Intensive lipid lowering with atorvastatin in patients with stable coronary disease

The new england journal of medicine Intensive Lipid Lowering with Atorvastatin John C. LaRosa, M.D., Scott M. Grundy, M.D., Ph.D., David D. Waters, M.D., Charles Shear, Ph.D., Philip Barter, M.D., Ph.D., Jean-Charles Fruchart, Pharm.D., Ph.D., Antonio M. Gotto, M.D., D.Phil., Heiner Greten, M.D., John J.P. Kastelein, M.D., James Shepherd, M.D., and Nanette K. Wenger, M.D., for the Treating to New Targets (TNT) Investigators* b a c k g r o u n d
Previous trials have demonstrated that lowering low-density lipoprotein (LDL) choles- From the State University of New York Health Science Center, Brooklyn (J.C.L.); the terol levels below currently recommended levels is beneficial in patients with acute cor- University of Texas Southwestern Medical onary syndromes. We prospectively assessed the efficacy and safety of lowering LDL Center, Dallas (S.M.G.); San Francisco Gen-cholesterol levels below 100 mg per deciliter (2.6 mmol per liter) in patients with stable eral Hospital, San Francisco (D.D.W.); Pfizer, Groton, Conn. (C.S.); the Heart Research In- stitute, Sydney (P.B.); Institut Pasteur, Lille,France (J.-C.F.); Weill Medical College of Cornell University, New York (A.M.G.); Uni-versitätsklinikum Eppendorf, Hamburg, A total of 10,001 patients with clinically evident CHD and LDL cholesterol levels of less Germany (H.G.); Academic Medical Cen- than 130 mg per deciliter (3.4 mmol per liter) were randomly assigned to double-blind ter, University of Amsterdam, Amsterdamtherapy and received either 10 mg or 80 mg of atorvastatin per day. Patients were fol- (J.J.P.K.); the University of Glasgow, Glas- gow, United Kingdom (J.S.); and Emory Uni- lowed for a median of 4.9 years. The primary end point was the occurrence of a first versity School of Medicine, Atlanta (N.K.W.).
major cardiovascular event, defined as death from CHD, nonfatal non–procedure-relat- Address reprint requests to Dr. LaRosa ated myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke.
the State University of New York HealthScience Center, 450 Clarkson Ave., Brooklyn,NY 11203, or at [email protected].
The mean LDL cholesterol levels were 77 mg per deciliter (2.0 mmol per liter) during *Participants in the TNT Study are listed treatment with 80 mg of atorvastatin and 101 mg per deciliter (2.6 mmol per liter) dur-ing treatment with 10 mg of atorvastatin. The incidence of persistent elevations in liver This article was published at www.nejm.
aminotransferase levels was 0.2 percent in the group given 10 mg of atorvastatin and org on March 8, 2005.
1.2 percent in the group given 80 mg of atorvastatin (P<0.001). A primary event oc- N Engl J Med 2005;352:1425-35.
curred in 434 patients (8.7 percent) receiving 80 mg of atorvastatin, as compared with Copyright 2005 Massachusetts Medical Society.
548 patients (10.9 percent) receiving 10 mg of atorvastatin, representing an absolutereduction in the rate of major cardiovascular events of 2.2 percent and a 22 percent rel-ative reduction in risk (hazard ratio, 0.78; 95 percent confidence interval, 0.69 to 0.89;P<0.001). There was no difference between the two treatment groups in overall mortality.
c o n c l u s i o n s
Intensive lipid-lowering therapy with 80 mg of atorvastatin per day in patients with sta-ble CHD provides significant clinical benefit beyond that afforded by treatment with10 mg of atorvastatin per day. This occurred with a greater incidence of elevated amino-transferase levels.
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lipoprotein (LDL) cholesterol levels in pre- The primary hypothesis of the study was that re- t venting major cardiovascular events and ducing LDL cholesterol levels to well below 100 mg stroke has been well documented. Recent studies per deciliter in patients with stable CHD and slightlyhave raised the issue of optimal treatment targets elevated LDL cholesterol levels (despite previousfor patients with coronary heart disease (CHD).1-4 therapy with low-dose atorvastatin) could yield anThe value of reducing LDL cholesterol levels sub- incremental clinical benefit. This hypothesis wasstantially below 100 mg per deciliter (2.6 mmol per tested in a double-blind, parallel-group design. Theliter) in patients with CHD, particularly those with occurrence of major cardiovascular outcomes wasstable nonacute disease, has not been clearly dem- compared in two groups of patients: one group re-onstrated.
ceived 10 mg of atorvastatin daily with the goal of The Third Report of the National Cholesterol Ed- an average LDL cholesterol level of 100 mg per deci- ucation Program (NCEP) Adult Treatment Panel5 liter, and the other group received 80 mg of ator-
and the most recent guidelines of the Third Joint vastatin daily with the goal of an average LDL cho-
Task Force of European and Other Societies on Car- lesterol level of 75 mg per deciliter (1.9 mmol per
diovascular Disease Prevention in Clinical Practice6 liter).
have recommended an LDL cholesterol level of less
than 100 mg per deciliter as the goal of therapy for patient population
patients at high risk for CHD. On the basis of data Eligible patients were men and women 35 to 75
from the Heart Protection Study (HPS)1 and the years of age who had clinically evident CHD, defined
Pravastatin or Atorvastatin Evaluation and Infec- by one or more of the following: previous myocar-
tion Trial (PROVE IT),2 the NCEP in conjunction dial infarction, previous or current angina with ob-
with the American Heart Association and the Amer- jective evidence of atherosclerotic CHD, and a his-
ican College of Cardiology subsequently introduced tory of coronary revascularization. The exclusion
a more aggressive, but optional, LDL cholesterol criteria have been described in detail previously.8
goal of less than 70 mg per deciliter (1.8 mmol per Randomization occurred between July 1998 and
liter) for patients at very high risk for CHD, even if December 1999.
baseline LDL cholesterol levels were below 100 mg
per deciliter.7 However, PROVE IT was conducted study protocol
in a population of patients with acute coronary syn- Any previously prescribed lipid-regulating drugs
dromes who were at very high risk for cardiovascu- were discontinued at screening, and all patients
lar disease, and although many patients in the HPS completed a washout period of one to eight weeks.
who began with an LDL cholesterol level of less than To ensure that, at baseline, all patients had LDL cho-
100 mg per deciliter benefited from statin therapy, lesterol levels consistent with then-current guide-
this benefit was in comparison with placebo. Thus, lines for the treatment of stable CHD, patients with
there is no definitive evidence that intensive stat- LDL cholesterol levels between 130 and 250 mg
in therapy, with a goal of reducing LDL cholesterol per deciliter (3.4 and 6.5 mmol per liter, respective-
levels to approximately 70 mg per deciliter, is asso- ly) and triglyceride levels of 600 mg per deciliter
ciated with better outcomes than moderate statin (6.8 mmol per liter) or less entered an eight-week
therapy, with a goal of reducing LDL cholesterol lev- run-in period of open-label treatment with 10 mg
els to about 100 mg per deciliter in patients with sta- of atorvastatin per day. At the end of the run-in
ble CHD. Data from the Treating to New Targets phase (week 0), patients with a mean LDL cholester-
(TNT) Study make it possible to test this hypothesis. ol level of less than 130 mg per deciliter (3.4 mmol
per liter) (determined four weeks and two weeksbefore randomization) were randomly assigned to double-blind therapy with either 10 mg or 80 mg The design of the TNT Study has been described of atorvastatin per day. During the double-blindin detail previously.8 All patients gave written in- period, follow-up visits occurred at week 12 andformed consent, and the study was approved by the at months 6, 9, and 12 in the first year and everylocal research ethics committee or institutional re- 6 months thereafter.
view board at each center.
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cording to the Kaplan–Meier method. The study The primary efficacy outcome was the occurrence of had a statistical power of only 40 percent to detecta major cardiovascular event, defined as death from a 10 percent reduction in the risk of death from anyCHD, nonfatal non–procedure-related myocardial cause with the use of a two-sided test at an alphainfarction, resuscitation after cardiac arrest, or fatal level of 0.05.
or nonfatal stroke. Secondary outcomes included a Two interim efficacy analyses were performed major coronary event (defined as death from CHD, and were based on a two-sided Peto type of moni-nonfatal non–procedure-related myocardial infarc- toring boundary. For the final primary analysis,tion, or resuscitation after cardiac arrest), a cere- an adjusted P value of 0.049 was considered to in-brovascular event, hospitalization for congestive dicate statistical significance, given a type I errorheart failure, peripheral-artery disease, death from rate of 0.05. For all secondary outcomes, a P valueany cause, any cardiovascular event, and any coro- of 0.05 was considered to indicate statistical sig-nary event.
nificance, and all tests were two-sided.
The sponsor initiated the study. The steering s t a t i s t i c a l a n a l y s i s
committee developed the protocol in collaboration Epidemiologic data suggested that the treatment- with the sponsor and took responsibility for therelated difference in LDL cholesterol levels between final version. ICON Clinical Research (North Wales,the two groups would translate into 20 to 30 percent Pennsylvania) managed all data. ICON and Pfizerfewer recurrent coronary events at five years in the provided site monitoring throughout the study.
group given 80 mg of atorvastatin than in the group An independent end-points committee adjudicat-given 10 mg of atorvastatin. The study’s original tar- ed all potential end points in a blinded fashion. Anget enrollment was approximately 8600 patients on independent data and safety monitoring board withthe basis of a projected number of 750 major coro- its independent statistical-support group from thenary events during an average follow-up of 5.5 years. University of Wisconsin performed interim mon-However, the recruitment rate was higher than ex- itoring and analyses of efficacy, safety, and datapected, and 10,003 patients underwent randomiza- quality. The data were analyzed by the sponsor ac-tion, all but 2 of whom received the study drug. cording to the statistical-analysis plan approved In February 2003, the steering committee added by the steering committee. The steering committee stroke (fatal or nonfatal) to the primary efficacy out- had unrestricted, request-based access to the studycome. This change was made before any data were data, which were retained by the sponsor, and wrotereviewed and preceded the first interim analysis by the article without constraints from the sponsor.
the independent data and safety monitoring board. The steering committee assumes overall responsi-At the time, evidence was accumulating of the ben- bility for the integrity of the data, for the accuracyeficial role of statins in reducing the risk of stroke. of the data analyses, and for the completeness ofThe change in the primary end point was made to the material reported. The data reported were thoseclarify this role. This modification led to an increase available to the steering committee as of Januaryin the projected number of primary events to 950 29, 2005.
(750 coronary events plus 200 strokes) during thetrial, providing the study with a statistical power of 85 percent to detect an absolute reduction of 17 per-
cent in the five-year cumulative rate of the primary patient population
efficacy outcome in the group given 80 mg of ator- A total of 18,469 patients were screened at 256
vastatin, as compared with the group given 10 mg sites in 14 countries (Fig. 1). Of these, 15,464 pa-
of atorvastatin, with the use of a two-sided test at tients (83.7 percent) were deemed eligible to enter
an alpha level of 0.05.
the open-label run-in period. A further 5461 patients All analyses were performed on an intention- were excluded after the open-label run-in phase.
to-treat basis. All randomized patients who were Most of these excluded patients (4634, or 84.9 per-dispensed one dose of the study drug were includ- cent) did not meet randomization criteria. Othered in the analyses. The primary and secondary com- reasons included adverse events in 197 (3.6 percent),posite end points were analyzed from the time of death or an ischemic event in 211 (3.9 percent), andthe first dose of study drug to the first event, ac- lack of compliance in 70 (1.3 percent).
Downloaded from nejm.org at COLUMBIA UNIV HEALTH SCIENCES LIB on April 18, 2012. For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine LDL cholesterol >130 mg/dl in 648 Triglycerides >600 mg/dl in 32ALT or AST (or both) >1.5¬ULN in 96 Figure 1. Screening, Enrollment, and Outcomes.
To convert value for cholesterol to millimoles per liter, multiply by 0.02586; to convert value for triglycerides to millimoles per liter, multiply by 0.0113. AST denotes aspartate aminotransferase, ALT alanine aminotransferase, and ULN upper limit of the normal range.
Downloaded from nejm.org at COLUMBIA UNIV HEALTH SCIENCES LIB on April 18, 2012. For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. i n t e n s i v e a t o r v a s t a t i n t h e r a p y f o r s t a b l e c o r o n a r y d i s e a s e A total of 10,001 patients underwent random- tient population, from a mean of 152 mg per deci- ization and received double-blind treatment with liter (3.9 mmol per liter) to a mean of 98 mg pereither 10 mg or 80 mg of atorvastatin. The time of deciliter (2.6 mmol per liter). Figure 2 summarizesrandomization was taken as the baseline for the post-randomization lipid values in the two groups.
study. Patients were followed for a median of 4.9 Mean LDL cholesterol levels during the study wereyears.
77 mg per deciliter (2.0 mmol per liter) among pa- The two groups were well matched at baseline tients receiving 80 mg of atorvastatin and 101 mg (Table 1), and the pattern of use of concomitant per deciliter (2.6 mmol per liter) among those re-medications was similar in the two groups. Blood ceiving 10 mg of atorvastatin (Fig. 2A).
pressure was controlled for the duration of the Total cholesterol levels (Fig. 2B) and triglycer- ide levels (Fig. 2C) decreased significantly frombaseline to week 12 in the group given 80 mg of c h a n g e i n l a b o r a t o r y v a l u e s
atorvastatin (P<0.001 for both comparisons), and During the open-label period, the LDL cholesterol the levels remained stable during the treatment pe-level was reduced by 35 percent in the overall pa- riod. Both doses of atorvastatin produced nonsig- Table 1. Baseline Characteristics of the Patients.*
Characteristic
10 mg of Atorvastatin (N=5006)
80 mg of Atorvastatin (N=4995)
* Plus–minus values are means ±SD. † Race was self-designated.
‡ Body-mass index is the weight in kilograms divided by the square of the height in meters.
§ To convert values for cholesterol to millimoles per liter, multiply by 0.02586; to convert values for triglycerides to milli- moles per liter, multiply by 0.0113. LDL denotes low-density lipoprotein, and HDL high-density lipoprotein.
Downloaded from nejm.org at COLUMBIA UNIV HEALTH SCIENCES LIB on April 18, 2012. For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine LDL Cholesterol (mg/dl)
Total Cholesterol (mg/dl)
Triglycerides (mg/dl)
HDL Cholesterol (mg/dl)
Figure 2. Mean Lipid Levels during the Study.
To convert values for cholesterol to millimoles per liter, multiply by 0.02586; to convert values for triglycerides to milli-moles per liter, multiply by 0.0113.
nificant increases over baseline in high-density lipo- Outcomes for individual components of the primaryprotein (HDL) cholesterol levels, with no significant end point are shown in Table 2. Relative reductionsdifference between the groups during the course of in the risk of death from CHD, nonfatal non–pro-the study (Fig. 2D).
cedure-related myocardial infarction, and fatal ornonfatal stroke with treatment with 80 mg of ator- e f f i c a c y o u t c o m e s
vastatin, as compared with 10 mg of atorvastatin, A total of 434 patients in the group given 80 mg of were all consistent with the reduction observed foratorvastatin and 548 patients in the group given 10 the primary composite outcome. There was no sta-mg of atorvastatin had a primary event during the tistical interaction for age or sex in the primary out-study, representing an event rate of 8.7 percent and come measure.
10.9 percent, respectively. This rate was equivalent As compared with patients given 10 mg of ator- to an absolute reduction of 2.2 percent in the group vastatin, patients given 80 mg of atorvastatin alsogiven 80 mg of atorvastatin. As compared with the had significant reductions in the risk of a major cor-group given 10 mg of atorvastatin, the group given onary event (hazard ratio, 0.80; 95 percent confi-80 mg had a 22 percent relative reduction in the pri- dence interval, 0.69 to 0.92; P=0.002), any coronarymary composite efficacy outcome of death from event (hazard ratio, 0.79; 95 percent confidenceCHD, nonfatal non–procedure-related myocardial interval, 0.73 to 0.86; P<0.001), a cerebrovascularinfarction, resuscitation after cardiac arrest, or fatal event (hazard ratio, 0.77; 95 percent confidenceor nonfatal stroke (hazard ratio, 0.78; 95 percent interval, 0.64 to 0.93; P=0.007), hospitalizationconfidence interval, 0.69 to 0.89; P<0.001) (Fig. 3). with a primary diagnosis of congestive heart fail-There were 545 major cardiovascular events (as a ure (hazard ratio, 0.74; 95 percent confidence inter-first or subsequent event) in the group given 80 mg val, 0.59 to 0.94; P=0.01), and any cardiovascularof atorvastatin and 715 events in the group given 10 event (hazard ratio, 0.81; 95 percent confidence in-mg of atorvastatin (Table 2 shows only first events). terval, 0.75 to 0.87; P<0.001) (Table 2). The effect Downloaded from nejm.org at COLUMBIA UNIV HEALTH SCIENCES LIB on April 18, 2012. For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. i n t e n s i v e a t o r v a s t a t i n t h e r a p y f o r s t a b l e c o r o n a r y d i s e a s e Event (%)
Event (%)
Major Coronary
Major Cardiovascular
No. at Risk
No. at Risk
from CHD (%)
Nonfatal MI or Death
Fatal or Nonfatal Stroke
No. at Risk
No. at Risk
Figure 3. Cumulative Incidence of a First Major Cardiovascular Event (Panel A), a First Major Coronary Event (Panel B),
Nonfatal Myocardial Infarction (MI) or Death from CHD (Panel C), and a First Fatal or Nonfatal Stroke (Panel D).
The primary end point was a first major cardiovascular event, and a first major coronary event was defined as death from CHD, nonfatal non–procedure-related MI, or resuscitation after cardiac arrest. HR denotes hazard ratio for the group given 80 mg of atorvastatin (ATV) as compared with the group given 10 mg of ATV.
of 80 mg of atorvastatin on the risk of peripheral- Cancer accounted for more than half the deaths artery disease did not differ significantly from that from noncardiovascular causes in both groups —of 10 mg of atorvastatin (hazard ratio, 0.97; 95 per- 75 in the group given 10 mg of atorvastatin (1.5 per-cent confidence interval, 0.83 to 1.15; P=0.76).
cent) and 85 in the group given 80 mg of atorva- The risk of death from any cause also did not statin (1.7 percent; hazard ratio, 1.13; 95 percent differ significantly between the two drug regimens confidence interval, 0.83 to 1.55; P=0.42) — and(hazard ratio, 1.01; 95 percent confidence interval, there were 43 deaths (0.9 percent) and 58 deaths0.85 to 1.19; P=0.92). There were 155 deaths from (1.2 percent), respectively, from nontraumatic caus-cardiovascular causes in the group given 10 mg of es other than cancer (hazard ratio, 1.35; 95 percentatorvastatin (3.1 percent) and 126 in the group giv- confidence interval, 0.91 to 2.00; P=0.13). Thereen 80 mg of atorvastatin (2.5 percent; hazard ratio, were 16 hemorrhagic strokes in the group given 800.80; 95 percent confidence interval, 0.64 to 1.08; mg of atorvastatin and 17 in the group given 10 mgP=0.08). There were 127 deaths from noncardio- of atorvastatin. Deaths from hemorrhagic strokevascular causes in the group given 10 mg of ator- or trauma (including accidental death, suicide, andvastatin (2.5 percent) and 158 in the group given homicide) were infrequent, and the rates did not80 mg of atorvastatin (3.2 percent; hazard ratio, differ significantly between the two groups.
1.25; 95 percent confidence interval, 0.99 to 1.57; No significant increase in adverse events of any type was identified among patients who had very Downloaded from nejm.org at COLUMBIA UNIV HEALTH SCIENCES LIB on April 18, 2012. For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Table 2. Estimated Hazard Ratio for Individual Components of the Primary and Secondary Efficacy Outcomes.*
10 mg of Atorvastatin
80 mg of Atorvastatin
(N=5006)
(N=4995)
Hazard Ratio (95% CI)
Primary outcome
Secondary outcomes
Hospitalization for congestive heart failure * In each row, only the first event for each patient is counted. CI denotes confidence interval.
† This was the original primary outcome (death from CHD, nonfatal non–procedure-related myocardial infarction, or resuscitation after cardiac ‡ A cerebrovascular event was defined as fatal or nonfatal stroke or transient ischemic attack.
§ Peripheral-artery disease was defined as any new diagnosis of peripheral-artery disease, any admission related to its treatment, or any incidental ¶ Any coronary event was defined as a major coronary event, revascularization procedure, procedure-related myocardial infarction, or document- low levels of LDL cholesterol (less than 70 mg per it of the normal range), as compared with 9 patientsdeciliter [1.8 mmol per liter]), as compared with receiving 10 mg of atorvastatin (1.2 percent vs. 0.2those with higher levels.
percent, P<0.001). There were no persistent eleva-tions in creatine kinase (defined as two consecutive measurements obtained 4 to 10 days apart that were Adverse events related to treatment occurred in 406 more than 10 times the upper limit of the normalpatients in the group given 80 mg of atorvastatin, range). Five cases of rhabdomyolysis were report-as compared with 289 patients in the group given ed (two in the group given 80 mg of atorvastatin10 mg of atorvastatin (8.1 percent vs. 5.8 percent, and three in the group given 10 mg of atorvastat-P<0.001). The respective rates of discontinuation in); relevant clinical information about these casesdue to treatment-related adverse events were 7.2 per- is presented in Table 3.
cent and 5.3 percent (P<0.001). Treatment-relatedmyalgia was reported by 241 patients in the group given 80 mg of atorvastatin and by 234 patients inthe group given 10 mg of atorvastatin (4.8 percent This trial provides evidence that the use of inten-and 4.7 percent, respectively; P=0.72). A total of sive atorvastatin therapy to reduce LDL cholester-60 patients receiving 80 mg of atorvastatin had a ol levels below 100 mg per deciliter is associatedpersistent elevation in alanine aminotransferase, with substantial clinical benefit in patients withaspartate aminotransferase, or both (defined as two stable CHD. Both atorvastatin groups had low ratesconsecutive measurements obtained 4 to 10 days of CHD events. The rate in the group given 10 mgapart that were more than three times the upper lim- of atorvastatin was lower than rates reported with Downloaded from nejm.org at COLUMBIA UNIV HEALTH SCIENCES LIB on April 18, 2012. For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. i n t e n s i v e a t o r v a s t a t i n t h e r a p y f o r s t a b l e c o r o n a r y d i s e a s e Table 3. Characteristics of Five Patients with Rhabdomyolysis.*
Characteristic
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
* The criteria of the American College of Cardiology, American Heart Association, and National Heart, Lung, and Blood Institute for rhabdomy- olysis are muscle symptoms plus a creatine kinase level that is more than 10 times the upper limit of the normal range (>10¬ULN) plus an elevation in creatinine or urinary abnormalities (e.g., myoglobinuria).9 Cases were identified by the investigator with direct responsibility for the patient; none of the cases were believed to be related to the study drug. MI denotes myocardial infarction.
statin treatment in placebo-controlled, secondary- stantially below 100 mg per deciliter extended be-prevention trials of populations with a baseline yond the CHD-related vasculature. As comparedrisk similar to that of our patients.1,10,11 with the 10-mg dose of atorvastatin, intensive ther- The relative reduction in the risk of the primary apy with high-dose atorvastatin reduced the risk of composite end point of death from CHD, nonfatal cerebrovascular events by 23 percent. There was nonon–procedure-related myocardial infarction, re- significant difference between groups in the num-suscitation after cardiac arrest, and fatal or nonfa- bers of hemorrhagic strokes as a first event.
tal stroke was 22 percent in the group given 80 mg The study was not adequately powered to de- of atorvastatin, as compared with the group given tect changes in the risk of death from any cause.
10 mg of atorvastatin. Our findings indicate that There were no significant differences between thethe quantitative relationship between reduced LDL two atorvastatin groups in the risk of death fromcholesterol levels and reduced CHD risk demon- cardiovascular or noncardiovascular causes. Thestrated in prior secondary-prevention trials of stat- rates of death from coronary causes in both groupsins holds true even at very low levels of LDL cho- were very low as compared with those in previouslesterol (Fig. 4). If these results were extrapolated secondary-prevention trials of statins, accountingto clinical practice, the use of an 80-mg dose of for only about one third of all deaths. As a conse-atorvastatin to reduce LDL cholesterol levels from quence, the 20 percent reduction in the risk ofa baseline of 101 mg per deciliter to 77 mg per death from CHD in the group given 80 mg of ator-deciliter in 1000 patients with stable CHD would vastatin as compared with the group given 10 mgprevent 34 major cardiovascular events over a pe- of atorvastatin was not large enough to have a sig-riod of five years; in other words, approximately nificant effect on the risk of death from any cause.
30 patients would need to be treated to prevent In both groups, cancer (mainly lung and gas- trointestinal) was the leading noncardiovascular Evaluation of individual components of the pri- cause of death; other causes included respiratory mary and secondary end points shows that treat- diseases, infection, degenerative diseases, and met-ment with 80 mg of atorvastatin had a consistent abolic abnormalities. Although for most of theseand significant beneficial effect on most measures noncardiovascular causes, the number of deathsof CHD-related morbidity and mortality. The clini- was slightly higher in the group given 80 mg of ator-cal benefit of reducing LDL cholesterol levels sub- vastatin than in the group given 10 mg of atorva- Downloaded from nejm.org at COLUMBIA UNIV HEALTH SCIENCES LIB on April 18, 2012. For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine rate of muscle-related adverse events during the In summary, our findings demonstrate that the use of an 80-mg dose of atorvastatin to reduce LDLcholesterol levels to 77 mg per deciliter provides additional clinical benefit in patients with stable CHD that is perceived to be well controlled at an LDL level of approximately 100 mg per deciliter.
Event (%)
These data confirm and extend the growing body of evidence indicating that lowering LDL choles- terol levels well below currently recommended lev-els can have clinical benefit.
Dr. LaRosa reports having received consulting fees from Pfizer, Merck, Bristol-Myers Squibb, and AstraZeneca and lecture fees LDL Cholesterol (mg/dl)
from Pfizer; Dr. Grundy lecture fees from Merck, Pfizer, Kos Phar-maceutical, Abbott, and AstraZeneca and grant support from Kos Figure 4. Event Rates Plotted against LDL Cholesterol Levels during Statin
Pharmaceutical and Merck; and Dr. Waters consulting fees from Therapy in Secondary-Prevention Studies.
AstraZeneca and Pfizer; lecture fees from Merck, Pfizer, and Novar- HPS denotes Heart Protection Study,1 CARE Cholesterol and Recurrent tis; and grant support from Merck and Johnson & Johnson. Dr. Shear is an employee of Pfizer and owns stock in that company. Dr. Barter Events Trial, LIPID Long-term Intervention with Pravastatin in Ischaemic reports having received consulting fees from Pfizer, AstraZeneca, Disease, and 4S Scandinavian Simvastatin Survival Study. Event rates and Sanofi-Aventis; lecture fees from Pfizer, AstraZeneca, Fournier- for HPS, CARE, and LIPID are for death from CHD and nonfatal myocardial Pharma, and Sanofi-Aventis; and grant support from Pfizer; and infarction. Event rates for 4S and the TNT Study also include resuscitation Dr. Fruchart consulting fees from Pfizer and Fournier and lecture after cardiac arrest. To convert values for LDL cholesterol to millimoles per fees from Merck, Fournier, Pierre Fabrie, and AstraZeneca. Dr.
Gotto reports having received consulting fees from AstraZeneca,Bristol-Myers Squibb, Merck, ScheringPlough, Pfizer, Novartis, andReliant and lecture fees from AstraZeneca, Merck, ScheringPlough,Pfizer, and Reliant and having testified before the Food and DrugAdministration on behalf of Johnson & Johnson–Merck. Dr. Gretenreports having received consulting and lecture fees from Pfizer, statin, no single cause (according to body system Merck, and ScheringPlough; Dr. Kastelein consulting fees, lec- ture fees, and grant support from Pfizer, Merck, ScheringPlough, or pathologic process) and no single type of can- AstraZeneca, Bristol-Myers Squibb, and Sankyo; Dr. Shepherd cer accounted for the nonsignificant difference in consulting fees from AstraZeneca, GlaxoSmithKline, Merck,deaths from any cause between the groups.
ScheringPlough and Oxford Biosensors and lecture fees fromAstraZeneca, Merck, and ScheringPlough; and Dr. Wenger consult- The findings regarding drug safety are consis- ing fees from Eli Lilly, Merck, Bristol-Myers Squibb, Pfizer, and Kos tent with the adverse-event profiles of these two Pharmaceuticals; lecture fees from Eli Lilly, Pfizer, Novartis, Merck,doses of atorvastatin reported in other large-scale Bristol-Myers Squibb, and Kos Pharmaceuticals; and grant support from Eli Lilly, Novartis, Bristol-Myers Squibb, and AstraZeneca.
trials of atorvastatin.2,3 The exclusion of 131 pa- We are indebted to all the trial participants; to the large number tients because of abnormal liver-function tests or of doctors, nurses, and hospital administrative staff in various coun-myalgia during the run-in phase is unlikely to ac- tries for their long-term commitment to the study; and to Diane Hessinger, Roger Chan, Andrei Breazna, Eric Gibson, Liz Cusenza, count for the low incidence of persistent eleva- Sheila Auster, Patrick Ferrebee, and Roddy Carter (all full-time em- tions in liver aminotransferase levels and the low ployees of Pfizer) for their contributions.
a p p e n d i x
The following persons participated in the TNT Study: Steering Committee: J. LaRosa (chair), New York; P. Barter, Sydney; J.-C. Fruchart,
Lille, France; A. Gotto, New York; H. Greten, Hamburg, Germany; S. Grundy, Dallas; D. Hunninghake, Minneapolis; J. Kastelein, Amster-
dam; J. Shepherd, Glasgow; D. Waters, San Francisco; N. Wenger, Atlanta; End-Points Committee: L. Cohen (chair), New Haven, Conn.; J.-M.
LaBlanche, Lille, France; H. Levine, Boston; U. Sechtem, Stuttgart, Germany; F. Welty, Boston; Data and Safety Monitoring Board: C. Hen-
nekens (chair), Miami; V. Brown, Atlanta; R. Carmena, Valencia, Spain; R. D’Agostino, Boston; S. Haffner, San Antonio, Tex.; E. Leitersdorf,
Jerusalem; Investigators (numbers of randomized patients in parentheses): Australia (608 patients): C. Aroney, P. Barter, J. Bradley, D. Colqu-
houn, A. Dart, M. d’Emden, J. Lefkovits, R. Minson, G. Nelson, R. O’Brien, P. Roberts-Thomson, A. Thomson, D. Sullivan, P. Thompson;
Austria (29 patients): H. Drexel, H. Sinzinger, F. Stockenhuber; Belgium (300 patients): P. Chenu, G. Heyndrickx, J. Van Cleemput, A. Van Dorpe,
W. Van Mieghem, P. Vermeersch; Canada (1052 patients): M. Arnold, R. Baigrie, J. Bergeron, C. Gagné, J. Davignon, J. Ducas, J. Genest, L.
Higginson, G. Hoag, J. Bonet, A. Ignaszewski, L. Leiter, S. LePage, P. Ma, M. McQueen, D. Mymin, B. O’Neill, B. Sussex, P. Theroux, G.
Tremblay, W. Tymchak, J. Warnica; France (207 patients): P. Attali, J. Bonnet, L. Caster, R. Constans, J. Demarcq, I. Ginon, J. Leymarie, J. Man-
sourati, J. Ollivier, F. Paillard, J. Ponsonnaille; Germany (144 patients): U. Beil, H. Fritz, D. Hüwel, W. Huppertz, W. Liebscher, K Schussmann,
E. Steinhagen-Thiessen; Ireland (53 patients): B. Buckley, P. Crean; Italy (75 patients): A. Branzi, P. Fioretti, G. Gensini, N. Mininni, G. Pinelli,
E. Uslenghi; the Netherlands (788 patients): R. Anthonio, J. Bonnier, H. Crijns, H. Dohmen, P. Dunselman, M. Galjee, B. Hamer, J. Hoorntje,
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i n t e n s i v e a t o r v a s t a t i n t h e r a p y f o r s t a b l e c o r o n a r y d i s e a s e J. Jukema, A. Oude-Ophuis, H. Plokker, J. Posma, J. Ruiter, M. Trip, A. van Boven; South Africa (523 patients): A. Dalby, L. Disler, A. Doubell,J. King, E. Lloyd, J. Marx, P. Roux; Spain (525 patients): M. Anguita, C. Brotons, C. Calvo, J. Cruz-Fernandez, F. Fernandez-Aviles, A. Fernan-dez-Cruz, I. Ferreira, E. Gonzalez, E. Lage, P. Mata, J. Mostaza, R. Muñoz-Aguilera, E. Lopez de Sa, G. Pedro, G. Permanyer, A. Pozuelo, R.
Querejeta, J. Ribera, E. Ros-Rahola, M. Vela; Switzerland (91 patients): W. Angehrn, L. Kappenberger, T. Moccetti, H. Saner; United Kingdom(299 patients): D. Brydie, A. Chauhan, R. Greenbaum, H. Kadr, C. Kaski, R. Mattu, W. McCrea, J. McMurray, D. Mikhailidis, A. Salmasi, N. Sa-mani, M. Shiu, A. Timmis, S. Turley, J. Wictome; United States (5309 patients): R. Abadier, S. Alexander, B. Asbill, J. Bagdade, B. Beard, J. Beck-er, V. Bittner, R. Blumenthal, M. Bolton, W. Bremner, D. Brewer, C. Brown, K. Browne, J. Carstens, W. Cefalu, J. Chambers, J. Cohen, M. Col-lins, S. Crespin, M. Cressman, R. Curry, M. Davidson, G. De Gent, J. de Lemos, P. Deedwania, D. Dixon, J. Duncan, C. East, D. Edmundowicz,B. Effron, M. Elam, M. Ettinger, R. Feldman, D. Fiske, J. Forrester, G. Fraser, Z. Freedman, S. Freeman, V. Fonseca, D. Frid, K. Friday, J. Geo-has, H. Ginsberg, A. Goldberg, E. Goldenberg, D. Goldner, D. Goldscher, B. Gordon, S. Gottlieb, M. Grayson, R. Guthrie, J. Guyton, J.
Haas, F. Handel, R. Hartman, J. Henry, M. Hepp, R. Heuser, D. Herrington, M. Hibbard, C. Hjemdahl-Monsen, G. Hopkins, V. Howard, J.
Hsia, D. Hunninghake, S. Jafri, P. Jones, P. Kakavas, J. Kane, L. Keilson, E. Kerut, R. Kloner, R. Knopp, J. Kostis, L. Kozlowski, R. Krasuski,A. Kugelmass, K. LaBresh, J. Larry, C. Lavie, B. Lewis, S. Lewis, M. Linton, P. Linz, R. Lloret, V. Lucarella, J. Maciejko, D. McElroy, J. McGhee,M. McGowan, W. McGuinn, M. Melucci, J. Merillat, M. Michalski, D. Miller, L. Miller, M. Miller, M. Mirro, V. Miscia, J. Mossberg, B. Musa,S. Nash, R. Nesto, M. Neustel, T. Noonan, J. O’Keefe, B. Olafsson, S. Oparil, T. Pearson, C. Pepine, G. Peterson, G. Pogson, K. Powers, D.
Rader, R. Reeves, J. Reusch, G. Revtyak, D. Robertson, J. Robinson, W. Robinson, M. Rocco, J. Robinson, J. Rodgers, R. Rosenson, E. Roth,S. Sadanandan, K. Salisbury, D. Sato, J. Saucedo, E. Schaefer, H. Schrott, L. Seman, G. Schectman, C. Schmalfuss, D. Schneider, B. Sobel, R.
Schneider, S. Schwartz, P. Seigel, M. Seyal, S. Sharp, D. Shindler, D. Smith, D. Sprecher, L. Solberg, E. Sontz, J. Stamper, E. Stein, V. Subbarao,A. Susmano, A. Talle, P. Thompson, J. Torelli, F. Torres, D. Triffon, G. Vetrovec, N. Vijay, W. Wickermeyer, K. Wool, M. Zakrzewski, S. Zar-ich, J. Zavoral, F. Zieve.
r e f e r e n c e s
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lation 2004;110:227-39. [Erratum, Circula- outcomes in managed-care patients with cor- onary heart disease treated aggressively in heart disease: the Scandinavian Simvastat- lipid-lowering disease management clinics: et al. Treating to New Targets (TNT) Study: the ALLIANCE study. J Am Coll Cardiol 2004; does lowering low-density lipoprotein cho- lesterol levels below currently recommend- Copyright 2005 Massachusetts Medical Society. full text of all journal articles on the world wide web
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