Incremental Decrease In Endpoints 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.

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.

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.

Effect of intensive lipid‐lowering therapy on cardiovascular outcome in patients with and those without inflammatory joint disease

To examine the effect of intensive lipid-lowering therapy on a composite cardiovascular outcome (cardiovascular disease [CVD]), consisting of mortality and morbidity end points, in patients with inflammatory joint disease (rheumatoid arthritis [RA], ankylosing spondylitis [AS], or psoriatic arthritis [PsA]) by post hoc analysis of 2 prospective trials of statins with a secondary end point of CVD outcome (the Treating to New Targets [TNT] and Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL] studies). Of the 18,889 patients participating in the 2 trials, 199 had RA, 46 had AS, and 35 had PsA. Lipid-lowering therapy consisted of an intensive regimen of atorvastatin 80 mg or a conventional/low-dose regimen of atorvastatin 10 mg or simvastatin 20-40 mg. The median duration of followup was nearly 5 years. Changes in lipid levels were examined by analyses of covariance. The effect on CVD was examined by Cox regression analyses, and heterogeneity tests were performed. Patients with RA and those with AS had lower baseline cholesterol levels than patients without inflammatory joint disease (least squares mean ± SEM 180.7 ± 2.3 mg/dl and 176.5 ± 4.7 mg/dl, respectively, versus 185.6 ± 0.2 mg/dl; P = 0.03 and P = 0.05, respectively). Statin treatment led to a comparable decrease in lipid levels and a 20% reduction in overall risk of CVD in both patients with and those without inflammatory joint disease. Our findings indicate that patients with and those without inflammatory joint disease experience comparable lipid-lowering effects and CVD risk reduction after intensive treatment with statins.

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.

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.

Genetic Association of the CCR5 Region With Lipid Levels in At-Risk Cardiovascular Patients

There is mounting evidence to suggest that chemokine receptor 5 (CCR5) plays an important role in the development and progression of atherosclerosis. A naturally occurring variant of the CCR5 gene CCR532, exists at allele frequencies of typically 10% in European populations and results in a nonfunctional CCR5 receptor. The CCR5Delta32 deletion and 26 other variants within the chemokine receptor 2-CCR5-chemokine receptor-like protein 2 (CCRL2) gene cluster spanning 59 kilobases of chromosome 3 were genotyped in 5748 subjects from the Treating to New Targets atorvastatin trial to determine whether genetic associations could be identified with circulating lipid values and cardiovascular disease. Our results demonstrate an association between the CCR5Delta32 deletion and increased plasma high-density lipoprotein cholesterol and decreased plasma triglycerides, both of which are beneficial from a cardiovascular perspective. Three single-nucleotide polymorphisms (rs1154428, rs6808835, and rs6791599) in CCRL2 in linkage disequilibrium (r(2)> or =0.65) with CCR5Delta32 and located up to 45 kilobases distal to it were associated with high-density lipoprotein cholesterol. The high-density lipoprotein cholesterol and triglycerides findings were replicated in an additional set of >6000 individuals from the Incremental Decrease in Endpoints through Aggressive Lipid Lowering atorvastatin trial. Our study provides evidence that a locus within the region of the genome encompassing the CCR5-CCRL2 region is associated with lipid levels and suggests that chemokine activity influences lipid levels in populations with preexisting cardiovascular disease. CLINICAL TRIAL REGISTRATION- clinicaltrials.gov. Identifier: TNT, NCT00327691; IDEAL, NCT00159835.

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

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

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.

Congestive heart failure is associated with lipoprotein components in statin-treated patients with coronary heart disease: Insights from the Incremental Decrease in End points Through Aggressive Lipid Lowering Trial (IDEAL)

Background Very few, if any, studies have assessed the ability of apolipoproteins to predict new-onset of congestive heart failure (HF) in statin-treated patients with coronary heart disease (CHD). Aims To employ the Incremental Decrease in End points Through Aggressive Lipid Lowering Trial (IDEAL) study database to assess the association of on-treatment lipoprotein components with prediction of HF events and to compare their predictive value with that of established risk factors such as hypertension and diabetes. Methods We used Cox regression models to study the relationships between on-treatment levels of apolipoproteins A1 and B to subsequent HF. Chi square information value from the log likelihood was used to compare the predictive value of lipoprotein components with established risk factors of HF. Findings In the IDEAL study, on-treatment apolipoproteins proved to be associated with the occurrence of new-onset HF. Variables related to low-density lipoprotein cholesterol (LDL-C) carried less predictive information than those related to high-density lipoprotein cholesterol (HDL-C), and apoA-1 was the single variable most strongly associated with HF. LDL-C was less predictive than both non-HDL-C (total cholesterol minus HDL-C) and apoB. The ratio of apoB to apoA-1 was most strongly related to HF after adjustment for potential confounders, among which diabetes had a stronger correlation with HF than did hypertension. ApoB/apoA-1 carried approximately 2.2 times more of the statistical information value than that of diabetes. Calculation of the net reclassification improvement index revealed that about 3.7% of the patients had to be reclassified into more correct categories of risk once apoB/apoA-1 was added to the adjustment factors. The reduction in risk by intensive lipid-lowering treatment as compared to usual-dose simvastatin was well predicted by the difference in apoB/apoA-1 on-treatment levels. Interpretation The on-treatment ratio of apoB/apoA-1 was the strongest predictor of HF in CHD patients of both IDEAL treatment arms combined, mostly driven by the strong association with apoA-1, whereas LDL-C and non-HDL-C were less able to predict HF outcome. The predictive information value contained within apoB/apoA-1 was about 2.2 times more than that of diabetes. Between-treatment group differences in HF were to a significant extent explained by on-treatment differences in apoB/apoA-1, mostly through the changes in apoB. We argue therefore, on-treatment lipoprotein components contribute to the overall future risk of HF in statin-treated patients with CHD.

Promise of Low-Density Lipoprotein–Lowering Therapy for Primary and Secondary Prevention

One of the foremost medical advances of the past 2 decades has been proof that elevated low-density lipoprotein (LDL) is a cause of atherosclerotic cardiovascular disease (ASCVD) and that lowering of LDL levels will reduce risk for ASCVD.1,2 The application of this knowledge in clinical and public health arenas offers the opportunity to greatly reduce morbidity and mortality from ASCVD. This article outlines the rationale underlying this opportunity. Response by Superko and King p 573 Although several major risk factors for ASCVD exist, the realization that elevated plasma LDL is the driving force of atherogenesis highlights the possibilities for prevention. Many studies in laboratory animals have shown that high serum cholesterol levels induce atherosclerotic lesions resembling those found in humans.1 Similarly, humans with severe forms of hypercholesterolemia commonly exhibit premature atherosclerotic disease. Epidemiological studies reveal a strong association between serum cholesterol levels and ASCVD prevalence3; moreover, in populations in which cholesterol levels are low, ASCVD is correspondingly low even when other risk factors are common.4 The latter observation has recently been confirmed through genetic epidemiology; in those persons who carry a mutation causing low cholesterol levels over a lifetime, ASCVD is virtually absent even in the presence of other risk factors.5 Finally, many recent clinical trials have documented that LDL-lowering therapy reduces risk for ASCVD.6 All told, these several lines of evidence indicate that a lifetime of low LDL levels lowers risk for ASCVD by up to 80% to 90% compared with the general population of the United States,5 whereas intensive LDL-lowering therapy even in the presence of advanced atherosclerotic disease reduces risk for major ASCVD events by 40% to 50%.6–8 However, the latter response leaves 50% to 60% of risk untouched; this has called been residual risk. Because of the …

Lipoprotein predictors of cardiovascular events in statin-treated patients with coronary heart disease. Insights from the Incremental Decrease in End-points through Aggressive Lipid-lowering Trial (IDEAL)

Background. Few studies have looked into the ability of measurements of apolipoprotein B (apoB) and apolipoprotein A-1 (apoA-1) or apoB/apoA-1 to predict new coronary heart disease (CHD) events in patients with CHD on statin treatment.Aims. In the IDEAL trial, to compare lipoprotein components to predict CHD events and to what degree differences in those parameters could explain the observed outcome.Methods. We compared the ability of treatment with atorvastatin 80 mg/day to that of simvastatin 20–40 mg/day to prevent CHD events in patients with CHD and used Cox regression models to study the relationships between on-treatment levels of lipoprotein components to subsequent major coronary events (MCE).Findings. Variables related to low-density lipoprotein cholesterol (LDL-C) carried more predictive information than those related to high-density lipoprotein cholesterol (HDL-C), but LDL-C was less predictive than both non-HDL-C and apoB. The ratio of apoB to apoA-1 was most strongly related to MCE. However, for estimating differences in relative risk reduction between the treatment groups, apoB and non-HDL-C were the strongest predictors.Interpretation. The on-treatment level of apoB/apoA-1 was the strongest predictor of MCE in the pooled patient population, whereas apoB and non-HDL-C were best able to explain the difference in outcome between treatment groups. Measurements of apoB and apoA-1 should be more widely available for routine clinical assessments.

What impact will current trial data have on future guideline recommendations?

The current Third Joint European Societies' Guidelines on Cardiovascular Disease Prevention in Clinical Practice reflect an active approach to cardiovascular disease (CVD) prevention. These guidelines have shifted the emphasis from coronary heart disease to total atherosclerotic CVD. A new risk prediction system, Systematic Coronary Risk Evaluation (SCORE), has been developed to define risk in terms of absolute 10-year risk of a fatal cardiovascular event. The definition of high risk has also been refined. The currently recommended goals for total and low-density lipoprotein (LDL) cholesterol are based on the evidence pool that was available at the time of publication. More recent evidence from the Heart Protection Study (HPS), the lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LLA), and the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial indicates that lowering LDL cholesterol levels beyond the currently recommended goals can produce incremental reductions in cardiovascular morbidity and mortality. Results from the recently completed Treating to New Targets (TNT) study lend further support to implementing lower lipid goals than those currently suggested by guidelines. Results from the ongoing Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL) trial may provide additional evidence in support of the implementation of lower lipid goals. Nevertheless, the scope of future guidelines extends well beyond lipid targets. Guidelines of the future are likely to provide increasingly comprehensive recommendations on combined risk reduction, to publicize the characteristics of healthy people by highlighting acceptable levels of all cardiovascular risk factors, and to refine the concept of evidence-based medicine by shifting the focus from drug therapy to preventive therapy.

Reassessment of National Cholesterol Education Program Adult Treatment Panel-III guidelines: one year later

Since the first Adult Treatment Panel (ATP) guidelines from the National Cholesterol Education Program (NCEP), the goals have evolved from national cholesterol awareness and reduction, to the use of increasingly aggressive lipid-lowering strategies in patients at highest risk for coronary heart disease (CHD). The most recent NCEP guidelines from the ATP-III 1 appropriately suggest the most aggressive reduction in low-density lipoprotein (LDL) cholesterol in an expanded group of patients considered to be at highest risk for CHD. Since these guidelines were published approximately 1 year ago, additional clinical trial data suggest that they are already, to a certain extent, out of date. It is now clear that cholesterol reduction may not just need to target certain lipid goals, but also be broadly applied to virtually any individual at high risk for atherosclerotic disease. REDEFINING AN “OPTIMAL” LDL CHOLESTEROL LEVEL The most striking trial data since ATP-III were from the Heart Protection Study (HPS), 2 which assessed the effects of simvastatin 40 mg and/or a combination of antioxidant vitamins versus placebo in a factorial design in 20,536 patients with high risk for CHD. The study population included subjects with history of CHD, other atherosclerotic diseases, and type 2 diabetes mellitus, all consistent with ATP-III “coronary risk equivalent” status. Although the vitamins provided no cardiovascular benefits, simvastatin therapy yielded a 24% mean relative risk reduction in vascular events. Furthermore, this event reduction was maintained whether the baseline LDL cholesterol was above the traditional ATP-III drug cutpoint of 130 mg/dl, in the range for which discretional use of pharmacotherapy is advised (100 to 129 mg/dl), or even below the targeted LDL cholesterol goal of 100 mg/dl. Although the core principle of the NCEP guidelines, the reduction of LDL cholesterol to reduce CHD risk, was validated by HPS, the extent to which this principle should be applied was underestimated by ATP-III. Although LDL cholesterol concentrations 100 mg/dl are considered “optimal” by ATP-III, the findings from HPS suggest high-risk patients benefit from statin therapy even when below this level. Although providing additional guidance for the management of these patients with CHD risk-equivalent status, HPS raises further questions. Has our definition of hyperlipidemia been skewed by the effects of a Westernized diet on lipid levels? Are some nonlipid benefit(s) of statin therapy responsible for the findings of HPS? Do we even need to measure cholesterol in our high-risk patients? Can we grossly simplify the treatment algorithm for high-risk patients by applying an approach similar to HPS? The last question will likely be answered by the Treat to New Targets (TNT) and Incremental Decrease in Endpoints through Aggressive Lipid-lowering (IDEAL) trials, which are currently in progress. These studies will compare the effects of maximal versus conventional doses of simvastatin and atorvastatin in reducing coronary events in large populations. In the interim, it seems prudent to lower LDL cholesterol to 100 mg/dl or by 35% (whichever is greater) utilizing a statin in the setting of CHD risk equivalency.

What does the future hold for diabetic dyslipidaemia?

Preliminary evidence from trials with the HMG-CoA reductase inhibitors (statins), simvastatin and pravastatin, suggests that aggressive treatment of diabetic dyslipidaemia will reduce coronary events. Questions regarding the prevention of cardiovascular events in diabetic patients are now being addressed in prospectively designed trials. The first question is, can aggressive treatment of dyslipidaemia lead to primary prevention of cardiovascular events in patients with type 2 diabetes? This is being addressed in the ongoing Atorvastatin Study for the Prevention of coronary heart disease Endpoints in NIDDM (ASPEN) and the Collaborative AtoRvastatin Diabetes Study (CARDS). These trials will randomize over 4000 patients with type 2 diabetes and no previous myocardial infarction to either atorvastatin or placebo for 4 years. The second question is, are there benefits for aggressive lipid lowering to levels below those recommended in current treatment guidelines, i.e. is lower better? Results from the recent Atorvastatin VErsus Revascularization Treatment (AVERT) trial suggest this to be the case. AVERT showed that, in stable coronary heart disease patients who had been referred for revascularization, aggressive lowering of low density lipoprotein (LDL) cholesterol with atorvastatin 80 mg/day (to a mean level of 2.0 mmol/L [77 mg/dL]) reduced the incidence of ischaemic events by 36% compared with angioplasty and usual care (which reduced LDL cholesterol to 3.1 mmol/L [119 mg/dL]). The 36% reduction in events with atorvastatin versus angioplasty and usual care trended towards significance (p=0.048). The benefits of aggressive lipid-lowering therapy are also being investigated in the ongoing Treating to New Targets (TNT) and Incremental Decrease in Endpoints through Aggressive Lipid lowering (IDEAL) trials. These studies will more closely examine the benefits of treating diabetic dyslipidaemia, and will determine how aggressively this abnormal lipid profile should be treated.

Effect of greater LDL-C reductions on prognosis-the incremental decrease in endpoints through aggressive lipid lowering (IDEAL) trial

Effect of greater LDL-C reductions on prognosis-the incremental decrease in endpoints through aggressive lipid lowering (IDEAL) trial