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.

Effects of carvedilol on left ventricular remodeling after acute myocardial infarction: the CAPRICORN Echo Substudy.

BACKGROUND: The CAPRICORN trial has shown that carvedilol improved outcome in patients with left ventricular dysfunction after acute myocardial infarction treated with ACE inhibitors. The aim of this substudy was to determine the effects of carvedilol on left ventricular remodeling in this patient group. METHODS AND RESULTS: Patients entering the CAPRICORN trial from 13 centers in New Zealand, Australia, and Spain were recruited for this echocardiographic substudy. In 127 patients, quantitative 2D echocardiography was performed according to a standard protocol before randomization and repeated after 1, 3, and 6 months of treatment with carvedilol or placebo. Left ventricular volumes, ejection fraction (Simpson's method), and wall motion score index were determined in a blinded analysis at the Core Echo Laboratory. At 6 months, left ventricular end systolic volume was 9.2 mL less in the carvedilol group than in the placebo group (P=0.023), and left ventricular ejection fraction was 3.9% higher (P=0.015). Left ventricular end diastolic volume and wall motion score index were not statistically different between the 2 groups at 6 months. CONCLUSIONS: In patients with left ventricular dysfunction after acute myocardial infarction treated with ACE inhibitors, carvedilol had a beneficial effect on ventricular remodeling, which may, in part, mediate the substantial clinical beneficial effects of carvedilol in this patient population.

Pseudonormal mitral filling pattern predicts hospital re-admission in patients with congestive heart failure.

OBJECTIVES: We sought to investigate whether pseudonormal (PN) filling was associated with death or hospital admission in patients with congestive heart failure (CHF). BACKGROUND: The high mortality rate associated with CHF is related to many clinical and echocardiographic variables. In particular, a short mitral deceleration time and restrictive diastolic filling predict death and/or hospital admission. We hypothesized that differentiating patients with nonrestrictive filling might identify an intermediate PN group that may be associated with intermediate risk. METHODS: A total of 115 patients admitted to the hospital for exacerbation of CHF symptoms underwent pre-discharge Doppler echocardiography to determine mitral inflow (before and after preload reduction) and pulmonary venous return. Patients were followed up for one year, and all-cause mortality and re-admission data were analyzed. RESULTS: The classification of filling patterns was: abnormal relaxation (AR) in 46 (40%) patients, pseudonormal (PN) filling in 42 (36.5%) patients and restrictive filling pattern (RFP) in 27 (23.4%) patients. When comparing the RFP group with the AR group, all-cause mortality was higher (38.4% vs. 17.4%, p = 0.033), hospital admission was higher (70.3% vs. 54.3%, p = 0.073), death/hospital admission was higher (77.8% vs. 56.5%, p = 0.02), CHF hospital admission was higher (40.7% vs. 15.2%, p = 0.01) and death/CHF hospital admission was higher (62.9% vs. 26.1%, p = 0.0005). Mortality in the PN group was not significantly different from that in the two other groups, but re-admissions were higher than the AR group (76.2% vs. 54.3%, p = 0.006), as was death/re-admission (78.6% vs. 56.5%, p = 0.004) and death/CHF re-admission (47.6% vs. 26.1%, p = 0.03). Re-admissions in the PN and RFP groups were comparable. CONCLUSIONS: In a general hospital population of older patients with CHF, PN filling was associated with hospital admission rates similar to those seen with restrictive filling. The combined end point of death/CHF hospital admission was similar for restrictive filling and AR. Measurement of these variables is easy to add to routine clinical echocardiography and may provide important prognostic information in a wide range of patients with CHF.

Plasma amino-terminal pro-brain natriuretic peptide and accuracy of heart-failure diagnosis in primary care: a randomized, controlled trial.

OBJECTIVES: The purpose of this study was to determine the effect of amino-terminal pro-brain natriuretic peptide (N-BNP) on the diagnostic accuracy of heart failure (HF) in primary care. BACKGROUND: The accurate diagnosis of patients with suspected HF presenting in primary care is difficult. Amino-terminal pro-brain natriuretic peptide is present in high levels in cardiac dysfunction and may improve the diagnostic accuracy of HF in primary care. METHODS: The Natriuretic Peptides in the Community Study was a prospective, randomized controlled trial of the effect of N-BNP on the accuracy of HF diagnosis. Patients presenting to their general practitioner (GP) with symptoms of dyspnea and/or peripheral edema were included. The GPs formulated an initial diagnosis based on clinical assessment. All patients underwent a full cardiologic assessment that included echocardiography and N-BNP. Each patient was randomized to the BNP group (GP received the N-BNP result) or the control group (GP did not receive the N-BNP result). Patients were then reviewed by their GP, and their diagnosis was reviewed. The primary end point was the accuracy of the GPs' diagnoses compared with the panel standard. RESULTS: A total of 305 patients were included; mean age was 72 years, 65% were female. Seventy-seven patients met the panel criteria for HF. The diagnostic accuracy improved 21% in the BNP group and 8% in the control group (p = 0.002). The main impact of N-BNP measurement on diagnostic accuracy was the GPs' correctly ruling out HF. The number needed to diagnose by N-BNP measurement was seven patients. CONCLUSION: This study demonstrates that N-BNP measurement significantly improves the diagnostic accuracy of HF by GPs over and above customary clinical review.

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.

Cardiovascular aging and heart failure.

The aging process is a major factor that contributes to changes seen in the cardiovascular system in older people. Stiffening of the arterial tree alters afterload and left ventricular geometry and although resting left ventricular systolic function is maintained, left ventricular diastolic function changes substantially. Cardiovascular function in older people during exercise is also significantly altered but can be modified by exercise training in older adults or genetic modification in animals. Age-related changes in cardiovascular structure and function also lower the threshold at which cardiac diseases become apparent. This review describes the changes in cardiovascular structure and function at rest and during exercise in older people and highlights their consequences.

Effect of tissue harmonic imaging and contrast upon between observer and test-retest reproducibility of left ventricular ejection fraction measurement in patients with heart failure.

AIMS: To investigate the effects of tissue harmonic imaging (THI) and contrast chamber opacification (LVO) upon measurement variability and reproducibility of echocardiographic left ventricular (LV) volume and ejection fraction (EF) measurements in patients with heart failure (HF). BACKGROUND: Echocardiography is often used in HF patients to determine LV volumes and EF. However, current echo methods are variable and may not be applicable for repeat testing in individual patients. THI and LVO have both been shown to improve endocardial visualisation, but it remains to be determined whether this results in better measurement reproducibility. METHODS: Thirty-one HF patients and 30 control subjects underwent echocardiography on two separate days. LV volumes were measured under four different imaging conditions: fundamental, THI, LVO and LVO with ECG-triggered Power Doppler. Chamber opacification, pulmonary transit time (PTT), endocardial enhancement, reproducibility and bias were assessed. RESULTS: Chamber opacification was inferior and the PTT longer in the HF patients. PTT was related to LV volumes, EF, jugular venous pressure and mitral filling pattern. THI improved endocardial visualisation, and although LVO improved endocardial visualisation in the controls, it offered no benefit over THI in the HF patients. LV volumes and EF were different for each method and THI was the least variable method for repeat measurements. CONCLUSIONS: THI improved endocardial visualisation and was the least variable of the techniques. LVO offered no further advantage in patients with HF and thus cannot be routinely advocated and since LV volumes and EF were different for each, these methods are neither comparable nor interchangeable for follow-up assessments.

Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON).

BACKGROUND: The association between sympathetic activation and mortality in chronic heart failure and the favorable effect of beta blocking drugs has raised the possibility of therapeutic efficacy for central sympathetic inhibition with sustained-release (SR) moxonidine, an imidazoline receptor agonist. METHODS: A randomized double-blind, placebo-controlled trial was initiated in 425 centers in 17 countries with a plan to enter 4533 patients with New York Heart Association class II-IV heart failure and a reduced ejection fraction. Moxonidine SR or matching placebo was titrated to a target dose of 1.5 mg BID. The trial was powered to detect a 20% reduction in mortality, which required a total of 724 deaths. FINDINGS: An early increase in death rate and adverse events in the moxonidine SR group led to premature termination of the trial because of safety concerns after 1934 patients were entered. Final analysis revealed 54 deaths (5.5%) in the moxonidine SR group and 32 deaths (3.4%) in the placebo group during the active treatment phase. Survival curves revealed a significantly (P=0.012) worse outcome in the moxonidine SR group. Hospitalization for heart failure, acute myocardial infarction and adverse events were also more frequent in the moxonidine SR group. Plasma norepinephrine was significantly decreased by moxonidine SR (-18.8% from baseline) vs. placebo (+6.9%). INTERPRETATION: Early termination of the trial limited conclusions regarding the long-term effects of central sympathetic inhibition. Nonetheless, the excess early mortality and morbidity suggest the likelihood of an adverse effect of moxonidine SR and raise concerns regarding the efficacy of generalized sympathetic inhibition in heart failure.

Left ventricular remodeling: pathophysiology and treatment.

Left ventricular (LV) remodeling, which can result from myocardial damage or ventricular pressure or volume overload, has genomic, cellular, and interstitial components with associated changes in ventricular size, shape, wall thickness, and function. It is a process that is detectable and measurable clinically, generally progressive, and associated with adverse outcomes. However, it is amenable to intervention, prevention, or reversal. Following myocardial infarction (MI), LV remodeling is particularly likely in patients with transmural or anterior infarction and in those with failed reperfusion or LV failure. Infarct artery patency and neurohormonal blockade are key management considerations for prevention or reversal of LV remodeling. Combination treatment with angiotensin-converting enzyme inhibition and beta-blockade is of proven benefit following MI, improving LV remodeling and long-term outcomes.

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.

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.