Prevalence and predictors of persistent health status impairment in patients referred to a vascular clinic with intermittent claudication.

BACKGROUND: The goal of treatment for lower extremity peripheral artery disease is often to improve health status. Factors associated with failure to improve are unknown. METHODS: Health status was assessed with the Peripheral Artery Questionnaire (PAQ) at baseline and 2 years in 344 patients referred to vascular clinics. Improvement was defined as an increase of ≥5 points on the PAQ Summary Score. Multivariable logistic regression identified patient and treatment characteristics associated with impaired baseline health status, and predictors of no improvement (<5 points). RESULTS: Older age, bilateral symptoms, female sex and prior revascularization were associated with impaired baseline health status. At 2 years 36% reported unimproved health status. Factors associated with no improvement were older age (Odds Ratio 1.67/decade, CI 1.28, 2.19), better baseline health status (OR 1.40/10-points, CI 1.24, 1.59), beta blocker use (OR 2.53, CI 1.37, 4.68), prior stroke (OR 4.12, CI 1.33, 12.77) and bilateral claudication (OR 1.79, CI 1.07, 2.99). SUMMARY: Older patients, women, and those with bilateral symptoms or prior revascularization have worse health status at vascular referral. Over 1/3 of patients' health status did not improve over 2 years; older patients and those with bilateral or milder symptoms, prior stroke or using beta blockers were less likely to improve.

Adjuvant statin therapy for oesophageal adenocarcinoma: the STAT-ROC feasibility study.

BACKGROUND: Statins inhibit proliferative signalling in oesophageal adenocarcinoma (OAC) and their use is associated with better survival in observational studies. The present study was undertaken to examine the feasibility of assessing adjuvant statin therapy in patients with operable OAC in a phase III RCT. METHODS: For this multicentre, double-blind, parallel-group, randomized, placebo-controlled feasibility trial, adults with OAC (including Siewert I-II lesions) who had undergone oesophagectomy were centrally allocated (1 : 1) to simvastatin 40 mg or matching placebo by block randomization, stratified by centre. Participants, clinicians and investigators were blinded to treatment allocation. Patients received treatment for up to 1 year. Feasibility outcomes were recruitment, retention, drug absorption, adherence, safety, quality of life, generalizability and survival. RESULTS: A total of 120 patients were assessed for eligibility at four centres, of whom 32 (26·7 per cent) were randomized, 16 in each group. Seven patients withdrew. Participants allocated to simvastatin had lower low-density lipoprotein cholesterol levels by 3 months (adjusted mean difference -0·83 (95 per cent c.i. -1·4 to -0·22) mmol/l; P = 0·009). Median adherence to medication was greater than 90 per cent between 3 and 12 months' follow-up. Adverse events were similar between the groups. Quality-of-life data were complete for 98·3 per cent of questionnaire items. Cardiovascular disease, diabetes and aspirin use were more prevalent in the non-randomized group, whereas tumour site, stage and grade were similar between groups. Survival estimates were imprecise. CONCLUSION: This RCT supports the conduct and informs the design considerations for a future phase III trial of adjuvant statin therapy in patients with OAC. Registration number: ISRCTN98060456 (www.isrctn/com).

ANTECEDENTES: Las estatinas inhiben las señalizaciones proliferativas en el adenocarcinoma de esófago (oesophageal adenocarcinoma, OAC) y su uso se asocia con mejor supervivencia en estudios observacionales. El presente estudio se llevó a cabo para examinar la viabilidad de evaluar el tratamiento adyuvante con estatinas en pacientes con OAC operable en un ensayo aleatorizado y controlado de fase III. MÉTODOS: En este ensayo de viabilidad controlado por placebo, aleatorizado, de grupos paralelos, doble ciego y multicéntrico, los pacientes adultos con OAC (incluyendo lesiones Siewert I/II) que fueron sometidos a esofaguectomía se asignaron de forma centralizada (1:1) a tratamiento con simvastatina 40 mg o placebo equivalente mediante aleatorización en bloques, estratificados por centro. Los participantes, los clínicos y los investigadores desconocían la asignación del tratamiento. Los pacientes recibieron el tratamiento hasta un año. Los resultados de viabilidad fueron reclutamiento, retención, absorción del fármaco, adherencia, seguridad, calidad de vida, generalización, y supervivencia. RESULTADOS: Un total de 120 pacientes fueron evaluados para elegibilidad en 4 centros, de los cuales 32 (26,7%) fueron aleatorizados, 16 en cada grupo. Siete pacientes abandonaron el ensayo. Los pacientes asignados a tratamiento con simvastatina tenían niveles de colesterol LDL más bajos a los 3 meses (diferencia media ajustada, −0,83 mmol/L, i.c. del 95% −1,4 a −0,22, P = 0,009). La mediana de la adherencia a la medicación fue mayor del 90% entre los 3-12 meses de seguimiento. Los eventos adversos fueron similares entre los grupos. Los datos de calidad de vida estaban completos en el 98,3% de las preguntas del cuestionario. Enfermedad cardiovascular, diabetes y uso de aspirina eran más prevalentes en el grupo no aleatorizado, mientras que la localización del tumor, el estadio y el grado fueron similares entre los grupos. Las estimaciones de supervivencia fueron imprecisas. CONCLUSIÓN: Este RCT apoya la realización e informa de las consideraciones de diseño para un futuro ensayo de fase III de tratamiento adyuvante con estatinas en pacientes con OAC.

Rationale and design of ACTIVE: the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events.

BACKGROUND: Atrial fibrillation (AF) is the most frequently occurring cardiac arrhythmia with often serious clinical consequences. Many patients have contraindications to anticoagulation, and it is often underused in clinical practice. The addition of clopidogrel to aspirin (ASA) has been shown to reduce vascular events in a number of high-risk populations. Irbesartan is an angiotensin receptor-blocking agent that reduces blood pressure and has other vascular protective effects. METHODS AND RESULTS: ACTIVE W is a noninferiority trial of clopidogrel plus ASA versus oral anticoagulation in patients with AF and at least 1 risk factor for stroke. ACTIVE A is a double-blind, placebo-controlled trial of clopidogrel in patients with AF and with at least 1 risk factor for stroke who receive ASA because they have a contraindication for oral anticoagulation or because they are unwilling to take an oral anticoagulant. ACTIVE I is a partial factorial, double-blind, placebo-controlled trial of irbesartan in patients participating in ACTIVE A or ACTIVE W. The primary outcomes of these studies are composites of vascular events. A total of 14000 patients will be enrolled in these trials. CONCLUSIONS: ACTIVE is the largest trial yet conducted in AF. Its results will lead to a new understanding of the role of combined antiplatelet therapy and the role of blood pressure lowering with an angiotensin II receptor blocker in patients with AF.

Admission ECG predicts long-term outcome in acute coronary syndromes without ST elevation.

BACKGROUND: Acute coronary syndromes (ACS) without ST elevation are a frequent cause of hospital admission, myocardial infarction and death. AIM: To explore the role of the ECG in stratifying ACS patients. DESIGN: Prospective, centrally-coordinated multicentre registry involving 56 centres throughout the UK. METHODS: Consecutive patients admitted with ACS without ST elevation on the presenting ECG (n = 1046) were followed for 6 months. A subgroup (n = 653) were flagged with the UK Office for National Statistics and followed-up for death over 4 years. RESULTS: Mean follow-up for the group as a whole was 2.4 years. In the first 6 months, the death rate was 7.3%. Survival at 1 year was 90.8% (95%CI 88.2%-92.8%); at 45 months it was 77.8% (95%CI 74.1%-81.1%). We compared data in those with ST depression or bundle branch block on the admission ECG (n = 304, 29%) with those with T wave inversion, Q waves and minor ST segment changes (n = 576, 55%) and those with a normal ECG (n = 166, 16%). Their respective incidences of death were 15%, 5% and 2% (p < 0.01) at 6 months, and 38%, 22% and 7% (p < 0.01) at 4 years. DISCUSSION: Rates of adverse events are high in patients admitted to UK hospitals with ACS without ST elevation. The ECG remains a very important and simple discriminator of both short- and long-term risk, enabling more aggressive, proven therapies to be targeted towards those at highest risk.

A cost-utility analysis of clopidogrel in patients with non-ST-segment-elevation acute coronary syndromes in the UK.

OBJECTIVE: To assess the long-term cost effectiveness of 1 year's treatment with clopidogrel on top of standard therapy (including aspirin; ASA) compared with standard therapy alone, in patients diagnosed with non-ST-segment-elevation acute coronary syndromes (ACS) in the UK. DESIGN: Cost utility analysis using a Markov model, incorporating clinical data from CURE (a multicentre randomised controlled trial, involving 12,562 patients) and data from UK observational studies. SETTING: Health economic evaluation carried out from the perspective of the UK NHS. PATIENTS: A representative cohort of 1000 UK patients aged 66 years, diagnosed with non-ST-segment-elevation ACS. INTERVENTIONS: Either a combination of 75 mg/day clopidogrel (300 mg loading dose, within 24 h prior to hospital admission) and standard therapy (including ASA, 75-325 mg/day) for 1 year followed by standard therapy alone for their remaining lifetime, or standard therapy alone (including ASA, 75-325 mg/day) for life. MAIN OUTCOME MEASURES: Incremental cost per life-year gained and incremental cost per quality-adjusted life-year (QALY) gained. RESULTS: In the base case, the incremental cost effectiveness of the clopidogrel combination vs standard therapy alone is estimated as pounds 6991 per life-year gained and pounds 7365 per QALY gained. The probability that clopidogrel remains cost effective within the generally accepted pounds 30,000 per QALY threshold is more than 80%. The confidence interval around the relative risk for vascular death was identified as the main parameter affecting the estimated cost effectiveness. CONCLUSIONS: One year's treatment with clopidogrel is a cost effective intervention compared with standard therapy that should be considered as a routine treatment for patients with non-ST-segment-elevation ACS.

Diuretics for heart failure.

BACKGROUND: Chronic heart failure is a major cause of morbidity and mortality world-wide. Diuretics are regarded as the first-line treatment for patients with congestive heart failure since they provide symptomatic relief. The effects of diuretics on disease progression and survival remain unclear. OBJECTIVES: To assess the harms and benefits of diuretics for chronic heart failure SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (Issue 2 2004), MEDLINE 1966-2004, EMBASE 1980-2004 and HERDIN database. We hand searched pertinent journals and reference lists of papers were inspected. We also contacted manufacturers and researchers in the field. SELECTION CRITERIA: Only double-blinded randomised controlled trials of diuretic therapy comparing one diuretic with placebo, or one diuretic with another active agent (e.g. ACE inhibitors, digoxin) in patients with chronic heart failure were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted the data and assessed the eligibility and methodological quality of each trial. Extracted data were entered into the Review Manager 4.2 computer software, and analysed by determining the odds ratio for dichotomous data, and difference in means for continuous data, of the treated group compared with controls. The likelihood of heterogeneity of the study population was assessed by the Chi-square test. If there was no evidence of statistical heterogeneity and pooling of results was clinically appropriate, a combined estimate was obtained using the fixed-effects model. MAIN RESULTS: We included 14 trials (525 participants), 7 were placebo-controlled, and 7 compared diuretics against other agents such as ACE inhibitors or digoxin. We analysed the data for mortality and for worsening heart failure. Mortality data were available in 3 of the placebo-controlled trials (202 participants). Mortality was lower for participants treated with diuretics than for placebo, odds ratio (OR) for death 0.24, 95% confidence interval (CI) 0.07 to 0.83; P = 0.02. Admission for worsening heart failure was reduced in those taking diuretics in two trials (169 participants), OR 0.07 (95% CI 0.01 to 0.52; P = 0.01). In four trials comparing diuretics to active control (91 participants), diuretics improved exercise capacity in participants with CHF, difference in means WMD 0.72 , 95% CI 0.40 to 1.04; P < 0.0001. AUTHORS' CONCLUSIONS: The available data from several small trials show that in patients with chronic heart failure, conventional diuretics appear to reduce the risk of death and worsening heart failure compared to placebo. Compared to active control, diuretics appear to improve exercise capacity.

Long term prognosis of heart failure after acute coronary syndromes without ST elevation.

BACKGROUND: Information about long term outcomes of patients with acute coronary syndromes (ACS) who have clinically diagnosed heart failure is scarce. METHODS: In a UK registry, this study evaluated patients with non-ST elevation ACS, recording treatment, and clinical outcomes for six months. In a subgroup, a four year mortality follow up was performed to estimate the impact of the clinical diagnosis of heart failure on survival. RESULTS: Of 1046 patients, 139 (13%) had a history of clinically diagnosed heart failure. At discharge, ACE inhibitors were prescribed for 58% and 28%, of those with and without a history of heart failure respectively (p<0.001). Rates of angiography, percutaneous intervention, and coronary artery bypass graft were 17.3% and 29.2% (p = 0.003), 5.0% and 8.4% (p = 0.17), and 5.0% and 7.5% (p = 0.3) for these groups respectively. Death or new myocardial infarction at six months occurred in 22% and 10% (p<0.001) and at four years death occurred in 60% and 20% of these groups respectively (p<0.001). In a multivariate analysis prior heart failure carried an odds ratio of 2.0 (p = 0.001) for death or myocardial infarction at six months and 2.4 (p<0.001) for death over four years. New heart failure was associated with an increased risk of death at six months (20% compared with 5%, p<0.001). CONCLUSION: A clinical history of heart failure carries a substantial risk of death in patients admitted with ACS without ST elevation. Nearly 60% of those with prior heart failure are dead after four years. After adjustment for confounding factors, prior heart failure more than doubles the risk compared with those with no history.

Hemodynamic effects of captopril and isosorbide mononitrate started early in acute myocardial infarction: a randomized placebo-controlled study.

OBJECTIVES: The aim of this study was to study the hemodynamic effects of orally administered captopril and isosorbide mononitrate in suspected acute myocardial infarction. BACKGROUND: Early treatment with converting enzyme inhibitors and nitrates in acute myocardial infarction may limit infarct expansion and prevent left ventricular dilation. METHODS: In a double-blind study, 81 patients were randomized within 36 h of the onset of symptoms of suspected acute myocardial infarction to 1 month of oral captopril (6.25 mg initial dose, followed 2 h later by 12.5 mg and continuing with 12.5 mg three times daily), isosorbide mononitrate (initial dose 20 mg followed by 20 mg three times daily) or matching placebo. The effects of treatment on changes from baseline in mean arterial blood pressure, heart rate, stroke volume, cardiac output and systemic vascular resistance were assessed noninvasively using Doppler echocardiography 1 h after the first dose, 1 week after infarction and at 6 weeks (that is, 2 weeks after the scheduled end of trial treatment). RESULTS: One hour after the start of treatment, blood pressure was reduced by approximately 10% with both captopril and isosorbide mononitrate, but this difference did not persist at 1 week. Captopril was associated with a significant increase in cardiac output compared with placebo of 13 +/- 3% at 1 h (p < 0.01), 23 +/- 5% at 1 week (p < 0.001) and 22 +/- 6% (p < 0.05) at 6 weeks (2 weeks after the end of trial treatment). This increase in cardiac output with captopril was mainly due to a substantial and sustained increase in stroke volume, although there was also a small increase in heart rate at 1 week. Both captopril and isosorbide mononitrate reduced systemic vascular resistance within 1 h of the start of treatment, but only the effect of captopril was sustained (perhaps because the three-times daily nitrate regimen induced tolerance). Study treatment was well tolerated, and the incidence of withdrawal of study treatment for hypotension was not significantly different from that with placebo. CONCLUSIONS: This study indicates that the hemodynamic effects of both captopril and isosorbide mononitrate are well tolerated in the acute phase of myocardial infarction and that captopril favorably influences cardiac function.

Clinical effects of early angiotensin-converting enzyme inhibitor treatment for acute myocardial infarction are similar in the presence and absence of aspirin: systematic overview of individual data from 96,712 randomized patients. Angiotensin-converting Enzyme Inhibitor Myocardial Infarction Collaborative Group.

OBJECTIVES: We sought to determine whether the clinical effects of early angiotensin-converting enzyme (ACE) inhibitor (ACEi) treatment for acute myocardial infarction (MI) are influenced by the concomitant use of aspirin (ASA). BACKGROUND: Aspirin and ACEi both reduce mortality when given early after MI. Aspirin inhibits the synthesis of vasodilating prostaglandins, and, in principle, this inhibition might antagonize some of the effects of ACEi. But it is uncertain whether, in practice, this influences the effects of ACEi on mortality and major morbidity after MI. METHODS: This overview sought individual patient data from all trials involving more than 1,000 patients randomly allocated to receive ACEi or control starting in the acute phase of MI (0-36 h from onset) and continuing for four to six weeks. Data on concomitant ASA use were available for 96,712 of 98,496 patients in four eligible trials (and for none of 1,556 patients in the one other eligible trial). RESULTS: Overall 30-day mortality was 7.1% among patients allocated to ACEi and 7.6% among those allocated to control, corresponding to a 7% (standard deviation [SD], 2%) proportional reduction (95% confidence interval 2% to 11%, p = 0.004). Angiotensin-converting enzyme inhibitor was associated with similar proportional reductions in 30-day mortality among the 86,484 patients who were taking ASA (6% [SD, 3%] reduction) and among the 10,228 patients who were not (10% [SD, 5%] reduction: chi-squared test of heterogeneity between these reductions = 0.4; p = 0.5). Angiotensin-converting enzyme inhibitor produced definite increases in the incidence of persistent hypotension (17.9% ACEi vs. 9.4% control) and of renal dysfunction (1.3% ACEi vs. 0.6% control), but there was no good evidence that these effects were different in the presence or absence of ASA (chi-squared for heterogeneity = 0.4 and 0.0, respectively; both not significant). Nor was there good evidence that the effects of ACEi on other clinical outcomes were changed by concomitant ASA use. CONCLUSIONS: Both ASA and ACEi are beneficial in acute MI. The present results support the early use of ACEi in acute MI, irrespective of whether or not ASA is being given.

Cost-effectiveness of alternative strategies for the initial medical management of non-ST elevation acute coronary syndrome: systematic review and decision-analytical modelling.

OBJECTIVES: To identify and prioritise key areas of clinical uncertainty regarding the medical management of non-ST elevation acute coronary syndrome (ACS) in current UK practice. DATA SOURCES: Electronic databases. Consultations with clinical advisors. Postal survey of cardiologists. REVIEW METHODS: Potential areas of important uncertainty were identified and 'decision problems' prioritised. A systematic literature review was carried out using standard methods. The constructed decision model consisted of a short-term phase that applied the results of the systematic review and a long-term phase that included relevant information from a UK observational study to extrapolate estimated costs and effects. Sensitivity analyses were undertaken to examine the dependence of the results on baseline parameters, using alternative data sources. Expected value of information analysis was undertaken to estimate the expected value of perfect information associated with the decision problem. This provided an upper bound on the monetary value associated with additional research in the area. RESULTS: Seven current areas of clinical uncertainty (decision problems) in the drug treatment of unstable angina patients were identified. The agents concerned were clopidogrel, low molecular weight heparin, hirudin and intravenous glycoprotein antagonists (GPAs). Twelve published clinical guidelines for unstable angina or non-ST elevation ACS were identified, but few contained recommendations about the specified decision problems. The postal survey of clinicians showed that the greatest disagreement existed for the use of small molecule GPAs, and the greatest uncertainty existed for decisions relating to the use of abciximab (a large molecule GPA). Overall, decision problems concerning the GPA class of drugs were considered to be the highest priority for further study. Selected papers describing the clinical efficacy of treatment were divided into three groups, each representing an alternative strategy. The strategy involving the use of GPAs as part of the initial medical management of all non-ST elevation ACS was the optimal choice, with an incremental cost-effectiveness ratio (ICER) of 5738 pounds per quality-adjusted life-year (QALY) compared with no use of GPAs. Stochastic analysis showed that if the health service is willing to pay 10,000 pounds per additional QALY, the probability of this strategy being cost-effective was around 82%, increasing to 95% at a threshold of 50,000 pounds per QALY. A sensitivity analysis including an additional strategy of using GPAs as part of initial medical management only in patients at particular high risk (as defined by age, ST depression or diabetes) showed that this additional strategy was yet more cost-effective, with an ICER of 3996 pounds per QALY compared with no treatment with GPA. Value of information analysis suggested that there was considerable merit in additional research to reduce the level of uncertainty in the optimal decision. At a threshold of 10,000 pounds per QALY, the maximum potential value of such research in the base case was calculated as 12.7 million pounds per annum for the UK as a whole. Taking account of the greater uncertainty in the sensitivity analyses including clopidogrel, this figure was increased to approximately 50 million pounds. CONCLUSIONS: This study suggests the use of GPAs in all non-ST elevation ACS patients as part of their initial medical management. Sensitivity analysis showed that virtually all of the benefit could be realised by treating only high-risk patients. Further clarification of the optimum role of GPAs in the UK NHS depends on the availability of further high-quality observational and trial data. Value of information analysis derived from the model suggests that a relatively large investment in such research may be worthwhile. Further research should focus on the identification of the characteristics of patients who benefit most from GPAs as part of medical management, the comparison of GPAs with clopidogrel as an adjunct to standard care, follow-up cohort studies of the costs and outcomes of high-risk non-ST elevation ACS over several years, and exploring how clinicians' decisions combine a normative evidence-based decision model with their own personal behavioural perspective.

Diabetic patients with acute coronary syndromes in the UK: high risk and under treated. Results from the prospective registry of acute ischaemic syndromes in the UK (PRAIS-UK).

OBJECTIVES: Short-term randomised trials suggest that patients with diabetes mellitus (DM), admitted with acute coronary syndromes (ACS) are at increased risk of subsequent adverse events. We tested whether this hypothesis was true for an unselected population of ACS patients with and without DM admitted with non-ST elevation MI or unstable angina, in a non-trial setting over a longer term of follow-up. METHODS: Prospective, centrally, coordinated multicenter registry involving 56 centers throughout the UK (half having angiographic facilities). Consecutive patients admitted with ACS without ST elevation on the presenting ECG were followed up to 6 months. A sub-group of patients were flagged with the UK Office for National Statistics and followed-up for death over 4 years. RESULTS: Data were collected on 1046 ACS patients of whom 170 (16%) had a prior diagnosis of DM. DM patients had higher baseline co-morbidities and unadjusted mortality rates at 6 months (11.8% vs. 6.4%, p=0.01). After correcting for clinical variables such as age, gender, smoking status and chest pain/ischaemic ECG changes on admission, prior history of any of myocardial infarction, heart failure, hypertension, hypercholesterolemia (on treatment), stroke or coronary revascularisation (PTCA or CABG), mortality rates for DM patients were no longer significantly raised (hazard ratio 1.35, 95% CI: 0.79-2.30; p=0.27 at 6 months and 1.15, 95% CI 0.72-1.83 at 4 years). 30% of diabetics were dead after 4 years of follow-up. Patients with DM were more likely to have been revascularised at 6 months and were more likely to receive ACE inhibitors. Based on the rate of recruitment and the population covered in the study, about 21,000 patients with DM will be admitted with non-ST elevation ACS each year in the UK. CONCLUSIONS: DM is common amongst patients admitted with ACS without ST elevation and is associated with significant morbidity and mortality: approximately 1 in 8 will not survive up to 6 months and 1 in 3 to 4 years. DM patients should be managed aggressively to reduce their risk of future complications.

Maximizing benefits of therapies in acute myocardial infarction.

Major advances in the management of acute myocardial infarction have been achieved by a combination of careful experimental work and development of effective pharmacologic and interventional strategies in conjunction with the conduct of large, reliable randomized trials. Current trials indicate that a combination of thrombolytic therapy, aspirin, and intravenous followed by oral beta blockers reduces mortality. There are a number of additional promising interventions, such as intravenous magnesium, nitrates, and the newer antithrombin agents. However, before these agents are used widely in clinical practice, clear proof of benefit and adequate safety should be available from the ongoing randomized trials. Following discharge from the hospital, long-term therapy with aspirin and beta blockers should be considered in all patients. In patients with heart failure and low ejection fraction, angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce mortality, reinfarction, and the need for further hospitalizations for heart failure. Therefore, these therapies, in conjunction with risk factor modification (cessation of cigarette smoking, treatment of hypercholesterolemia, treatment of hypertension), should be considered in all appropriate patients. A number of new strategies for the prevention of atherosclerosis and its complications are currently being evaluated in prospective randomized trials. These include the natural antioxidant vitamins, estrogen replacement therapy, tamoxifen therapy, and ACE inhibitors in patients without evidence of heart failure or left ventricular dysfunction.

Early and late changes in left ventricular filling after acute myocardial infarction and the effect of infarct size.

To characterize the early (1 week) and late (6 weeks) changes in left ventricular (LV) filling pattern associated with acute myocardial infarction (AMI) 45 patients (mean age 65 +/- 2 years) were studied by Doppler echocardiography. Based on clinical criteria, patients were divided into those with large (group L; n = 12) and those with small (group S; n = 33) infarcts and then compared with 16 age-matched control subjects. The following parameters were calculated from the mitral velocity waveform: (1) peak early and peak atrial velocities and their integrals; (2) peak early to atrial velocity ratio and velocity integral ratio; and (3) the pressure half-time of the early wave. One week after AMI, group L showed a decreased atrial and increased early velocity, velocity ratio and integral ratio, whereas the pressure half-time of the early wave was shorter than that in group S and in control subjects. At 6 weeks group L showed a reduction in early velocity, early to atrial velocity ratio and integral ratio, whereas pressure half-time increased. When groups S and L were combined there was a good inverse correlation between pressure half-time and infarct size as measured by peak enzyme release (r = -0.64, p < 0.001). These data suggest that, depending on infarct size, patients exhibit a "restrictive" filling pattern early after the acute event. This is manifested by the greater proportion of filling occurring in early diastole, reflecting an overall increase in chamber stiffness. At 6 weeks, this pattern is less pronounced presumably due to the remodeling process.

The Organization to Assess Strategies for Ischemic Syndromes (OASIS) registry in patients with unstable angina.

Clinical approaches to the prevention of the potentially catastrophic consequences of coronary ischemic phenomena such as unstable angina and suspected non-Q-wave myocardial infarction (MI) differ across the world. In addition to prevailing physician beliefs in different societies, the level of access to catheterization laboratories largely determines whether an interventionist or conservative strategy is adopted. The Organization to Assess Strategies for Ischemic Syndromes (OASIS)--a prospective registry of approximately 8,000 patients with acute myocardial ischemia with no ST elevation, treated in 95 hospitals across 6 countries--furnished a unique window into regional differences in clinical management and the frequency and timing of invasive procedures (i.e., angiography, percutaneous transluminal coronary angioplasty [PTCA], and coronary artery bypass graft [CABG] surgery), as well as the outcomes of these trends. At 6 months after symptom onset, patients in the United States and Brazil, where the catheterization laboratory facilities are more accessible, underwent significantly (p <0.001) more angiography (69.4%), PTCA (23.6%), and CABG (25.2%) than in Canada and Australia, where the corresponding rates were 48.4%, 17.0%, and 16.8% (p <0.001), respectively; and in Hungary and Poland, where the respective rates were 23.5%, 5.8%, and 10.9% (p <0.001). This relatively aggressive approach led at 6 months to a more substantial decrease in refractory angina in the United States and Brazil than in Canada and Australia (20.4% vs 13.9%; p <0.001), but no improvement in rates of cardiovascular mortality and MI (10.5% versus 10.5%; p = 0.36). There was a significant (p < or = 0.012) increase in stroke, (1.9% vs 1.3%; p = 0.010) and major bleeding (1.9% vs 1.1%; p = 0.009) events. Furthermore, an inverse correlation emerged between baseline cardiovascular risk status and frequency of angiography and PTCA interventions preferentially for low-risk compared with high-risk patients. In concert with findings from other recent randomized trials, the OASIS Registry data suggest that although there are fewer hospital readmissions for unstable angina, there is a trend toward increased rates of death, MI, and stroke. These data urge a cautious approach to the use of invasive procedures in patients with unstable angina unless future trials demonstrate a clear benefit with an aggressive approach.

Systematic review of the impact of beta blockers on mortality and hospital admissions in heart failure.

Heart failure is a common condition that carries a high burden of mortality and morbidity. Several randomised trials have evaluated the effects of beta blockers in heart failure. This paper gives a systematic overview of published randomised trials of beta blockers in heart failure using standard methods. In all, 22 randomised controlled trials were identified with a total of 10480 patients, and an average of 11 months of treatment. The average age was 61 years and 4% were female. Most studies excluded patients with severe heart failure. Death rates in patients randomised to receive beta blockers compared to controls were 458/5657 (8.0%) and 635/4951 (12.8%) respectively, odds ratio 0.63, 95% CI 0.55-0.72, P<0.00001. Similar reductions were observed for hospital admissions for worsening heart failure (11.3 vs. 17.1%, respectively, odds ratio 0.63) and for the composite outcome of death or heart-failure hospital admission (19.4 vs. 26.9%, respectively, odds ratio 0.66). These results show that beta blockers reduce the risk of mortality or the need for heart-failure hospital admission by approximately one third. Absolute reductions of 5-6% in event rates were observed over approximately 1 year of treatment period. These important benefits should be implemented as a priority, since treatment with beta blockers is inexpensive and heart failure carries a high risk of death and disability. Further information on the effect of beta blockers in elderly patients and women would be helpful.

Overview and meta-analysis of randomised trials of amiodarone in chronic heart failure.

Unlike other antiarrhythmic class I drugs, amiodarone showed in preliminary studies, benefits also in patients with left ventricular dysfunction. These positive results have induced the development of large randomised controlled studies: their results are reviewed and the controversial points are discussed. In a meta-analysis of randomised controlled trials the use of amiodarone in heart failure was associated with an approximate 20 to 25% reduction in deaths. However, amiodarone was also associated with a 120 to 124% increase in side effects.

Current evidence supporting the role of diuretics in heart failure: a meta analysis of randomised controlled trials.

OBJECTIVE: To summarise the current evidence from randomised controlled trials for diuretics in patients with congestive heart failure (CHF). DATA SOURCES: English-language randomised controlled trials and review papers referenced in Medline, Embase between 1966 and 1999. General literature review of pertinent journals was carried out and reference lists of papers were inspected. STUDY DESIGN: Meta-analysis of randomised controlled trials of diuretic therapy in patients with CHF. STUDY SELECTION: Studies were included if they were randomised comparisons of loop or thiazide diuretics and control, or one diuretic and another active agent (e.g. ACE inhibitors, ibopamine and digoxin). DATA ABSTRACTION: Using a standardised protocol, two reviewers independently abstracted the data and assessed the methodological quality of each paper. DATA SYNTHESIS: The odds ratio (OR) of treated group compared with control was estimated for each end-point outcome and plotted against each other using the fixed-effects model. THE MAIN OUTCOME MEASURES: The primary outcomes of our analysis were effects of diuretics on mortality and morbidity. RESULTS: Eighteen trials met our criteria and were eligible for analysis, involving 928 patients. Eight trials were placebo-controlled. We analysed the data for mortality and for worsening heart failure. A further ten trials compared diuretics against other agents such as ACE inhibitors, ibopamine, and digoxin. Mortality data were available in three of the placebo-controlled trials (n=221); the mortality rate was lower for patients treated with diuretics than for control [the odds ratio for death, 0.25; 95% confidence intervals (CI), 0.07-0.84; P=0.03]. Admissions for worsening heart failure in the four small trials (n=448) showed an odds ratio of 0.31 (95% CI 0.15-0.62; P=0.001). In six studies of diuretics compared to active control, diuretics significantly improved exercise capacity in patients with CHF [OR: 0.37; CI: 0.10-0.64, P=0.007]. CONCLUSION: Compared to active control, diuretics appear to reduce the risk of worsening disease and improve exercise capacity. The available data from small studies show that in CHF conventional diuretics reduce the risk of death and worsening heart failure compared to placebo.

Evolutionary pattern and prognostic importance of heart rate variability during the early phase of acute myocardial infarction.

AIMS: To investigate the evolution of time domain heart rate variability in the early phase of acute myocardial infarction (MI) and assess its prognostic ability. METHODS: We analysed several measures of heart rate variability (SDNN, SDANN, SDNN index, RMSSD) in 138 patients at days 0, 1 and 5+/-1 after hospital admission for acute MI. Results were correlated with infarct site, clinical variation and clinical outcome (death, MI, PTCA, CABG surgery). RESULTS: Measures of heart rate variability (SDNN, SDANN and SDNN index) declined during the first 24 h after acute MI (P<0.01) and increased to admission levels after about 5 days. SDNN values on day 0, 1 and 5 respectively were: 86+/-35, 75+/-28 and 87+/-27 ms. Patients with anterior infarction had lower heart rate variability than patients with inferior infarction on all test days but similar evolution patterns. After 3 years of follow-up there were 12 cardiac deaths (8.7%) and six resuscitated arrests and 33 (24%) new MIs, or revascularisation procedures. The evolutionary pattern of heart rate variability was similar in survivors to those who died although values were generally lower. Mortality was significantly higher in the group with SDNN<50 ms at day 1 (P<0.01) and 5 (P<0.05), but not at day 0. CONCLUSIONS: Our findings show that autonomic imbalance, already evident on the day of the acute event, progresses further over the next 24 h and recovers over the next few days. Low heart rate variability as early as 24 h after acute MI may be a useful predictor of cardiac mortality and contribute to the early risk stratification and therapeutic management of patients.

Early diagnosis of myocardial infarction by timed sequential enzyme measurements.

Serum samples from patients admitted to a coronary care unit with a history of acute chest pain suggestive of myocardial infarction in the previous 12 h were obtained on admission and at 6 and 12 h, thereafter. Creatine kinase (CK), CK-MB isoenzyme, CK-MM sub-bands, myoglobin, and lactate dehydrogenase (LD) isoenzymes were examined. Changes were evaluated in relation to the diagnosis obtained from clinical examination, serial electrocardiography and 'routine' cardiac enzymes (CK, aspartate transaminase and alpha-hydroxy butyrate dehydrogenase daily for 3 days following admission). The slope of the logarithms of CK, CK-MB activity and CK-MB concentration in the early post infarct period fully distinguished between infarct and non-infarct patients. Measurement of myoglobin and lactate dehydrogenase isoenzymes was less sensitive. Serial estimation of CK-MM sub-band patterns allowed the time from infarction to be estimated. Serial estimation of CK in the 12 h following admission can be substituted for conventional daily enzyme estimations for the diagnosis of acute myocardial infarction in patients with onset of chest pain within the previous 12 h. This could reduce laboratory and in-patient costs.