Published online before print September 28, 2009, doi: 10.1161/CIRCULATIONAHA.108.846931
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(Circulation. 2009;120:1491-1497.)
© 2009 American Heart Association, Inc.
Epidemiology and Prevention |
Cardiovascular Benefit of Magnitude of Low-Density Lipoprotein Cholesterol Reduction
A Comparison of Subgroups by Age
From the Massachusetts Veterans Epidemiology and Research Information Center (C.R.R.-T., E.V.L., R.E.S., J.M.G.), Boston VA Healthcare System, Boston, Mass; Divisions of Aging, Cardiology, and Preventative Medicine (C.R.R.-T., E.V.L., R.E.S., J.M.G.), Brigham and Women’s Hospital, Boston, Mass; and VeroScience, LLC (R.E.S.), Tiverton, RI.
Correspondence to Catherine Rahilly-Tierney, MD, MPH, 150 S Huntington Ave, MAVERIC-13th Floor, Jamaica Plain, MA 02130. E-mail Catherine.Rahilly{at}va.gov
Received December 23, 2008; accepted July 27, 2009.
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Abstract |
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Background— We examined the effect of the magnitude of low-density lipoprotein cholesterol (LDL-C) reduction across subjects of various ages in a retrospective cohort study.
Methods and Results— We selected 20 132 male veterans at high risk for an acute cardiovascular event and who had 2 or more LDL-C measurements before their first documented acute myocardial infarction, revascularization, death, or censoring date. LDL-C reduction was categorized as no reduction (<10 mg/dL; reference), small reduction (between 10 and 40 mg/dL), moderate reduction (between 40 and 70 mg/dL), or large reduction (
70 mg/dL). The primary outcome was combined acute myocardial infarction or revascularization. The first and last LDL-C levels in the databases were used to calculate the LDL-C reduction in patients who experienced no outcome or who died. Within each age quartile and in a subgroup of patients 80 years of age, a Cox proportional hazards model was used to determine hazard ratios for each category of LDL-C reduction compared with the reference category, with adjustment for age, body mass index, current smoking status, medications, and comorbidities. In all age groups, the magnitude of LDL-C reduction was proportional to the magnitude of cardiovascular risk reduction. Risk reduction for the combined outcome in patients who achieved a large LDL-C reduction was similar in all age quartiles, with multivariate-adjusted hazard ratios of approximately 0.30.
Conclusions— In a cohort of veterans at high risk for cardiovascular events, patients of all ages, including those 80 years or older, benefitted the most from large reductions in LDL-C.
Key Words: aging • lipids • lipoproteins • epidemiology • prevention
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Introduction |
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Observational studies and large clinical trials of hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) have demonstrated that cholesterol reduction achieves cardiovascular benefit.1–5 Meta-analyses of trial data have established a graded relationship between the magnitude of low-density lipoprotein cholesterol (LDL-C) reduction and the magnitude of cardiovascular risk reduction.6–8 A meta-analysis of trials comparing statin therapies of various intensities found that patients treated with more intensive lipid-lowering therapy had a greater risk reduction than those treated with therapy of moderate or low intensity.9
Clinical Perspective on p 1497
Historically, observational studies have suggested that cholesterol is not as strong a predictor of risk in older patients as it is in younger patients.6 Trials of cholesterol lowering included few older patients.1–5,10–16 Investigators who have examined cholesterol-modifying therapy in older patients in trial and observational cohorts have established that such therapy is beneficial.17–19 Moreover, studies have demonstrated that intensive cholesterol-modifying therapy with statins is more effective in older patients than moderate cholesterol-modifying therapy.20 The Study Assessing Goals in the Elderly (SAGE) demonstrated that patients 65 to 85 years of age who were given intensive lipid-lowering therapy compared with moderate therapy experienced greater LDL-C reduction, significantly fewer all-cause deaths, and fewer major cardiovascular events.21
Although studies to date suggest cholesterol lowering is beneficial in older patients, no researchers have examined the effect of the magnitude of LDL-C reduction in older patients. Moreover, no researcher has compared quantitatively the effect of LDL-C reduction in older patients with that seen in younger patients. We sought to determine whether the effect magnitude of LDL-C reduction differed in patients of various ages. We hypothesized that the reduction in cardiovascular risk associated with a small, moderate, or large reduction in LDL-C would be similar across subgroups of various ages.
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Methods |
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Study Population
We conducted a retrospective cohort study using data from the Veteran’s Affairs (VA) National Patient Care Database and regional healthcare databases within the New England Veterans Integrated Service Network (VISN-1). These databases contain detailed clinical information, including diagnoses and pharmacy, procedural, and demographic data, for patients who received medical care in New England’s VA facilities between September 30, 1997, and September 30, 2005. We used International Classification of Diseases version 9 (ICD-9) codes to capture inclusion diagnoses, outcomes, and comorbid conditions. The primary inclusion criterion for entry into the study cohort was at least 1 diagnosis that placed a subject at high risk for acute coronary events. Such diagnoses included diabetes mellitus (ICD-9 codes 250.0 to 250.9), ischemic heart disease (codes 412.0 to 414.9), or peripheral vascular disease (codes 440.0 to 443.0). We limited the sample to male patients with 2 or more LDL-C measurements documented before the date of their first cardiovascular outcome recorded in the databases, including acute myocardial infarction (codes 410.0 to 411.0), coronary artery bypass graft (code 36.1), or percutaneous transluminal angioplasty (code 36.0). We included subjects with no outcome if they had 2 or more LDL-C levels documented before the last date of available laboratory data or the date of their death if they died before September 30, 2005. To select patients likely to achieve a range of LDL-C reduction, we further limited the sample to patients with initial LDL-C levels of
100 mg/dL. Although we did not exclude subjects who changed the location of their care, we only captured subjects with multiple LDL-C levels in our databases, who would thus receive most of their care within the VISN-1. The Figure illustrates the inclusion and exclusion process we engaged in to select the final cohort for the present study.
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For each subject, we calculated the reduction in LDL-C by determining the difference between the first documented LDL-C level (referred to as the initial LDL-C level) and that level closest to but not on or after the date of the first cardiovascular outcome, death, or September 30, 2005 (referred to as the follow-up LDL-C level). LDL-C reduction was then categorized as follows: Patients whose LDL-C reduction was between 10 and 40 mg/dL achieved a "small" reduction, patients whose LDL-C reduction was between 40 and 70 mg/dL achieved a "moderate" reduction, and patients whose LDL-C reduction was 70 mg/dL achieved a "large" reduction. The reference group consisted of patients who achieved an LDL-C reduction <10 mg/dL or who demonstrated an increase in LDL-C between their initial and follow-up levels. Categories of LDL-C reduction were chosen to reflect the spectrum of LDL-C change typical for a population of veterans and because they reflected quantities of LDL-C change that could be meaningful to clinicians. We also extracted information on each subject’s age; body mass index (BMI); current smoking status; cholesterol-modifying therapy; other medications used, including angiotensin-converting enzyme inhibitors, aspirin, and β-blockers; and comorbidities, including renal disease (ICD-9 codes 403.0 to 404.0 and 584.0 to 586.0), thyroid disease (codes 240.0 to 246.0), hypertension (codes 401.1.0 to 405.0), and cerebrovascular disease (codes 430.0 to 438.0). These were examined as potential confounders of the relationship between LDL-C reduction and risk for the outcome. Each of the inclusion diagnoses, which included diabetes mellitus, ischemic heart disease, and peripheral vascular disease, were also examined as potential confounders of the relationship. We could not capture race as a potential confounder of the relation we were examining because this variable was missing at a rate of approximately 60% in the VISN-1 database, as it is in most VA clinical databases.
Statistical Analysis
The primary outcome was combined acute myocardial infarction, percutaneous transluminal angioplasty, or coronary artery bypass graft, whichever occurred first for a subject. We censored patients who had no event but who died before September 30, 2005, on the date of their death. We used proportional hazards analysis to compare each of the 3 categories of LDL-C reduction (small, moderate, and large) with the reference group (no change or increase in LDL-C) and determined hazard ratios (HRs) and 95% confidence intervals (CIs) for the combined outcome of acute myocardial infarction or revascularization. Follow-up for the outcome began on the date of each subject’s "follow-up" LDL-C measurement. We adjusted for age, BMI, current smoking status, statin or nonstatin cholesterol-modifying therapy use (each as binary variables), other cardiac medication use, and comorbidities (including renal disease, cerebrovascular disease, hypertension, and thyroid disease) in multivariate analyses. We report the simvastatin-equivalent dose by category of LDL-C reduction; however, we did not include this in the model because it is on the causal pathway of LDL-C reduction and adverse coronary events, and thus, we would expect it to be collinear with the predictor of interest. We adjusted for each of the inclusion diagnoses (ischemic heart disease, diabetes mellitus, and peripheral vascular disease) in a series of analyses, because all subjects in the cohort had at least 1 of these diagnoses. We included these in the model 1 at a time to determine whether any of them confounded the effect of the predictor of interest. We also ran analyses treating LDL-C reduction as a continuous predictor to determine the cardiovascular risk reduction achieved for every 10-mg/dL reduction in LDL-C, again adjusting for demographics, medications, and comorbidities. We divided the cohort into quartiles of age on the date of first visit to the VISN-1 and thus the first date each subject was eligible to be included in the cohort. We ran the analyses described above in each of these subgroups. We also ran these analyses in a subgroup of patients who were 80 years old or older.
To test the robustness of our results, we ran multiple sensitivity analyses in selected subgroups of the cohort. Some subjects in the data set had missing data on BMI. We therefore ran analyses that included only subjects with 100% complete data to evaluate whether missing data biased the present results. There were no missing data on LDL-C levels, smoking status, cholesterol-modifying therapy, other cardiac medications, or any of the comorbidities. Because we could not account for cholesterol-modifying treatment that subjects received before they received their care in the VA, we ran the analyses described above in a subgroup of subjects who received care in the VISN-1 for at least 6 months before their first prescription for lipid-lowering therapy. To account for possible early fluctuations in LDL-C change, we also ran analyses in subjects with at least 1 year between the 2 LDL-C levels used to define their exposure (LDL-C reduction). We included the first high-density lipoprotein cholesterol and triglyceride levels available in the database in our models to evaluate whether any of these confounded the relationship between the magnitude of LDL-C reduction and the outcome. Finally, we tested for interaction between categorical LDL-C reduction and statin use and for interaction between categorical LDL-C reduction and nonstatin cholesterol medication use. The Institutional Review Board of the Boston VA Healthcare System approved the use of the VISN-1 databases to perform the present study.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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We identified 20 132 subjects with 1 or more high-risk inclusion diagnosis; 2 or more LDL-C levels before their first outcome, their death, or September 30, 2005; and an initial LDL-C level of
100 mg/dL. The mean (SD) time to event or time to censor (depending on which was applicable) was 0.98 (1.27) years. The mean (SD) age of the cohort was 67.7 (10.1) years. The cohort consisted of patients with diabetes mellitus (39.5%), patients with peripheral vascular disease (59.2%), and patients with ischemic heart disease (61.5%). The mean (SD) initial LDL-C level was 137.8 (28.9) mg/dL. Statin therapy was prescribed to 76.7% of subjects, and 15.9% were prescribed nonstatin cholesterol-modifying therapy between September 30, 1997, and September 30, 2005. Among statin users, 62.0% were prescribed simvastatin, 30.7% were prescribed lovastatin, 5.5% were prescribed atorvastatin, and <1% were prescribed fluvastatin, pravastatin, rosuvastatin, or simvastatin/ezetimibe. Among users of nonstatin cholesterol medication, 60.5% were prescribed gemfibrozil, 23.9% were prescribed colestipol, 8.4% were prescribed niacin, 4.3% were prescribed ezetimibe, 2.2% were prescribed cholestyramine, and <1% were prescribed fenofibrate and colesevelam. The mean (SD) reduction in LDL-C was 35.6 (36.8) mg/dL; this included 15.1% who had an increase in LDL-C. Among those whose LDL-C decreased between their initial and follow-up levels, the mean (SD) reduction was 45.2 (30.4) mg/dL. The mean (SD) time between each subject’s initial and follow-up LDL-C level was 4.3 (2.3) years. The mean (SD) follow-up LDL-C achieved was 102.0 (32.3) mg/dL. In the overall cohort, 4932 patients (24.5%) achieved a minimal reduction or an increase in LDL-C (the reference group), 6277 (31.2%) achieved a small reduction, 5487 (27.4%) achieved a moderate reduction, and 3436 (17.1%) achieved a large reduction. Table 1 displays characteristics of the cohort by categories of LDL-C reduction.
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The ages of subjects within each of the 4 age quartiles were <61.1 years, 61.1 to 69.3 years, 69.3 to 75.3 years, and 75.3 years. Table 2 displays the characteristics of the cohort by age quartiles. The proportion of subjects with ischemic heart disease and diabetes mellitus decreased from younger to older quartiles. The proportion of subjects with peripheral vascular disease, hypertension, cerebrovascular disease, thyroid disease, and renal disease increased from younger to older quartiles. The initial LDL-C level decreased from younger to older quartiles, and the proportion of patients prescribed either a statin or nonstatin cholesterol-modifying therapy decreased from younger to older quartiles. The mean LDL-C reduction varied significantly across the age quartiles, with subjects between 61.1 and 75.3 years of age experiencing larger LDL-C reductions than the youngest and oldest subjects (P for ANOVA <0.0001).
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A total of 4268 subjects (21.2%) had an acute myocardial infarction or underwent revascularization between September 30, 1997, and September 30, 2005. Table 3 displays the proportion of events by LDL-C reduction category and age quartile. Within each LDL-C reduction category, the proportion of patients with events decreased from younger to older quartiles. Within each age quartile, the proportion of patients with events decreased with increasing magnitude of LDL-C reduction. Patients in all age quartiles who achieved a large LDL-C reduction of >70 mg/dL had the lowest rates of the combined outcome.
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Table 4 displays unadjusted and multivariate-adjusted HRs (95% CIs) for each of the categories of LDL-C reduction compared with the reference within each age quartile. After adjustment for age, BMI, current smoking status, angiotensin-converting enzyme inhibitor use, aspirin use, β-blocker use, and comorbidities, any LDL-C reduction was associated with a decreased risk for the combined outcome, with the magnitude of this benefit increasing as the magnitude of the LDL-C reduction increased. Additional adjustment for statin use and nonstatin cholesterol-modifying therapy did not alter the results. Although the association between statin use and the outcome varied somewhat across age quartiles because of the association of age and medication use (older subjects were less likely to be prescribed a statin), in all age quartiles, statin use was associated with an increased risk for the outcome of 2-fold or more because of confounding by indication (results not shown). In all age quartiles, patients with a large LDL-C reduction (70 mg/dL or more) had the greatest risk reduction, with point estimates falling within a narrow range of 0.26 to 0.38, depending on the age group. In analyses that treated LDL-C as a continuous variable, the HR (95% CI) for an LDL-C reduction of 10 mg/dL was 0.94 (0.92 to 0.95) in the youngest age quartile, 0.94 (0.92 to 0.95) in the second age quartile, 0.93 (0.91 to 0.95) in the third age quartile, and 0.91 (0.89 to 0.93) in the oldest quartile. Tests for interactions revealed that there were no significant interactions between LDL-C reduction and statin or nonstatin cholesterol medication use.
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The subgroup of patients 80 years old or older (n=1752) had a mean (SD) initial LDL-C of 134.5 (25.6) mg/dL. Compared with younger patients, these patients were the least likely to be prescribed statin therapy (63.2%) and had on average a smaller reduction in LDL-C of 33.0 (33.2) mg/dL. Absolute rates of the outcome in this subgroup were lower than in younger subgroups; therefore, at an average of 1.22 years after the start of follow-up, the absolute rate reduction in the group with a large LDL-C reduction compared with the reference group was 9.4% (19.7% in the reference group versus 10.3% in the large LDL-C reduction group among subjects 80 years of age). Multivariate-adjusted HRs (95% CI) for each of the LDL-C reduction categories in this subgroup of patients were 0.75 (0.55 to 1.01) for those with a small LDL-C reduction, 0.67 (0.48 to 0.94) for those with a moderate LDL-C reduction, and 0.52 (0.33 to 0.82) for those with a large LDL-C reduction. Therefore, in this oldest subgroup, as in each of the age quartiles, the largest risk reduction was achieved in veterans who attained the largest LDL-C reductions. In subjects 80 years old or older, the HR (95% CI) for an LDL-C reduction of 10 mg/dL was 0.93 (0.89 to 0.96).
In sensitivity analyses including 1 that excluded subjects (n=540) with missing data on BMI, 1 that included only subjects (n=13 643) who were cared for in the VISN-1 for 6 months before their first lipid-lowering medication prescription, and 1 that included only participants with at least 1 year between the 2 LDL-C levels (n=18 035) used to define their exposure (LDL-C reduction), findings were materially the same as those of the main analyses. The inclusion of initial high-density lipoprotein cholesterol and triglyceride levels in the model did not change the results.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In a cohort of veterans at high risk for adverse cardiovascular events, we found that the risk reduction for a given magnitude of LDL-C reduction (small, moderate, or large) was quantitatively similar in patients of various ages. Older subjects who achieved a large reduction in LDL-C (
70 mg/dL) experienced an approximately 70% reduced risk for cardiovascular events, about the same as that achieved in younger patients with a large LDL-C reduction. The present findings qualitatively and quantitatively corroborate those of previous authors who found in pooled observational and trial data that each 10-mg/dL reduction in LDL-C is associated with an approximately 10% reduction in cardiovascular risk in adults.6,7,22 Although data on the effect size of LDL-C reduction in older adults are more sparse than in the general population, subjects treated with intensive statin therapy in the SAGE trial achieved a 67% reduction in risk, similar to the approximate 70% reduction we found.21
Older subgroups in the present cohort, including those 80 years of age, had lower absolute rates than younger subgroups. Because older subjects in the present cohort were typically World War II–era veterans and younger ones were typically Vietnam-era veterans, we speculate that there may be lifestyle and socioeconomic differences that explain the higher rates of events in the younger subgroups. Some of these differences (namely, BMI and smoking) we measured, and these are reflected in Table 2. Despite lower absolute rates in all categories of LDL-C reduction among older subgroups, subjects with the largest LDL-C reductions achieved the largest relative risk reductions.
Several authors have demonstrated undertreatment of high-risk elderly patients relative to younger patients.23–27 Some have speculated that uncertainty about the effectiveness of cholesterol-modifying therapy in elderly patients compared with its effectiveness in younger patients could explain this undertreatment. Cournot et al28 found that many physicians cite "lack of indication" in untreated elderly patients who might benefit from lipid management. The present study demonstrates that the benefit from cholesterol-modifying therapy is quantitatively the same in older patients as it is in younger patients. The present findings suggest that the maximum benefit from cholesterol lowering in older patients is achieved by as large a reduction in LDL-C as is feasible, as is the case in younger patients.
There are some potential limitations to the present study. Missed outcomes might occur because some patients received care outside of the VA. However, given that all of the subjects in the present study had multiple lipid levels documented over many years in the VISN-1 and thus likely received most or all of their medical care within the VA, we would expect leakage of outcomes to be small. Previous researchers have shown that ICD-9 codes have a high positive predictive value for acute myocardial infarction and that codes for revascularizations are highly sensitive in large administrative databases.29 VA databases have high rates of missing data on race, so we could not include this as a covariate in the present analysis.30 The effect of LDL-C reduction in older subjects of various racial backgrounds remains an important area of future research. The present cohort consisted of males only, and therefore, the effect of LDL-C reduction in older women is another important area of future research. We could not account for some unmeasured differences across LDL-C reduction categories, such as compliance with other beneficial cardiovascular medications or lifestyle choices.
To test the robustness of the present results, we ran multiple sensitivity analyses. First, some subjects (2.7%) had missing data on BMI. Because the clinical databases from which the data set was constructed comprise a closed and complete electronic medical record, there were no missing data on any of the other covariates, including age, comorbidities, medications, or laboratory data. An analysis that included only subjects with 100% complete data (n=19 592) yielded the same results as for the overall cohort. Because we could not account for whether a subject received lipid-lowering therapy outside the VA before the present study, we ran sensitivity analyses in subjects who were cared for within the VISN-1 for 6 months before their first LDL-C and lipid-lowering therapy (n=13 643). Given the cost of cholesterol-lowering medications, especially statins, during the time period of the study and the generally low socioeconomic status of veterans of this age, it is unlikely there were many in this group who were receiving cholesterol-lowering medication outside the VA during the 6-month period before they received such medication within the VA. Because findings in this subgroup were identical to those in the overall cohort, treatment with lipid-lowering medications before capture in our databases did not likely bias the present results. A sensitivity analysis that included only those subjects (n=18 035) with at least 1 year between the 2 LDL-C levels used to define their exposure (LDL-C) change again yielded essentially similar results. We added initial high-density lipoprotein cholesterol and initial triglyceride levels to the model to test whether these confounded the effect of the predictor of interest, but the results were unchanged.
Like previous authors, we found that the effect size of LDL-C reduction in older patients is the same as that in younger patients who achieve the same LDL-C change. The present results further our understanding of cholesterol and cardiovascular risk in older patients by revealing that the benefit from cholesterol lowering is proportional to the magnitude of LDL-C lowering. These findings suggest that in high-risk elderly patients, including those 80 years old and older, the benefit from lipid management is optimized by attaining as large a reduction in LDL-C as is feasible.
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Acknowledgments |
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Sources of Funding
This research has been funded by the Epidemiology and Research Information Center of the Veterans Affairs Cooperative Studies Program.
Disclosures
Dr Lawler has a research grant from Merck and Co pending. The remaining authors report no conflicts.
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Guest Editor for this article was James T. Willerson, MD.
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