Reduced risk of myocardial infarct and revascularization following coronary artery bypass grafting compared with percutaneous coronary intervention in patients with chronic kidney disease.

Coronary atherosclerotic disease is highly prevalent in chronic kidney disease (CKD). Although revascularization improves outcomes, procedural risks are increased in CKD, and unbiased data comparing coronary artery bypass grafting (CABG) and percutaneous intervention (PCI) in CKD are sparse. To compare outcomes of CABG and PCI in stage 3 to 5 CKD, we identified randomized trials comparing these procedures. Investigators were contacted to obtain individual, patient-level data. Ten of 27 trials meeting inclusion criteria provided data. These trials enrolled 3993 patients encompassing 526 patients with stage 3 to 5 CKD of whom 137 were stage 3b-5 CKD. Among individuals with stage 3 to 5 CKD, mortality through 5 years was not different after CABG compared with PCI (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.67-1.46) or stage 3b-5 CKD (HR 1.29, CI 0.68-2.46). However, CKD modified the impact on survival free of myocardial infarction: it was not different between CABG and PCI for individuals with preserved kidney function (HR 0.97, CI 0.80-1.17), but was significantly lower after CABG in stage 3-5 CKD (HR 0.49, CI 0.29-0.82) and stage 3b-5 CKD (HR 0.23, CI 0.09-0.58). Repeat revascularization was reduced after CABG compared with PCI regardless, of baseline kidney function. Results were limited by unavailability of data from several trials and paucity of enrolled patients with stage 4-5 CKD. Thus, our patient-level meta-analysis of individuals with CKD randomized to CABG versus PCI suggests that CABG significantly reduces the risk of subsequent myocardial infarction and revascularization without affecting survival in these patients.

Treatment of stable angina pectoris by ivabradine in every day practice: the REDUCTION study.

BACKGROUND: The antianginal efficacy of ivabradine was studied in controlled clinical trials. Strict patient selection criteria may cause a discrepancy between the results of highly controlled clinical trials and everyday routine practice. The objective of this study was to evaluate the efficacy and safety of ivabradine in everyday routine practice. METHODS: In this multicenter study, 4,954 patients with stable angina pectoris received ivabradine in everyday routine practice and underwent follow-up for 4 months. The heart rate (HR), angina pectoris attacks, nitrate consumption, overall efficacy, and tolerance were evaluated. RESULTS: Within 4 months of treatment with ivabradine, HR was reduced by 12.4 +/- 12.2 beat/min from 82.9 +/- 15.3 to 70.4 +/- 9.2 beat/min (P < .0001). Angina pectoris attacks were reduced from 2.4 +/- 3.1 to 0.4 +/- 1.5 per week (P < .0001). Consumption of short-acting nitrates was reduced from 3.3 +/- 4.4 to 0.6 +/- 1.6 U/wk (P < .0001). Seventy-eight cases of adverse drug reactions were reported. The most common adverse drug reactions were nausea (n = 11, 0.22%) and dizziness (n = 9, 0.18%). Efficacy and tolerance were graded by physicians as being "excellent/very good" for 97% and 98% of the patients treated. CONCLUSION: Ivabradine reduces the HR and is highly effective and well tolerated in the treatment of patients with symptomatic coronary artery disease. The results confirm the findings of controlled clinical trials in a broad patient population in everyday routine practice.

Impaired capacity for acute endogenous fibrinolysis in smokers is restored by ascorbic acid.

Elevated levels of fibrinogen, C-reactive protein, and increased platelet aggregation are known to be increased by cigarette smoking, but the underlying mechanisms of the prothrombotic state in smokers are not completely understood. Since cigarette smoke contains several oxidants, we investigated the effect of the antioxidant ascorbic acid on stimulated fibrinolytic activity in smokers. Long-term heavy smokers and nonsmokers were studied by measurement of forearm blood flow; coinfusion of ascorbic acid was used to reduce oxidative stress. Concentrations of t-PA antigen and activity, of plasminogen activator inhibitor-1 (PAI-1) antigen and activity, and of C-reactive protein were determined by enzyme-linked immunosorbent assays and photometry, respectively. While dose-response curves of forearm blood flow elicited by substance P were not altered by the coadministration of ascorbic acid in nonsmokers, impaired flow in smokers markedly increased, P=0.003. Also, selectively in smokers, the maximal stimulated net release of t-PA antigen and of t-PA activity increased when ascorbic acid was infused simultaneously, P=0.002. In smokers CRP concentrations correlated significantly with the effect of ascorbic acid on maximal t-PA activity release, P<0.0001. Our data demonstrate that the endothelial capacity to acutely release t-PA is significantly reduced in heavy smokers and can be reversed by ascorbic acid. This association is particularly pronounced in smokers with high serum levels of C-reactive protein, suggesting that smoking-induced inflammation impairs fibrinolysis in these patients.

Association between eotaxin (CCL11), C-reactive protein, and antimicrobial antibodies in patients undergoing coronary angioplasty.

Eotaxin (CCL11) is a potent chemoattractant for eosinophils and lymphocytes. Apart from its functions in the eosinophilic system, eotaxin has been shown to be overexpressed in atherosclerosis. We therefore sought to determine whether chronic infection with Chlamydia pneumoniae or other infectious agents is correlated with concentrations of eotaxin or C-reactive protein since this mechanism could explain the finding that chronic infection stimulates smooth muscle cell migration and plaque development. Patients undergoing percutaneous coronary angioplasty (PCI) for acute coronary syndrome or stable angina were included in the study. Blood was drawn before PCI, at 6 weeks, and 6 and 12 months after coronary intervention. Eotaxin and C-reactive protein were determined by enzyme-linked immunosorbent assay (ELISA). Antibodies against Candida, C. pneumoniae, cytomegalovirus, Helicobacter pylori, and herpes simplex virus were measured by ELISA or immunofluorescence. Two hundred five consecutive patients undergoing PCI (stable angina, n = 136; acute coronary syndrome, n = 69) and 83 patients with normal coronary arteries were enrolled in the study. Eotaxin concentrations at inclusion were higher in patients with coronary artery disease than in control patients, p = .01, and comparable in patients with stable angina and those with acute coronary syndrome but did not correlate with C-reactive protein. Eotaxin concentrations at inclusion and during follow-up weakly correlated with concentrations of antibodies against C. pneumoniae, H. pylori, and herpes simplex virus but not with concentrations of antibodies against Candida or cytomegalovirus. Eotaxin concentrations and antibody titers against C. pneumoniae significantly increased following angioplasty and remained elevated thereafter. In conclusion, our data demonstrate that eotaxin concentrations are elevated independently from C-reactive protein in patients with coronary artery disease and correlate with antibodies against infectious agents known for chronic infection in humans.

A randomized trial in patients undergoing percutaneous coronary angioplasty: roxithromycin does not reduce clinical restenosis but angioplasty increases antibody concentrations against Chlamydia pneumoniae.

BACKGROUND: Elevated antibodies against Chlamydia pneumoniae have been associated with coronary artery disease. In patients undergoing percutaneous coronary angioplasty, we therefore investigated the effect of roxithromycin on symptomatic restenosis and determined antichlamydial antibodies as well as inflammatory and immunological parameters. METHODS: A total of 327 patients undergoing coronary angioplasty were randomized to roxithromycin or placebo and followed-up for 1 year. Antibodies were determined by microimmunofluorescence and enzyme-linked immunosorbent assay; C-reactive protein, interleukin-10, tumor necrosis factor-alpha (TNF-alpha), and eotaxin were determined by enzyme-linked immunosorbent assay. RESULTS: Although the frequency of restenosis was not affected by roxithromycin (25 restenoses vs 32 in the control group), antichlamydial antibodies increased during follow-up (anti-CP IgG +12 +/- 2%, P < .001). Concentrations of TNF-alpha and eotaxin increased as well (TNF-alpha +9 +/- 1% and eotaxin +10 +/- 2%) and correlated with antichlamydial antibody concentrations (TNF-alpha, r = 0.23, P = .02; eotaxin, r = 0.32, P = .002). CONCLUSIONS: Treatment with roxithromycin was not associated with a reduction of symptomatic restenoses. During follow-up, a marked increase in antichlamydial antibodies, TNF-alpha, and eotaxin was observed, suggesting that angioplasty-induced plaque rupture induces a specific immunological response without activation of inflammatory mechanisms as represented by C-reactive protein. Whether this mechanism occurs in all plaque ruptures remains to be determined.

Ivabradine for the treatment of stable angina pectoris in octogenarians.

PURPOSE: In patients >80 years (octogenarians), there is an increased incidence of bradycardia due to age-related alteration of the sinus node, AV node, and the conduction system. Therefore, the treatment of angina pectoris with beta-blockers may be limited by bradycardia. The REDUCTION multicenter study evaluated the efficacy of ivabradine in stable angina pectoris in everyday practice. This subgroup analysis evaluated the efficacy and safety of ivabradine in octogenarians. METHODS: A total of 4,954 patients were included in the REDUCTION study for treatment of stable angina pectoris. This group included 382 octogenarians (mean age 83 ± 2.9 years) who were followed up over 4 months. Patients were treated with ivabradine in flexible doses (2.5, 5, or 7.5 mg bid). Heart rate (HR), angina pectoris attacks, nitrate consumption, overall efficacy, and tolerance were evaluated. RESULTS: After 4 months of treatment with ivabradine, HR was reduced by 12.0 ± 12.0 bpm from 83.0 ± 15.4 to 71.0 ± 10.1 bpm (p < 0.0001). Angina pectoris attacks were reduced from 3.0 ± 4.6 to 0.8 ± 1.8 per week (p < 0.0001). Consumption of nitrates decreased from 4.2 ± 5.1 to 1.2 ± 2.7 (p < 0.0001). Four patients reported suspected adverse drug reactions. In one patient a syncope occurred. There was no symptomatic bradycardia reported. Efficacy and tolerance were assessed as 'very good/good' for 95 and 99%. CONCLUSIONS: The results demonstrate that ivabradine efficiently reduces HR, number of angina attacks, and nitrate consumption in octogenarian patients. The treatment was safe and well tolerated without relevant bradycardia.

Coronary angiography and intervention during hypothermia can be performed safely without cardiac arrhythmia or vasospasm.

PURPOSE: Mild therapeutic hypothermia is a neuroprotective procedure after cardiac arrest. Therefore, it is increasingly used. Likewise, there is a growing demand for coronary angiography and percutaneous coronary interventions under hypothermia. Case studies suggested that hypothermia may be associated with coronary vasospasm, heart rhythm events and platelet dysfunction. In this study, it was evaluated whether vasospasm, arrhythmia or bleeding occur to a relevant degree during cardiac catheterization under concomitant hypothermia. METHODS: In this prospective, single-center, open-label, non-interventional study, 29 patients after resuscitation for cardiac arrest were treated with mild hypothermia and underwent cardiac catheterization (coronary angiography n = 11, coronary angiography plus percutaneous intervention n = 18). The incidence of vasospasm, cardiac arrhythmia and relevant bleeding at the puncture site were evaluated. RESULTS: Mean temperature at cardiac catheterization was 33.9 ± 0.76°C. The mean heart rate was 82 ± 26 bpm at hospital admission and 67 ± 17 bpm under hypothermia (p < 0.05). There was no patient with relevant bradycardia beyond the expected hypothermia-induced rate reduction during the procedure. There were no unexpected ventricular tachycardias or episodes of ventricular fibrillation which might have been attributed to hypothermia. Twenty-nine of 29 patients (100%) were free from coronary vasospasm. There was no patient with a relevant bleeding at the puncture site. Potassium levels were low in 52% of the patients, even after resuscitation, which was partially attributed to hypothermia. CONCLUSION: Coronary angiography and percutaneous coronary interventions under mild therapeutic hypothermia were safe in this small cohort and were performed without hypothermia-induced vasospasm, relevant rhythm events or bleeding complications. This result has to be confirmed in a large series of patients.

Ivabradine in combination with beta-blocker therapy for the treatment of stable angina pectoris in every day clinical practice.

PURPOSE: The anti-anginal efficacy of the selective I(f) inhibitor ivabradine has been demonstrated in controlled clinical trials. However, there is limited information about the safety and efficacy of a combined treatment of ivabradine with beta-blockers, particularly outside of clinical trials in every day practice. This analysis from the REDUCTION study evaluated the safety and efficacy of a combined therapy of beta-blockers and ivabradine in every day practice. METHODS: In this multi-center study 4,954 patients with stable angina pectoris were treated with ivabradine in every day routine practice and underwent a clinical follow-up for 4 months. 344 of these patients received a co-medication with beta-blockers. Heart rate (HR), angina pectoris episodes, nitrate consumption, overall efficacy and tolerance were analyzed. RESULTS: After 4 months of treatment with ivabradine HR was reduced by 12.4 ± 11.6 bpm from 84.3 ± 14.6 to 72.0 ± 9.9 bpm, p < 0.0001. Angina pectoris episodes were reduced from 2.8 ± 3.3 to 0.5 ± 1.3 per week, p < 0.0001. Consumption of short-acting nitrates was reduced from 3.7 ± 5.6 to 0.7 ± 1.7 units per week, p < 0.0001. Five patients (1.5%) reported adverse drug reactions (ADR). The most common ADR were nausea and dizziness (<0.6% each). There was no clinically relevant bradycardia. Efficacy and tolerance were graded as 'very good/good' for 96 and 99% of the patients treated. CONCLUSION: Ivabradine effectively reduces heart rate and angina pectoris in combination with beta-blockers and is well tolerated by patients in every day practice.

Interleukin-3 is elevated in patients with coronary artery disease and predicts restenosis after percutaneous coronary intervention.

BACKGROUND: Interleukin-3 (IL-3) synthesized by activated T-lymphocytes is a mediator in chronic inflammation and is suspected to promote atherosclerosis. Since there is no data on IL-3 in patients with coronary artery disease (CAD) available, we compared IL-3 concentrations in different subsets of patients with CAD to healthy control patients. METHODS: 205 consecutive patients with CAD, 136 with stable angina and 69 with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention, 61 patients with asymptomatic CAD and 41 patients with normal coronary arteries were investigated. Serum concentrations of IL-3 and hs-CRP were assessed at baseline and after 6 weeks, 6, and 12 months. RESULTS: In patients undergoing coronary angioplasty, IL-3 was detectable more frequently than in those with asymptomatic CAD or without CAD, 21 vs. 8%, p=0.02, and 21 vs. 1%, p<0.001, respectively. Patients undergoing coronary angioplasty who developed symptomatic restenosis more frequently had detectable IL-3 levels than patients without restenosis, 45 vs. 17%, p=0.02. IL-3 was the only independent predictor for restenosis in a multivariate analysis. Hs-CRP was significantly elevated in patients with ACS, 230+/-170 mg/l vs. 100+/-140 mg/l, p=0.02, but did not correlate with IL-3 concentrations at any time. CONCLUSION: IL-3, an important regulator of chronic inflammation, is elevated in patients with CAD, particularly in symptomatic patients undergoing percutaneous coronary intervention. Furthermore, high IL-3 concentrations were found to be predictive of symptomatic restenosis.

13-year follow-up of the German angioplasty bypass surgery investigation.

AIMS: The German Angioplasty Bypass Surgery Investigation was designed to compare symptomatic efficacy and safety of percutaneous coronary balloon angioplasty (PTCA) with coronary artery bypass surgery (CABG) in patients with symptomatic multi-vessel disease. This follow-up study was performed to determine the long-term outcome of patients following these interventions. METHODS AND RESULTS: From 1986 to 1991, 359 patients with angina CCS class II-IV, age below 75 years, and coronary multi-vessel disease requiring revascularization of at least two major coronary vessels were recruited at eight German centres and randomized to PTCA or CABG. From 337 patients undergoing the planned procedure, 324 patients could be followed-up (96%). Baseline parameters were identical in both groups, 2.2+/-0.6 vessels were treated in CABG patients, whereas 1.9+/-0.5 vessels were treated in PTCA patients. Thirty-seven per cent of surgical patients received internal mammary artery grafts, while no stents were used in patients undergoing PTCA. At the end of the 13-year follow-up period, the degree of angina, the degree of dyspnea, and the utilization of nitrates were comparable in both groups. With a total number of 76 deaths, Kaplan-Meier analysis revealed a comparable distribution in both groups. Although time to first re-intervention was significantly shorter in the PTCA group, P<0.001, frequencies of re-intervention (CABG, n=94; PTCA, n=136) and crossover rates (CABG to PTCA, n=49; PTCA to CABG, n=51) were comparable in both groups. CONCLUSION: The results of our 13-year follow-up suggest that in patients with symptomatic multi-vessel disease, both PTCA and CABG are associated with a comparable long-term survival and symptomatic efficacy. How far these results may be altered by developments such as drug-eluting stents or off-pump surgery remains to be determined.

Endothelin-1 mRNA and protein in vascular wall cells is increased by reactive oxygen species.

A dysregulated metabolism of oxygen-derived free radicals, nitric oxide and endothelin-1(ET-1) in conditions such as hypercholesterolaemia or hypertension may promote the development of atherosclerosis. We therefore subjected cultured human umbilical vein endothelial cells and coronary artery smooth muscle cells to oxidative stress induced by xanthine oxidase or hydrogen peroxide and observed alterations in ET-1 metabolism. Incubation with oxygen-derived free radicals increased preproET-1 promoter activity, ET-1 mRNA synthesis and big ET-1 concentrations in both cell types. This interaction of oxidative stress and ET-1 expression may be relevant in atherogenic conditions such as hypercholesterolaemia and hypertension since our data indicate that oxidative stress further aggravates the injurious effects attributed to ET-1.