Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coronary Disease
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., Nanette K. Wenger, M.D., for the Treating to New Targets (TNT) Investigators
Background Previous trials have demonstrated that lowering low-densitylipoprotein (LDL) cholesterol levels below currently recommendedlevels is beneficial in patients with acute coronary syndromes.We prospectively assessed the efficacy and safety of loweringLDL cholesterol levels below 100 mg per deciliter (2.6 mmolper liter) in patients with stable coronary heart disease (CHD).
Methods A total of 10,001 patients with clinically evident CHDand LDL cholesterol levels of less than 130 mg per deciliter(3.4 mmol per liter) were randomly assigned to double-blindtherapy and received either 10 mg or 80 mg of atorvastatin perday. Patients were followed for a median of 4.9 years. The primaryend point was the occurrence of a first major cardiovascularevent, defined as death from CHD, nonfatal non–procedure-relatedmyocardial infarction, resuscitation after cardiac arrest, orfatal or nonfatal stroke.
Results The mean LDL cholesterol levels were 77 mg per deciliter(2.0 mmol per liter) during treatment with 80 mg of atorvastatinand 101 mg per deciliter (2.6 mmol per liter) during treatmentwith 10 mg of atorvastatin. The incidence of persistent elevationsin liver aminotransferase levels was 0.2 percent in the groupgiven 10 mg of atorvastatin and 1.2 percent in the group given80 mg of atorvastatin (P<0.001). A primary event occurredin 434 patients (8.7 percent) receiving 80 mg of atorvastatin,as compared with 548 patients (10.9 percent) receiving 10 mgof atorvastatin, representing an absolute reduction in the rateof major cardiovascular events of 2.2 percent and a 22 percentrelative reduction in risk (hazard ratio, 0.78; 95 percent confidenceinterval, 0.69 to 0.89; P<0.001). There was no differencebetween the two treatment groups in overall mortality.
Conclusions Intensive lipid-lowering therapy with 80 mg of atorvastatinper day in patients with stable CHD provides significant clinicalbenefit beyond that afforded by treatment with 10 mg of atorvastatinper day. This occurred with a greater incidence of elevatedaminotransferase levels.
The value of lowering low-density lipoprotein (LDL) cholesterollevels in preventing major cardiovascular events and strokehas been well documented. Recent studies have raised the issueof optimal treatment targets for patients with coronary heartdisease (CHD).1,2,3,4 The value of reducing LDL cholesterollevels substantially below 100 mg per deciliter (2.6 mmol perliter) in patients with CHD, particularly those with stablenonacute disease, has not been clearly demonstrated.
The Third Report of the National Cholesterol Education Program(NCEP) Adult Treatment Panel5 and the most recent guidelinesof the Third Joint Task Force of European and Other Societieson Cardiovascular Disease Prevention in Clinical Practice6 haverecommended an LDL cholesterol level of less than 100 mg perdeciliter as the goal of therapy for patients at high risk forCHD. On the basis of data from the Heart Protection Study (HPS)1and the Pravastatin or Atorvastatin Evaluation and InfectionTrial (PROVE IT),2 the NCEP in conjunction with the AmericanHeart Association and the American College of Cardiology subsequentlyintroduced a more aggressive, but optional, LDL cholesterolgoal of less than 70 mg per deciliter (1.8 mmol per liter) forpatients at very high risk for CHD, even if baseline LDL cholesterollevels were below 100 mg per deciliter.7 However, PROVE IT wasconducted in a population of patients with acute coronary syndromeswho were at very high risk for cardiovascular disease, and althoughmany patients in the HPS who began with an LDL cholesterol levelof less than 100 mg per deciliter benefited from statin therapy,this benefit was in comparison with placebo. Thus, there isno definitive evidence that intensive statin therapy, with agoal of reducing LDL cholesterol levels to approximately 70mg per deciliter, is associated with better outcomes than moderatestatin therapy, with a goal of reducing LDL cholesterol levelsto about 100 mg per deciliter in patients with stable CHD. Datafrom the Treating to New Targets (TNT) Study make it possibleto test this hypothesis.
Methods
The design of the TNT Study has been described in detail previously.8All patients gave written informed consent, and the study wasapproved by the local research ethics committee or institutionalreview board at each center.
Primary Hypothesis
The primary hypothesis of the study was that reducing LDL cholesterollevels to well below 100 mg per deciliter in patients with stableCHD and slightly elevated LDL cholesterol levels (despite previoustherapy with low-dose atorvastatin) could yield an incrementalclinical benefit. This hypothesis was tested in a double-blind,parallel-group design. The occurrence of major cardiovascularoutcomes was compared in two groups of patients: one group received10 mg of atorvastatin daily with the goal of an average LDLcholesterol level of 100 mg per deciliter, and the other groupreceived 80 mg of atorvastatin daily with the goal of an averageLDL cholesterol level of 75 mg per deciliter (1.9 mmol per liter).
Patient Population
Eligible patients were men and women 35 to 75 years of age whohad clinically evident CHD, defined by one or more of the following:previous myocardial infarction, previous or current angina withobjective evidence of atherosclerotic CHD, and a history ofcoronary revascularization. The exclusion criteria have beendescribed in detail previously.8 Randomization occurred betweenJuly 1998 and December 1999.
Study Protocol
Any previously prescribed lipid-regulating drugs were discontinuedat screening, and all patients completed a washout period ofone to eight weeks. To ensure that, at baseline, all patientshad LDL cholesterol levels consistent with then-current guidelinesfor the treatment of stable CHD, patients with LDL cholesterollevels between 130 and 250 mg per deciliter (3.4 and 6.5 mmolper liter, respectively) and triglyceride levels of 600 mg perdeciliter (6.8 mmol per liter) or less entered an eight-weekrun-in period of open-label treatment with 10 mg of atorvastatinper day. At the end of the run-in phase (week 0), patients witha mean LDL cholesterol level of less than 130 mg per deciliter(3.4 mmol per liter) (determined four weeks and two weeks beforerandomization) were randomly assigned to double-blind therapywith either 10 mg or 80 mg of atorvastatin per day. During thedouble-blind period, follow-up visits occurred at week 12 andat months 6, 9, and 12 in the first year and every 6 monthsthereafter.
Efficacy Outcomes
The primary efficacy outcome was the occurrence of a major cardiovascularevent, defined as death from CHD, nonfatal non–procedure-relatedmyocardial infarction, resuscitation after cardiac arrest, orfatal or nonfatal stroke. Secondary outcomes included a majorcoronary event (defined as death from CHD, nonfatal non–procedure-relatedmyocardial infarction, or resuscitation after cardiac arrest),a cerebrovascular event, hospitalization for congestive heartfailure, peripheral-artery disease, death from any cause, anycardiovascular event, and any coronary event.
Statistical Analysis
Epidemiologic data suggested that the treatment-related differencein LDL cholesterol levels between the two groups would translateinto 20 to 30 percent fewer recurrent coronary events at fiveyears in the group given 80 mg of atorvastatin than in the groupgiven 10 mg of atorvastatin. The study's original target enrollmentwas approximately 8600 patients on the basis of a projectednumber of 750 major coronary events during an average follow-upof 5.5 years. However, the recruitment rate was higher thanexpected, and 10,003 patients underwent randomization, all but2 of whom received the study drug.
In February 2003, the steering committee added stroke (fatalor nonfatal) to the primary efficacy outcome. This change wasmade before any data were reviewed and preceded the first interimanalysis by the independent data and safety monitoring board.At the time, evidence was accumulating of the beneficial roleof statins in reducing the risk of stroke. The change in theprimary end point was made to clarify this role. This modificationled to an increase in the projected number of primary eventsto 950 (750 coronary events plus 200 strokes) during the trial,providing the study with a statistical power of 85 percent todetect an absolute reduction of 17 percent in the five-yearcumulative rate of the primary efficacy outcome in the groupgiven 80 mg of atorvastatin, as compared with the group given10 mg of atorvastatin, with the use of a two-sided test at analpha level of 0.05.
All analyses were performed on an intention-to-treat basis.All randomized patients who were dispensed one dose of the studydrug were included in the analyses. The primary and secondarycomposite end points were analyzed from the time of the firstdose of study drug to the first event, according to the Kaplan–Meiermethod. The study had a statistical power of only 40 percentto detect a 10 percent reduction in the risk of death from anycause with the use of a two-sided test at an alpha level of0.05.
Two interim efficacy analyses were performed and were basedon a two-sided Peto type of monitoring boundary. For the finalprimary analysis, an adjusted P value of 0.049 was consideredto indicate statistical significance, given a type I error rateof 0.05. For all secondary outcomes, a P value of 0.05 was consideredto indicate statistical significance, and all tests were two-sided.
The sponsor initiated the study. The steering committee developedthe protocol in collaboration with the sponsor and took responsibilityfor the final version. ICON Clinical Research (North Wales,Pennsylvania) managed all data. ICON and Pfizer provided sitemonitoring throughout the study. An independent end-points committeeadjudicated all potential end points in a blinded fashion. Anindependent data and safety monitoring board with its independentstatistical-support group from the University of Wisconsin performedinterim monitoring and analyses of efficacy, safety, and dataquality. The data were analyzed by the sponsor according tothe statistical-analysis plan approved by the steering committee.The steering committee had unrestricted, request-based accessto the study data, which were retained by the sponsor, and wrotethe article without constraints from the sponsor. The steeringcommittee assumes overall responsibility for the integrity ofthe data, for the accuracy of the data analyses, and for thecompleteness of the material reported. The data reported werethose available to the steering committee as of January 29,2005.
Results
Patient Population
A total of 18,469 patients were screened at 256 sites in 14countries (Figure 1). Of these, 15,464 patients (83.7 percent)were deemed eligible to enter the open-label run-in period.A further 5461 patients were excluded after the open-label run-inphase. Most of these excluded patients (4634, or 84.9 percent)did not meet randomization criteria. Other reasons includedadverse events in 197 (3.6 percent), death or an ischemic eventin 211 (3.9 percent), and lack of compliance in 70 (1.3 percent).
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.
A total of 10,001 patients underwent randomization and receiveddouble-blind treatment with either 10 mg or 80 mg of atorvastatin.The time of randomization was taken as the baseline for thestudy. Patients were followed for a median of 4.9 years.
The two groups were well matched at baseline (Table 1), andthe pattern of use of concomitant medications was similar inthe two groups. Blood pressure was controlled for the durationof the study in both groups.
Table 1. Baseline Characteristics of the Patients.
Change in Laboratory Values
During the open-label period, the LDL cholesterol level wasreduced by 35 percent in the overall patient population, froma mean of 152 mg per deciliter (3.9 mmol per liter) to a meanof 98 mg per deciliter (2.6 mmol per liter). Figure 2 summarizespost-randomization lipid values in the two groups. Mean LDLcholesterol levels during the study were 77 mg per deciliter(2.0 mmol per liter) among patients receiving 80 mg of atorvastatinand 101 mg per deciliter (2.6 mmol per liter) among those receiving10 mg of atorvastatin (Figure 2A).
To convert values for cholesterol to millimoles per liter, multiply by 0.02586; to convert values for triglycerides to millimoles per liter, multiply by 0.0113.
Total cholesterol levels (Figure 2B) and triglyceride levels(Figure 2C) decreased significantly from baseline to week 12in the group given 80 mg of atorvastatin (P<0.001 for bothcomparisons), and the levels remained stable during the treatmentperiod. Both doses of atorvastatin produced nonsignificant increasesover baseline in high-density lipoprotein (HDL) cholesterollevels, with no significant difference between the groups duringthe course of the study (Figure 2D).
Efficacy Outcomes
A total of 434 patients in the group given 80 mg of atorvastatinand 548 patients in the group given 10 mg of atorvastatin hada primary event during the study, representing an event rateof 8.7 percent and 10.9 percent, respectively. This rate wasequivalent to an absolute reduction of 2.2 percent in the groupgiven 80 mg of atorvastatin. As compared with the group given10 mg of atorvastatin, the group given 80 mg had a 22 percentrelative reduction in the primary composite efficacy outcomeof death from CHD, nonfatal non–procedure-related myocardialinfarction, resuscitation after cardiac arrest, or fatal ornonfatal stroke (hazard ratio, 0.78; 95 percent confidence interval,0.69 to 0.89; P<0.001) (Figure 3). There were 545 major cardiovascularevents (as a first or subsequent event) in the group given 80mg of atorvastatin and 715 events in the group given 10 mg ofatorvastatin (Table 2 shows only first events). Outcomes forindividual components of the primary end point are shown inTable 2. Relative reductions in the risk of death from CHD,nonfatal non–procedure-related myocardial infarction,and fatal or nonfatal stroke with treatment with 80 mg of atorvastatin,as compared with 10 mg of atorvastatin, were all consistentwith the reduction observed for the primary composite outcome.There was no statistical interaction for age or sex in the primaryoutcome measure.
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.
Table 2. Estimated Hazard Ratio for Individual Components of the Primary and Secondary Efficacy Outcomes.
As compared with patients given 10 mg of atorvastatin, patientsgiven 80 mg of atorvastatin also had significant reductionsin the risk of a major coronary event (hazard ratio, 0.80; 95percent confidence interval, 0.69 to 0.92; P=0.002), any coronaryevent (hazard ratio, 0.79; 95 percent confidence interval, 0.73to 0.86; P<0.001), a cerebrovascular event (hazard ratio,0.77; 95 percent confidence interval, 0.64 to 0.93; P=0.007),hospitalization with a primary diagnosis of congestive heartfailure (hazard ratio, 0.74; 95 percent confidence interval,0.59 to 0.94; P=0.01), and any cardiovascular event (hazardratio, 0.81; 95 percent confidence interval, 0.75 to 0.87; P<0.001)(Table 2). The effect of 80 mg of atorvastatin on the risk ofperipheral-artery disease did not differ significantly fromthat of 10 mg of atorvastatin (hazard ratio, 0.97; 95 percentconfidence interval, 0.83 to 1.15; P=0.76).
The risk of death from any cause also did not differ significantlybetween the two drug regimens (hazard ratio, 1.01; 95 percentconfidence interval, 0.85 to 1.19; P=0.92). There were 155 deathsfrom cardiovascular causes in the group given 10 mg of atorvastatin(3.1 percent) and 126 in the group given 80 mg of atorvastatin(2.5 percent; hazard ratio, 0.80; 95 percent confidence interval,0.64 to 1.08; P=0.08). There were 127 deaths from noncardiovascularcauses in the group given 10 mg of atorvastatin (2.5 percent)and 158 in the group given 80 mg of atorvastatin (3.2 percent;hazard ratio, 1.25; 95 percent confidence interval, 0.99 to1.57; P=0.06).
Cancer accounted for more than half the deaths from noncardiovascularcauses in both groups — 75 in the group given 10 mg ofatorvastatin (1.5 percent) and 85 in the group given 80 mg ofatorvastatin (1.7 percent; hazard ratio, 1.13; 95 percent confidenceinterval, 0.83 to 1.55; P=0.42) — and there were 43 deaths(0.9 percent) and 58 deaths (1.2 percent), respectively, fromnontraumatic causes other than cancer (hazard ratio, 1.35; 95percent confidence interval, 0.91 to 2.00; P=0.13). There were16 hemorrhagic strokes in the group given 80 mg of atorvastatinand 17 in the group given 10 mg of atorvastatin. Deaths fromhemorrhagic stroke or trauma (including accidental death, suicide,and homicide) were infrequent, and the rates did not differsignificantly between the two groups.
No significant increase in adverse events of any type was identifiedamong patients who had very low levels of LDL cholesterol (lessthan 70 mg per deciliter [1.8 mmol per liter]), as comparedwith those with higher levels.
Safety
Adverse events related to treatment occurred in 406 patientsin the group given 80 mg of atorvastatin, as compared with 289patients in the group given 10 mg of atorvastatin (8.1 percentvs. 5.8 percent, P<0.001). The respective rates of discontinuationdue to treatment-related adverse events were 7.2 percent and5.3 percent (P<0.001). Treatment-related myalgia was reportedby 241 patients in the group given 80 mg of atorvastatin andby 234 patients in the group given 10 mg of atorvastatin (4.8percent and 4.7 percent, respectively; P=0.72). A total of 60patients receiving 80 mg of atorvastatin had a persistent elevationin alanine aminotransferase, aspartate aminotransferase, orboth (defined as two consecutive measurements obtained 4 to10 days apart that were more than three times the upper limitof the normal range), as compared with 9 patients receiving10 mg of atorvastatin (1.2 percent vs. 0.2 percent, P<0.001).There were no persistent elevations in creatine kinase (definedas two consecutive measurements obtained 4 to 10 days apartthat were more than 10 times the upper limit of the normal range).Five cases of rhabdomyolysis were reported (two in the groupgiven 80 mg of atorvastatin and three in the group given 10mg of atorvastatin); relevant clinical information about thesecases is presented in Table 3.
Table 3. Characteristics of Five Patients with Rhabdomyolysis.
Discussion
This trial provides evidence that the use of intensive atorvastatintherapy to reduce LDL cholesterol levels below 100 mg per deciliteris associated with substantial clinical benefit in patientswith stable CHD. Both atorvastatin groups had low rates of CHDevents. The rate in the group given 10 mg of atorvastatin waslower than rates reported with statin treatment in placebo-controlled,secondary-prevention trials of populations with a baseline risksimilar to that of our patients.1,10,11
The relative reduction in the risk of the primary compositeend point of death from CHD, nonfatal non–procedure-relatedmyocardial infarction, resuscitation after cardiac arrest, andfatal or nonfatal stroke was 22 percent in the group given 80mg of atorvastatin, as compared with the group given 10 mg ofatorvastatin. Our findings indicate that the quantitative relationshipbetween reduced LDL cholesterol levels and reduced CHD riskdemonstrated in prior secondary-prevention trials of statinsholds true even at very low levels of LDL cholesterol (Figure 4).If these results were extrapolated to clinical practice,the use of an 80-mg dose of atorvastatin to reduce LDL cholesterollevels from a baseline of 101 mg per deciliter to 77 mg perdeciliter in 1000 patients with stable CHD would prevent 34major cardiovascular events over a period of five years; inother words, approximately 30 patients would need to be treatedto prevent one event.
Figure 4. Event Rates Plotted against LDL Cholesterol Levels during Statin Therapy in Secondary-Prevention Studies.
HPS denotes Heart Protection Study,1 CARE Cholesterol and Recurrent Events Trial,10 LIPID Long-term Intervention with Pravastatin in Ischaemic Disease,11 and 4S Scandinavian Simvastatin Survival Study.12 Event rates for HPS, CARE, and LIPID are for death from CHD and nonfatal myocardial infarction. Event rates for 4S and the TNT Study also include resuscitation after cardiac arrest. To convert values for LDL cholesterol to millimoles per liter, multiply by 0.02586.
Evaluation of individual components of the primary and secondaryend points shows that treatment with 80 mg of atorvastatin hada consistent and significant beneficial effect on most measuresof CHD-related morbidity and mortality. The clinical benefitof reducing LDL cholesterol levels substantially below 100 mgper deciliter extended beyond the CHD-related vasculature. Ascompared with the 10-mg dose of atorvastatin, intensive therapywith high-dose atorvastatin reduced the risk of cerebrovascularevents by 23 percent. There was no significant difference betweengroups in the numbers of hemorrhagic strokes as a first event.
The study was not adequately powered to detect changes in therisk of death from any cause. There were no significant differencesbetween the two atorvastatin groups in the risk of death fromcardiovascular or noncardiovascular causes. The rates of deathfrom coronary causes in both groups were very low as comparedwith those in previous secondary-prevention trials of statins,accounting for only about one third of all deaths. As a consequence,the 20 percent reduction in the risk of death from CHD in thegroup given 80 mg of atorvastatin as compared with the groupgiven 10 mg of atorvastatin was not large enough to have a significanteffect on the risk of death from any cause.
In both groups, cancer (mainly lung and gastrointestinal) wasthe leading noncardiovascular cause of death; other causes includedrespiratory diseases, infection, degenerative diseases, andmetabolic abnormalities. Although for most of these noncardiovascularcauses, the number of deaths was slightly higher in the groupgiven 80 mg of atorvastatin than in the group given 10 mg ofatorvastatin, no single cause (according to body system or pathologicprocess) and no single type of cancer accounted for the nonsignificantdifference in deaths from any cause between the groups.
The findings regarding drug safety are consistent with the adverse-eventprofiles of these two doses of atorvastatin reported in otherlarge-scale trials of atorvastatin.2,3 The exclusion of 131patients because of abnormal liver-function tests or myalgiaduring the run-in phase is unlikely to account for the low incidenceof persistent elevations in liver aminotransferase levels andthe low rate of muscle-related adverse events during the study.
In summary, our findings demonstrate that the use of an 80-mgdose of atorvastatin to reduce LDL cholesterol levels to 77mg per deciliter provides additional clinical benefit in patientswith stable CHD that is perceived to be well controlled at anLDL level of approximately 100 mg per deciliter. These dataconfirm and extend the growing body of evidence indicating thatlowering LDL cholesterol levels well below currently recommendedlevels can have clinical benefit.
Funded by Pfizer.
Dr. LaRosa reports having received consulting fees from Pfizer,Merck, Bristol-Myers Squibb, and AstraZeneca and lecture feesfrom Pfizer; Dr. Grundy lecture fees from Merck, Pfizer, KosPharmaceutical, Abbott, and AstraZeneca and grant support fromKos Pharmaceutical and Merck; and Dr. Waters consulting feesfrom AstraZeneca and Pfizer; lecture fees from Merck, Pfizer,and Novartis; and grant support from Merck and Johnson &Johnson. Dr. Shear is an employee of Pfizer and owns stock inthat company. Dr. Barter reports having received consultingfees from Pfizer, AstraZeneca, and Sanofi-Aventis; lecture feesfrom Pfizer, AstraZeneca, FournierPharma, and Sanofi-Aventis;and grant support from Pfizer; and Dr. Fruchart consulting feesfrom Pfizer and Fournier and lecture fees from Merck, Fournier,Pierre Fabrie, and AstraZeneca. Dr. Gotto reports having receivedconsulting fees from AstraZeneca, Bristol-Myers Squibb, Merck,ScheringPlough, Pfizer, Novartis, and Reliant and lecture feesfrom AstraZeneca, Merck, ScheringPlough, Pfizer, and Reliantand having testified before the Food and Drug Administrationon behalf of Johnson & Johnson–Merck. Dr. Greten reportshaving received consulting and lecture fees from Pfizer, Merck,and ScheringPlough; Dr. Kastelein consulting fees, lecture fees,and grant support from Pfizer, Merck, ScheringPlough, AstraZeneca,Bristol-Myers Squibb, and Sankyo; Dr. Shepherd consulting feesfrom AstraZeneca, GlaxoSmithKline, Merck, ScheringPlough andOxford Biosensors and lecture fees from AstraZeneca, Merck,and ScheringPlough; and Dr. Wenger consulting fees from EliLilly, Merck, Bristol-Myers Squibb, Pfizer, and Kos Pharmaceuticals;lecture fees from Eli Lilly, Pfizer, Novartis, Merck, Bristol-MyersSquibb, and Kos Pharmaceuticals; and grant support from EliLilly, Novartis, Bristol-Myers Squibb, and AstraZeneca.
We are indebted to all the trial participants; to the largenumber of doctors, nurses, and hospital administrative staffin various countries for their long-term commitment to the study;and to Diane Hessinger, Roger Chan, Andrei Breazna, Eric Gibson,Liz Cusenza, Sheila Auster, Patrick Ferrebee, and Roddy Carter(all full-time employees of Pfizer) for their contributions.
* Participants in the TNT Study are listed in the Appendix.
Source Information
From the State University of New York Health Science Center, Brooklyn (J.C.L.); the University of Texas Southwestern Medical Center, Dallas (S.M.G.); San Francisco General Hospital, San Francisco (D.D.W.); Pfizer, Groton, Conn. (C.S.); the Heart Research Institute, Sydney (P.B.); Institut Pasteur, Lille, France (J.-C.F.); Weill Medical College of Cornell University, New York (A.M.G.); Universitätsklinikum Eppendorf, Hamburg, Germany (H.G.); Academic Medical Center, University of Amsterdam, Amsterdam (J.J.P.K.); the University of Glasgow, Glasgow, United Kingdom (J.S.); and Emory University School of Medicine, Atlanta (N.K.W.). This article was published at www.nejm.org on March 8, 2005.
Address reprint requests to Dr. LaRosa at the State University of New York Health Science Center, 450 Clarkson Ave., Brooklyn, NY 11203, or at jclarosa{at}downstate.edu.
References
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. [CrossRef][ISI][Medline]
Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-1504. [Free Full Text]
Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361:1149-1158. [CrossRef][ISI][Medline]
Koren MJ, Hunninghake DB. Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the ALLIANCE study. J Am Coll Cardiol 2004;44:1772-1779. [Free Full Text]
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. [Free Full Text]
De Backer G, Ambrosioni E, Borch-Johnsen K, et al. European guidelines on cardiovascular disease prevention in clinical practice: Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J 2003;24:1601-1610. [Free Full Text]
Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227-239. [Erratum, Circulation 2004;110:763.] [Free Full Text]
Waters DD, Guyton JR, Herrington DM, et al. 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. [CrossRef][ISI][Medline]
Pasternak RC, Smith SC Jr, Bairey-Merz CN, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Circulation 2002;106:1024-1028. [Free Full Text]
Sacks FM, Pfeffer MA, Moyé LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001-1009. [Free Full Text]
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. [Free Full Text]
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. [CrossRef][ISI][Medline]
Appendix
The following persons participated in the TNT Study: SteeringCommittee: 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, Amsterdam; 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; Dataand Safety Monitoring Board: C. Hennekens (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. Colquhoun, 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. Mansourati, 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, 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. Fernandez-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. Samani, M. Shiu, A. Timmis, S. Turley, J. Wictome;United States (5309 patients): R. Abadier, S. Alexander, B.Asbill, J. Bagdade, B. Beard, J. Becker, V. Bittner, R. Blumenthal,M. Bolton, W. Bremner, D. Brewer, C. Brown, K. Browne, J. Carstens,W. Cefalu, J. Chambers, J. Cohen, M. Collins, 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. Geohas, 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. Zarich, J. Zavoral, F. Zieve.
The SEARCH Collaborative Group,
(2008). SLCO1B1 Variants and Statin-Induced Myopathy -- A Genomewide Study. NEJM
0: NEJMoa0801936v1-1
[Abstract][Full Text]
Settergren, M., Bohm, F., Ryden, L., Pernow, J.
(2008). Cholesterol lowering is more important than pleiotropic effects of statins for endothelial function in patients with dysglycaemia and coronary artery disease. Eur Heart J
29: 1753-1760
[Abstract][Full Text]
Pedersen, T. R.
(2008). Overview of clinical trials on calcific aortic stenosis. Eur Heart J Suppl
10: E31-E40
[Abstract][Full Text]
Kastelein, J. J.P., van der Steeg, W. A., Holme, I., Gaffney, M., Cater, N. B., Barter, P., Deedwania, P., Olsson, A. G., Boekholdt, S. M., Demicco, D. A., Szarek, M., LaRosa, J. C., Pedersen, T. R., Grundy, S. M., for the TNT and IDEAL Study Groups,
(2008). Lipids, Apolipoproteins, and Their Ratios in Relation to Cardiovascular Events With Statin Treatment. Circulation
117: 3002-3009
[Abstract][Full Text]
Goldstein, L. B., Amarenco, P., Szarek, M., Callahan, A. III, Hennerici, M., Sillesen, H., Zivin, J. A., Welch, K.M.A., On behalf of the SPARCL Investigators,
(2008). Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study. Neurology
70: 2364-2370
[Abstract][Full Text]
Bloomgarden, Z. T.
(2008). Cardiovascular Disease in Diabetes. Diabetes Care
31: 1260-1266
[Full Text]
Hausenloy, D J, Yellon, D M
(2008). Targeting residual cardiovascular risk: raising high-density lipoprotein cholesterol levels. Heart
94: 706-714
[Abstract][Full Text]
Shah, S. J., Waters, D. D., Barter, P., Kastelein, J. J.P., Shepherd, J., Wenger, N. K., DeMicco, D. A., Breazna, A., LaRosa, J. C.
(2008). Intensive Lipid-Lowering With Atorvastatin for Secondary Prevention in Patients After Coronary Artery Bypass Surgery. J Am Coll Cardiol
51: 1938-1943
[Abstract][Full Text]
Ky, B., Burke, A., Tsimikas, S., Wolfe, M. L., Tadesse, M. G., Szapary, P. O., Witztum, J. L., FitzGerald, G. A., Rader, D. J.
(2008). The Influence of Pravastatin and Atorvastatin on Markers of Oxidative Stress in Hypercholesterolemic Humans. J Am Coll Cardiol
51: 1653-1662
[Abstract][Full Text]
Ambrose, J. A.
(2008). In Search of the "vulnerable plaque": can it be localized and will focal regional therapy ever be an option for cardiac prevention?. J Am Coll Cardiol
51: 1539-1542
[Abstract][Full Text]
Shepherd, J., Kastelein, J. J.P., Bittner, V., Deedwania, P., Breazna, A., Dobson, S., Wilson, D. J., Zuckerman, A., Wenger, N. K., for the TNT (Treating to New Targets) Investigator,
(2008). Intensive Lipid Lowering With Atorvastatin in Patients With Coronary Heart Disease and Chronic Kidney Disease: The TNT (Treating to New Targets) Study. J Am Coll Cardiol
51: 1448-1454
[Abstract][Full Text]
Kastelein, J. J.P., Akdim, F., Stroes, E. S.G., Zwinderman, A. H., Bots, M. L., Stalenhoef, A. F.H., Visseren, F. L.J., Sijbrands, E. J.G., Trip, M. D., Stein, E. A., Gaudet, D., Duivenvoorden, R., Veltri, E. P., Marais, A. D., de Groot, E., the ENHANCE Investigators,
(2008). Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia. NEJM
358: 1431-1443
[Abstract][Full Text]
Torabi, A., Cleland, J. G.F., Khan, N. K., Loh, P. H., Clark, A. L., Alamgir, F., Caplin, J. L., Rigby, A. S., Goode, K.
(2008). The timing of development and subsequent clinical course of heart failure after a myocardial infarction. Eur Heart J
29: 859-870
[Abstract][Full Text]
Arca, M., Conti, B., Montali, A., Pignatelli, P., Campagna, F., Barilla, F., Tanzilli, G., Verna, R., Vestri, A., Gaudio, C., Violi, F.
(2008). C242T Polymorphism of NADPH Oxidase p22phox and Recurrence of Cardiovascular Events in Coronary Artery Disease. Arterioscler. Thromb. Vasc. Bio.
28: 752-757
[Abstract][Full Text]
Wenger, N K, Lewis, S J, Welty, F K, Herrington, D M, Bittner, V, on behalf of the TNT Steering Committee and Invest,
(2008). Beneficial effects of aggressive low-density lipoprotein cholesterol lowering in women with stable coronary heart disease in the Treating to New Targets (TNT) study. Heart
94: 434-439
[Abstract][Full Text]
Athyros, V. G., Kakafika, A. I., Tziomalos, K., Karagiannis, A., Mikhailidis, D. P.
(2008). CORONA, Statins, and Heart Failure: Who Lost the Crown?. ANGIOLOGY
59: 5-8
Birnbaum, Y., Lin, Y., Ye, Y., Merla, R., Perez-Polo, J. R., Uretsky, B. F.
(2008). Pretreatment With High-Dose Statin, But Not Low-Dose Statin, Ezetimibe, or the Combination of Low-Dose Statin and Ezetimibe, Limits Infarct Size in the Rat. J CARDIOVASC PHARMACOL THER
13: 72-79
[Abstract]
Josan, K. MD, Majumdar, S. R. MD MPH, McAlister, F. A. MD MSc
(2008). The efficacy and safety of intensive statin therapy: a meta-analysis of randomized trials. CMAJ
178: 576-584
[Abstract][Full Text]
Bittner, V., Herrington, D., Wenger, N.
(2008). Analyzing the Results of the Treating to New Targets Study. ANN INTERN MED
148: 322-323
[Full Text]
Donner-Banzhoff, N., Sonnichsen, A.
(2008). Strategies for prescribing statins. BMJ
336: 288-289
[Full Text]
Zannad, F., Stough, W. G., Pitt, B., Cleland, J. G.F., Adams, K. F., Geller, N. L., Torp-Pedersen, C., Kirwan, B.-A., Follath, F.
(2008). Heart failure as an endpoint in heart failure and non-heart failure cardiovascular clinical trials: the need for a consensus definition. Eur Heart J
29: 413-421
[Abstract][Full Text]
Richards, N., Harris, K., Whitfield, M., O'Donoghue, D., Lewis, R., Mansell, M., Thomas, S., Townend, J., Eames, M., Marcelli, D.
(2008). Primary care-based disease management of chronic kidney disease (CKD), based on estimated glomerular filtration rate (eGFR) reporting, improves patient outcomes. Nephrol Dial Transplant
23: 549-555
[Abstract][Full Text]
Iakoubova, O. A., Sabatine, M. S., Rowland, C. M., Tong, C. H., Catanese, J. J., Ranade, K., Simonsen, K. L., Kirchgessner, T. G., Cannon, C. P., Devlin, J. J., Braunwald, E.
(2008). Polymorphism in KIF6 gene and benefit from statins after acute coronary syndromes: results from the PROVE IT-TIMI 22 study.. J Am Coll Cardiol
51: 449-455
[Abstract][Full Text]
Superko, H. R., King, S. III
(2008). Lipid Management to Reduce Cardiovascular Risk: A New Strategy Is Required. Circulation
117: 560-568
[Full Text]
Grundy, S. M.
(2008). Promise of Low-Density Lipoprotein-Lowering Therapy for Primary and Secondary Prevention. Circulation
117: 569-573
[Full Text]
Grundy, S. M.
(2008). Thyroid mimetic as an option for lowering low-density lipoprotein. Proc. Natl. Acad. Sci. USA
105: 409-410
[Full Text]
Nesto, R. W.
(2008). LDL Cholesterol Lowering in Type 2 Diabetes: What Is the Optimum Approach?. Clin. Diabetes
26: 8-13
[Abstract][Full Text]
Anand, D. V., Lim, E., Darko, D., Bassett, P., Hopkins, D., Lipkin, D., Corder, R., Lahiri, A.
(2007). Determinants of Progression of Coronary Artery Calcification in Type 2 Diabetes: Role of Glycemic Control and Inflammatory/Vascular Calcification Markers. J Am Coll Cardiol
50: 2218-2225
[Abstract][Full Text]
Holman, J. R.
(2007). Some Docs in Denial About Statin Side Effects. DOC News
4: 1-12
[Full Text]
Preston, R. A., Harvey, P., Herfert, O., Dykstra, G., Jukema, J. W., Sun, F., Gillen, D.
(2007). A Randomized, Placebo-Controlled Trial to Evaluate the Efficacy, Safety, and Pharmacodynamic Interaction of Coadministered Amlodipine and Atorvastatin in 1660 Patients With Concomitant Hypertension and Dyslipidemia: The Respond Trial. J Clin Pharmacol
47: 1555-1569
[Abstract][Full Text]
Chaturvedi, S., Turan, T. N., Lynn, M. J., Kasner, S. E., Romano, J., Cotsonis, G., Frankel, M., Chimowitz, M. I., For the WASID Study Group,
(2007). Risk factor status and vascular events in patients with symptomatic intracranial stenosis. Neurology
69: 2063-2068
[Abstract][Full Text]
Shepherd, J., Kastelein, J. J.P., Bittner, V., Deedwania, P., Breazna, A., Dobson, S., Wilson, D. J., Zuckerman, A., Wenger, N. K., for the Treating to New Targets Investigators,
(2007). Effect of Intensive Lipid Lowering with Atorvastatin on Renal Function in Patients with Coronary Heart Disease: The Treating to New Targets (TNT) Study. CJASN
2: 1131-1139
[Abstract][Full Text]
Mudd, J. O., Borlaug, B. A., Johnston, P. V., Kral, B. G., Rouf, R., Blumenthal, R. S., Kwiterovich, P. O. Jr
(2007). Beyond Low-Density Lipoprotein Cholesterol: Defining the Role of Low-Density Lipoprotein Heterogeneity in Coronary Artery Disease. J Am Coll Cardiol
50: 1735-1741
[Abstract][Full Text]
Marschner, I. C., Simes, R. J., Keech, A.
(2007). Biases in the Identification of Risk Factor Thresholds and J-Curves. Am J Epidemiol
166: 824-831
[Abstract][Full Text]
Cahoon, W. D Jr, Crouch, M. A
(2007). Preprocedural Statin Therapy in Percutaneous Coronary Intervention. The Annals of Pharmacotherapy
41: 1687-1693
[Abstract][Full Text]
Barter, P., Gotto, A. M., LaRosa, J. C., Maroni, J., Szarek, M., Grundy, S. M., Kastelein, J. J.P., Bittner, V., Fruchart, J.-C., the Treating to New Targets Investigators,
(2007). HDL Cholesterol, Very Low Levels of LDL Cholesterol, and Cardiovascular Events. NEJM
357: 1301-1310
[Abstract][Full Text]
Blanco, M., Nombela, F., Castellanos, M., Rodriguez-Yanez, M., Garcia-Gil, M., Leira, R., Lizasoain, I., Serena, J., Vivancos, J., Moro, M. A., Davalos, A., Castillo, J.
(2007). Statin treatment withdrawal in ischemic stroke: A controlled randomized study. Neurology
69: 904-910
[Abstract][Full Text]
Singh, I. M., Shishehbor, M. H., Ansell, B. J.
(2007). High-Density Lipoprotein as a Therapeutic Target: A Systematic Review. JAMA
298: 786-798
[Abstract][Full Text]
Stein, E. A.
(2007). Statins and Children: Whom Do We Treat and When?. Circulation
116: 594-595
[Full Text]
Leeper, N. J., Ardehali, R., deGoma, E. M., Heidenreich, P. A.
(2007). Statin Use in Patients With Extremely Low Low-Density Lipoprotein Levels Is Associated With Improved Survival. Circulation
116: 613-618
[Abstract][Full Text]
Afilalo, J., Majdan, A. A, Eisenberg, M. J
(2007). Intensive statin therapy in acute coronary syndromes and stable coronary heart disease: a comparative meta-analysis of randomised controlled trials. Heart
93: 914-921
[Abstract][Full Text]
Yu, C.-M., Zhang, Q., Lam, L., Lin, H., Kong, S.-L., Chan, W., Fung, J. W.-H., Cheng, K. K K, Chan, I. H.-S., Lee, S. W.-L., Sanderson, J. E, Lam, C. W.-K.
(2007). Comparison of intensive and low-dose atorvastatin therapy in the reduction of carotid intimal-medial thickness in patients with coronary heart disease. Heart
93: 933-939
[Abstract][Full Text]
Choudhry, N. K, Levin, R., Winkelmayer, W. C
(2007). Statins in elderly patients with acute coronary syndrome: an analysis of dose and class effects in typical practice. Heart
93: 945-951
[Abstract][Full Text]
Alsheikh-Ali, A. A., Maddukuri, P. V., Han, H., Karas, R. H.
(2007). Effect of the Magnitude of Lipid Lowering on Risk of Elevated Liver Enzymes, Rhabdomyolysis, and Cancer: Insights From Large Randomized Statin Trials. J Am Coll Cardiol
50: 409-418
[Abstract][Full Text]
Wenger, N. K., Lewis, S. J., Herrington, D. M., Bittner, V., Welty, F. K., for the Treating to New Targets Study Steering Com,
(2007). Outcomes of Using High- or Low-Dose Atorvastatin in Patients 65 Years of Age or Older with Stable Coronary Heart Disease. ANN INTERN MED
147: 1-9
[Abstract][Full Text]
Brewster, L. M., van Montfrans, G. A.
(2007). Letter by Brewster and van Montfrans Regarding Article, "Risks Associated With Statin Therapy: A Systematic Overview of Randomized Clinical Trials". Circulation
116: e7-e7
[Full Text]
Authors/Task Force Members, , Bassand, J.-P., Hamm, C. W., Ardissino, D., Boersma, E., Budaj, A., Fernandez-Aviles, F., Fox, K. A.A., Hasdai, D., Ohman, E. M., Wallentin, L., Wijns, W., ESC Committee for Practice Guidelines (CPG), , Vahanian, A., Camm, J., De Caterina, R., Dean, V., Dickstein, K., Filippatos, G., Kristensen, S. D., Widimsky, P., McGregor, K., Sechtem, U., Tendera, M., Hellemans, I., Gomez, J. L. Z., Silber, S., Funck-Brentano, C., Document Reviewers, , Kristensen, S. D., Andreotti, F., Benzer, W., Bertrand, M., Betriu, A., De Caterina, R., DeSutter, J., Falk, V., Ortiz, A. F., Gitt, A., Hasin, Y., Huber, K., Kornowski, R., Lopez-Sendon, J., Morais, J., Nordrehaug, J. E., Silber, S., Steg, P. G., Thygesen, K., Tubaro, M., Turpie, A. G.G., Verheugt, F., Windecker, S.
(2007). Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: The Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology. Eur Heart J
28: 1598-1660
[Full Text]
Nogueira, J., Weir, M.
(2007). The Unique Character of Cardiovascular Disease in Chronic Kidney Disease and Its Implications for Treatment with Lipid-Lowering Drugs. CJASN
2: 766-785
[Abstract][Full Text]
Timmis, A. D, Feder, G., Hemingway, H.
(2007). Prognosis of stable angina pectoris: why we need larger population studies with higher endpoint resolution. Heart
93: 786-791
[Abstract][Full Text]
Kostapanos, M.S., Liberopoulos, E.N., Goudevenos, J.A., Mikhailidis, D.P., Elisaf, M.S.
(2007). Do statins have an antiarrhythmic activity?. Cardiovasc Res
75: 10-20
[Abstract][Full Text]
Lindgren, P., Graff, J., Olsson, A. G., Pedersen, T. J., Jonsson, B., on behalf of the IDEAL Trial Investigators,
(2007). Cost-effectiveness of high-dose atorvastatin compared with regular dose simvastatin. Eur Heart J
28: 1448-1453
[Abstract][Full Text]
Tuzcu, E. M., Nicholls, S. J.
(2007). Statins: Targeting Inflammation by Lowering Low-Density Lipoprotein?. J Am Coll Cardiol
49: 2010-2012
[Full Text]
Chan, P. S., Nallamothu, B. K., Gurm, H. S., Hayward, R. A., Vijan, S.
(2007). Incremental Benefit and Cost-Effectiveness of High-Dose Statin Therapy in High-Risk Patients With Coronary Artery Disease. Circulation
115: 2398-2409
[Abstract][Full Text]
Garg, A., Simha, V.
(2007). Update on Dyslipidemia. J. Clin. Endocrinol. Metab.
92: 1581-1589
[Abstract][Full Text]
Sassano, A., Katsoulidis, E., Antico, G., Altman, J. K., Redig, A. J., Minucci, S., Tallman, M. S., Platanias, L. C.
(2007). Suppressive Effects of Statins on Acute Promyelocytic Leukemia Cells. Cancer Res.
67: 4524-4532
[Abstract][Full Text]
Davidson, M. H., Robinson, J. G.
(2007). Safety of Aggressive Lipid Management. J Am Coll Cardiol
49: 1753-1762
[Abstract][Full Text]
Oktem, M., Esinler, I., Eroglu, D., Haberal, N., Bayraktar, N., Zeyneloglu, H. B.
(2007). High-dose atorvastatin causes regression of endometriotic implants: a rat model. Hum Reprod
22: 1474-1480
[Abstract][Full Text]
Kastelein, J. J.P., van Leuven, S. I., Burgess, L., Evans, G. W., Kuivenhoven, J. A., Barter, P. J., Revkin, J. H., Grobbee, D. E., Riley, W. A., Shear, C. L., Duggan, W. T., Bots, M. L., the RADIANCE 1 Investigators,
(2007). Effect of Torcetrapib on Carotid Atherosclerosis in Familial Hypercholesterolemia. NEJM
356: 1620-1630
[Abstract][Full Text]
Boden, W. E., O'Rourke, R. A., Teo, K. K., Hartigan, P. M., Maron, D. J., Kostuk, W. J., Knudtson, M., Dada, M., Casperson, P., Harris, C. L., Chaitman, B. R., Shaw, L., Gosselin, G., Nawaz, S., Title, L. M., Gau, G., Blaustein, A. S., Booth, D. C., Bates, E. R., Spertus, J. A., Berman, D. S., Mancini, G.B. J., Weintraub, W. S., the COURAGE Trial Research Group,
(2007). Optimal Medical Therapy with or without PCI for Stable Coronary Disease. NEJM
356: 1503-1516
[Abstract][Full Text]
Song, J. C., Wang, C. C., Huang, Y.-C., Sanchez, J., Nguyen, T., Khan, S., Kim, M.-K., Li, P.
(2007). Use of maximum-dose simvastatin or atorvastatin in an ethnically diverse population. Am J Health Syst Pharm
64: 767-772
[Abstract][Full Text]
Crouse, J. R. III, Raichlen, J. S., Riley, W. A., Evans, G. W., Palmer, M. K., O'Leary, D. H., Grobbee, D. E., Bots, M. L., for the METEOR Study Group,
(2007). Effect of Rosuvastatin on Progression of Carotid Intima-Media Thickness in Low-Risk Individuals With Subclinical Atherosclerosis: The METEOR Trial. JAMA
297: 1344-1353
[Abstract][Full Text]
Patel, T. N., Shishehbor, M. H., Bhatt, D. L.
(2007). A review of high-dose statin therapy: targeting cholesterol and inflammation in atherosclerosis. Eur Heart J
28: 664-672
[Abstract][Full Text]
Ray, J. G., Norris, C. M., Udell, J. A., Tsuyuki, R. T., McAlister, F. A., Knudtson, M. L., Ghali, W. A.
(2007). Lipid-Lowering Therapy and Outcomes in Heart Failure. J CARDIOVASC PHARMACOL THER
12: 27-35
[Abstract]
Deedwania, P., Stone, P. H., Bairey Merz, C. N., Cosin-Aguilar, J., Koylan, N., Luo, D., Ouyang, P., Piotrowicz, R., Schenck-Gustafsson, K., Sellier, P., Stein, J. H., Thompson, P. L., Tzivoni, D.
(2007). Effects of Intensive Versus Moderate Lipid-Lowering Therapy on Myocardial Ischemia in Older Patients With Coronary Heart Disease: Results of the Study Assessing Goals in the Elderly (SAGE). Circulation
115: 700-707
[Abstract][Full Text]
Nicholls, S. J., Tuzcu, E. M., Sipahi, I., Grasso, A. W., Schoenhagen, P., Hu, T., Wolski, K., Crowe, T., Desai, M. Y., Hazen, S. L., Kapadia, S. R., Nissen, S. E.
(2007). Statins, High-Density Lipoprotein Cholesterol, and Regression of Coronary Atherosclerosis. JAMA
297: 499-508
[Abstract][Full Text]
Khush, K. K., Waters, D. D., Bittner, V., Deedwania, P. C., Kastelein, J. J.P., Lewis, S. J., Wenger, N. K.
(2007). Effect of High-Dose Atorvastatin on Hospitalizations for Heart Failure: Subgroup Analysis of the Treating to New Targets (TNT) Study. Circulation
115: 576-583
[Abstract][Full Text]
Bullano, M. F., Kamat, S., Wertz, D. A., Borok, G. M., Gandhi, S. K., McDonough, K. L., Willey, V. J.
(2007). Effectiveness of rosuvastatin versus atorvastatin in reducing lipid levels and achieving low-density-lipoprotein cholesterol goals in a usual care setting. Am J Health Syst Pharm
64: 276-284
[Abstract][Full Text]
Houslay, E. S, Sarma, J., Uren, N. G
(2007). The effect of intensive lipid lowering on coronary atheroma and clinical outcome. Heart
93: 149-151
[Abstract][Full Text]
Penning-van Beest, F. J.A., Termorshuizen, F., Goettsch, W. G., Klungel, O. H., Kastelein, J. J.P., Herings, R. M.C.
(2007). Adherence to evidence-based statin guidelines reduces the risk of hospitalizations for acute myocardial infarction by 40%: a cohort study. Eur Heart J
28: 154-159
[Abstract][Full Text]
Shor, R., Wainstein, J., Oz, D., Boaz, M., Matas, Z., Fux, A., Halabe, A.
(2007). Low Serum LDL Cholesterol Levels and the Risk of Fever, Sepsis, and Malignancy. Annals of Clinical & Laboratory Science
37: 343-348
[Abstract][Full Text]
Boodhwani, M., Mieno, S., Voisine, P., Feng, J., Sodha, N., Li, J., Sellke, F. W.
(2006). High-dose atorvastatin is associated with impaired myocardial angiogenesis in response to vascular endothelial growth factor in hypercholesterolemic swine. J. Thorac. Cardiovasc. Surg.
132: 1299-1306
[Abstract][Full Text]
de Lusignan, S., Belsey, J., Hague, N., Dhoul, N., van Vlymen, J.
(2006). Audit-based education to reduce suboptimal management of cholesterol in primary care: a before and after study. J Public Health (Oxf)
28: 361-369
[Abstract][Full Text]
Cuccurullo, C., Iezzi, A., Fazia, M. L., De Cesare, D., Di Francesco, A., Muraro, R., Bei, R., Ucchino, S., Spigonardo, F., Chiarelli, F., Schmidt, A. M., Cuccurullo, F., Mezzetti, A., Cipollone, F.
(2006). Suppression of Rage as a Basis of Simvastatin-Dependent Plaque Stabilization in Type 2 Diabetes. Arterioscler. Thromb. Vasc. Bio.
26: 2716-2723
[Abstract][Full Text]
Ritz, E., Wanner, C.
(2006). Lipid Changes and Statins in Chronic Renal Insufficiency. J. Am. Soc. Nephrol.
17: S226-S230
[Abstract][Full Text]
Cohen, J. S., East, J. E., Elkind, M. S.V., Khan, N. A., Mascitelli, L., Pezzetta, F., Welch, K.M.A., the SPARCL Investigators, , Kent, D.
(2006). Statin Therapy after Stroke or Transient Ischemic Attack. NEJM
355: 2368-2371
[Full Text]
Davidson, M. H., McKenney, J. M., Shear, C. L., Revkin, J. H.
(2006). Efficacy and Safety of Torcetrapib, a Novel Cholesteryl Ester Transfer Protein Inhibitor, in Individuals With Below-Average High-Density Lipoprotein Cholesterol Levels. J Am Coll Cardiol
48: 1774-1781
[Abstract][Full Text]
McKenney, J. M., Davidson, M. H., Shear, C. L., Revkin, J. H.
(2006). Efficacy and Safety of Torcetrapib, a Novel Cholesteryl Ester Transfer Protein Inhibitor, in Individuals With Below-Average High-Density Lipoprotein Cholesterol Levels on a Background of Atorvastatin. J Am Coll Cardiol
48: 1782-1790
[Abstract][Full Text]
Milani, R. V., Lavie, C. J.
(2006). Cholesteryl Ester Transfer Protein Inhibition: The Next Frontier in Combating Coronary Artery Disease?. J Am Coll Cardiol
48: 1791-1792
[Full Text]
Waters, D. D., LaRosa, J. C., Barter, P., Fruchart, J.-C., Gotto, A. M. Jr, Carter, R., Breazna, A., Kastelein, J. J.P., Grundy, S. M.
(2006). Effects of High-Dose Atorvastatin on Cerebrovascular Events in Patients With Stable Coronary Disease in the TNT (Treating to New Targets) Study. J Am Coll Cardiol
48: 1793-1799
[Abstract][Full Text]
Previous
