Analyses of randomized clinical trials are usually restricted to examination of time to first event. However, because many patients have multiple events, this approach precludes much potentially useful clinical and economic data. To assess the effect on overall disease burden in the Treating to New Targets (TNT) study, we evaluated the effect of treatment with atorvastatin 80 versus 10 mg in the period after the occurrence of a first cardiovascular event. In TNT, 10,001 patients with stable coronary heart disease received double-blind therapy with atorvastatin 80 or 10 mg and were followed for 4.9 years. Post hoc time-to-event analysis was used to estimate separate hazard ratios for time to any first, second, third, fourth, and fifth recurrent cardiovascular events. During TNT, 3,082 patients had a first recurrent cardiovascular event, with 1,516, 698, 345, and 197 developing second, third, fourth, and fifth recurrent events, respectively. In patients receiving atorvastatin 80 mg, the relative risk of a first recurrent event was significantly decreased compared to those receiving atorvastatin 10 mg. Significant benefit with the 80-mg dose was also observed for second, third, fourth, and fifth recurrent events. Similar findings were recorded in 5,854 patients with type 2 diabetes mellitus and/or metabolic syndrome and in 3,809 patients ≥65 years of age compared to younger patients. In conclusion, treatment with atorvastatin 80 mg continued to significantly decrease the risk of any cardiovascular event over time compared to atorvastatin 10 mg in patients who had survived previous events. In TNT, analyses limited to the primary end point significantly underestimated the decrease in total cardiovascular disease burden achieved by intensive low-density lipoprotein cholesterol lowering.
The risk of recurrent myocardial infarction, stroke, and other cardiovascular events is increased in patients with existing coronary heart disease (CHD). Results of the Treating to New Targets (TNT) trial showed that intensive lipid lowering with atorvastatin 80 mg significantly decreased the risk of cardiovascular disease compared to atorvastatin 10 mg in patients with stable CHD. However, analyses of randomized clinical trials such as TNT are usually restricted to examination of time to occurrence of a first primary event or end point. Although time-to-first-event analysis is appropriate for analyses of trial efficacy, for a chronic disease with recurrent events it underestimates the total impact of the intervention over the course of the study. Because a significant number of patients in long-term studies develop multiple events, limiting trial reports to the first event precludes much potentially useful clinical and health economic information. To provide a truer reflection of the effect of the intervention on overall cardiovascular burden, we evaluated the effect of treatment with atorvastatin 80 versus 10 mg in patients with stable CHD in the trial period after the occurrence of a first cardiovascular event.
Methods
The study protocol and outcome measurements for the TNT study have been published previously. In brief, patients with clinically evident CHD (defined as previous myocardial infarction, previous or present angina with objective evidence of atherosclerotic CHD, and/or who had undergone a coronary revascularization procedure) commenced 8 weeks of open-label treatment with atorvastatin 10 mg/day. After this run-in period, 10,001 patients with a low-density lipoprotein cholesterol level <130 mg/dl (3.4 mmol/L) were randomized to double-blind therapy with atorvastatin 80 or 10 mg/day. Patients were followed for a median of 4.9 years. The primary end point was the time to first occurrence of a major cardiovascular event, defined as CHD death, nonfatal nonprocedure-related myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke.
Time-to-event analysis was used to estimate the treatment hazard ratio (HR) separately for time to first, second, third, fourth, and fifth recurrences of any cardiovascular event, defined as any coronary event (CHD death, nonfatal myocardial infarction, resuscitated cardiac arrest, revascularization procedure, procedure-related myocardial infarction, or documented angina); a cerebrovascular event (fatal or nonfatal stroke, transient ischemic attack); a new diagnosis of peripheral artery disease; or first hospitalization with a primary diagnosis of congestive heart failure. Even if a patient’s treatment changed after a first recurrent event, the study cohort continued to be analyzed according to an intention-to-treat principle. Any cardiovascular event was chosen as an end point for consideration to maximize the power for statistical analysis. Events occurring within 48 hours of one another were reviewed together by the end-point committee but were only adjudicated as 1 event, with the most severe of the events taking preference. All reported cardiovascular end points in the TNT trial were adjudicated using the method of Wei et al. Analyses applied Cox proportional hazards model for marginal distribution for each cardiovascular event adjusting for age and gender.
In addition to the overall study cohort, separate subgroup analyses were conducted in (1) patients with type 2 diabetes and/or metabolic syndrome at screening and (2) patients ≥65 years of age. Type 2 diabetes was defined as previous diabetes noted on a patient’s prescreening form (fasting glucose levels at screening were not used). Metabolic syndrome was defined as the presence of ≥3 of the following risk factors: body mass index ≥28 kg/m 2 , triglycerides ≥150 mg/dl (1.7 mmol/L), high-density lipoprotein-cholesterol <40 mg/dl (1.0 mmol/L) in men or <50 mg/dl (1.3 mmol/L) in women, blood pressure ≥130/85 mm Hg, or fasting glucose level ≥100 mg/dl (5.6 mmol/L). This definition was based on that proposed by the National Cholesterol Education Program Adult Treatment Panel, and a more recent modification by the American Heart Association and National Heart, Lung, and Blood Institute. In our analysis, however, body mass index ≥28 kg/m 2 replaced a waist circumference ≥102 cm in men or ≥88 cm in women, because waist circumference was not recorded at screening.
Differences between treatment groups for the first occurrence of a major cardiovascular event during the 5-year follow-up period were based on log-rank analyses. Relative risks, HRs, and their 95% confidence intervals (CIs) were also calculated using the Cox regression model. Two-sided p values <0.05 were regarded as statistically significant. Intention-to-treat analysis was performed on all randomized patients.
For the present analysis, treatment HRs from Cox regression models were examined at successive monthly intervals for the following end points: major cardiovascular events, major coronary events, stroke, and any cardiovascular event.
Results
In the overall study population, intensive therapy with atorvastatin 80 mg significantly decreased the rate of major cardiovascular events compared to atorvastatin 10 mg. The relative and absolute risk decreases were 22% and 2.2%, respectively (HR 0.78, 95% CI 0.69 to 0.89, p <0.001).
During the course of the TNT study, 3,082 patients (1,405 on atorvastatin 80 mg and 1,677 on atorvastatin 80 mg, p <0.001) developed any cardiovascular event ( Table 1 ). In total, 2,863 events were recorded in those receiving atorvastatin 80 mg and 3,563 events in those receiving atorvastatin 10 mg. The numbers with second, third, fourth, and fifth recurrent cardiovascular events were 1,516, 698, 345, and 197, respectively. A summary of cardiovascular events is presented in Table 2 . The most common end point was angina as a first recurrent event and coronary revascularization for all subsequent events.
| Subjects With Cardiovascular Event | |||
|---|---|---|---|
| Overall | Atorvastatin 10 mg | Atorvastatin 80 mg | |
| First event | 3,082 | 1,677 | 1,405 |
| Second event | 1,516 | 841 | 675 |
| Third event | 698 | 394 | 304 |
| Fourth event | 345 | 200 | 145 |
| Fifth event | 197 | 115 | 82 |
| Cardiovascular Event | Subjects With Event | ||||
|---|---|---|---|---|---|
| First Event | Second Event | Third Event | Fourth Event | Fifth Event | |
| Angina pectoris | 927 | 240 | 153 | 57 | 42 |
| Coronary revascularization | 774 | 696 | 253 | 137 | 64 |
| CHD death | 107 | 55 | 25 | 10 | 7 |
| Congestive heart failure | 160 | 101 | 61 | 42 | 28 |
| Procedure-related myocardial infarction | 5 | 5 | 4 | 3 | 0 |
| Nonfatal myocardial infarction | 374 | 94 | 56 | 38 | 19 |
| Peripheral artery disease | 394 | 220 | 83 | 38 | 23 |
| Resuscitated cardiac arrest | 22 | 5 | 3 | 1 | 1 |
| Stroke | 182 | 62 | 33 | 12 | 8 |
| Transient ischemic attack | 137 | 38 | 27 | 7 | 5 |
In patients receiving atorvastatin 80 mg the relative risk of a first recurrent cardiovascular event was significantly decreased by 19% (HR 0.81, 95% CI 0.75 to 0.87, p <0.0001) compared to those receiving atorvastatin 10 mg. Similar findings were present for the occurrence of second, third, fourth, and fifth events ( Figure 1 ).
