- Email: [email protected]
Treating to New Targets (TNT) Study: does lowering low-density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit?
Treating to New Targets (TNT) Study: Does Lowering Low-Density Lipoprotein Cholesterol Levels Below Currently Recommended Guidelines Yield Incremental Clinical Benefit? David D. Waters, MD, John R. Guyton, MD, David M. Herrington, MD, MHS, Mary P. McGowan, MD, Nanette K. Wenger, MD, and Charles Shear, PhD, for the TNT Steering Committee Members and Investigators The Treating to New Targets (TNT) trial is a parallelgroup study that has randomized 10,003 patients from 14 countries to double-blind treatment with either atorvastatin 10 or 80 mg. During the double-blind period, low-density lipoprotein (LDL) cholesterol levels are expected to reach approximate mean values of 100 mg/dl (2.6 mmol/L) for the low-dose atorvastatin group and 75 mg/dl (1.9 mmol/L) for the high-dose group. Randomized patients are expected to be followed for an average of 5 years. The primary end point is the time to
occurrence of a major cardiovascular event, defined as coronary heart disease death, nonfatal myocardial infarction, resuscitated cardiac arrest, or stroke. The large patient numbers in the TNT study and long follow-up should ensure that there is adequate power to definitively determine if reducing LDL cholesterol levels to approximately 75 mg/dl (1.9 mmol/L) can provide additional clinical benefit. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;93:154 –158)
he low-density lipoprotein (LDL) cholesterol treatment goal currently proposed for patients with T atherosclerosis is ⱕ100 mg/dl (ⱕ2.6 mmol/L). In
achieves an average LDL cholesterol of approximately 100 mg/dl (2.6 mmol/L) and 1 that achieves an average LDL cholesterol of approximately 75 mg/dl (1.9 mmol/L). Men and women aged 35 to 75 years with clinically evident coronary heart disease (CHD), defined as previous myocardial infarction (MI), previous or present angina with objective evidence of atherosclerotic CHD, and who have undergone a coronary revascularization procedure, are eligible for study entry. Major exclusion criteria include any of the following: hypersensitivity to statins; active liver disease or hepatic dysfunction defined as alanine aminotransferase or aspartate aminotransferase ⬎1.5 times the upper limit of normal; women who are pregnant or breastfeeding; patients with nephrotic syndrome; uncontrolled diabetes mellitus; uncontrolled hypothyroidism; uncontrolled hypertension (as defined by the investigator) at the screening visit; a MI, coronary revascularization procedure or severe/unstable angina within 1 month of screening; any planned surgical procedure for the treatment of atherosclerosis; an ejection fraction ⬍30%; hemodynamically important valvular disease; gastrointestinal disease limiting drug absorption or partial ileal bypass; any nonskin malignancy, malignant melanoma or other survival-limiting disease; unexplained creatine phosphokinase levels ⬎6 times the upper limit of normal; concurrent therapy with long-term immunosuppressants; concurrent therapy with lipid-regulating drugs not specified as study treatment in the protocol; history of alcohol abuse; and participation in another clinical trial concurrently or within 30 days before screening. At
1,2
the recently published Heart Protection Study,3 patients whose LDL cholesterol was below this level at baseline still derived substantial clinical benefit from cholesterol lowering with a statin drug. In patients whose LDL cholesterol levels have been lowered to 100 mg/dl (2.6 mmol/L) from higher levels, it is unclear whether additional benefit would accrue from additional LDL cholesterol lowering.4,5 Treating to New Targets (TNT) Study: The primary hypothesis of the TNT study is that incremental reduction in cardiovascular risk can be achieved by lowering LDL cholesterol levels beyond currently recommended minimum targets. To test the hypothesis, 2 doses of atorvastatin (10 and 80 mg once daily) are being used in a double-blind parallel group design. The occurrence of major cardiovascular end points will be compared in 2 groups of patients: 1 that From the University of California, San Francisco School of Medicine, San Francisco, California; Duke University Medical Center, Durham, North Carolina; Wake Forest University School of Medicine, WinstonSalem, North Carolina; New England Medical Center, Boston, Massachusetts; Emory University School of Medicine, Atlanta, Georgia; and Pfizer Inc., Groton, Connecticut. This study was supported by a research grant from Pfizer Inc., Groton, Connecticut. Manuscript received August 8, 2003; revised manuscript received and accepted September 16, 2003. Address for reprints: David D. Waters, MD, Division of Cardiology, Room 5G1, San Francisco General Hospital, 1001 Potrero Avenue, San Francisco, California 94110. E-mail: dwaters@ medsfgh.ucsf.edu. *A list of members and investigators appears in the Appendix.
154
©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 93 January 15, 2004
0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2003.09.031
screening (visit 1) an informed consent is signed, demographic characteristics assessed, vital signs measured, all concomitant medications documented, and a medical history recorded. Blood samples are collected to determine fasting lipid levels and the patient’s standard clinical profile. Patients receive dietary information to obtain compliance with the National Cholesterol Education Program (NCEP) Step I, Step II, or other equivalent diet. Any previously prescribed lipid-regulating drugs are discontinued at screening, and patients require a wash-out period of ⱖ6 weeks before visit 2. After discontinuation of previous lipid-lowering therapies, all eligible patients commence treatment with atorvastatin 10 mg/day on an open-label basis (visit 2; week ⫺8). Patients with LDL cholesterol between 130 and 250 mg/dl (3.4 to 6.5 mmol/L) and triglycerides ⱕ600 mg/dl (6.8 mmol/L) at visit 2 are eligible to continue the study during the run-in period. At visit 3 (week ⫺4) and visit 4 (week ⫺2), lipid levels are determined, dietary counseling continued, and treatment with atorvastatin 10 mg/day maintained. At the end of the run-in period (week 0), those patients with a mean LDL cholesterol ⬍130 mg/dl (3.4 mmol/L) at visits 3 and 4 are randomized to double-blind therapy with either atorvastatin 10 or 80 mg/day. During the first year of the double-blind period, 4 follow-up visits are scheduled at week 12 and at months 6, 9, and 12. After the first year of active treatment, patients have scheduled study visits every 6 months. At each visit, vital signs, clinical end points, adverse events, and concurrent medication information are collected. In addition, on alternating visits (i.e., annually), physical examinations and electrocardiograms are performed and laboratory specimens collected. An end point committee reviews (blinded) all potential primary and secondary end points to adjudicate the end point designation. The committee members who perform patient end point review are not investigators or subinvestigators in the trial. Differences in patient review designations are adjudicated through scheduled conference calls or regular meetings. A separate Manual of Operations fully describes the methods to be used by the end point committee. Study-specific, data-driven algorithms are used to achieve end point consensus. The primary end point is the time to occurrence of a major cardiovascular event, defined as CHD death, nonfatal MI, resuscitated cardiac arrest, and fatal or nonfatal stroke. Secondary study outcomes are any occurrence of the following: major coronary event (CHD death, nonfatal MI, or resuscitated cardiac arrest), any coronary event (major coronary event, revascularization procedure, procedure-related MI, or documented angina); cerebrovascular event (fatal or nonfatal stroke, transient ischemic attack); peripheral vascular disease; hospitalization with primary diagnosis of congestive heart failure; any cardiovascular event (any of the previous); and all cause mortality. An independent Data Safety Monitoring Board (DSMB) periodically evaluates safety and efficacy
FIGURE 1. Patient disposition.
data and makes recommendations regarding continuation or modification of the study or study procedures. Interim analyses for the TNT study will begin after a median 3-year follow-up. The timing and number of interim analyses will be at the discretion of the DSMB. Interim monitoring for efficacy is based on the primary end point using a log-rank test with 2-sided Peto-type monitoring boundaries (Z) of ⫾3.0. Interim monitoring for harm is based on all-cause mortality using a log-rank test with O’Brien Fleming boundaries. The LDL cholesterol inclusion/exclusion criteria were selected to achieve an average level of 100 mg/dl (2.6 mmol/L) in the atorvastatin 10 mg/day treatment arm, utilizing National Health and Nutrition Examination Survey (NHANES) III adult distributions together with expected LDL cholesterol reductions based on published clinical trials. To reach an average LDL cholesterol level in the comparator group of approximately 75 mg/dl (1.9 mmol/L), atorvastatin 80 mg/day was chosen. It was estimated that the difference in LDL cholesterol levels between these groups would reduce the number of 5-year recurrent coronary events in the atorvastatin 80 mg/day treatment arm by 20% to 30% compared with atorvastatin 10 mg/day based on published reports of secondary prevention trials, their meta-analyses, and overviews of the epidemiologic literature of the relation between cholesterol and CHD occurrence. The trial originally planned to randomize 8,600 patients with 91% power for a 1-tailed test (␣ 0.05) and 85% power for a 2-tailed test (␣ 0.05) to detect a 22% reduction in 5-year recurrent coronary events between treatment groups, assuming a 9% recurrence rate for atorvastatin 10 mg/day (based on experience from the pravastatin 40 mg group in the Cholesterol and Recurrent Events [CARE] trial), a 7% recurrence
CORONARY ARTERY DISEASE/TREATING TO NEW TARGETS STUDY
155
TABLE 1 Baseline Characteristics of Patients Randomized to Atorvastatin 10 or 80 mg Baseline characteristics and history Men (mean age) (yrs) Women (mean age) (yrs) Age (yrs) ⬍40 40–44 45–49 50–54 55–59 60–64 65–69 ⱖ70 subtotal Mean age Race White Black Asian Other Qualifying event (have ⱖ1 of the following) Prior MI Angina with evidence of coronary disease Prior coronary revascularization ⱖ2 qualifying events Yrs since qualifying event (most recent) Current smoker Ex-smoker History of systemic hypertension Diabetes mellitus Obesity (body mass index ⬎30 kg/m2) Cerebrovascular disease Peripheral vascular disease Congestive heart failure Other treatment Aspirin  blocker Calcium antagonist ACE inhibitor Nitrates Current hormone replacement therapy Digitalis* Spironolactone* Angiotensin-receptor blockers* Coronary revascularization Angioplasty only Coronary bypass only Both angioplasty and bypass Dyspnea: Grade (New York Heart Association Class)* I II IIIa IIIb IV
TABLE 2 Fasting Serum Levels of Lipids, Glucose, and Glycosylated Hemoglobin
No. of Patients 8,101 (59.7 ⫾ 8.8) 1,902 (62.8 ⫾ 8.5) 109 347 866 1,370 1,719 1,869 2,038 1,685 60.3
(1.1%) (3.5%) (8.7%) (13.7%) (17.2%) (18.7%) (20.4%) (16.8%) ⫾ 8.8
9,409 290 103 201
(94.1%) (2.9%) (1.0%) (2.0%)
8,227 (82.2%) 4,343 Maximum of 44 (13.4%) (63.2%) (53.7%) (15.0%) (30.1%)
516 (5.2%) 1,098 (11.0%) 765 (7.6%) 8,763 5,513 2,562 2,761 3,179 581
(87.6%) (55.1%) (25.6%) (27.6%) (31.8%) (30.5% of women)
Total cholesterol High-density lipoprotein cholesterol LDL cholesterol Triglycerides Total/high-density lipoprotein ratio Apolipoprotein A-1 Apolipoprotein B Hemoglobin A1c* Glucose
175 47 98 151 3.9 146 111 6.5 108
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
26 11 19 78 0.9 25 20 1.3 31
mmol/L ⫾ 0.7 ⫾ 0.3 ⫾ 0.5 ⫾ 0.9 — — — — 6.0 ⫾ 1.7
4.5 1.2 2.5 1.7
nition of CHD death, nonfatal MI, or resuscitated cardiac arrest. In February 2003, stroke (fatal and nonfatal) was added to the definition of the primary end point and it is now anticipated that approximately 950 primary end points (750 coronary events plus an additional 200 stroke events) will accrue over the expected duration of the trial, thereby providing 91% power for a 1-sided test at an ␣ of 0.05 and 85% power for a 2-sided test at ␣ of 0.05 to detect a 17% reduction in the 5 year cumulative primary end point rate for atorvastatin 80 mg compared with atorvastatin 10 mg. Subgroup analyses will be performed to investigate variation in the treatment effect of the primary and secondary efficacy end points by the following: age, gender, smoking status, and presence or absence of diabetes; triglycerides (⬍200 mg/dl [2.3 mmol/L], ⱖ200 mg/dl [2.3 mmol/L]) and other lipid parameters; congestive heart failure and other prevalent preexisting condition categories of the study cohort; and prevalent concomitant medication use, including hormone replacement therapy, aspirin,  blockers, or calcium channel blockers.
BASELINE DATA FROM THE TNT STUDY
171 (22.4%) 14 (1.8%) 54 (7.1%) 3,951 (39.5%) 3,198 (32.0%) 1,455 (14.5%)
421 (60.0%) 241 (34.3%) 40 (5.7%) — —
*For patients with congestive heart failure only. ACE ⫽ Angiotensin-converting enzyme.
rate for atorvastatin 80 mg/day, and a 10% drop-in/ drop-out/noncompliance rate over the course of the trial (the impact of other lipid level differences in the treatment groups was not considered for these estimates). This corresponded to a total of 750 primary events based on the original primary end point defi156 THE AMERICAN JOURNAL OF CARDIOLOGY姞
mg/dl
*HbA1c is from visit 1(screening); all other measures are from visit 5 (end of atorvastatin 10 mg/day open-label run-in period).
4,186 (41.8%) 2,414 (24.1%)
1,341 6,322 5,367 1,496 3,000
Concentration
VOL. 93
The TNT population is comprised of patients from 14 countries across 4 continents. The first patient was recruited in April 1998. Randomizations occurred from July 1998 to December 1999. Of the 18,468 patients screened, 15,432 entered the open-label run-in period and 10,003 were randomized to doubleblind treatment with either atorvastatin 10 or 80 mg (Figure 1). Selected baseline characteristics of randomized patients are shown in Table 1. Serum lipid concentrations at baseline are given in Table 2, and the changes observed in these levels during the prerandomization period are shown in Figure 2. A comparison of baseline demographics of the TNT population with those of the 4 major secondary prevention statin trials3,6 – 8 is presented in Table 3.
DISCUSSION Other trials due for completion in the next few years should provide results that will be complemenJANUARY 15, 2004
FIGURE 2. Changes during the prerandomization period of the TNT study in (A) LDL cholesterol, (B) triglycerides, (C) high-density lipoprotein cholesterol, and (D) total cholesterol. Horizontal axis values represent the midpoints of numeric intervals. TABLE 3 A Comparison of Baseline Demographics of the Scandinavian Simvastatin Survival Study (4S), the Cholesterol And Recurrent Events (CARE) Trial, the Long-term Intervention With Pravastatin in Ischemic Disease (LIPID) Study, and the Heart Protection Study (HPS) With the Treat to New Targets (TNT) Study Study Age range (yrs) ⱖ65 yrs Mean age (yrs) Men Yrs since qualifying event Smokers Hypertension Diabetes Treatments Aspirin  blocker Calcium antagonist Lipid changes versus baseline or placebo Total cholesterol LDL cholesterol HDL cholesterol Triglycerides
4S6 (n ⫽ 4,444)
CARE7 (n ⫽ 4,159)
LIPID8 (n ⫽ 9,014)
HPS3 (n ⫽ 20,536)
TNT (n ⫽ 10,003)
35–69 22% 58 (men)/60 (women) 81% 3.35 ⫾ 3.46 26% 26% 4.5%
21–75
31–75 39%
59 86% 10 mo 21% 43% 14%
83% 1.0 (0.5, 1.9) 10% 41% 9%
40–80 52% — 75% — 14% 41% 29%
29–76 37% 60 81% 1.73 ⫾ 2.61 13% 54% 15%
37% 57% 31%
83% 40% 39%
82% 47% 35%
63% 26% —
88% 55% 26%
⫺20% ⫺28% ⫹5% ⫺14%
⫺18% ⫺25% ⫹5% ⫺11%
⫺20% ⫺29% ⫹3% ⫺14%
⫺25% ⫺35% ⫹8% ⫺10%
HDL ⫽ high-density lipoprotein.
CORONARY ARTERY DISEASE/TREATING TO NEW TARGETS STUDY
157
tary to the results of TNT. The Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL) study is comparing atorvastatin 80 mg/day with simvastatin 20 to 40 mg/day in 8,888 coronary patients to examine whether a higher dose of a stronger statin provides additional coronary benefit. The Study of the Effectiveness of Additional Reductions of Cholesterol and Homocysteine (SEARCH) will compare simvastatin 20 and 80 mg/day in 12,000 patients with a history of MI. In all of these studies, large patient numbers and follow-up periods of ⱖ5 years should ensure that there is adequate power to definitively determine if reducing LDL cholesterol levels to approximately 75 mg/dl (1.9 mmol/L) can provide additional clinical benefit.
APPENDIX TNT Committee Members: Steering Committee: J. LaRosa (Chairman), New York, New York; P. Barter, Sydney, Australia; J.-C. Fruchart, Lille, France; A. Gotto, New York, New York; H. Greten, Hamburg, Germany; S. Grundy, Dallas, Texas; D. Hunninghake, Minneapolis, Minnesota; J. Kastelein, Amsterdam, The Netherlands; J. Shepherd, Glasgow, United Kingdom; D. Waters, San Francisco, California; N. Wenger, Atlanta, Georgia. End Point Committee: L. Cohen (Chairman), New Haven, Connecticut; J.-M. LaBlanche, Lille, France; H. Levine, Boston, Massachusetts; U. Sechtem, Stuttgart, Germany; F. Welty, Boston, Massachusetts.
158 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 93
Data Safety Monitoring Board: C. Hennekens (Chairman), Miami, Florida; V. Brown, Atlanta, Georgia; R. Carmena, Valencia, Spain; R. D’Agostino, Boston, Massachusetts; S. Haffner, San Antonio, Texas; E Leitersdorf, Jerusalem, Israel. 1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Choles-
terol 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. 2. American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care 1999;22(suppl 1):S56 –S59. 3. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20, 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22. 4. Grundy SM. Statin trials and goals of cholesterol-lowering therapy. Circulation 1998;97:1436 –1439. 5. Jones PH. Lipid-lowering treatment in coronary artery disease: how low should cholesterol go? Drugs 2000;59:1127–1135. 6. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–1389. 7. Sacks FM, Pfeffer MA, Moye´ LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun CC, Davis BR, Braunwald EB, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–1009. 8. The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349 –1357.
JANUARY 15, 2004
occurrence of a major cardiovascular event, defined as coronary heart disease death, nonfatal myocardial infarction, resuscitated cardiac arrest, or stroke. The large patient numbers in the TNT study and long follow-up should ensure that there is adequate power to definitively determine if reducing LDL cholesterol levels to approximately 75 mg/dl (1.9 mmol/L) can provide additional clinical benefit. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;93:154 –158)
he low-density lipoprotein (LDL) cholesterol treatment goal currently proposed for patients with T atherosclerosis is ⱕ100 mg/dl (ⱕ2.6 mmol/L). In
achieves an average LDL cholesterol of approximately 100 mg/dl (2.6 mmol/L) and 1 that achieves an average LDL cholesterol of approximately 75 mg/dl (1.9 mmol/L). Men and women aged 35 to 75 years with clinically evident coronary heart disease (CHD), defined as previous myocardial infarction (MI), previous or present angina with objective evidence of atherosclerotic CHD, and who have undergone a coronary revascularization procedure, are eligible for study entry. Major exclusion criteria include any of the following: hypersensitivity to statins; active liver disease or hepatic dysfunction defined as alanine aminotransferase or aspartate aminotransferase ⬎1.5 times the upper limit of normal; women who are pregnant or breastfeeding; patients with nephrotic syndrome; uncontrolled diabetes mellitus; uncontrolled hypothyroidism; uncontrolled hypertension (as defined by the investigator) at the screening visit; a MI, coronary revascularization procedure or severe/unstable angina within 1 month of screening; any planned surgical procedure for the treatment of atherosclerosis; an ejection fraction ⬍30%; hemodynamically important valvular disease; gastrointestinal disease limiting drug absorption or partial ileal bypass; any nonskin malignancy, malignant melanoma or other survival-limiting disease; unexplained creatine phosphokinase levels ⬎6 times the upper limit of normal; concurrent therapy with long-term immunosuppressants; concurrent therapy with lipid-regulating drugs not specified as study treatment in the protocol; history of alcohol abuse; and participation in another clinical trial concurrently or within 30 days before screening. At
1,2
the recently published Heart Protection Study,3 patients whose LDL cholesterol was below this level at baseline still derived substantial clinical benefit from cholesterol lowering with a statin drug. In patients whose LDL cholesterol levels have been lowered to 100 mg/dl (2.6 mmol/L) from higher levels, it is unclear whether additional benefit would accrue from additional LDL cholesterol lowering.4,5 Treating to New Targets (TNT) Study: The primary hypothesis of the TNT study is that incremental reduction in cardiovascular risk can be achieved by lowering LDL cholesterol levels beyond currently recommended minimum targets. To test the hypothesis, 2 doses of atorvastatin (10 and 80 mg once daily) are being used in a double-blind parallel group design. The occurrence of major cardiovascular end points will be compared in 2 groups of patients: 1 that From the University of California, San Francisco School of Medicine, San Francisco, California; Duke University Medical Center, Durham, North Carolina; Wake Forest University School of Medicine, WinstonSalem, North Carolina; New England Medical Center, Boston, Massachusetts; Emory University School of Medicine, Atlanta, Georgia; and Pfizer Inc., Groton, Connecticut. This study was supported by a research grant from Pfizer Inc., Groton, Connecticut. Manuscript received August 8, 2003; revised manuscript received and accepted September 16, 2003. Address for reprints: David D. Waters, MD, Division of Cardiology, Room 5G1, San Francisco General Hospital, 1001 Potrero Avenue, San Francisco, California 94110. E-mail: dwaters@ medsfgh.ucsf.edu. *A list of members and investigators appears in the Appendix.
154
©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 93 January 15, 2004
0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2003.09.031
screening (visit 1) an informed consent is signed, demographic characteristics assessed, vital signs measured, all concomitant medications documented, and a medical history recorded. Blood samples are collected to determine fasting lipid levels and the patient’s standard clinical profile. Patients receive dietary information to obtain compliance with the National Cholesterol Education Program (NCEP) Step I, Step II, or other equivalent diet. Any previously prescribed lipid-regulating drugs are discontinued at screening, and patients require a wash-out period of ⱖ6 weeks before visit 2. After discontinuation of previous lipid-lowering therapies, all eligible patients commence treatment with atorvastatin 10 mg/day on an open-label basis (visit 2; week ⫺8). Patients with LDL cholesterol between 130 and 250 mg/dl (3.4 to 6.5 mmol/L) and triglycerides ⱕ600 mg/dl (6.8 mmol/L) at visit 2 are eligible to continue the study during the run-in period. At visit 3 (week ⫺4) and visit 4 (week ⫺2), lipid levels are determined, dietary counseling continued, and treatment with atorvastatin 10 mg/day maintained. At the end of the run-in period (week 0), those patients with a mean LDL cholesterol ⬍130 mg/dl (3.4 mmol/L) at visits 3 and 4 are randomized to double-blind therapy with either atorvastatin 10 or 80 mg/day. During the first year of the double-blind period, 4 follow-up visits are scheduled at week 12 and at months 6, 9, and 12. After the first year of active treatment, patients have scheduled study visits every 6 months. At each visit, vital signs, clinical end points, adverse events, and concurrent medication information are collected. In addition, on alternating visits (i.e., annually), physical examinations and electrocardiograms are performed and laboratory specimens collected. An end point committee reviews (blinded) all potential primary and secondary end points to adjudicate the end point designation. The committee members who perform patient end point review are not investigators or subinvestigators in the trial. Differences in patient review designations are adjudicated through scheduled conference calls or regular meetings. A separate Manual of Operations fully describes the methods to be used by the end point committee. Study-specific, data-driven algorithms are used to achieve end point consensus. The primary end point is the time to occurrence of a major cardiovascular event, defined as CHD death, nonfatal MI, resuscitated cardiac arrest, and fatal or nonfatal stroke. Secondary study outcomes are any occurrence of the following: major coronary event (CHD death, nonfatal MI, or resuscitated cardiac arrest), any coronary event (major coronary event, revascularization procedure, procedure-related MI, or documented angina); cerebrovascular event (fatal or nonfatal stroke, transient ischemic attack); peripheral vascular disease; hospitalization with primary diagnosis of congestive heart failure; any cardiovascular event (any of the previous); and all cause mortality. An independent Data Safety Monitoring Board (DSMB) periodically evaluates safety and efficacy
FIGURE 1. Patient disposition.
data and makes recommendations regarding continuation or modification of the study or study procedures. Interim analyses for the TNT study will begin after a median 3-year follow-up. The timing and number of interim analyses will be at the discretion of the DSMB. Interim monitoring for efficacy is based on the primary end point using a log-rank test with 2-sided Peto-type monitoring boundaries (Z) of ⫾3.0. Interim monitoring for harm is based on all-cause mortality using a log-rank test with O’Brien Fleming boundaries. The LDL cholesterol inclusion/exclusion criteria were selected to achieve an average level of 100 mg/dl (2.6 mmol/L) in the atorvastatin 10 mg/day treatment arm, utilizing National Health and Nutrition Examination Survey (NHANES) III adult distributions together with expected LDL cholesterol reductions based on published clinical trials. To reach an average LDL cholesterol level in the comparator group of approximately 75 mg/dl (1.9 mmol/L), atorvastatin 80 mg/day was chosen. It was estimated that the difference in LDL cholesterol levels between these groups would reduce the number of 5-year recurrent coronary events in the atorvastatin 80 mg/day treatment arm by 20% to 30% compared with atorvastatin 10 mg/day based on published reports of secondary prevention trials, their meta-analyses, and overviews of the epidemiologic literature of the relation between cholesterol and CHD occurrence. The trial originally planned to randomize 8,600 patients with 91% power for a 1-tailed test (␣ 0.05) and 85% power for a 2-tailed test (␣ 0.05) to detect a 22% reduction in 5-year recurrent coronary events between treatment groups, assuming a 9% recurrence rate for atorvastatin 10 mg/day (based on experience from the pravastatin 40 mg group in the Cholesterol and Recurrent Events [CARE] trial), a 7% recurrence
CORONARY ARTERY DISEASE/TREATING TO NEW TARGETS STUDY
155
TABLE 1 Baseline Characteristics of Patients Randomized to Atorvastatin 10 or 80 mg Baseline characteristics and history Men (mean age) (yrs) Women (mean age) (yrs) Age (yrs) ⬍40 40–44 45–49 50–54 55–59 60–64 65–69 ⱖ70 subtotal Mean age Race White Black Asian Other Qualifying event (have ⱖ1 of the following) Prior MI Angina with evidence of coronary disease Prior coronary revascularization ⱖ2 qualifying events Yrs since qualifying event (most recent) Current smoker Ex-smoker History of systemic hypertension Diabetes mellitus Obesity (body mass index ⬎30 kg/m2) Cerebrovascular disease Peripheral vascular disease Congestive heart failure Other treatment Aspirin  blocker Calcium antagonist ACE inhibitor Nitrates Current hormone replacement therapy Digitalis* Spironolactone* Angiotensin-receptor blockers* Coronary revascularization Angioplasty only Coronary bypass only Both angioplasty and bypass Dyspnea: Grade (New York Heart Association Class)* I II IIIa IIIb IV
TABLE 2 Fasting Serum Levels of Lipids, Glucose, and Glycosylated Hemoglobin
No. of Patients 8,101 (59.7 ⫾ 8.8) 1,902 (62.8 ⫾ 8.5) 109 347 866 1,370 1,719 1,869 2,038 1,685 60.3
(1.1%) (3.5%) (8.7%) (13.7%) (17.2%) (18.7%) (20.4%) (16.8%) ⫾ 8.8
9,409 290 103 201
(94.1%) (2.9%) (1.0%) (2.0%)
8,227 (82.2%) 4,343 Maximum of 44 (13.4%) (63.2%) (53.7%) (15.0%) (30.1%)
516 (5.2%) 1,098 (11.0%) 765 (7.6%) 8,763 5,513 2,562 2,761 3,179 581
(87.6%) (55.1%) (25.6%) (27.6%) (31.8%) (30.5% of women)
Total cholesterol High-density lipoprotein cholesterol LDL cholesterol Triglycerides Total/high-density lipoprotein ratio Apolipoprotein A-1 Apolipoprotein B Hemoglobin A1c* Glucose
175 47 98 151 3.9 146 111 6.5 108
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
26 11 19 78 0.9 25 20 1.3 31
mmol/L ⫾ 0.7 ⫾ 0.3 ⫾ 0.5 ⫾ 0.9 — — — — 6.0 ⫾ 1.7
4.5 1.2 2.5 1.7
nition of CHD death, nonfatal MI, or resuscitated cardiac arrest. In February 2003, stroke (fatal and nonfatal) was added to the definition of the primary end point and it is now anticipated that approximately 950 primary end points (750 coronary events plus an additional 200 stroke events) will accrue over the expected duration of the trial, thereby providing 91% power for a 1-sided test at an ␣ of 0.05 and 85% power for a 2-sided test at ␣ of 0.05 to detect a 17% reduction in the 5 year cumulative primary end point rate for atorvastatin 80 mg compared with atorvastatin 10 mg. Subgroup analyses will be performed to investigate variation in the treatment effect of the primary and secondary efficacy end points by the following: age, gender, smoking status, and presence or absence of diabetes; triglycerides (⬍200 mg/dl [2.3 mmol/L], ⱖ200 mg/dl [2.3 mmol/L]) and other lipid parameters; congestive heart failure and other prevalent preexisting condition categories of the study cohort; and prevalent concomitant medication use, including hormone replacement therapy, aspirin,  blockers, or calcium channel blockers.
BASELINE DATA FROM THE TNT STUDY
171 (22.4%) 14 (1.8%) 54 (7.1%) 3,951 (39.5%) 3,198 (32.0%) 1,455 (14.5%)
421 (60.0%) 241 (34.3%) 40 (5.7%) — —
*For patients with congestive heart failure only. ACE ⫽ Angiotensin-converting enzyme.
rate for atorvastatin 80 mg/day, and a 10% drop-in/ drop-out/noncompliance rate over the course of the trial (the impact of other lipid level differences in the treatment groups was not considered for these estimates). This corresponded to a total of 750 primary events based on the original primary end point defi156 THE AMERICAN JOURNAL OF CARDIOLOGY姞
mg/dl
*HbA1c is from visit 1(screening); all other measures are from visit 5 (end of atorvastatin 10 mg/day open-label run-in period).
4,186 (41.8%) 2,414 (24.1%)
1,341 6,322 5,367 1,496 3,000
Concentration
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The TNT population is comprised of patients from 14 countries across 4 continents. The first patient was recruited in April 1998. Randomizations occurred from July 1998 to December 1999. Of the 18,468 patients screened, 15,432 entered the open-label run-in period and 10,003 were randomized to doubleblind treatment with either atorvastatin 10 or 80 mg (Figure 1). Selected baseline characteristics of randomized patients are shown in Table 1. Serum lipid concentrations at baseline are given in Table 2, and the changes observed in these levels during the prerandomization period are shown in Figure 2. A comparison of baseline demographics of the TNT population with those of the 4 major secondary prevention statin trials3,6 – 8 is presented in Table 3.
DISCUSSION Other trials due for completion in the next few years should provide results that will be complemenJANUARY 15, 2004
FIGURE 2. Changes during the prerandomization period of the TNT study in (A) LDL cholesterol, (B) triglycerides, (C) high-density lipoprotein cholesterol, and (D) total cholesterol. Horizontal axis values represent the midpoints of numeric intervals. TABLE 3 A Comparison of Baseline Demographics of the Scandinavian Simvastatin Survival Study (4S), the Cholesterol And Recurrent Events (CARE) Trial, the Long-term Intervention With Pravastatin in Ischemic Disease (LIPID) Study, and the Heart Protection Study (HPS) With the Treat to New Targets (TNT) Study Study Age range (yrs) ⱖ65 yrs Mean age (yrs) Men Yrs since qualifying event Smokers Hypertension Diabetes Treatments Aspirin  blocker Calcium antagonist Lipid changes versus baseline or placebo Total cholesterol LDL cholesterol HDL cholesterol Triglycerides
4S6 (n ⫽ 4,444)
CARE7 (n ⫽ 4,159)
LIPID8 (n ⫽ 9,014)
HPS3 (n ⫽ 20,536)
TNT (n ⫽ 10,003)
35–69 22% 58 (men)/60 (women) 81% 3.35 ⫾ 3.46 26% 26% 4.5%
21–75
31–75 39%
59 86% 10 mo 21% 43% 14%
83% 1.0 (0.5, 1.9) 10% 41% 9%
40–80 52% — 75% — 14% 41% 29%
29–76 37% 60 81% 1.73 ⫾ 2.61 13% 54% 15%
37% 57% 31%
83% 40% 39%
82% 47% 35%
63% 26% —
88% 55% 26%
⫺20% ⫺28% ⫹5% ⫺14%
⫺18% ⫺25% ⫹5% ⫺11%
⫺20% ⫺29% ⫹3% ⫺14%
⫺25% ⫺35% ⫹8% ⫺10%
HDL ⫽ high-density lipoprotein.
CORONARY ARTERY DISEASE/TREATING TO NEW TARGETS STUDY
157
tary to the results of TNT. The Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL) study is comparing atorvastatin 80 mg/day with simvastatin 20 to 40 mg/day in 8,888 coronary patients to examine whether a higher dose of a stronger statin provides additional coronary benefit. The Study of the Effectiveness of Additional Reductions of Cholesterol and Homocysteine (SEARCH) will compare simvastatin 20 and 80 mg/day in 12,000 patients with a history of MI. In all of these studies, large patient numbers and follow-up periods of ⱖ5 years should ensure that there is adequate power to definitively determine if reducing LDL cholesterol levels to approximately 75 mg/dl (1.9 mmol/L) can provide additional clinical benefit.
APPENDIX TNT Committee Members: Steering Committee: J. LaRosa (Chairman), New York, New York; P. Barter, Sydney, Australia; J.-C. Fruchart, Lille, France; A. Gotto, New York, New York; H. Greten, Hamburg, Germany; S. Grundy, Dallas, Texas; D. Hunninghake, Minneapolis, Minnesota; J. Kastelein, Amsterdam, The Netherlands; J. Shepherd, Glasgow, United Kingdom; D. Waters, San Francisco, California; N. Wenger, Atlanta, Georgia. End Point Committee: L. Cohen (Chairman), New Haven, Connecticut; J.-M. LaBlanche, Lille, France; H. Levine, Boston, Massachusetts; U. Sechtem, Stuttgart, Germany; F. Welty, Boston, Massachusetts.
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Data Safety Monitoring Board: C. Hennekens (Chairman), Miami, Florida; V. Brown, Atlanta, Georgia; R. Carmena, Valencia, Spain; R. D’Agostino, Boston, Massachusetts; S. Haffner, San Antonio, Texas; E Leitersdorf, Jerusalem, Israel. 1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Choles-
terol 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. 2. American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care 1999;22(suppl 1):S56 –S59. 3. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20, 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22. 4. Grundy SM. Statin trials and goals of cholesterol-lowering therapy. Circulation 1998;97:1436 –1439. 5. Jones PH. Lipid-lowering treatment in coronary artery disease: how low should cholesterol go? Drugs 2000;59:1127–1135. 6. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–1389. 7. Sacks FM, Pfeffer MA, Moye´ LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun CC, Davis BR, Braunwald EB, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–1009. 8. The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349 –1357.
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