Danielle M. Brennan

Relationship of Paraoxonase 1 (PON1) Gene Polymorphisms and Functional Activity With Systemic Oxidative Stress and Cardiovascular Risk

CONTEXT Paraoxonase 1 (PON1) is reported to have antioxidant and cardioprotective properties. The relationship between PON1 genotypes and functional activity with systemic measures of oxidative stress and cardiovascular disease (CVD) risk in humans has not been systematically investigated. OBJECTIVE To investigate the relationship of genetic and biochemical determinants of PON1 activity with systemic measures of oxidative stress and CVD risk in humans. DESIGN, SETTING, AND PARTICIPANTS The association between systemic PON1 activity measures and a functional polymorphism (Q192R) resulting in high PON1 activity with prevalent CVD and future major adverse cardiac events (myocardial infarction, stroke, or death) was evaluated in 1399 sequential consenting patients undergoing diagnostic coronary angiography between September 2002 and November 2003 at the Cleveland Clinic. Patients were followed up until December 2006. Systemic levels of multiple structurally defined fatty acid oxidation products were also measured by mass spectrometry in 150 age-, sex-, and race-matched patients and compared with regard to PON1 genotype and activity. MAIN OUTCOME MEASURES Relationship between a functional PON1 polymorphism and PON1 activity with global indices of systemic oxidative stress and risk of CVD. RESULTS The PON1 genotype demonstrated significant dose-dependent associations (QQ192 > QR192 > RR192) with decreased levels of serum PON1 activity and with increased levels of systemic indices of oxidative stress. Compared with participants with either the PON1 RR192 or QR192 genotype, participants with the QQ192 genotype demonstrated an increased risk of all-cause mortality (43/681 deaths [6.75%] in RR192 and QR192 and 62/584 deaths [11.1%] in QQ192; adjusted hazard ratio, 2.05; 95% confidence interval [CI], 1.32-3.18) and of major adverse cardiac events (88/681 events [13.6%] in RR192 and QR192 and 102/584 events [18.0%] in QQ192; adjusted hazard ratio, 1.48; 95% CI, 1.09-2.03; P = .01). The incidence of major adverse cardiac events was significantly lower in participants in the highest PON1 activity quartile (23/315 [7.3%]) and 235/324 [7.7%] for paraoxonase and arylesterase, respectively) compared with those in the lowest activity quartile (78/311 [25.1%] and 75/319 [23.5%]; P < .001 for paraoxonase and arylesterase, respectively). The adjusted hazard ratios for major adverse cardiac events between the highest and lowest PON1 activity quartiles were, for paraoxonase, 3.4 (95% CI, 2.1-5.5; P < .001) and for arylesterase, 2.9 (95% CI, 1.8-4.7; P < .001) and remained independent in multivariate analysis. CONCLUSION This study provides direct evidence for a mechanistic link between genetic determinants and activity of PON1 with systemic oxidative stress and prospective cardiovascular risk, indicating a potential mechanism for the atheroprotective function of PON1.

Lack of Adverse Clopidogrel-Atorvastatin Clinical Interaction From Secondary Analysis of a Randomized, Placebo-Controlled Clopidogrel Trial

Background—Statins primarily metabolized by cytochrome P450 3A4 (CYP3A4) reportedly reduce clopidogrel’s metabolism to active metabolite, thus attenuating its inhibition of platelet aggregation ex vivo. However, the clinical impact of this interaction has not been evaluated. Methods and Results—Clopidogrel for the Reduction of Events During Observation (CREDO) was a double-blind, placebo-controlled, randomized trial comparing pretreatment (300 mg) and 1-year (75 mg/d) clopidogrel therapy (clopidogrel) with no pretreatment and 1-month clopidogrel therapy (75 mg/d) (control) after a planned percutaneous coronary intervention. All patients received aspirin. The 1-year primary end point was a composite of death, myocardial infarction, and stroke. We performed a post hoc analysis to evaluate the clinical efficacy of concomitant clopidogrel and statin administration, categorizing baseline statin use to those predominantly CYP3A4-metabolized (atorvastatin, lovastatin, simvastatin, and cerivastatin) (CYP3A4-MET) or others (pravastatin and fluvastatin) (non-CYP3A4-MET). Of the 2116 patients enrolled, 1001 received a CYP3A4-MET and 158 a non-CYP3A4-MET statin. For the overall study population, the primary end point was significantly reduced in the clopidogrel group (8.5% versus 11.5%, RRR 26.9%; P =0.025). This clopidogrel benefit was similar with statin use, irrespective of treatment with a CYP3A4-MET (7.6% clopidogrel, 11.8% control, RRR 36.4%, 95% CI 3.9 to 57.9; P =0.03) or non-CYP3A4-MET statin (5.4% clopidogrel, 13.6% control, RRR 60.6%, 95% CI −23.9 to 87.4; P =0.11). Patients given atorvastatin or pravastatin had similar 1-year event rates. Additionally, concomitant therapy with statins had no impact on major or minor bleeding rates. Conclusions—Although ex vivo testing has suggested a potential negative interaction when coadministering a CYP3A4-metabolized statin with clopidogrel, this was not clinically observed statistically in a post hoc analysis of a placebo-controlled study.

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.

Cholesteryl Ester Transfer Protein Inhibition, High-Density Lipoprotein Raising, and Progression of Coronary Atherosclerosis Insights From ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation)

Background— Despite favorable effects on high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol, the cholesteryl ester transfer protein inhibitor torcetrapib failed to slow atherosclerosis progression and increased mortality. We investigated the relationship between lipid changes and progression of coronary atherosclerosis. Methods and Results— Intravascular ultrasound was performed at baseline and follow-up in 910 participants randomized to torcetrapib/atorvastatin or atorvastatin monotherapy. The relationship between changes in lipoprotein levels and the primary intravascular ultrasound end point, change in percent atheroma volume, was investigated. Compared with atorvastatin monotherapy, torcetrapib raised HDL-C by 61%, lowered low-density lipoprotein cholesterol by 20%, raised serum sodium (0.44±0.14 mmol/L, P=0.02), and lowered serum potassium (0.11±0.02 mmol/L, P<0.0001). Despite substantial increases in HDL-C, no effect was found of torcetrapib on percent atheroma volume. In torcetrapib-treated patients, an inverse relationship was observed between changes in HDL-C and percentage atheroma volume (r=−0.17, P<0.001). Participants with regression had greater increases in HDL-C (mean±SE, 62.9±37.4% versus 54.0±39.1%, P=0.002). Compared with the lowest quartile, torcetrapib-treated patients in the highest quartile of HDL-C change showed the least progression (−0.31±0.27 versus 0.88±0.27%, P=0.001). The highest on-treatment HDL-C quartile showed significant regression of percent atheroma volume (−0.69±0.27%, P=0.01). In multivariable analysis, changes in HDL-C levels independently predicted the effect on atherosclerosis progression (P=0.001). Conclusions— The majority of torcetrapib-treated patients demonstrated no regression of coronary atherosclerosis. Regression was only observed at the highest HDL-C levels. Torcetrapib raised serum sodium and lowered potassium, consistent with an aldosterone-like effect, which may explain the lack of favorable effects in the full study cohort. Accordingly, other cholesteryl ester transfer protein inhibitors, if they lack this off-target toxicity, may successfully slow atherosclerosis progression.

Lack of benefit from intravenous platelet glycoprotein IIb/IIIa receptor inhibition as adjunctive treatment for percutaneous interventions of aortocoronary bypass grafts: a pooled analysis of five randomized clinical trials.

Background—Despite widespread use of platelet glycoprotein (GP) IIb/IIIa receptor inhibitors for percutaneous coronary interventions (PCI) of bypass grafts, data supporting this strategy are lacking. Methods and Results—A pooled analysis of 5 randomized intravenous GP IIb/IIIa inhibitor trials (EPIC, EPILOG, EPISTENT, IMPACT II, and PURSUIT) was performed, and outcomes of graft interventions were assessed at 30 days and 6 months. Compared with PCI of native circulation (n=13 158), graft interventions (n=627) were associated with worse outcomes and in particular with a doubling of mortality at 30 days (2.1% versus 1.0%, P =0.006) and 6 months (4.7% versus 2.0%, P <0.001). Revascularization of a graft was identified as an independent predictor of death, myocardial infarction, or revascularization at 6 months (hazard ratio, 1.42; 95% CI, 1.24 to 1.63;P <0.001). Among patients undergoing graft PCI, the incidence of the triple end point at 30 days was 16.5% in the platelet GP IIb/IIIa inhibitor group and 12.6% in the placebo group (odds ratio, 1.38; 95% CI, 0.85 to 2.24;P =0.18). At 6 months, 39.4% of patients randomized to GP IIb/IIIa inhibitors and 32.7% of patients allocated to placebo had an ischemic event (hazard ratio, 1.29; 95% CI, 0.97 to 1.72;P =0.07). Conclusions—Intravenous platelet GP IIb/IIIa receptor inhibition does not improve outcomes after PCI of bypass grafts. In the absence of mechanical emboli protection, this procedure is associated with high incidence of death and nonfatal ischemic events.

Bleeding Complications With Dual Antiplatelet Therapy Among Patients With Stable Vascular Disease or Risk Factors for Vascular Disease Results From the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) Trial

Background— Uncertainty exists about the frequency, correlates, and clinical significance of bleeding with dual antiplatelet therapy (DAPT), particularly over an extended period in a stable population. We sought to determine the frequency and time course of bleeding with DAPT in patients with established vascular disease or risk factors only; identify correlates of bleeding; and determine whether bleeding is associated with mortality. Methods and Results— We analyzed 15 603 patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, a double-blind, placebo-controlled, randomized trial comparing long-term clopidogrel 75 mg/d versus placebo; all patients received aspirin (75 to 162 mg) daily. Patients had either established stable vascular disease or multiple risk factors for vascular disease without established disease. Median follow-up was 28 months. Bleeding was assessed with the use of the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) criteria. Severe bleeding occurred in 1.7% of the clopidogrel group versus 1.3% on placebo (P=0.087); moderate bleeding occurred in 2.1% versus 1.3%, respectively (P<0.001). The risk of bleeding was greatest the first year. Patients without moderate or severe bleeding during the first year were no more likely than placebo-treated patients to have bleeding thereafter. The frequency of bleeding was similar in patients with established disease and risk factors only. In multivariable analysis, the relationship between moderate bleeding and all-cause mortality was strong (hazard ratio, 2.55; 95% confidence interval, 1.71 to 3.80; P<0.0001), along with myocardial infarction (hazard ratio, 2.92; 95% confidence interval, 2.04 to 4.18; P<0.0001) and stroke (hazard ratio, 4.20; 95% confidence interval, 3.05 to 5.77; P<0.0001). Conclusions— In CHARISMA, there was an increased risk of bleeding with long-term clopidogrel. The incremental risk of bleeding was greatest in the first year and similar thereafter. Moderate bleeding was strongly associated with mortality. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00050817.

Aspirin to Prevent Cardiovascular Disease: The Association of Aspirin Dose and Clopidogrel With Thrombosis and Bleeding

Context The optimal aspirin dose for prevention of cardiovascular events is unknown. Contribution This post hoc analysis of CHARISMA trial data suggests no overall differences in efficacy or safety by aspirin dose. However, in the subgroup of patients randomly assigned to clopidogrel, there was a hint of reduced efficacy and increased harm with higher doses. Caution Patients were not randomly assigned to aspirin dose. Implication Lower aspirin doses (75 to 81 mg/d) may optimize efficacy and safety for patients requiring aspirin for long-term prevention, especially those taking clopidogrel. The Editors Aspirin is the most widely used drug worldwide for the prevention of thrombotic cardiovascular events. Of note, the doses of aspirin used most often clinically or recommended in guidelines are based not on the results of trials designed to identify the most efficacious or safest dose, but on a combination of historical precedents and trials in which specific doses of aspirin were mandated by protocol. This practice has led to a wide range in aspirin doses (75 to 325 mg/d) recommended by the U.S. Food and Drug Administration (1) for the management of cardiovascular disease in various populations. Although as little as 30 mg of aspirin daily is needed to fully inhibit platelet thromboxane production (2), doses more than 10 times higher than this are routinely used in long-term prevention of cardiovascular disease. Because aspirin has been used clinically for more than a century and is a mainstay of therapy for patients who have or are at risk for atherosclerotic disease and other common ailments, its risks are often underappreciated. However, given that more than one third of U.S. adults are estimated to take aspirin daily for cardiovascular disease (3), even a very small incidence of hemorrhagic complications places a large number of people at risk. Consistent with this is a recent analysis of hospitalizations for adverse drug effects that found aspirin to be one of the most common causal agents (4). The gastrointestinal tract is the leading source of bleeding events in aspirin-treated patients because of inhibition of gastroprotective prostacyclins, with an excess risk for upper gastrointestinal complications of 5 cases per 1000 aspirin users per year (5). Prospective evaluation of aspirin-treated patients with coronary artery disease identified an incidence of upper gastrointestinal bleeding of 1.5% per year, with substantial associated morbidity (6). Because inhibition of gastric prostacyclin is dose-dependent and not maximal until a daily dose of about 1300 mg is reached (4), minimizing the dose of aspirin to that needed to fully inhibit platelet thromboxane production would probably offer the greatest potential benefit with the lowest possible risk. In several observational studies of large prospective trials, lower doses of aspirin (<162 mg/d) have been associated with the lowest incidence of thrombotic events (7, 8) and a trend toward fewer bleeding events (8). These favorable trends in efficacy and safety were confirmed in the CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) trial (9) of dual antiplatelet therapy with clopidogrel plus aspirin versus placebo plus aspirin. On the basis of these results, the design of the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance) trial (10), which randomly assigned 15603 patients at high risk for atherothrombotic events to clopidogrel or placebo in conjunction with aspirin, mandated a daily aspirin dose of 75 to 162 mg. We performed a post hoc analysis of associations between investigator-determined daily aspirin dose and thrombotic and hemorrhagic outcomes in the prospective CHARISMA trial. Methods The design, methods, and primary results of the CHARISMA study are reported elsewhere (10). In brief, CHARISMA was a multicenter, double-blind, randomized, placebo-controlled trial of long-term clopidogrel (75 mg/d) treatment versus placebo in patients 45 years or older who had established atherosclerotic disease or were asymptomatic but at high risk because of a combination of risk factors. All patients also received low-dose aspirin therapy, which was limited by protocol to between 75 and 162 mg/d. Patients were excluded if they had an established indication for clopidogrel therapy, such as a recent acute coronary syndrome or stent implantation. Clinical follow-up was done at 1, 3, and 6 months and every 6 months thereafter until the end of the trial. The actual dose of aspirin being taken was confirmed at each evaluation. The ethics committee at each of the 768 participating hospitals worldwide, as well as the appropriate national ethics committee for each of the 32 participating countries, reviewed and approved the study protocol. All patients provided written informed consent before enrollment. The primary efficacy end point was the first occurrence of myocardial infarction, stroke, or cardiovascular death. The primary safety end point was severe or life-threatening bleeding according to the GUSTO-I (Global Utilization of Streptokinase and TPA for Occluded coronary arteries) criteria (11): intracerebral bleeding or bleeding resulting in substantial hemodynamic compromise requiring treatment. A secondary safety end point was the combined incidence of severe or life-threatening bleeding or moderate bleeding by the GUSTO-I criteria, with moderate defined as bleeding requiring transfusion but not resulting in hemodynamic compromise (11). Of note, patients believed to be at high risk for bleeding were excluded from enrollment. Aspirin dose was not randomized; rather, it was selected at the discretion of the treating physician. We prospectively divided patients into 3 major groups according to clear demarcations in aspirin dose at baseline: less than 100 mg/d, represented almost entirely by doses of either 75 or 81 mg/d; 100 mg/d; and greater than 100 mg/d, represented by either 150 or 162 mg/d. We evaluated the relative efficacy and safety of the different doses of aspirin among all patients, and we evaluated the efficacy and safety end points between the treatment (clopidogrel) versus placebo groups by aspirin dose category. Statistical Analysis We performed all data analyses on the intention-to-treat population. We performed hypothesis tests by using 2-sided tests at the 5% significance level. Baseline characteristics were compared by using chi-square tests for discrete variables and t tests for continuous variables. We calculated cumulative KaplanMeier estimates of the event rates and assessed differences in the unadjusted rates of primary efficacy and safety end points across the aspirin groups by using a 2-sided log-rank test. We used log-rank weights to compute a test for trend across aspirin dose categories. We estimated the treatment effect, measured by the hazard ratio and its 95% CI, by using the Cox proportional hazards model. Multivariable modeling was performed to determine whether aspirin dose was independently associated with the primary efficacy and safety outcomes after controlling for potentially confounding factors. Because patients could have had more than 1 efficacy or safety event, we defined the time to the primary efficacy end point as the first occurrence of myocardial infarction, stroke, or cardiovascular death. We defined the time to the primary safety end point as the first occurrence of severe or life-threatening bleeding according to the GUSTO-I criteria (11). We selected variables for inclusion in the models on the basis of differences in baseline characteristics among patients in the 3 aspirin dose categories or their clinical relevance to the outcomes. Covariates included in the multivariable model for the primary efficacy end point were the continuous variables of age, weight, and systolic blood pressure and the categorical variables of sex; race or ethnicity (white or Hispanic vs. other); hypertension; hypercholesterolemia; history of congestive heart failure; previous myocardial infarction; previous stroke; previous transient ischemic attack; diabetes mellitus; atrial fibrillation; peripheral arterial disease; diabetic nephropathy; current smoking; primary (vs. secondary) prevention and past use of statins, nitrates, and antiplatelet agents other than aspirin. We developed models with and without inclusion of interaction terms for randomized treatment assignment by aspirin dose category. Adjustment variables in the multivariable model for the primary safety end point (GUSTO-I severe or life-threatening bleeding) included age and weight as continuous variables and the categorical variables of stable angina with multivessel disease, sex, race or ethnicity (white or Hispanic vs. other), history of congestive heart failure, previous myocardial infarction, previous stroke, previous transient ischemic attack, diabetes mellitus, atrial fibrillation, peripheral arterial disease, diabetic nephropathy, hypertension, hypercholesterolemia, primary prevention (vs. secondary), and current smoking. We developed models with and without inclusion of interaction terms for randomized treatment assignment by daily aspirin dose category. To adjust for geographical region without estimating its effect, we used region (categorized as United States, Canada, Western Europe, Eastern Europe, Latin America, Asia and Australia, or Africa) as a stratification variable in models for both end points. We assessed the interaction of aspirin dose and randomized treatment in both models. We calculated and tested the difference between the maximum likelihood ratios with and without 2 interaction terms (randomized treatment assignment by daily aspirin dose of 100 mg and greater than 100 mg). We assessed proportional hazards by multiplying each covariate by the log of the time to the event. A Wald test was performed to test the linear hypotheses of the regression coefficients. The proportional hazards

The efficacy and safety of short- and long-term dual antiplatelet therapy in patients with mild or moderate chronic kidney disease: results from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial.

BACKGROUND Mild and moderate chronic kidney disease (CKD) is associated with decreased survival and increased adverse events after a percutaneous coronary intervention (PCI). Therapy with clopidogrel decreases adverse events in large patient populations. Therefore, we sought to determine the efficacy and safety of long-term clopidogrel therapy in patients with CKD. METHODS Two thousand two patients from the CREDO trial in whom an elective PCI of a single or multiple vessels was planned were analyzed. Patients were randomly assigned to a 300-mg loading dose of clopidogrel before PCI followed by clopidogrel 75 mg/d for a year versus a placebo loading dose at the time of the PCI procedure and clopidogrel 75 mg/d for 28 days and placebo for the remainder of a year. Patients were categorized by their estimated creatinine clearance (>90 [normal, n = 999], 60-89 [mild CKD, n = 672], <60 mL/min [moderate CKD, n = 331]). RESULTS Diminished renal function was associated with worse outcomes. Patients with normal renal function who received 1 year of clopidogrel had a marked reduction in death, myocardial infarction, or stroke compared with those who received placebo (10.4% vs 4.4%, P < .001), whereas patients with mild and moderate CKD did not have a significant difference in outcomes with clopidogrel therapy versus placebo (mild: 12.8% vs 10.3%, P = .30; moderate: 13.1% vs 17.8%, P = .24). Clopidogrel use was associated with an increased relative risk of major or minor bleeding, but this increased risk was not different based on renal function (relative risk 1.2, 1.3, 1.1). CONCLUSIONS Clopidogrel in mild or moderate CKD patients may not have the same beneficial effect as it does in patients with normal renal function, but was not associated with a greater relative risk of bleeding based on renal function. Further studies are needed to define the role of clopidogrel therapy in patients with CKD.

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.

Serum uric acid is an independent predictor of all-cause mortality in patients at high risk of cardiovascular disease: A preventive cardiology information system (PreCIS) database cohort study

OBJECTIVE Uric acid is a product of the activity of xanthine oxidase, an enzyme linked to oxidative stress, endothelial dysfunction, and heart failure. It is unclear whether adding uric acid levels to the assessment of cardiovascular risk might contribute to the improved ability to stratify cardiovascular risk. The purpose of this study was to evaluate the prognostic value of serum uric acid levels in a large cohort of men and women at high risk of cardiovascular disease. METHODS Serum uric acid levels were determined in all patients seen for primary/secondary cardiovascular disease prevention at the Cleveland Clinic Section of Preventive Cardiology and Rehabilitation between 1998 and 2004, and all data were entered into the Preventive Cardiology Information System (PreCIS) database. Vital status of the patients was determined through the Social Security Death Index. Death from all causes was summarized across quartiles of uric acid values. RESULTS A total of 3,098 patients (age range 18-87 years) were identified in the database, among whom 43% had cardiovascular disease. There were 156 deaths (5%) during the 14,262 person-years of followup. For each 1-mg/dl increase in the serum uric acid level, there was a 39% increase in the risk of death (by Cox regression analysis). After adjusting for age, sex, smoking status, alcohol consumption, weight, body mass index, waist circumference, blood pressure, history of cardiovascular disease, estimated glomerular filtration rate, levels of cholesterol fractions, and plasma glucose levels, the serum uric acid level continued to predict the risk of death (hazard ratio = 1.26 [95% confidence interval 1.15-1.38], P < 0.001). This association was present regardless of diuretic use. Concordance index (C statistic) analyses showed that uric acid significantly improved the predictive accuracy of a model that included Framingham Heart Study score factors, metabolic syndrome components, and fibrinogen levels. CONCLUSION Serum uric acid levels are an independent predictor of death in patients at high risk of cardiovascular disease. Further studies are warranted to evaluate its prognostic implications and potential utility in the monitoring of therapy.