Showing papers by "John G.F. Cleland published in 2001"

The CARE-HF study (CArdiac REsynchronisation in Heart Failure study): rationale, design and end-points

Abstract: Background: Cardiac resynchronisation is a promising new intervention for patients with heart failure, left ventricular systolic dysfunction and ventricular dyssynchrony. Objective: The CARE-HF trial is designed to evaluate the long-term effects of cardiac (atrio-bi-ventricular) resynchronisation on the mortality and morbidity of patients with heart failure due to left ventricular systolic dysfunction already receiving diuretics and optimal medical therapy with ACE inhibitors and beta-blockers (where indicated and tolerated). Methods and Results: Approximately 800 patients will be randomised to device therapy or control and followed for a minimum of 18 months. A pragmatic study design has been chosen that does not attempt to conceal allocation from investigators or patients because it is impossible to guarantee maintenance of blinding for the duration of the study. The end-points committee will adjudicate events in a blinded fashion. Since cardiac resynchronisation may alter other aspects of the management of the patient, as would occur in clinical practice, the study should be considered a comparison of strategies rather than simply of a device. The primary end-point is all-cause mortality or unplanned cardiovascular hospitalisation. The study should complete recruitment during 2002 and report in 2004.

Clinical Trials Update: CAPRICORN, COPERNICUS, MIRACLE, STAF, RITZ‐2, RECOVER and RENAISSANCE and cachexia and cholesterol in heart failure. Highlights of the Scientific Sessions of the American College of Cardiology, 2001

Abstract: This is a synopsis of presentations made at the American College of Cardiology (ACC) in 2001 summarising recent research developments relating to heart failure. Clinical studies of particular interest to physicians with an interest in heart failure and its prevention are reviewed. The COPERNICUS trial lends further support to the use of the beta-blocker, carvedilol, in severe heart failure and the CAPRICORN trial to its use in patients with post-infarction left ventricular systolic dysfunction. The MIRACLE study reinforces the evidence from three smaller trials that cardiac resynchronisation therapy is an effective treatment for the relief of symptoms in patients with severe heart failure and cardiac dyssynchrony. The STAF trial casts further doubt on the wisdom of cardioversion as a routine strategy for the management of chronic atrial fibrillation. The RITZ-2 trial suggests that an intravenous, non-selective endothelin antagonist is effective in improving haemodynamics and symptoms and possibly in reducing morbidity in severe heart failure. Observational studies in heart failure suggest that a moderate excess of body fat and elevated blood cholesterol may be desirable in patients with heart failure, challenging the current non-evidenced-based vogue for cholesterol lowering therapy in heart failure. The RENAISSANCE and RECOVER outcome studies of etanercept, a tumour necrosis factor (TNF) receptor analogue that blocks the effect of TNF, were stopped because of lack of evidence of benefit shortly after the ACC.

Clinical events leading to the progression of heart failure: insights from a national database of hospital discharges.

Abstract: Aims To describe the sequence of clinically apparent events causing readmission and antedating death, subsequent to a first-time hospital admission for heart failure, in order to give insights into the natural history and mechanisms of progression of heart failure Methods A national database of linked hospital discharge and mortality data for Scotland (population 5·1 million) was used Patients with a first-time admission to hospital with heart failure in 1992 (index population) were identified and, using a record linkage system, hospital readmissions and their cause according to the hospital physician and deaths were recorded over the subsequent 3 years A flowchart showing the sequence of events leading to death or recurrent admission was constructed Results 12640 patients had first-time admissions with heart failure in 1992; their mean age was 74 years and 46·2% were men A cohort of 2922 (23%) patients died on their first admission Among the remaining 9718 patients there were 22747 readmissions and 4877 deaths over the subsequent 3 years; only 15% had neither event reported Nine per cent of patients died without any readmission and a further 6% without a further readmission for cardiovascular reasons A cohort of 5992 (61% of patients at risk) had at least one cardiovascular readmission and half of these had occurred within 6 months Heart failure without a report of any cardiovascular precipitating event was responsible for 37% (2188 patients) of first cardiovascular readmissions and of these patients approximately 12% had evidence of renal failure or acute respiratory infection as possible triggers for readmission Acute ischaemic events including myocardial infarction (19%), myocardial infarction alone (8%) and atrial fibrillation (11%) were associated with a substantial number of first readmissions First readmission precipitated by acute myocardial infarction was associated with a particularly poor prognosis (40% inpatient mortality) Conclusions Recurrent ischaemic events and atrial fibrillation may be the predominant mechanisms leading to exacerbation of and progression of heart failure and death A substantial proportion of readmissions appear related to heart failure alone Whether this reflects progressive ventricular remodelling leading to worsening heart failure or other unidentified mechanisms cannot be discerned from this data

Toleration of High Doses of Angiotensin-Converting Enzyme Inhibitors in Patients With Chronic Heart Failure: Results From the ATLAS Trial

Abstract: Background Treatment with angiotensin-converting enzyme (ACE) inhibitors reduces mortality and morbidity in patients with chronic heart failure (CHF), but most affected patients are not receiving these agents or are being treated with doses lower than those found to be efficacious in trials, primarily because of concerns about the safety and tolerability of these agents, especially at the recommended doses. The present study examines the safety and tolerability of high- compared with low-dose lisinopril in CHF. Methods The Assessment of Lisinopril and Survival study was a multicenter, randomized, double-blind trial in which patients with or without previous ACE inhibitor treatment were stabilized receiving medium-dose lisinopril (12.5 or 15.0 mg once daily [OD]) for 2 to 4 weeks and then randomized to high- (35.0 or 32.5 mg OD) or low-dose (5.0 or 2.5 mg OD) groups. Patients with New York Heart Association classes II to IV CHF and left ventricular ejection fractions of no greater than 0.30 (n = 3164) were randomized and followed up for a median of 46 months. We examined the occurrence of adverse events and the need for discontinuation and dose reduction during treatment, with a focus on hypotension and renal dysfunction. Results Of 405 patients not previously receiving an ACE inhibitor, doses in only 4.2% could not be titrated to the medium doses required for randomization because of symptoms possibly related to hypotension (2.0%) or because of renal dysfunction or hyperkalemia (2.3%). Doses in more than 90% of randomized patients in the high- and low-dose groups were titrated to their assigned target, and the mean doses of blinded medication in both groups remained similar throughout the study. Withdrawals occurred in 27.1% of the high- and 30.7% of the low-dose groups. Subgroups presumed to be at higher risk for ACE inhibitor intolerance (blood pressure, Conclusions These findings demonstrate that ACE inhibitor therapy in most patients with CHF can be successfully titrated to and maintained at high doses, and that more aggressive use of these agents is warranted.

Clinical trials update: highlights of the scientific sessions of the XXIII Congress of the European Society of Cardiology — WARIS II, ESCAMI, PAFAC, RITZ‐1 and TIME

Abstract: This article continues a series of reports updating recent research developments of particular interest to personnel involved in the treatment and management of patients with heart failure. This is a summary of selected presentations made at the Scientific Sessions of the XXIII Annual Congress of the European Society of Cardiology. Summaries of the following clinical studies are included: WARIS-II, ESCAMI, PAFAC, RITZ-I and TIME.

Clinical trials update: Highlights of the Scientific Sessions of Heart Failure 2001, a meeting of the Working Group on Heart Failure of the European Society of Cardiology. CONTAK-CD, CHRISTMAS, OPTIME-CHF

Abstract: This article continues a series of reports summarising recent research developments pertinent to the topic of heart failure. This is a summary of presentations made at Scientific Sessions of Heart Failure 2001, a meeting of the Working Group on Heart Failure of the European Society of Cardiology. Clinical studies of particular interest to people caring for patients with heart failure include CONTAK-CD, CHRISTMAS and further updates on OPTIME-CHF. A brief review of the current status of cardiac resynchronisation therapy is included.

Cardiovascular critical event pathways for the progression of heart failure; a report from the ATLAS study

Abstract: Aims To determine the sequence of critical cardiovascular events in the progression of heart failure, and whether aetiology or high-dose vs low-dose lisinopril affected these pathways. Methods and Results This was a post-hoc investigation of the ATLAS database, which comprised 3164 patients with chronic heart failure, randomized to low- (2·5–5·0mg.day−1) or high-dose (32·5–35·0mg.day−1) lisinopril, followed up for a median of 46 months. Two-thirds (64·3%) of patients had heart failure attributed to ischaemic heart disease. During the study, most patients (61·1%) had at least one cardiovascular hospitalization and 42·5% of all patients died: most deaths (88·2%) were cardiovascular. Nearly half (49·7%) of the cardiovascular deaths were considered sudden and 45·2% of cardiovascular deaths occurred as the first cardiovascular event. A third (30·2%) of deaths resulted from heart failure and were generally preceded by hospitalization, either for heart failure (85·5%), myocardial ischaemic events (21·7%) or arrhythmias (18·0%). Compared with low-dose, high-dose lisinopril was associated with a lower risk of death or hospitalization for any reason ( P =0·002) and death or hospitalization with worsening heart failure ( P <0·001). High-dose lisinopril delayed the time to all-cause mortality and hospitalization for chronic heart failure by 7·1 months. Conclusions Vascular and arrhythmic events may not only be important precipitants of sudden death, but were also seen to contribute to the progression of heart failure. A reduction in vascular events, as well as benefits on ventricular remodelling, could account for the decrease in death or hospitalization with high-dose lisinopril.

Endothelin antagonists for chronic heart failure: do they have a role?

Abstract: Over the last two decades, the vascular endothelium has been shown to produce a variety of vasoactive substances that are crucial for the regulation of vascular tone, both in health and disease. This concept emerged in 1980, with the discovery of endothelium-derived relaxing factor, later characterized as nitric oxide. In 1985 Hickey et al. reported the existence of a vasoconstricting factor derived from cultured bovine endothelial cells. Yanagisawa et al. were, however, the first to purify, sequence and clone the 21 amino acid structure of endothelin (ET) and its mRNA from the culture supernatant of porcine aortic endothelial cells in 1988. The authors stated that ‘endothelin, having a potent, strong and characteristically long-lasting vasoconstrictor activity, may be important in systemic blood pressure and/or local blood flow: disturbances in the control of endothelin production could contribute to the pathogenesis of hypertension and that of pathological vascular spasm’. Since that original report remarkable advances have been made in our understanding of the molecular basis of ET biosynthesis and action. ET has been implicated as playing an important physiological role in cardiovascular regulation and a putative pathophysiological role in a wide range of disease states, including chronic heart failure. The aim of this review article is to focus on the role of endothelin in chronic heart failure and in particular, the potential therapeutic benefits of ET receptor antagonists for patients with chronic heart failure.

Clinical trials update: highlights of the scientific sessions of the American Heart Association year 2000: Val HeFT, COPERNICUS, MERIT, CIBIS-II, BEST, AMIOVIRT, V-MAC, BREATHE, HEAT, MIRACL, FLORIDA, VIVA and the first human cardiac skeletal muscle myoblast transfer for heart failure.

Abstract: This article continues a series of reports summarising recent research developments pertinent to the topic of heart failure. This is a summary of presentations made at scientific sessions of the American Heart Association in November 2000. Clinical studies of particular interest to people caring for patients with heart failure include Val-HeFT, AMIOVIRT and V-MAC. New data from beta-blockers trials are reviewed, highlights from some important developments in post-infarction care, including MIRACL and FLORIDA, discussed and results of some early studies of gene therapy reported.

Does aspirin attenuate the effect of angiotensin-converting enzyme inhibitors in hypertension or heart failure?

Abstract: There is a wealth of data that suggests an important interaction between aspirin and angiotensin-converting enzyme inhibitors in patients with chronic stable cardiovascular disease. The interaction is less obvious in the postinfarction setting, possibly reflecting the fact that many patients stop their aspirin therapy within a few months of such an event. An interaction is biologically plausible, because there is considerable evidence that angiotensin-converting enzyme inhibitors exert important effects through increasing the production of vasodilator prostaglandins, whereas aspirin blocks their production through inhibition of cyclooxygenase, even at low doses. There is some evidence that low-dose aspirin may raise systolic and diastolic blood pressure. There is also considerable evidence that aspirin may entirely neutralize the clinical benefits of angiotensin-converting enzyme inhibitors in patients with heart failure. In addition, aspirin may have an adverse effect on outcome in patients with heart failure that is independent of any interaction with angiotensin-converting enzyme inhibitors, possibly by blocking endogenous vasodilator prostaglandin production and enhancing the vasoconstrictor potential of endothelin. The evidence is not sufficient to justify advising long-term aspirin therapy for patients with cardiovascular disease in general, and for those with heart failure in particular. Thus, the lack of evidence of benefit with aspirin in patients with heart failure and coronary disease, along with growing evidence that aspirin is directly harmful in patients with heart failure and that aspirin may negate the benefits of angiotensin-converting enzyme inhibitors suggest that, unless there is an opportunity to randomize the patient into a study of antithrombotic strategies, then aspirin should be withdrawn or possibly substituted with an anticoagulant or an antiplatelet agent that does not block cyclooxygenase. In contrast, there is fairly robust evidence for a benefit of both aspirin and angiotensin-converting enzyme inhibitors during the first 5 weeks after a myocardial infarction, with little evidence of an interaction. The combination of aspirin and angiotensin-converting enzyme inhibitors is warranted during this period, after which discontinuation or substitution of aspirin with another agent should be considered.

What is the optimal medical management of ischaemic heart failure

Abstract: Ischaemic heart disease is probably the most important cause of heart failure. All patients with heart failure may benefit from treatment designed to retard progressive ventricular dysfunction and arrhythmias. Patients with heart failure due to ischaemic heart disease may also, theoretically, benefit from treatments designed to relieve ischaemia and prevent coronary occlusion and from revascularisation. However, there is little evidence to show that effective treatments, such as angiotensin converting enzyme (ACE) inhibitors and beta-blockers, exert different effects in patients with heart failure with or without coronary disease. Moreover, there is no evidence that treatment directed specifically at myocardial ischaemia, whether or not symptomatic, or coronary disease alters outcome in patients with heart failure. Some agents, such as aspirin, designed to reduce the risk of coronary occlusion appear ineffective or harmful in patients with heart failure. There is no evidence, yet, that revascularisation improves prognosis in patients with heart failure, even in patients who are demonstrated to have extensive myocardial hibernation. On current evidence, revascularisation should be reserved for the relief of angina. Large-scale, randomised controlled trials are currently underway investigating the role of specific treatments targeted at coronary syndromes in patients who have heart failure. The CHRISTMAS study is investigating the effects of carvedilol in a large cohort of patients with and without hibernating myocardium. The WATCH study is comparing the efficacy of aspirin, clopidogrel and warfarin. The HEART-UK study is assessing the effect of revascularisation on mortality in patients with heart failure and myocardial hibernation. Smaller scale studies are currently assessing the safety and efficacy of statin therapy in patients with heart failure. Only when the results of these and other studies are known will it be possible to come to firm conclusions about whether patients with heart failure and coronary disease should be treated differently from other patients with heart failure due to left ventricular systolic dysfunction.

Validation of an echocardiographic wall motion index in heart failure due to ischaemic heart disease.

Abstract: Aims: the echocardiographic assessment of left ventricular ejection fraction (LVEF) by geometric methods is limited in many patients because of inadequate views and also in the presence of regional wall motion abnormalities due to ischaemic heart disease (IHD). This study aimed to examine the application of a wall motion index (WMI) method, using a nine-segment LV model in patients with chronic heart failure (CHF) due to IHD. Methods and Results: echocardiography was performed in 71 consecutive subjects with CHF due to IHD. WMI could be derived in 70 subjects (99%). The inter-observer variability (repeatability coefficient) of WMI was 0.66, i.e. LVEF±20%. In 66 subjects, LVEF was measured, within 4 weeks, using radionuclide ventriculography (RNV-EF). The inter-observer variability of RNV-EF was ±3.1%. Using the mean of two observations for each method, the Bland–Altman range of agreement for LVEF was 26% (±13%). Conclusion: WMI is a widely applicable echocardiographic method for assessing LV systolic function and has moderate agreement with RNV-EF. Unlike RNV-EF, however, WMI is not likely to be a suitable method for the measurement of small, but prognostically important, changes in LV function that may occur in CHF.

ACE inhibitors for 'diastolic' heart failure? reasons not to jump to premature conclusions about the efficacy of ACE inhibitors among older patients with heart failure.

Abstract: Guidelines for the management of heart failure highlight the importance of ACE inhibitors for the management of patients with left ventricular systolic dysfunction 1 . However, guidelines make no recommendation for their use in patients with heart failure and preserved left ventricular systolic function. The pathophysiology and diagnosis of ‘diastolic’ heart failure is complex. There are sound theoretical reasons why ACE inhibitors might improve symptoms and prognosis in this setting but little evidence. The entry criteria for the V-HeFT and CONSENSUS-1 trials did not exclude patients with relatively preserved systolic function. In V-HeFT-II, in a subset of 218 patients, enalapril, compared to hydrallazine and nitrates, reduced all-cause mortality, in particular sudden death 2 . However, in an echocardiographic subgroup analysis of 54 patients enrolled in the CONSENSUS-1 study, patients with relatively preserved systolic function appeared to have less benefit from enalapril 3 . Neither of the studies randomised enough patients with preserved systolic function to produce a convincing result, and in neither trial was it a pre-specified outcome of interest. Heart failure in patients with preserved left ventricular systolic function may be more often secondary to hypertension and or atrial fibrillation than due predominantly to ischaemic heart disease, as observed in patients with left ventricular systolic dysfunction 4 . ACE inhibitors are effective anti-hypertensive agents, but have not yet been proven significantly superior to other classes of agent. ACE inhibitors have not been shown to reduce the risk of developing heart failure among patients with hypertension to a greater extent than other agents 5 . ACE inhibitors are a reasonable therapy for the control of hypertension in patients with heart failure and preserved systolic function, but they are not mandatory. ACE inhibitors do reduce the risk of developing atrial fibrillation in patients with post-infarction left ventricular systolic dysfunction, but this is not generally considered a major effect of ACE inhibitors 5 . The HOPE 6 and PROGRESS 7 studies suggest that ACE inhibitors might be effective for a broad range of patients at risk of vascular events. However, patients with heart failure, regardless of its origin, were excluded. These studies add little to the argument in favour of using ACE inhibitors for patients with diastolic heart failure. Most patients with ‘diastolic’ heart failure are aged 75 years and perhaps the majority of patients with heart failure aged 75 years have preserved left ventricular systolic dysfunction. The mean age of patients in key studies such as SOLVD, HOPE and Ž . Ž . PROGRESS ranged from 59 SOLVD to 66 HOPE years; in the SOLVD study, patients aged 80 years were excluded 8,9 . Few patients aged 75 years have been included in placebo-controlled trials of ACE inhibitors and patients with renal dysfunction, the normal situation among elderly patients with heart failure, were effectively excluded. Analyses of outcomes in the SOLVD-treatment study by age tercile are shown in Fig. 1a 3c. Fewer than 500 patients were aged between 70 and 80 years. In this subgroup of patients with left ventricular systolic dysfunction,

Pharmacoeconomics in heart failure : impact of drug and non-drug based treatment

Abstract: Heart failure is a common and increasing problem associated with a high morbidity and mortality. The high morbidity of heart failure imposes the majority of costs of its treatment. Hospitalization among patients with heart failure is frequent, increasing, recurrent and often prolonged and constitutes about 65% of health spending on heart failure. A number of strategies can be envisaged to reduce recurrent heart failure hospitalization. ACE inhibitors (especially high-dose), beta-blockers, spironolactone and possibly digoxin, have all been shown to reduce substantially all-cause hospitalization in patients with heart failure in double-blind controlled trials. The most common single reason for re-admission is for worsening heart failure which may frequently be exacerbated by incomplete and unpredictable absorption of some diuretics. The loop diuretic, torasemide, because of its favourable pharmacokinetic and pharmacodynamic profile may be able to prevent worsening of underlying heart failure developing into a crisis, leading to hospitalization. Studies confirm that treatment with torasemide can reduce the rate of hospitalization due to worsening heart failure and is cost-effective, A stumbling block to progress that is often encountered is the unwillingness of budget holders to spend a small amount of money on better drugs and outpatient services in order to prevent hospitalization. This is exacerbated in many countries by a separate system for care of patients in and out of hospital.

Long term anticoagulation or antiplatelet treatment. Only warfarin has been shown to reduce stroke risk in patients with atrial fibrillation

Abstract: Editor—The conclusions of Taylor et al about the use of aspirin for atrial fibrillation are misleading and potentially dangerous for clinical practice.1 Firstly, when considering anticoagulation or aspirin for the management of heart failure it is appropriate first to compare each against placebo. Overall, aspirin has no effect compared with placebo in preventing thromboembolic events or death among patients with atrial fibrillation, whereas warfarin exerts a significant reduction in both outcomes compared with placebo.2 Secondly, Taylor et al excluded a key study, stroke prevention in atrial fibrillation (SPAF) III, from their analysis.3 This study showed that full dose warfarin versus low dose warfarin combined with aspirin exerted a significantly greater reduction in stroke (1.7% v 5.6%; P=0.0007) with a trend to reduced total mortality (5.9% v 7.2%).3 Thirdly, the BMJ has previously published the mortality data from the aspirin (28 deaths) and placebo (30 deaths) arms of the AFASAK study, allowing mortality in the warfarin arm (13 deaths) to be calculated.4 Thus, the all cause mortality data from AFASAK is available contrary to the assertions of Taylor et al. Only warfarin has been shown to reduce the risk of stroke in atrial fibrillation, and only warfarin seems to reduce mortality in patients with atrial fibrillation. If the risk associated with atrial fibrillation is considered low enough to warrant treatment with aspirin then there is insufficient evidence to recommend any antithrombotic treatment at all.