- Email: [email protected]
Comparison of 80 versus 10 mg of Atorvastatin on Occurrence of Cardiovascular Events After the First Event (from the Treating to New Targets [TNT] Trial)
Comparison of 80 versus 10 mg of Atorvastatin on Occurrence of Cardiovascular Events After the First Event (from the Treating to New Targets [TNT] Trial) John C. LaRosa, MDa,*, Prakash C. Deedwania, MDc, James Shepherd, MDd, Nanette K. Wenger, MDe, Heiner Greten, MDf, David A. DeMicco, PharmDb, and Andrei Breazna, PhDb, on behalf of the TNT Investigators 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. © 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:283–287) 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.1 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
a State University of New York, Health Science Center, Brooklyn, and Pfizer, Inc., New York, New York; cVA Central California Healthcare System and UCSF School of Medicine, Fresno, California; dUniversity of Glasgow, Glasgow, United Kingdom; eEmory University, Atlanta, Georgia; and fHanseatic Heart Center, Asklepios Klinik St. Georg, Hamburg, Germany. Manuscript received June 9, 2009; revised manuscript received and accepted September 16, 2009. The TNT study was funded by Pfizer, Inc., New York, New York. *Corresponding author: Tel: 718-270-2611; fax: 718-270-4732. E-mail address: [email protected] (J.C. LaRosa).
b
0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.09.025
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.1,2 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 nonprocwww.AJConline.org
284
The American Journal of Cardiology (www.AJConline.org)
Table 1 Occurrence of cardiovascular events in overall Treating to New Targets (TNT) study cohort Subjects With Cardiovascular Event
First event Second event Third event Fourth event Fifth event
Overall
Atorvastatin 10 mg
Atorvastatin 80 mg
3,082 1,516 698 345 197
1,677 841 394 200 115
1,405 675 304 145 82
edure-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.3 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 ⱖ65 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 ⱖ3 of the following risk factors: body mass index ⱖ28 kg/m2, triglycerides ⱖ150 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 ⱖ130/85 mm Hg, or fasting glucose level ⱖ100 mg/dl (5.6 mmol/L). This definition was based on that proposed by the National Cholesterol Education Program Adult Treatment Panel,4 and a more recent modification by the American Heart Association and National Heart, Lung, and Blood Institute.5 In our analysis, however, body mass index ⱖ28 kg/m2 replaced a waist circumference ⱖ102 cm in men or ⱖ88 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
Table 2 Summary of cardiovascular events in overall Treating to New Targets (TNT) study cohort Cardiovascular Event
Angina pectoris Coronary revascularization CHD death Congestive heart failure Procedure-related myocardial infarction Nonfatal myocardial infarction Peripheral artery disease Resuscitated cardiac arrest Stroke Transient ischemic attack
Subjects With Event First Event
Second Event
Third Event
Fourth Event
Fifth Event
927 774 107 160 5
240 696 55 101 5
153 253 25 61 4
57 137 10 42 3
42 64 7 28 0
374
94
56
38
19
394 22 182 137
220 5 62 38
83 3 33 27
38 1 12 7
23 1 8 5
Figure 1. Risk decrease in cardiovascular events.
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
Coronary Artery Disease/Sustained Benefit With High-Dose Atorvastatin
285
Figure 2. Risk decrease in cardiovascular events in patients (A) with type 2 diabetes and/or metabolic syndrome and (B) ⱖ65 years of age.
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. 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). In total, 5,854 patients with stable CHD and type 2 diabetes mellitus and/or metabolic syndrome were randomized in the TNT study (270 patients with type 2 diabetes/no metabolic syndrome; 4,352 patients with metabolic syndrome/no type 2 diabetes; 1,232 patients with type 2 diabetes and metabolic syndrome). Of these 5,854 patients, 2,002 developed a first recurrent cardiovascular event. As with the total study population, treatment with atorvastatin 80 mg continued to significantly decrease the risk of any cardiovascular event over the entire follow-up period compared to atorvastatin 10 mg in patients with type 2 diabetes or metabolic syndrome who developed multiple cardiovascular events (Figure 2). Similar findings were recorded in the 3,809 patients ⱖ65 years of age (Figure 2). Treatment with atorvastatin 80 versus 10 mg was associated with a decrease in major cardiovascular events from early after-treatment initiation. After 1 month, the HR was ⬍1.0 favoring the atorvastatin 80-mg group, although the
Figure 3. (A–D) Time to benefit with atorvastatin 80 versus 10 mg.
benefit was not statistically significant at this time. This beneficial effect reached ongoing statistical significance (time at which HR and 95% CI were consistently ⬍1.0) at month 16 and was sustained for the duration of the study (Figure 3). A quantitatively homogenous early effect of high-dose atorvastatin was observed across all outcomes evaluated. Statistically significant decreases in major coronary events (982 events; Figure 3), stroke (272 events; Figure 3), any cardiovascular event (3,082 events; Figure 3), and revascularization (1,571 events; data not plotted) were observed after 28, 59, 4, and 3 months, respectively. Discussion In the TNT study, intensive lipid lowering with atorvastatin 80 mg continued to decrease the risk of any cardiovascular event over time compared to atorvastatin 10 mg in patients who had survived previous events. Relative risk decreases increased and remained significant for patients with second, third, fourth, and fifth such events. Although the results of statin trials are usually based on the occurrence of the first event only, the present analysis differed by evaluating all cardiovascular events developed
286
The American Journal of Cardiology (www.AJConline.org)
by patients during the course of the study. This more accurately represents real-world clinical practice, in which consideration of treatment beyond an initial cardiovascular outcome is important because recurrent events are associated with more testing and procedures, hospital visits, medications, physician time, and ultimately increased costs. For the patient, multiple events are also likely to result in a higher level of morbidity and a decreased quality of life. Our results correspond with those of the Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL) study, which was the first to use the analyses of Wei et al6 in a cardiovascular disease prevention trial. In IDEAL, treatment with atorvastatin 80 mg decreased the risk of first to fifth recurrent cardiovascular events compared to standard statin therapy of simvastatin 20 to 40 mg. The larger number of events in TNT compared to IDEAL is likely the reason that significance was maintained in patients with fourth and fifth events in TNT, but not in the corresponding patient groups in IDEAL. Together, these data from TNT and IDEAL indicate that patients with CHD who have had multiple events continue to benefit from long-term intensive statin therapy. Time-to-first-event analysis is a robust statistical device and remains an important means for evaluating the significance of a treatment effect and a straightforward way of comparing outcomes among trials. However, our data suggest that such traditional analyses of results, when limited to the primary end point, may significantly underestimate the decrease in the total clinical burden of cardiovascular disease events achieved by intensive low-density lipoprotein cholesterol lowering. Extending the assessment of efficacy beyond the first event reported by a patient in trials provides important information about the longer-term effects of statin therapy and increases the clinical and economic relevance and impact of these data. Potential limitations of this type of analysis have been discussed previously.6 Such analyses do not provide the ability to explore the inter-relation among event times and how previous events, in their type and severity, affect the risk of subsequent outcomes. However, a strength of this method is that even if a patient’s treatment may have changed after a first recurrent event the study cohort continued to be analyzed according to the intention-to-treat principle, which gives us a conservative estimate of the treatment effect. Risk of future events in patients with existing coronary disease is further heightened by concomitant risk factors, and the necessity to decrease the risk of subsequent cardiovascular end points is therefore even greater. Previous timeto-first-event subgroup analyses of the TNT trial showed that treatment with atorvastatin 80 mg significantly decreased the risk of cardiovascular disease compared to atorvastatin 10 mg in patients with stable CHD ⱖ65 years of age7 and in those with type 2 diabetes8 or metabolic syndrome.9 Further analyses of the TNT cohort demonstrated that sustained benefit beyond a first recurrent cardiovascular event observed with intensive lipid lowering in the overall population extends to these higher-risk subgroups. For the 5,854 patients with type 2 diabetes and/or metabolic syndrome, intensive therapy with atorvastatin 80 mg progressively decreased the relative risk of future cardiovascular
episodes with increasing numbers of events. A similar trend was observed in the 3,809 patients ⱖ65 years of age, although significance was lost for the fifth recurrent event, possibly due to a smaller number of events. In separate analyses, assessment of treatment HRs at successive monthly intervals demonstrated that the additional clinical benefit observed in patients with stable CHD receiving atorvastatin 80 mg in the TNT study was apparent soon after treatment initiation. A decrease in major cardiovascular events with intensive lipid lowering was observed within 1 month of commencement of therapy and a statistically significant difference between treatment groups was reached after 16 months. For all end points analyzed, atorvastatin 80 mg had a consistent effect providing an early treatment benefit that was sustained for the duration of the study. This finding, although not in any way conclusive, does not support the idea of different mechanisms for benefits observed in different vascular beds. The time taken for ongoing statistical significance to be attained in a given event “category” was dependent on the number of outcomes within that category reported during the trial. More events provide greater power to detect a difference between groups; the larger the number of end points the shorter will be the estimated time to benefit. For the category of any cardiovascular event, for which there were ⬎3,000 end points over the course of the study, significant clinical benefit with intensive lipid lowering was apparent after 4 months. Data from TNT are consistent with those from similar analyses of the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22 (PROVE IT–TIMI 22) study in which intensive therapy with atorvastatin 80 mg was associated with a significant decrease in clinical events compared to pravastatin 40 mg after only 30 days in patients with acute coronary syndromes.10 Early clinical benefit has also been demonstrated with low-dose atorvastatin versus placebo in primary prevention patients with multiple risk factors11 and type 2 diabetes.12 Acknowledgment: Editorial support was provided by John Bilbruck at UBC Scientific Solutions (Horsham, West Sussex, United Kingdom) and was funded by Pfizer, Inc., New York, New York. 1. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425–1435. 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 –158. 3. Wei LJ, Lin DY, Weissfeld L. Regression analysis of multivariate incomplete failure time data by modeling marginal distributions. Am Stat J Assoc 1989;84:1065–1073. 4. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486 –2497.
Coronary Artery Disease/Sustained Benefit With High-Dose Atorvastatin 5. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Costa F; American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation 2005;112:2735–2752. 6. Tikkanen MJ, Szarek M, Fayyad R, Holme I, Cater NB, Faergeman O, Kastelein JJP, Olsson AG, Lytken Larsen M Lindahl C, Pedersen TR; IDEAL Investigators. Total cardiovascular disease burden— comparing intensive with moderate statin therapy: insights from the IDEAL trial. J Am Coll Cardiol 2009;54:2353-2357. 7. 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. 8. Shepherd J, Barter P, Carmena R, Deedwania P, Fruchart JC, Haffner S, Hsia J, Breazna A, LaRosa J, Grundy S, Waters D. Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes. The Treating to New Targets (TNT) study. Diabetes Care 2006;29:1220 –1226.
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9. Deedwania P, Barter P, Carmena R, Deedwania P, Fruchart JC, Haffner S, Hsia J, Breazna A, LaRosa J, Grundy S, Waters D. Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the Treating to New Targets study. Lancet 2006;368:919 –928. 10. Ray KK, Cannon CP, McCabe CH, Cairns R, Tonkin AM, Sacks FM, Jackson G, Braunwald E; PROVE IT-TIMI 22 Investigators. Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 2005;46:1405–1410. 11. Sever PS, Poulter NR, Dahlof B, Wedel H; Anglo-Scandinavian Cardiac Outcomes Trial Investigators. Different time course for prevention of coronary and stroke events by atorvastatin in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA). Am J Cardiol 2005;96:39F– 44F. 12. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Fuller JH; CARDS Investigators. Rapid emergence of effect of atorvastatin on cardiovascular outcomes in the Collaborative Atorvastatin Diabetes Study (CARDS). Diabetologia 2005;48:2482–2485.
a State University of New York, Health Science Center, Brooklyn, and Pfizer, Inc., New York, New York; cVA Central California Healthcare System and UCSF School of Medicine, Fresno, California; dUniversity of Glasgow, Glasgow, United Kingdom; eEmory University, Atlanta, Georgia; and fHanseatic Heart Center, Asklepios Klinik St. Georg, Hamburg, Germany. Manuscript received June 9, 2009; revised manuscript received and accepted September 16, 2009. The TNT study was funded by Pfizer, Inc., New York, New York. *Corresponding author: Tel: 718-270-2611; fax: 718-270-4732. E-mail address: [email protected] (J.C. LaRosa).
b
0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.09.025
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.1,2 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 nonprocwww.AJConline.org
284
The American Journal of Cardiology (www.AJConline.org)
Table 1 Occurrence of cardiovascular events in overall Treating to New Targets (TNT) study cohort Subjects With Cardiovascular Event
First event Second event Third event Fourth event Fifth event
Overall
Atorvastatin 10 mg
Atorvastatin 80 mg
3,082 1,516 698 345 197
1,677 841 394 200 115
1,405 675 304 145 82
edure-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.3 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 ⱖ65 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 ⱖ3 of the following risk factors: body mass index ⱖ28 kg/m2, triglycerides ⱖ150 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 ⱖ130/85 mm Hg, or fasting glucose level ⱖ100 mg/dl (5.6 mmol/L). This definition was based on that proposed by the National Cholesterol Education Program Adult Treatment Panel,4 and a more recent modification by the American Heart Association and National Heart, Lung, and Blood Institute.5 In our analysis, however, body mass index ⱖ28 kg/m2 replaced a waist circumference ⱖ102 cm in men or ⱖ88 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
Table 2 Summary of cardiovascular events in overall Treating to New Targets (TNT) study cohort Cardiovascular Event
Angina pectoris Coronary revascularization CHD death Congestive heart failure Procedure-related myocardial infarction Nonfatal myocardial infarction Peripheral artery disease Resuscitated cardiac arrest Stroke Transient ischemic attack
Subjects With Event First Event
Second Event
Third Event
Fourth Event
Fifth Event
927 774 107 160 5
240 696 55 101 5
153 253 25 61 4
57 137 10 42 3
42 64 7 28 0
374
94
56
38
19
394 22 182 137
220 5 62 38
83 3 33 27
38 1 12 7
23 1 8 5
Figure 1. Risk decrease in cardiovascular events.
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
Coronary Artery Disease/Sustained Benefit With High-Dose Atorvastatin
285
Figure 2. Risk decrease in cardiovascular events in patients (A) with type 2 diabetes and/or metabolic syndrome and (B) ⱖ65 years of age.
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. 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). In total, 5,854 patients with stable CHD and type 2 diabetes mellitus and/or metabolic syndrome were randomized in the TNT study (270 patients with type 2 diabetes/no metabolic syndrome; 4,352 patients with metabolic syndrome/no type 2 diabetes; 1,232 patients with type 2 diabetes and metabolic syndrome). Of these 5,854 patients, 2,002 developed a first recurrent cardiovascular event. As with the total study population, treatment with atorvastatin 80 mg continued to significantly decrease the risk of any cardiovascular event over the entire follow-up period compared to atorvastatin 10 mg in patients with type 2 diabetes or metabolic syndrome who developed multiple cardiovascular events (Figure 2). Similar findings were recorded in the 3,809 patients ⱖ65 years of age (Figure 2). Treatment with atorvastatin 80 versus 10 mg was associated with a decrease in major cardiovascular events from early after-treatment initiation. After 1 month, the HR was ⬍1.0 favoring the atorvastatin 80-mg group, although the
Figure 3. (A–D) Time to benefit with atorvastatin 80 versus 10 mg.
benefit was not statistically significant at this time. This beneficial effect reached ongoing statistical significance (time at which HR and 95% CI were consistently ⬍1.0) at month 16 and was sustained for the duration of the study (Figure 3). A quantitatively homogenous early effect of high-dose atorvastatin was observed across all outcomes evaluated. Statistically significant decreases in major coronary events (982 events; Figure 3), stroke (272 events; Figure 3), any cardiovascular event (3,082 events; Figure 3), and revascularization (1,571 events; data not plotted) were observed after 28, 59, 4, and 3 months, respectively. Discussion In the TNT study, intensive lipid lowering with atorvastatin 80 mg continued to decrease the risk of any cardiovascular event over time compared to atorvastatin 10 mg in patients who had survived previous events. Relative risk decreases increased and remained significant for patients with second, third, fourth, and fifth such events. Although the results of statin trials are usually based on the occurrence of the first event only, the present analysis differed by evaluating all cardiovascular events developed
286
The American Journal of Cardiology (www.AJConline.org)
by patients during the course of the study. This more accurately represents real-world clinical practice, in which consideration of treatment beyond an initial cardiovascular outcome is important because recurrent events are associated with more testing and procedures, hospital visits, medications, physician time, and ultimately increased costs. For the patient, multiple events are also likely to result in a higher level of morbidity and a decreased quality of life. Our results correspond with those of the Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL) study, which was the first to use the analyses of Wei et al6 in a cardiovascular disease prevention trial. In IDEAL, treatment with atorvastatin 80 mg decreased the risk of first to fifth recurrent cardiovascular events compared to standard statin therapy of simvastatin 20 to 40 mg. The larger number of events in TNT compared to IDEAL is likely the reason that significance was maintained in patients with fourth and fifth events in TNT, but not in the corresponding patient groups in IDEAL. Together, these data from TNT and IDEAL indicate that patients with CHD who have had multiple events continue to benefit from long-term intensive statin therapy. Time-to-first-event analysis is a robust statistical device and remains an important means for evaluating the significance of a treatment effect and a straightforward way of comparing outcomes among trials. However, our data suggest that such traditional analyses of results, when limited to the primary end point, may significantly underestimate the decrease in the total clinical burden of cardiovascular disease events achieved by intensive low-density lipoprotein cholesterol lowering. Extending the assessment of efficacy beyond the first event reported by a patient in trials provides important information about the longer-term effects of statin therapy and increases the clinical and economic relevance and impact of these data. Potential limitations of this type of analysis have been discussed previously.6 Such analyses do not provide the ability to explore the inter-relation among event times and how previous events, in their type and severity, affect the risk of subsequent outcomes. However, a strength of this method is that even if a patient’s treatment may have changed after a first recurrent event the study cohort continued to be analyzed according to the intention-to-treat principle, which gives us a conservative estimate of the treatment effect. Risk of future events in patients with existing coronary disease is further heightened by concomitant risk factors, and the necessity to decrease the risk of subsequent cardiovascular end points is therefore even greater. Previous timeto-first-event subgroup analyses of the TNT trial showed that treatment with atorvastatin 80 mg significantly decreased the risk of cardiovascular disease compared to atorvastatin 10 mg in patients with stable CHD ⱖ65 years of age7 and in those with type 2 diabetes8 or metabolic syndrome.9 Further analyses of the TNT cohort demonstrated that sustained benefit beyond a first recurrent cardiovascular event observed with intensive lipid lowering in the overall population extends to these higher-risk subgroups. For the 5,854 patients with type 2 diabetes and/or metabolic syndrome, intensive therapy with atorvastatin 80 mg progressively decreased the relative risk of future cardiovascular
episodes with increasing numbers of events. A similar trend was observed in the 3,809 patients ⱖ65 years of age, although significance was lost for the fifth recurrent event, possibly due to a smaller number of events. In separate analyses, assessment of treatment HRs at successive monthly intervals demonstrated that the additional clinical benefit observed in patients with stable CHD receiving atorvastatin 80 mg in the TNT study was apparent soon after treatment initiation. A decrease in major cardiovascular events with intensive lipid lowering was observed within 1 month of commencement of therapy and a statistically significant difference between treatment groups was reached after 16 months. For all end points analyzed, atorvastatin 80 mg had a consistent effect providing an early treatment benefit that was sustained for the duration of the study. This finding, although not in any way conclusive, does not support the idea of different mechanisms for benefits observed in different vascular beds. The time taken for ongoing statistical significance to be attained in a given event “category” was dependent on the number of outcomes within that category reported during the trial. More events provide greater power to detect a difference between groups; the larger the number of end points the shorter will be the estimated time to benefit. For the category of any cardiovascular event, for which there were ⬎3,000 end points over the course of the study, significant clinical benefit with intensive lipid lowering was apparent after 4 months. Data from TNT are consistent with those from similar analyses of the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22 (PROVE IT–TIMI 22) study in which intensive therapy with atorvastatin 80 mg was associated with a significant decrease in clinical events compared to pravastatin 40 mg after only 30 days in patients with acute coronary syndromes.10 Early clinical benefit has also been demonstrated with low-dose atorvastatin versus placebo in primary prevention patients with multiple risk factors11 and type 2 diabetes.12 Acknowledgment: Editorial support was provided by John Bilbruck at UBC Scientific Solutions (Horsham, West Sussex, United Kingdom) and was funded by Pfizer, Inc., New York, New York. 1. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425–1435. 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 –158. 3. Wei LJ, Lin DY, Weissfeld L. Regression analysis of multivariate incomplete failure time data by modeling marginal distributions. Am Stat J Assoc 1989;84:1065–1073. 4. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486 –2497.
Coronary Artery Disease/Sustained Benefit With High-Dose Atorvastatin 5. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Costa F; American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation 2005;112:2735–2752. 6. Tikkanen MJ, Szarek M, Fayyad R, Holme I, Cater NB, Faergeman O, Kastelein JJP, Olsson AG, Lytken Larsen M Lindahl C, Pedersen TR; IDEAL Investigators. Total cardiovascular disease burden— comparing intensive with moderate statin therapy: insights from the IDEAL trial. J Am Coll Cardiol 2009;54:2353-2357. 7. 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. 8. Shepherd J, Barter P, Carmena R, Deedwania P, Fruchart JC, Haffner S, Hsia J, Breazna A, LaRosa J, Grundy S, Waters D. Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes. The Treating to New Targets (TNT) study. Diabetes Care 2006;29:1220 –1226.
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9. Deedwania P, Barter P, Carmena R, Deedwania P, Fruchart JC, Haffner S, Hsia J, Breazna A, LaRosa J, Grundy S, Waters D. Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the Treating to New Targets study. Lancet 2006;368:919 –928. 10. Ray KK, Cannon CP, McCabe CH, Cairns R, Tonkin AM, Sacks FM, Jackson G, Braunwald E; PROVE IT-TIMI 22 Investigators. Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 2005;46:1405–1410. 11. Sever PS, Poulter NR, Dahlof B, Wedel H; Anglo-Scandinavian Cardiac Outcomes Trial Investigators. Different time course for prevention of coronary and stroke events by atorvastatin in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA). Am J Cardiol 2005;96:39F– 44F. 12. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Fuller JH; CARDS Investigators. Rapid emergence of effect of atorvastatin on cardiovascular outcomes in the Collaborative Atorvastatin Diabetes Study (CARDS). Diabetologia 2005;48:2482–2485.