© 2002 European Society of Cardiology
Clinical trials update: highlights of the scientific sessions of The American College of Cardiology 2002: LIFE, DANAMI 2, MADIT-2, MIRACLE-ICD, OVERTURE, OCTAVE, ENABLE 1 & 2, CHRISTMAS, AFFIRM, RACE, WIZARD, AZACS, REMATCH, BNP trial and HARDBALL
Department of Academic Cardiology Castle Hill Hospital, Cottingham, Kingston upon Hull, HU16 5JQ, UK
* Corresponding author. Tel.: +44-1482-624084; fax: +44-1482-624085. E-mail address: g.m.porter{at}hull.ac.uk
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Abstract |
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 Top Abstract 1. LIFE (Losartan Intervention...2. DANAMI-2 (DANish multicentre...3. MADIT-2 (Multicentre...4. MIRACLE-ICD (Multicenter...5. OVERTURE and OCTAVE6. ENABLE 1 &...7. CHRISTMAS (Carvediolol...8. AFFIRM and RACE...9. WIZARD and AZACS...10. REMATCH (Randomised...11. BNP trial (Breathing...12. HARDBALL (Heart Allograft...References |
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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 American College of Cardiology 51st Annual Scientific Session held in Atlanta on 17–20 March 2002. Reports of the following clinical studies are included: LIFE, DANAMI 2, MADIT-2, MIRACLE-ICD, OVERTURE, OCTAVE, ENABLE 1 & 2, CHRISTMAS, AFFIRM, RACE, WIZARD, AZACS, REMATCH, BNP trial and HARDBALL.
Key Words: LIFE • DANAMI 2 • MADIT-2 • MIRACLE-ICD • OVERTURE • OCTAVE • ENABLE 1 & 2 • CHRISTMAS • AFFIRM • RACE • WIZARD • AZACS • REMATCH • BNP trial • HARDBALL
Received March 28, 2002; Revised April 8, 2002; Accepted April 9, 2002
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1. LIFE (Losartan Intervention For Endpoint Reduction in Hypertension Study) |
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TopAbstract1. LIFE (Losartan Intervention...2. DANAMI-2 (DANish multicentre...3. MADIT-2 (Multicentre...4. MIRACLE-ICD (Multicenter...5. OVERTURE and OCTAVE6. ENABLE 1 &...7. CHRISTMAS (Carvediolol...8. AFFIRM and RACE...9. WIZARD and AZACS...10. REMATCH (Randomised...11. BNP trial (Breathing...12. HARDBALL (Heart Allograft...References |
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This study was presented at the ACC and published the same week in the Lancet [1,2]. The study randomised 9193 patients with essential hypertension and ECG evidence of left ventricular hypertrophy to losartan or atenolol. The primary end-point of the study was cardiovascular death, stroke or myocardial infarction. Either drug could be titrated up to 100 mg/day and hydrochlorothiazide could be added for additional blood pressure control. Blood pressure control was similar in each group. Thirteen percent of patients had diabetes and 25% had a pre-existing clinical history of vascular disease. The mean follow-up was 4.8 years, 22.5% of losartan patients and 27.1% of patients on atenolol discontinued treatment during the follow-up period.
Losartan reduced the primary end-point by 14.6% (unadjusted; P=0.009) compared to atenolol. This was mostly driven by a reduction in fatal and non-fatal stroke (25.8% reduction; P=0.0006) with a smaller contribution from cardiovascular death (13.3% reduction; ns), but with a non-significant difference in favour of atenolol for non-fatal or fatal myocardial infarction (–5.0%). 314 patients (3.4%) had a hospitalisation for heart failure during follow-up but no difference between treatments was noticed. A trend to reduced all-cause mortality was not significant (10.3%) Losartan was also slightly superior to atenolol in reducing left ventricular hypertrophy by ECG or echo criteria.
Subgroup analysis suggested an even more striking effect in patients who had diabetes at baseline. In this group, losartan reduced not only the primary end-point (by 26%, P=0.03), but also all-cause mortality (by 39%; P=0.002). Losartan was also associated with a 25% reduction in new onset diabetes (P<0.001), defined mainly by routine blood glucose screening. The clinical significance of this finding is unclear. A reduction in the primary end-point was also observed in a low risk subgroup without diabetes or pre-existing cardiovascular disease (by 19%, P=0.03). Data on the final group of patients (those with pre-existing cardiovascular disease but without diabetes) was not shown, but by extrapolation, little or no effect must have been observed in this subgroup (perhaps 20% of the patients in the study). The corollary of accepting greater benefit in one group is accepting that less than average benefits must have occurred in another. Unless the reader is equally willing to accept the negative messages as well as the positive messages from subgroup analysis, they should be reluctant to pay attention to them at all.
This result, combined with its favourable side-effect profile, establishes losartan as a first-line therapy for hypertension. It is less clear how cost-effective losartan is. No data were presented to show whether losartan reduced non-fatal, disabling stroke, the major health economic driver of this outcome. Although atenolol enjoys widespread use, concerns exist about its efficacy compared to other beta-blockers. The differences in outcome in LIFE should not be assumed to be a class effect for ARB's or beta-blockers.
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2. DANAMI-2 (DANish multicentre randomised study on thrombolytic therapy vs. acute coronary angioplasty in Acute Myocardial Infarction) |
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TopAbstract1. LIFE (Losartan Intervention...2. DANAMI-2 (DANish multicentre...3. MADIT-2 (Multicentre...4. MIRACLE-ICD (Multicenter...5. OVERTURE and OCTAVE6. ENABLE 1 &...7. CHRISTMAS (Carvediolol...8. AFFIRM and RACE...9. WIZARD and AZACS...10. REMATCH (Randomised...11. BNP trial (Breathing...12. HARDBALL (Heart Allograft...References |
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This study randomised 1572 patients with acute (<12 h) myocardial infarction to thrombolysis (front-loaded tPA) or primary angioplasty. The primary end-point was death, non-fatal MI or disabling stroke at 30 days. The majority of patients were recruited from community hospitals and received thrombolysis in the community hospital or were transferred to the invasive centre by ambulance according to their treatment group. The time to administration of thrombolysis was 2 h 40 min, and to angioplasty, 3 h 20 min amongst patients randomised in community hospitals. There were no deaths in transit, although 1.6% developed ventricular fibrillation, and presumably some of these were officially declared dead after arrival at the invasive centre. However, it is not clear that outcome in these patients was affected by the transfer.
The primary end-point was reached by 13.7% in the thrombolysis group vs. 8.0% in the angioplasty group (P=0.0003). This was mainly driven by a reduction in non-fatal myocardial infarction (6.3% vs. 1.6%; P<0.0001) with no reduction in mortality (6.6% vs. 7.6%; ns) and a non-significant trend to a reduction in disabling stroke (2.0 vs. 1.1%; ns). There was also a reduction in readmissions with chest pain and in the need for a new attempt at revascularisation (16.6% vs. 5.9%).
The lack of effect on mortality suggests that the recurrent myocardial infarctions were not, on average, major events. This implies that a conservative strategy for angioplasty is still acceptable. However, the reduction in recurrent events and the potential to reduce the risk of stroke especially in older patients (in whom streptokinase might often be preferable to tPa) suggest that primary angioplasty might now be the most appropriate course of management for acute myocardial infarction, if adequate staff and facilities exist.
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3. MADIT-2 (Multicentre Automatic Defibrillator Implantation Trial—II) [3,4] |
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TopAbstract1. LIFE (Losartan Intervention...2. DANAMI-2 (DANish multicentre...3. MADIT-2 (Multicentre...4. MIRACLE-ICD (Multicenter...5. OVERTURE and OCTAVE6. ENABLE 1 &...7. CHRISTMAS (Carvediolol...8. AFFIRM and RACE...9. WIZARD and AZACS...10. REMATCH (Randomised...11. BNP trial (Breathing...12. HARDBALL (Heart Allograft...References |
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The MADIT-2 study compared defibrillator (ICD) implantation vs. no implantation, in patients with LVEF<30% (67% had LVEF<25%) and a history of remote (>1 month; 87%>6 months since last infarct) myocardial infarction. Thirty-five percent of patients were aged >70 years. Due to the uncertain value of electrophysiological testing in this setting, this test was not included in the protocol. The original protocol required patients to have repetitive ventricular ectopic beats on 24-h Holter monitoring, but this was revised after only a few patients had been recruited because almost all patients who fulfilled the ejection fraction criterion also fulfilled the arrhythmia criterion. It is not clear how many patients were recruited according to these additional arrhythmia criteria, since any change would have taken months to implement through ethics committees and many investigators would have consciously or sub-consciously, continued to recruit patients with these arrhythmia criteria. The primary endpoint was death from any cause.
One thousand, two hundred and thirty-two patients were recruited and followed for a mean of 20 months. Seventy percent were taking ACE inhibitors and 70% beta-blockers (hopefully not sotalol, but we are not told); few patients were taking any other anti-arrhythmic drug. The mortality rate in the control group was 19.8%, which indicates that this was not a particularly high-risk population, especially considering that they had ischaemic heart disease. ICD implantation reduced mortality to 14.2% (31% reduction; P=0.016), mostly by reducing sudden death (Table 1). The survival benefit was similar across subgroups stratified by age, sex, LVEF, NYHA class and the QRS interval. The mortality curves did not separate until 9 months. As the hazard of sudden death is fairly constant within a population this implies that early benefit may be neutralised by some adverse effect of ICD implantation. ICD implantation was associated with a strong trend to an increase in hospitalisation for heart failure.
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The presenters suggested that there may be approximately 10 000 eligible existing patients and 1000 new cases per year per million population. If very frail patients with multiple co-morbidity are denied or refuse this therapy, an estimate of approximately 2500 patients per million might be more reasonable, with approximately 250 new cases per year. Given a cost of approximately
25 000 for the device and the costs of implantation and follow-up, the cost of providing this service is likely to exceed 10 million per year per 1 million population. To these costs must be added the increased costs of managing patients whose lives have been saved. Improved survival in the ICD group probably accounts for the observation of an increase in hospitalisation for heart failure in this group. Alternatively, ICD shocks and back-up pacing may be causing ventricular damage, which could lead to a loss of benefit from ICDs in the longer term. The implications are that a large number of electrophysiologists and heart failure physicians will be required to manage these patients, and more facilities will be required to deliver this treatment. Although the effects of the ICD in MADIT-II were in addition to medical therapy, they need to be put in the context of pharmacological trials. The magnitude of benefit with an ICD in MADIT-II may be somewhat less than with a beta-blocker (Fig. 1). Also, beta-blockers (with, perhaps, the exception of sotalol!) are highly effective at increasing left ventricular ejection fraction, reducing serious supra-ventricular and ventricular arrhythmias and preventing sudden death. It is not clear if all patients should first be given a 6–12-month trial of beta-blocker therapy, with implantation of a defibrillator only in those whose LVEF does not rise sufficiently.
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The above considerations suggest that it is imperative that the MADIT-II results are corroborated by at least one other trial before its results are implemented. Several, including SCD-HeFT and COMPANION are continuing. Also, it should be remembered that ICD trials in patients with dilated cardiomyopathy have been neutral or have shown a trend to harm [5], despite encouraging data from observational studies [6]. Also, it is important to determine whether there are subgroups of patients who do not benefit from ICD's. This should be done in further prospective trials rather than by retrospective analysis of existing data and will require intelligent study designs.
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4. MIRACLE-ICD (Multicenter InSync Randomised Clinical Evaluation) |
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TopAbstract1. LIFE (Losartan Intervention...2. DANAMI-2 (DANish multicentre...3. MADIT-2 (Multicentre...4. MIRACLE-ICD (Multicenter...5. OVERTURE and OCTAVE6. ENABLE 1 &...7. CHRISTMAS (Carvediolol...8. AFFIRM and RACE...9. WIZARD and AZACS...10. REMATCH (Randomised...11. BNP trial (Breathing...12. HARDBALL (Heart Allograft...References |
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This study, which was conducted in a near-identical fashion to the MIRACLE trial [7], implanted an InSync-ICD device into 362 patients with a conventional indication for an ICD, LVEF<35% and NYHA III/IV heart failure. At the time of this report, 284 patients had died or completed 6 months of follow-up. The defibrillator function was activated in all patients; therefore, this trial has no possibility of showing the benefits or harm from ICD therapy. Patients were randomised double blind to (cardiac resynchronisation, CR)-on or CR-off.
CR therapy improved quality of life (P<0.01), NYHA class (P<0.03) and treadmill exercise capacity (P<0.001), but not 6-min hall walk test. There were 15 deaths in control vs. 12 with CR therapy on.
Elsewhere in the meeting, a further report from the MIRACLE study suggested a marked reduction in days in hospital for heart failure (77%; P=0.012), in the use of intravenous therapy for heart failure (57%; P<0.001) and the outcome of death or worsening heart failure (40%; P=0.033) during long-term follow-up. However, the CONTAK-CD trial indicated no reduction in hospitalisation [8], all-cause or for heart failure. It is unclear whether this difference in outcome reflects an adverse effect of ICD implantation (MIRACLE-ICD would suggest not, but MADIT-II suggests maybe) Table 2.
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5. OVERTURE and OCTAVE |
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TopAbstract1. LIFE (Losartan Intervention...2. DANAMI-2 (DANish multicentre...3. MADIT-2 (Multicentre...4. MIRACLE-ICD (Multicenter...5. OVERTURE and OCTAVE6. ENABLE 1 &...7. CHRISTMAS (Carvediolol...8. AFFIRM and RACE...9. WIZARD and AZACS...10. REMATCH (Randomised...11. BNP trial (Breathing...12. HARDBALL (Heart Allograft...References |
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Omapatrilat vs. enalapril randomised trial of utility in reducing events (heart failure).
Omapatrilat cardiovascular treatment assessment vs. enalapril (hypertension).
Omapatrilat is the first of a new class of agent that inhibit not only the angiotensin converting enzyme but also neutral endopeptidase, resulting in a reduction in angiotensin II formation while blocking the degradation of bradykinin (more powerfully than an ACE inhibitor alone) and of natriuretic peptides. This profile renders this class of agent very effective at reducing blood pressure, theoretically very attractive for the management of heart failure, but at increased risk of provoking side effects such as cough and angio-oedema.
The Overture study randomised 5770 patients with LVEF<30%, NYHA II–IV heart failure and hospitalisation for heart failure within the previous 12 months to omapatrilat 40 mg/day or enalapril 10 mg bd. The primary end-point of the study was all-cause mortality or hospitalisation with worsening heart failure and was designed not only to ask whether omapatrilat was superior to enalapril, but also to exclude the possibility that omapatrilat was worse than enalapril (equivalence-defined as 95% CI interval excluding a hazard ratio of 1.09).
The mean age of the patients was 63 years, 80% were male, the mean LVEF was 24%, 30% had diabetes and 52% were on beta-blockers, 40% on spironolactone and 60% on digoxin.
The trial achieved only one of its primary endpoints (equivalence), suggesting that treatments were similar. There was a slight excess risk of angio-oedema, although the incidence was much lower than observed in hypertension, and of hypotension, but trends to less impairment of renal function. Outcome in patients with low arterial pressure tended to favour enalapril, while the outcome in patients with systolic arterial pressure 
140 mmHg favoured omapatrilat. Also, different doses of these agents might have achieved different results. The CONSENSUS study had a target dose of enalapril of 20 mg bd, and the ATLAS study [10] suggested that the difference between low-dose and high-dose ACE inhibition was similar to or greater than the difference observed in OVERTURE (Table 3).
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The OCTAVE study included about 25 000 hypertensive patients who were randomised to omapatrilat or enalapril. The primary aim of the study was to assess the safety of omapatrilat, especially in relation to angio-oedema. Omapatrilat proved to have superior anti-hypertensive effects, requiring less up-titration in dose and add-on therapy while maintaining a 2–3 mmHg greater reduction in systolic blood pressure compared to enalapril. Overall, 2.17% of patients on omapatrilat developed angio-oedema, compared to 0.68% on enalapril. Rates were 2–3 times higher in African–American patients and smokers than in patients who did not have these characteristics. Events also appeared more severe with omapatrilat, with approximately half the patients requiring steroids or epinephrine for treatment. Most events occurred on the first day of dosing, but not all. Only two patients required intubation and none died.
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6. ENABLE 1 & 2 (ENdothelin Antagonist Bosentan for Lowering cardiac Events) |
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TopAbstract1. LIFE (Losartan Intervention...2. DANAMI-2 (DANish multicentre...3. MADIT-2 (Multicentre...4. MIRACLE-ICD (Multicenter...5. OVERTURE and OCTAVE6. ENABLE 1 &...7. CHRISTMAS (Carvediolol...8. AFFIRM and RACE...9. WIZARD and AZACS...10. REMATCH (Randomised...11. BNP trial (Breathing...12. HARDBALL (Heart Allograft...References |
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The ENABLE (1 & 2) trial randomised 1613 patients to receive either bosentan (initial dose 62.5 mg bd for 4 weeks with uptitration to 125 mg twice a day thereafter) or matching placebo, in addition to therapy with diuretics, ACE inhibitors, and β-blockers. The dose of bosentan was only 25% of that initially targeted in previous trials. Entry criteria were NYHA IIIb or IV heart failure, LVEF<30% and hospitalisation for heart failure in the previous year. The primary endpoint was a composite of death and hospitalisation for heart failure.
During a mean follow-up of 18 months, no difference in the primary composite endpoint or all-cause mortality was observed (Table 4). Further exploration of the results showed evidence of an early and sustained weight gain (approx. 0.6 kg) accompanied by a fall in haemoglobin (of approx. 1 g/dl) and an increase in reports of peripheral oedema. These effects appeared to be due to fluid retention and (anecdotally) disappeared rapidly on discontinuation of the drug. The persistence of the weight gain throughout the trial implies that it is relatively diuretic resistant. In both parts of the trial, one conducted in Europe and one in the North America, more patients reported worsening than improvement. Even at the low doses used, elevations in liver enzymes were observed. This effect is believed to be due to inhibition of the bile acid transporter in hepatocytes. It is not clear whether this is benign.
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Overall, little harm from bosentan was observed in this trial. Studies with higher doses of bosentan and with other non-selective agents have also suggested an early risk, which has sometimes persisted. Studies with selective agents have also shown toxicity at higher doses. The results of ENABLE are important in at least three respects. Firstly, it shows how little understanding we have of the endothelin system and how poorly animal experiments have predicted clinical outcome. Secondly, it suggests that blocking the endothelial ETB receptor which mediates prostaglandin mediated vasodilatation may be much more deleterious than expected by many. Thirdly, it will cause future studies of selective and non-selective agents to be conducted with much lower doses. It is unlikely that medical research is ready to give up on this class of agent for heart failure yet. Heart failure is a common cause of pulmonary hypertension and bosentan does appear effective in primary pulmonary hypertension.
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7. CHRISTMAS (Carvediolol Hibernation Reversible ISchemia Trial: MArker of Success) |
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TopAbstract1. LIFE (Losartan Intervention...2. DANAMI-2 (DANish multicentre...3. MADIT-2 (Multicentre...4. MIRACLE-ICD (Multicenter...5. OVERTURE and OCTAVE6. ENABLE 1 &...7. CHRISTMAS (Carvediolol...8. AFFIRM and RACE...9. WIZARD and AZACS...10. REMATCH (Randomised...11. BNP trial (Breathing...12. HARDBALL (Heart Allograft...References |
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The increase in LVEF in response to beta-blockers is much more variable in patients with LVSD secondary to ischaemic heart disease than amongst patients with dilated cardiomyopathy. The CHRISTMAS study [11] investigated the possibility that this was due to the heterogeneity in the myocardial substrate and that patients who had a large volume of hibernating myocardium would have a more marked response than those that did not. The study was an international, multi-centre, randomised trial comparing placebo and carvedilol in patients stratified according to the presence or absence of hibernation. The primary endpoint was the increase in LVEF after a mean follow-up of about 6 months.
The study included patients with heart failure, ischaemic heart disease and a wall motion index <1.3 (equivalent to <40%) using a nine-segment model. Patients with severe angina were excluded and 75% of patients included had little or no angina. Most patients were receiving diuretics and ACE inhibitors.
Hibernation was defined as severe regional contractile dysfunction by echocardiography in a segment that demonstrated preserved myocardial uptake of technetium sestamibi. Myocardial ischaemia was defined as a reversible, exercise-induced myocardial perfusion defect.
The study showed that over 50% of patients had evidence of myocardial hibernation affecting two or more segments (defined as hibernators) and that almost 80% of patients had a substantial volume of myocardium affected by either hibernation or ischaemia. There was a non-significant trend for patients designated as hibernators to show a greater LVEF response to carvedilol than non-hibernators. However, patients who had a large volume of hibernating myocardium had much greater improvement in LVEF (+1% if only one segment vs. +11% for four or more segments; P<0.001 for linear trend). The study suggests that carvedilol, by virtue of its beta-blocker and/or anti-oxidant properties, may be an effective treatment for hibernating myocardium. Whether a role for revascularisation still exists is currently being investigated in the HEART-UK trial.
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8. AFFIRM and RACE (Atrial Fibrillation Follow-up Investigation of Rhythm Management) |
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TopAbstract1. LIFE (Losartan Intervention...2. DANAMI-2 (DANish multicentre...3. MADIT-2 (Multicentre...4. MIRACLE-ICD (Multicenter...5. OVERTURE and OCTAVE6. ENABLE 1 &...7. CHRISTMAS (Carvediolol...8. AFFIRM and RACE...9. WIZARD and AZACS...10. REMATCH (Randomised...11. BNP trial (Breathing...12. HARDBALL (Heart Allograft...References |
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(Rate Control vs. Electrical Cardioversion for Persistent Atrial Fibrillation)
Approximately 25% of patients with heart failure will have atrial fibrillation, although it is not clear that this co-morbidity confers either an increased risk of stroke (stroke risk is high in patients with heart failure even in patients with sinus rhythm) or a worse prognosis [12,13]. Nevertheless, atrial fibrillation may precipitate heart failure or its symptomatic worsening and is an important target for treatment in heart failure. Two small studies, which included few patients with heart failure, have suggested that there is little advantage in attempting to cardiovert patients with AF to sinus rhythm. Two much larger studies reported at the ACC have now come to the same conclusion.
The AFFIRM study randomised 4060 patients to rate or rhythm control with a follow-up of 3.5 years. The primary outcome measure was all-cause mortality. Approximately half the patients randomised to rate control were receiving digoxin or beta-blockers at baseline, whilst 41% received CCBs and 39% received amiodarone. Overall, approximately 60% of patients received amiodarone during the course of the study. Anti-coagulants could be stopped if sinus rhythm was maintained for >1 month. After 3.5 years, 60% of patients in the rhythm control group were in normal sinus rhythm, whilst successful rate control was achieved in 80% of rate-control patients. Approximately 90% of patients in the rate-control group and 70% in the rhythm control group were receiving anti-coagulants at the end of the study.
All-cause mortality was not significantly different between the two groups, although the survival curves did appear to separate at around 1.5–2 years in favour of the rate control group. No difference in functional status or quality of life was observed. Death and disabling stroke, hospitalisations or new arrhythmias all tended to be less common in the group managed conservatively by rate control.
The RACE study randomised 522 patients to rate control or a stepwise algorithm of cardioversion and anti-arrhythmic drugs to maintain sinus rhythm, amiodarone being the last rather than first choice agent. Follow-up was for 3 years. The primary endpoint of the study was a composite of cardiovascular death, hospitalisation for heart failure, thromboembolic complications, severe bleeding, pacemaker implantation, or severe drug side effects. The primary endpoint was reached in 17.2% of patients randomised to rate control and 22% randomised to rhythm control. Patients in the rhythm control group experienced more thromboembolic complications, more heart failure, and more adverse drug effects.
At least two further studies focussing solely on patients with atrial fibrillation and heart failure, patients in whom the success of cardioversion is likely to be lower, but in whom the potential benefits of cardioversion are greater, have recently started to randomise patients. For the moment, the default position when faced with a patient with atrial fibrillation must be to manage them conservatively rather than attempt cardioversion. This has the potential to dramatically simplify therapy (Table 5).
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9. WIZARD and AZACS (Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders) |
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TopAbstract1. LIFE (Losartan Intervention...2. DANAMI-2 (DANish multicentre...3. MADIT-2 (Multicentre...4. MIRACLE-ICD (Multicenter...5. OVERTURE and OCTAVE6. ENABLE 1 &...7. CHRISTMAS (Carvediolol...8. AFFIRM and RACE...9. WIZARD and AZACS...10. REMATCH (Randomised...11. BNP trial (Breathing...12. HARDBALL (Heart Allograft...References |
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(Azithromycin in Acute Coronary Syndromes)
A hypothesis exists that coronary disease and events may be provoked by infectious agents, with Chlamydia pneumoniae a favoured culprit. Several small trials have produced conflicting evidence of benefit.
In WIZARD, patients with prior myocardial infarction and elevated C pneumoniae titers were randomised to either azithromycin [600 mg QID for 3 days, then 600 mg a week for 11 weeks (n=3868), or placebo (n=3856)]. The primary endpoint was a composite of all-cause mortality, recurrent MI, revascularisation and hospitalisation for angina over a mean follow-up of 2 years. There was no significant difference between the two groups (7% reduction in the azithromycin group (hazard ratio 0.93; ns).
In AZACS, 1400 patients with an acute coronary syndrome were randomised to either azithromycin (500 mg for 1 day, followed by 250 mg for 4 days) or placebo. The 6-month primary endpoint was a composite of death from any cause, non-fatal MI or recurrent ischaemia requiring revascularisation. Again, no difference was observed, although the study was not large enough to exclude a modest reduction in mortality.
Other larger, longer-term treatment trials are being conducted and should report over the next few years (ACES, PROVE IT). Other agents targeting other infections may also be tried.
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10. REMATCH (Randomised Evaluation of Mechanical Assistance for the treatment of Congestive Heart Failure) |
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TopAbstract1. LIFE (Losartan Intervention...2. DANAMI-2 (DANish multicentre...3. MADIT-2 (Multicentre...4. MIRACLE-ICD (Multicenter...5. OVERTURE and OCTAVE6. ENABLE 1 &...7. CHRISTMAS (Carvediolol...8. AFFIRM and RACE...9. WIZARD and AZACS...10. REMATCH (Randomised...11. BNP trial (Breathing...12. HARDBALL (Heart Allograft...References |
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This trial randomised patients with severe heart failure who were not eligible for heart transplantation to a left ventricular assist device (LVAD) or control. Results have been reported previously [14]. A subgroup analysis suggested that there was no effect on survival in patients not on inotropic support. All of the benefit occurred in the 91 patients who were already receiving inotropic infusions at baseline, raising the question of whether the predominant benefit of the LVAD was achieved by avoiding inotropic agents. If this were the case, then avoiding the use of such agents or using agents that appear to exert beneficial effects on survival would be a simpler, less expensive option (Table 6).
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11. BNP trial (Breathing Not Properly) |
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TopAbstract1. LIFE (Losartan Intervention...2. DANAMI-2 (DANish multicentre...3. MADIT-2 (Multicentre...4. MIRACLE-ICD (Multicenter...5. OVERTURE and OCTAVE6. ENABLE 1 &...7. CHRISTMAS (Carvediolol...8. AFFIRM and RACE...9. WIZARD and AZACS...10. REMATCH (Randomised...11. BNP trial (Breathing...12. HARDBALL (Heart Allograft...References |
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This study used a rapid point-of-care (C-terminal) BNP test to assist in the diagnosis of 1586 patients presenting to hospital with breathlessness. Clinical diagnosis was compared to the BNP test result and the results of an evaluation of the patient records by two independent cardiologists. Approximately 50% of patients were believed to have breathlessness due to heart failure. BNP concentrations rose in proportion to the severity of heart failure. Overall, BNP had a sensitivity of 90%, and specificity of 74%, and diagnostic accuracy of 81% compared to a diagnostic accuracy using clinical judgement alone of 74%. The reviewers indicated diagnostic uncertainty in 43% of cases; this was reduced to 11% by BNP. This trial adds to the growing evidence of the utility of natriuretic peptides for the diagnosis of heart failure.
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12. HARDBALL (Heart Allograft Rejection: Detection with Breath Alkane in Low Level) |
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TopAbstract1. LIFE (Losartan Intervention...2. DANAMI-2 (DANish multicentre...3. MADIT-2 (Multicentre...4. MIRACLE-ICD (Multicenter...5. OVERTURE and OCTAVE6. ENABLE 1 &...7. CHRISTMAS (Carvediolol...8. AFFIRM and RACE...9. WIZARD and AZACS...10. REMATCH (Randomised...11. BNP trial (Breathing...12. HARDBALL (Heart Allograft...References |
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Non-invasive identification of patients with heart transplant rejection could be of major benefit by reducing patient morbidity and health-care costs. Alkanes, measured from a 2-min breath sample, which can be transported to a central laboratory, can detect transplant rejection with a sensitivity of 79% and specificity of 62% compared to expert histologists. Local pathologists managed only 60% sensitivity and 59% specificity. The study indicated that a positive breath alkane test was of limited value in predicting class 3 transplant rejection (positive predictive accuracy 6%). However, when the test was negative, a positive biopsy was unlikely, leading to a negative predictive accuracy in excess of 97%. This could reduce the need for biopsy by >50%.
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References |
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TopAbstract1. LIFE (Losartan Intervention...2. DANAMI-2 (DANish multicentre...3. MADIT-2 (Multicentre...4. MIRACLE-ICD (Multicenter...5. OVERTURE and OCTAVE6. ENABLE 1 &...7. CHRISTMAS (Carvediolol...8. AFFIRM and RACE...9. WIZARD and AZACS...10. REMATCH (Randomised...11. BNP trial (Breathing...12. HARDBALL (Heart Allograft...References |
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