Effects of angiotensin-converting enzyme inhibition in low-risk patients early after coronary artery bypass surgery.

BACKGROUND: Early after coronary artery bypass surgery (CABG), activation of numerous neurohumoral and endogenous vasodilator systems occurs that could be influenced favorably by angiotensin-converting enzyme inhibitors. METHODS AND RESULTS: The Ischemia Management with Accupril post-bypass Graft via Inhibition of the coNverting Enzyme (IMAGINE) trial tested whether early initiation (< or = 7 days) of an angiotensin-converting enzyme inhibitor after CABG reduced cardiovascular events in stable patients with left ventricular ejection fraction > or = 40%. The trial was a double-blind, placebo-controlled study of 2553 patients randomly assigned to quinapril, target dose 40 mg/d, or placebo, who were followed up to a maximum of 43 months. The mean (SD) age was 61 (10) years. The incidence of the primary composite end point (cardiovascular death, resuscitated cardiac arrest, nonfatal myocardial infarction, coronary revascularization, unstable angina or heart failure requiring hospitalization, documented angina, and stroke) was 13.7% in the quinapril group and 12.2% in the placebo group (hazard ratio 1.15, 95% confidence interval 0.92 to 1.42, P=0.212) over a median follow-up of 2.95 years. The incidence of the primary composite end point increased significantly in the first 3 months after CABG in the quinapril group (hazard ratio 1.52, 95% confidence interval 1.03 to 2.26, P=0.0356). Adverse events also increased in the quinapril group, particularly during the first 3 months after CABG. CONCLUSIONS: In patients at low risk of cardiovascular events after CABG, routine early initiation of angiotensin-converting enzyme inhibitor therapy does not appear to improve clinical outcome up to 3 years after CABG; however, it increases the incidence of adverse events, particularly early after CABG. Thus, early after CABG, initiation of angiotensin-converting enzyme inhibitor therapy should be individualized and continually reassessed over time according to risk.

Angiotensin-converting enzyme inhibition in patients with coronary artery disease and preserved left ventricular function Ischemia Management with Accupril post-bypass graft via inhibition of angiotensin-converting enzyme (IMAGINE) compared with the other major trials in coronary artery disease.

It has been hypothesized that angiotensin-converting enzyme (ACE) inhibition, independent from its effect on ventricular function and blood pressure, could affect the atherosclerotic process and reduce the incidence of ischemic events and its complications. Several large clinical outcome trials were designed to test this hypothesis: QUIET, HOPE, EUROPA, PEACE, and IMAGINE. The results of the PEACE study were recently reported, leaving the IMAGINE study as the last chapter in our efforts to evaluate the role of ACE inhibition in coronary artery disease with preserved left ventricular function. In this report, we compare these studies with respect to their methodology and patient population and analyze the unique nature of the last ongoing study, IMAGINE. The reported studies show that patients with coronary artery disease who are at low-to-moderate or high risk should receive an ACE inhibitor if tolerated. However, when the absolute risk of a patient decreases, and intensive contemporary management is given, with good control of risk factors, the absolute and perhaps relative benefits of an ACE inhibitor decrease and their routine use in these patients may not be warranted. The role of ACE inhibition started early post-coronary artery bypass graft in patients with preserved left ventricular function, and intensive contemporary management remains to be determined and should get answered by the IMAGINE study. Moreover, the IMAGINE population is not only a lower risk population than those enrolled in HOPE or EUROPA, but also the risk for this population is bimodal in nature (early post-revascularization inflammation and thrombosis vs long-term atherosclerosis progression) and may provide further insight into underlying mechanisms.

Inflammatory biomarkers CRP, MCP-1, serum amyloid alpha and interleukin-18 in patients with HTN and dyslipidemia: impact of diabetes mellitus on metabolic syndrome and the effect of statin therapy.

The objective of this study was to determine the relationship of HTN (HTN) and the inflammatory markers C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), amyloid alpha (AA) and interleukin-18 (IL-18) in persons with HTN, considering concomitant diabetes mellitus (DM) or metabolic syndrome (MS). This was a multicenter twelve-week, single-step titration, open-label study of individuals with dyslipidemia, assigned according to their initial risk assessment, to atorvastatin starting doses of 10, 20, 40 or 80 mg. In subjects with HTN (N=677) versus no HTN (N=581), there were significantly (P<0.02) higher levels of CRP, IL-18, MCP-1 and AA but not for IL-18 when combined with DM or MS, and AA or CRP when combined with MS. Systolic blood pressure significantly (P<0.02) correlated with CRP, MCP-1 and AA but not IL-18. The greatest increase in CRP was with HTN plus DM. Statin therapy produced significant dose-dependent reductions in CRP but not with similar changes in other inflammatory markers. In summary, these data suggest a complex relationship between inflammation and HTN with dyslipidemia. Although HTN is associated with an increase in these inflammatory markers, the associated conditions DM or MS lead to different patterns of increases-MCP-1 being the most consistently increased with HTN, the greatest CRP increase was with HTN and DM, and no relationship was found with IL-18 and HTN in the presence of DM or MS. In addition, there are different responses to statins depending on the nature of the inflammatory marker.

Achieving cholesterol targets by individualizing starting doses of statin according to baseline low-density lipoprotein cholesterol and coronary artery disease risk category: the CANadians Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (CanACTFAST) study.

BACKGROUND: Despite an increasing body of evidence on the benefit of lowering elevated levels of low-density lipoprotein cholesterol (LDL-C), there is still considerable concern that patients are not achieving target LDL-C levels. OBJECTIVE: The CANadians Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (CanACTFAST) trial tested whether an algorithm-based statin dosing approach would enable patients to achieve LDL-C and total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C) ratio targets quickly. METHODS: Subjects requiring statin therapy, but with an LDL-C level of 5.7 mmol/L or lower, and triglycerides of 6.8 mmol/L or lower at screening participated in the 12-week study, which had two open-label, six-week phases: a treatment period during which patients received 10 mg, 20 mg, 40 mg or 80 mg of atorvastatin based on an algorithm incorporating baseline LDL-C value and cardiovascular risk; and patients who achieved both LDL-C and TC/HDL-C ratio targets at six weeks continued on the same atorvastatin dose. Patients who did not achieve both targets received dose uptitration using a single-step titration regimen. The primary efficacy outcome was the proportion of patients achieving target LDL-C levels after 12 weeks. RESULTS: Of 2016 subjects screened at 88 Canadian sites, 1258 were assigned to a study drug (1101 were statin-free and 157 were statin-treated at baseline). The proportion of subjects who achieved LDL-C targets after 12 weeks of treatment was 86% (95% CI 84% to 88%) for statin-free patients and 54% (95% CI 46% to 61%) for statin-treated patients. Overall, 1003 subjects (80%; 95% CI 78% to 82%) achieved both lipid targets. CONCLUSIONS: Algorithm-based statin dosing enables patients to achieve LDL-C and TC/HDL-C ratio targets quickly, with either no titration or a single titration.

Impact of previous percutaneous transluminal coronary angioplasty and/or stenting revascularization on outcomes after surgical revascularization: insights from the imagine study.

AIM: To determine the impact of previous coronary artery revascularization by percutaneous transluminal coronary angioplasty and/or stenting (PCI) on outcome after subsequent coronary artery bypass grafting (CABG). METHODS AND RESULTS: The ischaemia management with Accupril post-bypass Graft via Inhibition of the coNverting Enzyme (IMAGINE) trial, conducted between November 1999 and September 2004, tested whether early initiation of an angiotensin-converting enzyme inhibitor post-CABG, in stable patients with LVEF >or=40%, would reduce cardiovascular events. Of the 2489 patients included in the IMAGINE trial, undergoing their first operation, 430 had a history of PCI prior to surgery (PCI group), and 2059 were referred to surgery without previous PCI (non-PCI group). There was a significant increase in the primary IMAGINE endpoint in the PCI group, HR = 1.53 [1.17-1.98], P = 0.0016. Coronary revascularization, HR = 1.80 [1.13-2.87], P = 0.014, unstable angina requiring hospitalization, HR = 2.43 [1.52-3.89], P = 0.0002, were the two individual components that significantly increased in the PCI group, even when adjusted for baseline characteristics (age, sex, history of myocardial infarction or stroke, diabetes, treatment group, or off-pump surgery). CONCLUSION: Patients with left ventricular ejection fraction >or=40% having a history of PCI prior to surgery had a worse outcome post-CABG than those with no prior PCI. Further studies are needed to investigate whether these results apply for drug eluting stents.