© 2005 European Society of Cardiology
Clinical trials update from the European Society of Cardiology meeting 2005: CARE-HF extension study, ESSENTIAL, CIBIS-III, S-ICD, ISSUE-2, STRIDE-2, SOFA, IMAGINE, PREAMI, SIRIUS-II and ACTIVE
a Department of Cardiology, University of Hull, Castle Hill Hospital Cottingham, Kingston-upon-Hull, HU15 5JQ, UK
b Department of Cardiology, Hull Royal Infirmary Anlaby Road, Kingston-upon-Hull, HU3 2JZ, UK
c Division of Cardiology, Mount Sinai Hospital, University Health Network 600 University Avenue, Toronto, ON, Canada M5J 1X5
* Corresponding author. Tel.: +44 1482 624086; fax: +44 1482 624085. E-mail address: a.p.coletta{at}hull.ac.uk
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Abstract |
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 Top Abstract 1. CARE-HF extension study...2. ESSENTIAL: (The studies...3. CIBIS-III (Cardiac...4. S-ICD: a prospective,...5. ISSUE-2 (International Study...6. STRIDE-2: (A placebo...7. SOFA (Study on...8. IMAGINE (Ischaemia Management...9. PREAMI (Perindopril and...10. SIRIUS-II (Safety and...11. ACTIVE (Atrial fibrillation...References |
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This article provides information and a commentary on trials presented at the European Society of Cardiology meeting held in September 2005, relevant to the pathophysiology, prevention and treatment of heart failure. All reports should be considered as preliminary data, as analyses may change in the final publication. In the CARE-HF extension study, the benefits of cardiac resynchronisation therapy (CRT) observed in the original study were maintained over an increased follow-up period. A study of oral enoximone (25–50 mg t.i.d.) in advanced heart failure (ESSENTIAL) showed limited benefit compared to placebo. The CIBIS-III study showed that heart failure therapy could be safely initiated with bisoprolol followed by the addition of enalapril. A subcutaneous ICD system (S-ICD) showed potential as an alternative to a transvenous ICD. In the ISSUE-2 study, an implantable loop recorder was used to guide therapy in patients with recurrent syncope. The selective endothelin antagonist sitaxsentan improved 6-MWT and functional class in patients with pulmonary arterial hypertension in the STRIDE-2 study. In SOFA, fish oil had no beneficial effect on the incidence of life-threatening arrhythmias in patients with an ICD. In IMAGINE, quinapril showed no benefit when administered to patients following CABG. Perindopril reduced cardiac remodelling in post-MI patients with normal LV function in PREAMI. SIRIUS-II showed encouraging results for the use of intravenous ularitide in symptomatic decompensated chronic heart failure. The ACTIVE W study of warfarin versus aspirin plus clopidogrel in atrial fibrillation has been stopped due to superiority of warfarin.
Key Words: CARE-HF extension study • ESSENTIAL • CIBIS-III • S-ICD • ISSUE-2 • STRIDE-2 • SOFA • IMAGINE • PREAMI • SIRIUS-II • ACTIVE
Received September 15, 2005; Revised September 20, 2005; Accepted September 20, 2005
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1. CARE-HF extension study (CArdiac REsynchronisation in Heart Failure) |
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TopAbstract1. CARE-HF extension study...2. ESSENTIAL: (The studies...3. CIBIS-III (Cardiac...4. S-ICD: a prospective,...5. ISSUE-2 (International Study...6. STRIDE-2: (A placebo...7. SOFA (Study on...8. IMAGINE (Ischaemia Management...9. PREAMI (Perindopril and...10. SIRIUS-II (Safety and...11. ACTIVE (Atrial fibrillation...References |
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Results presented by John Cleland, Castle Hill Hospital, Kingston-upon-Hull, UK
The results of the main CARE-HF study, which completed follow-up on 30th September 2004, have been reported [1–4]. Prior to knowledge of the results, on the recommendation of the DSMB, an extension phase lasting until May 2005 was planned and implemented with all-cause mortality as the primary endpoint. The mean duration of follow-up increased from 29.4 months to 36.4 months and 95 patients originally assigned to the control group had a CRT device implanted and activated. During the extension phase, a further 19 patients in the CRT group and 34 more patients in the control group died. Thus the benefits observed in the main study were maintained or increased (Table 1). No difference in non-cardiovascular mortality was observed. Deaths due to worsening heart failure and sudden deaths were both reduced significantly. A health economic analysis suggested that the cost per quality adjusted life-year saved was about 20,000 euros, assuming that clinicians paid the average European list price for devices (about 6000 euros). This cost may well fall as more CRT devices are used. Data from the Cost-Effectiveness Analysis Registry [5] shows that CRT is as cost-effective as many routinely recommended interventions for cardiovascular diseases (Fig. 1).
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2. ESSENTIAL: (The studies of oral enoximone therapy in advanced heart failure) |
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TopAbstract1. CARE-HF extension study...2. ESSENTIAL: (The studies...3. CIBIS-III (Cardiac...4. S-ICD: a prospective,...5. ISSUE-2 (International Study...6. STRIDE-2: (A placebo...7. SOFA (Study on...8. IMAGINE (Ischaemia Management...9. PREAMI (Perindopril and...10. SIRIUS-II (Safety and...11. ACTIVE (Atrial fibrillation...References |
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Results presented by Marco Metra, Cattedra di Cardiologia University of Bresica, Italy
This trial compared the effects of oral enoximone, an agent that exerts its inotropic action by inhibiting phosphodiesterase III (PDE-III), and placebo in patients with severe heart failure treated with beta-blockers. The results were neutral.
The management of patients with severe heart failure associated with low cardiac output, leading to arterial hypotension and renal dysfunction, remains unsatisfactory. Interventions to improve symptoms, quality of life, morbidity and mortality in such patients and allow discharge from hospital and maintenance in the community are desirable. Currently, robust evidence exists only for cardiac resynchronisation in this setting and only when the patient has cardiac dyssynchrony. Many approaches, including levosimendan, left ventricular assist devices, arginine vasopressin antagonists and erythropoiesis-stimulating proteins are being explored. A safe, orally active inotropic agent might also be useful. Unfortunately, trials of oral inotropic agents, predominantly with PDE-III inhibitors conducted in the 1980s, demonstrated that they had limited ability to improve symptoms and uniformly increased mortality. Accordingly, development was suspended. However, the clinical environment has changed. Fewer patients receive digoxin and more now receive beta-blockers. The inotropic effects of PDE-III inhibitors are maintained in the presence of a beta-blocker and beta-blockers would be expected to attenuate adverse effects on heart rate, arrhythmias and, possibly, intrinsic myocardial function [6,7]. Accordingly, the concept of using enoximone, a PDE-III inhibitor, for the management of patients with severe heart failure, protected by beta-blockers, has been developed. A pilot study, EMOTE, which showed that enoximone may be effective for weaning severe heart failure patients from intravenous inotropic therapy, has previously been reported in this journal [8].
ESSENTIAL (n=1854) was made up of two component trials, one conducted in North and South America and the other in Europe. The trial was event-driven (923 events) and designed to show improvements in the composite of cardiovascular hospitalisation or death, in the 6-min walk test, in patient global symptom assessment and to exclude an important increase in mortality (hazard ratio 1.3). Inclusion criteria were NYHA III or IV, LVEF <30%, LVEDD >60 mm (or >32 mm/m2) and treatment with a beta-blocker and ACEi or ARB, unless contra-indicated. After a 1-week run-in phase, patients were randomised to placebo (n=928) or enoximone (n=926) at a dose of 25 mg t.i.d. After 2 weeks, in-patients who weighed >50 kg the dose could be increased to 50 mg t.i.d. It should be noted that the target dose in the trials conducted in the 1980s that was shown to increase mortality was up to 150 mg t.i.d. [9].
The mean age of the patients was 62 years, 82% were men, 91% were in NYHA III, 52% had ischaemic heart disease, the mean LVEF was 23.6%, heart rate was 74 bpm and systolic blood pressure was 116 mmHg. Europeans tended to have less severe cardiac dysfunction and fewer had ICDs (5% vs. 21%). 96% were taking an ACEi or ARB and 87% a beta-blocker (carvedilol in 51%).
Over a mean follow-up of 16.4 months, 411 patients (22%) died and 1201 completed the study. The incidence of cardiovascular hospitalization or death was similar between the treatment groups (Table 2). The 6-min walk test improved by 10 m (p=0.025) in American patients, but not in their less severely affected European counterparts (1.5 m). This difference appeared to be explained by a benefit in patients with lower LVEF and SBP. Changes in symptoms were similar with placebo and enoximone. Patients assigned to enoximone were more likely to have diarrhoea and palpitations.
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Overall, this study suggests that enoximone at this dose is safe but of limited benefit. Further sub-group analysis may identify a group of patients in whom enoximone has clear benefits and is safe. Alternatively, higher doses of enoximone, possibly tailored on an individual patient basis, may prove more effective and equally safe. Further research to explore these possibilities is clearly needed.
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3. CIBIS-III (Cardiac Insufficiency BIsoprolol Study) |
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TopAbstract1. CARE-HF extension study...2. ESSENTIAL: (The studies...3. CIBIS-III (Cardiac...4. S-ICD: a prospective,...5. ISSUE-2 (International Study...6. STRIDE-2: (A placebo...7. SOFA (Study on...8. IMAGINE (Ischaemia Management...9. PREAMI (Perindopril and...10. SIRIUS-II (Safety and...11. ACTIVE (Atrial fibrillation...References |
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Results presented by Ronnie Willenheimer, Malmo, Sweden
This trial assessed the effects of 6 months mono-therapy with bisoprolol or enalapril in patients with mild heart failure, followed by combination treatment with both drugs for 6–24 months. The original study design [10] and results [11] have been published.
In summary, 1010 patients aged >65 years, with NYHA II/III heart failure and LVEF <35% were randomised and followed for a mean of 1.25 years. Use of bisoprolol followed by the addition of enalapril was generally associated with slightly better outcomes, except for a greater propensity for hospitalization with worsening heart failure. The authors concluded that either clinical practice was acceptable and that clinicians should use their judgement in deciding which agent to use first. However, the trial design is neither compatible with current guidelines nor usual clinical practice, as guidelines do not recommend such a long period of mono-therapy. The clinical practice of many is to initiate both agents in low doses, to titrate ACE inhibitors to target doses within 2–3 weeks and to titrate beta-blockers more slowly (over 2–3 months). In essence, CIBIS-III was a study of bisoprolol versus enalapril for 6 months, which should have had a third, combination-arm as in CARMEN [12]. The CARMEN study suggested that combination therapy (carvedilol and enalapril) had a greater effect on ventricular remodelling than either agent used alone. Also, changes in the rules for the futility analysis occurred during the conduct or analysis of the study that further weaken the interpretation of this study's findings.
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4. S-ICD: a prospective, randomised comparison in humans of defibrillation efficacy of a standard transvenous ICD system with a totally subcutaneous ICD system |
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TopAbstract1. CARE-HF extension study...2. ESSENTIAL: (The studies...3. CIBIS-III (Cardiac...4. S-ICD: a prospective,...5. ISSUE-2 (International Study...6. STRIDE-2: (A placebo...7. SOFA (Study on...8. IMAGINE (Ischaemia Management...9. PREAMI (Perindopril and...10. SIRIUS-II (Safety and...11. ACTIVE (Atrial fibrillation...References |
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Results presented by AA Grace, Cambridge, UK
This was a study to assess the feasibility of implanting subcutaneous leads with a minimally invasive approach to deliver shocks from an implanted defibrillator in 53 patients. The subcutaneous device proved successful but required higher energy shocks than transvenous systems to ensure cardioversion. Such devices will therefore probably have a shorter battery life, may deliver more painful shocks and could put bystanders at greater risk. However, for patients who do not require CRT or pacing and who are not likely to require frequent shocks, this could be a useful option.
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5. ISSUE-2 (International Study on Syncope of Uncertain Etiology 2) |
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TopAbstract1. CARE-HF extension study...2. ESSENTIAL: (The studies...3. CIBIS-III (Cardiac...4. S-ICD: a prospective,...5. ISSUE-2 (International Study...6. STRIDE-2: (A placebo...7. SOFA (Study on...8. IMAGINE (Ischaemia Management...9. PREAMI (Perindopril and...10. SIRIUS-II (Safety and...11. ACTIVE (Atrial fibrillation...References |
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Results presented by Michele Brignole, Ospedali del Tigullio, Lavagna, Italy
This observational study enrolled 422 patients with three or more episodes of unexplained syncope and implanted a loop recorder. Over 2 years, the type of syncope could be documented in 103 patients, and this was used to guide subsequent therapy (47 patients had pacemakers, 6 had anti-tachyarrhythmia therapy and 50 were left untreated). Treatment (n=53 patients) reduced the rate of syncope from 0.83 episodes per year to 0.07 per year. However, the value of the data were questioned (Prof. J.J. Blanc from Brest) as it was calculated that 700 loop recorders, resulting in 100 pacemaker implants would be required to prevent 28 episodes of syncope. Of course, in patients with heart failure requiring a device for other reasons, the device diagnostics can be very helpful in diagnosing the cause of syncope.
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6. STRIDE-2: (A placebo-controlled study for sitaxsentan in pulmonary arterial hypertension) |
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TopAbstract1. CARE-HF extension study...2. ESSENTIAL: (The studies...3. CIBIS-III (Cardiac...4. S-ICD: a prospective,...5. ISSUE-2 (International Study...6. STRIDE-2: (A placebo...7. SOFA (Study on...8. IMAGINE (Ischaemia Management...9. PREAMI (Perindopril and...10. SIRIUS-II (Safety and...11. ACTIVE (Atrial fibrillation...References |
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Results presented by Nazzareno Galie, University of Bologna, Italy
One of the commonest causes of pulmonary hypertension, albeit not usually severe, is heart failure [13]. Increases in pulmonary vascular resistance reflect increased left atrial and pulmonary capillary pressure and ‘protective— pulmonary arteriolar vasoconstriction. Increased pulmonary vascular resistance in patients with heart failure appears to be mediated, in part, by endothelin and indicates a worse prognosis [14]. Although endothelin antagonists have not been shown to be effective in the overall population of patients with heart failure, agents that reduce pulmonary vascular resistance might be useful in the subset with pulmonary hypertension.
The endothelin antagonist bosentan is effective for the treatment of pulmonary arterial hypertension, however, it is non-selective, blocking both ETA and ETB receptors. Sitaxsentan is an oral endothelin receptor antagonist which selectively inhibits the ETA receptor.
The aim of the STRIDE-2 study was to assess the safety and efficacy of two dose levels of sitaxsentan compared to placebo and bosentan, in patients with pulmonary arterial hypertension. 246 patients were randomised to treatment with either sitaxsentan (100 mg or 50 mg daily), placebo or open label bosentan for 18 weeks. The primary endpoint was 6-min walk test distance.
Sitaxsentan 100 mg daily improved 6-MWT distance and WHO functional class compared to placebo; overall, the treatment was well tolerated with a low incidence of adverse effects on liver function. The possible dose-related effect provides further evidence for an important role of endothelin antagonists for this relatively uncommon but serious problem. There is some evidence to suggest that non-selective blockade of both ETA and ETB receptors might be helpful and the value of selective blockade is not certain.
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7. SOFA (Study on Omega-3 Fatty acid and ventricular Arrhythmia) |
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TopAbstract1. CARE-HF extension study...2. ESSENTIAL: (The studies...3. CIBIS-III (Cardiac...4. S-ICD: a prospective,...5. ISSUE-2 (International Study...6. STRIDE-2: (A placebo...7. SOFA (Study on...8. IMAGINE (Ischaemia Management...9. PREAMI (Perindopril and...10. SIRIUS-II (Safety and...11. ACTIVE (Atrial fibrillation...References |
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Results presented by Ingeborg Brouwer, Wageningen Centre for Food Sciences, The Netherlands
This study randomised 546 patients with ICDs from eight European cardiology centres to double-blind treatment with either placebo or 2 g of fish oil per day, in addition to standard therapy. The primary endpoint was all-cause mortality or an assumed life threatening arrhythmia based on the diagnostics of the defibrillator. There was no difference in the number of patients who reached a primary endpoint between the treatment groups (Table 3). Subgroup analysis suggested a possible effect in patients with a previous myocardial infarction. SOFA supports previously reported neutral data [15] in a similar patient population. The possible effect in patients with previous myocardial infarction could reflect a reduction in coronary events (one of the potential effects of fish oils). Alternatively, it is possible that patients with LV dysfunction are the ones who benefit. This is being tested in GISSI-CHF [16]. It is becoming increasingly clear that device discharge, even when considered appropriate, is not a surrogate for sudden death, as comparative randomised trials show that the rate of ‘appropriate— discharge is many times higher than the rate of sudden death in the control group. However, treatments to reduce shocks, whether they are appropriate or not, would be a valuable addition to ICD therapy.
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8. IMAGINE (Ischaemia Management with Accupril post bypass Graft via Inhibition of the coNverting Enzyme |
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TopAbstract1. CARE-HF extension study...2. ESSENTIAL: (The studies...3. CIBIS-III (Cardiac...4. S-ICD: a prospective,...5. ISSUE-2 (International Study...6. STRIDE-2: (A placebo...7. SOFA (Study on...8. IMAGINE (Ischaemia Management...9. PREAMI (Perindopril and...10. SIRIUS-II (Safety and...11. ACTIVE (Atrial fibrillation...References |
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Results presented by WH van Gilst, Groningen, The Netherlands
This study randomised 2553 patients within 7 days of CABG to quinapril (40 mg/day) or placebo and followed them for 43 months. The risk of cardiovascular events was very low and no benefit of quinapril on death, vascular events or heart failure was observed. Quinapril use was associated with more side effects. The results are consistent with the overall results of trials of ACE inhibitors in patients with coronary disease and indicate that unless the patient is in a higher risk category, the harm of intervention may outweigh the benefit [17].
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9. PREAMI (Perindopril and Remodelling in Elderly with Acute Myocardial Infarction) |
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TopAbstract1. CARE-HF extension study...2. ESSENTIAL: (The studies...3. CIBIS-III (Cardiac...4. S-ICD: a prospective,...5. ISSUE-2 (International Study...6. STRIDE-2: (A placebo...7. SOFA (Study on...8. IMAGINE (Ischaemia Management...9. PREAMI (Perindopril and...10. SIRIUS-II (Safety and...11. ACTIVE (Atrial fibrillation...References |
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Results presented by Roberto Ferrari, University of Ferrara, Italy
This study randomised 1252 patients aged >65 years who had had a recent myocardial infarction which had not resulted in major LVSD (LVEF >40%) to placebo or perindopril (initially 4 mg but titrated to 8 mg/day). The aim was to investigate the effects of therapy on a composite of clinical outcomes and LV remodelling (defined as an increase in LVEDV >8%) over 1 year. The study was under-powered to show an effect on clinical outcomes alone. Mortality was low and not different between the treatment groups. There was no significant effect on the development of heart failure (risk reduction 27%; p=0.24). However, the incidence of adverse LV remodelling was reduced by 46% (from 51.2% to 27.7%; p<0.001) by the administration of perindopril. There was no change in mean LVEDV on perindopril but an approximate 4-ml increase on placebo. The small change in mean LVEDV in both groups requires explanation given the large proportion of patients who showed adverse remodelling. Either many ventricles recovered during follow-up, offsetting the increase in volumes amongst those with adverse remodelling or there was a lot of measurement ‘noise— with a consequent regression to the mean. 28% of patients had an inadequate echo at 1-year follow-up. Viewed in isolation, the outcome of this study is unimpressive but it is consistent with other data showing the benefits of ACE inhibition in patients with vascular disease without heart failure [17]. However, the mechanism of benefit is disputed. A recent report for the HOPE study reopens the argument that the benefit observed in these trials is mediated by a reduction in blood pressure and not specifically by inhibition of ACE [18].
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10. SIRIUS-II (Safety and efficacy of an Intravenous placebo controlled Randomised Infusion of Ularitide in a prospective double-blind Study in patients with symptomatic decompensated chronic heart failure) |
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TopAbstract1. CARE-HF extension study...2. ESSENTIAL: (The studies...3. CIBIS-III (Cardiac...4. S-ICD: a prospective,...5. ISSUE-2 (International Study...6. STRIDE-2: (A placebo...7. SOFA (Study on...8. IMAGINE (Ischaemia Management...9. PREAMI (Perindopril and...10. SIRIUS-II (Safety and...11. ACTIVE (Atrial fibrillation...References |
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Results presented by Veselin Mitrovic, Kerckhoff Clinic, Bad Nauheim, Germany
Ularitide is a natriuretic peptide analogue with an activity profile similar to nesiritide. This was a haemodynamic study of patients with heart failure and breathlessness at rest or minimal exertion: pulmonary capillary wedge pressure >18 mmHg and cardiac index <2.5 L/min/m2. Two hundred and twenty-one patients, mean age 61 years, were randomly assigned to placebo (n=53) or ularitide infusions of 7.5 (n=60), 15 (n=53) and 30 (n=55) ng/kg/min for 24 h. 78% were men, 52% had ischaemic heart disease, 72% had LVEF <30%, median NT-proBNP was 3200 pg/ml, mean systolic BP was 125 mmHg, mean PCWP was 25 mmHg and mean cardiac index was 1.9 L/min/m2.
About 25% patients were deemed to have improved on placebo versus about 40% with each dose of ularitide. PCWP fell by a mean of 4 mmHg on placebo and by 11 mmHg on the highest dose of ularitide. Mean cardiac index increased by 0.1 L/min/m2 on placebo and by 0.4 L/min/m2 on ularitide. Mean systolic BP fell by up to 15 mmHg, heart rate did not change and NT-proBNP levels fell over the 24-h infusion period with the two higher doses of ularitide. No additional diuresis was noted with ularitide and serum creatinine increased similarly on placebo and ularitide except at the 15 ng/kg/min dose. There were 7 deaths on placebo, 1 on the highest dose of ularitide and 2 in each of the other groups. The two higher doses were associated with a reduction in the length of hospital stay.
These results are encouraging although the similarities between the mode of action of this agent and nesiritide give grounds for concern given the recent adverse reports on the latter agent. In particular the large fall in systolic blood pressure indicates that it should be used with care or not all except in patients with well-maintained or increased blood pressure, a large proportion of patients with acute heart failure.
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11. ACTIVE (Atrial fibrillation Clopidogrel Trial with Irbesartan for the prevention of Vascular Events) |
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TopAbstract1. CARE-HF extension study...2. ESSENTIAL: (The studies...3. CIBIS-III (Cardiac...4. S-ICD: a prospective,...5. ISSUE-2 (International Study...6. STRIDE-2: (A placebo...7. SOFA (Study on...8. IMAGINE (Ischaemia Management...9. PREAMI (Perindopril and...10. SIRIUS-II (Safety and...11. ACTIVE (Atrial fibrillation...References |
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The ACTIVE study aims to evaluate several different treatment regimes for the prevention of vascular events in patients with AF. The study comprises three different treatment "arms" called ACTIVE W, ACTIVE A and ACTIVE I. The ACTIVE W arm is an open comparison of warfarin versus aspirin plus clopidogrel. Patients who are unable or unwilling to take warfarin are randomised to treatment either with aspirin or with aspirin plus clopidogrel (ACTIVE A). Hypertensive patients from both ACTIVE A and ACTIVE W can then be randomised to treatment with either irbesartan or placebo, to evaluate whether blood pressure lowering with an ARB has a further effect on the incidence of vascular events: this arm is called ACTIVE I.
The ACTIVE W arm, comparing the effects of warfarin with a combination of aspirin plus clopidogrel on vascular events, was reported during the meeting to have been stopped prematurely due to clear benefits with warfarin. This provides further evidence that warfarin is the gold-standard against which other agents should be compared for the reduction of death and thrombo-embolic events in patients with atrial fibrillation. Aspirin also increases the risk of recurrent hospitalisation compared to warfarin in patients with heart failure in sinus rhythm, providing further evidence in support of the use of anticoagulants [19,20]. Ximelagatran, a direct oral thrombin antagonist, is the one agent which has shown equivalence to warfarin in terms of efficacy, with a superior safety profile [21,22]. Unfortunately, concerns by regulatory authorities over apparently minor abnormalities in liver function have led to delays in the approval of this compound.
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References |
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TopAbstract1. CARE-HF extension study...2. ESSENTIAL: (The studies...3. CIBIS-III (Cardiac...4. S-ICD: a prospective,...5. ISSUE-2 (International Study...6. STRIDE-2: (A placebo...7. SOFA (Study on...8. IMAGINE (Ischaemia Management...9. PREAMI (Perindopril and...10. SIRIUS-II (Safety and...11. ACTIVE (Atrial fibrillation...References |
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