Blair J. O'Neill

Angiotensin-Converting Enzyme Inhibition With Quinapril Improves Endothelial Vasomotor Dysfunction in Patients With Coronary Artery Disease

Background Angiotensin-converting enzyme (ACE) inhibitors may exert some of their benefits in the therapy of hypertension, congestive heart failure, and acute myocardial infarction by their improvement of endothelial dysfunction. TREND (Trial on Reversing ENdothelial Dysfunction) investigated whether quinapril might improve endothelial dysfunction in normotensive patients with coronary artery disease and no heart failure, cardiomyopathy, or major lipid abnormalities so that confounding variables that affect endothelial dysfunction could be minimized. Methods and Results Using a double-blind, randomized, placebo-controlled design, we measured the effects of quinapril (40 mg daily) on coronary artery diameter responses to acetylcholine using quantitative coronary angiography. The primary response variable was the net change in the acetylcholine-provoked constriction of target segments between the baseline (prerandomization) and 6-month follow-up angiograms. The constrictive responses to acetylcholine were c...

Angiotensin-Converting Enzyme Inhibition With Quinapril Improves Endothelial Vasomotor Dysfunction in Patients With Coronary Artery Disease The TREND (Trial on Reversing ENdothelial Dysfunction) Study

BACKGROUND Angiotensin-converting enzyme (ACE) inhibitors may exert some of their benefits in the therapy of hypertension, congestive heart failure, and acute myocardial infarction by their improvement of endothelial dysfunction. TREND (Trial on Reversing ENdothelial Dysfunction) investigated whether quinapril might improve endothelial dysfunction in normotensive patients with coronary artery disease and no heart failure, cardiomyopathy, or major lipid abnormalities so that confounding variables that affect endothelial dysfunction could be minimized. METHODS AND RESULTS Using a double-blind, randomized, placebo-controlled design, we measured the effects of quinapril (40 mg daily) on coronary artery diameter responses to acetylcholine using quantitative coronary angiography. The primary response variable was the net change in the acetylcholine-provoked constriction of target segments between the baseline (prerandomization) and 6-month follow-up angiograms. The constrictive responses to acetylcholine were comparable in the placebo (n = 54) and quinapril (n = 51) groups at baseline. After 6 months, only the quinapril group showed significant net improvement in response to incremental concentrations of acetylcholine (4.5 +/- 3.0% [mean +/- SEM] versus -0.1 +/- 2.8% at 10(-6) mol/L and 12.1 +/- 3.0% versus -0.8 +/- 2.9% at 10(-4) mol/L, quinapril versus placebo, respectively; overall P = .002). CONCLUSIONS TREND shows that ACE inhibition with quinapril improved endothelial dysfunction in patients who were normotensive and who did not have severe hyperlipidemia or evidence of heart failure. These benefits of ACE inhibition are likely due to attenuation of the contractile effects and superoxide-generating effects of angiotensin II and to enhancement of endothelial cell release of nitric oxide secondary to diminished breakdown of bradykinin.

Standardized Approaches to the Investigation of Syncope: Canadian Cardiovascular Society Position Paper

Syncope is a very common presentation in the emergency department, and the combination of a wide differential diagnosis, a range of prognoses, and infrequent documentation of the faint leads to a high proportion of patients being admitted. These problems are mirrored in the investigation of inpatients with syncope, for which the high proportion of patients with benign outcomes and the profound risk aversion of health care providers make for expensive and inefficient assessment. Difficulties such as this in health services delivery can be improved by standardized approaches, such as guidelines, pathways, and checklists. Accordingly, emergency department decision rules, specialized syncope-monitoring units, and formal diagnostic algorithms have been developed to provide standardized approaches to the investigation of syncope. To provide guidance in the management of syncope, the Canadian Cardiovascular Society commissioned a position paper on standardized approaches to syncope investigation in adults. A primary panel first reviewed the literature systematically, then undertook iterative syntheses of data, and finally took positions with specific recommendations according to the GRADE framework. This paper summarizes the evidence and its quality and makes recommendations on the specific approaches meriting adoption. The position paper was then reviewed by a secondary panel, which provided suggestions for revisions leading to the final document as presented here. Overall, the position group concluded that there is little persuasive evidence that emergency department syncope rules and diagnostic syncope units provide efficient care and improved outcomes but that formal diagnostic algorithms with specialist support show promise.

A novel enoxaparin regime for ST elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: a WEST sub-study.

Objective: To evaluate the anticoagulation effect of subcutaneous (SQ) and intravenous (IV) enoxaparin through systematic anti‐Xa sampling during primary PCI for acute STEMI. Background: Although appropriate anticoagulation is essential to maximize the efficacy and safety of primary PCI, the optimal dosing of enoxaparin in this setting is unclear. Methods: STEMI patients randomized to primary PCI received ASA, clopidogrel 300 mg and enoxaparin 1 mg/kg SQ at earliest point of care, including prehospital. Plasma anti‐Xa determination occurred just prior to and after primary PCI. Supplemental IV enoxaparin (0.3–0.5 mg/kg) and abciximab was encouraged prior to PCI. Results: The 1st anti‐Xa level 56 min (median, IQR 47–77) post SQ enoxaparin was 0.28 U/ml (0.23–0.41); 85% of patients (28/33) were <0.5 U/ml (the recommended therapeutic level). Following PCI, 126 min (118–185) after SQ enoxaparin in those without IV dosing (8/33) the 2nd anti‐Xa level was 0.44 U/ml (0.29–0.53); 6 of 8 patients remained <0.5 U/ml. With IV enoxaparin (25/33) the 2nd anti‐Xa was 0.96 U/ml (0.82–1.16) 97 min (82–109) after SQ enoxaparin: all were ≥0.5 U/ml and 2 had levels 1.5 U/ml. Conclusion: A single SQ enoxaparin dose fails to achieve anti‐Xa levels ≥0.5 U/ml in the majority of STEMI patients. When combined with a strategy of supplemental IV enoxaparin, adequate anti‐Xa levels were achieved in all patients with few having levels >1.5 U/ml. This regime of SQ injection with additional IV enoxaparin provides an attractive strategy enhancing effective early anti‐thrombotic therapy at first medical contact prior to primary PCI.

A Novel Approach to Cardiovascular Health By Optimizing Risk Management (ANCHOR): Behavioural Modification in Primary Care Effectively Reduces Global Risk

BACKGROUND Primary care is well positioned to facilitate cardiovascular risk improvement and reduce future cardiovascular disease (CVD) burden. METHODS The efficacy of risk factor screening, behavioural counselling, and pharmacological treatment to lower CVD risk was assessed via a prospective pre- and postintervention health risk assessment, individualized intervention with behaviour modification, risk factor treatment, and linkage to community programs, with 1-year follow-up and final health risk assessment. Primary outcome was the proportion of subjects with moderate and high baseline Framingham Risk Score (FRS) reducing their risk by 10% and 25%, respectively; the secondary end point was the proportion dropping ≥ 1 risk category. RESULTS Patients were enrolled (N = 1509) from March 2006 through October 2008 and 72% completed the study. This analysis focuses on 563 subjects with moderate or high baseline FRS, and excluded 325 low-risk patients and 205 with established CVD or diabetes mellitus. Median age was 56 years, 57.7% were female. The primary outcome was achieved in 31.8% (N = 112; 95% confidence interval [CI], 26.9%-36.6%) of moderate risk FRS participants and 47.9% (N = 101; 95% CI, 41.2%-54.6%) of high-risk participants. The secondary outcome was achieved by 37.2% (N = 210; 95% CI, 33.2%-41.2%). Prevalence of metabolic syndrome fell from 79.2% (N = 446; 95% CI, 75.9%-82.6%) at entry to 52.8% (N = 303; 95% CI, 48.7%-56.9%) at study end. Significant improvements in all modifiable risk factors occurred through lifestyle modification. CONCLUSIONS Global cardiovascular risk can be effectively decreased via lifestyle changes informed by readiness to change assessment and individualized counselling targeting specific behaviours. TRIAL REGISTRATION ClinicalTrials.gov number NCT01620996.

Influence of Smoking Status on Angiotensin-Converting Enzyme Inhibition–Related Improvement in Coronary Endothelial Function

Summary. Our study evaluated the influence of smoking status on coronary endothelial function in normotensive patients with coronary artery disease who received placebo or the angiotensin-converting enzyme inhibitor quinapril in the TREND study (Trial on Reversing Endothelial Dysfunction). In this retrospective analysis of data from the previously published study, patients were classified as either smokers (n = 23) or nonsmokers (n = 82). Patients underwent coronary angiography at baseline and again after 6 months follow-up. The primary response variable was the net change in acetylcholine-induced diameter of the target coronary artery segments (n = 105) between the baseline and 6-month follow-up angiograms. The secondary response variables were based on analysis of all segments (n = 300) and the mean diameter responses of target and all segments at 6 months. At baseline, coronary artery vasomotor responses were similar in smokers and nonsmokers in the placebo and quinapril groups. There was a significant improvement in the primary response variable for both smokers (P = 0.008) and nonsmokers (P = 0.047) randomized to quinapril compared with placebo. At 6 months follow-up, nonsmokers in the placebo group showed no significant change in the mean vasoconstrictor responses (8.3% vs. 8.0% at acetylcholine 10-4 mol/L), whereas nonsmokers in the quinapril-treated group showed significantly less vasoconstriction (2.7% vs. 13.2%; P = 0.003). Among smokers in the placebo group, vasoconstriction increased nonsignificantly (21.7% vs. 17.2% at baseline) but decreased significantly in the quinapril group (0.5% vs. 17.9%; P = 0.002). These results indicate that ACE inhibition improves the coronary vasomotor response in both smokers and nonsmokers, but that smokers apparently derive greater benefit.

A Novel Approach to Cardiovascular Health by Optimizing Risk Management (ANCHOR): A Primary Prevention Initiative Examining the Impact of Health Risk Factor Assessment and Management on Cardiac Wellness

Cardiovascular disease (CVD) represents an increasing burden to health care systems. Modifiable risk factors figure prominently in the population-attributable risk for premature coronary artery disease. Primary care is well placed to facilitate CVD risk improvement. We plan to evaluate the ability of a novel primary care intervention providing systematic risk factor screening, risk-weighted behavioural counselling and pharmacological intervention to achieve 2 objectives: (1) optimized management of global CVD risk of patients and (2) increased patient adherence to lifestyle and pharmaceutical interventions aimed at decreasing global CVD risk. A pre-post longitudinal prospective design with a nonrandomized comparison group is being undertaken in 2 geographically diverse primary care practices in Nova Scotia with differing reimbursement models. Participants will complete a readiness to change and pre-post health risk assessment (HRA), that will trigger a 1-year intervention individualized around risk and readiness. The primary outcome will be the proportion of participants with Framingham moderate and high-risk strata that reduce their absolute risk by 10% and 25%, respectively. The secondary outcome will be the proportion of moderate and high-risk participants who reduce their risk category. The impact of the intervention on clinical and behavioural variables will also be examined. Low risk participants will be separately analyzed. Data from participants unable to change from the high risk category because of diabetes mellitus or established atherosclerotic disease will also be analyzed separately, with changes in clinical measures from baseline being assessed. A health economic analysis is planned.

Role of the fractalkine receptor CX3CR1 polymorphisms V249I and T280M as risk factors for early‐onset coronary artery disease in patients with no classic risk factors

Objectives. CX3CR1 is a monocyte chemokine receptor and adhesion molecule. Two CX3CR1 mutations, V249I and T280M, reportedly decrease coronary artery disease (CAD) risk independent of established risk factors. An I249 protective effect is attributed to reducing CX3CR1 binding to fractalkine, its ligand. Material and methods. We examined the frequencies of V249I and T280M among early‐onset CAD patients (G1; n = 149; <50 years), late‐onset CAD patients (G2; n = 150; >65 years) and healthy controls (HC; n = 149, 47–93 years) without known CAD risk factors. We compared plasma total cholesterol (TC)/high density lipoprotein‐C (HDL‐C) and apolipoprotein B (APOB)/apolipoprotein AI (APOAI) ratios among the groups and mutation carriers and non‐carriers, and the prevalence of the mutations in G1 and G2 patients with multiple coronary vessel disease (MVD) and myocardial infarction (MI). Results. G1 patients had non‐significantly lower frequencies of I249 versus (vs.) G2 or controls (G1; 51 %, G2: 61 %, controls: 58 %, p = 0.19), with no difference in T280M (p = 0.8). TC/HDL‐C and APOB/APOAI ratios were significantly higher in G1 patients vs. G2 and controls (p<0.0001) independently of either mutation. More G2 patients had MVD than younger ones (p<0.0001); however, more G1 patients were homozygous for V249 compared to G2 patients, who more often had the I249 allele (p<0.02). There was no such association with T280M (p = 0.38). Although more G1 patients had MI, this was not mutation related. Conclusions. There were significantly higher lipid ratios in G1 compared to G2 and HC (G1>G2>HC), but not in mutation prevalence. I249 mutation was associated with MVD in older patients, while V249 homozygosity was associated with the early‐onset CAD. Neither allele affected MI or lipid levels.

Aligning Health Care Policy With Evidence-Based Medicine: The Case for Funding Direct Oral Anticoagulants in Atrial Fibrillation

Misalignment between evidence-informed clinical care guideline recommendations and reimbursement policy has created care gaps that lead to suboptimal outcomes for patients denied access to guideline-based therapies. The purpose of this article is to make the case for addressing this growing access barrier to optimal care. Stroke prevention in atrial fibrillation (AF) is discussed as an example. Stroke is an extremely costly disease, imposing a significant human, societal, and economic burden. Stroke in the setting of AF carries an 80% probability of death or disability. Although two-thirds of these strokes are preventable with appropriate anticoagulation, this has historically been underprescribed and poorly managed. National and international guidelines endorse the direct oral anticoagulants as first-line therapy for this indication. However, no Canadian province has provided these agents with an unrestricted listing. These decisions appear to be founded on silo-based cost assessment-the drug costs rather than the total system costs-and thus overlook several important cost-drivers in stroke. The discordance between best scientific evidence and public policy requires health care providers to use a potentially suboptimal therapy in contravention of guideline recommendations. It represents a significant obstacle for knowledge translation efforts that aim to increase the appropriate anticoagulation of Canadians with AF. As health care professionals, we have a responsibility to our patients to engage with policy-makers in addressing and resolving this barrier to optimal patient care.

Applying the new STEMI guidelines: 1. Reperfusion in acute ST-segment elevation myocardial infarction.

Case A 50-year-old woman experiences jaw discomfort while at work. It increases in intensity, accompanied by diaphoresis and nausea. An ambulance is called 40 minutes after symptom onset. On arrival to the emergency department, the woman has moderate pain, a blood pressure of 150/85 mm Hg and a