1 Division of Preventive Medicine and the Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
2 Department of Biostatistics, Harvard School of Public Health, Boston, MA
Correspondence to Dr. Robert J. Glynn, Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Avenue, Boston, MA 02215 (e-mail: rglynn{at}rics.bwh.harvard.edu).
Received for publication October 7, 2004. Accepted for publication June 7, 2005.
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ABSTRACT |
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arteriosclerosis; cerebrovascular accident; coronary disease; models, statistical; proportional hazards models; risk factors; survival analysis; thromboembolism
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INTRODUCTION |
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Whether factors known to be associated with risk of CHD and total stroke also predict venous thromboembolism (VTE) is controversial. The presence of such associations would suggest testable strategies to prevent VTE (8). Previous prospective studies of cardiovascular risk factors and the occurrence of VTE have varying results. The Nurses' Health Study found obesity, cigarette smoking, and hypertension, but not diabetes or elevated cholesterol, to be independent predictors of pulmonary embolism (9
). In a follow-up of participants in the Heart and Estrogen/progestin Replacement Study (HERS) trial, use of hormone replacement therapy was associated with increased risk of VTE and use of aspirin or statins with reduced risk, but body mass index, blood pressure, smoking, and diabetes had no independent association with risk (10
). The Swedish Study of Men Born in 1913 found only smoking and obesity to be independent risk factors for VTE (11
). A larger prospective study, combining information from the Atherosclerosis Risk in Communities and Cardiovascular Health Studies, found a strong association of higher body mass index with increased risk and an increased risk for those with diabetes, but no association of smoking, hypertension, dyslipidemia, physical inactivity, or alcohol consumption with risk (12
).
Some of the apparent divergence in results is due to small numbers of VTE events in some studies, such that reliable estimates of the associations of multiple risk factors are not possible. Comparisons of relative risk for different endpoints would benefit from approaches that account for competing risks and allow for formal evaluation of differences in associations. We used prospectively collected data on more than 18,000 physicians followed for a median of 20.1 years in the Physicians' Health Study to compare explicitly the relative risks of atherosclerotic and venous thrombotic events associated with established risk factors.
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MATERIALS AND METHODS |
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Exposure and outcome measures
We considered potential risk factors that were measured at baseline and were previously shown to be related to risk of CHD or stroke in this and other populations (15, 16
). Cardiovascular risk factors were determined at baseline by self-report, using mailed questionnaires. Participants reported their height and weight, any history of diabetes, current and former smoking status, hypertension (reported systolic blood pressure
140 mmHg, diastolic blood pressure
90 mmHg, or use of antihypertensive medication), frequency of alcohol consumption, frequency of exercise vigorous enough to work up a sweat (scored 16 for the following categories: rarely/never, 13 times/month, 1 time/week, 24 times/week, 56 times/week, daily), and history of high total cholesterol (reported cholesterol of
240 mg/dl or drug treatment for hypercholesterolemia). Available information supports the validity of these self-reports in physicians (17
).
The primary endpoint for this analysis was a first occurrence of CHD, stroke, or VTE. CHD included confirmed incident myocardial infarction plus death confirmed to be due to CHD (International Classification of Diseases, Ninth Revision, codes 410414). We studied total stroke because that was a primary endpoint of the trial and previous risk prediction models included both hemorrhagic and ischemic stroke (2). VTE was defined as either deep vein thrombosis or pulmonary embolism. All reports of myocardial infarction, coronary death, stroke, and VTE required confirmation through record review by the trial's Endpoints Committee. Each follow-up questionnaire, sent to participants every 6 months for the first year and annually thereafter, inquired about the occurrence of myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism. Those reporting events including next-of-kin of decedents were asked for permission to obtain their medical record.
A diagnosis of myocardial infarction was confirmed if the reported event met the World Health Organization criteria for myocardial infarction, which include symptoms plus either elevations in cardiac enzyme levels or diagnostic changes on the electrocardiogram (18). Silent infarctions were not included because they could not be accurately dated. A diagnosis of stroke was considered confirmed if the patient had a new focal neurologic deficit and if the symptoms and signs persisted for more than 24 hours. Confirmation of stroke required review of medical records and reports of brain imaging. Reported episodes of deep vein thrombosis or pulmonary embolism were evaluated by review of hospital records, death certificates, and autopsy reports. Diagnosis of deep vein thrombosis was confirmed by a positive report of venous ultrasound or venography, whereas diagnosis of pulmonary embolism was considered confirmed in the presence of either a positive angiogram or a ventilation-perfusion scan with two or more mismatched defects. Unprovoked deep vein thrombosis or pulmonary embolism was defined as occurring in the absence of known malignancy (diagnosed either before or up to 3 months after the VTE) or trauma or surgery within 90 days before the VTE. Provoked deep vein thrombosis or pulmonary embolism included events that occurred in patients with cancer or during or shortly after trauma or surgery. Deaths due to CHD, stroke, or pulmonary embolism were confirmed when autopsy reports, symptoms, circumstances of death, and medical history were consistent with this diagnosis. Rates of confirmation for reports of the four outcomes of myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism ranged from 67 percent for myocardial infarction to 73 percent for stroke.
Statistical analysis
This analysis considered the 18,662 participants in the Physicians' Health Study who had no reported VTE before baseline and for whom information on cardiovascular risk factors was complete. For each participant, we calculated the time in years from baseline until the first occurrence of CHD, stroke, or VTE. We considered only the first event because of concern that this event would change both risk factors and the risk of events of other types. Four participants who had a myocardial infarction and a stroke on the same day had both outcomes, and three participants with VTE on the day of their coronary death had these two outcomes. All other subjects had at most one of the three outcomes on the day of first occurrence. In sensitivity analyses, we randomly assigned the four subjects with both events to either CHD or stroke and the three men with both CHD death and VTE on the same day to CHD only (because death certificates suggested that the VTE was secondary to existing CHD). These analyses are not shown in this paper because they produced results similar to those that included the additional seven outcomes. We followed participants without any of these outcomes until they died or reached the end of follow-up on February 21, 2003.
Initial analyses evaluated the association of age with each of the three outcomes. We considered five age groups (4049, 5059, 6069, 7079, and 80 years) and calculated incidence rates; subjects were allowed to contribute time to two or more groups as they aged. Interpretation of Kaplan-Meier curves in the setting of competing risks is problematic, so we used the method of Pepe and Mori (19
) to calculate the conditional probability of each of CHD, stroke, and VTE at each year of age, conditional on remaining free of the alternative outcomes. These conditional probabilities are taken as measures of cumulative incidence.
Because each of the three outcomes had a strong but different association with age, multivariable survival analyses used age as the time scale (20) and stratified on type of outcome. Specifically, the approach described by Lunn and McNeil (21
) that stratifies on event type allows for estimation of the separate associations of each risk factor with the relative hazard of each outcome under a proportional hazards assumption and can be readily implemented in a standard statistical software package for this model through the use of data augmentation.
Data preparation requires that each subject have a separate observation for each outcome. We started with a model that assumes different associations of each covariate with each of the three outcomes. Preliminary analyses suggested that the two continuous covariates and the ordinal exercise variable had reasonably linear associations with the log-hazard of each of the three outcomes. Thus, the initial model yielded estimates of relative hazards for each of 10 potential risk factors on each of three outcomes. Additionally, all models allowed for a specific and nonparametric association of age with each outcome through consideration of age as the time scale and also included indicator variables for each of the randomized treatment assignments. To evaluate the robustness of the standard errors in view of the two outcomes for seven subjects, we applied generalized estimating equations, as described by Lee et al. (22).
We were interested in comparing this model that assumes different associations with each outcome with simpler alternative models to provide evidence on two questions: whether a risk factor had a similar association with CHD and stroke, and whether a cardiovascular risk factor had any influence on the risk of VTE. For both questions, one can use likelihood ratio tests because simpler models that equate effects or set effects to zero are nested within the larger model that assumes different associations of each risk factor with each outcome. For each of the risk factors of interest, we fitted two simpler models, one with the effect of that risk factor equated for CHD and stroke, and another with that risk factor assumed to have no association with VTE. In each of these additional models, effects of risk factors on all other outcomes were allowed to be different so that the additional model differed from the initial model for only one variable. In the case of risk factors characterized by two indicator variables (smoking and alcohol consumption), both variables were equated for CHD and stroke, or eliminated for VTE, and likelihood ratio tests had two degrees of freedom.
One could use a formal stepwise-down procedure to equate similar associations between CHD and stroke and eliminate nonsignificant associations with VTE. However, to limit the amount of significance testing, we compared the fit of a single simplified model suggested by these several one-step models. Specifically, we considered a model that equated all associations between CHD and stroke with p > 0.10 and eliminated all associations with VTE for which p > 0.10. In our example, use of a more strict p value of 0.05 to maintain variables would have produced the same model. We then compared this simpler model with the initial full model by using a likelihood ratio test. We also tested possible interactions between risk factors and randomized treatment assignments by considering a likelihood ratio test that compared the model with only main effects with the model with all two-way interactions with treatments.
We considered potential confounding by birth cohort through stratification on categories of birth year in the proportional hazards model (20). Patterns in Schoenfeld residuals with time were considered to identify possible violations of the proportional hazards assumption (23
). To describe the effects of apparent changes in relative hazards over time, we fitted separate models for time to events in the first 10 years of follow-up and thereafter.
Because of the possibility that effects of risk factors might differ for provoked and unprovoked VTE, we extended this model to allow for separate associations of each risk factor with each of CHD, stroke, unprovoked VTE, and provoked VTE. A likelihood ratio test evaluated the hypothesis that the associations of risk factors were the same for provoked and unprovoked VTE.
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RESULTS |
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Evaluation of the proportional hazards assumption through consideration of Schoenfeld residuals revealed some evidence for violation of this assumption. Consideration of separate models that related baseline covariates to outcomes in the first 10 years and thereafter indicated that hypertension, elevated cholesterol, diabetes, and current smoking had slightly stronger associations with early risk of CHD and stroke (data not shown). This finding may be due to change in these risk factors over time. However, baseline measures of all of these variables continued to have strong associations with risk of these outcomes beyond 10 years. Baseline body mass index and height had similarly strong associations with risk of VTE in early and late follow-up.
To evaluate the possibility that risk factors might have different associations with provoked and unprovoked VTE, we extended the model from table 2 to consider separate associations with these two outcomes in addition to CHD and stroke (table 4). The overall likelihood ratio test of the hypothesis that associations are the same for both types of VTE does not reject this null hypothesis (p = 0.41). The associations of taller height and increased exercise were more pronounced for risk of provoked VTE, but confidence intervals for associations of these variables on unprovoked VTE broadly overlapped those for provoked VTE. In particular, greater body mass index was associated with a substantial increase in risk for both manifestations of VTE. No other cardiovascular risk factors were associated with a substantial increase in risk of either provoked or unprovoked VTE, although power for these subgroup evaluations was limited.
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DISCUSSION |
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Studies of cardiovascular risk in other populations indicate that hypertension has a generally stronger association with risk of stroke versus CHD whereas cholesterol has a generally stronger influence on risk of CHD (1, 2
). Measurement error due to reliance on self-reported risk factors probably diminished our ability to distinguish these associations. However, equating the effects of these and several other cardiovascular risk factors may produce a simpler model with nearly equivalent predictive ability (5
, 7
, 24
). Furthermore, consideration of a composite endpoint can enable a broader evaluation of the potential benefits or risks of an intervention.
Our data on the risk of VTE corroborate the conclusion of others (12) that venous and arterial thrombosis have different etiologies. The estimated relative rates of VTE from our study are in general agreement with those from the large, prospective study of Tsai et al. (12
). As in their study, we found a strong association of greater body mass index with increased risk and no association of hypertension, hypercholesterolemia, smoking, and alcohol consumption. Unlike their study, we did not find that diabetes was associated with increased risk of VTE, but we did find an increased risk associated with more frequent exercise. The increased risk with exercise was particular to provoked VTE; however, it was not anticipated and might be due to chance. We could not find any estimates from other studies on the association of height with risk of VTE. The magnitude and precision of the association of greater height with risk, and the consistency of the association in early and late follow-up, suggest that the observed association cannot be explained by chance. It is possible that taller height exerts a direct effect on risk of VTE, possibly due to venous stasis.
Our study is limited by its reliance on self-reported information on risk factors and by absence of information on some potentially important risk factors. However, available evidence indicates that self-reports agree well with measured values of cardiovascular risk factors in physicians (17). Restriction of the population to physicians also affects the generalizability of results. However, restriction to physicians controls for socioeconomic status and studies a population with excellent follow-up rates and high-quality exposure and outcome information.
Use of methods for competing risk survival analysis offers several advantages to compare the associations of risk factors with possibly related outcomes. Joint modeling of associations with related outcomes allows for explicit comparisons of the associations of a risk factor with these different outcomes. In particular, likelihood ratio tests can evaluate the evidence for the similarity of associations as well as whether a risk factor has any association with a particular component. Simplified models can give a parsimonious description of risk for composite endpoints. Readily available diagnostic tools can evaluate assumptions such as proportional hazards. For example, consideration of Schoenfeld residuals can provide insight into possibly time-varying associations. An alternative approach would consider polytomous logistic regression (7). This alternative modeling strategy would have the advantages of a full-likelihood setting and diagnostic tools such as receiver operating characteristic curves to evaluate discrimination. However, the survival analysis approach offers precise incorporation of censoring times, direct estimation of relevant hazard ratios, and the use of stratification to accommodate heterogeneity such as the very different associations of age with the three outcomes considered here. Both approaches can readily accommodate time-varying covariates using accessible software packages, including SAS (SAS Institute, Inc., Cary, North Carolina), Stata (Stata Corporation, College Station, Texas), and S-PLUS (Insightful Corporation, Seattle, Washington).
Our study produced both methodological and substantive conclusions. Our substantive results contrast the similarities between risk of CHD and stroke with the differences in risk of VTE. Use of competing risk survival analysis provides a clear approach to characterize these similarities and differences.
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ACKNOWLEDGMENTS |
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Conflict of interest: none declared.
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References |
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