NCEP) guidelines for high-risk individuals. The authors applied these algorithms to all study subjects. Univariate as well as multivariate associations for target lipid levels and statin implementation were then evaluated utilizing pertinent demographic, clinical, and laboratory data.
Results: Of 2,894 subjects in the analysis dataset, 38% were women; 71% were recruited in the United States and 29% in Canada. Of 769 high-risk subjects, 262 (34%) had a low-density lipoprotein (LDL) level
130 mg/dL and 124 of these (47%) were not on statin. Among those high-risk persons on statin treatment, only 42% had an LDL
100 mg/dL. Subjects in the overall cohort were more likely to be on a statin if they were treated in the United States or had a history of hypertension or coronary artery disease.
Conclusions: Approximately one out of three guideline-eligible high vascular risk ischemic stroke patients in this study had low-density lipoprotein cholesterol concentrations above qualifying levels for pharmacologic therapy, but half of these patients were not taking a statin, and of those receiving statin treatment, less than half were within recommended lipid goals.
The Vitamin Intervention for Stroke Prevention (VISP) trial was a multicenter, double-blind, randomized controlled clinical trial performed at centers across the United States (n = 45) and Canada (n = 10) designed to determine whether best medical therapy and a multivitamin containing high-dose folic acid, pyridoxine, and cobalamin given to lower total homocysteine levels would reduce the incidence of recurrent cerebral infarction in patients with a nondisabling cerebral infarction.6
In this study, we aimed to 1) evaluate the percent utilization of statin treatment among the subset of ATP-eligible high vascular risk individuals who had experienced a recent stroke and the change in utilization over the course of the VISP study; 2) determine the proportion of such high-risk individuals with a recent stroke whose lipid levels were within the target range recommended by national guidelines; and 3) describe lipid profiles among all individuals with a recent ischemic stroke and to identify factors associated with statin utilization in them.
| Methods. |
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We evaluated the achievement of target lipid goals and statin utilization in the VISP cohort at baseline enrollment, to define their determinants in patients with ischemic stroke. Algorithms for initiating statin therapy in high-risk individuals were those defined by the ATP II guidelines that were in effect for most of the VISP study enrollment period. For the VISP cohort, the ATP II indicator conditions for high risk were the presence of coronary artery disease or history of carotid endarterectomy or other obstructive vascular disease. To examine hypothetical treatment rates and lipid level targets for the VISP population under the 2001 ATP III guidelines (which were only partly in effect during the study period), criteria for initiating statin therapy in high-risk individuals were those defined by that panel.2 ATP III differed from ATP II principally due to expansion of the highest risk group for whom treatment should be initiated at a low-density lipoprotein (LDL) cholesterol above 130 mg/dL with a target of <100 mg/dL. This included the addition of patients with diabetes and those whose 10-year absolute coronary artery disease (CAD) risk exceeded 20% according to the Framingham Coronary Artery Disease Risk Model.79
To calculate absolute 10-year CAD risk in the patients free of vascular disease or diabetes in the VISP cohort, we collected the following data corresponding to the CAD risk factors in the Framingham profile: age; sex; systolic blood pressure and blood pressure treatment; total cholesterol; high-density lipoprotein (HDL) cholesterol; use of antihypertensive therapy; and current cigarette smoking. These factors were used to arrive at each individuals absolute CHD risk using the ATP III Coronary Heart Disease Risk Assessment Calculator tool.10
For each patient meeting a clinical condition indication under ATP II, and ATP III, we assessed LDL cholesterol concentrations at baseline, and applied thresholds for therapy initiation that had been specified in the various panel guidelines. We calculated LDL cholesterol using Friedewalds formula because this method has been used in clinical trials documenting the benefits of cholesterol-lowering therapy and is recommended by the ATP.11
We compared actual treatment rates and target lipid levels achieved in the VISP cohort to those specified under the governing national guidelines of the time (ATP II) and under the ATP III guidelines. Subjects were excluded if they did not have a complete lipid panel (n = 382), had missing lipid lowering agent data (n = 179), had triglycerides >400 mg/dL, or if the relative difference between the recorded LDL and that estimated for the individual using the Friedewald formula based on the total cholesterol, triglyceride, and HDL cholesterol exceeded 5% (n = 120). After these exclusions, the final sample size was n = 2,894. We also collected data on statin use at baseline, 6, 12, and 24 months.
Statistical analysis.
Various demographic and clinical factors were compared between patients at high risk and those not at high risk according to ATP II. Significance was assessed between these two independent groups using a standard
2 test for categorical variables and a t test for continuous variables.
Univariate and multivariate associations were examined to identify significant predictors of lipid levels above target ATP II goals in high-risk subgroup, as well as the frequency of statin use in the overall VISP cohort. For multivariable association, we established the logistic regression models using all the prognostic factors chosen a priori as explanatory variables regardless of their statistical significance and model predictability, and the individual association was summarized in terms of OR with all other risk factors adjusted.
We also assessed the prevalence of statin use over the entire study period. The trend over time was tested using the Cochran-Armitage statistic.12
A determination was then made of the proportion of high vascular risk patients at baseline who were within target LDL-C range, and who were receiving statin treatment according to treatment initiation goals as specified by the various ATP guidelines. For all tests for univariate associations, the standard
2 test was used. Two sided hypotheses are assumed for statistical testing and inference.
| Results. |
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Low-density lipoprotein cholesterol concentrations above the ATP II treatment initiation level.
The ATP II guidelines specified an LDL cholesterol of 130 mg/dL as a level that should trigger initiation of therapy in high-risk patients. For the VISP cohort 262/769 high-risk patients had LDL cholesterol
130. Characteristics of patients that led them to exceed this threshold are outlined in table 2. Multivariate predictors of LDL-C
130 mg/dL were younger age (for example, those above the median age had 60% of the adjusted odds of exceeding the initiation level as those below the median age), no history of CAD, no history of diabetes, and not being on statin treatment. Of 262 high-risk subjects (United States + Canada) who had an LDL level
130 mg/dL, 47% were not on statin therapy.
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Low-density lipoprotein cholesterol concentrations above the ATP II target goal.
The ATP-II guidelines identified an LDL-C
100 mg/dL as a goal for high-risk patients. A total of 278/769 (36%) high-risk VISP subjects met this goal at the time of baseline enrollment, while 491 patients had LDL cholesterol that exceeded 100 mg/dL. Characteristics of these patients are outlined in table 3. Multivariate predictors of LDL-C >100 mg/dL were no history of CAD, hypertension, and diabetes, as well as not being on statin treatment. A total of 228 subjects with LDL cholesterol over 100 mg/dL were not taking a statin. Of all those patients on statin treatment (n = 453), 42% had LDL <100 mg/dL.
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Comparison of the application of various ATP guidelines to VISP high-risk subjects. Table 4 shows the proportion of VISP high-risk subjects in the United States and Canada with baseline LDL-C concentrations above target and treatment initiation goals according to the ATP II and ATP III guidelines (published during the course of the study), and their relationship to statin use. There was a significant difference in statin utilization between both countries among these high-risk persons with LDL-C concentrations above target lipid goals. There also appeared to be a decrease in adherence to the more expansive ATP III target treatment initiation goals and lipid levels compared to ATP II in the United States.
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Statin utilization profiles. Table 5 describes the predictors of being on a statin among subjects in the overall VISP cohort in univariate and multivariate regression models. For the multivariate analysis, non-black race, treatment in the United States, history of coronary artery disease, and history of hypertension remained significantly associated with being on a statin prescription.
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Table E-1 (on the Neurology Web site at www.neurology.org) displays percent statin utilization rates over the period of the VISP study, revealing an increase in statin use from baseline enrollment (46%) to 24-month study completion (58%) in the United States, and 36% to 52% in Canada, demonstrating significant increases with p < 0.001. There was also a significant increase in statin use following the issuance of the 2001 ATP III guidelines as evidenced by a comparison of 12-month and 24-month visits done throughout the study (table E-2).
| Discussion. |
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Perhaps even more worrisome was that almost half of the high vascular risk subjects were not prescribed a statin even though they had LDL-C concentrations above the ATP target for treatment initiation. When we applied the more aggressive LDL-C target goals recommended in the more recent ATP III guidelines, we found an even higher rate of potential undertreatment among high-risk persons, as expected.
With widening indications for statins, as per recent Food and Drug Administration labeling to include individuals with any evidence of cerebrovascular disease, and more recent studies suggesting that pretreatment with statins may result in lesser stroke severity,18 and better functional outcomes after a stroke,19 we evaluated the correlates of treatment with statins among ischemic stroke survivors regardless of ATP-defined risk status. As was shown, CAD patients tended to receive statin treatment more often, and statin therapy was more prevalent in the United States than in Canada.
One possible reason for the underutilization of lipid treatment in ischemic stroke survivors may be decades of prior research which have yielded inconsistent results regarding the role of cholesterol in ischemic stroke,2022 and this may have generally fostered a reluctance on the part of clinicians to take the treatment of lipid levels in patients with ischemic stroke very seriously. The more recent ATP III guidelines suggest an expanded role for the use of statins in preventing coronary events among ischemic stroke survivors because in addition to those with known CAD, it recommends aggressive lipid lowering treatment for those with indicator conditions such as diabetes, and other CAD risk equivalents.2 Indeed, we noted a significant increase over the course of the VISP study period particularly around the time the ATP III guidelines were issued, suggesting perhaps some penetration of guideline recommendations among caregivers, albeit clearly insufficient. However, the potential for further expansion may exist, since only patients with cerebral ischemia due to symptomatic carotid artery disease are regarded as harboring a CAD risk equivalent, and not those with atherosclerotic disease in the aortic arch, the vertebral arteries, the basilar artery, the middle cerebral arteries, and intracranial branch atheromatosis.23 The results of the SPARCL study will shed further light on the role of lipid-lowering and statin therapy in patients with ischemic stroke without known CAD.24
The implementation of vascular protection strategies as a whole among patients with stroke has been variable and suboptimal.2528 It is not uncommon to find that among health care professionals attending to patients with stroke, the focus is primarily on secondary stroke prevention. It is true that shortly after an ischemic stroke the highest vascular risk is for another stroke,29 however, patients with stroke are at a greater long-term risk of death due to recurrent cardiac events (which make up 40% of deaths over 5 years of follow-up) than recurrent stroke.30 Aggressive management of risk factors, like cholesterol, could have a significant and positive impact on the natural history of atherosclerotic cardiovascular disease.
With heightened recognition of vascular risk factors, recent clinical trial evidence, and updated national guidelines, there is likely to be a gradual trend toward an increase in the statin eligible patients with stroke. As such, the issue of underdiagnosis and undertreatment of high vascular risk individuals may be compounded. It would appear that a number of directed quality improvement interventions are needed to improve the quality of cholesterol management in patients with CVD. Alongside the implementation of prompt diet and lifestyle modification, the screening and initiation of treatment with statins before hospital discharge may be a simple and effective intervention with the potential to substantially reduce cardiovascular morbidity and mortality in this vulnerable population. Indeed, the systematic predischarge treatment initiation strategy has been shown to be feasible,31,32 predict longer-term community care,33 and result in improved vascular outcomes.32,34
In this study we directly compared dyslipidemia management in a high-risk population in the United States and Canada. Although it appeared that statin treatment was more prevalent in the United States than Canada, the percent of high-risk patients above the LDL concentration initiation threshold (130 mg/dL) for statin treatment and below the LDL concentration upper goal (= or <100 mg/dL) appeared to be similar in the United States and Canada.
This study has limitations. We used the ATP II guidelines for the major analyses of the VISP cohort because these were the guidelines in place during its study enrollment, and although we performed an analysis applying the current ATP III guidelines to the VISP subjects, it is difficult to predict how VISP-associated physicians or VISP patients would have fared under the newer guidelines. However, if recent stroke studies35,36 showing that fewer than 50% of hospitalized patients with stroke receive a lipid panel are relevant, it would appear unlikely that there has been substantial improvement. Another important consideration is that we do not know if and how many patients might have been offered and declined, started and discontinued, or received inadequate doses of statins,37 in the outpatient setting prior to VISP enrollment. Furthermore, we lack information on potential complications of statin therapy, such as myalgias, that may have limited statin use. We excluded investigation of use of lipid lowering agents other than statins from this study, because most of the landmark lipid lowering trials used statins, recent guidelines focus on statins,5 and statins remain the most effective and best-tolerated drugs for lowering LDL-C. It should also be pointed out that since VISP patients were encountered in a research oriented setting, they were probably better and more aggressively treated than stroke survivors seen in routine medical practice. Finally, in our application of ATP III criteria, we may have underestimated the proportion of high-risk individuals because some individuals identified as low risk by Framingham score were on statins, and the effect of statins on total cholesterol concentration may have led to their misclassification.
In order to reduce the burden of vascular disease, particularly CAD, the diagnosis of dyslipidemia and treatment with therapeutic targets must be improved. Our study suggests that despite the availability of ATP guidelines for the identification and management of high blood cholesterol, appropriate use of ATP therapeutic algorithms remains inadequate. More specifically, statins were underutilized for the secondary prevention of CAD in this at-risk population. This is of concern since patients at high risk for initial or recurrent CHD events constitute the population most likely to benefit from comprehensive risk factor management.
Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the April 25 issue to find the title link for this article.
Editorial, see page 1140
*The VISP Study Investigators are listed in the Appendix on the Neurology Web site at www.neurology.org.
Supported by the National Institute of Neurological Disorders and Stroke grant RO1 NS34447 (J.F.T.).
Disclosure: Bruce Oviagele has received consultancy fees from Bristol-Myers-Squibb. The authors report no conflicts of interest.
Received October 13, 2005. Accepted in final form January 13, 2006.
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