Estimated individual lifetime benefit from PCSK9 inhibition in statin-treated patients with coronary artery disease.

OBJECTIVE: In statin-treated patients with stable coronary artery disease (CAD), residual risk of cardiovascular events is partly explained by plasma levels of low-density lipoprotein cholesterol (LDL-C). This study aimed to estimate individual benefit of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition in CAD patients already treated with high-dose statin. METHODS: Individual lifetime benefit was estimated in months gain free of stroke or myocardial infarction (MI) until age 80 years. Predictions were based on two competing risk models developed in data from 4853 patients with CAD originating from the atorvastatin 80 mg arm of the Treating to New Targets (TNT) trial. The relative effect of PCSK9 inhibition was added to the models and was assumed based on average estimates from large clinical trials. We accounted for individual LDL-C levels, assuming 50% LDL-C reduction by PCSK9 inhibition and 21% cardiovascular risk reduction per mmol/L (39 mg/dL) LDL-C lowering. RESULTS: Estimated individual gain was <6 months in 61% of the patients, 6-12 months in 28% of the patients and ≥12 months in 10% of the patients (median 5, quartiles 2-8 months). Highest estimated benefit was observed in younger patients (aged 40-60 years) with high risk factor burden, particularly if LDL-C levels were >1.8 mmol/L (>70 mg/dL). Estimated benefit was lowest (≤5 months) in older patients (≥70 years), in particular if LDL-C and other risk factors levels were low. CONCLUSION: The individual estimated lifetime benefit from PCSK9 inhibition in patients with stable CAD on high-dose statin varied from <6 to ≥12 months free of stroke or MI. Highest benefit is expected in younger patients (age 40-60 years) with high risk factor burden and relatively high LDL-C levels. TRIAL REGISTRATION NUMBER: NCT00327691; Post-results.

High-dose atorvastatin is superior to moderate-dose simvastatin in preventing peripheral arterial disease.

OBJECTIVES: To study whether high-dose versus usual-dose statin treatment reduces the incidence of peripheral artery disease (PAD) and what is the effect of high-dose statin treatment on cardiovascular disease (CVD) outcome in patients with PAD. METHODS AND RESULTS: In the Incremental Decrease in End Points Through Aggressive Lipid Lowering trial, 8888 post-myocardial infarction patients were randomised to high-dose or usual-dose statin therapy (atorvastatin 80 mg/day vs simvastatin 20-40 mg/day). We investigated the effect of high-dose versus usual-dose statins on the pre-specified outcome PAD incidence, and additionally performed a posthoc analysis of the efficacy of high-dose statins in reducing CVD risk among patients with PAD. During a median follow-up of 4.8 years, 94 patients (2.2%) receiving atorvastatin and 135 patients (3.2%) receiving simvastatin developed PAD (HR=0.70, 95% CI 0.53 to 0.91; p=0.007). The risk of major coronary events was almost twofold higher in patients with PAD at baseline, but was no longer significant after adjusting for the adverse cardiovascular risk profile. In PAD patients, major coronary events occurred in fewer patients in the atorvastatin group (14.4%) than in the simvastatin group (20.1%), but the difference did not reach statistical significance. (HR=0.68, 95% CI 0.41 to 1.11; p=0.13). Atorvastatin treatment significantly reduced overall cardiovascular (p=0.046) and coronary events (p=0.004), and coronary revascularisation (p=0.007) in these patients. CONCLUSIONS: High-dose statin therapy with atorvastatin significantly reduced the incidence of PAD compared with usual-dose statin therapy with simvastatin. Patients with a history of PAD at baseline were at higher risk of future coronary events and this risk was reduced by high-dose atorvastatin treatment. TRIAL REGISTRATION NUMBER: NCT00159835 (URL: http://clinicaltrials.gov/show/NCT00159835).

Impact of high-dose atorvastatin therapy and clinical risk factors on incident aortic valve stenosis in patients with cardiovascular disease (from TNT, IDEAL, and SPARCL).

Clinical trials have not provided evidence for a role of statin therapy in reducing aortic valve stenosis (AVS) severity in patients with documented AVS. However, whether statin therapy could prevent the onset of AVS is unknown. Our objectives were (1) to compare the incidence rates of AVS among patients treated with high-dose versus usual-dose statin or placebo and (2) to identify clinical risk factors associated with the development of AVS. We conducted post hoc analyses in 23,508 participants from 3 large-scale multicenter atorvastatin randomized blinded clinical trials: Treating to New Targets, the Incremental Decrease in End Points Through Aggressive Lipid Lowering, and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels. The main outcome measure was the incidence of clinical AVS over a median follow-up of 4.9 years (82 cases). Among patients who developed AVS, 39 (47.6%) were treated with atorvastatin 80 mg and 43 (52.4%) were treated with lower dose statin (atorvastatin 10 mg in Treating to New Targets, simvastatin 20 to 40 mg in Incremental Decrease in End Points Through Aggressive Lipid Lowering, or placebo in Stroke Prevention by Aggressive Reduction in Cholesterol Levels; hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.59 to 1.41, p=0.67). In multivariate analyses forcing treatment, sex, and race into the model, factors that were significantly associated with AVS included age (HR 2.17, 95% CI 1.61 to 2.93, p<0.0001 per 1-SD increment), diabetes (HR 1.67, 95% CI 1.00 to 2.80, p=0.05), vitamin K antagonist use (HR 3.25, 95% CI 2.06 to 5.16, p<0.0001), and previous statin use (HR 2.65, 95% CI 1.54 to 4.60, p=0.0008). In conclusion, random allocation to high-dose versus usual-dose statin therapy or placebo did not impact the incidence of AVS among patients without known AVS. Age, diabetes, vitamin K antagonists, and previous statin use were significant predictors of incident AVS in these high-risk patients.

On-treatment non-high-density lipoprotein cholesterol, apolipoprotein B, triglycerides, and lipid ratios in relation to residual vascular risk after treatment with potent statin therapy: JUPITER (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin).

OBJECTIVES: The goal of this study was to determine whether residual risk after high-dose statin therapy for primary prevention individuals with reduced levels of low-density lipoprotein cholesterol (LDL-C) is related to on-treatment apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL-C), trigylcerides, or lipid ratios, and how they compare with on-treatment LDL-C. BACKGROUND: Guidelines focus on LDL-C as the primary target of therapy, yet residual risk for cardiovascular disease (CVD) among statin-treated individuals remains high and not fully explained. METHODS: Participants in the randomized placebo-controlled JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) trial were adults without diabetes or CVD, with baseline LDL-C levels <130 mg/dl, high-sensitivity C-reactive protein levels ≥2 mg/l, and triglyceride concentrations <500 mg/dl. Individuals allocated to receive rosuvastatin 20 mg daily with baseline and on-treatment lipids and lipoproteins were examined in relation to the primary endpoint of incident CVD (nonfatal myocardial infarction or stroke, hospitalization for unstable angina, arterial revascularization, or cardiovascular death). RESULTS: Using separate multivariate Cox models, statistically significant associations of a similar magnitude with residual risk of CVD were found for on-treatment LDL-C, non-HDL-C, apolipoprotein B, total cholesterol/HDL-C, LDL-C/HDL-C, and apolipoprotein B/A-I. The respective adjusted standardized hazard ratios (95% confidence intervals) for each of these measures were 1.31 (1.09 to 1.56), 1.25 (1.04 to 1.50), 1.27 (1.06 to 1.53), 1.22 (1.03 to 1.44), 1.29 (1.09 to 1.52), and 1.27 (1.09 to 1.49). The overall residual risk and the risk associated with these measures decreased among participants achieving on-treatment LDL-C ≤70 mg/dl, on-treatment non-HDL-C ≤100 mg/dl, or on-treatment apolipoprotein B ≤80 mg/dl. In contrast, on-treatment triglycerides showed no association with CVD. CONCLUSIONS: In this primary prevention trial of nondiabetic individuals with low LDL-C and elevated high-sensitivity C-reactive protein, on-treatment LDL-C was as valuable as non-HDL-C, apolipoprotein B, or ratios in predicting residual risk. (JUPITER-Crestor 20mg Versus Placebo in Prevention of Cardiovascular [CV] Events; NCT00239681).

Determinants of residual risk in secondary prevention patients treated with high- versus low-dose statin therapy: the Treating to New Targets (TNT) study.

BACKGROUND: Cardiovascular events occur among statin-treated patients, albeit at lower rates. Risk factors for this "residual risk" have not been studied comprehensively. We aimed to identify determinants of this risk above and beyond lipid-related risk factors. METHODS AND RESULTS: A total of 9251 coronary patients with low-density lipoprotein cholesterol <130 mg/dL randomized to double-blind atorvastatin 10 or 80 mg/d in the Treating to New Targets (TNT) study had complete on-treatment 1-year lipid data. Median follow-up was 4.9 years. The primary end point was major cardiovascular events (n=729): coronary death, nonfatal myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke. Multivariable determinants of increased risk were older age (adjusted hazard ratio [aHR], 1.13 per 1 SD [8.8 years]; 95% confidence interval [CI], 1.04-1.23), increased body mass index (aHR, 1.09; 95% CI, 1.02-1.17 per 4.5 kg/m(2)), male sex (aHR, 1.33; 95% CI, 1.07-1.65), hypertension (aHR, 1.38; 95% CI, 1.17-1.63), diabetes mellitus (aHR, 1.33; 95% CI, 1.11-1.60), baseline apolipoprotein B (aHR, 1.19; 95% CI, 1.11-1.28 per 19 mg/dL), and blood urea nitrogen (aHR, 1.10; 95% CI, 1.03-1.17 per 4.9 mg/dL), in addition to current smoking, prior cardiovascular disease, and calcium channel blocker use. Determinants of decreased risk were high-dose statin (aHR, 0.82; 95% CI, 0.70-0.94), aspirin use (aHR, 0.67; 95% CI, 0.56-0.81), and baseline apolipoprotein A-I (aHR, 0.91; 95% CI, 0.84-0.99 per 25 mg/dL). On-treatment 1-year lipids or apolipoproteins were not additionally associated with risk in multivariable models. Known baseline variables performed moderately well in discriminating future cases from noncases (Harrell c index=0.679). CONCLUSIONS: Determinants of residual risk in statin-treated secondary prevention patients included lipid-related and nonlipid factors such as baseline apolipoproteins, increased body mass index, smoking, hypertension, and diabetes mellitus. A multifaceted prevention approach should be underscored to address this risk. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00327691.

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.

BACKGROUND: 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. METHODS AND RESULTS: 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). CONCLUSIONS: 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.

HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial.

BACKGROUND: HDL-cholesterol concentrations are inversely associated with occurrence of cardiovascular events. We addressed, using the JUPITER trial cohort, whether this association remains when LDL-cholesterol concentrations are reduced to the very low ranges with high-dose statin treatment. METHODS: Participants in the randomised placebo-controlled JUPITER trial were adults without diabetes or previous cardiovascular disease, and had baseline concentrations of LDL cholesterol of less than 3.37 mmol/L and high-sensitivity C-reactive protein of 2 mg/L or more. Participants were randomly allocated by a computer-generated sequence to receive rosuvastatin 20 mg per day or placebo, with participants and adjudicators masked to treatment assignment. In the present analysis, we divided the participants into quartiles of HDL-cholesterol or apolipoprotein A1 and sought evidence of association between these quartiles and the JUPITER primary endpoint of first non-fatal myocardial infarction or stroke, hospitalisation for unstable angina, arterial revascularisation, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT00239681. FINDINGS: For 17,802 patients in the JUPITER trial, rosuvastatin 20 mg per day reduced the incidence of the primary endpoint by 44% (p<0.0001). In 8901 (50%) patients given placebo (who had a median on-treatment LDL-cholesterol concentration of 2.80 mmol/L [IQR 2.43-3.24]), HDL-cholesterol concentrations were inversely related to vascular risk both at baseline (top quartile vs bottom quartile hazard ratio [HR] 0.54, 95% CI 0.35-0.83, p=0.0039) and on-treatment (0.55, 0.35-0.87, p=0.0047). By contrast, among the 8900 (50%) patients given rosuvastatin 20 mg (who had a median on-treatment LDL-cholesterol concentration of 1.42 mmol/L [IQR 1.14-1.86]), no significant relationships were noted between quartiles of HDL-cholesterol concentration and vascular risk either at baseline (1.12, 0.62-2.03, p=0.82) or on-treatment (1.03, 0.57-1.87, p=0.97). Our analyses for apolipoprotein A1 showed an equivalent strong relation to frequency of primary outcomes in the placebo group but little association in the rosuvastatin group. INTERPRETATION: Although measurement of HDL-cholesterol concentration is useful as part of initial cardiovascular risk assessment, HDL-cholesterol concentrations are not predictive of residual vascular risk among patients treated with potent statin therapy who attain very low concentrations of LDL cholesterol. FUNDING: AstraZeneca.