Aspirin for primary prevention: yes or no?

AIM: To assess benefit versus harm of aspirin for cardiovascular disease (CVD) primary prevention by age group, gender and risk category and to interpret these results in light of current New Zealand CVD risk assessment and management guidelines. METHODS: Rates of benefit (avoided vascular events) and harm (additional major extracranial bleeds) for each gender and age group were calculated from data from the six randomised controlled trials included in the Anti-Thrombotic Trialists' (ATT) Collaboration meta-analysis. These rates were applied to CVD risk categories to calculate the net benefit or net harm likely to occur from the use of aspirin in primary prevention of CVD as monotherapy and when added to lipid and blood pressure-loweringtherapies. RESULTS: Benefits of aspirin monotherapy outweigh the harms for both men and women aged up to 80 years with calculated five-year CVD risk >15% in primary prevention. Harm may outweigh benefit for primary prevention for those over 80 years. For men 70-79 years the benefit of aspirin in primary prevention is marginal when added to lipid and blood pressure-lowering therapies. DISCUSSION: The recent ATT Collaboration meta-analysis has raised doubts about the relative safety of aspirin in primary prevention of CVD. However, modelling by risk category and age group suggests that current guidelines are justified in recommending aspirin for primary prevention of CVD in those with five-year CVD risk > or = 15% up to the age of 80 years. For men 70-79, consider lipid and blood pressure-lowering therapies first then reassess whether aspirin adds additional net benefit.

Effects of the end point adjudication process on the results of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS).

BACKGROUND AND PURPOSE: End point adjudication committees (EPAC) are widely used in large-scale clinical trials to ensure the robustness of diagnosis for end points. METHODS: The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was a double-blind randomized trial of blood pressure lowering in 6105 participants with pre-existing cerebrovascular disease. Separate estimates of the effects of randomized treatment were determined using Cox regression models that were based on the unadjudicated events initially reported by the investigator and on the final events assigned by the EPAC. RESULTS: There were 992 strokes initially reported by the investigators and 894 (90%) retained these diagnoses after adjudication by the EPAC. The hazard ratios (95% CIs) for the effect of randomized treatment on stroke were 0.74 (0.64 to 0.85) based on the investigator diagnoses and 0.72 (0.62 to 0.83) based on the EPAC diagnoses (P homogeneity=0.7). For each stroke subtype reported, the corresponding numbers of diagnoses (investigators/EPAC) were ischemic (593/565), hemorrhagic (124/111), and unknown (124/93) with no impact of the EPAC review on the estimates of treatment effects (all P homogeneity >0.3). There was likewise no detectable effect of reclassification of diagnoses for the effect estimates calculated for myocardial infarction or the main causes of death (all P homogeneity >0.5). CONCLUSIONS: The EPAC process had no discernible impact on the trial conclusions. Very large trials powered to detect effects on stroke subtypes might obtain real scientific gain from an EPAC, but in the case of PROGRESS, the value of the EPAC was in the reassurance it provided.

Did it fall or was it pushed? The contribution of trends in established risk factors to the decline in premature coronary heart disease mortality in New Zealand.

OBJECTIVE: To estimate the contribution of trends in three risk factors--systolic blood pressure (SBP), total blood cholesterol (TBC) and cigarette smoking--to the decline in premature coronary heart disease (CHD) mortality in New Zealand from 1980-2004. METHOD: Risk factor prevalence data by 10-year age group (35-64 years) and sex was sourced from six national or Auckland regional health surveys and three population censuses (the latter only for smoking). The data were smoothed using two-point moving averages, then further smoothed by fitting quadratic regression equations (SBP and TBC) or splines (smoking). Risk factor/CHD mortality hazard ratios estimated by expert working groups for the World Health Organization Global Burden of Disease Study 2001 were used to translate average annual changes in risk factor prevalences to the corresponding percentage changes in premature CHD mortality. The expected trends in CHD mortality were then compared with the observed trend to estimate the contribution of each risk factor to the decline. FINDINGS: Approximately 80% (73% for males, 87% for females) of the decline in premature CHD mortality from 1980 to 2004 is estimated to have resulted from the joint trends in population SBP and TBC distributions and smoking prevalence. Overall, approximately 42%, 36% and 22% of the joint risk factor effect was contributed by trends in SBP, TBC and smoking respectively. CONCLUSION: Our estimate for the joint risk factor contribution to the CHD mortality decline of 80% exceeds those of two earlier New Zealand studies, but agrees closely with a similar Australian study. This provides an indicator of the scope that still remains for further reduction in CHD mortality through primary and secondary prevention.

How low can it go? Projecting ischaemic heart disease mortality in New Zealand to 2015.

AIMS: This study aims to identify how ischaemic heart disease (IHD) mortality rates in New Zealand have varied between successive cohorts and time periods. This information is then used to project IHD mortality rates and counts (burdens) out to year 2011-15. METHODS: Age/period/cohort models were constructed (5-year periods and 5-year age groups, generating 10-year overlapping cohorts) using both frequentist and Bayesian methods. Data were available from 1956 for the total population and from 1981 for Maori. The projection period was 2001-5 to 2011-15. Uncertainty was quantified as the Bayesian 90% credible interval. RESULTS: IHD mortality rates for all age by gender groups increased from 1956-60 to peak in 1966-70, then declined by more than 60% to current (1996-2000) levels. However, the decline has been much shallower for Maori. This decline has resulted from increasingly favourable period effects since 1971-75 (less marked for Maori). However, no substantive cohort effects have been seen, at least from the 1891 to the 1951 cohort. Our model suggests that, for the first time, a substantive and unfavourable cohort effect may be emerging among recent birth cohorts. CONCLUSIONS: IHD mortality rates are projected to continue to fall from 2001-05 to 2011-15, albeit more slowly than in the past as the increasing (favourable) period effect is partly offset by an emerging (unfavourable) cohort effect. The result is a relatively small projected decline in absolute IHD mortality burden overall, but an actual increase among Maori.

Comparison of B-type natriuretic peptides for assessment of cardiac function and prognosis in stable ischemic heart disease.

UNLABELLED: In 1,049 patients with stable ischemic heart disease (IHD), brain natriuretic peptide (BNP) and amino terminal pro-brain natriuretic peptide (NTproBNP) correlated closely (r = 0.09, p < 0.001) and were similarly related to left ventricular ejection fraction (LVEF) (r = -0.50 and -0.46, respectively), age (0.44 and 0.47), and creatinine clearance (-0.51 and -0.51). Receiver-operating characteristic curves for detection of LVEF <30% were similar (area under the curves = 0.83 and 0.80, both p < 0.001), and both peptides had strong negative predictive value (95% and 94%). Both independently predicted all-cause mortality and/or heart failure with closely overlapping event-free survival curves; BNP and NTproBNP display strong, near-identical test performance in ruling about severely reduced LVEF and in prediction of all-cause mortality or heart failure in stable IHD. OBJECTIVES: The aim of this work was to test B-type natriuretic peptides for assessment of function and prognosis in stable ischemic heart disease (IHD) and to compare brain natriuretic peptide (BNP) with amino terminal pro-brain natriuretic peptide (NTproBNP), including the relative effects of age and renal function on test performance. BACKGROUND: Brain natriuretic peptide and NTproBNP are emerging diagnostic and prognostic markers in heart failure and acute coronary syndromes. Their performance in assessing function and prognosis in stable IHD is unknown. Whether one marker is superior and the relative effects of age and renal function on test performance are uncertain. METHODS: In 1,049 patients with stable IHD, left ventricular ejection fraction (LVEF) was measured by radionuclide scanning and creatinine clearance estimated by the Cockroft-Gault equation. Age, gender, and body mass index were recorded. Twelve-month all-cause mortality or admission with heart failure was prospectively recorded; BNP and NTproBNP were measured by radioimmunoassay. RESULTS: Brain natriuretic peptide and NTproBNP correlated closely (r = 0.90, p < 0.001) and had similar relationships to LVEF (r = -0.50 and -0.46, respectively, both p < 0.001), age (0.44 and 0.47, both p < 0.001), and creatinine clearance (-0.51 and -0.51, both p < 0.001). Areas under receiver-operating characteristic curves for detection of LVEF <30% were similar (0.83 and 0.80, both p < 0.001) with strong negative predictive values for both (95% and 94%). Both markers independently predicted the clinical end point with closely overlapping event-free survival curves. CONCLUSIONS: In stable IHD, BNP and NTproBNP display strong and near-identical test performance in ruling out severely reduced LVEF and in prediction of all-cause mortality or heart failure despite significant effects of age, gender, and renal function on levels of both markers.

The HOPE TIPS: the HOPE study translated into practices.

The HOPE TIPS study assessed the practicality and tolerability of ramipril titration to a target dose of 10 mg (as achieved in definitive efficacy studies) in a clinical practice setting. 3881 patients at high cardiovascular risk (HOPE study criteria) were recruited in primary and specialist care settings in 9 countries by 439 investigators. Dose titration of ramipril from 2.5 mg to 10 mg daily took place over 9-12 weeks. The mean age of the patients was 64 years, 60% were male and 79% Asian. The target dosage of 10 mg daily was reached in 73% of patients with 96% of patients achieving 5 mg or 10 mg daily. During the study period uncontrolled hypertension (> 160/90) was recorded in 15% of patients, myocardial infarction or unstable angina 1.6%, heart failure 0.4%, new diabetes 0.6%. Only 9.8% of patients discontinued treatment with 5.9% attributed to treatment side-effects and 4% related to cough. The large majority of patients in a wide range of clinical practice settings with high cardiovascular risk can be treated with ramipril titrated to 10 mg daily with good tolerability.

Quantitative evaluation of regional endocardial visualisation with second harmonic imaging and contrast left ventricular opacification in heart failure patients.

AIMS: Wall motion score index (WMSI) is an important prognostic indicator in heart failure (HF) patients but requires endocardial visualisation. This study evaluated the role tissue harmonic imaging (THI) and contrast opacification (LVO) for improving endocardial visualisation and the determination of WMSI in HF patients. METHODS AND RESULTS: Thirty-one HF patients and 30 controls underwent apical echocardiography with fundamental imaging (FUND), THI and THI with contrast agent (Levovist). Visualisation and motion were graded in the six segments from each of the apical two and four chamber views. Both THI and LVO reduced the percentage of non-visualised segments (FUND 13.6%, THI 5.6%, LVO 2.8%, p=0.01) in the controls, but in HF patients, only THI improved visualisation (% segments not visualised FUND 9.7%, THI 3.5%, LVO 4.8%, p=0.06). The anterior and lateral walls were the least well visualised with FUND, but improved with LVO (anterior p=0.0026, lateral p=0.0003). No improvement was seen in the inferior wall (p=0.30) or septum (p=0.2). WMSI was similar by all methods and negatively correlated with ejection fraction (FUND r=-0.69, THI r=-0.74, LVO r=-0.77, all p<0.001). CONCLUSION: THI improved endocardial visualisation in all subjects and LVO offered additional benefit in the controls, but not in HF patients. Regional endocardial visualisation was inconsistent. Thus, both patient factors and wall segment site need to be considered when using contrast agents for endocardial visualisation.

Cardiac remodeling in coronary artery disease.

Cardiac remodeling is a central mechanism of heart failure progression in patients with coronary artery disease (CAD). The remodeling effect of beta-blockade with carvedilol has been studied in patients with left ventricular dysfunction after myocardial infarction and in patients with chronic heart failure of ischemic etiology. Carvedilol has been found to prevent progressive adverse ventricular remodeling in both conditions. This effect is concordant with the improvement in long-term clinical outcomes established for carvedilol in such patients. Thus, ventricular remodeling appears to be an important treatment target in patients with CAD and is likely to mediate at least part of the clinical improvement achieved with carvedilol.