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)†
Article Outline
High-dose statin therapy has been demonstrated to provide incremental benefit when low-density lipoprotein (LDL) cholesterol concentrations are lowered well below recommended target levels. This secondary analysis of the Treating to New Targets (TNT) study was conducted to investigate whether the attainment of very low LDL cholesterol levels was associated with a further reduction in major cardiovascular events compared with higher LDL cholesterol concentrations and whether any incremental benefit was achieved without additional safety risk. Patients with coronary heart disease and LDL cholesterol levels <130 mg/dl (3.4 mmol/L) were randomized to therapy with atorvastatin 10 mg/day (n = 5,006) or 80 mg/day (n = 4,995). The primary end point was the occurrence of a first major cardiovascular event. Clinical outcomes and safety data were compared across on-treatment LDL cholesterol quintiles. There was a highly significant reduction in the rate of major cardiovascular events with descending achieved levels of on-treatment LDL cholesterol (p <0.0001 for trend across LDL cholesterol). Analysis of individual components of the primary end point demonstrated similar results. Death from any cause and from noncardiovascular causes was lowest in patients with the lowest on-treatment LDL cholesterol levels. Cardiovascular deaths were also reduced with lower levels of on-treatment LDL cholesterol. There were no clinically important differences in adverse event rates across quintiles. Specifically, no increase in muscle complaints, suicide, hemorrhagic stroke, or cancer deaths was observed at the lowest LDL cholesterol levels. In conclusion, the present analysis adds support to the concept that for patients with established atherosclerotic cardiovascular disease, a further risk reduction without sacrifice of safety can be achieved by reducing LDL cholesterol to very low levels.
The Treating to New Targets (TNT) study showed that intensive lipid-lowering with atorvastatin 80 mg to a low-density lipoprotein (LDL) cholesterol level of 77 mg/dl (2.0 mmol/L) provided significant additional benefit in patients with stable coronary heart disease (CHD) perceived to be well controlled at levels of approximately 100 mg/dl (2.6 mmol/L).1 This improved clinical outcome was achieved without significant additional safety risk. This report describes a post hoc analysis of TNT conducted to investigate the efficacy and safety of lipid-lowering therapy with atorvastatin across the range of achieved LDL cholesterol levels. The purpose of this analysis was to determine whether very low LDL cholesterol levels were associated with further reduction in major cardiovascular events and whether any incremental benefit was achieved without additional safety risk.
Methods
Study design and patients
The study protocol and outcome measures for the TNT trial have been published previously.1, 2 All patients gave written informed consent, and the study was approved by the local research ethics committee or institutional review board at each center. In brief, patients with clinically evident CHD (defined as previous myocardial infarction [MI] or previous or present angina with objective evidence of atherosclerotic CHD and/or those who had undergone coronary revascularization procedures) commenced 8 weeks of open-label treatment with atorvastatin 10 mg/day. After this run-in period, 10,001 patients with LDL cholesterol levels <130 mg/dl (3.4 mmol/L) were randomized to double-blind therapy with atorvastatin 10 or 80 mg/day. Patients were followed for a median of 4.9 years. The primary end point was the time to the first occurrence of a major cardiovascular event, defined as CHD death, nonfatal non-procedured–related MI, resuscitated cardiac arrest, and fatal or nonfatal stroke.
Cholesterol inclusion and exclusion criteria were selected to attain an average level of 100 mg/dl (2.6 mmol/L) in the atorvastatin 10 mg/day treatment arm. To achieve an average LDL cholesterol level in the comparator group of approximately 75 mg/dl (1.9 mmol/L), atorvastatin 80 mg/day was chosen. All analyses were performed on an intention-to-treat basis. End points were analyzed from the time the first dose of study drug was dispensed to the first event, according to the Kaplan-Meier method. For the primary analysis, differences between the atorvastatin 80 mg and 10 mg treatment groups were based on log-rank analyses of the first occurrence of an end point during the 5-year follow-up period in each group. In a number of secondary analyses, relative risks, hazard ratios, and their 95% confidence intervals were also calculated in univariate and multivariate models using Cox regression with ≥1 predictor in the same model. Use of Cox regression models allowed predictors to be dichotomous or continuous variables; in some cases, categorical variables were used to perform stratified calculations.
For this analysis, we studied the effect of on-treatment LDL cholesterol levels (measured after 3 months of the double-blind period) on a number of end points. Statistical estimations and tests were performed using Cox regression models with on-treatment LDL cholesterol as a continuous variable-predictor. Separate analyses were run covarying for and stratifying by randomized treatment; LDL cholesterol values in individual treatment groups were also analyzed separately. For the purposes of summarizing and visualizing the data, we stratified the total patient cohort into quintiles on the basis of on-treatment LDL cholesterol. We made this choice so that the lowest strata would contain patients who achieved very low LDL cholesterol levels.
Role of the funding source
The TNT study was funded by Pfizer, Inc. (New York, New York). The steering committee developed the protocol in collaboration with the funding source and took responsibility 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 report independently, without constraints from the sponsor. We take responsibility for the integrity of the data. All investigators have read and agree to the report as written.
Results
Patient population
In the TNT study, 10,001 patients were randomized and given double-blind treatment with atorvastatin 10 or 80 mg. Of these, 9,769 (97.7%) had LDL cholesterol measurements taken after 3 months, and this group was stratified into quintiles (Table 1).
Table 1. Definition of quintiles
| Quintile | LDL-C (mg/dl) | No. of Patients | |||
|---|---|---|---|---|---|
| Range | Mean ± SD | Atorvastatin 10 mg | Atorvastatin 80 mg | Total | |
| 1 | <64 | 53.9 ±7.6 | 114 | 1,722 | 1,836 |
| 2 | 64–<77 | 70.2±3.6 | 529 | 1,403 | 1,932 |
| 3 | 77–<90 | 82.9±3.7 | 1,019 | 968 | 1,987 |
| 4 | 90–<106 | 97.0±4.7 | 1,515 | 515 | 2,030 |
| 5 | ≥106 | 121.9±15.6 | 1,718 | 266 | 1,984 |
Baseline characteristics across quintiles are listed in Table 2. Patients in the quintile with the lowest levels of on-treatment LDL cholesterol concentrations were slightly more likely to be older, to be men, to have lower systolic and diastolic blood pressures, and to have lower body mass indexes than patients in the other quintiles. Patients who achieved the lowest LDL cholesterol levels were slightly more likely to have diabetes, histories of MI and angina, or previous coronary angioplasties and less likely to have congestive heart failure compared with those in the other quintiles.
Table 2. Baseline characteristics of randomized patients
| LDL Cholesterol Quintile (mg/dl) | |||||
|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | |
| <64 | 64–<77 | 77–<90 | 90–<106 | ≥106 | |
| Variable | (1,722/114)⁎ | (1,403/529)⁎ | (968/1,019)⁎ | (515/1,515)⁎ | (266/1,718)⁎ |
| Age (yrs) | 61.7±8.8 | 61.6±8.6 | 61.0±8.9 | 60.9±8.8 | 59.9±9.0 |
| Men | 1,509(82.2%) | 1,560(80.7%) | 1,604(80.7%) | 1,651(81.3%) | 1,589(80.1%) |
| White | 1,725(94.0%) | 1,830(94.7%) | 1,880(94.6%) | 1,918(94.5%) | 1,841(92.8%) |
| Systolic blood pressure (mm Hg) | 130±17 | 131±17 | 131±16 | 131±17 | 131±17 |
| Diastolic blood pressure (mm Hg) | 77±9 | 78±9 | 78±9 | 78±10 | 79±10 |
| Body mass index (kg/m2) | 28.0±4.2 | 28.5±4.4 | 28.6±4.4 | 28.8±4.7 | 28.8±4.9 |
| Current smoker | 236(12.9%) | 223(11.5%) | 237(11.9%) | 274(13.5%) | 336(16.9%) |
| Ex-smoker | 1,145(62.4%) | 1,251(64.8%) | 1,292(65.0%) | 1,288(63.4%) | 1,199(60.4%) |
| Systemic hypertension | 978(53.3%) | 1,051(54.4%) | 1,041(52.4%) | 1,089(53.6%) | 1,131(57.0%) |
| History of diabetes mellitus | 302(16.4%) | 300(15.5%) | 284(14.3%) | 297(14.6%) | 284(14.3%) |
| Myocardial infarction | 1,089(59.3%) | 1,118(57.9%) | 1,168(58.8%) | 1,197(59.0%) | 1,126(56.8%) |
| Angina pectoris | 1,512(82.4%) | 1,585(82.0%) | 1,622(81.6%) | 1,638(80.7%) | 1,606(80.9%) |
| Cerebrovascular accident | 84(4.6%) | 83(4.3%) | 118(5.9%) | 103(5.1%) | 117(5.9%) |
| Peripheral vascular disease | 189(10.3%) | 232(12.0%) | 246(12.4%) | 251(12.4%) | 227(11.4%) |
| Congestive heart failure | 100(5.4%) | 144(7.5%) | 178(9.0%) | 175(8.6%) | 155(7.8%) |
| Arrhythmia | 328(17.9%) | 363(18.8%) | 359(18.1%) | 384(18.9%) | 354(17.8%) |
| Coronary revascularization | |||||
| Coronary angioplasty | 1,017(55.4%) | 1,062(55.0%) | 1,087(54.7%) | 1,086(53.5%) | 1,035(52.2%) |
| Coronary bypass | 812(44.2%) | 867(44.9%) | 942(47.4%) | 992(48.9%) | 938(47.3%) |
| Mean lipid level(mg/dl) | |||||
| LDL cholesterol | 84±14 | 93±15 | 97±16 | 101±15 | 112±15 |
| Total cholesterol | 161±21 | 170±22 | 173±23 | 178±21 | 190±22 |
| Triglycerides | 148±73 | 147±67 | 149±68 | 151±75 | 157±71 |
| High-density lipoprotein cholesterol | 47±11 | 48±11 | 47±11 | 47±11 | 48±11 |
⁎Numbers of patients: atorvastatin 80 mg/atorvastatin 10 mg. |
Patients with lower on-treatment LDL cholesterol concentrations had lower baseline LDL cholesterol, total cholesterol, and triglyceride levels. Baseline high-density lipoprotein cholesterol levels, however, did not differ across quintiles.
Efficacy outcomes
For the total patient cohort, there was a highly significant reduction in the rate of major cardiovascular events with descending achieved levels of on-treatment LDL cholesterol (p <0.0001 for trend across LDL cholesterol), with the lowest rate occurring in the quintile of patients with LDL cholesterol <64 mg/dl (1.7 mmol/L) (Figure 1).
Figure 1.
Rate of major cardiovascular events across quintiles.
Analysis of individual components of the primary end point demonstrated similar results. Rates of CHD death (p <0.01), nonfatal non-procedure–related MI (p <0.0001), and fatal or nonfatal stroke (p <0.05) were also significantly reduced with decreasing levels of LDL cholesterol (Figure 1). The number of resuscitated cardiac arrest events was small (6, 7, 7, 5, and 4, respectively, across quintiles 1 to 5), and no equivalent trend was observed. Although there was no statistically significant trend for mortality across quintiles, death from any cause and from noncardiovascular causes was lowest in patients with the lowest on-treatment LDL cholesterol levels (Figure 2). Cardiovascular deaths were also reduced with lower levels of on-treatment LDL cholesterol (p =0.060).
Figure 2.
Mortality rates across quintiles.
Safety and tolerability
There were no clinically important differences in treatment-associated adverse event rates across quintiles (Table 3). The rate of withdrawals because of adverse events related to treatment was also independent of the achieved level of on-treatment LDL cholesterol. There was no significant association between the incidence of muscle side effects and attained LDL cholesterol concentration. Rates of myalgia were low and similar across quintiles. There were no persistent elevations in creatine kinase (defined as 2 consecutive measurements obtained 4 to 10 days apart that were >10 times the upper limit of the normal range). Five cases of rhabdomyolysis were identified by the on-site investigators. None were believed to be directly attributable to the study drug. Persistent elevations of liver enzymes were infrequent and slightly more prevalent at the lowest LDL cholesterol levels. Analysis of suicide, cancer deaths, and hemorrhagic stroke demonstrated no significant trend across quintiles (Table 4). In particular, no increase in any of these outcomes was observed at the lowest on-treatment LDL cholesterol levels.
Table 3. Adverse event profiles across quintiles
| LDL Cholesterol Quintile(mg/dl) | |||||
|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | |
| <64 | 64–<77 | 77–<90 | 90–<106 | ≥106 | |
| Variable | (1,722/114)⁎ | (1,403/529)⁎ | (968/1,019)⁎ | (515/1,515)⁎ | (266/1,718)⁎ |
| Patients experiencing adverse events | |||||
| All | 96.1% | 95.3% | 95.7% | 96.3% | 95.1% |
| Treatment associated | 7.6% | 6.6% | 5.9% | 6.2% | 7.8% |
| Withdrawals because of adverse events | |||||
| All | 8.8% | 8.6% | 7.6% | 7.9% | 10.5% |
| Treatment associated | 6.6% | 5.5% | 5.0% | 5.2% | 7.2% |
| Treatment-associated myalgia | 4.6% | 4.4% | 4.7% | 4.7% | 5.2% |
| Persistent† CK >10 × ULN | 0% | 0% | 0% | 0% | 0% |
| Persistent† ALT/AST >3 × ULN | 1.1% | 0.8% | 0.9% | 0.4% | 0.5% |
⁎Numbers of patients: atorvastatin 80 mg/atorvastatin 10 mg. |
†Occurring twice within 4 to 10 days. |
Table 4. Incidence of suicide, cancer deaths, and hemorrhagic stroke across quintiles
| LDL Cholesterol Quintile(mg/dl) | |||||
|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | |
| <64 | 64–<77 | 77–<90 | 90–<106 | ≥106 | |
| Variable | (1,722/114)⁎ | (1,403/529)⁎ | (968/1,019)⁎ | (515/1,515)⁎ | (266/1,718)⁎ |
| Suicide | 1(0.1%) | 0 | 1(0.1%) | 1(0.0%) | 1(0.1%) |
| Cancer death | 21(1.1%) | 37(1.9%) | 34(1.7%) | 32(1.6%) | 30(1.5%) |
| Hemorrhagic stroke | 6(0.3%) | 5(0.3%) | 6(0.3%) | 8(0.4%) | 7(0.4%) |
⁎Numbers of patients: atorvastatin 80 mg/atorvastatin 10 mg. |
Efficacy and safety in patients with LDL cholesterol <40 mg/dl (1.0 mmol/L)
Within the overall TNT population, 98 patients had LDL cholesterol measurements taken after 3 months that were <40 mg/dL (1.0 mmol/L) (the mean on-treatment LDL cholesterol level within this subgroup was 34 mg/dl [0.9 mmol/L]). Compared with the quintile groups, patients in this subgroup tended to be older, with a higher incidence of diabetes and a lower incidence of previous angina, MI, and revascularization. They also presented with lower LDL cholesterol (72 mg/dl [1.9 mmol/L]) and total cholesterol (155 mg/dl [4.0 mmol/L]) levels and higher triglyceride levels (194 mg/dl [2.2 mmol/L]) at baseline.
During the course of the study, patients in this subgroup experienced 3 major cardiovascular events (2 nonfatal MIs and 1 nonfatal stroke). Rates of withdrawals because of treatment-related adverse events (4.1%) and treatment-related myalgia (3.1%) in patients with LDL cholesterol <40 mg/dl (1.0 mmol/L) were slightly lower than in any of the individual quintiles. Two patients (2.0%) in this subgroup experienced persistent elevations in liver enzymes.
Effect of achieved LDL cholesterol on major cardiovascular events
Figure 3 provides further evidence that achieved LDL cholesterol levels at 3 months in all TNT patients were predictive of benefit. This association held true when on-treatment LDL cholesterol was covaried for or stratified by randomized treatment (atorvastatin 10 mg vs atorvastatin 80 mg) and when LDL cholesterol values in individual treatment groups were analyzed separately. For the total TNT cohort, each 1 mg/dl reduction in LDL cholesterol was associated with a 0.7% relative risk reduction in major cardiovascular events (p <0.0001). The primary efficacy analysis of TNT demonstrated that patients receiving atorvastatin 80 mg had a 22% relative reduction in major cardiovascular events compared with the group receiving atorvastatin 10 mg (p = 0.0002). However, this effect lost significance when adjusted for 3-month LDL cholesterol level (Figure 3).
Figure 3.
Effect of (A) 3-month on-treatment LDL cholesterol levels and (B) dose of atorvastatin on the risk for major cardiovascular events.
Discussion
The present analysis supports the quantitative relation between reduced LDL cholesterol and reduced CHD risk and demonstrates that this association exists even at very low LDL cholesterol levels. In the TNT cohort, there was a consistent and highly significant reduction in the rate of major cardiovascular events with decreasing levels of on-treatment LDL cholesterol, with the lowest event rate observed in patients with LDL cholesterol <64 mg/dl (1.7 mmol/L). The incremental clinical benefit at very low LDL cholesterol levels was not associated with a corresponding increase in adverse events. A consistent observation was also made in a subgroup of patients with LDL cholesterol levels <40 mg/dl (1.0 mmol/L).
The findings of this post hoc analysis of the TNT study are congruent with those of a number of studies in primary and secondary prevention settings that have shown that additional reductions in the risk for major coronary events are achieved with reductions in LDL cholesterol well below 100 mg/dl (2.6 mmol/L).3, 4, 5, 6, 7, 8 Most recently, the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study compared the effects of intensive lipid lowering with atorvastatin 80 mg to a LDL cholesterol level of 81 mg/dl (2.1 mmol/L) with more moderate therapy with simvastatin 20 to 40 mg to a LDL cholesterol level of 104 mg/dl (2.7 mmol/L) in patients with previous MIs.9 Although the prespecified primary end point did not achieve statistical significance (p = 0.07), there were significant reductions in nonfatal acute MI and in the secondary composite end points of any CHD event and any major cardiovascular events. Other data from surrogate end point studies have demonstrated that it is possible to fully halt, or even reverse, the progression of atherosclerotic disease with intensive statin therapy that reduces LDL cholesterol to very low levels.10, 11
In the recently published Cholesterol Treatment Trialists’ (CTT) Collaboration, a prospective meta-analysis of data from 90,056 subjects in 14 randomized statin trials, proportional reductions in the incidence of major coronary events, coronary revascularization, and stroke were linearly related to the absolute reductions in LDL cholesterol achieved,12 a finding reproduced in this analysis.
Univariate analysis further demonstrated that achieved LDL cholesterol level was predictive of cardiovascular benefit and that this association remained significant when covaried for or stratified by randomized treatment. However, similar analysis of dose effect showed that significance was lost when adjusted for 3-month LDL cholesterol level. This suggests that the observed benefit on major cardiovascular events in TNT is more closely related to achieved on-treatment LDL cholesterol levels than drug dose per se.
There was no significant association between attained on-treatment LDL cholesterol level and the incidence of treatment-related adverse events. The rate of reported myalgia was also low and similar across quintiles. In the entire TNT cohort, persistent elevations in liver transaminases were infrequent but slightly more prevalent in patients receiving atorvastatin 80 mg than those receiving atorvastatin 10 mg. Even in the quintile with the lowest on-treatment LDL cholesterol levels, persistent elevations in alanine aminotransferase and/or aspartate aminotransferase were uncommon (1.1%).
In the prestatin era, concern about LDL lowering focused on the possible increased risk for hemorrhagic stroke, cancer, and trauma death.13, 14, 15 In this study, deaths from these causes were infrequent and did not differ significantly at the lowest on-treatment LDL cholesterol levels (Table 4).
Overall, these safety data provide further evidence that very low levels of LDL cholesterol are not harmful. Our data are consistent with previous analyses conducted in patients randomized to the atorvastatin 80 mg arm of the Pravastatin or Atorvastatin Evaluation and Infection Trial (PROVE-IT).16 Compared with patients treated to a LDL cholesterol level of 80 to 100 mg/dl (2.1 to 2.6 mmol/L), there was no adverse effect on safety parameters when lower LDL levels (including a group of patients ≤40 mg/dl [1.0 mmol/L]) were achieved and apparent improved clinical efficacy.
The TNT study was not powered to detect a treatment impact on all-cause mortality. Although there was no significant reduction in death from any cause with decreasing levels of LDL cholesterol, overall mortality was lowest in patients with on-treatment LDL cholesterol <64 mg/dl (1.7 mmol/L).
The imbalance in noncardiovascular deaths associated with atorvastatin 80 mg compared with atorvastatin 10 mg in the main TNT analysis has been the subject of concern.17 The present analysis, however, demonstrated no trend toward higher noncardiovascular mortality at lower LDL cholesterol (and higher dose atorvastatin) levels. Death from noncardiovascular causes was actually lowest in the quintile with the lowest cholesterol levels. Nevertheless, this issue cannot be resolved by reference to TNT alone. In the IDEAL trial, atorvastatin 80 mg was associated with a small and nonsignificant reduction in noncardiovascular mortality compared with simvastatin, implying that the TNT finding may be the result of chance.
Acknowledgment
A full list of TNT investigators has been published previously.1 We acknowledge the contributions made by Andrei Breazna, Liz Cusenza, Sheila Auster, and Miriam Marshood, all employees of Pfizer, in the collection and analysis of the data and John Bilbruck of Envision Pharma, Inc., Horsham, United Kingdom (a medical writer funded by Pfizer), for editorial assistance.
References
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- † Conflicts of interest: Dr. LaRosa has served as a consultant to Pfizer, Inc., New York, New York; Merck Whitehouse Station, New Jersey; Bristol-Myers Squibb, New York, New York; and AstraZeneca, Wilmington, Delaware; and has received lecture fees from Pfizer. Dr. Grundy has consulted with Abbott, Chicago, Illinois; GlaxoSmithKline, Durham, North Carolina, Pfizer, AstraZeneca, and Sanofi-Aventis, Bridgewater, New Jersey; received lecture fees from Merck Schering Plough, Kenilworth, New Jersey; Kos, Edison, New Jersey, Pfizer, GlaxoSmithKline, Lilly, and Bristol-Myers Squibb; and received research support from Abbott and GlaxoSmithKline. Dr. Kastelein has received consulting fees, lecture fees, and grant support from Pfizer, Merck Schering Plough, Bristol-Myers Squibb, and Sankyo, Munich, Germany; Dr. Kostis has served as a consultant to Pfizer, Schering Plough, Berlex, Montville, New Jersey; Taisho, Tokyo, Japan; Forest Laboratories, New York, New York; and Sankyo; received lecture fees from Pfizer, Merck, Bristol-Myers Squibb, AstraZeneca, Sanofi Aventis, and Otsuka, Rockville, Maryland; and received grant support from Pfizer and Schering Plough. Dr. Greten has received consulting and lecturing fees from Pfizer, Merck, Schering Plough, and Kowa Company, Nagoya, Japan.
The Treating to New Targets study was funded by Pfizer, Inc., New York, New York.
PII: S0002-9149(07)00990-3
doi:10.1016/j.amjcard.2007.03.102
© 2007 Elsevier Inc. All rights reserved.
