Ralph Stewart

Darapladib for Preventing Ischemic Events in Stable Coronary Heart Disease

BACKGROUND Elevated lipoprotein-associated phospholipase A2 activity promotes the development of vulnerable atherosclerotic plaques, and elevated plasma levels of this enzyme are associated with an increased risk of coronary events. Darapladib is a selective oral inhibitor of lipoprotein-associated phospholipase A2. METHODS In a double-blind trial, we randomly assigned 15,828 patients with stable coronary heart disease to receive either once-daily darapladib (at a dose of 160 mg) or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the components of the primary end point as well as major coronary events (death from coronary heart disease, myocardial infarction, or urgent coronary revascularization for myocardial ischemia) and total coronary events (death from coronary heart disease, myocardial infarction, hospitalization for unstable angina, or any coronary revascularization). RESULTS During a median follow-up period of 3.7 years, the primary end point occurred in 769 of 7924 patients (9.7%) in the darapladib group and 819 of 7904 patients (10.4%) in the placebo group (hazard ratio in the darapladib group, 0.94; 95% confidence interval [CI], 0.85 to 1.03; P=0.20). There were also no significant between-group differences in the rates of the individual components of the primary end point or in all-cause mortality. Darapladib, as compared with placebo, reduced the rate of major coronary events (9.3% vs. 10.3%; hazard ratio, 0.90; 95% CI, 0.82 to 1.00; P=0.045) and total coronary events (14.6% vs. 16.1%; hazard ratio, 0.91; 95% CI, 0.84 to 0.98; P=0.02). CONCLUSIONS In patients with stable coronary heart disease, darapladib did not significantly reduce the risk of the primary composite end point of cardiovascular death, myocardial infarction, or stroke. (Funded by GlaxoSmithKline; STABILITY ClinicalTrials.gov number, NCT00799903.).

Increased Plasma Natriuretic Peptide Levels Reflect Symptom Onset in Aortic Stenosis

Background—The onset of symptoms is a critical point in the natural history of aortic stenosis and the cardinal indication for valve replacement. This study assessed the associations between natriuretic peptide levels, disease severity, and cardiac symptoms in aortic stenosis. Methods and Results—Seventy-four patients with isolated aortic stenosis underwent independent assessment of symptoms, transthoracic echocardiography, and measurement of plasma levels of atrial natriuretic peptide, brain natriuretic peptide (BNP), and N-BNP. Natriuretic peptide levels were also measured in 100 clinically normal control subjects. The aortic valve area was smaller in symptomatic patients (n=45) than in asymptomatic patients (n=29; mean, 0.71±0.23 cm2 and 0.99±0.31 cm2, respectively;P <0.0001). Plasma natriuretic peptide levels were higher in symptomatic patients than in asymptomatic patients (for N-BNP: median, 112 versus 33 pmol/L; interquartile range, 70 to 193 versus 16 to 58 pmol/L, respectively;P =0.0002). After adjustment for age, sex, serum creatinine, aortic valve area, and left ventricular ejection fraction, N-BNP levels were 1.74 times higher (95% confidence interval, 1.12 to 2.69) for symptomatic than asymptomatic patients with aortic stenosis (P =0.014). Natriuretic peptide levels increased with the New York Heart Association class (for N-BNP median values were 13, 34, 105, and 202 pmol/L for normal control subjects, class I, class II, and class III/IV patients, respectively; interquartile ranges for the same patients were 8 to 21, 16 to 58, 57 to 159, and 87 to 394 pmol/L;P <0.0001). Similar associations were observed for BNP and atrial natriuretic peptide. Conclusions—Plasma natriuretic peptide levels are elevated in symptomatic patients with aortic stenosis. Measurement of natriuretic peptides may complement clinical and echocardiographic evaluation of patients with aortic stenosis.

Plasma natriuretic peptide levels increase with symptoms and severity of mitral regurgitation

OBJECTIVES This paper will describe associations between plasma natriuretic peptide levels and the severity and symptoms of mitral regurgitation (MR). BACKGROUND A biochemical test that assisted grading of the severity of MR and the interpretation of symptoms would be of clinical value. METHODS Forty-nine patients with isolated MR and left ventricular (LV) ejection fractions (EFs) of >55% underwent transthoracic echocardiography, assessment of symptoms, and measurement of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and its amino-terminal portion, N-BNP. RESULTS The level of each natriuretic peptide rose with increasing severity of MR and with increases in left atrial (LA) dimensions (p < 0.001 for all comparisons), but no significant correlation existed between any natriuretic peptide and the LV dimensions or EF. Natriuretic peptide levels were higher in symptomatic MR (n = 16, BNP geometric mean 16.9 [95% confidence interval (CI) 13.3 to 21.4] pmol/l) compared with asymptomatic MR (n = 33, BNP 7.1 [95% CI 6.0 to 8.4] pmol/l, p < 0.001), and higher in asymptomatic MR than in normal controls (n = 100, BNP 5.3 [95% CI 4.8 to 5.8] pmol/l, p < 0.0001). These differences were similar for N-BNP and ANP and remained statistically significant (p < 0.05) after adjustment for echocardiographic measures of LV function and severity of MR. Both the sensitivity and the specificity for symptoms for the natriuretic peptides (area under receiver-operator characteristic curve for BNP = 0.90, N-BNP = 0.89, ANP = 0.89) were similar to the MR score (0.88) and greater than for LA dimension (0.81), vena contracta width (0.82), and LV end-systolic dimension (0.63). CONCLUSIONS Plasma natriuretic peptides levels increase with the severity of MR and are higher in symptomatic compared to asymptomatic patients, even when LV EF is normal.

Study design and rationale for the clinical outcomes of the STABILITY Trial (STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY) comparing darapladib versus placebo in patients with coronary heart disease

BACKGROUND Elevated plasma levels of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) are associated with increased risk of cardiovascular (CV) events. Direct inhibition of this proinflammatory enzyme with darapladib may benefit CV patients when given as an adjunct to standard of care, including lipid-lowering and antiplatelet therapies. METHODS STABILITY is a randomized, placebo-controlled, double-blind, international, multicenter, event-driven trial. The study has randomized 15,828 patients with chronic coronary heart disease (CHD) receiving standard of care to darapladib enteric-coated (EC) tablets, 160 mg or placebo. RESULTS The primary end point is the composite of major adverse cardiovascular events (MACE): CV death, nonfatal myocardial infarction, and nonfatal stroke. The key secondary end points will include major coronary events, total coronary events, individual components of MACE, and all-cause mortality. Prespecified substudies include 24-hour ambulatory blood pressure monitoring, albuminuria progression, changes in cognitive function, and pharmacokinetic and biomarker analyses. Health economic outcomes and characterization of baseline lifestyle risk factors also will be assessed. The study will continue until 1,500 primary end points have occurred to achieve 90% power to detect a 15.5% reduction in the primary end point. The median treatment duration is anticipated to be 2.75 years. CONCLUSIONS STABILITY will assess whether direct inhibition of Lp-PLA(2) with darapladib added to the standard of care confers clinical benefit to patients with CHD.

The ABC (age, biomarkers, clinical history) stroke risk score: a biomarker-based risk score for predicting stroke in atrial fibrillation

Abstract Aims Atrial fibrillation (AF) is associated with an increased risk of stroke, which is currently estimated by clinical characteristics. The cardiac biomarkers N-terminal fragment B-type natriuretic peptide (NT-proBNP) and cardiac troponin high-sensitivity (cTn-hs) are independently associated with risk of stroke in AF. Our objective was to develop and validate a new biomarker-based risk score to improve prognostication of stroke in patients with AF. Methods and results A new risk score was developed and internally validated in 14 701 patients with AF and biomarkers levels determined at baseline, median follow-up of 1.9 years. Biomarkers and clinical variables significantly contributing to predicting stroke or systemic embolism were assessed by Cox-regression and each variable obtained a weight proportional to the model coefficients. External validation was performed in 1400 patients with AF, median follow-up of 3.4 years. The most important predictors were prior stroke/transient ischaemic attack, NT-proBNP, cTn-hs, and age, which were included in the ABC ( A ge, B iomarkers, C linical history) stroke risk score. The ABC-stroke score was well calibrated and yielded higher c-indices than the widely used CHA 2 DS 2 -VASc score in both the derivation cohort (0.68 vs. 0.62, P < 0.001) and the external validation cohort (0.66 vs. 0.58, P < 0.001). Moreover, the ABC-stroke score consistently provided higher c-indices in several important subgroups. Conclusion A novel biomarker-based risk score for predicting stroke in AF was successfully developed and internally validated in a large cohort of patients with AF and further externally validated in an independent AF cohort. The ABC-stroke score performed better than the presently used clinically based risk score and may provide improved decision support in AF. ClinicalTrials. gov identifier NCT00412984, NCT00799903.

Importance of frailty in patients with cardiovascular disease

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality. With the ageing population, the prognostic determinants among others include frailty, health status, disability, and cognition. These constructs are seldom measured and factored into clinical decision-making or evaluation of the prognosis of these at-risk older adults, especially as it relates to high-risk interventions. Addressing this need effectively requires increased awareness and their recognition by the treating cardiologists, their incorporation into risk prediction models when treating an elderly patient with underlying complex CVD, and timely referral for comprehensive geriatric management. Simple measures such as gait speed, the Fried score, or the Rockwood Clinical Frailty Scale can be used to assess frailty as part of routine care of elderly patients with CVD. This review examines the prevalence and outcomes associated with frailty with special emphasis in patients with CVD.

MRI phase contrast velocity and flow errors in turbulent stenotic jets

To clarify the use of MRI phase contrast (PC), as an alternative to Doppler echocardiography, when measuring high‐velocity turbulent jets associated with stenotic valvular disease.

Effects of High and Low Fat Dairy Food on Cardio-Metabolic Risk Factors: A Meta-Analysis of Randomized Studies

Importance Clear guidelines on the health effects of dairy food are important given the high prevalence of obesity, cardiovascular disease and diabetes, and increasing global consumption of dairy food. Objective To evaluate the effects of increased dairy food on cardio metabolic risk factors. Data Sources Searches were performed until April 2013 using MEDLINE, Science Direct, Google,Embase, the Cochrane Central Register of Controlled Trials, reference lists of articles, and proceedings of major meetings. Study Selection Randomized controlled studies with healthy adults randomized to increased dairy food for more than one month without additional interventions. Data Extraction and Synthesis A standard list was used to extract descriptive, methodological and key variables from all eligible studies. If data was not included in the published report corresponding authors were contacted. Results 20 studies with 1677 participants with a median duration of dietary change of 26 (IQR 10-39) weeks and mean increase in dairy food intake of 3.6 (SD 0.92) serves/day were included. There was an increase in weight with low (+0.82, 0.35 to 1.28 kg, p<0.001) and whole fat dairy food (+0.41, 0.04 to 0.79kg, p=0.03), but no significant change in waist circumference (-0.07 , -1.24 to 1.10 cm) ; HOMA –IR (-0.94 , -1.93 to 0.04 units); fasting glucose (+1.32 , 0.19 to 2.45 mg/dl) ; LDL-c (1.85 ,-2.89 to 6.60 mg/dl); HDL-c (-0.19 , -2.10 to 1.71 mg/dl); systolic BP (-0.4, -1.6 to 0.8 mmHg); diastolic BP (-0.4 , -1.7 to 0.8 mmHg) or CRP (-1.07 , -2.54 to 0.39 mg/L). Changes in other cardio-metabolic risk factors were similar for low and whole fat dairy interventions. Limitations Most clinical trials were small and of modest quality. . Conclusion Increasing whole fat and low fat dairy food consumption increases weight but has minor effects on other cardio-metabolic risk factors. Trial Registration ACTRN Australian New Zealand Clinical Trials Registry ACTRN12613000401752, http://www.anzctr.org.au Ethics Approval Number NTX/10/11/115

A mobile phone intervention increases physical activity in people with cardiovascular disease: Results from the HEART randomized controlled trial

Aim To determine the effectiveness and cost-effectiveness of a mobile phone intervention to improve exercise capacity and physical activity behaviour in people with ischaemic heart disease (IHD). Methods and results In this single-blind, parallel, two-arm, randomized controlled trial adults (n = 171) with IHD were randomized to receive a mobile phone delivered intervention (HEART; n = 85) plus usual care, or usual care alone (n = 86). Adult participants aged 18 years or more, with a diagnosis of IHD, were clinically stable as outpatients, able to perform exercise, able to understand and write English, and had access to the Internet. The HEART (Heart Exercise And Remote Technologies) intervention involved a personalized, automated package of text messages and a secure website with video messages aimed at increasing exercise behaviour, delivered over 24 weeks. All participants were able to access usual community-based cardiac rehabilitation, which involves encouragement of physical activity and an offer to join a local cardiac support club. All outcomes were assessed at baseline and 24 weeks and included peak oxygen uptake (PVO2; primary outcome), self-reported physical activity, health-related quality of life, self-efficacy and motivation (secondary outcomes). Results showed no differences in PVO2 between the two groups (difference −0.21 ml kg−1 min−1, 95% CI: −1.1, 0.7; p = 0.65) at 24 weeks. However significant treatment effects were observed for selected secondary outcomes, including leisure time physical activity (difference 110.2 min/week, 95% CI: −0.8, 221.3; p = 0.05) and walking (difference 151.4 min/week, 95% CI: 27.6, 275.2; p = 0.02). There were also significant improvements in self-efficacy to be active (difference 6.2%, 95% CI: 0.2, 12.2; p = 0.04) and the general health domain of the SF36 (difference 2.1, 95% CI: 0.1, 4.1; p = 0.03) at 24 weeks. The HEART programme was considered likely to be cost-effective for leisure time activity and walking. Conclusions A mobile phone intervention was not effective at increasing exercise capacity over and above usual care. The intervention was effective and probably cost-effective for increasing physical activity and may have the potential to augment existing cardiac rehabilitation services.

Longitudinal left ventricular contractile dysfunction after exercise in aortic stenosis

Objective: To determine whether longitudinal left ventricular systolic function measured by Doppler tissue imaging (DTI) after exercise can identify early left ventricular dysfunction in asymptomatic patients with moderate–severe aortic stenosis. Design: Case–control study. Setting: Outpatient cardiology departments. Patients: 20 patients with aortic stenosis, with or without equivocal symptoms, a peak aortic valve velocity ⩾3 m/s, and left ventricular ejection fraction >50% and 15 aged-matched normal controls. Interventions: Echocardiogram performed at rest and immediately after treadmill exercise. Main outcome measures: The peak systolic velocity of the lateral mitral annulus (S’) by DTI at rest and immediately after exercise, exercise capacity, exercise systolic blood pressure and the plasma level of B-type natriuretic peptide (BNP). Results: For patients with aortic stenosis, mean (SD) aortic valve area was 0.95 (0.3) cm2. At rest, S’ was similar for patients with aortic stenosis and controls, respectively (8.5 (1.5) vs 9.1 (1.8) cm/s, p = 0.15). However, after exercise, S’ (12.2 (3.2) vs 17 (2.8) cm/s, p<0.001) and the increase in S’ between rest and exercise (4 (3) vs 7.9 (1.5) cm/s, p<0.001) were lower in patients with aortic stenosis. In patients with aortic stenosis, a smaller increase in S’ after exercise was associated with lower exercise capacity (r = 0.5, p = 0.02), a smaller increase in exercise systolic blood pressure (r = 0.6, p = 0.005) and higher plasma level of BNP (r = 0.66, p = 0.002). Conclusion: In asymptomatic patients with moderate–severe aortic stenosis a lower than normal increase in peak systolic mitral annular velocity after treadmill exercise is a marker of early left ventricular systolic dysfunction.