Leslie Cho

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.

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.

An abundant dysfunctional apolipoprotein A1 in human atheroma

Recent studies have indicated that high-density lipoproteins (HDLs) and their major structural protein, apolipoprotein A1 (apoA1), recovered from human atheroma are dysfunctional and are extensively oxidized by myeloperoxidase (MPO). In vitro oxidation of either apoA1 or HDL particles by MPO impairs their cholesterol acceptor function. Here, using phage display affinity maturation, we developed a high-affinity monoclonal antibody that specifically recognizes both apoA1 and HDL that have been modified by the MPO-H2O2-Cl− system. An oxindolyl alanine (2-OH-Trp) moiety at Trp72 of apoA1 is the immunogenic epitope. Mutagenesis studies confirmed a critical role for apoA1 Trp72 in MPO-mediated inhibition of the ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol acceptor activity of apoA1 in vitro and in vivo. ApoA1 containing a 2-OH-Trp72 group (oxTrp72-apoA1) is in low abundance within the circulation but accounts for 20% of the apoA1 in atherosclerosis-laden arteries. OxTrp72-apoA1 recovered from human atheroma or plasma is lipid poor, virtually devoid of cholesterol acceptor activity and demonstrated both a potent proinflammatory activity on endothelial cells and an impaired HDL biogenesis activity in vivo. Elevated oxTrp72-apoA1 levels in subjects presenting to a cardiology clinic (n = 627) were associated with increased cardiovascular disease risk. Circulating oxTrp72-apoA1 levels may serve as a way to monitor a proatherogenic process in the artery wall.

Clinical benefit of glycoprotein IIb/IIIa blockade with abciximab is independent of gender: Pooled analysis from EPIC, EPILOG and EPISTENT trials

OBJECTIVES We sought to determine the efficacy and safety of platelet glycoprotein IIb/IIIa receptor (GP IIb/IIIa) blockade with abciximab in women undergoing percutaneous coronary intervention. BACKGROUND Although gender differences in response to platelet glycoprotein IIb/IIIa receptor blockade have been described, there have been no large clinical studies to assess these differences. METHODS Outcomes were determined using meta-analysis technique. RESULTS In the pooled analysis, the primary end point of death, myocardial infarction (MI) or urgent revascularization within 30 days was reduced from 11.3% to 5.8% (p<0.001) in men and from 12.7% to 6.5% (p<0.001) in women treated with abciximab. At six months, death, MI or urgent revascularization was reduced from 14.1% to 8.3% (p<0.001) in men and 16.0% to 9.9% (p<0.001) in women receiving abciximab. At one year, mortality was reduced from 2.7% to 1.9% (p = 0.06) in men and 4.0% to 2.5% (p = 0.03) in women treated with abciximab. Major bleeding events occurred in 2.9% versus 3.0% (p = 0.96) of women and 2.7% versus 1.3% (p = 0.003) of men treated with placebo versus abciximab, respectively. Minor bleeding events occurred in 4.7% versus 6.7% (p = 0.01) of women and 2.3% versus 2.2% (p = 0.94) of men treated with placebo versus abciximab, respectively. CONCLUSIONS This pooled analysis demonstrated no gender difference in protection from major adverse outcomes with GP IIb/IIIa inhibition with abciximab. Although women had higher rates of both major and minor bleeding events with abciximab compared with men, major bleeding in women was similar with and without abciximab. There was a small increased risk of minor bleeding with abciximab in women.

Targeted Metabolomic Evaluation of Arginine Methylation and Cardiovascular Risks. Potential Mechanisms Beyond Nitric Oxide Synthase Inhibition

Background—We examine the relationship of related posttranslational modification products of arginine methylation and coronary artery disease (CAD) phenotypes. Methods and Results—Plasma was isolated from 1011 consecutive consenting subjects undergoing elective diagnostic cardiac catheterization, and future major adverse cardiac events (MACE, including myocardial infarction, stroke, and death) at 3 years were investigated. Plasma levels of asymmetrical dimethylarginine (ADMA, endogenous nitric oxide synthase [NOS] inhibitor), symmetrical dimethylarginine (SDMA, which lacks NOS inhibitory activity), N-mono-methylarginine (MMA, a potent NOS inhibitor), methyl-lysine (Methyl-Lys, an unrelated methylated amino acid), arginine, and its major catabolites (citrulline and ornithine) were quantified simultaneously by stable isotope dilution HPLC with online electrospray ionization tandem mass spectrometry and adjusted for traditional risk factors, C-reactive protein, and estimated creatinine clearance. High SDMA levels (adjusted odds ratio [OR] 1.6, 95%CI, 1.1 to 2.6, P<0.001), low MMA (adjusted OR 0.5, 95%CI 0.4 to 0.8, P=0.007), but not ADMA (adjusted OR 1.3, 95%CI 0.88 to 2.0, P=0.177) were associated with increased prevalence of significantly obstructive CAD. Elevated levels of SDMA (adjusted Hazard Ratio [HR] 2.4, 95%CI 1.2 to 4.6, P=0.009), ADMA (adjusted HR 2.2, 95%CI 1.2 to 4.0, P=0.015), as well as an integrated index of arginine methylation [ArgMI=(ADMA+SDMA)/MMA] (adjusted HR 2.4, 95%CI 1.3 to 4.5, P=0.006) were significant independent predictors of incident MACE. ArgMI was predictive of incident MACE even following adjustments for global arginine bioavailability, particularly within secondary prevention patients. Conclusions—ADMA, SDMA, and the integrated quantification of arginine methylation (in the form of a methylation index) provided independent risk prediction for both significantly obstructive CAD and incident MACE in stable patients undergoing cardiac evaluation. These results suggest that factors beyond direct NOS inhibition contribute to the clinical associations between methylarginines and CAD outcomes.

Diminished global arginine bioavailability and increased arginine catabolism as metabolic profile of increased cardiovascular risk.

OBJECTIVES We hypothesized that an integrated assessment of arginine with its catabolic products might better predict cardiovascular risks than arginine levels alone. BACKGROUND Arginine is the sole nitrogen source for nitric oxide (NO) synthesis. The major catabolic products of arginine are ornithine and citrulline. METHODS Plasma levels of free arginine, ornithine, citrulline, and the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) were measured with liquid chromatography coupled with tandem mass spectrometry. We examined the relationship of global arginine bioavailability ratio (GABR) (defined as arginine/[ornithine + citrulline]) versus arginine and its catabolic metabolites to prevalence of significantly obstructive coronary artery disease (CAD) and incidence of major adverse cardiovascular events (MACE) (death, myocardial infarction, stroke) over a 3-year follow-up in 1,010 subjects undergoing elective cardiac catheterization. RESULTS Patients with significantly obstructive CAD had significantly lower GABR (median [interquartile range]: 1.06 [0.75 to 1.31] vs. 1.27 [0.96 to 1.73], p < 0.001) and arginine levels [mean: 68 +/- 20 micromol/l vs. 74 +/- 24 micromol/l, p < 0.001) than those without significantly obstructive CAD. After adjusting for Framingham risk score, C-reactive protein, and renal function, lower GABR (but not arginine levels) and higher citrulline levels remained significantly associated with both the prevalence of significantly obstructive CAD (adjusted odds ratio: 3.93, p < 0.001, and 5.98, p < 0.001, respectively) and 3-year risk for the incidence of MACE (adjusted hazard ratio: 1.98, p = 0.025, and 2.40, p = 0.01, respectively) and remained significant after adjusting for ADMA. CONCLUSIONS GABR might serve as a more comprehensive concept of reduced NO synthetic capacity compared with systemic arginine levels. Diminished GABR and high citrulline levels are associated with both development of significantly obstructive atherosclerotic CAD and heightened long-term risk for MACE.

Treatment strategies in patients with statin intolerance: the Cleveland Clinic experience.

BACKGROUND Statin therapy is a proven effective treatment of hyperlipidemia. However, a significant number of patients cannot tolerate statins. This study was conducted to review treatment strategies for patients intolerant to statin therapy with a focus on intermittent statin dosing. METHODS AND RESULTS We performed a retrospective analysis of medical records of 1,605 patients referred to the Cleveland Clinic Preventive Cardiology Section for statin intolerance between January 1995 and March 2010 with at least a 6-month follow-up. The changes in lipid profile, achievement of low-density lipoprotein cholesterol (LDL-C) goals, and statin tolerance rate were analyzed. Most (72.5%) of patients with prior statin intolerance were able to tolerate a statin for the median follow-up time of 31 months. Patients on intermittent statin dosing (n = 149) had significantly lower LDL-C reduction compared with daily dosing group (n = 1,014; 21.3% ± 4.0% vs 27.7% ± 1.4%, P < .04). However, compared with the statin discontinued group (n = 442), they had a significantly higher LDL-C reduction (21.3% ± 4.0% vs 8.3 ± 2.2%, P < .001), and a significantly higher portion achieved their Adult Treatment Panel III goal of LDL-C (61% vs 44%, P < .05). There was a trend toward a decrease in all-cause mortality at 8 years for patients on daily and intermittent statin dosing compared with those who discontinued statin (P = .08). CONCLUSIONS Most patients with previous statin intolerance can tolerate subsequent trial of statin. A strategy of intermittent statin dosing can be an effective therapeutic option in some patients and may result in reduction in LDL-C and achievement of LDL-C goals.

Effect of Timing of Chronic Preoperative Aspirin Discontinuation on Morbidity and Mortality in Coronary Artery Bypass Surgery

Background— Aspirin (ASA) has been shown to reduce postoperative coronary artery bypass grafting (CABG) mortality and ischemic events; however, the timing of chronic ASA discontinuation before surgery is controversial because of concern about postoperative bleeding. We evaluated the effect of the timing of ASA discontinuation before CABG on major adverse cardiovascular outcomes and postoperative bleeding using the Cleveland Clinic Cardiovascular Information Registry database. Methods and Results— At the Cleveland Clinic between January 1, 2002, and January 31, 2008, 4143 patients undergoing CABG were taking preoperative chronic ASA. Of these, 2298 discontinued ASA 6 or more days before surgery (early discontinuation), and 1845 took ASA within 5 days of the surgery (late use). Because of substantial differences between these 2 groups, propensity score analysis, and matching based on 31 variables were used for fair comparison of outcomes. This resulted in 1519 well-matched pairs of patients (73%). There was no significant difference between those with early discontinuation and late ASA use with regard to the composite outcome of in-hospital mortality, myocardial infarction, and stroke (1.7% versus 1.8%, P=0.80). Late use was associated with more intraoperative transfusions (23% versus 20%, P=0.03) and postoperative transfusions (30% versus 26%, P=0.009) but a similar number of reoperations for bleeding (3.4% versus 2.4% P=0.10). Conclusions— Among patients undergoing isolated CABG, late discontinuation of ASA resulted in no difference in postoperative cardiovascular outcomes; however, there was an increased transfusion requirement. Thus, we recommend weighing the risks and benefits of late ASA use in these patients.

The homocysteine hypothesis: still relevant to the prevention and treatment of cardiovascular disease?

Although evidence suggests that the homocysteine hypothesis is still relevant as a predictor of cardiovascular risk, we cannot conclude that measuring the homocysteine level is useful in guiding treatment. Furthermore, studies of primary and secondary prevention show no evidence that taking folic acid or other B vitamins lowers the risk of cardiovascular events. Elevated homocysteine is a risk factor, and vitamins lower homocysteine levels. But does vitamin supplementation prevent cardiovascular events?

Impact of Exercise on Heart Rate Recovery

Background— Abnormal heart rate recovery (HRR) has been shown to predict mortality. Although small studies have found that HRR can be improved with cardiac rehabilitation, it is unknown whether an improvement would affect mortality. The aim of this study was to determine whether HRR could be improved with cardiac rehabilitation and whether it would be predictive of mortality. Methods and Results— We evaluated 1070 consecutive patients who underwent exercise stress testing before and after completion of a phase 2 cardiac rehabilitation program. Heart rate recovery, defined as the difference between heart rate at peak exercise and exactly 1 minute into the recovery period, and mortality were followed up as the primary end points. Of 544 patients with abnormal baseline HRR, 225 (41%) had normal HRR after rehabilitation. Of the entire cohort, 197 patients (18%) died. Among patients with an abnormal HRR at baseline, failure to normalize after rehabilitation predicted a higher mortality (P<0.001). After multivariable adjustment, the presence of an abnormal HRR at exit was predictive of death in all patients (hazard ratio, 2.15; 95% confidence interval 1.43–3.25). Patients with abnormal HRR at baseline who normalized afterward had survival rates similar to those of the group with normal HRR at baseline and after cardiac rehabilitation (P=0.143). Conclusions— Heart rate recovery improved after phase 2 cardiac rehabilitation in the overall cohort. There was a strong association of abnormal HRR at exit with all-cause mortality. Patients with abnormal HRR at baseline who normalized HRR with exercise had a mortality similar to that of individuals with baseline normal HRR.