Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

A Comparison of Genome-Wide DNA Methylation Patterns between Different Vascular Tissues from Patients with Coronary Heart Disease

Epigenetic mechanisms of gene regulation in context of cardiovascular diseases are of considerable interest. So far, our current knowledge of the DNA methylation profiles for atherosclerosis affected and healthy human vascular tissues is still limited. Using the Illumina Infinium Human Methylation27 BeadChip, we performed a genome-wide analysis of DNA methylation in right coronary artery in the area of advanced atherosclerotic plaques, atherosclerotic-resistant internal mammary arteries, and great saphenous veins obtained from same patients with coronary heart disease. The resulting DNA methylation patterns were markedly different between all the vascular tissues. The genes hypomethylated in athero-prone arteries to compare with atherosclerotic-resistant arteries were predominately involved in regulation of inflammation and immune processes, as well as development. The great saphenous veins exhibited an increase of the DNA methylation age in comparison to the internal mammary arteries. Gene ontology analysis for genes harboring hypermethylated CpG-sites in veins revealed the enrichment for biological processes associated with the development. Four CpG-sites located within the MIR10B gene sequence and about 1 kb upstream of the HOXD4 gene were also confirmed as hypomethylated in the independent dataset of the right coronary arteries in the area of advanced atherosclerotic plaques in comparison with the other vascular tissues. The DNA methylation differences observed in vascular tissues of patients with coronary heart disease can provide new insights into the mechanisms underlying the development of pathology and explanation for the difference in graft patency after coronary artery bypass grafting surgery

Dynamics of parameters of psychological status of patients with stable ischemic heart disease and coronary artery bypass surgery

Aim. Assessment and analysis of parameters of psychological status of patients with coronary heart disease (CHD) referred for coronary artery bypass surgery (CABG).&#x0D; Materials and Methods. A study of parameters of psychological status, in particular, of the attitude to illness, coping strategies, and lifelong orientations was conducted in 58 male patients aged 40 to 74 years with a stable form of CHD before and after CABG surgery. The parameters were evaluated by a clinical psychologist in 2-3 days after admission of the patient to the hospital and in 7-8 days after CABG. Clinical and psychological diagnostics was carried out using the following questionnaires: TOBOL (L.I. Wasserman, et al.), Life-Purpose Orientations (D.A. Leontiev), Coping Behavior Strategies (R. Lazarus, adapted version of T.A. Kryukova). Statistical analysis was performed with use of computer Statistica 10.0 software program.&#x0D; Results. After CABG patients with coronary artery disease show a significant reduction of the parameters of the anxious variant of the internal picture of the disease on the basis of TOBOL questionnaire, of the positive re-evaluation coping strategy on the basis of evaluation of stress-coping behavior and of the level of Aim scale on the basis of evaluation of the level of neurotization using the Life-Purpose test.&#x0D; Conclusion. The results of the study indicate reduction of the level of adaptation to the disease in patients with coronary artery disease after CABG in result of behavioral disorders and difficulties in setting further aims for recovery. To increase postoperative adaptation, the psychocorrection measures may be targeted to the coping strategy for positive re-evaluation and assistance in setting aims in the postoperative stage of CABG.</jats:p

Type 2 diabetes mellitus first diagnosed before surgery affects the immediate prognosis for coronary artery bypass grafting

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Federal State Budgetary Institution “Research Institute for Complex Issues of Cardiovascular Diseases” Purpose To study the preoperative status and assess the rate of in-hospital complications in patients with newly diagnosed type 2 diabetes mellitus (DM) undergoing coronary artery bypass grafting compared to patients with previously diagnosed DM and normoglycemia. Materials and Methods. 708 consecutive patients who underwent coronary artery bypass grafting (CABG) between 2011 to 2012 at the Research Institute for Complex Issues of Cardiovascular Diseases were included in the study. All patients without positive history of diabetes underwent an oral glucose tolerance test (ОGTT). The lab findings were interpreted in accordance with the recommended diagnostic criteria for diabetes and other glycemic disorders. Results. DM screening before coronary artery bypass grafting allowed to diagnose type 2 diabetes in 8.9% (n = 63) and prediabetes in 10.4% (n = 74) of the study population. The preoperative screening increased the number of patients with DM from 15.2% (n = 108) to 24.1% (n = 171), and with prediabetes from 3.0% (n = 21) to 13.4% (n = 95). The total number of patients with carbohydrate metabolism disorders increased from 18.2% (n = 129) to 37.5% (n = 266). The study groups did not differ in the rate of in-hospital complications due to a relatively low number of occurred events. However, a trend towards higher rate of in-hospital complications after CABG was defined among patients with newly diagnosed and previously diagnosed DM. The regression analysis demonstrated the presence of the relationships between the previously diagnosed DM2 and the total number of significant complications (odds ratio (OR) - 1.350, 95% confidence interval (CI): 1.057-1.723, p = 0.020) and prolonged in-hospital stay (OR 1.609, 95% CI: 1.202-2.1555, p = 0.001). The significance of the mentioned above relationships increased with the addition of newly diagnosed diabetes to the regression model as a probable predictor (for in-hospital complications: OR = 1.731, 95% CI: 1.131-2.626, p = 0.012; for prolonged in-hospital stay: OR 2.229, 95% CI: 1.412-3.519, p &amp;lt;0.001). Moreover, additional associations between DM and the risk of developing multiple organ dysfunction (OR 2.911, 95% CI 1.072-7.901, p = 0.039), urgent lower extremity surgery (OR 1.638, 95% CI 1.009-15.213, p = 0.020) and the need for extracorporeal correction of hemostasis (OR 3.472, 95% CI: 1.042-11.556, p = 0.044) have been defined. Importantly, the presence of these associations would not have been identified without including newly diagnosed DM in the regression model. Conclusion The newly diagnosed diabetes mellitus affects the prognosis of CABG as well as the previously diagnosed DM. The obtained results suggest the importance of active preoperative DM screening. </jats:sec