Incremental Decrease In End Points Through Aggressive Lipid Lowering Research Articles

Prediction of future cardiovascular disease with an equation to estimate apolipoprotein B in patients with high cardiovascular risk: an analysis from the TNT and IDEAL study

BackgroundApolipoprotein B (apoB) is known to be a more powerful predictor of cardiovascular disease than conventional lipids. We aimed to determine the clinical relevance of a newly developed equation to estimate serum apoB levels based on total cholesterol, HDL cholesterol, and triglycerides in patients with high cardiovascular risk.MethodsThe occurrence of a major cardiovascular event (MCVE) was assessed using the data from the Treating to New Targets (TNT) and Incremental Decrease in End points through Aggressive Lipid lowering (IDEAL) trials.ResultsPooled analysis of these two data sets showed that both directly-measured apoB (HR per 1-SD (95% CI): 1.16 (1.11–1.21), P < 0.001) and apoB estimated from the eq. (HR per 1-SD (95% CI): 1.14 (1.09–1.19), P < 0.001) were significantly associated with the development of a future MCVE. Prediction of MCVEs by the apoB eq. (C statistic 0.650) was nearly identical to that of directly-measured apoB (0.651). In addition, the net reclassification indices indicated no difference in the prediction of MCVEs between models including the apoB equation and directly-measured apoB (1% (−1.3–4.0), P = 0.31).ConclusionsOur equation to predict apoB levels showed MCVE risk prediction comparable to directly-measured apoB in high risk patients with previous coronary heart disease.

Distribution of Estimated 10-Year Risk of Recurrent Vascular Events and Residual Risk in a Secondary Prevention Population.

Among patients with clinically manifest vascular disease, the risk of recurrent vascular events is likely to vary. We assessed the distribution of estimated 10-year risk of recurrent vascular events in a secondary prevention population. We also estimated the potential risk reduction and residual risk that can be achieved if patients reach guideline-recommended risk factor targets. The SMART score (Second Manifestations of Arterial Disease) for 10-year risk of myocardial infarction, stroke, or vascular death was applied to 6904 patients with vascular disease. The risk score was externally validated in 18 436 patients with various manifestations of vascular disease from the TNT (Treating to New Targets), IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering), SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), and CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trials. The residual risk at guideline-recommended targets was estimated by applying relative risk reductions from meta-analyses to the estimated risk for targets for systolic blood pressure, low-density lipoprotein cholesterol, smoking, physical activity, and use of antithrombotic agents. The external performance of the SMART risk score was reasonable, apart from overestimation of risk in patients with 10-year risk >40%. In patients with various manifestations of vascular disease, median 10-year risk of a recurrent major vascular event was 17% (interquartile range, 11%-28%), varying from <10% in 18% to >30% in 22% of the patients. If risk factors were at guideline-recommended targets, the residual 10-year risk would be <10% in 47% and >30% in 9% of the patients (median, 11%; interquartile range, 7%-17%). Among patients with vascular disease, there is very substantial variation in estimated 10-year risk of recurrent vascular events. If all modifiable risk factors were at guideline-recommended targets, half of the patients would have a 10-year risk <10%. These data suggest that even with optimal treatment, many patients with vascular disease will remain at >20% and even >30% 10-year risk, clearly delineating an area of substantial unmet medical need.

Differing predictive relationships between baseline LDL-C, systolic blood pressure, and cardiovascular outcomes

BackgroundTraditional cardiovascular risk factors, such as hypertension and dyslipidemia, predispose individuals to cardiovascular disease, particularly patients with diabetes. We investigated the predictive value of baseline systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C) on the risk of vascular outcomes in a large population of patients at high risk of future cardiovascular events. MethodsData were pooled from the TNT (Treating to New Targets), CARDS (Collaborative Atorvastatin Diabetes Study), and IDEAL (Incremental Decrease in End-Points Through Aggressive Lipid Lowering) trials and included a total of 21,727 patients (TNT: 10,001; CARDS: 2838; IDEAL: 8888). The effect of baseline SBP and LDL-C on cardiovascular events, coronary events, and stroke was evaluated using a multivariate Cox proportional-hazards model. ResultsOverall, risk of cardiovascular events was significantly higher for patients with higher baseline SBP or LDL-C. Higher baseline SBP was significantly predictive of stroke but not coronary events. Conversely, higher baseline LDL-C was significantly predictive of coronary events but not stroke. Results from the subgroup with diabetes (5408 patients; TNT: 1501; CARDS: 2838; IDEAL: 1069) were broadly consistent with those of the total cohort: baseline SBP and LDL-C were significantly predictive of cardiovascular events overall, with the association to LDL-C predominantly related to an effect on coronary events. However, baseline SBP was not predictive of either coronary or stroke events in the pooled diabetic population. ConclusionsIn this cohort of high-risk patients, baseline SBP and LDL-C were significantly predictive of cardiovascular outcomes, but this effect may differ between the cerebrovascular and coronary systems.Trial Registration Number: NCT00327691 (TNT); NCT00327418 (CARDS); NCT00159835 (IDEAL).

2013 Cholesterol Guidelines Revisited: Percent LDL Cholesterol Reduction or Attained LDL Cholesterol Level or Both for Prognosis?

BackgroundThe 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guideline on the treatment of blood cholesterol recommends moderate- to high-intensity statins for patients with atherosclerotic cardiovascular disease but departs from the traditional treat-to-target approach. Whether percent low-density lipoprotein cholesterol (LDL-C) reduction or attained LDL-C levels add incremental prognostic value to statin dose is not known. MethodsPatients in the Treating to New Targets (TNT), Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL), and Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trials (patient-level data) randomized to a statin arm (atorvastatin 80 mg/10 mg or simvastatin 20 mg) were chosen. Patients were divided into groups based on attained LDL-C levels (≤70 vs >70 mg/dL) and percent LDL-C reduction (≥50% vs <50%). Primary outcome was major cardiovascular event defined as death due to coronary heart disease, nonfatal myocardial infarction, resuscitated cardiac arrest, or stroke. Incremental prognostic value was assessed by using a forward conditional Cox proportional hazards model. Two models were tested: Model 1: Step 1 statin dose; Step 2 add attained LDL-C levels (continuous variable); Step 3 add percent LDL-C reduction (continuous variable). Model 2: Steps 2 and 3 were reversed. ResultsAmong 13,937 patients included in this study, percent LDL-C reduction added incremental prognostic value over both statin dose and attained LDL-C levels (global chi-square increased from 3.64 to 26.1 to 47.5; P <.0001). However, attained LDL-C level did not provide incremental prognostic value over statin dose and percent LDL-C reduction (global chi-square increased from 3.64 to 47.5 to 47.5; P <.0001 and .94, respectively). Among patients with attained LDL-C ≤70 mg/dL, those with percent LDL-C reduction of <50% had a significantly higher risk of primary outcome (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.16-1.97; P = .002) and stroke (HR, 2.07; 95% CI, 1.46-2.93; P <.0001) and a numerically higher risk of death (HR, 1.37; 95% CI, 0.98-1.90; P = .06) when compared with the group with percent LDL-C reduction of ≥50%. ConclusionsIn patients with atherosclerotic cardiovascular disease, percent LDL-C reduction provides incremental prognostic value over statin dose and attained LDL-C levels. However, the attained LDL-C level does not provide additional prognostic value over statin dose and percent LDL-C reduction.

Impact of Female Sex on Lipid Lowering, Clinical Outcomes, and Adverse Effects in Atorvastatin Trials

The aim of this study was to evaluate the effect of atorvastatin on lipid lowering, cardiovascular (CV) events, and adverse events in women compared with men in 6 clinical trials. In the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) trial (atorvastatin 80 mg vs simvastatin 20 to 40 mg), the Treating to New Targets (TNT) trial (atorvastatin 80 vs 10 mg), the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial (atorvastatin 80 mg vs placebo), and the Collaborative Atorvastatin Diabetes Study (CARDS), the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), and the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN) (atorvastatin 10 mg vs placebo), lipid changes on treatment were compared between genders with studies grouped by dose. The association of on-study low-density lipoprotein (LDL) cholesterol and CV events by gender was evaluated in the combined studies and the impact of gender on adverse events in each study separately. Major CV events occurred in 3,083 of 30,000 men (10.3%) and 823 of 9,173 women (9.0%). Changes in lipids were similar in women and men. Major CV events were associated with gender-specific quintiles of on-treatment LDL cholesterol for women and men. In women, LDL cholesterol was a significant predictor of stroke, but not in men. Discontinuation rates due to adverse events were higher in women in 4 of 6 trials, but in only 1 trial was a significant treatment-gender interaction seen. Myalgia rates were slightly higher in women in both statin and placebo groups. In conclusion, the response of women to atorvastatin was similar to that of men, with slightly more discontinuations due to adverse events. Higher on-treatment LDL cholesterol was significantly associated with more CV events in both genders, but the association was stronger for stroke in women and for coronary heart disease death in men.

Statin and the Risk of Renal-Related Serious Adverse Events: Analysis from the IDEAL, TNT, CARDS, ASPEN, SPARCL, and Other Placebo-Controlled Trials

A recent study has shown an association between high-potency statins and risk of acute kidney injury. However, these data are from observational studies, and it is not clear if similar signal is seen from randomized controlled trials. We evaluated the risk of renal-associated serious adverse events (SAEs) using statins versus placebo trials and the high-dose versus low-dose statin trials that were available to us. The outcome of interest was renal-related SAEs. The incidence of adverse events relating to kidney injury was determined through review of the adverse event database. The following outcomes were evaluated: (1) renal-related SAEs within 120 days of randomization (primary outcome), (2) renal-related SAEs after 120 days of randomization (secondary), and (3) drug discontinuation due to renal-related SAEs (secondary). There was no difference in the incidence of renal-related SAEs at 120 days (0.04% vs 0.10%, p = 0.162) between atorvastatin and placebo in the 24 placebo-controlled trials (10,345 patients on atorvastatin (10 to 80 mg/day) versus 8,945 patients on placebo) or in the high-dose versus low-dose statin trials including the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study (0.05% vs 0.02%, p = 0.625) or the Treating to New Targets (TNT) trial (0.0% vs 0.04%, p = 0.500) trial. Results were similar for renal-related SAEs after 120 days (placebo controlled trials [0.38% vs 0.36%, p = 0.905], IDEAL trial [0.56% vs 0.65%, p = 0.683], or the TNT trial [0.76% vs 1.04%, p = 0.168]) and for drug withdrawal due to renal-related SAE (placebo controlled trials [0.05% vs 0.04%, p = 1.00], IDEAL trial [0.02% vs 0.0%, p = 0.499], or the TNT trial [0.08% vs 0.12%, p = 0.754]). In conclusion, the results from clinical trials with data from 149,882 patient-years of follow-up fail to show any increase in renal-related SAEs with statins compared with controls.

Clinical determinants of incident aortic valve stenosis in patients treated with atorvastatin: results from three large randomized clinical trials

Background: Aortic valve stenosis (AVS) is the most common valvular heart disease in the Western world, and may share some risk factors with coronary heart disease (CHD). Clinical trials have failed to show a benefit for statin therapy in delaying the progression of AVS among asymptomatic individuals with known AVS. Whether statin therapy may decrease the incidence of AVS in populations enriched with CHD risk factors is unknown. Our objective was to compare the incidence rates of AVS among patients treated with high- versus low-dose statin or placebo and to identify clinical risk factors associated with the risk of AVS. Methods and results: Results from three large-scale atorvastatin trials were included in this study, the Treating to New Targets (TNT) trial, in which 80 mg and 10 mg/day of atorvastatin were compared in patients with stable coronary disease, the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) trial, in which atorvastatin 80 mg was compared to simvastatin 20 mg/day in post-myocardial infarction patients, and the Stroke Prevention by Aggressive Reduction in Cholesterol levels (SPARCL) trial, in which 80 mg/day of atorvastatin was compared to placebo in patients with a recent stroke or transient ischemic attack. All patients with known AVS at baseline were excluded from this analysis. During the follow-up (median=4.9 years), 45 patients developed AVS in TNT, 28 in IDEAL and 9 in SPARCL. Among the 82 patients who developed AVS, 39 (47.6%) patients were treated with atorvastatin 80 mg and 43 (52.4%) were treated with low-dose statin or placebo (hazard ratio [HR]=0.91 [95% CI, 0.59-1.41], p=0.67). Risk factors that showed a significant association in univariate regression analyses were entered into a multivariate model. These risk factors included age, height, weight, body mass index, diabetes, angina, previous coronary artery bypass grafting, peripheral vascular disease, warfarin and antiplatelets use, prior use of statins and calcium channel blockers use. In multivariate analyses forcing treatment, sex and race into the model, age (hazard ratio [HR]=2.24 [95% CI, 1.66-3.02], p<0.0001 per 1-SD increment), diabetes (HR=1.69 [1.00-2.82], p=0.05), warfarin and antiplatelets use (HR=2.89 [1.80-4.62], p<0.0001) and prior statin use (HR=2.56 [1.48-4.44], p=0.03) were significantly associated with the onset of AVS. Conclusions: In this study, high-dose statin therapy did not impact the incidence of AVS. We found that age, diabetes, warfarin and antiplatelets use and prior use of statins were significant predictors of incident AVS in these high-risk patients.

Cardiovascular Event Reduction Versus New-Onset Diabetes During Atorvastatin Therapy

The purpose of this study was to compare the incidence of new-onset diabetes (NOD) with cardiovascular (CV) event reduction at different levels of NOD risk. Statins reduce the number of CV events but increase the incidence of NOD. We previously reported that 4 factors independently predicted NOD: fasting blood glucose >100 mg/dl, fasting triglycerides >150 mg/dl, body mass index >30 kg/m(2), and history of hypertension. We compared NOD incidence with CV event reduction among 15,056 patients with coronary disease but without diabetes at baseline in the TNT (Treating to New Targets) (n = 7,595) and IDEAL (Incremental Decrease in Endpoints Through Aggressive Lipid Lowering) (n = 7,461) trials. CV events included coronary heart disease death, myocardial infarction, stroke, and resuscitated cardiac arrest. Among 8,825 patients with 0 to 1 of the aforementioned NOD risk factors at baseline, NOD developed in 142 of 4,407 patients in the atorvastatin 80 mg group and in 148 of 4,418 in the atorvastatin 10 mg and simvastatin 20 to 40 mg groups (3.22% vs. 3.35%; hazard ratio [HR]: 0.97; 95% confidence intervals [CI]: 0.77 to 1.22). Among the remaining 6,231 patients with 2 to 4 NOD risk factors, NOD developed in 448 of 3,128 in the atorvastatin 80 mg group and in 368 of 3,103 in the lower-dose groups (14.3% vs. 11.9%; HR: 1.24; 95% CI: 1.08 to 1.42; p = 0.0027). The number of CV events was significantly reduced with atorvastatin 80 mg in both NOD risk groups. Compared with lower-dose statin therapy, atorvastatin 80 mg/day did not increase the incidence of NOD in patients with 0 to 1 NOD risk factors but did, by 24%, among patients with 2 to 4 NOD risk factors. The number of CV events was significantly reduced with atorvastatin 80 mg in both NOD risk groups.

The 719Arg Variant of KIF6 and Cardiovascular Outcomes in Statin-Treated, Stable Coronary Patients of the Treating to New Targets and Incremental Decrease in End Points Through Aggressive Lipid-Lowering Prospective Studies

Carriers of the KIF6 719Arg variant may be at increased risk for CVD and may benefit more from statin therapy, in terms of CVD risk reduction, than noncarriers. Our objective was to investigate whether carriers of the KIF6 719Arg genetic variant (rs20455) are at increased cardiovascular risk and obtain more benefit from high-dose statin therapy than do noncarriers. We used an adjusted Cox proportional hazard model to assess the hazard ratio (HR) for the reduction of major cardiovascular events by 80 mg/d atorvastatin over 10 mg/d atorvastatin in 4599 patients of the Treating to New Targets (TNT) study and by 80 mg/d atorvastatin over 20-40 mg/d simvastatin in 6541 patients of the Incremental Decrease in End Points Through Aggressive Lipid-Lowering (IDEAL) study. A total of 381 and 648 patients had a cardiovascular event during follow-up in TNT and IDEAL, respectively. Heterozygotes and homozygotes for the minor allele were not at increased risk compared with noncarriers. In TNT, for noncarriers of the 719Arg allele, the HR for high- versus low-dose atorvastatin was 0.81 (95% confidence interval, 0.59-1.11). In carriers of 1 or 2 minor alleles, the HR was 0.85 (0.66-1.11) and carriers of 2 copies of the minor allele obtained a significant risk reduction (HR: 0.44, 95% confidence interval, 0.23-0.84). In IDEAL, the respective HRs were 0.85 (0.67-1.10), 0.88 (0.62-1.07) and 0.91 (0.58-1.43). The interaction term for carrier status by treatment was also nonsignificant (P=0.810 in TNT and P=0.909 in IDEAL). In these 2 large, randomized clinical trials, carriers of the KIF6 719Arg allele were not at increased cardiovascular risk and did not obtain consistent cardiovascular benefit from high-dose statin therapy compared with noncarriers.

Predictors of New-Onset Diabetes in Patients Treated With Atorvastatin: Results From 3 Large Randomized Clinical Trials

We sought to examine the incidence and clinical predictors of new-onset type 2 diabetes mellitus (T2DM) within 3 large randomized trials with atorvastatin.Statin therapy might modestly increase the risk of new-onset T2DM.We used a standard definition of diabetes and excluded patients with prevalent diabetes at baseline. We identified baseline predictors of new-onset T2DM and compared the event rates in patients with and without new-onset T2DM.In the TNT (Treating to New Targets) trial, 351 of 3,798 patients randomized to 80 mg of atorvastatin and 308 of 3,797 randomized to 10 mg developed new-onset T2DM (9.24% vs. 8.11%, adjusted hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 0.94 to 1.29, p = 0.226). In the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial, 239 of 3,737 patients randomized to atorvastatin 80 mg/day and 208 of 3,724 patients randomized to simvastatin 20 mg/day developed new-onset T2DM (6.40% vs. 5.59%, adjusted HR: 1.19, 95% CI: 0.98 to 1.43, p = 0.072). In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, new-onset T2DM developed in 166 of 1,905 patients randomized to atorvastatin 80 mg/day and in 115 of 1,898 patients in the placebo group (8.71% vs. 6.06%, adjusted HR: 1.37, 95% CI: 1.08 to 1.75, p = 0.011). In each of the 3 trials, baseline fasting blood glucose, body mass index, hypertension, and fasting triglycerides were independent predictors of new-onset T2DM. Across the 3 trials, major cardiovascular events occurred in 11.3% of patients with and 10.8% of patients without new-onset T2DM (adjusted HR: 1.02, 95% CI: 0.77 to 1.35, p = 0.69).High-dose atorvastatin treatment compared with placebo in the SPARCL trial is associated with a slightly increased risk of new-onset T2DM. Baseline fasting glucose level and features of the metabolic syndrome are predictive of new-onset T2DM across the 3 trials.

LDL cholesterol goals and cardiovascular risk during statin treatment: the IDEAL study

We assessed the proportion of patients treated with either simvastatin 20 or 40 mg or atorvastatin 80 mg who achieved low-density lipoprotein cholesterol (LDL-C) goals of 2.5 or 2.0 mmol/l in the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study. We explored how lipoprotein components related to cardiovascular disease (CVD) outcomes in these groups. For subjects who reached on-treatment LDL-C goals, Cox regression models were used to assess the ability of lipoprotein components to predict CVD events. Treatment with simvastatin or atorvastatin resulted in 40 per cent and 80 per cent of patients, respectively, reaching the 2.5 mmol/l goal and 12 per cent and 52 per cent, respectively, reaching the 2.0 mmol/l goal, after 1 year (all p < 0.001 between groups). Adjusting for baseline LDL-C levels, hazard ratio (HR) for those reaching 2.0-2.5 mmol/l LDL-C versus those reaching <2.0 mmol/l was 1.16 (95% confidence interval [CI], 1.02-1.33, p = 0.023). An increase of the apolipoprotein B/A1 (apoB/A1) ratio by 1 standard deviation in participants who reached 2.0 mmol/l showed a HR for CVD of 1.14 (95% CI, 1.04-1.25, p = 0.004). More CVD patients treated with atorvastatin than simvastatin achieved either LDL-C goal and those reaching the 2.0 mmol/l goal exhibited significantly less CVD than those only reaching 2.5 mmol/l. In those reaching the 2.0 mmol/l goal, the apoB/A1 ratio still bears a relation to CVD outcome. The use of apoB/A1 ratio may provide additional predictive value to that of LDL-C.

Impact of Smoking on Cardiovascular Events in Patients With Coronary Disease Receiving Contemporary Medical Therapy (from the Treating to New Targets [TNT] and the Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL] Trials)

To define the incremental risk of cigarette smoking in patients with coronary disease receiving contemporary medical therapy, we performed a post hoc analysis of 18,885 patients by combining data from the Treating to New Targets (TNT) and the Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) trials. These studies compared high-dose treatment (atorvastatin 80 mg/day) to moderate-dose treatment (atorvastatin 10 mg/day in TNT and simvastatin 20 to 40 mg/day in IDEAL) in patients with established coronary heart disease. The primary end point of this pooled analysis was major cardiovascular events, a composite of cardiac death, myocardial infarction, stroke, or resuscitated cardiac arrest. At baseline 4,196 patients had never smoked, 11,513 were ex-smokers, and 3,176 were current smokers. The adjusted hazard ratio for current smokers compared to never smokers was 1.68 (95% confidence interval 1.46 to 1.94) and that for current smokers compared to ex-smokers was 1.57 (95% confidence interval 1.41 to 1.76). Event rates for current smokers compared to ex-smokers were similarly increased in each treatment group. The difference in absolute event rates between current and ex-smokers in this pooled analysis was 4.5%, which is >2 times as large as the decrease in absolute event rates between high-dose and moderate-dose statin therapy found in the IDEAL (1.7%) and TNT (2.2%) trials, respectively. In conclusion, in patients with coronary disease receiving modern medical therapy, smoking cessation is of substantial benefit with a number needed to treat of 22 to prevent a major cardiovascular event over 5 years. Smoking cessation deserves greater emphasis in secondary prevention.

Intensive lipid lowering in patients with rheumatoid arthritis and previous myocardial infarction: an explorative analysis from the incremental decrease in endpoints through aggressive lipid lowering (IDEAL) trial

Documentation on secondary prevention with statins in RA patients with coronary heart disease (CHD) is limited, despite the increased risk of CHD in RA. Our objective was to describe the effect of statin treatment on lipid levels and cardiovascular disease (CVD) events in patients with RA who participated in the incremental decrease in endpoints through aggressive lipid lowering (IDEAL) study. Patients with previous myocardial infarction (MI) were randomly assigned to atorvastatin 80 mg daily or simvastatin 20-40 mg daily and followed for 4.8 years. We focused on changes in lipid levels in the current exploratory analyses and used the composite secondary endpoint in the IDEAL study: any CVD event. Out of the 8888 patients in the IDEAL study, 87 had RA. RA patients had significantly lower baseline levels of total- and low-density lipoprotein (LDL) cholesterol than patients without RA; 4.8 + 1.0 vs 5.1 + 1.0 (P = 0.023) and 2.9 + 0.9 vs 3.1 + 0.9 mmol/l (P = 0.034) for total cholesterol and LDL, respectively. The lipid reductions with either simvastatin or atorvastatin were comparable. Cardiovascular events occurred in 23/87 (26.4%) of the RA patients compared with 2523/8801 (28.7%; P = 0.70) in the general IDEAL population. The occurrence of these events was not related to the duration of RA, age, gender or treatment assignment. Patients with RA and previous MI had comparable lipid-lowering effect and similar rates of cardiovascular events as those without RA, although the RA patients had lower baseline cholesterol levels than patients without RA.

Increased Coronary Heart Disease Risk Determined by High High-Density Lipoprotein Cholesterol and C-Reactive Protein: Modulation by Variation in the CETP Gene

Epidemiological evidence strongly favors the notion that the risk of cardiovascular disease (CVD) is inversely related to the plasma high-density lipoprotein (HDL) cholesterol concentration.1 Low HDL cholesterol is still predictive of high CVD risk in subjects with low LDL cholesterol,2 as well as during statin treatment.3 These observational data and other studies, which show that HDL particles contain a large number of antioxidative, antiinflammatory, and antiproliferative proteins, underlie the generally held view that HDL particles have atheroprotective properties.1–5 However, evidence is accumulating supporting the concept that high HDL cholesterol levels do not always predict reduced CVD risk. The Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) trial and the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk case-control study revealed that (recurrent) CVD risk is not decreased in subjects with the highest HDL cholesterol and the greatest mean HDL particle size.6 More recently, a high HDL cholesterol, high C-reactive protein (CRP) subgroup of individuals at increased risk for a first cardiovascular event was identified in the community-dwelling Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort using the “outcome event mapping approach,” a graphical exploratory data analysis tool that has been originally developed by Corsetti et al.7 Applying this analytic method to the Thrombogenic Factors and Recurrent Coronary Events (THROMBO) postinfarction cohort, the presence of a subgroup …

Cardiovascular outcomes and their relationships to lipoprotein components in patients with and without chronic kidney disease: results from the IDEAL trial

In Incremental Decrease in Endpoints through Aggressive Lipid-lowering (IDEAL), we compared cardiovascular outcomes in patients with and without chronic kidney disease (CKD) (estimated glomerular filtration rate <60 mL min(-1) 1.73 m(-2)) and analysed relationships between lipoprotein components (LC) and major coronary events (MCE) and other cardiovascular (CV) events. Exploratory analysis of CV endpoints in a randomized trial comparing high dose of atorvastatin to usual dose of simvastatin on MCE. Patients with CKD were compared with the non-CKD patients. Cox regression models were used to study the relationships between on-treatment levels of LC and incident MCE. Chronic kidney disease was strongly associated with cardiovascular end-points including total mortality. In patients with CKD, a significant benefit of high dose atorvastatin treatment was found for any CV events, stroke and peripheral artery disease, but not for MCE. However, all cardiovascular end-points except stroke and CV mortality were reduced in the non-CKD group. Differential changes in LC or relationships to LC could not explain the different treatment outcomes in MCE in the two groups. Chronic kidney disease was a powerful risk factor for all cardiovascular end-points. The reason why the significant reductions achieved by high-dose statin treatment in most CV end-points in the non-CKD group were only in part matched by similar reductions in the CKD patients is not apparent. This difference did not result from differential changes in or relations to LC, but limited power may have increased the possibility of chance findings.

Total Cardiovascular Disease Burden: Comparing Intensive With Moderate Statin Therapy: Insights From the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) Trial

This post-hoc analysis of the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial was designed to assess the comparative treatment efficacy of high-dose atorvastatin and usual-dose simvastatin for the prevention of events subsequent to the first event, using the Wei, Lin, and Weissfeld method. Time-to-first-event analysis of data is frequently utilized to provide efficacy outcome information in coronary heart disease prevention trials. However, during the course of such long-term trials, a large number of events occur subsequent to the first event, the analysis of which will be precluded by this approach. The Wei, Lin, and Weissfeld method allows the analysis of repeated occurrence of events of the same type or of entirely different natures. It regards the recurrence times as multivariate event (failure) times, and models the marginal (individual) distribution for each event with the Cox proportional hazards model. In the IDEAL trial, compared with patients taking simvastatin 20 to 40 mg daily, patients receiving atorvastatin 80 mg daily had their relative risk of a first cardiovascular event reduced by 17% (p < 0.0001), of a second by 24% (p < 0.0001), of a third by 19% (p = 0.035), of a fourth by 24% (p = 0.058), and of a fifth by 28% (p = 0.117). Our results indicate that intensive statin therapy continues to be more effective than standard statin therapy, even beyond the first event, and suggest that clinicians should not hesitate to prescribe high-dose statin therapy for patients experiencing multiple recurrent cardiovascular events.

Economic evaluation of high-dose (80 mg/day) atorvastatin treatment compared with standard-dose (20 mg/day to 40 mg/day) simvastatin treatment in Canada based on the Incremental Decrease in End-Points Through Aggressive Lipid-Lowering (IDEAL) trial

The Incremental Decrease in End-Points Through Aggressive Lipid-Lowering (IDEAL) trial demonstrated incremental cardiovascular benefit of treatment with high-dose atorvastatin (80 mg/ day) versus standard-dose simvastatin (20 mg/day to 40 mg/day) in 8888 patients with a previous myocardial infarction (MI) over a median follow-up period of 4.8 years. To assess the cost-effectiveness of high-dose atorvastatin versus standard-dose simvastatin treatment in patients with a history of MI from a Canadian societal perspective. In a within-trial analysis, end point-related events, resources used and productivity losses occurring during the IDEAL trial were aggregated by treatment arm on an intention-to-treat basis to calculate the incremental cost per event avoided. Additionally, quality-adjusted survival was projected using a lifetime Markov model. Transition probabilities, workdays lost, use of study medication and cardiovascular hospitalization rates were based on IDEAL trial data. Hospitalization, study medication and productivity costs were included. Probabilistic and deterministic sensitivity analyses were performed. Compared with standard-dose simvastatin, atorvastatin 80 mg led to 0.099 fewer events per patient and cost savings over 4.8 years of treatment. Over a lifetime horizon, atorvastatin 80 mg led to 0.023 qualityadjusted life years (QALYs) gained per patient at an incremental cost of $26,795/QALY gained. The incremental cost-effectiveness ratio remained below $50,000/QALY in 78% of 1000 simulations. Exclusion of indirect costs resulted in an incremental cost-effectiveness ratio of $38,834/QALY. Results were relatively sensitive to baseline age, but robust with respect to sex, baseline low-density lipoprotein cholesterol levels, diabetes status and hospitalization costs. From a Canadian societal perspective, high-dose atorvastatin is cost-effective compared with standard-dose simvastatin in patients with a previous MI.

Plasma Triglycerides and Cardiovascular Events in the Treating to New Targets and Incremental Decrease in End-Points Through Aggressive Lipid Lowering Trials of Statins in Patients With Coronary Artery Disease

We determined the ability of in-trial measurements of triglycerides (TGs) to predict new cardiovascular events (CVEs) using data from the Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) and Treating to New Targets (TNT) trials. The trials compared atorvastatin 80 mg/day with moderate-dose statin therapy (simvastatin 20 to 40 mg/day in IDEAL and atorvastatin 10 mg/day in TNT) in patients with clinically evident coronary heart disease or a history of myocardial infarction. The outcome measurement in the present research was CVE occurring after the first year of the trial. After adjusting for age, gender, and study, risk of CVEs increased with increasing TGs (p <0.001 for trend across quintiles of TGs). Patients in the highest quintile had a 63% higher rate of CVEs than patients in the lowest quintile (hazard ratio 1.63, 95% confidence interval 1.46 to 1.81) and the relation of TGs to risk was apparent even within the normal range of TGs. The ability of TG measurements to predict risk decreased when high-density lipoprotein cholesterol and apolipoprotein B:apolipoprotein A-1 were included in the statistical analysis, and it was abolished with inclusion of further variables (diabetes, body mass index, glucose, hypertension, and smoking; (p = 0.044 and 0.621, respectively, for trend across quintiles of TGs). Similar results were obtained in patients in whom low-density lipoprotein cholesterol had been lowered to guideline-recommended levels. In conclusion, even slightly increased TG levels are associated with higher risk of recurrence of CVEs in statin-treated patients and should be considered a useful marker of risk.

Primary Prevention and Statins: Is It Just About Going to Class?

Primary Prevention and Statins: Is It Just About Going to Class?

Beyond LDL-Cholesterol: The Role of Low HDL-Cholesterol and Elevated TG in Residual Cardiovascular Risk Remaining After Statin Therapy

One of the most effective classes of medications for preventing cardiovascular events is 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, more commonly known as statins. Statin therapy has been shown to decrease cardiovascular morbidity and mortality rates in virtually every patient population studied and will likely continue to be a mainstay of cardiovascular risk prevention for years to come. However, close examination of statin clinical trial data reveals that, even though this class of drugs has been highly effective, an unacceptably large number of patients on statins still experience cardiovascular events. For example, in the Scandinavian Simvastatin Survival Study (4S) trial, which studied patients with very high levels of low-density lipoprotein cholesterol (LDL-C and known coronary heart disease (CHD), a significant risk reduction was observed with statin treatment. A greater percentage of patients on placebo (28%) experienced a major cardiovascular event than did patients on statin therapy (19%), and the relative risk of a major cardiovascular event in the statin-treated patients was 0.66.27 On the other hand, those results from 4S also indicate that, over the 5 years of the study, almost 20% of statin-treated patients still had a cardiovascular event. In several major statin trials, significant residual cardiovascular risk remained even after significant reductions in LDL-C had been achieved.27-32 Thus, despite the decrease in cardiovascular events due to statin treatment, two-thirds of the adverse cardiovascular events still occurred, which indicates that both patient lifestyle changes and new pharmacological strategies are necessary to address cardiovascular disease.33 Additional trials have included high-risk patients with CHD or diabetes who were treated with intensive LDL-lowering statin therapy. In 3 of these trials, as shown in Figure 1, lowering LDL-C to approximately 100 mg per dL was compared with more intensive LDL-C lowering to approximately 70 mg per dL to investigate cardiovascular event reduction even in high-risk patient populations.14-16,34 In the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) study, 4,162 patients with acute coronary syndrome (ACS) were treated with either pravastatin 40 mg or atorvastatin 80 mg. Treatment with pravastatin reduced LDL-C to 95 mg per dL, whereas treatment with high-dose atorvastatin reduced LDL-C to 62 mg per dL.14 Clinical events were reduced in the high-dose atorvastatin group versus the pravastatin group; however, over the course of the 2-year trial, 22.4% of the individuals treated with intensive statin therapy (atorvastatin 80 mg) still suffered a major cardiovascular event.14 Similar results have been observed in the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study and the Treating to New Targets (TNT) study. After 4.8 years in the IDEAL study, 12.0% of patients experienced a major cardio vascular event even after intensive LDL-C lowering with 80 mg per day of atorvastatin.16 In the TNT trial, after 4.9 years of follow-up, 8.7% of patients receiving 80 mg per day of atorvastatin still suffered a major cardiovascular event.15 Thus, significant residual cardiovascular risk remains in patients even after intensive statin therapy that achieves LDL-C goals < 100 mg per dL.14-16,34 Patients with diabetes, another high-risk population, show significant cardiovascular risk reduction when treated with statins. A meta-analysis of 14 statin trials by the Cholesterol Treatment Trialists’ Collaborators examined data of major vascular events in patients with diabetes.2 A reduction in LDL-C in individuals with a prior history of CHD and either with or without diabetes was associated with a significant reduction in cardiovascular events. There was a 9% proportional reduction in all-cause mortality per 1 mmol per L (39 mg per dL) reduction in LDL-C in individuals with diabetes (P = 0.02) and a 13% reduction in those without diabetes (P < 0.001). Moreover, there was a significant 21% reduction in major vascular events per 1 mmol per L (39 mg per dL) reduction in LDL-C in people with diabetes (P < 0.001) and those without diabetes (P < 0.001).2 Nonetheless, in patients with diabetes treated with statin therapy, the cardiovascular event rate (i.e., residual cardiovascular risk) remained unacceptably high, and was even higher than the cardiovascular event rate of those patients without diabetes who received placebo.2 It is clear, then, that residual cardiovascular risk remains in all patients treated with statins, and that the residual cardiovascular risk is particularly high in patients with diabetes treated with statins.