Detection of atherosclerotic cardiovascular disease influences the perceived need for aggressive lipid management

Background and aims Overt atherosclerotic cardiovascular disease (ASCVD) warrants aggressive lipid lowering. Imaging for ambiguous symptoms suggesting ischemia or for clarification of CV risk in asymptomatic individuals often uncovers previously unknown ASCVD. Guidelines do not provide clear recommendations for aggressive lipid lowering in such cases. We explored physicians' perception, as influenced by tests that detect ASCVD, regarding appropriateness of getting to lipid goals and for theoretically accessing proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i). Methods A questionnaire was developed including cases of low to high CV risk, chronic kidney disease (CKD) or type 2 diabetes mellitus (T2DM). Each case was considered with or without angina symptoms and, in turn, whether testing identified previously unknown advanced, early/subclinical or no ASCVD. Synthesis of responses was facilitated by using a scale for perceived appropriateness from 1 (lowest) to 9 (highest). Results Getting to goal and, if not achieved by statins and/or ezetimibe, accessing PCSK9i was considered appropriate in patients with T2DM with preclinical or advanced ASCVD, patients with moderate or high CV risk and advanced ASCVD, patients with CKD or low CV risk with angina symptoms and advanced ASCVD. For most of the remaining cases adding PCSK9i was considered only possibly appropriate. Conclusions Physicians' perception of appropriateness for achieving lipid goals, including access to PCSK9i, is markedly influenced by detection of previously unknown ASCVD. Since these commonly encountered scenarios do not clearly meet current indications for PCSK9i, our data identify pressing areas requiring further research

Time-dependent cardiovascular treatment benefit model for lipid-lowering therapies.

Background With the availability of new lipid-lowering therapy options, there is a need to compare the expected clinical benefit of different treatment strategies in different patient populations and over various time frames. We aimed to develop a time-dependent model from published randomized controlled trials summarizing the relationship between low-density lipoprotein cholesterol lowering and cardiovascular risk reduction and to apply the model to investigate the effect of treatment scenarios over time. Methods and Results A cardiovascular treatment benefit model was specified with parameters as time since treatment initiation, magnitude of low-density lipoprotein cholesterol reduction, and additional patient characteristics. The model was estimated from randomized controlled trial data from 22 trials for statins and nonstatins. In 15 trials, the new time-dependent model had better predictions than cholesterol treatment trialists' estimations for a composite of coronary heart disease death, nonfatal myocardial infarction, and ischemic stroke. In explored scenarios, absolute risk reduction ≥2% with intensive treatment with high-intensity statin, ezetimibe, and high-dose proprotein convertase subtilisin/kexin type 9 inhibitor compared with high- or moderate-intensity statin alone were achieved in higher-risk populations with 2 to 5 years of treatment, and lower-risk populations with 9 to 11 years of treatment. Conclusions The time-dependent model accurately predicted treatment benefit seen from randomized controlled trials with a given lipid-lowering therapy by incorporating patient profile, timing, duration, and treatment type. The model can facilitate decision making and scenario analyses with a given lipid-lowering therapy strategy in various patient populations and time frames by providing an improved assessment of treatment benefit over time

Reduction of low density lipoprotein- cholesterol and cardiovascular events with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and statins: an analysis of FOURIER, SPIRE, and the Cholesterol Treatment Trialists Collaboration

Treatment with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors reduce low density lipoprotein cholesterol (LDL-C) by approximately 45–60%, whether used alone or in combination with a statin.1,2 Two large cardiovascular outcomes trials have now reported that lowering LDL-C with a PCSK9 inhibitor when added to treatment with a statin reduces the risk of major cardiovascular events.3,4 We sought to compare the efficacy of PCSK9 inhibitors and statins for reducing the risk of cardiovascular events by comparing the results of the FOURIER and SPIRE trials with the results of the Cholesterol Treatment Trialists (CTT) meta-analysis of statin trials.5,

Associations between lower levels of low-density lipoprotein cholesterol and cardiovascular events in very high-risk patients: Pooled analysis of nine ODYSSEY trials of alirocumab versus control.

BACKGROUND AND AIMS: Guidelines recommend high-intensity statins for patients with atherosclerotic cardiovascular disease (ASCVD). Subgroups with comorbidities that increase cardiovascular risk, such as diabetes mellitus (DM), chronic kidney disease (CKD) or polyvascular disease (PoVD), may derive greater absolute benefit from addition of non-statin therapies. We assessed the relationship between lower low-density lipoprotein cholesterol (LDL-C) and major adverse cardiovascular events (MACE) risk reduction during alirocumab phase III ODYSSEY trials among these subgroups. METHODS: Patient data were pooled from nine trials comparing alirocumab with control (placebo/ezetimibe), predominantly on background maximally tolerated statin. Patients with baseline ASCVD were stratified into subgroups with DM, CKD or PoVD, or without comorbidities, and between-group relative and absolute benefits were compared. RESULTS: Among 3505 patients with ASCVD, 1573 had no comorbidities, 981 had DM, 660 had CKD and 943 had PoVD, with overlap between comorbidities; mean baseline LDL-C levels were 119 (ASCVD overall), 123, 117, 114 and 113 mg/dL, respectively. Overall, each 39 mg/dL lower on-study LDL-C was associated with a 25% lower MACE risk, hazard ratio 0.75 (95% confidence interval, 0.62-0.90, p = 0.0023), with a similar lower risk observed in each very high-risk subgroup (DM, CKD or PoVD; 30-35%) but not in the subgroup without these comorbidities (9%). Absolute benefits were greater for very high-risk subgroups; lowering LDL-C from 120 to 40 mg/dL would result in 2.76-4.35 fewer MACE/100 patient-years versus 0.3 for no comorbidities. CONCLUSIONS: Among patients with ASCVD and mean baseline LDL-C >100 mg/dL, patients with DM, CKD or PoVD appeared to derive greater absolute cardiovascular benefits from further LDL-C reduction than those without

Reductions in Atherogenic Lipids and Major Cardiovascular Events: A Pooled Analysis of 10 ODYSSEY Trials Comparing Alirocumab to Control

BACKGROUND: -A continuous relationship between reductions in low-density lipoprotein cholesterol (LDL-C) and major adverse cardiovascular events (MACE) has been observed in statin and ezetimibe outcomes trials, down to achieved levels of 54 mg/dL. However, it is uncertain whether this relationship extends to LDL-C levels <50 mg/dL. We assessed the relationship between additional LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B100 (apoB) reductions and MACE among patients within the ODYSSEY trials that compared alirocumab versus controls (placebo/ezetimibe), mainly as add on to maximally tolerated statin. METHODS: -Data were pooled from 10 double-blind trials (6699 patient-years follow-up). Randomization was to alirocumab 75/150 mg every 2 weeks or control for 24-104 weeks, added to background statin therapy in 8 trials. This analysis included 4974 patients (3182 alirocumab, 1174 placebo, 618 ezetimibe). In a post hoc analysis, the relationship between average on treatment lipid levels and percent reductions in lipids from baseline were correlated with MACE (coronary heart disease death, non-fatal myocardial infarction [MI], ischemic stroke, or unstable angina requiring hospitalization) using multivariable analyses. RESULTS: -Overall, 33.1% of the pooled cohort achieved average LDL-C <50 mg/dL (44.7-52.6% allocated to alirocumab, 6.5% allocated to ezetimibe, and 0% allocated to placebo). In total, 104 patients experienced MACE (median time to event: 36 weeks). For every 39 mg/dL lower achieved LDL-C, the risk of MACE appeared to be 24% lower (adjusted hazard ratio [HR] 0.76, 95% confidence interval [CI]: 0.63-0.91; P=0.0025). Percent reductions in LDL-C from baseline were inversely correlated with MACE rates (HR 0.71 [0.57 to 0.89] per additional 50% reduction from baseline; P=0.003). Materially similar strengths of association to those described for LDL-C were observed with achieved non-HDL-C and apoB levels or percentage reductions. CONCLUSIONS: -In a post hoc analysis from 10 ODYSSEY trials greater percentage reductions in LDL-C and lower on-treatment LDL-C were associated with a lower incidence of MACE, including very low levels of LDL-C (<50 mg/dL). These findings require further validation in the ongoing prospective ODYSSEY OUTCOMES trial. Clinical Trial Registration-clinicaltrials.gov identifiers: NCT01507831, NCT01623115, NCT01709500, NCT01617655, NCT01644175, NCT01644188, NCT01644474, NCT01730040, NCT01730053, NCT01709513

Lipoprotein(a) reductions from PCSK9 inhibition and major adverse cardiovascular events: Pooled analysis of alirocumab phase 3 trials

Background and aims: Elevated lipoprotein(a) [Lp(a)] levels are considered a causal factor for cardiovascular disease. In phase 3 ODYSSEY trials, alirocumab reduced levels of low-density lipoprotein cholesterol (LDL-C) and Lp(a), with concomitant reductions in the risk of major adverse cardiovascular events (MACE). We assessed whether lower on-study and greater percentage reductions in Lp(a) are associated with a lower risk of MACE. Methods: Post-hoc analysis of data pooled from 10 phase 3 ODYSSEY trials comparing alirocumab with control (placebo or ezetimibe) in patients (n = 4983) with cardiovascular disease and/or risk factors, and hypercholesterolemia despite statin/other lipid-lowering therapies. Results: Median (Q1, Q3) baseline Lp(a) levels were 23.5 (8.0, 67.0) mg/dL. Median Lp(a) changes from baseline with alirocumab were −25.6% vs. −2.5% with placebo (absolute reductions 6.8 vs. 0.5 mg/dL) in placebo-controlled trials, and −21.4% vs. 0.0% with ezetimibe (4.5 vs. 0.0 mg/dL) in ezetimibe-controlled trials. During follow-up (6699 patient-years), 104 patients experienced MACE. A 12% relative risk reduction in MACE per 25% reduction in Lp(a) (p=0.0254) was no longer significant after adjustment for LDL-C changes: hazard ratio per 25% reduction: 0.89 (95% confidence interval, 0.79–1.01; p=0.0780). In subgroup analysis, the association between Lp(a) reduction and MACE remained significant in a fully adjusted model among participants with baseline Lp(a) ≥50 mg/dL (p-interaction vs. Lp(a) < 50 mg/dL: 0.0549). Conclusions: In this population, Lp(a) reductions were not significantly associated with MACE independently of LDL-C reductions. Reducing the risk of MACE by targeting Lp(a) may require greater reductions in Lp(a) with more potent therapies and/or higher initial Lp(a) levels

Lower on-treatment low-density lipoprotein cholesterol and major adverse cardiovascular events in women and men: pooled analysis of 10 ODYSSEY phase 3 alirocumab trials

Background- — In statin trials, men and women derived similar relative risk reductions in cardiovascular events per 39 mg/dL low- density lipoprotein cholesterol (LDL-C) reduction. We explored whether lower LDL-C levels and greater LDL-C percentage reductions than those achieved with statins are associated with reduced major adverse cardiovascular event (MACE) rates in women as well as men. Methods and Results- — Data pooled from 10 phase 3 ODYSSEY randomized trials (n = 4983) comparing alirocumab with control (placebo/ezetimibe) were assessed for association between 39 mg/dL lower on-treatment LDL-C and percentage LDL-C change from baseline, and MACE risk by sex, using multivariable Cox regression. Mean baseline LDL-C was 135 mg/dL (women) and 121 mg/dL (men). Average on-treatment LDL-C levels with alirocumab, ezetimibe, and placebo were 71, 114, and 134 mg/dL, respectively, in women (n = 1882) and 52, 93, and 122 mg/dL, respectively, in men (n = 3090). Overall, 36.5% and 58.7% of women and men, respectively, achieved on-treatment LDL-C < 50 mg/dL. Each 39 mg/dL lower LDL-C was associated with a 33% and 22% lower risk of MACE in women ( P = 0.0209) and men ( P = 0.0307), respectively, with no signi fi cant between-sex difference ( P for heterogeneity = 0.4597). Results were similar when analyzed per 50% LDL-C reduction, 24% ( P = 0.1094) and 29% ( P = 0.0125) lower MACE risk in women and men, respectively ( P for heterogeneity = 0.7499). Alirocumab was generally well tolerated in both sexes. Conclusions- — The present analysis reinforces the notion that both sexes derive a similar cardiovascular bene fi t from LDL-C lowering. Although women had slightly higher on-treatment LDL-C than men, both sexes showed a similar lower MACE risk with lower LDL-C