Impact of Bempedoic Acid on Total Cardiovascular Events: A Prespecified Analysis of the CLEAR Outcomes Randomized Clinical Trial.

Importance: The ATP citrate lyase (ACL) inhibitor, bempedoic acid, reduces low-density lipoprotein cholesterol (LDL-C) level and major adverse cardiovascular events (MACE) by 13% in patients at high cardiovascular risk with intolerance of statin and high-intensity statin medications. The effects of bempedoic acid on total cardiovascular events remain unknown. Objective: To determine the impact of bempedoic acid on the total incidence of MACE. Design, Setting, and Participants: Included in this prespecified analysis of the Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes trial were patients with, or at high risk for, cardiovascular disease, with hypercholesterolemia and inability to take guideline-recommended statins. Study data were analyzed from December 2016 to November 2022. Interventions: Patients were randomly assigned to treatment with bempedoic acid or placebo daily. Main Outcomes and Measures: The primary end point was the time to first event for a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization (MACE-4). The key secondary end point was time to first event for cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke (MACE-3). This prespecified analysis compared the total number of cardiovascular events in the treatment groups. Results: A total of 13 970 patients (mean [SD] age, 65 [9] years; 7230 male [51.8%]) were included in the study. A total of 9764 participants (69.9%) had prior atherosclerotic cardiovascular disease and a baseline LDL-C level of 139 mg/dL; treatment with bempedoic acid resulted in a 21% reduction in LDL-C level and a 22% reduction in high-sensitivity C-reactive protein (hsCRP) level at 6 months. Median (IQR) follow-up was 3.4 (3.1-3.9) years. A total of 1746 positively adjudicated first MACE-4 events and 915 additional MACE events in 612 patients were recorded, with coronary revascularization representing 32.8% (573 of 1746) of first events and 69.4% (635 of 915) of additional events. For the total incidence of cardiovascular events, treatment with bempedoic acid was associated with a reduction in risk of MACE-4 (hazard ratio [HR], 0.80; 95% CI, 0.72-0.89; P <.001), MACE-3 (HR, 0.83; 95% CI, 0.73-0.93; P = .002), myocardial infarction (HR, 0.69; 95% CI, 0.58-0.83; P < .001), and coronary revascularization (HR, 0.78; 95% CI, 0.68-0.89; P <.001), although no statistically significant difference was observed for stroke (HR, 0.80; 95% CI, 0.63-1.03). A lower HR for protection with bempedoic acid was observed with increasing number of MACE events experienced by patients. Conclusion and Relevance: Lowering LDL-C level with bempedoic acid reduced the total number of cardiovascular events in patients with high cardiovascular risk, statin therapy intolerance, and elevated LDL-C levels.

Efficacy and safety of bempedoic acid among patients with and without diabetes: prespecified analysis of the CLEAR Outcomes randomised trial.

BACKGROUND: Statins reduce LDL cholesterol and cardiovascular events among those with or without diabetes but have been reported to increase new-onset diabetes. The CLEAR Outcomes trial demonstrated that bempedoic acid reduced the risk of major adverse cardiovascular events among statin-intolerant patients at high cardiovascular risk. In this prespecified analysis, our dual aims were to evaluate the cardiovascular benefits of bempedoic acid, an ATP-citrate lyase inhibitor, in individuals with diabetes, and to evaluate the risk of new-onset diabetes and HbA1c among those without diabetes in the CLEAR Outcomes trial. METHODS: CLEAR Outcomes was a randomised, double-blind, placebo-controlled trial conducted across 1250 primary care and outpatient sites in 32 countries. Patients with or without cardiovascular disease who were unwilling or unable to take guideline-recommended doses of statins and an LDL cholesterol of 2·59 mmol/L or more were randomly assigned (1:1) in a double-blinded manner to either bempedoic acid 180 mg once per day or placebo. In this prespecified analysis, the efficacy endpoint was a time-to-event analysis of four-component major adverse cardiovascular event (MACE-4), which is the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularisation, using the intention-to-treat population stratified by baseline glycaemia status. The prespecified analysis of risk of new-onset diabetes and HbA1c increase was evaluated in patients without diabetes at baseline. The CLEAR Outcomes trial was completed on Nov 7, 2022, and is registered with ClinicalTrials.gov (NCT02993406). FINDINGS: Between Dec 22, 2016, and Nov 7, 2022, 13 970 patients were screened and randomly assigned; 6373 (45·6%) with diabetes, 5796 (41·5%) with prediabetes, and 1801 (12·9%) with normoglycaemia. Over a median of 3·4 years follow up, patients with diabetes had significant relative and absolute cardiovascular risk reductions in MACE-4 endpoints with bempedoic acid (HR 0·83; 95% CI 0·72-0·95; absolute risk reduction of 2·4%) compared to placebo, with no statistical evidence of effect modification across glycaemic strata (interaction p=0·42). The proportion of patients who developed new-onset diabetes were similar between the bempedoic acid and placebo groups, with 429 of 3848 (11·1%) with bempedoic acid versus 433 of 3749 (11·5%) with placebo (HR 0·95; 95% CI 0·83-1·09). HbA1c concentrations at month 12 and the end of the study were similar between randomised groups in patients who had prediabetes and normoglycaemia. Placebo-corrected LDL cholesterol concentrations and high-sensitivity C-reactive protein at 6 months were reduced in each glycaemic stratum (diabetes, prediabtes, and normoglycaemia) for patients randomly assigned to bempedoic acid (all p<0·001). INTERPRETATION: Among patients with diabetes, bempedoic acid reduces LDL cholesterol and high-sensitivity C-reactive protein and risk of cardiovascular events. Patients without diabetes had no increase in new-onset diabetes or worsening HbA1c with bempedoic acid. The efficacy and cardiometabolic safety profile of bempedoic acid makes it a clinical option for those with and without diabetes. FUNDING: Esperion Therapeutics.

Bempedoic Acid for Primary Prevention of Cardiovascular Events in Statin-Intolerant Patients.

Importance: The effects of bempedoic acid on cardiovascular outcomes in statin-intolerant patients without a prior cardiovascular event (primary prevention) have not been fully described. Objective: To determine the effects of bempedoic acid on cardiovascular outcomes in primary prevention patients. Design, Setting, and Participants: This masked, randomized clinical trial enrolled 13 970 statin-intolerant patients (enrollment December 2016 to August 2019 at 1250 centers in 32 countries), including 4206 primary prevention patients. Interventions: Participants were randomized to oral bempedoic acid, 180 mg daily (n = 2100), or matching placebo (n = 2106). Main Outcome Measures: The primary efficacy measure was the time from randomization to the first occurrence of any component of a composite of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary revascularization. Results: Mean participant age was 68 years, 59% were female, and 66% had diabetes. From a mean baseline of 142.2 mg/dL, compared with placebo, bempedoic acid reduced low-density lipoprotein cholesterol levels by 30.2 mg/dL (21.3%) and high-sensitivity C-reactive protein levels by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L. Follow-up for a median of 39.9 months was associated with a significant risk reduction for the primary end point (111 events [5.3%] vs 161 events [7.6%]; adjusted hazard ratio [HR], 0.70 [95% CI, 0.55-0.89]; P = .002) and key secondary end points, including the composite of cardiovascular death, MI, or stroke (83 events [4.0%] vs 134 events [6.4%]; HR, 0.64 [95% CI, 0.48-0.84]; P < .001); MI (29 events [1.4%] vs 47 events [2.2%]; HR, 0.61 [95% CI, 0.39-0.98]); cardiovascular death (37 events [1.8%] vs 65 events [3.1%]; HR, 0.61 [95% CI, 0.41-0.92]); and all-cause mortality (75 events [3.6%] vs 109 events [5.2%]; HR, 0.73 [95% CI, 0.54-0.98]). There was no significant effect on stroke or coronary revascularization. Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels. Conclusions: In a subgroup of high-risk primary prevention patients, bempedoic acid treatment was associated with reduced major cardiovascular events. Trial Registration: ClinicalTrials.gov Identifier: NCT02993406.

Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients.

BACKGROUND: Bempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events; its effects on cardiovascular outcomes remain uncertain. METHODS: We conducted a double-blind, randomized, placebo-controlled trial involving patients who were unable or unwilling to take statins owing to unacceptable adverse effects ("statin-intolerant" patients) and had, or were at high risk for, cardiovascular disease. The patients were assigned to receive oral bempedoic acid, 180 mg daily, or placebo. The primary end point was a four-component composite of major adverse cardiovascular events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. RESULTS: A total of 13,970 patients underwent randomization; 6992 were assigned to the bempedoic acid group and 6978 to the placebo group. The median duration of follow-up was 40.6 months. The mean LDL cholesterol level at baseline was 139.0 mg per deciliter in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg per deciliter; the observed difference in the percent reductions was 21.1 percentage points in favor of bempedoic acid. The incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients [11.7%] vs. 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P = 0.004), as were the incidences of a composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (575 [8.2%] vs. 663 [9.5%]; hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P = 0.006); fatal or nonfatal myocardial infarction (261 [3.7%] vs. 334 [4.8%]; hazard ratio, 0.77; 95% CI, 0.66 to 0.91; P = 0.002); and coronary revascularization (435 [6.2%] vs. 529 [7.6%]; hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = 0.001). Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause. The incidences of gout and cholelithiasis were higher with bempedoic acid than with placebo (3.1% vs. 2.1% and 2.2% vs. 1.2%, respectively), as were the incidences of small increases in serum creatinine, uric acid, and hepatic-enzyme levels. CONCLUSIONS: Among statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization). (Funded by Esperion Therapeutics; CLEAR Outcomes ClinicalTrials.gov number, NCT02993406.).

Comparative Effects of Low-Dose Rosuvastatin, Placebo, and Dietary Supplements on Lipids and Inflammatory Biomarkers.

BACKGROUND: Supplements are commonly used by individuals with indications for lipid-lowering therapy, but evidence of their effectiveness to lower low-density lipoprotein cholesterol (LDL-C) is lacking, particularly when compared with statins. OBJECTIVES: The trial objective was to compare the efficacy of a low-dose statin with placebo and 6 common supplements in impacting lipid and inflammatory biomarkers. METHODS: This was a single-center, prospective, randomized, single-blind clinical trial among adults with no history of atherosclerotic cardiovascular disease (ASCVD), an LDL-C of 70 to 189 mg/dL, and an increased 10-year risk of ASCVD. Participants were randomized to rosuvastatin 5 mg daily, placebo, fish oil, cinnamon, garlic, turmeric, plant sterols, or red yeast rice. The primary endpoint was the percent change in LDL-C from baseline for rosuvastatin 5 mg daily compared with placebo and each supplement after 28 days. The primary endpoint was evaluated in a hierarchical fashion with rosuvastatin first compared with placebo, then each supplement in a prespecified order using analysis of covariance. RESULTS: A total of 190 participants completed the study. The percent LDL-C reduction with rosuvastatin was greater than all supplements and placebo (P < 0.001). The difference in LDL-C reduction with rosuvastatin compared with placebo was -35.2% (95% CI: -41.3% to -29.1%; P < 0.001). None of the dietary supplements demonstrated a significant decrease in LDL-C compared with placebo. Adverse event rates were similar across study groups. CONCLUSIONS: Among individuals with increased 10-year risk for ASCVD, rosuvastatin 5 mg daily lowered LDL-C significantly more than placebo, fish oil, cinnamon, garlic, turmeric, plant sterols, and red yeast rice. (Supplements, Placebo, or Rosuvastatin Study [SPORT]; NCT04846231).

Erratum to "C-Reactive Protein Levels and Plaque Regression with Evolocumab: Insights From GLAGOV" [American Journal of Preventive Cardiology 3C (2020) 100091].

[This corrects the article DOI: 10.1016/j.ajpc.2020.100091.].

Double-blind randomized proof-of-concept trial of canakinumab in patients with COVID-19 associated cardiac injury and heightened inflammation.

Aims: In coronavirus disease 2019 (COVID-19), myocardial injury is associated with systemic inflammation and higher mortality. Our aim was to perform a proof of concept trial with canakinumab, a monoclonal antibody to interleukin-1ß, in patients with COVID-19, myocardial injury, and heightened inflammation. Methods and results: This trial required hospitalization due to COVID-19, elevated troponin, and a C-reactive protein concentration more than 50 mg/L. The primary endpoint was time to clinical improvement at Day 14, defined as either an improvement of two points on a seven-category ordinal scale or discharge from the hospital. The secondary endpoint was mortality at Day 28. Forty-five patients were randomly assigned to canakinumab 600 mg (n = 15), canakinumab 300 mg (n = 14), or placebo (n = 16). There was no difference in time to clinical improvement compared to placebo [recovery rate ratio (RRR) for canakinumab 600 mg 1.15, 95% confidence interval (CI) 0.46-2.91; RRR for canakinumab 300 mg 0.61, 95% CI 0.23-1.64]. At Day 28, 3 (18.8%) of 15 patients had died in the placebo group, compared with 3 (21.4%) of 14 patients with 300 mg canakinumab, and 1 (6.7%) of 15 patients with 600 mg canakinumab. There were no treatment-related deaths, and adverse events were similar between groups. Conclusion: There was no difference in time to clinical improvement at Day 14 in patients treated with canakinumab, and no safety concerns were identified. Future studies could focus on high dose canakinumab in the treatment arm and assess efficacy outcomes at Day 28.

Canakinumab to reduce deterioration of cardiac and respiratory function in SARS-CoV-2 associated myocardial injury with heightened inflammation (canakinumab in Covid-19 cardiac injury: The three C study).

BACKGROUND: In patients with Covid-19, myocardial injury and increased inflammation are associated with morbidity and mortality. We designed a proof-of-concept randomized controlled trial to evaluate whether treatment with canakinumab prevents progressive respiratory failure and worsening cardiac dysfunction in patients with SARS-CoV2 infection, myocardial injury, and high levels of inflammation. HYPOTHESIS: The primary hypothesis is that canakiumab will shorten time to recovery. METHODS: The three C study (canakinumab in Covid-19 Cardiac Injury, NCT04365153) is a double-blind, randomized controlled trial comparing canakinumab 300 mg IV, 600 mg IV, or placebo in a 1:1:1 ratio in hospitalized Covid-19 patients with elevations in troponin and C-reactive protein (CRP). The primary endpoint is defined as the time in days from randomization to either an improvement of two points on a seven category ordinal scale or discharge from the hospital, whichever occurs first up to 14 days postrandomization. The secondary endpoint is mortality at day 28. A total of 45 patients will be enrolled with an anticipated 5 month follow up period. RESULTS: Baseline characteristics for the first 20 randomized patients reveal a predominantly male (75%), elderly population (median 67 years) with a high prevalence of hypertension (80%) and hyperlipidemia (75%). CRPs have been markedly elevated (median 16.2 mg/dL) with modest elevations in high-sensitivity troponin T (median 21 ng/L), in keeping with the concept of enrolling patients with early myocardial injury. CONCLUSIONS: The three C study will provide insights regarding whether IL-1ß inhibition may improve outcomes in patients with SARS-CoV2 associated myocardial injury and increased inflammation.

C-reactive protein levels and plaque regression with evolocumab: Insights from GLAGOV.

OBJECTIVE: On-treatment levels of high sensitivity C-reactive protein (hsCRP) in statin-treated patients predict plaque progression and the prospective risk of atherosclerotic cardiovascular events. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors produce additional LDL-C lowering, reduce plaque burden and improve cardiovascular outcomes in statin-treated patients. It is unknown whether residual systemic inflammation attenuates their favorable effects on plaque burden. METHODS: GLAGOV compared the effects of treatment for 78 weeks with evolocumab or placebo on progression of coronary atherosclerosis in statin-treated patients with coronary artery disease.Clinical demographics, biochemistry and changes in both the burden (percentage atheroma volume (PAV), total atheroma volume (TAV), n â€‹= â€‹413) and composition (n â€‹= â€‹162) of coronary plaque were evaluated in evolocumab-treated patients according to baseline hsCRP strata (<1, 1-3, >3 â€‹mg/L). RESULTS: The study cohort comprised 413 evolocumab-treated patients (32% low [<1 â€‹mg/L], 41% intermediate [1-3 â€‹mg/L] and 27% high [>3 â€‹mg/L] baseline hsCRP levels). Patients in the highest hsCRP stratum were more likely to be female and had a higher prevalence of diabetes, hypertension, and the metabolic syndrome. LDL-C levels were similar across the groups, however participants with higher hsCRP levels had higher triglyceride and lower HDL-C levels at baseline. At follow-up, the change in PAV from baseline (-0.87% [low] vs. -0.84% [intermediate] vs. -1.22% [high], p â€‹= â€‹0.46) and the proportion of patients experiencing any degree of regression (65.9% vs. 63.5% vs. 63.1%, p â€‹= â€‹0.88) was similar across hsCRP strata and when evaluated by levels of achieved LDL-C. There were no serial differences in plaque composition by hsCRP strata. CONCLUSION: The ability of evolocumab to induce regression in statin-treated patients is not attenuated by the presence of enhanced systemic inflammation. This underscores the potential benefits of intensive lipid lowering, even in the presence of heightened inflammatory states.

Remnant cholesterol, coronary atheroma progression and clinical events in statin-treated patients with coronary artery disease.

AIM: Remnant cholesterol has been proposed to promote atherosclerotic cardiovascular disease independent of low-density lipoprotein cholesterol, yet the underlying mechanisms are not well understood. We aimed to study the association of remnant cholesterol with coronary atheroma progression and clinical events. METHODS: We analyzed data from 5754 patients with coronary artery disease undergoing serial intravascular ultrasonography who were enrolled in 10 trials examining various medical therapies. Remnant cholesterol was calculated as (non-high-density lipoprotein cholesterol - low-density lipoprotein cholesterol (estimated using the Hopkins-Martin equation)). Changes in percentage atheroma volume and 2-year major adverse cardiovascular events were compared across various levels of remnant cholesterol, and multivariable models were used to assess the independent relationship of remnant cholesterol with changes in percentage atheroma volume. RESULTS: The mean age was 58.1 ± 9.2 years, 28% were women and 96% received a statin. Percentage atheroma volume progression (changes in percentage atheroma volume > 0) occurred in a linear fashion at on-treatment remnant cholesterol levels of 25 mg/dL or greater. The highest on-treatment remnant cholesterol quartile demonstrated greater percentage atheroma volume progression (+0.53 ± 0.26 vs. -0.15 ± 0.25%, P < 0.001) and 2-year major adverse cardiovascular events (23% vs. 14%, log-rank P < 0.001) compared with the lowest. In multivariable analyses, changes in percentage atheroma volume significantly correlated with on-treatment remnant cholesterol (P < 0.001] independent of low-density lipoprotein cholesterol, apolipoprotein B, C-reactive protein, high-density lipoprotein cholesterol levels and clinical risk factors. Changes in percentage atheroma volume also significantly correlated with changes in remnant cholesterol following multivariable adjustment. CONCLUSIONS: In statin-treated patients with atherosclerotic cardiovascular disease, remnant cholesterol was associated with coronary atheroma progression regardless of conventional lipid parameters, C-reactive protein or clinical risk factors. Higher remnant cholesterol levels also correlated with higher major adverse cardiovascular events. These data support further investigations into remnant cholesterol-lowering interventions in statin-treated patients harboring residual atherosclerotic cardiovascular disease risk.

Plasma Aldosterone Levels Are Not Associated With Cardiovascular Events Among Patients With High-Risk Vascular Disease: Insights From the ACCELERATE Trial.

Background The failure of cholesteryl ester transfer protein inhibitor torcetrapib was associated with an off-target increase in plasma aldosterone. We sought to evaluate the impact of evacetrapib on plasma aldosterone level and determine the association between plasma aldosterone level and major adverse cardiovascular events among patients with stable high-risk vascular disease enrolled in the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial. Methods and Results We included all patients with a plasma aldosterone level (N=1624) and determined the impact of evacetrapib exposure compared with placebo on plasma aldosterone levels after 12 months of treatment. Using baseline and postexposure aldosterone levels, hazard ratios for major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, cerebrovascular accident, hospitalization for unstable angina, and revascularization) with increasing quartile of baseline and percentage change in plasma aldosterone level at follow-up were calculated. The average age was 65.2 years, 75.7% were men, 93.7% were hypertensive, 73.3% were diabetic, and 57.6% had a prior myocardial infarction. Baseline plasma aldosterone level (85.2 [43, 150] versus 86.8 [43, 155] pmol/L; P=0.81) and follow-up percentage change (13.6% [-29, 88] versus 17.9% [-24, 87]; P=0.23) were similar between those who received evacetrapib and placebo. During median follow-up of 28 months, major adverse cardiovascular events occurred in 263 patients (16.2%). The hazard ratios for increasing quartile of baseline or percentage change in plasma aldosterone level at follow-up were not significant for major adverse cardiovascular events. These findings remained consistent when adjusting for significant characteristics. Conclusions Exposure to evacetrapib did not result in significant change in plasma aldosterone levels compared with placebo. Among patients with stable high-risk vascular disease, plasma aldosterone levels were not a predictor for future cardiovascular events. Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01687998.

Effect of Evolocumab on Coronary Plaque Composition.

BACKGROUND: Incremental low-density lipoprotein (LDL) cholesterol lowering with the proprotein convertase subtilisin kexin type 9 inhibitor evolocumab regresses coronary atherosclerosis in statin-treated patients. OBJECTIVES: The purpose of this study was to evaluate the effect of adding evolocumab to statin therapy on coronary plaque composition. METHODS: A total of 968 statin-treated coronary artery disease patients underwent serial coronary intravascular ultrasound imaging at baseline and following 76 weeks of treatment with placebo or evolocumab 420 mg monthly. Plaque composition changes were determined in 331 patients with evaluable radiofrequency analysis of the ultrasound backscatter signal. RESULTS: Compared with statin monotherapy, evolocumab further reduced LDL cholesterol (33.5 mg/dl vs. 89.9 mg/dl; p < 0.0001) and induced regression of percent atheroma volume (-1.2% vs. +0.17%; p < 0.0001) and total atheroma volume (-3.6 mm3 vs. -0.8 mm3; p = 0.04). No difference was observed between the evolocumab and placebo groups in changes in calcium (1.0 ± 0.3 mm3 vs. 0.6 ± 0.3 mm3; p = 0.49), fibrous (-3.0 ± 0.6 mm3 vs. -2.4 ± 0.6 mm3; p = 0.49), fibrofatty (-5.0 ± 1.0 mm3 vs. -3.0 ± 1.0 mm3; p = 0.49), and necrotic (-0.6 ± 0.5 mm3 vs. -0.1 ± 0.5 mm3; p = 0.49) volumes. An inverse correlation was observed between changes in LDL cholesterol and plaque calcification (r = -0.15; p < 0.001). CONCLUSIONS: The addition of evolocumab to a statin did not produce differential changes in plaque composition compared with statin monotherapy. This suggests that evaluation of plaque morphology using virtual histology imaging may provide no incremental information about the plaque effects of evolocumab beyond measurement of plaque burden. (GLobal Assessment of Plaque reGression With a PCSK9 antibOdy as Measured by intraVascular Ultrasound [GLAGOV]; NCT01813422).

Correlation of High-Density Lipoprotein-Associated Paraoxonase 1 Activity With Systemic Inflammation, Disease Activity, and Cardiovascular Risk Factors in Psoriatic Disease.

OBJECTIVE: To compare the activity of high-density lipoprotein (HDL)-associated paraoxonase 1 (PON1) in patients with psoriasis (PsO) and patients with psoriatic arthritis (PsA), and to evaluate the association of PON1 activity with the extent of disease activity and severity of the cardiovascular disease (CVD) burden in these patients. METHODS: Serum levels of paraoxonase and arylesterase activity (both measures of PON1 function in humans) were measured in patients with PsA (n = 198, 51.0% male) and patients with PsO (n = 145, 50.3% male) who were enrolled in a longitudinal psoriatic disease biorepository. Data on PsA disease activity (using the Disease Activity Score in 28 joints [DAS28], Clinical Disease Activity Index, and painful/swollen joint counts), preexistent CVD and CVD risk factors (including diabetes, dyslipidemia, hypertension, and smoking), Framingham Risk Scores for CVD, quality of life measures, and laboratory test findings (erythrocyte sedimentation rate, C-reactive protein level, and lipid profiles) were recorded. RESULTS: Serum arylesterase activities were significantly lower in patients with PsO and patients with PsA (mean ± SD 111.1 ± 25.5 µmoles/minute/ml and 124.4 ± 33.4 µmoles/minute/ml, respectively) compared to healthy controls (144.3 ± 33.4 µmoles/minute/ml) (each P < 0.001 versus healthy controls). Serum arylesterase activity decreased in parallel with increasing levels of disease activity (DAS28 scores, P = 0.012), older age (P = 0.013), higher body mass index (P = 0.042), greater incidence of metabolic syndrome (P = 0.004) and hypertension (P = 0.014), and worsening Framingham Risk Scores (P = 0.001). However, no correlation was seen between serum arylesterase activity and the extent of disease activity or CVD burden in patients with PsO. Serum paraoxonase activity trended lower both in patients with PsO and in patients with PsA (each P = 0.073 versus healthy controls). However, no association was seen between serum paraoxonase activity and the extent of disease activity or CVD burden in either of the patient cohorts. CONCLUSION: PON1 activity is decreased in psoriatic diseases. In the PsA cohort, decreases in arylesterase activity correlated with increasing severity of joint disease and CVD burden. Arylesterase activity, as compared to paraoxonase activity, appeared to serve as a more sensitive predictor of preexisting CV risk factors in the PsA cohort. However, this correlation was not observed in the PsO population.

The Risk of Major NSAID Toxicity with Celecoxib, Ibuprofen, or Naproxen: A Secondary Analysis of the PRECISION Trial.

BACKGROUND: The relative safety of long-term use of nonsteroidal anti-inflammatory drugs is unclear. Patients and providers are interested in an integrated view of risk . We examined the risk of major nonsteroidal anti-inflammatory drug toxicity in the PRECISION trial. METHODS: We conducted a post hoc analysis of a double-blind, randomized, controlled, multicenter trial enrolling 24,081 patients with osteoarthritis or rheumatoid arthritis at moderate or high cardiovascular risk. Patients were randomized to receive celecoxib 100 to 200 mg twice daily, ibuprofen 600 to 800 mg thrice daily, or naproxen 375 to 500 mg twice daily. All patients were provided with a proton pump inhibitor. The outcome was major nonsteroidal anti-inflammatory drug toxicity, including time to first occurrence of major adverse cardiovascular events, important gastrointestinal events, renal events, and all-cause mortality. RESULTS: During follow-up, 4.1% of subjects sustained any major toxicity in the celecoxib arm, 4.8% in the naproxen arm, and 5.3% in the ibuprofen arm. Analyses adjusted for aspirin use and geographic region found that subjects in the naproxen arm had a 20% (95% CI 4-39) higher risk of major toxicity than celecoxib users and that 38% (95% CI 19-59) higher risk. These risks translate into numbers needed to harm of 135 (95% CI, 72-971) for naproxen and 82 (95% CI, 53-173) for ibuprofen, both compared with celecoxib. CONCLUSIONS: Among patients with symptomatic arthritis who had moderate to high risk of cardiovascular events, approximately 1 in 20 experienced a major toxicity over 1 to 2 years. Patients using naproxen or ibuprofen experienced significantly higher risk of major toxicity than those using celecoxib.

Comparing SF-36® scores versus biomarkers to predict mortality in primary cardiac prevention patients.

BACKGROUND: Risk stratification plays an important role in evaluating patients with no known cardiovascular disease (CVD). Few studies have investigated health-related quality of life questionnaires such as the Medical Outcomes Study Short Form-36 (SF-36®) as predictive tools for mortality, particularly in direct comparison with biomarkers. Our objective is to measure the relative effectiveness of SF-36® scores in predicting mortality when compared to traditional and novel biomarkers in a primary prevention population. METHODS: 7056 patients evaluated for primary cardiac prevention between January 1996 and April 2011 were included in this study. Patient characteristics included medical history, SF-36® questionnaire and a laboratory panel (total cholesterol, triglycerides, HDL, LDL, ApoA, ApoB, ApoA1/ApoB ratio, homocysteine, lipoprotein (a), fibrinogen, hsCRP, uric acid and urine ACR). The primary outcome was all-cause mortality. RESULTS: A low SF-36® physical score independently predicted a 6-fold increase in death at 8years (above vs. below median Hazard Ratio [95% confidence interval] 5.99 [3.86-9.35], p<0.001). In a univariate analysis, SF-36® physical score had a c-index of 0.75, which was superior to that of all the biomarkers. It also carried incremental predictive ability when added to non-laboratory risk factors (Net Reclassification Index=59.9%), as well as Framingham risk score components (Net Reclassification Index=61.1%). Biomarkers added no incremental predictive value to a non-laboratory risk factor model when combined to SF-36 physical score. CONCLUSION: The SF-36® physical score is a reliable predictor of mortality in patients without CVD, and outperformed most studied traditional and novel biomarkers. In an era of rising healthcare costs, the SF-36® questionnaire could be used as an adjunct simple and cost-effective predictor of mortality to current predictors.

Use of Sex-Specific Clinical and Exercise Risk Scores to Identify Patients at Increased Risk for All-Cause Mortality.

Importance: Risk assessment tools for exercise treadmill testing may have limited external validity. Cardiovascular mortality has decreased in recent decades, and women have been underrepresented in prior cohorts. Objectives: To determine whether exercise and clinical variables are associated with differential mortality outcomes in men and women and to assess whether sex-specific risk scores better estimate all-cause mortality. Design, Setting, and Participants: This retrospective cohort study included 59 877 patients seen at the Cleveland Clinic Foundation (CCF cohort) from January 1, 2000, through December 31, 2010, and 49 278 patients seen at the Henry Ford Hospital (FIT cohort) from January 1, 1991, through December 31, 2009. All patients were 18 years or older and underwent exercise treadmill testing. Data were analyzed from January 1, 2000, to October 27, 2011, in the CCF cohort and from January 1, 1991, to April 1, 2013, in the FIT cohort. Main Outcomes and Measurements: The CCF cohort was divided randomly into derivation and validation samples, and separate risk scores were developed for men and women. Net reclassification, C statistics, and integrated discrimination improvement were used to compare the sex-specific risk scores with other tools that have all-cause mortality as the outcome. Discrimination and calibration were also evaluated with these sex-specific risk scores in the FIT cohort. Results: The CCF cohort included 59 877 patients (59.4% men; 40.5% women) with a median (interquartile range [IQR]) age of 54 (45-63) years and 2521 deaths (4.2%) during a median follow-up of 7 (IQR, 4.1-9.6) years. The FIT cohort included 49 278 patients (52.5% men; 47.4% women) with a median (IQR) age of 54 (46-64) years and 6643 deaths (13.5%) during a median (IQR) follow-up of 10.2 (7-13.4) years. C statistics for the sex-specific risk scores in the CCF validation sample were higher (0.79 in women and 0.81 in men) than C statistics using other tools in women (0.70 for Duke Treadmill Score; 0.74 for Lauer nomogram) and men (0.72 for Duke Treadmill Score; 0.75 for Lauer nomogram). Net reclassification and integrated discrimination improvement were superior with the sex-specific risk scores, mostly owing to correct reclassification of events. The sex-specific risk scores in the FIT cohort demonstrated similar discrimination (C statistic, 0.78 for women and 0.79 for men), and calibration was reasonable. Conclusions and Relevance: Sex-specific risk scores better estimate mortality in patients undergoing exercise treadmill testing. In particular, these sex-specific risk scores help to identify patients at the highest residual risk in the present era.

Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial.

Importance: Reducing levels of low-density lipoprotein cholesterol (LDL-C) with intensive statin therapy reduces progression of coronary atherosclerosis in proportion to achieved LDL-C levels. Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors produce incremental LDL-C lowering in statin-treated patients; however, the effects of these drugs on coronary atherosclerosis have not been evaluated. Objective: To determine the effects of PCSK9 inhibition with evolocumab on progression of coronary atherosclerosis in statin-treated patients. Design, Setting, and Participants: The GLAGOV multicenter, double-blind, placebo-controlled, randomized clinical trial (enrollment May 3, 2013, to January 12, 2015) conducted at 197 academic and community hospitals in North America, Europe, South America, Asia, Australia, and South Africa and enrolling 968 patients presenting for coronary angiography. Interventions: Participants with angiographic coronary disease were randomized to receive monthly evolocumab (420 mg) (n = 484) or placebo (n = 484) via subcutaneous injection for 76 weeks, in addition to statins. Main Outcomes and Measures: The primary efficacy measure was the nominal change in percent atheroma volume (PAV) from baseline to week 78, measured by serial intravascular ultrasonography (IVUS) imaging. Secondary efficacy measures were nominal change in normalized total atheroma volume (TAV) and percentage of patients demonstrating plaque regression. Safety and tolerability were also evaluated. Results: Among the 968 treated patients (mean age, 59.8 years [SD, 9.2]; 269 [27.8%] women; mean LDL-C level, 92.5 mg/dL [SD, 27.2]), 846 had evaluable imaging at follow-up. Compared with placebo, the evolocumab group achieved lower mean, time-weighted LDL-C levels (93.0 vs 36.6 mg/dL; difference, -56.5 mg/dL [95% CI, -59.7 to -53.4]; P < .001). The primary efficacy parameter, PAV, increased 0.05% with placebo and decreased 0.95% with evolocumab (difference, -1.0% [95% CI, -1.8% to -0.64%]; P < .001). The secondary efficacy parameter, normalized TAV, decreased 0.9 mm3 with placebo and 5.8 mm3 with evolocumab (difference, -4.9 mm3 [95% CI, -7.3 to -2.5]; P < .001). Evolocumab induced plaque regression in a greater percentage of patients than placebo (64.3% vs 47.3%; difference, 17.0% [95% CI, 10.4% to 23.6%]; P < .001 for PAV and 61.5% vs 48.9%; difference, 12.5% [95% CI, 5.9% to 19.2%]; P < .001 for TAV). Conclusions and Relevance: Among patients with angiographic coronary disease treated with statins, addition of evolocumab, compared with placebo, resulted in a greater decrease in PAV after 76 weeks of treatment. Further studies are needed to assess the effects of PCSK9 inhibition on clinical outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT01813422.

Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial.

IMPORTANCE: Muscle-related statin intolerance is reported by 5% to 20% of patients. OBJECTIVE: To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab. DESIGN, SETTING, AND PARTICIPANTS: Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks. INTERVENTIONS: Phase A: atorvastatin (20 mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily). MAIN OUTCOME AND MEASURES: Coprimary end points were the mean percent change in LDL-C level from baseline to the mean of weeks 22 and 24 levels and from baseline to week 24 levels. RESULTS: Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9] mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72] mg/dL). For the mean of weeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, -16.7% (95% CI, -20.5% to -12.9%), absolute change, -31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, -54.5% (95% CI, -57.2% to -51.8%); absolute change, -106.8 mg/dL (P < .001). LDL-C level at week 24 with ezetimibe was 181.5 mg/dL; mean percent change, -16.7% (95% CI, -20.8% to -12.5%); absolute change, -31.2 mg/dL and with evolocumab was 104.1 mg/dL; mean percent change, -52.8% (95% CI, -55.8% to -49.8%); absolute change, -102.9 mg/dL (P < .001). For the mean of weeks 22 and 24, between-group difference in LDL-C was -37.8%; absolute difference, -75.8 mg/dL. For week 24, between-group difference in LDL-C was -36.1%; absolute difference, -71.7 mg/dL. Muscle symptoms were reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drug was stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%). CONCLUSIONS AND RELEVANCE: Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01984424.