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JAMA-EXPRESS
High-Dose Atorvastatin vs Usual-Dose Simvastatin for Secondary Prevention After Myocardial Infarction
The IDEAL Study: A Randomized Controlled Trial
Terje R. Pedersen, MD, PhD;
Ole Faergeman, MD, DMSc;
John J. P. Kastelein, MD, PhD;
Anders G. Olsson, MD, PhD;
Matti J. Tikkanen, MD, PhD;
Ingar Holme, PhD;
Mogens Lytken Larsen, MD, DMSc;
Fredrik S. Bendiksen, MD;
Christina Lindahl, MD;
Michael Szarek, MS;
John Tsai, MD; for the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group
JAMA. 2005;294:2437-2445.
ABSTRACT
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Context Evidence suggests that more intensive lowering of low-density lipoprotein cholesterol (LDL-C) than is commonly applied clinically will provide further benefit in stable coronary artery disease.
Objective To compare the effects of 2 strategies of lipid lowering on the risk of cardiovascular disease among patients with a previous myocardial infarction (MI).
Design, Setting, and Participants The IDEAL study, a prospective, randomized, open-label, blinded end-point evaluation trial conducted at 190 ambulatory cardiology care and specialist practices in northern Europe between March 1999 and March 2005 with a median follow-up of 4.8 years, which enrolled 8888 patients aged 80 years or younger with a history of acute MI.
Interventions Patients were randomly assigned to receive a high dose of atorvastatin (80 mg/d; n = 4439), or usual-dose simvastatin (20 mg/d; n = 4449).
Main Outcome Measure Occurrence of a major coronary event, defined as coronary death, confirmed nonfatal acute MI, or cardiac arrest with resuscitation.
Results During treatment, mean LDL-C levels were 104 (SE, 0.3) mg/dL in the simvastatin group and 81 (SE, 0.3) mg/dL in the atorvastatin group. A major coronary event occurred in 463 simvastatin patients (10.4%) and in 411 atorvastatin patients (9.3%) (hazard ratio [HR], 0.89; 95% CI, 0.78-1.01; P = .07). Nonfatal acute MI occurred in 321 (7.2%) and 267 (6.0%) in the 2 groups (HR, 0.83; 95% CI, 0.71-0.98; P = .02), but no differences were seen in the 2 other components of the primary end point. Major cardiovascular events occurred in 608 and 533 in the 2 groups, respectively (HR, 0.87; 95% CI, 0.77-0.98; P = .02). Occurrence of any coronary event was reported in 1059 simvastatin and 898 atorvastatin patients (HR, 0.84; 95% CI, 0.76-0.91; P<.001). Noncardiovascular death occurred in 156 (3.5%) and 143 (3.2%) in the 2 groups (HR, 0.92; 95% CI, 0.73-1.15; P = .47). Death from any cause occurred in 374 (8.4%) in the simvastatin group and 366 (8.2%) in the atorvastatin group (HR, 0.98; 95% CI, 0.85-1.13; P = .81). Patients in the atorvastatin group had higher rates of drug discontinuation due to nonserious adverse events; transaminase elevation resulted in 43 (1.0%) vs 5 (0.1%) withdrawals (P<.001). Serious myopathy and rhabdomyolysis were rare in both groups.
Conclusions In this study of patients with previous MI, intensive lowering of LDL-C did not result in a significant reduction in the primary outcome of major coronary events, but did reduce the risk of other composite secondary end points and nonfatal acute MI. There were no differences in cardiovascular or all-cause mortality. Patients with MI may benefit from intensive lowering of LDL-C without an increase in noncardiovascular mortality or other serious adverse reactions.
Trial Registration ClinicalTrials.gov Identifier: NCT00159835.
INTRODUCTION
Lowering of low-density lipoprotein cholesterol (LDL-C) with statins has in the last decade become part of the standard treatment regimen in patients with established coronary heart disease (CHD). Following the publication of the results of the Scandinavian Simvastatin Survival Study (4S) in 1994,1 the most common treatment regimen for such patients in northern Europe has been simvastatin, 20 to 40 mg/d. In a recent trial among patients with acute coronary syndromes, incremental benefit was demonstrated with more intensive lowering of LDL-C to well below 100 mg/dL.2 In the Treating to New Targets (TNT) study comparing high and low doses of atorvastatin in stable nonacute CHD, a significant improvement in prognosis with respect to cardiovascular disease was demonstrated.3 In that study, however, the benefit of reduced cardiovascular mortality appeared to have been offset by a higher number of deaths due to noncardiovascular causes. Although this difference did not reach statistical significance and could well be due to the play of chance, it led to a call for further safety information on the use of atorvastatin at a dose of 80 mg/d.4
The Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice5 in 2003 recommended an LDL-C target level of less than 100 mg/dL (2.5 mmol/L) for CHD patients. The Third Report of the National Cholesterol Education Program (NCEP) Adult Treatment Panel recently introduced a new target of less than 70 mg/dL (1.8 mmol/L) for patients at very high risk.6 The main hypothesis of the current study, the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study, was that intensive lowering of LDL-C with atorvastatin at the highest recommended dose would yield incremental benefit compared with the moderate, most widely used dose of simvastatin.
METHODS
Study Design and Participants
The IDEAL study was a multicenter, prospective, randomized, open-label, blinded end-point classification trial (the so-called PROBE design7) carried out at 190 ambulatory cardiology and private specialist centers in Denmark, Finland, Iceland, the Netherlands, Norway, and Sweden. A detailed description of the study design and baseline characteristics of the patients has been published elsewhere.8 In brief, recruitment and randomization took place from March 1999 to March 2001 and patients were followed up until March 2005. Records of patients previously treated at the centers were screened for the main eligibility criteria. Potentially eligible patients were invited for a screening visit. Written informed consent was obtained from all patients, and the study was approved by the national or regional review board in all countries and by governmental reimbursing institutions in countries where the main sponsor did not cover all costs.
Men and women aged 80 years or younger with a history of a definite myocardial infarction and who qualified for statin therapy according to national guidelines at the time of recruitment were eligible. The main exclusion criteria were any known contraindications to statin therapy, previous intolerance to statins in low or high doses, liver enzyme levels more than 2 times the upper limit of normal, pregnancy or breastfeeding, nephrotic syndrome, uncontrolled diabetes mellitus, uncontrolled hypothyroidism, plasma triglyceride levels higher than 600 mg/dL (6.8 mmol/L), congestive heart failure (New York Heart Association classification IIIb or IV), hemodynamically important valvular heart disease, gastrointestinal conditions affecting absorption of drugs, treatment with other drugs that seriously affect the pharmacokinetics of statins, and treatment with other lipid-lowering drugs. Patients previously treated with statins qualified if they had not already had titration to a dose higher than the equivalent of 20 mg/d of simvastatin.
After dietary counseling, patients fulfilling the eligibility criteria were randomized to receive simvastatin, 20 mg/d, or atorvastatin, 80 mg/d (Figure 1). Study medication was assigned via a central interactive voice response system (ClinPhone, Nottingham, England). Allocation numbers were given out in blocks of 24. Allocation was balanced by center; no other stratification was used. There was no run-in or washout period. Study medication was provided by prescription except in Finland, where it was dispensed at the expense of the sponsor.
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Figure 1. Flow of Participants Through the Trial
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Patients were followed up at the centers after 12 and 24 weeks and every 6 months thereafter. If, at 24 weeks, plasma total cholesterol level was higher than 190 mg/dL (5.0 mmol/L), the dose of simvastatin could be increased to 40 mg/d. The dose of atorvastatin could be decreased to 40 mg/d for adverse events. If LDL-C decreased to less than 39 mg/dL (1.0 mmol/L), an investigator would be notified and could consider reducing the statin dose.
All lipid and lipoprotein levels were measured from fasting blood samples. Such measurements, along with liver enzymes and other laboratory measurements, were made at baseline, at 12 and 24 weeks, at 1 year, and yearly thereafter. All measurements were made at a central laboratory. The results of lipid and lipoprotein measurements were not revealed to study personnel during the study except in cases of titration of simvastatin at 24 weeks.
Study Outcomes
The primary clinical outcome was time to first occurrence of a major coronary event, defined as coronary death, hospitalization for nonfatal acute myocardial infarction, or cardiac arrest with resuscitation. Potential myocardial infarction cases were adjudicated according to current guidelines of the Joint European Society of Cardiology/American College of Cardiology. There were 3 prespecified composite secondary outcomes: (1) major cardiovascular events (any primary event plus stroke; the diagnosis of stroke required evidence of a neurological deficit, usually localized, lasting  24 hours or until death, usually confirmed by diagnostic imaging); (2) any CHD event (any primary event, any coronary revascularization procedure, or hospitalization for unstable angina); (3) any cardiovascular events (any of the former plus hospitalization with a primary diagnosis of congestive heart failure and peripheral arterial disease, defined as new clinical diagnosis or hospitalization for such disease). In addition, individual components of the composite end points were also prespecified as secondary outcomes, as was all-cause mortality.
In addition to per-protocol reporting by investigators, monitors reviewed patient records at regular intervals to search for potential end points. An end-point classification committee blindly reviewed reports on potential end points and adjudicated outcomes at regular meetings. All reports were first screened by an independent center (Inveresk, Raleigh, NC) for blinding of treatment allocation.
Statistical Analysis
Based on previous experience, it was projected that simvastatin therapy would produce a mean 35% reduction in LDL-C from untreated levels, while the reduction with atorvastatin, 80 mg/d, would be at least 55%, creating a difference in plasma levels of about 40 mg/dL (1 mmol/L). The trial was designed to have 90% power to detect an anticipated 21% relative risk reduction (from 10% to 7.9%) in the primary outcome variable with atorvastatin over 5 years using a 2-tailed  level of .05. Because the risk of the patients first recruited was recalculated to be lower than first anticipated, the originally planned sample size of 7700 patients was increased to 8888. A data and safety monitoring board performed interim analyses when approximately 50% and 75% of the predetermined final number of 774 patients had experienced a primary end point.
The study was initiated by the investigators and scientifically led by a steering committee consisting of independent researchers and investigators and 3 members employed by the sponsor. Monitoring of data collection was provided by the sponsor. A contract research organization (Covance, Horsham, England) reviewed the data for errors and inconsistencies and sent queries to the investigators for clarification. This organization provided the interim reports for the data and safety monitoring board. The final statistical analysis was performed by the sponsor. An independent academic statistician of the steering committee (I.H.) had full access to all of the data at the completion of data collection and verified the analyses of the results.
Kaplan-Meier hazard rates were used to examine incidence over time and the log-rank test was used to assess group differences. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).9 Statistical analysis was performed using SAS, version 8.2 (SAS Institute Inc, Cary, NC). All analyses in this report are based on the intention-to-treat principle including all randomized patients. Two-sided P values of <.05 were regarded as statistically significant.
RESULTS
After screening of patients’ records, 9689 potentially eligible patients were called in for a screening visit. Of these, 8888 met the eligibility criteria and were randomized (Figure 1). The main reasons for exclusion were patients’ use of higher statin doses than the equivalent of 20 mg/d of simvastatin, unwillingness to participate, and previous adverse experience with statins.
The median follow-up time was 4.8 years (range of surviving participants, 4.0-5.9 years). Six patients were lost to follow-up and 48 patients withdrew consent prior to study close, but vital status was known for 35 of these at the close of the study. Data for these patients have been included in the analysis for the period prior to loss or withdrawal. Vital status at the end of the trial is thus unknown for 19 patients.
Baseline characteristics were well balanced between the 2 treatment groups (Table 1). The median time since last myocardial infarction was 22 months in the simvastatin group and 21 months in the atorvastatin group.
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Table 1. Baseline Participant Characteristics*
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At 24 weeks of follow-up, 900 patients (21%) in the simvastatin group had their dosage increased to 40 mg/d. At the end of the study, 1034 (23%) were prescribed simvastatin, 40 mg/d. In patients allocated to receive atorvastatin, 80 mg/d, 250 (6%) had their dosage reduced to 40 mg/d by 24 weeks; in 587 patients(13%), the final dose was 40 mg. Overall adherence, defined as total study medication exposure as a percentage of total follow-up time, was 89% in the atorvastatin group and 95% in the simvastatin group. By the end of the study, 14% of the atorvastatin-allocated and 7% of the simvastatin-allocated patients had permanently discontinued study medication. Most patients who stopped taking the study drug switched to a different statin. In the simvastatin group, 360 patients took a different statin at some point; in 123 (2.8%), it was atorvastatin. In the atorvastatin group, 645 patients took a different statin; in 364 (8.2%), it was simvastatin.
Since the majority of patients allocated to receive simvastatin therapy were already taking simvastatin, 20 mg/d, or another statin at an equivalent dose at the time of randomization, the changes in lipid and lipoprotein levels for the group as a whole were small (Table 2). Patients in the simvastatin group who were not taking a statin at the time of randomization had, on average, a reduction in LDL-C of 33% after 12 weeks. In the group allocated to atorvastatin, 80 mg/d, statin-naive patients had a mean reduction in LDL-C of 49%. During treatment, mean (SE) LDL-C levels were 104 (0.3) mg/dL (2.7 [0.008] mmol/L) in the simvastatin group and 81 (0.3) mg/dL (2.1 [0.008] mmol/L) in the atorvastatin group. Total cholesterol and triglyceride levels were also significantly lower in the atorvastatin group compared with the simvastatin group, whereas high-density lipoprotein cholesterol (HDL-C) levels were slightly but significantly higher in the simvastatin group. Apolipoprotein levels changed correspondingly (Table 2).
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Table 2. Baseline and Follow-up Levels of Lipids and Lipoproteins*
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In December 2004, reports of 702 patients with a confirmed primary end point had arrived at the coordinating centers. Based on this information, the steering committee decided that the study close-out procedures should be concluded by April 2005, when it was anticipated that the protocol-specified target of 774 patients with a primary end point would have occurred. When all study close-out visits had been performed, a total of 874 patients had actually experienced a primary end point.
The primary end point of coronary death, acute myocardial infarction, or cardiac arrest with resuscitation occurred in 463 patients (10.4%) in the simvastatin group and in 411 (9.3%) in the atorvastatin group (Table 3). This corresponds to a relative risk reduction of 11% with atorvastatin, 80 mg/d (HR, 0.89; 95% CI, 0.78-1.01; P = .07) (Figure 2). A post hoc Cox regression analysis of the primary end point with adjustment for sex, age, statin use at randomization, duration since last myocardial infarction, total cholesterol, and HDL-C resulted in an HR of 0.87 (95% CI, 0.76-0.99; P = .04). A preliminary analysis of prespecified subgroups defined by sex and age did not reveal any statistically significant treatment group interactions.
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Table 3. Incidence of and Hazard Ratios for Primary and Secondary Efficacy Outcomes
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Figure 2. Cumulative Hazard of Cardiovascular Disease
Major coronary event (MCE) was defined as death from coronary disease, nonfatal myocardial infarction, or cardiac arrest with resuscitation. Major cardiovascular disease indicates MCE plus stroke. Any coronary heart disease indicates MCE plus hospitalization for unstable angina pectoris and coronary revascularization procedures. Any cardiovascular disease indicates any of the above plus peripheral vascular disease and hospitalization for nonfatal congestive heart failure. HR indicates hazard ratio; CI, confidence interval.
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There were 178 coronary deaths (4.0%) in the simvastatin group vs 175 (3.9%) in the atorvastatin group (HR, 0.99; 95% CI, 0.80-1.22; P = .90). Nonfatal myocardial infarction occurred in 321 patients (7.2%) in the simvastatin group and in 267 (6.0%) in the atorvastatin group (HR, 0.83; 95% CI, 0.71-0.98; P = .02). The composite secondary end point of a major cardiovascular event including stroke was reduced in the atorvastatin group (HR, 0.87; 95% CI, 0.78-0.98; P = .02). Similarly, there were reductions in the risk of nonfatal myocardial infarction, any CHD event, and any cardiovascular event. Hemorrhagic strokes occurred in 6 patients in each treatment group. Kaplan-Meier hazard rates for selected components of the secondary end points are shown in Figure 3.
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Figure 3. Cumulative Hazard of Nonfatal Myocardial Infarction, Stroke, Coronary Revascularization, and Peripheral Artery Disease
HR indicates hazard ratio; CI, confidence interval.
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The risk of death from any cause was similar in both study groups (HR, 0.98; 95% CI, 0.85-1.13; P = .80) (Table 3). There were no significant differences in noncardiovascular deaths between the treatment groups. In particular, mortality due to cancer was similar in the 2 groups, at 112 (2.5%) in the simvastatin group and 99 (2.2%) in the atorvastatin group. There were no significant differences in cancer mortality for any particular body system.
There were no significant differences in the frequency of serious clinical adverse experiences between the 2 groups. There were, however, more patients in the atorvastatin group who discontinued study medication because of investigator-reported adverse effects (Table 4). Elevation of liver enzyme levels occurred more frequently in the atorvastatin group, but this was not related to any increased incidence of clinical liver disease. Myalgias occurred more frequently in the atorvastatin group, but myopathy rates were exceedingly low in both the atorvastatin and simvastatin groups.
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Table 4. Frequency of Adverse Events and Most Relevant Liver Enzyme Elevations
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COMMENT
The majority of trials on statin therapy in the last decade have examined the effect of lowering LDL-C by 25% to 40%. In the 4S study, the mean LDL-C reduction was 35%.1 The IDEAL study intended to explore whether a strategy of reducing LDL-C even further would yield incremental benefit. The prespecified primary end point did not achieve statistical significance (P = .07), but there were significant reductions in nonfatal acute myocardial infarction and in the secondary composite end points of any CHD event and major or any cardiovascular events. There was no difference in all-cause or cardiovascular mortality. Thus, although the reductions were more modest than expected and although the primary end point was not met, these results indicate that more intensive lowering of LDL-C than usual in patients with previous myocardial infarction might prevent 68 first cardiovascular events (95% CI, 39-97) per 1000 patients over 5 years.
There are several possible reasons why statistical significance was not reached for the primary end point. One explanation might be insufficient difference in levels of LDL-C between the groups since the observed difference was slightly smaller than projected. The initial LDL-C reduction of 49% in statin-naive patients taking atorvastatin, 80 mg/d, was less than expected, and although adherence with this therapy was excellent, it was not as good as in the simvastatin group.
A second possible explanation was that the follow-up duration was only a median of 4.8 years even though the study protocol anticipated the prespecified number of primary end points to be reached after a median of 5.5 years. A third possibility is that the effect of simvastatin on HDL-C would attenuate the difference produced by the improved effect of atorvastatin on LDL-C. However, the impact of statins on HDL-C has not yet been shown to influence patient outcomes.
Design and Adherence
The IDEAL study was carried out with the PROBE design and, thus, did not have the advantages of a double-blind trial. However, the end-point classification was conducted by a blinded clinical end-points committee with the idea of minimizing bias. The open-label design with prescription of study medication had the advantage of being more like a "real-world" setting, but the possibility of bias for some of the physician-initiated end points, such as coronary revascularization and hospitalization for unstable angina, cannot be excluded. The fact that most patients had to pay part of the cost of the study drug apparently did not affect prescription rates, because the cost for the patients of the 2 study drugs was identical.
The apparent adherence to atorvastatin was high and better than that in other comparable trials. The adherence in the simvastatin group was, however, exceptional (95%). The higher adherence to study medication in the simvastatin group than in the atorvastatin group may be explained by the fact that 51% of the patients had been taking simvastatin prior to randomization and were probably comfortable with it, while in an open-label design a high dose of atorvastatin might have led to hesitation by some patients and investigators, especially early in the trial. This also makes it difficult to make reliable comparisons of reported adverse experiences between the 2 treatment regimens.
Comparison With Other Trials
The Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) study compared pravastatin, 40 mg/d, with atorvastatin, 80 mg/d, in patients with recent acute coronary syndromes.2 In that study, the difference in LDL-C levels between the treatment groups averaged 33 mg/dL (0.86 mmol/L), which produced a 16% relative reduction in the HR of the primary composite end point, which included death, myocardial infarction, unstable angina, coronary revascularization, and stroke. Thus, in that study the patient population was different, since only 11% of the IDEAL population had a recent myocardial infarction (<2 months); in addition, the difference in LDL-C between the treatment groups was larger and the definition of the primary end point was different.
In the TNT study, the primary end point included stroke.3 When comparing the primary end point of the TNT trial with the same end point in the IDEAL study, the difference between treatment groups was smaller in IDEAL (HR, 0.78 vs 0.87), but the 95% CIs for the HRs overlap. Comparison of the broader end point of any cardiovascular events, however, reveals more similar HRs of 0.81 and 0.84 in the 2 trials, respectively.
A recent prospective meta-analysis of 14 cholesterol-lowering statin trials with more than 90 000 patients found a 23% proportional reduction in the incidence of major coronary events and a 21% proportional reduction in the incidence of major cardiovascular events per 1 mmol/L of LDL-C reduction (corresponding to a 5.5% and 5% reduction in incidences per 10 mg/dL reduction in LDL-C, respectively).10 Our results are consistent with these findings and are also in accordance with other meta-analyses and epidemiological data on the relationship of cholesterol levels and CHD risk10-14 and by findings from internal subgroup analyses of results of previous trials.15-16 Recent findings in trials of other comparative drugs3, 17 and in different clinical settings2, 18 have provided evidence of the same relationship.
The IDEAL trial was not powered to detect a significant difference in all-cause mortality. In the 4S study, the comparator was placebo, and in the placebo group 74% of the deaths were coronary.1 In IDEAL, only 48% of the deaths in the simvastatin group had a coronary cause, which is considerably lower than the 61% of deaths having a coronary cause in the simvastatin group in 4S. This decline in coronary mortality may well reflect improvements in coronary prevention and care during the last decade. While this improvement must be welcomed, it has made it more difficult for trialists to demonstrate further benefit in survival.
Safety
In the IDEAL study, there was a small and nonsignificant excess of 13 more noncardiovascular deaths in the simvastatin group than in the atorvastatin group. In contrast, atorvastatin, 80 mg/d, was associated with a small and nonsignificant increase in noncardiovascular deaths compared with atorvastatin, 10 mg/d, in the TNT study. Such small differences are likely to have occurred by chance. There was no difference between the groups in the frequency of adverse events that were rated as serious. There were, however, more nonserious adverse events resulting in drug discontinuation in the atorvastatin group. This difference may reflect real nontolerance to a high dose of atorvastatin, but the possibility of reporting bias is present given the open-label design of the trial.
The proportion of patients developing liver enzyme elevation with atorvastatin, 80 mg/d, was low and is comparable with results of other similar trials. The proportion of patients in the simvastatin group who developed liver enzyme elevations was exceptionally small and was significantly lower than in the atorvastatin group. This reporting was not subject to bias, since it was performed by the central laboratory that transferred the results directly to the study database. The low frequency is readily explained by the fact that half of the patients had received simvastatin prior to randomization and were selected as "simvastatin-tolerant."
In summary, when comparing standard and intensive LDL-C–lowering therapies in patients with previous myocardial infarction, there was no statistically significant reduction in the primary end point of major coronary events, but there was reduced risk of other composite secondary end points and nonfatal acute myocardial infarction. There were no differences in cardiovascular and all-cause mortality. The results indicate that patients with myocardial infarction may benefit from intensive lowering of LDL-C without increase in noncardiovascular mortality or other serious adverse reactions.
AUTHOR INFORMATION
Corresponding Author: Terje R. Pedersen, MD, PhD, Centre for Preventive Medicine, Ullevål University Hospital, Kirkeveien 166, Bldg 19, N-0407 Oslo, Norway (t.r.pedersen{at}medisin.uio.no).
Author Contributions: Dr Pedersen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Pedersen, Faergeman, Tikkanen, Holme, Larsen, Bendiksen, Lindahl.
Acquisition of data: Pedersen, Faergeman, Kastelein, Larsen, Szarek, Tsai.
Analysis and interpretation of data: Pedersen, Faergeman, Kastelein, Olsson, Tikkanen, Holme, Larsen, Lindahl, Szarek, Tsai.
Drafting of the manuscript: Pedersen, Faergeman, Tikkanen, Holme, Lindahl, Szarek.
Critical revision of the manuscript for important intellectual content: Faergeman, Kastelein, Olsson, Tikkanen, Holme, Larsen, Bendiksen, Szarek, Tsai.
Statistical analysis: Pedersen, Faergeman, Holme, Szarek.
Obtained funding: Pedersen, Bendiksen.
Administrative, technical, or material support: Pedersen, Kastelein, Larsen, Lindahl, Tsai.
Study supervision: Pedersen, Faergeman, Olsson, Tikkanen, Larsen.
Financial Disclosures: Dr Pedersen has received consultation fees and speaker’s honoraria from Pfizer, Merck, Merck AG, and AstraZeneca and research grants and steering committee fees from Pfizer and Merck. Dr Kastelein has received research grants from Pfizer. Drs Olsson and Holme have received honoraria from Pfizer as steering committee members. Dr Bendiksen was previously employed by Pfizer Norway and has received honoraria from Pfizer as a steering committee member. No other disclosures were reported.
Independent Statistical Analysis: Dr Holme is a statistician at the Ullevål University Hospital, Oslo, Norway, and performed an independent statistical analysis of the raw data set. That analysis confirmed all results reported in this article.
Funding/Support: This study was sponsored by Pfizer Inc.
Role of the Sponsor: Members of the steering committee employed by Pfizer contributed to the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript.
The IDEAL Study Group: Denmark (1987 patients enrolled): S. Abildstrøm, København; E. Agner, Helsingør; B. Alsbjerg, Skive; F. Andersen, Silkeborg; L. Andersen, Nykøbing; L. Andersen, Randers; M. Andersen, Fredericia; N. Andersen, Slagelse; U. Andersen, Slagelse; M. Bay, København; J. Böttzauw, Odder; B. Brendorp, København; H. Brockstedt, Silkeborg; J. Brønnum-Schou, København; J. Buhl, Silkeborg; L. Bune, København; L. Buttenschøn, Holbæk; T. Clausen, København; P. Clemmensen, København; P. Corell, Frederiksberg; J. Dahlin, København; C. Dahlstrøm, Slagelse; M. Dalsgaard, København; D. Damgaard, Århus; H. Dominguez, København; K. Egstrup, Svendborg; P. Eliasen, Holbæk; O. Færgeman, Århus; N. Falstie-Jensen, Hjørring; L. Fog, Hjørring; F. Frandsen, Fredericia; B. Fredenhardt, Holbæk; M. Frederiksen, København; P. Fruergaard, Roskilde; G. Gislason, København; B. Glintborg, Kalundborg; T. Glud, Middelfart; L. Gøtzsche, Randers; P. Grande, København; P. Gustavsen, Næstved; H. Halgreen, Køge; D. Hansen, Holbæk; J. Hansen, København; F. Henriksen, Fredericia; T. Hermann, København; P. Hildebrandt, Frederiksberg; E. Høgh, Odder; L. Holmvang, København; M. Husic, Svendborg; N. Ihlemann, København; T. Jakobsen, Frederiksberg; J. Jaque, Holbæk; B. Jastrup, Odder; G. Jensen, Roskilde; H. Jensen, Hjørring; J. Jensen, Odder; P. Jensen, Holstebro; T. Jensen, Fredericia; T. Jensen, Randers; H. Julsgaard, København; B. Jurlander, København; J. Kanters, Helsingør; V. Kirk, København; T. Kjeld, København; K. Klarlund, Køge; L. Køber, København; C. Kragelund, Frederiksberg; N. Kriegbaum, København; K. Kristensen, Holbæk; M. Kyhn, Næstved; C. Lange, København; C. Larsen, København; J. Larsen, Næstved; M. Larsen, Århus; M. Lessing, Kalundborg; K. Lindvig, København; P. Lomholt, Randers; H. Madsen, Kalundborg; L. Madsen, Frederiksberg; L. Madsen, Holstebro; A. Major-Pedersen, København; J. Markenvard, Fredericia; A. McNair, Frederikssund; T. Melchior, Roskilde; M. Misiorna-Böhme, Svendborg; N. Møller, Svendborg; B. Nielsen, Silkeborg; H. Nielsen, København; I. Nielsen, Roskilde; T. Nielsen, Esbjerg; W. Nielsen, Hvidovre; C. Nøjgaard, Holbæk; O. Nyvad, Holstebro; J. Olsen, Holbæk; E. Olsen, Roskilde; M. Olsen, Frederikssund; M. Ottesen, København; S. Pedersen, Odder; E. Petersen, Hjørring; J. Petersen, Hjørring; J. Poulsen, Middelfart; M. Præstholm, Randers; N. Ralfkiær, Helsingør; H. Rasmussen, København; S. Rasmussen, Hvidovre; V. Rasmussen, Hvidovre; C. Ravens, Fredericia; S. Ravn, Kalundborg; H. Rickers, Grenå; F. Rømer, Silkeborg; N. Roseva-Nielsen, Holbæk; P. Schnohr, København; K. Schultz, Holbæk; M. Schultz, Frederiksberg; B. Sigurd, København; E. Søndergaard, Svendborg; F. Steffensen, Randers; S. Stentebjerg, Skive; T. Svendsen, Holbæk; R. Sykulski, Næstved; A. Teisner, København; C. Terkelsen, Silkeborg; P. Thaning, København; K. Thomsen, Esbjerg; N. Thorball, Roskilde; J. Thorsen, Næstved; C. Torp-Pedersen, København; H. Ulriksen, Skive; M. Vaage-Nilsen, Frederikssund; N. Valeur, København; L. Vigh, Grenå; Finland (506 patients enrolled): M. Äärynen, Siaraalamäki; J. Alanko, Tampere; H. Gylling, Helsinki; R. Heikkilä, Lohja; E. Hussi, Heinola; R. Hyttinen, Jyväskylä; E. Jukka, Rauma; A. Ketomäki, Helsinki; M. Ketonen, Joensuu; R. Kettunen, Mikkeli; L. Koivunen, Lohja; A. Koponen, Lappeenranta; P. Korhonen, Rauma; M. Laakso, Kuopio; M. Lampinen, Salo; S. Lehto, Kuopio; C. Lindström, Tammisaari; K. Luotola, Lappeenranta; J. Melin, Jyväskylä; T. Miettinen, Helsinki; J. Nurminen, Joensuu; H. Oksa, Tampere; T. Olli, Jyväskylä; T. Pekkarinen, Vantaa; O. Penttilä, Lahti; M. Puhakka, Kuopio; R. Radhakrishnan, Helsinki; M. Rajamäki, Lahti; H. Relas, Helsinki; J. Rinne, Tammisaari; A. Strandberg, Kerava; T. Strandberg, Helsinki; R. Sulosaari, Kerava; H. Vanhanen, Helsinki; Iceland (82 patients enrolled): J. Högnason, Reykjavik; G. Oddsson, Reykjavik; G. Sigurdsson, Reykjavik; G. Thorgeirsson, Reykjavik; G. Thorgeirsson, Reykjavik; the Netherlands (1351 patients enrolled): W. Aarnoudse, Eindhoven; E. Badings, Deventer; G. Bartels, Groningen; D. Basart, Hoorn; M. Baselier, Breda; G. Bech, Eindhoven; D. Beelen, Delft; P. Bernink, Groningen; E. Birkhoff-Pieters, Rotterdam; L. Bouwens, Deventer; A. Bredero, Utrecht; P. Bruggink-André de la Porte, Deventer; E. Bruijns, Goes; M. Buijs, Rotterdam; T. Cherpanath, Breda; J. Chin, Weert; P. Chin A Fo, Delft; R. Claessens, ‘s-Hertogenbosch; A. Constantinescu, Breda; J. De Boo, Goes; I. de Bruin, Capelle aan den IJSSEL; M. de Groot, Eindhoven; S. de la Fuente, Eindhoven; M. de Leeuw, Assen; E. de Melker, Amsterdam; W. de Voogt, Amsterdam; F. Den Hartog, Ede; J. DeWarrimont-Henquet, Heerlen; H. Dohmen, ‘s-Hertogenbosch; P. Dunselman, Breda; R. Entjes, Eindhoven; M. Faverey, Breda; R. Feld, Heerlen; Y. Foolen, Eindhoven; M. Galjee, Enschede; H. Groeneveld, Deventer; D. Groot, Eindhoven; R. Groutars, Amsterdam; J. Hartog, Utrecht; H. Heijmen, Eindhoven; J. Henneman, Alkmaar; W. Hermans, Tilburg; F. Hersbach, Eindhoven; D. Hertzberger, Nijmegen; A. Herweijer, Zwijndrecht; N. Holwerda, Tilburg; J. Hoorntje, Zwolle; P. Huinink, Eindhoven; C. Janus, Hoorn; H. Klomps, Weert; A. Kloppenberg-Oey, Groningen; M. Kofflard, Zwijndrecht; J. Kooistra-Huizer, Delft; H. Koornstra-Wortel, Oss; J. Kragten, Heerlen; K. Krasznai, Eindhoven; P. Kuijer, Oss; K. K lek i, Eindhoven; J. Levert, Delft; A. Liem, Goes; D. Lok, Deventer; J. Louwerenburg, Enschede; P. Melman, Tilburg; H. Michels, Eindhoven; W. Muijs van de Moer, Capelle aan den IJSSEL; P. Nierop, Rotterdam; F. Nijland, Amsterdam; S. Nio, Capelle aan den IJSSEL; A. Oude Ophuis, Nijmegen; J. Peels, Alkmaar; H. Penn, Weert; J. Posma, Groningen; R. Pruijsten, Capelle aan den IJSSEL; P. Rademaker, Eindhoven; A. Ramdat Misier, Zwolle; S. Roeffel, Eindhoven; H. Roeters Van Lennep, Goes; B. Schölzel, Breda; H. Schaafsma, Ede; J. Schroeder-Tanka, Amsterdam; A. Sewnaik-Asarfi, Capelle aan den IJSSEL; F. Smeets, Eindhoven; A. Stammen, Breda; H. Suryapranata, Zwolle; L. Takens, Groningen; T. Tan, Amsterdam; F. Tietge, Deventer; P. Tilon, Hoorn; W. Tonino, Eindhoven; M. Trip, Amsterdam; Y. Tuininga, Deventer; V. Umans, Alkmaar; G. Uytdehaag, Breda; P. Van Bergen, Hoorn; B. Van den Berg, Capelle aan den IJSSEL; B. Van den Branden, Breda; M. Van Der Schaaf, Hoorn; I. Van Eede, Assen; A. Van Es, Enschede; P. Van Kalmthout, Ede; T. Van Loenhout, Ede; R. Van Rijswijk, Tilburg; R. Van Roosmalen, Assen; M. Van Schoot, Enschede; J. Van Wijngaarden, Deventer; L. Van Woerkens, Zwijndrecht; M. Veerhoek, Rotterdam; J. Visser, Amsterdam; A. Weevers, Eindhoven; R. Weidgraaf, Enschede; R. Weijers, Eindhoven; A. Willems, Amsterdam; A. Withagen, Delft; P. Zwart, Oss; Norway (2453 patients enrolled): C. Aase, Haugesund; W. Aasebø, Lørenskog; E. Aaser, Rud; K. Åkre, Stord; S. Andresen, Mysen; P. Antonsen, Bodø; K. Arnesen, Lørenskog; K. Aronsen, Hammerfest; O. Aronsen, Karasjok; I. Asmussen, Førde; I. Axelsson, Notodden; M. Bækkevar, Tønsberg; T. Baisa, Notodden; H. Bjørnstad, Bergen; K. Bjørnstad, Trondheim; H. Dalen, Levanger; R. Dalen, Hammerfest; A. Dimmen, Kristiansund; S. Dyb, Prsgrunn; K. Dyrkorn, Kragerø; F. Erchinger, Odda; H. Fadnes, Stord; S. Fredwall, Mysen; Ø. Furnes, Hammerfest; K. Gisholt, Nesttun; S. Gravdal, Bergen; T. Graven, Levanger; S. Gudnason, Bergen; H. Haaland, Ålesund; O. Haanæs, Tynset; O. Hagen, Moss; B. Halvorsen, Moss; P. Hamre, Stavanger; V. Hansteen, Oslo; S. Hareide, Volda; E. Hauge, Bergen; T. Haugnes, Mosjøen; M. Heese, Odda; K. Helander, Mo i Rana; A. Hervold, Stavanger; A. Herzog, Oslo; A. Heskestad, Molde; S. Hewitt, Oslo; V. Høeg, Tynset; A. Hognestad, Rikshospitalet, Oslo; L. Holst-Larsen, Haugesund; M. Hosseini, Bergen; A. Hovland, Bodø; U. Hurtig, Tynset; K. Jacobsen, Ålesund; H. Janniche, Tynset; K. Johnsen, Karasjok; O. Jordal, Bergen; R. Karlsen, Stavanger; A. Kask, Bergen; J. Kjekshus, Oslo; J. Kleinau, Levanger; B. Klykken, Levanger; F. Kontny, Oslo; S. Kornstad, Sandvika; A. Koss, Jessheim; B. Kulseng, Trondheim; K. Langaker, Oslo; D. Langvoll, Hammerfest; K. Larsby, Hammerfest; T. Le, Lørenskog; N. Lid, Notodden; A. Lied, Molde; F. Lindberg, Oslo; I. Løfsnes, Rud; M. Mastroianni, Lørenskog; T. Meling, Stavanger; G. Mo, Mosjøen; O. Mortensen, Tønsberg; I. Mujic, Kristiansund; L. Mundal, Førde; P. Munk, Stavanger; S. Nabizadeh, Moss; S. Nadirpour, Haugesund; P. Nesje, Mo i Rana; S. Nitter-Hauge, Oslo; E. Øfjord, Paradis; J. Øvermo, Hammerfest; M. Øwre, Oslo; T. Omland, Flekkefjord; A. Oppdal, Bergen; T. Pedersen, Oslo; Z. Radunovic, Bergen; N. Ringdal, Molde; K. Risberg, Skedsmokorset; G. Schneider, Bodø; H. Selsås, Ålesund; A. Semb, Oslo; P. Sirnes, Hobøl; A. Skag, Paradis; G. Skjelvan, Trondheim; J. Solli, Kristiansand; L. Sommervoll, Tønsberg; J. Sparby, Kongsvinger; T. Steen, Oslo; T. Sund, Lillestrøm; A. Svilaas, Kongsberg; K. Thon, Moss; R. Thorshaug, Bergen; H. Tjønndal, Larvik; S. Toft, Bergen; S. Tonstad, Oslo; T. Torjussen, Kristiansand; T. Torjussen, Mysen; H. Torsvik, Rud; D. Torvik, Prsgrunn; A. Totland, Haugesund; K. Valnes, Oslo; J. Vegsundvåg, Ålesund; C. Von Brandis, Stavanger; B. Von Hoff, Kristiansund; F. Wandel, Odda; M. Wolff, Stavanger; A. Zalmai, Oslo; Sweden (2509 patients enrolled): L. Ahlberg, Finspång; P. Ahlström, Motala; B. Åkerström, Mariestad; H. Åkesson, Karlskoga; S. Akravi, Fagersta; M. Alam, Stockholm; J. Alfredsson, Norrköping; M. Ali, Jönköping; B. Andersson, Göteborg; L. Andersson, Borås; K. Ångman, Hudiksvall; Å. Appelqvist, Uddevalla; B. Atmer, Stockholm; I. Axelsson, Stockholm; J. Bäck, Köping; J. Bäckman, Karlskoga; H. Bastani, Stockholm; A. Berglund, Malmö; S. Berglund, Falun; P. Bhiladvala, Malmö; S. Bhuiyan, Uddevalla; E-B. Billberg, Sala; Ö. Bjuhr, Mölndal; A. Bjurman, Lycksele; K. Boman, Skellefteå; P-Å. Boström, Malmö; H. Brodersson, Gävle; J. Carlsäter, Sala; R. Carlsson, Karlstad; T. Carlsson, Vargberg; C. Dahlén, Falun Lasarett, Falun; G. Dahlén, Grästorp; A. Dahlqvist, Gävle; D. Dalima, Uddevalla; C. Digerfeldt, Norrköping; R. Dziamski, Malmö; E. Eizyk, Ängelholm; L. Ekholm, Ljungby; J. Ellström, Sandviken; P-O. Enander, Lidköping; L. Engqvist, Värnamo; B-O. Ericsson, Fagersta; U-B. Ericsson, Malmö; H. Fahlhammar, Sala; L. Falk, Mölndal; G. Finnas, Katrineholm; B. Frederiksson, Borås; J-E. Frisell, Ludvika; G. Frithz, Eskilstuna; A-M. Fröderberg, Finspång; F. Frogner, Ängelholm; G. Gustafsson, Gävle; P-E. Gustafsson, Gävle; E. Hammarström, Stockholm; O. Hansen, Malmö; S. Hansen, Eksjö; P. Hårdhammar, Halmstad; L. Härdig, Mölndal; M. Hartford, Göteborg; R. Hässler, Finspång; B. Hedbäck, Linköping; M. Henning, Uddevalla; J. Herlitz, Göteborg; P-O. Hermansson, Gävle; O. Herterich, Köping; L-G. Hjerne, Södertälje; C. Höglund, Stockholm; H. Holmberg, Mölndal; C. Ingmar, Karlstad; J-H. Jansson, Skellefteå; J. Jabro, Norrköping; I. Jamil, Karlskoga; D. Javid, Uddevalla; S. Jensen, Karlshamn; T. Jernberg, Stockholm; H. Joborn, Västervik; A. Johansson, Luleå; G. Johansson, Lidköping; L. Johansson, Skellefteå; T. Johansson, Alingsås; T. Jonson, Borås; H. Jul-Nielsen, Grästorp; P. Kalén, Ångelholm; A. Kallryd, Skövde; L. Kareld, Skene; B. Karlson, Göteborg; A-C. Karlsson, Halmstad; B. Karlsson, Kristinehamn; J-E. Karlsson, Jönköping; C. Kihlström, Motala; J. Kjellberg, Alingsås; L. Klintberg, Mölndal; L-E. Larsson, Västervik; L. Lidberg, Finspång; K. Lindberg, Södertälje; B. Linde, Falun; M. Lindgren, Halmstad; B. Lindström, Karlskrona; J. Lindström, Karlstad; M. Lindström, Jönköping; P. Lindström, Bålsta; T. Lindström, Mölndal; H. Lindvall, Karlskoga; P. Löfdahl, Helsingborg; L. Lundkvist, Hudiksvall; B. Malmros, Köping; A. Månsson, Kalmar; B. Moberg, Kristinehamn; D. Mohaupt, Gävle; P-Å. Moström, Mölndal; A. Moum-Nordlund, Uddevalla; P. Nicol, Köping; H. Nilsson, Fagersta; J. Nilsson, Luleå; O. Nilsson, Norrköping; H. Nordström, Alingsås; A. Norrby, Göteborg; P. Nyman, Helsingborg; K. Olsson, Strömstad; W. Osika, Karlskoga; A-M. Ottosson, Norrköping; K. Pedersen, Helsingborg; B. Persson, Mölndal; J. Persson, Malmö; M. Peterson, Lidköping; B. Pettersson, Strömstad; A. Pischel, Uddevalla; B. Polhem, Grästorp; F. Randers, Mölndal; P. Reinius, Kalmar; G. Renklint, Lycksele; A. Richter, Linköping; P. Rindevall, Ludvika; A. Rindner, Skene; M. Risenfors, Mölndal; U. Rosenqvist, Motala; G. Rüter, Helsingborg; V. Salagean, Finspång; K. Saldeen-Niléhn, Göteborg; S. Salovaara, Katrineholm; R. Samo-Ayou, Skövde; S. Sandgren, Borås; A. Sandström, Lycksele; L. Sandström, Stockholm; X. Shatri, Finspång; B. Sinnerstad, Västervik; A. Sjögren, Värnamo; S. Sjögren, Falköping; E. Skarfors, Halmstad; M. Stagmo, Malmö; H. Stakeberg, Vänersborg; G. Stehn, Hässleholm; H. Strömblad, Karlshamn; L. Svennberg, Gävle; K-A. Svensson, Ljungby; O. Svensson, Jönköping; A. Tholén, Strömstad; S. Thorsén, Värnamo; I. Timberg, Hässleholm; H. Tygesen, Borås; G. Ulvenstam, Göteborg; C. Valladares, Norrköping; K. Viidas, Uddevalla; F. Wagner, Helsingborg; S. Wåhlin, Bålsta; N. Wallén, Mariestad; I. Westbom, Karlstad; C. Wettervik, Borås; E. Winger, Sala; P. Wodlin, Motala; R. Zlatewa-Cuenca, Stockholm; Steering Committee: T. R. Pedersen (chair), O. Faergeman, J. J. P. Kastelein, A. G. Olsson, M. J. Tikkanen, I. Holme, M. Lytken Larsen, F. S. Bendiksen, C. Lindahl, S. Maehlum, J. Tsai; Data and Safety Monitoring Board: D. G. Julian (chair), C. Ballantyne, K. Rasmussen, H. Wedel; End Point Committee: C. Thygesen (chair), B. Johannesen, P. Lund Johansen; Data Analysis: S. Auster, T. Karam, R. Chan, M. Szarek; Study Management and Monitoring Offices (Pfizer Inc): J. Tsai, N. Cater, B. Suri, C. Elliott, T. Thomas (United States), B. Nicolaisen, I. Stenersen (Norway), J. Versteden (the Netherlands), B. Steenberg (Denmark), P. Kindblom (Sweden), P. Eloranta (Finland); Central Laboratory: Medilab, Stockholm, Sweden; Data Management: Covance, Horsham, England; End-Point Blinding and Management: Inveresk, Raleigh, NC.
Author Affiliations: Centre for Preventive Medicine, Ullevål University Hospital, Oslo, Norway (Drs Pedersen and Holme); Department of Medicine–Cardiology A, Århus University Hospital, Århus, Denmark (Drs Faergeman and Larsen); Academic Hospital Amsterdam, Amsterdam, the Netherlands (Dr Kastelein); Department of Internal Medicine, University Hospital, Linköping, Sweden (Dr Olsson); Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland (Dr Tikkanen); Pfizer Sweden, Täby, Sweden (Dr Lindahl); and Pfizer Inc, New York, NY (Mr Szarek and Dr Tsai). Dr Bendiksen is in private practice in Hamar, Norway.
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Primary and Secondary Prevention of Cardiovascular Diseases: A Practical Evidence-Based Approach
O'Keefe et al.
Mayo Clin Proc. 2009;84:741-757.
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Effect of high-intensity statin treatment in rheumatoid arthritis: a case with possible coronary atheroma regression and progression of rheumatoid valve degeneration
Semb et al.
BMJ Case Reports 2009;2009:bcr0820080717-bcr0820080717.
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PLTP activity is a risk factor for subsequent cardiovascular events in CAD patients under statin therapy: the AtheroGene Study
Schlitt et al.
J. Lipid Res. 2009;50:723-729.
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Macrovascular Complications of Diabetes Mellitus
Nuzum and Merz
Journal of Pharmacy Practice 2009;22:135-148.
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Controversies in familial hypercholesterolaemia: recommendations of the NICE Guideline Development Group for the identification and management of familial hypercholesterolaemia
Minhas et al.
Heart 2009;95:584-587.
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Intensive Lowering of Low-Density Lipoprotein Cholesterol Levels for Primary Prevention of Coronary Artery Disease
Karalis
Mayo Clin Proc. 2009;84:345-352.
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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
Scirica et al.
Clin. Chem. 2009;55:265-273.
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Meta-analysis of the relationship between non-high-density lipoprotein cholesterol reduction and coronary heart disease risk.
Robinson et al.
J Am Coll Cardiol 2009;53:316-322.
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Association Between Statin Use and Risk for Keratinocyte Carcinoma in the Veterans Affairs Topical Tretinoin Chemoprevention Trial
Dore et al.
ANN INTERN MED 2009;150:9-18.
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JUPITER to Earth: A statin helps people with normal LDL-C and high hs-CRP, but what does it mean?
SHISHEHBOR and HAZEN
Cleveland Clinic Journal of Medicine 2009;76:37-44.
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The Effect of Atorvastatin in Patients with Polycystic Ovary Syndrome: A Randomized Double-Blind Placebo-Controlled Study
Sathyapalan et al.
J. Clin. Endocrinol. Metab. 2009;94:103-108.
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Statins: established indications and controversial subgroups
Jukema and Bergheanu
Heart 2008;94:1656-1662.
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Primary Prevention and Statins: Is It Just About Going to Class?
Krasuski
Mayo Clin Proc. 2008;83:1313-1315.
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Comparison of Cardiovascular Event Rates in Patients Without Cardiovascular Disease in Whom Atorvastatin or Simvastatin Was Newly Initiated
Jacobson et al.
Mayo Clin Proc. 2008;83:1316-1325.
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Targeting residual cardiovascular risk: raising high-density lipoprotein cholesterol levels
Hausenloy and Yellon
Postgrad. Med. J. 2008;84:590-598.
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Review: Recurrent stroke: where do we stand with the secondary prevention of noncardioembolic ischaemic strokes?
Talelli and Greenwood
Ther Adv Cardiovasc Dis 2008;2:387-405.
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Primary Prevention of Cardiovascular Disease and Type 2 Diabetes in Patients at Metabolic Risk: An Endocrine Society Clinical Practice Guideline
Rosenzweig et al.
J. Clin. Endocrinol. Metab. 2008;93:3671-3689.
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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
Giraldez et al.
J Am Coll Cardiol 2008;52:914-920.
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Aggressive Therapy Is Not Always the Best Therapy
Bruschke and Jukema
J Am Coll Cardiol 2008;52:921-923.
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The safety and tolerability of atorvastatin 10 mg in the Collaborative Atorvastatin Diabetes Study (CARDS)
Newman et al.
Diabetes and Vascular Disease Research 2008;5:177-183.
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SLCO1B1 Variants and Statin-Induced Myopathy -- A Genomewide Study
The SEARCH Collaborative Group
NEJM 2008;359:789-799.
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The Effects of Medications on Myocardial Perfusion
Zoghbi et al.
J Am Coll Cardiol 2008;52:401-416.
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Statins and Heart Failure
Filippatos and Mikhailidis
ANGIOLOGY 2008;59:58S-61S.
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Cholesterol lowering is more important than pleiotropic effects of statins for endothelial function in patients with dysglycaemia and coronary artery disease
Settergren et al.
Eur Heart J 2008;29:1753-1760.
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Do People With Diabetes Need Statins?
White
The Diabetes Educator 2008;34:664-673.
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Lipids, Apolipoproteins, and Their Ratios in Relation to Cardiovascular Events With Statin Treatment
Kastelein et al.
Circulation 2008;117:3002-3009.
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Targeting residual cardiovascular risk: raising high-density lipoprotein cholesterol levels
Hausenloy and Yellon
Heart 2008;94:706-714.
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Cholesterol Synthesis Inhibition Elicits an Integrated Molecular Response in Human Livers Including Decreased ACAT2
Parini et al.
Arterioscler. Thromb. Vasc. Bio. 2008;28:1200-1206.
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Intensive Lipid-Lowering With Atorvastatin for Secondary Prevention in Patients After Coronary Artery Bypass Surgery
Shah et al.
J Am Coll Cardiol 2008;51:1938-1943.
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Estrogen Receptor-Negative Breast Cancer Is Less Likely to Arise among Lipophilic Statin Users
Kumar et al.
Cancer Epidemiol. Biomarkers Prev. 2008;17:1028-1033.
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Lipoprotein Management in Patients With Cardiometabolic Risk: Consensus Conference Report From the American Diabetes Association and the American College of Cardiology Foundation
Brunzell et al.
J Am Coll Cardiol 2008;51:1512-1524.
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Effect of Lower Targets for Blood Pressure and LDL Cholesterol on Atherosclerosis in Diabetes: The SANDS Randomized Trial
Howard et al.
JAMA 2008;299:1678-1689.
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Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia
Kastelein et al.
NEJM 2008;358:1431-1443.
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Lipoprotein Management in Patients With Cardiometabolic Risk: Consensus statement from the American Diabetes Association and the American College of Cardiology Foundation
Brunzell et al.
Diabetes Care 2008;31:811-822.
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Beneficial effects of aggressive low-density lipoprotein cholesterol lowering in women with stable coronary heart disease in the Treating to New Targets (TNT) study
Wenger et al.
Heart 2008;94:434-439.
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Achieving Vascular Risk Factor Targets: A Survey of a London General Practice
Levine et al.
ANGIOLOGY 2008;59:36-46.
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The efficacy and safety of intensive statin therapy: a meta-analysis of randomized trials
Josan et al.
CMAJ 2008;178:576-584.
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High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: significance for cardiovascular risk: the IDEAL and EPIC-Norfolk studies.
van der Steeg et al.
J Am Coll Cardiol 2008;51:634-642.
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Lipid Management to Reduce Cardiovascular Risk: A New Strategy Is Required
Superko and King
Circulation 2008;117:560-568.
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Thyroid mimetic as an option for lowering low-density lipoprotein
Grundy
Proc. Natl. Acad. Sci. USA 2008;105:409-410.
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LDL Cholesterol Lowering in Type 2 Diabetes: What Is the Optimum Approach?
Nesto
Clin. Diabetes 2008;26:8-13.
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Low low-density lipoprotein cholesterol and cancer risk.
Strandberg
J Am Coll Cardiol 2008;51:91-92.
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Impact of Patient and Plan Design Factors on Switching to Preferred Statin Therapy
Cox et al.
The Annals of Pharmacotherapy 2007;41:1946-1953.
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Effect of Intensive Lipid Lowering with Atorvastatin on Renal Function in Patients with Coronary Heart Disease: The Treating to New Targets (TNT) Study
Shepherd et al.
CJASN 2007;2:1131-1139.
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Beyond Low-Density Lipoprotein Cholesterol: Defining the Role of Low-Density Lipoprotein Heterogeneity in Coronary Artery Disease
Mudd et al.
J Am Coll Cardiol 2007;50:1735-1741.
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Biases in the Identification of Risk Factor Thresholds and J-Curves
Marschner et al.
Am J Epidemiol 2007;166:824-831.
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Statins and Children: Whom Do We Treat and When?
Stein
Circulation 2007;116:594-595.
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Statin Use in Patients With Extremely Low Low-Density Lipoprotein Levels Is Associated With Improved Survival
Leeper et al.
Circulation 2007;116:613-618.
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Intensive statin therapy in acute coronary syndromes and stable coronary heart disease: a comparative meta-analysis of randomised controlled trials
Afilalo et al.
Heart 2007;93:914-921.
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Statins in elderly patients with acute coronary syndrome: an analysis of dose and class effects in typical practice
Choudhry et al.
Heart 2007;93:945-951.
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Atorvastatin Treatment and Vaccination Efficacy
Packard et al.
J Clin Pharmacol 2007;47:1022-1027.
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Effect of the Magnitude of Lipid Lowering on Risk of Elevated Liver Enzymes, Rhabdomyolysis, and Cancer: Insights From Large Randomized Statin Trials
Alsheikh-Ali et al.
J Am Coll Cardiol 2007;50:409-418.
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Outcomes of Using High- or Low-Dose Atorvastatin in Patients 65 Years of Age or Older with Stable Coronary Heart Disease
Wenger et al.
ANN INTERN MED 2007;147:1-9.
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Do statins have an antiarrhythmic activity?
Kostapanos et al.
Cardiovasc Res 2007;75:10-20.
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Cost-effectiveness of high-dose atorvastatin compared with usual-dose simvastatin: less than IDEAL?
Kaul
Eur Heart J 2007;0:ehm168v1-2.
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Cost-effectiveness of high-dose atorvastatin compared with regular dose simvastatin
Lindgren et al.
Eur Heart J 2007;28:1448-1453.
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Statins: Targeting Inflammation by Lowering Low-Density Lipoprotein?
Tuzcu and Nicholls
J Am Coll Cardiol 2007;49:2010-2012.
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Incremental Benefit and Cost-Effectiveness of High-Dose Statin Therapy in High-Risk Patients With Coronary Artery Disease
Chan et al.
Circulation 2007;115:2398-2409.
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Which statin, what dose?
DTB 2007;45:33-37.
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Update on Dyslipidemia
Garg and Simha
J. Clin. Endocrinol. Metab. 2007;92:1581-1589.
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Suppressive Effects of Statins on Acute Promyelocytic Leukemia Cells
Sassano et al.
Cancer Res. 2007;67:4524-4532.
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Safety of Aggressive Lipid Management
Davidson and Robinson
J Am Coll Cardiol 2007;49:1753-1762.
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Use of maximum-dose simvastatin or atorvastatin in an ethnically diverse population
Song et al.
Am J Health Syst Pharm 2007;64:767-772.
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A review of high-dose statin therapy: targeting cholesterol and inflammation in atherosclerosis
Patel et al.
Eur Heart J 2007;28:664-672.
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Lipid-Lowering Therapy and Outcomes in Heart Failure
Ray et al.
J CARDIOVASC PHARMACOL THER 2007;12:27-35.
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Coronary Heart Disease in Patients With Diabetes: Part I: Recent Advances in Prevention and Noninvasive Management
Berry et al.
J Am Coll Cardiol 2007;49:631-642.
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Statins, High-Density Lipoprotein Cholesterol, and Regression of Coronary Atherosclerosis
Nicholls et al.
JAMA 2007;297:499-508.
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The effect of intensive lipid lowering on coronary atheroma and clinical outcome
Houslay et al.
Heart 2007;93:149-151.
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Is it Time for a Cardiovascular Primary Prevention Trial in the Elderly?
Robinson et al.
Stroke 2007;38:441-450.
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Adherence to evidence-based statin guidelines reduces the risk of hospitalizations for acute myocardial infarction by 40%: a cohort study
Penning-van Beest et al.
Eur Heart J 2007;28:154-159.
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Rational therapy of mixed dyslipidaemia in a patient with diabetes
Reasner
British Journal of Diabetes & Vascular Disease 2007;7:25-30.
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The Cardiovascular Disease Continuum Validated: Clinical Evidence of Improved Patient Outcomes: Part I: Pathophysiology and Clinical Trial Evidence (Risk Factors Through Stable Coronary Artery Disease)
Dzau et al.
Circulation 2006;114:2850-2870.
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Fibrates after the FIELD study: some answers, more questions
Wierzbicki
Diabetes and Vascular Disease Research 2006;3:166-171.
ABSTRACT
Cholesteryl Ester Transfer Protein Inhibition: The Next Frontier in Combating Coronary Artery Disease?
Milani and Lavie
J Am Coll Cardiol 2006;48:1791-1792.
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Analysis of Efficacy and Safety in Patients Aged 65-75 Years at Randomization: Collaborative Atorvastatin Diabetes Study (CARDS).
Neil et al.
Diabetes Care 2006;29:2378-2384.
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Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem.
Hayward et al.
ANN INTERN MED 2006;145:520-530.
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The gap between theory and practice: what do the trials tell us?
Pedersen
Eur Heart J Suppl 2006;8:F10-F16.
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Reducing risk by raising HDL-cholesterol: the evidence
Drexel
Eur Heart J Suppl 2006;8:F23-F29.
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Niaspan(R) in the management of dyslipidaemia: the evidence
Brown
Eur Heart J Suppl 2006;8:F60-F67.
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Achieving the therapeutic benefits of Niaspan(R) in daily practice
Reasner
Eur Heart J Suppl 2006;8:F68-F73.
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Evidence to support aggressive management of HDL-cholesterol: implications of recent trials
Taylor
Eur Heart J Suppl 2006;8:F74-F80.
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The Effect of Early, Intensive Statin Therapy on Acute Coronary Syndrome: A Meta-analysis of Randomized Controlled Trials.
Hulten et al.
Arch Intern Med 2006;166:1814-1821.
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The Argument Against the Appropriateness of Over-the-Counter Statins
Barter and Rye
Circulation 2006;114:1315-1320.
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