FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 350:1495-1504 April 8, 2004 Number 15 Next

Abstract PDF PDA Full Text PowerPoint Slide Set Editorial by Topol, E. J. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear Related Article PubMed Citation

ABSTRACT

Background Lipid-lowering therapy with statins reduces the risk of cardiovascular events, but the optimal level of low-density lipoprotein (LDL) cholesterol is unclear.

Methods We enrolled 4162 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and compared 40 mg of pravastatin daily (standard therapy) with 80 mg of atorvastatin daily (intensive therapy). The primary end point was a composite of death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke. The study was designed to establish the noninferiority of pravastatin as compared with atorvastatin with respect to the time to an end-point event. Follow-up lasted 18 to 36 months (mean, 24).

Results The median LDL cholesterol level achieved during treatment was 95 mg per deciliter (2.46 mmol per liter) in the standard-dose pravastatin group and 62 mg per deciliter (1.60 mmol per liter) in the high-dose atorvastatin group (P<0.001). Kaplan–Meier estimates of the rates of the primary end point at two years were 26.3 percent in the pravastatin group and 22.4 percent in the atorvastatin group, reflecting a 16 percent reduction in the hazard ratio in favor of atorvastatin (P=0.005; 95 percent confidence interval, 5 to 26 percent). The study did not meet the prespecified criterion for equivalence but did identify the superiority of the more intensive regimen.

Conclusions Among patients who have recently had an acute coronary syndrome, an intensive lipid-lowering statin regimen provides greater protection against death or major cardiovascular events than does a standard regimen. These findings indicate that such patients benefit from early and continued lowering of LDL cholesterol to levels substantially below current target levels.

Methods

Patient Population

Between November 15, 2000, and December 22, 2001, 4162 patients were enrolled at 349 sites in eight countries (see the Appendix). The protocol was approved by the relevant institutional review boards, and written informed consent was obtained from all patients. As described previously,¹¹ men and women who were at least 18 years old were eligible for inclusion if they had been hospitalized for an acute coronary syndrome — either acute myocardial infarction (with or without electrocardiographic evidence of ST-segment elevation) or high-risk unstable angina — in the preceding 10 days. Patients had to be in stable condition and were to be enrolled after a percutaneous revascularization procedure if one was planned. Finally, patients had to have a total cholesterol level of 240 mg per deciliter (6.21 mmol per liter) or less, measured at the local hospital within the first 24 hours after the onset of the acute coronary syndrome or up to six months earlier if no sample had been obtained during the first 24 hours. Patients who were receiving long-term lipid-lowering therapy at the time of their index acute coronary syndrome had to have a total cholesterol level of 200 mg per deciliter (5.18 mmol per liter ) or less at the time of screening in the local hospital.

Patients were ineligible for the study if they had a coexisting condition that shortened expected survival to less than two years, were receiving therapy with any statin at a dose of 80 mg per day at the time of their index event or lipid-lowering therapy with fibric acid derivatives or niacin that could not be discontinued before randomization, had received drugs that are strong inhibitors of cytochrome P-450 3A4 within the month before randomization or were likely to require such treatment during the study period (because atorvastatin is metabolized by this pathway), had undergone percutaneous coronary intervention within the previous six months (other than for the qualifying event) or coronary-artery bypass surgery within the previous two months or were scheduled to undergo bypass surgery in response to the index event, had factors that might prolong the QT interval, had obstructive hepatobiliary disease or other serious hepatic disease, had an unexplained elevation in the creatine kinase level that was more than three times the upper limit of normal and that was not related to myocardial infarction, or had a creatinine level of more than 2.0 mg per deciliter (176.8 µmol per liter).

Study Protocol

The protocol specified that patients were to receive standard medical and interventional treatment for acute coronary syndromes, including aspirin at a dose of 75 to 325 mg daily, with or without clopidogrel or warfarin. Patients were not permitted to be treated with any lipid-modifying therapy other than the study drug. Eligible patients were randomly assigned in a 1:1 ratio to receive 40 mg of pravastatin or 80 mg of atorvastatin daily in a double-blind, double-dummy fashion. In addition, patients were also randomly assigned to receive with the use of a two-by-two factorial design a 10-day course of gatifloxacin or placebo every month during the trial. The results of the antibiotic component of the trial are not reported here.

Patients were seen for follow-up visits and received dietary counseling⁸ at 30 days, at 4 months, and every 4 months thereafter until their final visit in August or September 2003. Patients who discontinued the study drug during the trial were followed by means of telephone calls. Blood samples were obtained at randomization, at 30 days, at 4, 8, 12, and 16 months, and at the final visit for the measurement of lipids and other components that were part of the safety assessment. Measurements were made at the core laboratories listed in the Appendix. LDL cholesterol levels were monitored, and the protocol specified that the dose of pravastatin was to increase to 80 mg in a blinded fashion if the LDL cholesterol level exceeded 125 mg per deciliter (3.23 mmol per liter) on two consecutive visits and the patient had been taking study medication and had returned for the required study visits. The dose of either study drug could be halved in the event of abnormal liver-function results, elevations in creatine kinase levels, or myalgias.

Patients were followed for 18 to 36 months, with an average follow-up of 24 months. The trial continued until 925 events had been reported to the coordinating center, after which time all patients were requested to return for a final study visit. Eight patients (0.2 percent) were lost to follow-up.

End Points

The primary efficacy outcome measure was the time from randomization until the first occurrence of a component of the primary end point: death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization with either percutaneous coronary intervention or coronary-artery bypass grafting (if these procedures were performed at least 30 days after randomization), and stroke. Myocardial infarction was defined by the presence of symptoms suggestive of ischemia or infarction, with either electrocardiographic evidence (new Q waves in two or more leads) or cardiac-marker evidence of infarction, according to the standard TIMI and American College of Cardiology definition.^12,13 Unstable angina was defined as ischemic discomfort at rest for at least 10 minutes prompting rehospitalization, combined with one of the following: ST-segment or T-wave changes, cardiac-marker elevations that were above the upper limit of normal but did not meet the criteria for myocardial infarction, or a second episode of ischemic chest discomfort lasting more than 10 minutes and that was distinct from the episode that had prompted hospitalization. Secondary end points were the risk of death from coronary heart disease, nonfatal myocardial infarction, or revascularization (if it was performed at least 30 days after randomization), the risk of death from coronary heart disease or nonfatal myocardial infarction, and the risk of the individual components of the primary end point.

Statistical Analysis

Although the trial was designed as a time-to-event study, the definition of noninferiority was arrived at through a consideration of two-year event rates. For the comparison of pravastatin with atorvastatin, we defined the prespecified boundary for noninferiority as an upper limit of the one-sided 95 percent confidence interval of the relative risk at two years of less than 1.17 (corresponding to a hazard ratio throughout follow-up of 1.198). Assuming a two-year event rate of 22 percent in the atorvastatin group and that the two treatments had equivalent efficacy, we determined that enrollment of 2000 patients per group would give the study a statistical power of 87 percent and that this power would be preserved if follow-up continued until 925 end-point events had occurred.¹⁴ A central randomization system was used that involved a permuted-block design in which assignment was stratified according to center. Three interim assessments of efficacy and safety were carried out by the data and safety monitoring board. Rules for stopping the study early in the event that the superiority of either treatment was established were not prespecified.

All efficacy analyses are based on the intention-to-treat principle. Estimates of the hazard ratios and associated 95 percent confidence intervals comparing pravastatin with atorvastatin were obtained with the use of the Cox proportional-hazards model, with randomized treatment as the covariate and stratification according to the receipt of gatifloxacin or placebo. (Using the two-by-two factorial design, we conducted a preliminary test for interaction and found none. For the primary end point, the interaction P value was 0.90 and the hazard ratios comparing pravastatin with atorvastatin were almost identical for the gatifloxacin and placebo groups.) When it was determined that noninferiority was not demonstrated, the subsequent assessment of superiority was carried out with the use of two-sided confidence intervals. The investigators designed the trial and had free and complete access to the data. Data coordination was performed by the Nottingham Clinical Research Group (see the Appendix). Investigators at TIMI, the sponsor, and members of the Nottingham Clinical Research Group performed data analysis jointly.

Results

The two groups of patients were well matched with regard to base-line characteristics, with the exception of a history of peripheral arterial disease, which was more common in the pravastatin group than the atorvastatin group (P=0.03) (Table 1). Their average age was 58 years, and 22 percent were women. Before their index event, 18 percent of patients had had a myocardial infarction, 11 percent had previously undergone coronary-artery bypass surgery, and 18 percent had diabetes mellitus. The index event was high-risk unstable angina in approximately one third of the patients, myocardial infarction without electrocardiographic evidence of ST-segment elevation in approximately one third, and myocardial infarction with ST-segment elevation in one third. Sixty-nine percent of patients underwent percutaneous coronary intervention for the treatment of their index acute coronary syndrome before randomization. One quarter of the patients were taking statin drugs at the time of the index event. Concomitant medications were administered to patients during the treatment period as follows: aspirin to 93 percent, warfarin to 8 percent, clopidogrel or ticlodipine to 72 percent initially and 20 percent at one year, beta-blockers to 85 percent, angiotensin-converting–enzyme inhibitors to 69 percent, and angiotensin-receptor blockers to 14 percent.

View this table: [in this window] [in a new window]   Table 1. Base-Line Characteristics of the Patients.

 
At the time of randomization, a median of seven days after the onset of the index event, the median LDL cholesterol levels were 106 mg per deciliter (2.74 mmol per liter) before treatment in each group (Figure 1). The LDL cholesterol levels achieved during follow-up were 95 mg per deciliter (2.46 mmol per liter; interquartile range, 79 to 113 mg per deciliter [2.04 to 2.92 mmol per liter]) in the pravastatin group and 62 mg per deciliter (1.60 mmol per liter; interquartile range, 50 to 79 mg per deciliter [1.29 to 2.04 mmol per liter]) in the atorvastatin group (P<0.001). Among 2985 patients (75 percent) who had not previously received statin therapy, the median LDL cholesterol levels had fallen by 22 percent at 30 days in the pravastatin group and by 51 percent in the atorvastatin group (P<0.001). As anticipated, among the 990 patients who had previously received statin therapy (25 percent), LDL cholesterol levels were essentially unchanged from base line (during statin therapy) in the pravastatin group, whereas they fell by an additional 32 percent in the atorvastatin group (P<0.001). Median high-density lipoprotein cholesterol levels rose during follow-up by 8.1 percent in the pravastatin group and 6.5 percent in the atorvastatin group (P<0.001). Median C-reactive protein levels fell from 12.3 mg per liter at base line in each group to 2.1 mg per liter in the pravastatin group and 1.3 mg per liter in the atorvastatin group (P<0.001).

View larger version (7K): [in this window] [in a new window]   Figure 1. Median Low-Density Lipoprotein (LDL) Cholesterol Levels during the Study. To convert values for LDL cholesterol to millimoles per liter, multiply by 0.02586.

 
Primary End Point

For all randomized patients, the Kaplan–Meier event rates of the primary end point at two years were 26.3 percent in the standard-dose pravastatin group and 22.4 percent in the high-dose atorvastatin group, representing a 16 percent reduction in the hazard ratio favoring atorvastatin (P=0.005; 95 percent confidence interval, 5 to 26 percent) (Figure 2); this difference did not meet the criteria for equivalence. The benefit of high-dose atorvastatin as compared with standard-dose pravastatin emerged as early as 30 days and was consistent over time (Figure 3). The risk of the secondary end point of death due to coronary heart disease, myocardial infarction, or revascularization was similarly reduced by 14 percent in the atorvastatin group (P=0.029), with a two-year event rate of 19.7 percent, as compared with 22.3 percent in the pravastatin group. The risk of death, myocardial infarction, or urgent revascularization was reduced by 25 percent in the atorvastatin group (P<0.001).

View larger version (8K): [in this window] [in a new window]   Figure 2. Kaplan–Meier Estimates of the Incidence of the Primary End Point of Death from Any Cause or a Major Cardiovascular Event. Intensive lipid lowering with the 80-mg dose of atorvastatin, as compared with moderate lipid lowering with the 40-mg dose of pravastatin, reduced the hazard ratio for death or a major cardiovascular event by 16 percent.

 

View larger version (9K): [in this window] [in a new window]   Figure 3. Hazard Ratio for the the Primary End Point of Death from Any Cause or a Major Cardiovascular Event at 30, 90, and 180 Days and at the End of Follow-up in the High-Dose Atorvastatin Group, as Compared with the Standard-Dose Pravastatin Group. Event rates are Kaplan–Meier estimates censored at the time points indicated with the use of the average duration of follow-up (two years). CI denotes confidence interval.

 
Among the individual components of the primary end point, there was a consistent pattern of benefit favoring high-dose atorvastatin over standard-dose pravastatin, which included a significant 14 percent reduction in the need for revascularization (P=0.04), a 29 percent reduction in the risk of recurrent unstable angina (P=0.02), and nonsignificant reductions in the rates of death from any cause (28 percent, P=0.07) and of death or myocardial infarction (18 percent, P=0.06) (Figure 4). Stroke was infrequent, but the rates did not differ significantly between the groups.

View larger version (16K): [in this window] [in a new window]   Figure 4. Estimates of the Hazard Ratio for the Secondary End Points and the Individual Components of the Primary End Point in the High-Dose Atorvastatin Group, as Compared with the Standard-Dose Pravastatin Group. CI denotes confidence interval, CHD coronary heart disease, and MI myocardial infarction. Revascularization was performed at least 30 days after randomization.

 
The benefit of high-dose atorvastatin was consistent across the prespecified subgroups, including men and women, patients with unstable angina and those with myocardial infarction, and those with and those without diabetes mellitus (Figure 5). The benefit appeared to be greater among patients with a base-line LDL cholesterol level of at least 125 mg per deciliter, a prespecified subgroup, with a 34 percent reduction in the hazard ratio, as compared with a 7 percent reduction among patients with a base-line LDL cholesterol below 125 mg per deciliter (P for interaction = 0.02).

View larger version (27K): [in this window] [in a new window]   Figure 5. Two-Year Event Rates and Estimates of the Hazard Ratio for the Primary End Point in the High-Dose Atorvastatin Group, as Compared with the Standard-Dose Pravastatin Group, According to Base-Line Characteristics. A test for interaction was significant only for a base-line low-density lipoprotein (LDL) value of at least 125 mg per deciliter, as compared with a value of less than 125 mg per deciliter (P=0.02). LDL cholesterol was measured at base line in a total of 3976 patients, and high-density lipoprotein (HDL) cholesterol was measured in 3995. Two patients did not have information regarding the electrocardiographic type of acute coronary syndrome, and one patient had missing information regarding prior statin use. MI denotes myocardial infarction.

 
Tolerability and Safety

The rates of discontinuation of treatment because of an adverse event or the patient's preference or for other reasons were 21.4 percent in the pravastatin group and 22.8 percent in the atorvastatin group at one year (P=0.30) and 33.0 percent and 30.4 percent, respectively, at two years (P=0.11). During treatment, the dose of pravastatin was increased to 80 mg in 8 percent of patients, and the dose was halved among 1.4 percent of the patients in the pravastatin group and 1.9 percent of those in the atorvastatin group (P=0.20), owing to side effects or liver-function abnormalities. The percentages of patients who had elevations in alanine aminotransferase levels that were more than three times the upper limit of normal were 1.1 percent in the pravastatin group and 3.3 percent in the atorvastatin group (P<0.001). The study medication was discontinued by the investigators because of a report of myalgias or muscle aches or elevations in creatine kinase levels in 2.7 percent of pravastatin-treated patients, as compared with 3.3 percent of atorvastatin-treated patients (P=0.23). There were no cases of rhabdomyolysis in either group.

Discussion

In this comparison of two statin regimens of different lipid-lowering intensities for the prevention of cardiovascular events, intensive therapy with high-dose atorvastatin resulted in a median LDL cholesterol level of 62 mg per deciliter, as compared with a level of 95 mg per deciliter for standard-dose pravastatin. Among patients who had recently been hospitalized for an acute coronary syndrome, the more intensive regimen resulted in a lower risk of death from any cause or major cardiac events than did a more moderate degree of lipid lowering with the use of a standard dose of a statin. Although prior placebo-controlled studies have shown that a standard-dose statin is beneficial,^{1,2,3,4,5,6,7} we demonstrated that more intensive lipid lowering significantly increased this clinical benefit.

Although the exact mechanism of the benefit cannot be established solely on the basis of our results, the extent of the benefit afforded by the 80-mg dose of atorvastatin is in keeping with what would be expected on the basis of the greater degree of lipid lowering produced by this regimen. In the Heart Protection study, statin treatment resulted in an LDL cholesterol level that was 40 mg per deciliter (1.03 mmol per liter) lower than the value in the placebo group and that was accompanied by a 25 percent reduction in cardiovascular events. In our study, the LDL cholesterol level was 33 mg per deciliter (0.85 mmol per liter) lower in the atorvastatin group than in the pravastatin group. This difference should translate into a 20 percent reduction in clinical events, which is very similar to the 16 percent reduction we observed and suggests that much of the benefit is attributable to the difference in the degree of LDL cholesterol lowering. However, we cannot exclude the possibility that the difference in clinical outcomes may be due in part to non–lipid-related pleiotropic effects, which may differ between the two statins we used.¹⁵ Future trials involving different doses of a single statin should help address this possibility.

Intensive therapy with high-dose atorvastatin had a consistent beneficial effect on cardiac events, including a significant 29 percent reduction in the risk of recurrent unstable angina and a 14 percent reduction in the need for revascularization. The reduction in the rate of death from any cause was of borderline significance (28 percent, P=0.07), suggesting that more aggressive lipid lowering is important not only to reduce the risk of recurrent ischemia, but possibly also to decrease the risk of fatal events.

The reduction in clinical events with the more intensive lipid-lowering therapy was apparent as early as 30 days after the start of therapy. This rapid time frame is similar to that reported with statin treatment in the placebo-controlled Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial¹⁶ and in prior observational studies.^17,18 We studied patients who had been hospitalized for an acute coronary syndrome and enrolled them immediately after their condition had stabilized. Three quarters of the patients were treated with an early invasive strategy, and the majority were treated with multiple medications for secondary prevention, including antiplatelet therapy, beta-blockers, and angiotensin-converting–enzyme inhibitors (and a statin as part of the trial design). Nonetheless, early and continued separation of the event curves was observed in the more intensive lipid-lowering group. This early reduction in event rates in patients with acute coronary syndromes contrasts with the lag of approximately one to two years in prior studies of statins in patients with chronic atherosclerosis.^1,2,3,4,5,6 These data suggest that this population of patients with acute coronary syndromes, who have a culprit lesion and frequently multiple additional vulnerable plaques as well,^19,20 can derive particular benefit from early and intensive lipid lowering with statins. The current guidelines of the American College of Cardiology and American Heart Association recommend instituting lipid-lowering therapy at the time of hospital discharge in patients with acute coronary syndromes, on the theory that it will improve patients' compliance with the use of statins for long-term secondary prevention.²¹ Our data are evidence that such therapy will also provide protection against early recurrent cardiovascular events.

After the early separation of the clinical-event curves, we also observed a continued benefit of atorvastatin therapy throughout the follow-up period of two and one-half years (Figure 2). It cannot be determined from this study whether this longer-term benefit was due to ongoing intensive lipid-lowering therapy or was the result of an early benefit in stabilizing vulnerable plaques with the early and intensive treatment after the acute event. It also cannot be determined whether other differences between the two statins used explain the observed clinical benefit. Nonetheless, our findings suggest that patients with acute coronary syndromes who receive early and intensive lipid-lowering therapy continue to derive benefit in the chronic phase of atherosclerosis when high-dose statin therapy is maintained.

Our finding of a continued benefit of intensive lipid-lowering therapy during the follow-up phase is consistent with studies showing that such an approach results in a slower rate of progression of atherosclerosis in patients with stable coronary artery disease²² or in those who undergo coronary-artery bypass grafting,²³ as well as in greater reductions in carotid intimal–medial thickening.^24,25,26 Although our study documented a benefit for up to an average of two years of follow-up, several large, ongoing trials involving patients with stable atherosclerosis will determine the five-year outcomes of intensive as compared with moderate lipid lowering.²⁷

It is important to note that our safety and efficacy results were obtained in a carefully selected and monitored study population (for example, we excluded patients who were concomitantly receiving strong inhibitors of cytochrome P-450 3A4, because this is integral to the route of metabolism of atorvastatin). Although both drugs were generally well tolerated, there were significantly more liver-related side effects with high-dose atorvastatin than with standard-dose pravastatin. Patients in clinical practice generally have more coexisting conditions than did our patients, and they may not tolerate a high-dose statin regimen as well as our patients did. Thus, clinicians must take these factors into account when applying the results of our trial in clinical practice.

The National Cholesterol Education Program and European guidelines currently recommend that the goal of treatment in patients with established coronary artery disease should be an LDL cholesterol level of less than 100 mg per deciliter.^8,9 Although our data provide support for the use of this approach, given the substantially lower LDL cholesterol levels achieved in the group given 80 mg of atorvastatin daily (median, 62 mg per deciliter), our results suggest that after an acute coronary syndrome, the target LDL cholesterol level may be lower than that recommended in the current guidelines.

Supported by Bristol-Myers Squibb and Sankyo.

Drs. Rader and Pfeffer report having received consulting fees and lecture fees from Bristol-Myers Squibb. Drs. Joyal and Belder are employees of Bristol-Myers Squibb and have equity in the company. Dr. Rouleau reports having received consulting fees and lecture fees from Novartis.

^* The investigators and research coordinators who participated in the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) study are listed in the Appendix.

Source Information

From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (C.P.C., E.B., C.H.M., M.A.P.); the University of Pennsylvania, Philadelphia (D.J.R.); the University of Montreal, Montreal (J.L.R.); Bristol-Myers Squibb, Princeton, N.J. (R.B., S.V.J.); and the Nottingham Clinical Research Group, Nottingham, United Kingdom (K.A.H., A.M.S.).

This article was published at www.nejm.org on March 8, 2004.

Address reprint requests to Dr. Cannon at the TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115, or at cpcannon{at}partners.org.

References

1. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4 444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-1389. [CrossRef][Web of Science][Medline]
2. Sacks RM, Pfeffer MA, Moye 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]
3. 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]
4. 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][Web of Science][Medline]
5. Shepard J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301-1307. [Free Full Text]
6. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279:1615-1622. [Free Full Text]
7. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623-1630. [CrossRef][Web of Science][Medline]
8. 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]
9. De Backer G, Ambrosioni E, Borch-Johnsen K, et al. European guidelines on cardiovascular disease and prevention in clinical practice. Atherosclerosis 2003;171:145-155. [CrossRef][Web of Science][Medline]
10. Davidson MH, Nawrocki JW, Weiss SR, et al. Effectiveness of atorvastatin for reducing low-density lipoprotein cholesterol to National Cholesterol Education Program treatment goals. Am J Cardiol 1997;80:347-348. [CrossRef][Web of Science][Medline]
11. Cannon CP, McCabe CH, Belder R, Breen J, Braunwald E. Design of the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT)-TIMI 22 trial. Am J Cardiol 2002;89:860-861. [CrossRef][Web of Science][Medline]
12. Cannon CP, McCabe CH, Wilcox RG, et al. Oral glycoprotein IIb/IIIa inhibition with orbofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial. Circulation 2000;102:149-156. [Free Full Text]
13. Cannon CP, Battler A, Brindis RG, et al. American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes: a report of the American College of Cardiology Task Force on Clinical Data Standards (Acute Coronary Syndromes Writing Committee). J Am Coll Cardiol 2001;38:2114-2130. [Free Full Text]
14. Lachin JM, Foulkes MA. Evaluation of sample size and power for analyses of survival with allowance for nonuniform patient entry, losses to follow-up, noncompliance, and stratification. Biometrics 1986;42:507-519. [CrossRef][Web of Science][Medline]
15. Bonetti PO, Lerman LO, Napoli C, Lerman A. Statin effects beyond lipid lowering -- are they clinically relevant? Eur Heart J 2003;24:225-248. [Free Full Text]
16. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001;285:1711-1718. [Free Full Text]
17. Stenestrand U, Wallentin L. Early statin treatment following acute myocardial infarction and 1-year survival. JAMA 2001;285:430-436. [Free Full Text]
18. Aronow HD, Topol EJ, Roe MT, et al. Effect of lipid-lowering therapy on early mortality after acute coronary syndromes: an observational study. Lancet 2001;357:1063-1068. [CrossRef][Web of Science][Medline]
19. Asakura M, Ueda Y, Yamaguchi O, et al. Extensive development of vulnerable plaques as a pan-coronary process in patients with myocardial infarction: an angioscopic study. J Am Coll Cardiol 2001;37:1284-1288. [Free Full Text]
20. Goldstein JA, Demetriou D, Grines CL, Pica M, Shoukfeh M, O'Neill WW. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med 2000;343:915-922. [Free Full Text]
21. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction -- 2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). Circulation 2002;106:1893-1900. [Free Full Text]
22. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis. JAMA 2004;291:1071-1080. [Free Full Text]
23. Campeau L, Hunninghake DB, Knatterud GL, et al. Aggressive cholesterol lowering delays saphenous vein graft atherosclerosis in women, the elderly, and patients with associated risk factors: NHLBI post coronary artery bypass graft clinical trial. Circulation 1999;99:3241-3247. [Free Full Text]
24. Taylor AJ, Kent SM, Flaherty PJ, Coyle LC, Markwood TT, Vernalis MN. ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness. Circulation 2002;106:2055-2060. [Free Full Text]
25. Kent SM, Coyle LC, Flaherty PJ, Markwood TT, Taylor AJ. Marked low-density lipoprotein cholesterol reduction below current National Cholesterol Education Program targets provides the greatest reduction in carotid atherosclerosis. Clin Cardiol 2004;27:17-21. [Medline]
26. Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 2001;357:577-581. [CrossRef][Web of Science][Medline]
27. LaRosa JC. New and emerging data from clinical trials of statins. Curr Atheroscler Rep 2004;6:12-19. [Medline]

The following investigators and research coordinators participated in the study (the complete list of investigators and coordinators is available at www.timi.org): Operations Committee — E. Braunwald (Study Chair), C. Cannon (Principal Investigator), T. Grayston, B. Muhlestein, D. Rader, J. Rouleau, and members of the Data Coordinating Center and Sponsor are indicated with an asterisk; Steering Committee — Members of the Operations Committee and R. Byington, A. Castaigne, H. Darius, G. DeFerrari, B. Gersh, D. Gilbert, S. Grundy, G. Jackson, R. Knopp, I. Meredith, E. Ofili, M. Pfeffer, F. Sacks, P. Shah, S. Smith, A. Tonkin, J. Velasco; TIMI Study Group — C. McCabe (Project Director),* S. McHale (Project Manager); Sponsor (Bristol-Myers Squibb, Princeton, N.J., and Wallingford, Conn.) — R. Belder,* J. Breen,* G. Cucinotta, S. Joyal,* C.-S. Lin, K. Natarajan,* S. Nichols; Data Coordinating Center (Nottingham Clinical Research Group, Nottingham, United Kingdom) — A. Skene,* K. Hill; Clinical Events Committee — M. Pfeffer (Chairman), R. Guertin-Mercier; J. Potzka, R. Messing; Physician Reviewers — E. Ascher, P. Finn, R. Giugliano, J. Kirdar, D. Lee, A. Mirza, T. Rocco; Biomarker Core Laboratory (Brigham and Women's Hospital, Boston) — D. Morrow, P. Ridker, E. Danielson, G. Borkowski; Chlamydia/Serology Core Laboratory (Johns Hopkins University, Baltimore) — T. Quinn; C. Gaydos, B. Wood; Electrocardiographic Core Laboratory (eResearch Technology, Philadelphia) — J. Morganroth; Special Lipid Core Laboratory (University of Pennsylvania, Philadelphia) — D. Rader, M. Wolfe; Chemistry Core Laboratory (LabCorp, Raritan, N.J.); Data and Safety Monitoring Board — A. Gotto (Chair), J. Bartlett, D. DeMets, J. Banas, T. Pearson; Clinical Centers Enrolling the Most Patients (in order of enrollment) — Huntsville Hospital, Huntsville, Ala.: W. Haught and K. Griffin; Fremantle Hospital, Fremantle, Western Australia: R. Hendriks and D. Greenwell; Detar Hospital, Victoria, Tex.: H. Chandna and D. Holly; St. Francis Hospital, Tulsa, Okla.: J. Cassidy and N. Ritchie; Advanced Health Institute, Galax, Va.: J. Puma and E. Jones; Michigan Heart, Ypsilanti: J. Bengtson and C. Carulli; North Mississippi Medical Center, Tupelo: B. Bertolet and M. Jones; Wilford Hall Medical Center, Lackland Air Force Base, Lackland, Tex.: R. Krasuski and U. Ward; Queen Elizabeth Hospital, Woodville, Saskatchewan, Canada: J. Horowitz and R. Prideaux; Moses H. Cone Hospital, Greensboro, N.C.: T. Kelly and K. Cochran; Deaconess Medical Center, Spokane Wash.: D. Hollenbaugh and J. Mansfield; Louisiana Cardiology Associates, Baton Rouge: J. McLachlan and A. Yoches; New Mexico Heart Institute, Albuquerque: R. Orchard and S. Justice; River Cities Cardiology, Jeffersonville, Ind.: D. Denny and B. Vanvactor; Laval Hospital, Quebec, Canada: P. Bogaty and L. Boyer; Altru Health System Research Center, Grand Forks, N.D.: A. Ahmed and D. Vold; Iowa Heart Center, Des Moines: W. Wickmeyer and N. Coffman; MetroHealth Medical Center, Cleveland: R. Finkelhor and M. Dettmer; Scarborough Cardiology Research, Scarborough, Ont., Canada: A. Ricci, and B. Bozek; Moses Cone Hospital, Greensboro, N.C.: T. Stuckey and S. Milks; Lake Forest Hospital, Bannockburn, Ill.: J. Alexander and K. Anderson; Centre Hospitalier Universitaire, Fleurimont, Que., Canada: S. LePage and L. Larrivee; Butterworth Hospital, Grand Rapids, Mich.: R. McNamara and B. Van Over; Centre Hospitalier Regional de Lanaudière, Quebec, Canada: S. Kouz and M. Roy; Craigavaon Area Hospital, Portadown, County Armagh, United Kingdom: A. Moriarty and D. McEneaney.

Abstract PDF PDA Full Text PowerPoint Slide Set Editorial by Topol, E. J. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear Related Article PubMed Citation

Related Letters:

Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes
van der Harst P., Voors A. A., van Veldhuisen D. J., Miller M., Gotto A. M. Jr., Paradis J.-M., LeLorier J., Auer J., Weber T., Eber B., Cannon C. P., Braunwald E.
Extract | Full Text | PDF  
N Engl J Med 2004; 351:714-717, Aug 12, 2004. Correspondence

This article has been cited by other articles:

• Jackevicius, C. A., Cox, J. L., Carreon, D., Tu, J. V., Rinfret, S., So, D., Johansen, H., Kalavrouziotis, D., Demers, V., Humphries, K., Pilote, L., for the Canadian Cardiovascular Outcomes Research, (2009). Long-term trends in use of and expenditures for cardiovascular medications in Canada. CMAJ 181: E19-E28 [Abstract] [Full Text]  
• Schiele, F., Meneveau, N., Seronde, M. F., Chopard, R., Descotes-Genon, V., Dutheil, J., Bassand, J.-P., on behalf on the 'Reseau de Cardiologie de Franche, (2009). C-reactive protein improves risk prediction in patients with acute coronary syndromes. Eur Heart J 0: ehp273v1-ehp273 [Abstract] [Full Text]  
• Tsai, M. Y., Ordovas, J. M. (2009). APOC3 Mutation, Serum Triglyceride Concentrations, and Coronary Heart Disease. Clin. Chem. 55: 1274-1276 [Full Text]  
• Miller, M. (2009). Dyslipidemia and cardiovascular risk: the importance of early prevention. QJM 0: hcp065v1-hcp065 [Abstract] [Full Text]  
• Leone, A. M., Valgimigli, M., Giannico, M. B., Zaccone, V., Perfetti, M., D'Amario, D., Rebuzzi, A. G., Crea, F. (2009). From bone marrow to the arterial wall: the ongoing tale of endothelial progenitor cells. Eur Heart J 30: 890-899 [Abstract] [Full Text]  
• Schlitt, A., Blankenberg, S., Bickel, C., Lackner, K. J., Heine, G. H., Buerke, M., Werdan, K., Maegdefessel, L., Raaz, U., Rupprecht, H. J., Munzel, T., Jiang, X.-C. (2009). PLTP activity is a risk factor for subsequent cardiovascular events in CAD patients under statin therapy: the AtheroGene Study. J. Lipid Res. 50: 723-729 [Abstract] [Full Text]  
• Stein, E. A. (2009). Low-Density Lipoprotein Cholesterol Reduction and Prevention of Cardiovascular Disease. Mayo Clin Proc. 84: 307-309 [Full Text]  
• Karalis, D. G. (2009). Intensive Lowering of Low-Density Lipoprotein Cholesterol Levels for Primary Prevention of Coronary Artery Disease. Mayo Clin Proc. 84: 345-352 [Abstract] [Full Text]  
• Chhatriwalla, A. K., Nicholls, S. J., Wang, T. H., Wolski, K., Sipahi, I., Crowe, T., Schoenhagen, P., Kapadia, S., Tuzcu, E. M., Nissen, S. E. (2009). Low levels of low-density lipoprotein cholesterol and blood pressure and progression of coronary atherosclerosis.. J Am Coll Cardiol 53: 1110-1115 [Abstract] [Full Text]  
• Ray, K. K., Cannon, C. P., Cairns, R., Morrow, D. A., Ridker, P. M, Braunwald, E. (2009). Prognostic Utility of ApoB/AI, Total Cholesterol/HDL, Non-HDL Cholesterol, or hs-CRP as Predictors of Clinical Risk in Patients Receiving Statin Therapy After Acute Coronary Syndromes: Results From PROVE IT-TIMI 22. Arterioscler. Thromb. Vasc. Bio. 29: 424-430 [Abstract] [Full Text]  
• Lester, S. J., Eleid, M. F., Khandheria, B. K., Hurst, R. T. (2009). Carotid Intima-Media Thickness and Coronary Artery Calcium Score as Indications of Subclinical Atherosclerosis. Mayo Clin Proc. 84: 229-233 [Abstract] [Full Text]  
• Fitzgerald, T. N, Popp, C., Dardik, A., Federman, D. G (2009). Lipid goal achievement and trends in lipid-lowering therapy in veterans undergoing carotid endarterectomy. Vasc Med 14: 21-27 [Abstract]  
• Scirica, B. M., Cannon, C. P., Sabatine, M. S., Jarolim, P., Sloane, S., Rifai, N., Braunwald, E., Morrow, D. A., for the PROVE IT-TIMI 22 Investigators, (2009). Concentrations of C-Reactive Protein and B-Type Natriuretic Peptide 30 Days after Acute Coronary Syndromes Independently Predict Hospitalization for Heart Failure and Cardiovascular Death. Clin. Chem. 55: 265-273 [Abstract] [Full Text]  
• Robinson, J. G., Wang, S., Smith, B. J., Jacobson, T. A. (2009). Meta-analysis of the relationship between non-high-density lipoprotein cholesterol reduction and coronary heart disease risk.. J Am Coll Cardiol 53: 316-322 [Abstract] [Full Text]  
• Ganz, P., Hsue, P. Y. (2009). Individualized approach to the management of coronary heart disease identifying the nonresponders before it is too late.. J Am Coll Cardiol 53: 331-333 [Full Text]  
• Choudhry, N. K. (2009). Copayment Levels and Medication Adherence: Less Is More. Circulation 119: 365-367 [Full Text]  
• Liu, P.-Y., Liu, Y.-W., Lin, L.-J., Chen, J.-H., Liao, J. K. (2009). Evidence for Statin Pleiotropy in Humans: Differential Effects of Statins and Ezetimibe on Rho-Associated Coiled-Coil Containing Protein Kinase Activity, Endothelial Function, and Inflammation. Circulation 119: 131-138 [Abstract] [Full Text]  
• SHISHEHBOR, M. H., HAZEN, S. L. (2009). JUPITER to Earth: A statin helps people with normal LDL-C and high hs-CRP, but what does it mean?. Cleveland Clinic Journal of Medicine 76: 37-44 [Abstract] [Full Text]  
• Whayne, T. F. Jr (2009). Is There a Problem With Ezetimibe or Just ENHANCEd Hype?. ANGIOLOGY 59: 661-663  
• Spatz, E. S., Canavan, M. E., Desai, M. M. (2009). From Here to JUPITER: Identifying New Patients for Statin Therapy Using Data From the 1999-2004 National Health and Nutrition Examination Survey. Circ Cardiovasc Qual Outcomes 2: 41-48 [Abstract] [Full Text]  
• McConnell, J. P., Jaffe, A. S. (2009). The Spin Stops Here: Inhibition of Lipoprotein-Associated Phospholipase A2-- A Promising Target but a Negative Initial Trial?. Clin. Chem. 55: 21-23 [Full Text]  
• American Diabetes Association, (2009). Standards of Medical Care in Diabetes--2009. Diabetes Care 32: S13-S61 [Full Text]  
• Caron, S., Staels, B. (2008). Apolipoprotein CIII: A Link Between Hypertriglyceridemia and Vascular Dysfunction?. Circ. Res. 103: 1348-1350 [Full Text]  
• Mukherjee, R., Locke, K. T., Miao, B., Meyers, D., Monshizadegan, H., Zhang, R., Search, D., Grimm, D., Flynn, M., O'Malley, K. M., Zhang, L., Li, J., Shi, Y., Kennedy, L. J., Blanar, M., Cheng, P. T., Tino, J., Srivastava, R. A. (2008). Novel Peroxisome Proliferator-Activated Receptor {alpha} Agonists Lower Low-Density Lipoprotein and Triglycerides, Raise High-Density Lipoprotein, and Synergistically Increase Cholesterol Excretion with a Liver X Receptor Agonist. J. Pharmacol. Exp. Ther. 327: 716-726 [Abstract] [Full Text]  
• Jukema, J W., Bergheanu, S. C (2008). Statins: established indications and controversial subgroups. Heart 94: 1656-1662 [Full Text]  
• Krasuski, R. A. (2008). Primary Prevention and Statins: Is It Just About Going to Class?. Mayo Clin Proc. 83: 1313-1315 [Full Text]  
• Jacobson, T. A., Wertz, D. A., Hoy, T., Kuznik, A., Grochulski, D., Cziraky, M. (2008). Comparison of Cardiovascular Event Rates in Patients Without Cardiovascular Disease in Whom Atorvastatin or Simvastatin Was Newly Initiated. Mayo Clin Proc. 83: 1316-1325 [Abstract] [Full Text]  
• Mills, E. J., Rachlis, B., Wu, P., Devereaux, P. J., Arora, P., Perri, D. (2008). Primary Prevention of Cardiovascular Mortality and Events With Statin Treatments A Network Meta-Analysis Involving More Than 65,000 Patients.. J Am Coll Cardiol 52: 1769-1781 [Abstract] [Full Text]  
• Fruchart, J.-C., Sacks, F. M, Hermans, M. P, Assmann, G., Brown, W V., Ceska, R., Chapman, M J., Dodson, P. M, Fioretto, P., Ginsberg, H. N, Kadowaki, T., Lablanche, J.-M., Marx, N., Plutzky, J., Reiner, Z., Rosenson, R. S, Staels, B., Stock, J. K, Sy, R., Wanner, C., Zambon, A., Zimmet, P. (2008). The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patients. Diabetes and Vascular Disease Research 5: 319-335 [Abstract]  
• van der Hoorn, J. W.A., de Haan, W., Berbee, J. F.P., Havekes, L. M., Jukema, J. W., Rensen, P. C.N., Princen, H. M.G. (2008). Niacin Increases HDL by Reducing Hepatic Expression and Plasma Levels of Cholesteryl Ester Transfer Protein in APOE*3Leiden.CETP Mice. Arterioscler. Thromb. Vasc. Bio. 28: 2016-2022 [Abstract] [Full Text]  
• O'Keefe, J. H., Bybee, K. A., Lavie, C. J. (2008). Is Carotid Intima-Media Thickness a Reliable Clinical Predictor?-Reply-I. Mayo Clin Proc. 83: 1300-1301 [Full Text]  
• Roe, M. T., Ou, F.-S., Alexander, K. P., Newby, L. K., Foody, J. M., Gibler, W. B., Boden, W. E., Ohman, E. M., Smith, S. C. Jr, Peterson, E. D. (2008). Patterns and prognostic implications of low high-density lipoprotein levels in patients with non-ST-segment elevation acute coronary syndromes. Eur Heart J 29: 2480-2488 [Abstract] [Full Text]  
• Johnson, E. L., Brosseau, J. D., Soule, M., Kolberg, J. (2008). Treatment of Diabetes in Long-Term Care Facilities: A Primary Care Approach. Clin. Diabetes 26: 152-156 [Abstract] [Full Text]  
• Rosenzweig, J. L., Ferrannini, E., Grundy, S. M., Haffner, S. M., Heine, R. J., Horton, E. S., Kawamori, R. (2008). Primary Prevention of Cardiovascular Disease and Type 2 Diabetes in Patients at Metabolic Risk: An Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 93: 3671-3689 [Abstract] [Full Text]  
• Giraldez, R. R., Giugliano, R. P., Mohanavelu, S., Murphy, S. A., McCabe, C. H., Cannon, C. P., Braunwald, E. (2008). Baseline Low-Density Lipoprotein Cholesterol Is an Important Predictor of the Benefit of Intensive Lipid-Lowering Therapy: A PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) Analysis. J Am Coll Cardiol 52: 914-920 [Abstract] [Full Text]  
• Bruschke, A. V.G., Jukema, J. W. (2008). Aggressive Therapy Is Not Always the Best Therapy. J Am Coll Cardiol 52: 921-923 [Full Text]  
• Serruys, P. W., Garcia-Garcia, H. M., Buszman, P., Erne, P., Verheye, S., Aschermann, M., Duckers, H., Bleie, O., Dudek, D., Botker, H. E., von Birgelen, C., D'Amico, D., Hutchinson, T., Zambanini, A., Mastik, F., van Es, G.-A., van der Steen, A. F.W., Vince, D. G., Ganz, P., Hamm, C. W., Wijns, W., Zalewski, A., for the Integrated Biomarker and Imaging Study-2 I, (2008). Effects of the Direct Lipoprotein-Associated Phospholipase A2 Inhibitor Darapladib on Human Coronary Atherosclerotic Plaque. Circulation 118: 1172-1182 [Abstract] [Full Text]  
• FELDMAN, L. S., BROTMAN, D. J. (2008). Perioperative statins: More than lipid-lowering?. Cleveland Clinic Journal of Medicine 75: 654-662 [Abstract] [Full Text]  
• Newman, C. B, Szarek, M., Colhoun, H. M, Betteridge, D J., Durrington, P. N, Hitman, G. A, Neil, H A. W, Demicco, D. A, Auster, S., Fuller, J. H (2008). The safety and tolerability of atorvastatin 10 mg in the Collaborative Atorvastatin Diabetes Study (CARDS). Diabetes and Vascular Disease Research 5: 177-183 [Abstract]  
• Gill, J. M., Yingxia Chen, (2008). Quality of Lipid Management in Outpatient Care: A National Study Using Electronic Health Records. American Journal of Medical Quality 23: 375-381 [Abstract]  
• The SEARCH Collaborative Group, (2008). SLCO1B1 Variants and Statin-Induced Myopathy -- A Genomewide Study. NEJM 359: 789-799 [Abstract] [Full Text]  
• Zoghbi, G. J., Dorfman, T. A., Iskandrian, A. E. (2008). The Effects of Medications on Myocardial Perfusion. J Am Coll Cardiol 52: 401-416 [Abstract] [Full Text]  
• Steinberg, D., Glass, C. K., Witztum, J. L. (2008). Evidence Mandating Earlier and More Aggressive Treatment of Hypercholesterolemia. Circulation 118: 672-677 [Full Text]  
• Chan, M. Y., Mahaffey, K. W., Sun, L. J., Pieper, K. S., White, H. D., Aylward, P. E., Ferguson, J. J., Califf, R. M., Roe, M. T. (2008). Prevalence, Predictors, and Impact of Conservative Medical Management for Patients With Non-ST-Segment Elevation Acute Coronary Syndromes Who Have Angiographically Documented Significant Coronary Disease. J Am Coll Cardiol Intv 1: 369-378 [Abstract] [Full Text]  
• Woodard, J., Sassano, A., Hay, N., Platanias, L. C. (2008). Statin-Dependent Suppression of the Akt/Mammalian Target of Rapamycin Signaling Cascade and Programmed Cell Death 4 Up-Regulation in Renal Cell Carcinoma. Clin. Cancer Res. 14: 4640-4649 [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]  
• DAVIDSON, M. H. (2008). Is ezetimibe/simvastatin no better than simvastatin alone? Lessons learned and clinical implications. Cleveland Clinic Journal of Medicine 75: 479-496 [Full Text]  
• White, J. R. Jr (2008). Do People With Diabetes Need Statins?. The Diabetes Educator 34: 664-673 [Abstract] [Full Text]  
• Geisler, T., Zurn, C., Paterok, M., Gohring-Frischholz, K., Bigalke, B., Stellos, K., Seizer, P., Kraemer, B. F., Dippon, J., May, A. E., Herdeg, C., Gawaz, M. (2008). Statins do not adversely affect post-interventional residual platelet aggregation and outcomes in patients undergoing coronary stenting treated by dual antiplatelet therapy. Eur Heart J 29: 1635-1643 [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]  
• 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]  
• Bunch, T. J., Rihal, C. S., Gumina, R. J., Cooper, L., Caplice, N. M. (2008). Progression of Nonculprit Plaque Stenosis Following Successful Percutaneous Intervention. ANGIOLOGY 59: 236-239 [Abstract]  
• Mohler, E. R. III, Ballantyne, C. M., Davidson, M. H., Hanefeld, M., Ruilope, L. M., Johnson, J. L., Zalewski, A., for the Darapladib Investigators, (2008). The Effect of Darapladib on Plasma Lipoprotein-Associated Phospholipase A2 Activity and Cardiovascular Biomarkers in Patients With Stable Coronary Heart Disease or Coronary Heart Disease Risk Equivalent: The Results of a Multicenter, Randomized, Double-Blind, Placebo-Controlled Study. J Am Coll Cardiol 51: 1632-1641 [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]  
• Pitt, B., Loscalzo, J., Ycas, J., Raichlen, J. S. (2008). Lipid Levels After Acute Coronary Syndromes. J Am Coll Cardiol 51: 1440-1445 [Abstract] [Full Text]  
• Miller, M. (2008). Lipid Levels in the Post-Acute Coronary Syndrome Setting: Destabilizing Another Myth?. J Am Coll Cardiol 51: 1446-1447 [Full Text]  
• Howard, B. V., Roman, M. J., Devereux, R. B., Fleg, J. L., Galloway, J. M., Henderson, J. A., Howard, Wm. J., Lee, E. T., Mete, M., Poolaw, B., Ratner, R. E., Russell, M., Silverman, A., Stylianou, M., Umans, J. G., Wang, W., Weir, M. R., Weissman, N. J., Wilson, C., Yeh, F., Zhu, J. (2008). Effect of Lower Targets for Blood Pressure and LDL Cholesterol on Atherosclerosis in Diabetes: The SANDS Randomized Trial. JAMA 299: 1678-1689 [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]  
• Kastelein, J. J.P., de Groot, E. (2008). Ultrasound imaging techniques for the evaluation of cardiovascular therapies. Eur Heart J 29: 849-858 [Abstract] [Full Text]  
• Ibanez, B., Vilahur, G., Cimmino, G., Speidl, W. S., Pinero, A., Choi, B. G., Zafar, M. U., Santos-Gallego, C. G., Krause, B., Badimon, L., Fuster, V., Badimon, J. J. (2008). Rapid change in plaque size, composition, and molecular footprint after recombinant apolipoprotein A-I Milano (ETC-216) administration: magnetic resonance imaging study in an experimental model of atherosclerosis.. J Am Coll Cardiol 51: 1104-1109 [Abstract] [Full Text]  
• Lewis, E. F., Velazquez, E. J., Solomon, S. D., Hellkamp, A. S., McMurray, J. J.V., Mathias, J., Rouleau, J.-L., Maggioni, A. P., Swedberg, K., Kober, L., White, H., Dalby, A. J., Francis, G. S., Zannad, F., Califf, R. M., Pfeffer, M. A. (2008). Predictors of the first heart failure hospitalization in patients who are stable survivors of myocardial infarction complicated by pulmonary congestion and/or left ventricular dysfunction: a VALIANT study. Eur Heart J 29: 748-756 [Abstract] [Full Text]  
• 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]  
• Miller, M., Cannon, C. P., Murphy, S. A., Qin, J., Ray, K. K., Braunwald, E., for the PROVE IT-TIMI 22 Investigators, (2008). Impact of Triglyceride Levels Beyond Low-Density Lipoprotein Cholesterol After Acute Coronary Syndrome in the PROVE IT-TIMI 22 Trial.. J Am Coll Cardiol 51: 724-730 [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]  
• Nesto, R. W. (2008). LDL Cholesterol Lowering in Type 2 Diabetes: What Is the Optimum Approach?. Clin. Diabetes 26: 8-13 [Abstract] [Full Text]  
• Baker, W. L., Gutierrez-Williams, G., White, C. M., Kluger, J., Coleman, C. I. (2008). Effect of Cinnamon on Glucose Control and Lipid Parameters. Diabetes Care 31: 41-43 [Abstract] [Full Text]  
• Kinlay, S., Schwartz, G. G., Olsson, A. G., Rifai, N., Szarek, M., Waters, D. D., Libby, P., Ganz, P., for the Myocardial Ischemia Reduction with Aggress, (2008). Inflammation, Statin Therapy, and Risk of Stroke After an Acute Coronary Syndrome in the MIRACL Study. Arterioscler. Thromb. Vasc. Bio. 28: 142-147 [Abstract] [Full Text]  
• American Diabetes Association, (2008). Standards of Medical Care in Diabetes--2008. Diabetes Care 31: S12-S54 [Full Text]  
• Kaneda, A., Wang, C. J., Cheong, R., Timp, W., Onyango, P., Wen, B., Iacobuzio-Donahue, C. A., Ohlsson, R., Andraos, R., Pearson, M. A., Sharov, A. A., Longo, D. L., Ko, M. S. H., Levchenko, A., Feinberg, A. P. (2007). Enhanced sensitivity to IGF-II signaling links loss of imprinting of IGF2 to increased cell proliferation and tumor risk. Proc. Natl. Acad. Sci. USA 104: 20926-20931 [Abstract] [Full Text]  
• O'Neil, C. E., Nicklas, T. A. (2007). State of the Art Reviews: Relationship Between Diet/ Physical Activity and Health. AMERICAN JOURNAL OF LIFESTYLE MEDICINE 1: 457-481 [Abstract]  
• 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]  
• Ardigo, D., Assimes, T. L., Fortmann, S. P., Go, A. S., Hlatky, M., Hytopoulos, E., Iribarren, C., Tsao, P. S., Tabibiazar, R., Quertermous, T., for the ADVANCE Investigators, (2007). Circulating chemokines accurately identify individuals with clinically significant atherosclerotic heart disease. Physiol. Genomics 31: 402-409 [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]  
• Gortney, J. S., Sanders, R. M. (2007). Impact of C-reactive protein on treatment of patients with cardiovascular disease. Am J Health Syst Pharm 64: 2009-2016 [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]  
• Scirica, B. M., Morrow, D. A., Cannon, C. P., de Lemos, J. A., Murphy, S., Sabatine, M. S., Wiviott, S. D., Rifai, N., McCabe, C. H., Braunwald, E., for the Thrombolysis in Myocardial Infarction (TIM, (2007). Clinical Application of C-Reactive Protein Across the Spectrum of Acute Coronary Syndromes. Clin. Chem. 53: 1800-1807 [Abstract] [Full Text]  
• Ferreira, G. A., Navarro, T. P., Telles, R. W., Andrade, L. E. C., Sato, E. I. (2007). Atorvastatin therapy improves endothelial-dependent vasodilation in patients with systemic lupus erythematosus: an 8 weeks controlled trial. Rheumatology (Oxford) 46: 1560-1565 [Abstract] [Full Text]  
• Laudi, S., Trump, S., Schmitz, V., West, J., McMurtry, I. F., Mutlak, H., Christians, U., Weimann, J., Kaisers, U., Steudel, W. (2007). Serotonin transporter protein in pulmonary hypertensive rats treated with atorvastatin. Am. J. Physiol. Lung Cell. Mol. Physiol. 293: L630-L638 [Abstract] [Full Text]  
• Donahoe, S. M., Stewart, G. C., McCabe, C. H., Mohanavelu, S., Murphy, S. A., Cannon, C. P., Antman, E. M. (2007). Diabetes and Mortality Following Acute Coronary Syndromes. JAMA 298: 765-775 [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]  
• Anderson, J. L., Adams, C. D., Antman, E. M., Bridges, C. R., Califf, R. M., Casey, D. E. Jr, Chavey, W. E. II, Fesmire, F. M., Hochman, J. S., Levin, T. N., Lincoff, A. M., Peterson, E. D., Theroux, P., Wenger, N. K., Wright, R. S., Smith, S. C. Jr, Jacobs, A. K., Adams, C. D., Anderson, J. L., Antman, E. M., Halperin, J. L., Hunt, S. A., Krumholz, H. M., Kushner, F. G., Lytle, B. W., Nishimura, R., Ornato, J. P., Page, R. L., Riegel, B. (2007). ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol 50: e1-e157 [Full Text]  
• Anderson, J. L., Adams, C. D., Antman, E. M., Bridges, C. R., Califf, R. M., Casey, D. E. Jr, Chavey, W. E. II, Fesmire, F. M., Hochman, J. S., Levin, T. N., Lincoff, A. M., Peterson, E. D., Theroux, P., Wenger, N. K., Wright, R. S., Smith, S. C. Jr, Jacobs, A. K., Adams, C. D., Anderson, J. L., Antman, E. M., Halperin, J. L., Hunt, S. A., Krumholz, H. M., Kushner, F. G., Lytle, B. W., Nishimura, R., Ornato, J. P., Page, R. L., Riegel, B. (2007). ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol 50: 652-726 [Full Text]