Nanette K. Wenger, MD; Sandra J. Lewis, MD; David M. Herrington, MD; Vera Bittner, MD; Francine K. Welty, MD, PhD; Treating to New Targets Study Steering Committee and Investigators
Acknowledgments: The authors thank Andrei Breazna, Attila Kursun, David DeMicco, Liz Cusenza, Sheila Auster, and Miriam Marshood (all full-time employees of Pfizer) for their contributions in the collection and analysis of the data and John Bilbruck of Envision Pharma for editorial assistance.
Potential Financial Conflicts of Interest: Consultancies: N.K. Wenger (Eli Lilly Inc., SmithKline Beecham, DuPont Pharma, Pfizer Inc., Merck & Co. Inc., Bristol-Myers Squibb, Aventis, Sanofi-Aventis, Schering-Plough, GlaxoSmithKline, AstraZeneca, Abbott), S.J. Lewis (Pfizer Inc., Merck & Co. Inc., Bristol-Myers Squibb, AstraZeneca), D.M. Herrington (Merck & Co. Inc.), V. Bittner (Reliant Pharmaceuticals, Pfizer Inc., CV Therapeutics, Novartis), F.K. Welty (AstraZeneca); Honoraria: N.K. Wenger (Aventis, Pfizer Inc., Novartis, Merck & Co. Inc., Bristol-Myers Squibb, Eli Lilly Inc., DuPont Pharma, Searle), S.J. Lewis (Pfizer Inc., AstraZeneca, Merck & Co. Inc., Bristol-Myers Squibb), V. Bittner (Merck & Co. Inc., Merck Schering-Plough, Kos Pharmaceuticals, Pfizer Inc.), F.K. Welty (AstraZeneca, Pfizer Inc.); Grants received: N.K. Wenger (Eli Lilly Inc., AstraZeneca, Bristol-Myers Squibb, Pfizer Inc., Wyeth Ayerst, Merck & Co. Inc.), S.J. Lewis (Pfizer Inc., AstraZeneca), D.M. Herrington (Pfizer Inc.), V. Bittner (Pfizer Inc., Merck & Co. Inc., National Institutes of Health, Kos Pharmaceuticals); Grants pending: V. Bittner (Merck & Co. Inc.); Receipt of payment for manuscript preparation: V. Bittner (Pfizer Inc; attended investigator meetings at which the manuscript was discussed); Other: N.K. Wenger (data safety monitoring boards of Procter & Gamble, Knoll Pharmaceuticals, Pfizer Inc.).
Requests for Single Reprints: Nanette K. Wenger, MD, Division of Cardiology, Emory University School of Medicine, 49 Jesse Hill Jr. Drive SE, Atlanta, GA 30303; e-mail, email@example.com.
Current Author Addresses: Dr. Wenger: Division of Cardiology, Emory University School of Medicine, 49 Jesse Hill Jr. Drive SE, Atlanta, GA 30303.
Dr. Lewis: Northwest Cardiovascular Institute, 2222 North West Lovejoy Street, Suite 606, Portland, OR 97210.
Dr. Herrington: Department of Internal Medicine/Cardiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston–Salem, NC 27157-1045.
Dr. Bittner: Division of Cardiovascular Disease, University of Alabama at Birmingham, 701 19th Street South, LHRB 310, Birmingham, AL 35294-0007.
Dr. Welty: Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215.
Author Contributions: Conception and design: N.K. Wenger, S.J. Lewis, V. Bittner.
Analysis and interpretation of the data: N.K. Wenger, S.J. Lewis, D.M. Herrington, V. Bittner, F.K. Welty.
Drafting of the article: N.K. Wenger, F.K. Welty.
Critical revision of the article for important intellectual content: N.K. Wenger, S.J. Lewis, D.M. Herrington, V. Bittner, F.K. Welty.
Final approval of the article: N.K. Wenger, S.J. Lewis, D.M. Herrington, V. Bittner, F.K. Welty.
Provision of study materials or patients: S.J. Lewis, D.M. Herrington, V. Bittner.
Collection and assembly of data: V. Bittner, F.K. Welty.
Wenger NK, Lewis SJ, Herrington DM, Bittner V, Welty FK, . Outcomes of Using High- or Low-Dose Atorvastatin in Patients 65 Years of Age or Older with Stable Coronary Heart Disease. Ann Intern Med. 2007;147:1-9. doi: 10.7326/0003-4819-147-1-200707030-00002
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Published: Ann Intern Med. 2007;147(1):1-9.
Data on the benefits of intensive lipid-lowering treatment for elderly persons with heart disease are sparse.
This secondary analysis of a trial examined outcomes of 3809 adults 65 years of age or older with coronary heart disease who were randomly assigned to receive atorvastatin, 80 or 10 mg/d. Patients achieved average low-density lipoprotein cholesterol levels of approximately 1.81 mmol/L (70 mg/dL) and 2.59 mmol/L (100 mg/dL), respectively. Fewer patients who received 80 mg of atorvastatin had major fatal or nonfatal cardiovascular events than did those who received 10 mg of atorvastatin (10.3% vs. 12.6%).
The researchers could not determine whether benefits were due to the higher statin dose, lower achieved cholesterol levels, or both factors.
The age profile of the population in most industrialized countries is changing as life expectancy increases. Because cardiovascular risk increases steadily with age, this demographic transition is associated with an increase in the burden of chronic cardiovascular disease (CVD), including coronary heart disease (CHD) and stroke (1).
Subgroup analyses from large, randomized, placebo-controlled clinical trials (2–4) demonstrated that decreasing low-density lipoprotein (LDL) cholesterol levels with statin therapy statistically significantly reduced the risk for CHD in older persons. On the basis of these early trial data, the Third Report of the National Cholesterol Education Program Adult Treatment Panel (5) recommended that persons older than 65 years of age should not be denied the benefits of lipid-lowering therapy. Since publication of the panel's report, results of the Heart Protection Study (6) and PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) (7) further support the efficacy and safety of statin treatment in older persons. The outcomes of these 2 studies, along with previous evidence, led the National Cholesterol Education Program to conclude that these data provide a strong justification for intensive LDL cholesterol–lowering therapy in high-risk older persons with established CVD (8).
Recent secondary prevention guidelines from the American Heart Association (AHA) and the American College of Cardiology (ACC) state that it is reasonable to reduce LDL cholesterol levels to less than 1.8 mmol/L (<70 mg/dL) in any patient with established CHD (9). In the ACC and AHA guidelines (10), the writing group acknowledged that elderly patients were underrepresented in many clinical trials and urged physicians and patients to participate in trials that will provide additional evidence for therapeutic strategies in elderly patients.
In the TNT (Treating to New Targets) study, intensive lipid-lowering treatment with 80 mg of atorvastatin in patients with stable CHD provided clinically significant benefit beyond treatment with 10 mg of atorvastatin (11). Our prespecified secondary analysis reports data from the TNT study on the efficacy and safety of high-dose atorvastatin treatment in patients 65 years of age or older.
Details of the TNT study design and outcome measures are published elsewhere (11, 12). After a washout phase, men and women 35 to 75 years of age with established CHD, LDL cholesterol levels between 3.4 and 6.5 mmol/L (130 and 250 mg/dL), and triglyceride levels less than 6.8 mmol/L (<600 mg/dL) were eligible to enter an 8-week, open-label, run-in period with atorvastatin, 10 mg/d. At the end of the run-in phase, 10 001 patients with LDL cholesterol levels less than 3.4 mmol/L (<130 mg/dL) were randomly assigned to receive double-blind therapy with atorvastatin, 10 or 80 mg/d. The time of randomization was used as the baseline, and patients were followed for a median of 4.9 years. The primary study outcome was the time to the first occurrence of a major cardiovascular event, defined as death due to CHD, nonfatal non–procedure-related myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke. The prespecified secondary outcomes were a major coronary event, a cerebrovascular event, peripheral arterial disease, hospitalization with a primary diagnosis of congestive heart failure, death from any cause, any cardiovascular event, and any coronary event. An independent end point committee that was blinded to treatment assignment adjudicated all primary and secondary outcomes.
We tested the statistical significance of treatment effect on end points by using the log-rank test. We calculated hazard ratios with 95% CIs from a Cox regression model that we present where appropriate. We performed homogeneity tests for treatment interaction with age by using a Cox proportional hazards model to determine whether the treatment effects observed in patients 65 years of age or older differed from those in patients younger than 65 years.
The TNT study was funded by Pfizer. The steering committee developed the protocol in collaboration with the funding source and was responsible for the final version. ICON Clinical Research, North Wales, Pennsylvania, managed all data. ICON and Pfizer provided site monitoring throughout the study. The data were analyzed by the funding source according to the statistical analysis plan approved by the steering committee. The steering committee had unrestricted, request-based access to the study data, which were retained by the funding source, and developed the article independently without constraints from the sponsor.
Of 10 001 patients randomly assigned in the overall TNT study cohort, 3809 (38%) were 65 years of age or older (1872 received 10 mg of atorvastatin and 1937 received 80 mg). Baseline characteristics and LDL, high-density lipoprotein, and total cholesterol and triglyceride levels were similar between the 2 treatment groups (Table 1). The mean age of the older cohort was 69.9 years. In this group, 2033 patients were 65 to 69 years of age (1000 received 10 mg of atorvastatin and 1033 received 80 mg) and 1776 patients were 70 years of age or older (872 received 10 mg and 904 received 80 mg). The demographic and cardiovascular profiles of patients age 70 years or older were similar to those of the total elderly cohort, including lipid values and previous CVD at baseline.
During the open-label period, LDL cholesterol levels among patients 65 years of age or older decreased from 4.2 mmol/L (163 mg/dL) to 2.5 mmol/L (96 mg/dL). At week 12, mean LDL cholesterol levels were 1.9 mmol/L (72 mg/dL) among those who received 80 mg of atorvastatin and 2.5 mmol/L (97 mg/dL) among those who received 10 mg. Levels of LDL cholesterol in both groups remained stable for the duration of the study.
Total cholesterol and triglyceride levels decreased from baseline to week 12 in patients who received 80 mg of atorvastatin and were maintained at this reduced level for the duration of the study. High-density lipoprotein cholesterol levels changed little from baseline levels: At study end, levels had increased by 0.3% for patients who received 10 mg and 0.17% for patients who received 80 mg. Figure 1 shows postrandomization LDL cholesterol and triglyceride levels among patients 65 years of age or older.
To convert LDL cholesterol values to mg/dL, divide by 0.02586. To convert triglyceride values to mg/dL, divide by 0.01129.
Among patients 65 years of age or older, a primary event occurred in 199 patients (10.3%) who received 80 mg of atorvastatin and 235 patients (12.6%) who received 10 mg. This is a 2.3% absolute reduction in the rate of major cardiovascular events and a 19% relative reduction in risk in favor of the high-dose group (hazard ratio, 0.81 [95% CI, 0.67 to 0.98]; P = 0.032) (Table 2). After adjustment for well-established risk factors (sex, race, smoking status, history of diabetes, and history of hypertension), the risk reductions associated with 80 mg were similar to the unadjusted results (hazard ratio, 0.81 [CI, 0.67 to 0.98]; P = 0.032). The number needed to treat for benefit for 80 mg versus 10 mg was 35. This value is the number of patients who need to be treated to prevent 1 cardiovascular event over 4.9 years.
Table 2 shows the incidence of each component of the primary composite outcome among older patients. Rates of death due to CHD, nonfatal non–procedure-related myocardial infarction, and fatal and nonfatal stroke (ischemic, embolic, hemorrhagic, or unknown origin) were lower in the 80-mg group than in the 10-mg group. For each individual component, however, the difference was not statistically significant. Eight patients (0.4%) who received 80 mg and 15 patients (0.8%) who received 10 mg had hemorrhagic stroke, which caused 3 deaths in each group. The risk for any cardiovascular event (P < 0.001), a major coronary event (P = 0.128), any coronary event (P < 0.001), a cerebrovascular event (P = 0.010), and hospitalization for congestive heart failure (P = 0.008) was lower in the 80-mg group than in the 10-mg group. The 2 groups did not statistically significantly differ for all-cause mortality and for rates of death due to cardiovascular and noncardiovascular causes.
The rate of death due to cardiovascular causes was lower in the 80-mg group than in the 10-mg group (78 patients [4.0%] vs. 83 patients [4.4%]; hazard ratio, 0.91 [CI, 0.67 to 1.24]; P = 0.55). However, more patients in the 80-mg group than the 10-mg group died of noncardiovascular causes (98 patients [5.1%] vs. 76 patients [4.1%]; hazard ratio, 1.26 [CI, 0.93 to 1.70]; P = 0.129). These hazard ratios are consistent with those in the overall population (0.81 [CI, 0.64 to 1.03] for cardiovascular death [P = 0.085] and 1.25 [CI, 0.99 to 1.57] for noncardiovascular death [P = 0.065]).
Cancer accounted for more than one half of deaths due to noncardiovascular causes in older patients who received 80 mg (55 patients [2.8%]) and 10 mg (40 patients [2.1%]). No specific body system or type of cancer contributed disproportionately to the small difference in deaths due to cancer between the treatment groups. Rates of death from nontraumatic causes other than cancer were similar between the 80-mg group and 10-mg group (39 patients [2.0%] vs. 31 patients [1.7%], respectively). Deaths from suicide, homicide, and other traumatic causes were infrequent (4 patients [0.2%] vs. 5 patients [0.3%], respectively).
The rate of treatment-related adverse events among patients age 65 years or older was 8.3% for the 80-mg group and 5.2% for the 10-mg group. In the cohort with older patients, 4.4% of those who received 80 mg and 2.2% of those who received 10 mg withdrew from the study because of adverse events that the investigator considered to be associated with the treatment. The rates of persistent (occurring twice within 4 to 10 days) elevations in alanine aminotransferase or aspartate aminotransferase levels to greater than 3 times the upper limit of normal were 1.3% (n = 24) in the 80-mg group and 0.1% (n = 1) in the 10-mg group. No documented cases of persistent elevation in creatine kinase levels to greater than 10 times the upper limit of normal occurred.
Patients 65 years of age or older were more likely than patients younger than 65 years of age to be female and to be white. Hypertension and diabetes mellitus were more prevalent and current cigarette smoking was less prevalent among older patients than younger patients. Older patients more often than younger patients had a history of angina, coronary artery bypass graft surgery, cerebrovascular disease, peripheral arterial disease, and congestive heart failure but were less likely to have had a previous myocardial infarction or a previous coronary angioplasty.
The relative reduction in the rate of major cardiovascular events was slightly higher (24%) in the younger group than in the older group, although the absolute risk reduction was the same (2.3%; hazard ratio, 0.76 [CI, 0.64 to 0.90]; P = 0.001) (Figure 2, top). For the younger patients, the number needed to treat for benefit for 80 mg versus 10 mg was 26.
The hazard ratio for a major cardiovascular event is 0.81 (95% CI, 0.67 to 0.98) (P = 0.03) among patients 65 years of age or older and 0.76 (CI, 0.64 to 0.90) (P = 0.001) among patients younger than 65 years of age. The hazard ratio for fatal or nonfatal stroke is 0.79 (CI, 0.57 to 1.09) (P = 0.158) and 0.70 (CI, 0.49 to 1.00) (P = 0.048), respectively.
The relative reduction in the risk for stroke was also higher (30%) in younger patients than in older patients (hazard ratio, 0.70 [CI, 0.49 to 1.00]; P = 0.048), although the absolute risk reduction (0.7%) was similar (Figure 2, bottom). Among the younger patients, 8 (0.3%) who received 80 mg of atorvastatin and 3 (0.1%) who received 10 mg had hemorrhagic stroke.
No statistically significant heterogeneity of treatment effect for age was evident for the primary outcome (or its individual components) or secondary outcomes (Figure 3). Hazard ratios for younger and older patients were similar to those for the overall study sample. For older and younger patients, there were small differences between the 80-mg and 10-mg groups in adverse events and withdrawals related to treatment (Table 3). Rates of liver function abnormalities were consistent for both doses and were similar for younger and older patients (Table 3). No patient younger than 65 years experienced persistent elevations in creatine kinase levels.
CA = cardiac arrest; CHD = coronary heart disease; CHF = congestive heart failure; CV = cardiovascular; MI = myocardial infarction; PAD = peripheral artery disease; PR = procedure-related. *P value for heterogeneity (patients ≥65 years vs. patients <65 years).
For patients 65 years of age or older with stable CHD, intensive lipid-lowering treatment with 80 mg of atorvastatin statistically significantly reduced the rate of major cardiovascular events compared with 10 mg of atorvastatin. Our analysis, which involves 2 active therapies, extends the findings of previous placebo-controlled studies (6, 7) and, consistent with current ACC and AHA secondary prevention recommendations (9), suggests that additional clinical benefit can be achieved by aggressively treating older patients to reduce LDL cholesterol levels to less than 2.6 mmol/L (<100 mg/dL).
Prevention of stroke among older patients is of great importance because of the potential for severe long-term physical and mental disability and the large associated economic cost (14). Rates of stroke in the TNT study are indicative of the increased burden of stroke among elderly persons. Among patients 65 years of age or older, the incidence of fatal stroke, nonfatal stroke, or both was approximately twice that observed among younger patients (in contrast to the rates of coronary events, which were similar between the 2 age cohorts). In our analysis, the rate of fatal and nonfatal stroke in patients 65 years of age or older was lower in the 80-mg group than in the 10-mg group, although the difference was not statistically significant. Other studies (3, 6, 15) have demonstrated the benefit of statin therapy (compared with placebo) in reducing the risk for stroke in older patients. In contrast to the TNT study, however, statistical significance in these trials was reached among older patients. In PROSPER (7), no reduction in stroke was observed among patients older than 70 years of age who received statin therapy compared with those who received placebo; this finding may have been due to a shorter duration of follow-up.
All cardiovascular and coronary events were statistically significantly reduced in older patients who received 80 mg of atorvastatin compared with those who received 10 mg. Among older patients, intensive lipid-lowering treatment was also associated with reductions in the risk for major coronary events, cerebrovascular events, and hospitalization for congestive heart failure (which reached statistical significance for cerebrovascular events and congestive heart failure) for those who received 80 mg compared with those who received 10 mg. For older patients, and consistent with the overall population, the 2 treatment groups did not statistically significantly differ in death from any cause. In the TNT study, the overall mortality rate was low, and the rate of death due to noncardiovascular causes exceeded the rate of death due to cardiovascular causes among patients who received intensive lipid-lowering therapy. As a result, we cannot confidently rule out a small increase or decrease in overall death in the total cohort or in the 2 age-defined subgroups that we examined.
Statins must be used with increased vigilance in older patients. For patients 65 years of age or older, the small differences between treatment groups in adverse event profiles were similar to that observed in the overall study sample (11). The improved clinical outcome in these patients was not associated with persistent elevations in creatine kinase levels. Also, occurrence of liver function abnormalities was low and was consistent at both doses with levels reported in other large-scale trials of atorvastatin (16–18).
Although older patients treated with 80 mg of atorvastatin had a slightly lower relative risk reduction than those who received 10 mg compared with younger persons, the absolute clinical benefit (2.3%) was the same in both age groups. Kaplan–Meier curves for the 2 age cohorts show that patients 65 years of age or older who received 80 mg had a reduced risk for major cardiovascular events that approximately equaled that observed for patients younger than 65 years who received 10 mg (Figure 3).
The numbers needed to treat for benefit based on these results were low for both older and younger patients (35 for patients ≥ 65 years vs. 26 for patients < 65 years). The values represent the number of patients who must be treated with intensive lipid-lowering therapy over 4.9 years to prevent 1 additional cardiovascular event greater than that achievable by using a moderate drug regimen.
Secondary analyses and meta-analyses of large randomized, placebo-controlled trials have also demonstrated that the cardiovascular benefits of statin therapy observed in a sample of older patients with CHD are similar to those in younger patients. In the Heart Protection Study (6), the absolute risk reduction in major vascular events compared with placebo among patients 65 years of age or older who received simvastatin (5.6%) was slightly higher than that in patients younger than 65 years (5.2%). Investigators reported similar results in the Cholesterol Treatment Trialists' collaboration, a prospective meta-analysis of more than 90 000 patients in 14 randomized trials of statins (19). Although most studies in the Cholesterol Treatment Trialists' analysis are of samples different from that in the TNT study (and involve relatively low statin doses), the absolute risk reduction was the same in patients older than 65 years and those 65 years or younger. The PROSPER (7), the only major trial to our knowledge that was conducted exclusively in older individuals (age 70 to 82 years), also showed a significant reduction in major cardiovascular events among patients who received statin therapy compared with those who received placebo, but it showed no reduction in risk for stroke. Other analyses of the effects of statin treatment in patients with CHD have demonstrated higher absolute reductions in the risk for major coronary events among older patients compared with younger patients (2–4).
The small increase in the rates of treatment-related adverse events and withdrawals among older patients who received 80 mg of atorvastatin compared with that of younger patients is consistent with that reported in previous statin trials (2).
Although our findings add to previous data about the benefit of decreasing LDL cholesterol levels in elderly patients, our analysis has limitations. Inclusion of more older patients would have strengthened our ability to detect subtle treatment effects with confidence. Nevertheless, with more than 3800 older patients and 400 primary outcomes, we detected a roughly 20% treatment effect at the 0.03 level of statistical significance. The ability to detect treatment effects of similar size for some less frequent secondary outcomes was limited.
In addition, we could not determine whether the clinical benefit observed among older patients was related to the higher statin dose, lower resultant LDL cholesterol levels, or both factors. Thus, we recommend that physicians choosing dose titration for patients 65 years of age or older be guided by clinical judgment and existing treatment guidelines. The safety data we present should also encourage physicians to follow titration guidelines for this age group.
In conclusion, patients 65 years of age or older treated with intensive lipid-lowering therapy with 80 mg of atorvastatin experienced additional benefit beyond that achieved with 10 mg of atorvastatin in preventing potentially disabling cardiovascular events. Older patients who received 80 mg had reduced risk for major cardiovascular events that was approximately the same as that for patients younger than 65 years treated with 10 mg. Although treatment with 80 mg conferred a smaller relative risk reduction for older patients than for younger patients, the absolute risk reduction remained as high. Our findings support the recommendations of the recent National Cholesterol Education Program guidelines for use of intensive LDL cholesterol–lowering therapy in high-risk older persons with established CVD (8) and ACC and AHA guidelines to reduce LDL cholesterol levels to much less than 2.6 mmol/L (<100 mg/dL) in any patient with established CHD (9).
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robert a. alter
July 6, 2007
65 years or older does not equal 65 to 75
The title of the Wegner, NK et.al. article is misleading. The study design of the TNT study notes a maximum age of 75. Hence, a more accurate title would replace "in patients 65 years of age or older" with "in patients 65 to 75 years of age". All of the figures and tables should include similar language. Such figures and tables are often cited and pictured in articles, textbooks and advertisements without a description of the study population. When the study population age is clearly defined, imprecise terms that inappropriately generalize the results should be avoided.
Roy C Ziegelstein
Johns Hopkins University School of Medicine
July 8, 2007
Isn't 80 Considered 65 Years of Age or Older?
About 1 of every 100 Americans is an individual at least 80 years old with coronary heart disease. This fact will not surprise the internists, geriatricians, and cardiologists across the country who care for these patients. The United States Census Bureau's statistics,1 indicate that as of 2005, there were 288,378,137 people in this country. Of the 141,274,964 men, 2.4% were 80 years of age and older and of the 147,103,173 women, that percentage was 3.9%. The American Heart Association tells us that 32.7% and 21.6% of men and women, respectively, 80 years of age and older have coronary heart disease.2 Taking a moment to do the math, one finds that 1,108,726 men and 1,239,197 women 80 years of age and older have cardiovascular disease in this country, approximately 1% of the population. And we should recall that the US Census Bureau data excludes individuals who reside in institutions; if it did not, these numbers would be far greater.
The report by Wenger, et al. from the Treating to New Targets (TNT) study3 shows that intensive lowering of low-density lipoprotein cholesterol has advantages in some patients 65 years of age or older with stable coronary heart disease, but it does not address any of the almost 2.5 million individuals over age 80 or even the many individuals with coronary heart disease who are 76 to 79 years of age. No doubt, though, many clinicians will extrapolate the data in the study by Wenger et al.3 to all individuals over age 65 with stable coronary heart disease. And who could really blame a clinician who, after reading this study, recommends an increase in statin dose for an 83 year-old with stable coronary heart disease and a low-density lipoprotein cholesterol level of 94 mg/dL? After all, the title of the article, the abstract, and the manuscript itself all indicate that the study group is comprised of "patients 65 years of age or older" with no mention, except for a single line in the Methods, that only individuals up to 75 years of age were included in this study. This important limitation should be highlighted, and clinicians should be cautioned not to extrapolate the results of this study to the many individuals with stable coronary disease who are older than 75 years of age.
1. United States 2005 American Community Survey. Accessed at http://factfinder.census.gov/servlet/STTable?_bm=y&-geo_id=01000US&- qr_name=ACS_2005_EST_G00_S0101&-ds_name=ACS_2005_EST_G00_ on 8 July 2007.
2. Rosamond W, Flegal K, Friday G, Furie K, Go A, Greenlund K, et al.; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007;115:e69-171.
3. Wenger NK, Lewis SJ, Herrington DM, Bittner V, Welty FK; Treating to New Targets Study Steering Committee and Investigators. Outcomes of using high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary heart disease. Ann Intern Med. 2007;147:1-9.
Cardiology Service, Ospedale di San Vito al Tagliamento, Italy
July 10, 2007
Concerns about efficacy and safety of high-dose atorvastatin.
TO THE EDITOR "“ When making therapeutic decisions, physicians need to balance benefits, risks and costs. We feel that the application in clinical practice of the suggestions by Wenger and colleagues from the Treating to New Targets (TNT) study (1) may be very hard. The TNT study (2) screened 18,468 patients up to 75 years, but after an ingenious selection and an open-label run-in phase, only 10,003 persons were randomized, thus excluding patients with concomitant medical conditions which might increase the risk of statin-related side-effects, and persons with major comorbidities: in clinical practice, the drug may be given to most of these patients. Notwithstanding these criteria of selection, the reduction of major fatal or nonfatal cardiovascular events (2,3%) in patients 65 to 75 years of age were lower than the increase in treatment- related adverse events (3,1%). Furthermore, although the TNT study (1, 2) was neither designed nor powered to detect a reduction in all-cause mortality (but why not?), it's disturbing to note that high-dose atorvastatin in the secondary prevention of cardiovascular disease does not improve survival when compared to a very lower dose.
1. Wenger NK, Lewis SJ, Herrington DM, Bittner V, Welty FK; Treating to New Targets Study Steering Committee and Investigators. Outcomes of using high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary heart disease. Ann Intern Med. 2007;147:1-9.
2. Waters DD, Guyton JR, Herrington DM, McGowan MP, Wenger NK, Shear C; TNT Steering Committee Members and Investigators. Treating to New Targets (TNT) Study: does lowering low-density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit? Am J Cardiol. 2004; 93: 154-8.
Comando Brigata alpina Julia, Udine 33100 Italy
Failure of atorvastatin [LipitorÂ®] to save lives.
The analysis of the TNT trial by Wenger et al (1) suggests benefit in over 65 year old cardiac patients from top-dose atorvastatin. However, the 22 more deaths from noncardiovascular causes more than offset the 5 fewer deaths from cardiovascular causes (versus patients on low dose), a result consistent with the entire TNT study population.
This is ominous considering that this subgroup had the following characteristics at baseline: mean age 70 years, 82% had suffered angina,18% had diabetes, 53% had suffered a myocardial infarction, 49% angioplasty and 55% bypass operations.
Since stable angina is a non-fatal pain, the significant reduction in angina in the ASCOT study (2) may well underlie much of the non-fatal 'event' benefit of this and other trials and that reported no mortality benefit from atorvastatin, versus placebo.
When 'event' benefit may result from the amount of hospital visits but without lowering all cause mortality, we are clearly dealing with symptoms and not with causes. This should be made clear in statin stake- holder written articles, such as the one in question, especially when not presenting discordant evidence.
Another placebo controlled trial, SPARCL (3), ended with non significantly more deaths on top dose atorvastatin and the sponsor of the TNT trial, Pfizer, in March 2007 refused [letter on file] to release the mortality data regarding 49 in-house atorvastatin studies (4).
There are no placebo controlled trials or meta-analysis that show a mortality benefit from statin treatment in women (5). It is thus unfortunate that the authors did not publish the Kaplan-Meier all-cause mortality curves regarding both women and men in the TNT study and this in the same fashion as Figure 2 of the article in question.
While the authors suggest but do not prove benefit from more aggressive treatment, the main purpose of cardiologists is preventing deaths. Here, the role of atorvastatin should be clearly reported to gender and age-based patient groups whose motivation to take atorvastatin may be the belief that it may prolong their lives, which is not the case based the trial data published so far. The release of the relevant age and gender based Kaplan-Meier mortality curves would help patients and prescribers.
Luca Mascitelli, M.D., Udine, Italy
Eddie Vos, M. Eng, Sutton (Qc) Canada
1. Wenger NK, Lewis SJ, Herrington DM, Bittner V, Welty FK. Outcomes of using high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary heart disease. Ann Intern Med. 2007; 147: 1-9. Medline 17606955
2. Sever PS, DahlÃ¶f B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, et al Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than- average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003; 361: 1149-58. Medline 12686036
3. Amarenco P, Bogousslavsky J, Callahan A, Goldstein LB, Hennerici M, Rudolph AE, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med.; 355: 549-59. Medline 16899775
4. Newman C, Tsai J, Szarek M, Luo D, Gibson E. Comparative safety of atorvastatin 80 mg versus 10 mg derived from analysis of 49 completed trials in 14,236 patients. Am J Cardiol. 2006; 97: 61-7. Medline 16377285
5. Vos E, Rose CP. Questioning the benefits of statins. CMAJ. 2005; 173: 1207. Medline 16275976
Mark R. Goldstein
Are We Trading Heart Disease for Cancer?
In their secondary analysis of the Treating to New Targets (TNT) study, the investigators concluded that the findings support the use of intensive low-density lipoprotein-cholesterol lowering therapy in elderly individuals with established cardiovascular disease (1). Close scrutiny of the data contradict their conclusion.
The secondary analysis of TNT compared the outcomes using either atorvastatin 10 mg daily or 80 mg daily in the 3809 patients 65 years of age or older for the 4.9 year study duration. The overall rate of death over the duration of the study was 9.1% in subjects randomized to 80 mg of atorvastatin daily and 8.5% in subjects randomized to 10 mg of atorvastatin daily.
The trend towards increased death in the high-dose atorvastain group was largely due to an increase in cancer death, which was 2.8% in that group and 2.1% in the low- dose atorvastatin group. Coronary heart disease death was 3.0% in the high-dose atorvastin group and 3.3% in the low-dose atorvastatin group.
Therefore, the increase in cancer death was greater than the decrease in coronary heart disease death in the high-dose atorvastatin group. Perhaps, the investigators can provide additional data on the incidence of new non-fatal cancer dignoses in each group, just as they provided data on non-fatal coronary heart disease events.
Other trials have demonstrated an increase in cancer incidence and death in elderly subjects randomized to statins compared to placebo, which cancelled any mortality benefit of decreasing coronary heart disease (2). The TNT study suggests that there might be a dose response of statin therapy in increasing cancer in elderly subjects.
With these uncertainties, the suggestion that this study supports the use of intensive low-density lipoprotein cholesterol-lowering therapy in elderly subjects with established cardiovascular disease is on shaky grounds.
1) Wenger NK, Lewis SJ, Herrington DM, Bittner V, Welty FK, for the Treating to New Targets Study Steering Committee and Investigators. Outcomes of using high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary heart disease. Ann Intern Med. 2007; 147: 1-9.
2) Shepherd J, Blauw GJ, Murphy MB, et al, on behalf of the PROSPER study group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002; 360: 1623-30.
William B. Greenough
Johns Hopkins Bayview Medical Center
July 11, 2007
Response to Wenger and colleagues
To the Editor:
Wenger and colleagues' secondary analysis of atorvastatin in elderly patients with coronary heart disease shows that both death and resuscitation from cardiac arrest were more likely in the group of patients assigned to high-dose atorvastatin. Neither difference was significant.
Since atorvastatin might make it more likely that your heart will stop, it seems perhaps premature to tout "additional clinical benefit". The authors do acknowledge 6 contributors who collected and analyzed data, all Pfizer employees, and a medical writer, and all authors get money from Pfizer. We impute no sinister motives, but wonder whether the phrase "clinical benefit" originated with the authors or their writer.
William B. Greenough Thomas E. Finucane
LAC+USC Medical Center
July 12, 2007
Inflammation and Statin Myopathy: Is the future rosy for atorvastatin?
It is with great interest that we reviewed the article "Outcomes of Using High- or Low-Dose Atorvastatin in Patients 65 Years of Age or Older with Stable Coronary Heart Disease" by Wenger et al. However, there are several areas for which further elucidation would be of benefit. As a medical resident currently on a Rheumatology teaching service we have seen several adverse events to statins in consultation.
Our concerns are as follows-
First, in clinical practice we would be apprehensive to start patients especially the elderly on very high dose statins as initial therapy due to perceived higher discontinuation rates secondary to a greater incidence of "muscle cramps". In our clinical experience we often stop the statins when they are having symptoms with a mildly elevated CPK. Such patients rarely return to the initial statin and often are reluctant to change to newer agent at any dose. Only once have seen a 10 fold increase in CPK, wherein the patient's CPK was >80,000 and was quite ill. Subsequent work up revealed polymyositis which ultimately was felt to be unrelated to his statin use. It is widely known that the high dose of statins especially in elderly population is related to increased incidence of statin-induced myopathy which was not touched upon in the article which only states that "adverse events" were about 3.1%. We feel that true clinical incidence of statin related myopathy is under-reported using the " greater than 10 fold increase in CPK" criteria.
Second, the role of inflammation as measured by CRP in MI is a key area of investigation for cardiac morbidity and mortality. Unfortunately, this was not measured in this large otherwise well designed study emphasizing CHD risk. In Rheumatology, statins have been investigated in RA for potential benefits which may add to the significance of inflammation in lipid lowering therapy.
Third, we agree with prior correspondants that the higher cancer rates are an area of concern.
Overall, despite our initial excitement in reading this article there are several gray areas. Hopefully, future studies will include the role of inflammation and myopathic events in high dose statin therapy.
Nanette K Wenger
Emory University School of Medicine
August 15, 2007
We thank Drs. Alter, Mascitelli, Vos, Eng, and Goldstein for their careful review of our manuscript. Treatment effect was qualitatively similar in subjects 35-64 and 65-75 years providing some reassurance that age does not importantly modify treatment effect. With a treatment duration of 4.9 years, some follow-up derived from subjects >75 years. Nonetheless, we concur that TNT does not provide definitive efficacy or safety information for the 5% of the U.S. population >75 years. A manuscript comparing outcomes by gender is currently under review.
The primary study outcome for TNT overall and this subanalysis was time to first occurrence of a major cardiovascular event: CHD death, nonfatal non-procedure-related myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke. Angina was not included in the primary TNT endpoint and neither the overall trial nor this subanalysis were powered to determine if small differences in total mortality were real or simply due to the play of chance. Apparent differences in total and noncardiovascular mortality between subgroups should be interpreted with great caution, especially in an older population where competing causes of death (such as cancer) closer to the end of normal lifespan are likely to play a larger role. Analyses by type of cancer in this and other statin trials do not show any organ specificity [2,3]. Ancillary analysis of noncardiovascular mortality in TNT  showed no relationship between cancer mortality and achieved LDL-C level; participants in the lowest quintile of achieved LCL-C (the majority taking 80 mg atorvastatin) had the lowest cancer mortality . Data on incidence of nonfatal cancer by age subgroup is not available. Given study design and power, such analyses are unlikely to yield definitive results. We agree that our study does not support intensive lipid-lowering therapy among older or younger patients to reduce total mortality; but mortality should not be the sole measure of treatment benefit. Nonfatal cardiovascular events such as myocardial infarction and stroke significantly impact functional status and quality of life, worsen prognosis, and result in substantial health care expenditures. We affirm our conclusion that intensive lipid-lowering therapy in patients with established CHD 65 years of age or older (atorvastatin 80 mg vs. atorvastatin 10 mg daily) prevents potentially disabling cardiovascular events, with an absolute risk reduction comparable to that in younger individuals.
REFERENCES 1. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425-35.
2. Shepherd J, Blauw GJ, Murphy MB et al. on behalf of the PROSPER study group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002; 360: 1623- 30.
3. LaRosa JC, Grundy SM, Kastelein JJP, Kostis JB, Greten H, on behalf of the Treating to New Targets (TNT) Steering Committee and Investigators. Safety and efficacy of atorvastatin-induced very low- density lipoprotein cholesterol levels in patients with coronary heart disease (a post hoc analysis of the Treating to New Targets (TNT) study. Am J Cardiol In Press, 2007.
Vera Bittner, David Herrington, and Nanette Wenger, on behalf of the Treating to New Targets (TNT) Steering Committee and Investigators.
August 29, 2007
Reply to Drs. Greenough and Finucane
The term "clinical benefit" derives from the primary TNT manuscript as written by the trial Steering Committee, NEJM 352:1425, 2005.
We call to your attention the attestations of the authors on the final page of the Annals manuscript of their contributions to conception and design, analysis and interpretation of the data, drafting of the article, clinical revision of the article for important intellectual content, final approval of the article, and correction and assembly of data.
Francine K. Welty, M.D. Sandra J. Lewis, M.D. Nanette K. Wenger, M.D.
See original manuscript
Cardiology, Dyslipidemia, Coronary Risk Factors, Prevention/Screening.
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