© 2000 European Society of Cardiology
Clinical trials update: IMPROVEMENT-HF, COPERNICUS, MUSTIC, ASPECT-II, APRICOT and HEART
Academic Department of Cardiology, University of Hull Castle Hill Hospital, Castle Road, Kingston upon Hull HU16 5JQ, UK
* Corresponding author. Tel.: +44-1482-623732; fax: +44-1482-624087. E-mail address: g.m.porter{at}medschool.hull.ac.uk (K. Witte).
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Abstract |
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 Top Abstract 1. The IMPROVEMENT of...2. COPERNICUS (Carvedilol...3. MUSTIC (MUlti-site...4. APRICOT II and...References |
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Important new studies relevant to the field of heart failure reported at the annual congress of the European Society of Cardiology (ESC), held in Amsterdam in August 2000, are reviewed. The IMPROVEMENT of Heart Failure survey investigated the knowledge and perceptions of over 1300 primary care physicians from 14 ESC member nations and the actual practice in over 11000 of their patients. Guidelines and clinical practice were compared. The survey suggested, in this large sample, that the quality of care was higher than previous smaller surveys have suggested but have also identified important deficiencies in knowledge and management that should be rectified. The COPERNICUS study demonstrated that carvedilol was remarkably well tolerated even in patients with very severe heart failure and that treatment was associated with a substantial reduction in mortality even among patients that would conventionally not be considered, by many, for beta-blocker therapy. The MUSTIC trial suggested that cardiac resynchronisation using biventricular pacing improved patients symptomatically whether or not the patient was in atrial fibrillation. Morbidity and mortality studies of cardiac resynchronisation are now underway. The ASPECT-II and APRICOT-II studies investigated the role of warfarin, aspirin and their combination for the long-term management of myocardial infarction. One interpretation of the data from these studies is that the combination of aspirin and warfarin is about as effective as warfarin alone but with a much higher incidence of side effects. Warfarin alone appeared superior to aspirin alone. In summary, the annual congress of the ESC provided important new information for clinical practice and, to date, was, by far, the most important cardiology congress in the world this year.
Key Words: Heart failure • Beta-blocker therapy • Warfarin • Aspirin
Received September 8, 2000; Accepted September 12, 2000
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1. The IMPROVEMENT of Heart Failure Survey (Phase 1) (Improvement programme on evaluation and management of heart failure) |
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The purpose and protocol of this study has been reported previously in this journal [1]. In brief, the survey is the first phase of a three-part initiative. Phase 1 is designed to determine whether or not ESC guidelines on diagnosis [2] and treatment [3] of heart failure are being followed in primary care. Phase 2 is an educational programme designed to reinforce strengths and correct deficiencies in the current quality of care. Phase 3 is a repeat survey to determine the impact of the educational programme.
1.1. Design
Phase 1 itself consisted of two parts. Part 1, the perception survey, was a survey of primary care physician's (PCPs) knowledge about heart failure, what they believed was important in its management and whether they thought that they practised what they believed. PCPs were selected at random from lists provided for each participating region in the 14 ESC countries involved. Part 2, the actual practice survey, investigated how individual patients were managed. Patients were identified using a patients enrolment log for 6–8 weeks. The case notes were reviewed from up to nine patients with either heart failure or myocardial infarction.
1.2. Population
1363 PCPs participated and over 11 000 patients were surveyed. Altogether approximately 80% of invited doctors consented to participate. Participating doctors tended to be younger than the average age of PCPs in Europe. There were large international variations in the gender of PCPs with over 80% being women in Russia but only 6% in France.
1.3. Results
The perception survey revealed that PCPs generally requested electrocardiograms (ECGs) and chest X-rays for diagnosis. However, overall, less than 50% said they would usually request an echocardiogram with large international variations (10% in the Netherlands but 73% in France). Knowledge about interpreting the results of echocardiography appeared more limited with only approximately one-third of PCPs distinguishing between systolic and diastolic left ventricular dysfunction. Lifestyle advice also showed marked international variation. Only 23% of Swedish but 96% of Russian PCPs indicated that they usually recommended salt restriction, while 29% of Russian compared to 75% of French PCPs recommended regular exercise. Almost 80% of PCPs suggested that they would routinely or frequently use an ACE inhibitor, ranging from 94% in Italy to 67% in the UK. Only 11% of PCPs said they routinely used a beta-blocker, varying from 17% in Russia to 4% in the UK.
The current report from the actual practice survey concentrated on over 8000 (75%) patients with symptomatic heart failure or receiving treatment with diuretics (most patients had both). More than 90% of patients had had an ECG and in more than 90% it was reported as abnormal. Chest X-rays had a similarly high uptake. There was marked international variation in the use of echocardiography with only 61% of Polish and Swedish patients having this test vs. 95% in the UK. The great majority of echocardiograms were reported as abnormal. There was evidence that application of lifestyle advice was patchy. Use of ACE inhibitors was generally high, ranging from a high of 76% in Hungary to a low of 53% in Turkey. However, in some countries up to 80% of ACE inhibitors were initiated by hospitals. ACE inhibitors were frequently not up-titrated, with once daily ACE inhibitors such as Lisinopril and Perindopril more likely to achieve the target doses specified in guidelines [3]. Use of beta-blockers was generally low ranging from 52% in Hungary to 9% in Turkey.
In summary, this preliminary report from the Improvement study has identified deficiencies in the perception and practice of heart failure management in primary care, in particular a lack of awareness about the differentiation between systolic and diastolic dysfunction. Uptake of ACE inhibitors was higher than expected, but as many patients did not have major left ventricular systolic dysfunction further information is required on appropriateness of use. Beta-blockers are currently used in only a small minority of patients with heart failure perhaps reflecting PCPs uncertainty about their use.
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2. COPERNICUS (Carvedilol Prospective RaNdomIsed Cumulative Survival) Trial |
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TopAbstract1. The IMPROVEMENT of...2. COPERNICUS (Carvedilol...3. MUSTIC (MUlti-site...4. APRICOT II and...References |
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There is overwhelming evidence that beta-blockers should be administered to all patients with mild to moderate heart failure secondary to left ventricular systolic dysfunction unless contra-indications exist [4–6]. Uncertainty exists regarding the benefits, safety and tolerability of beta-blockers in patients with very severe heart failure. This uncertainty was heightened by the results of the BEST study [7], which failed to show a benefit with bucindolol, a beta-blocker reputed to have increased intrinsic sympathomimetic activity, in patients with severe heart failure. The COPERNICUS trial set out to address this issue using carvedilol, a vasodilating beta-blocker of proven benefit.
2.1. Design
The study was a randomised, double-blind trial comparing carvedilol and placebo in 2289 patients with severe chronic heart failure. There was no active run-in period. Carvedilol or matching placebo was uptitrated at two weekly intervals from 3.125 to 25 mg b.d.
2.2. Inclusion/exclusion criteria
Patients had to have EF <25%, with symptoms of dyspnoea and/or fatigue at rest or minimal exertion. Patients receiving intravenous diuretics or vasodilators could be included, but those dependent on inotropic support were excluded. Patients could be randomised while in hospital for an episode of heart failure. Recruitment of patients with gross fluid overload, for instance those with marked oedema was strongly discouraged.
2.3. Population
Patients (2289), mean age 63 years, with mean EF 20%. About 65% had been hospitalised in the previous 12 months.
2.4. Outcome
The primary outcome was all cause mortality.
2.5. Results
Patients (73.9%) randomised to carvedilol reached the target dose of 25 mg b.d. vs. 81% reaching the ‘target dose’ of placebo. Permanent withdrawal due to intolerance was less in the carvedilol-treated group. No patients were lost to follow up over a mean follow-up of approximately 1 year (maximum 29 months).
The trial was stopped early because of a marked benefit of carvedilol on mortality. There were 190 deaths in the placebo group and 130 in the patients taking carvedilol over the course of the trial (Table 1). The survival curves began to separate at 3–4 months and continued to diverge. The benefit on mortality was observed across subgroups including age, gender, and aetiology of heart failure. Patients with an EF <15%, those with 
3 admissions in the preceding year, those on intravenous therapy, those initiated during an admission and even those who showed some evidence of continuing fluid overload benefited. Subgroups with an annual mortality as high as 25.3% in the placebo group had this reduced to 16.7% with carvedilol treatment. No subgroup analysed failed to benefit.
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No data on the effect of carvedilol on hospitalisations were presented.
2.6. Interpretation
The COPERNICUS trial further extends the range of patients who should be treated with beta-blockers. Carvedilol proved remarkably well tolerated even in this group of sick patients. The relative risk reduction in COPERNICUS (35%) was remarkably similar to that observed in CIBIS-II (with bisoprolol, 34%) [8] and MERIT (with metoprolol, 34%) [9,10]. However, the absolute risk reduction in COPERNICUS was far greater than for these trials, reflecting the different severities in the populations being treated (Table 2). Thus, it is inappropriate to assume that these three agents have similar efficacy. It is remarkable that >70% of patients reached the target dose of carvedilol in COPERNICUS, vs. 64% in MERIT but only 43% in CIBIS-II. These differences may reflect the growing confidence with which cardiologists are using beta-blockers or different dose titration regimens but it is also possible that carvedilol, due to its vasodilating alpha-blocker properties, is genuinely better tolerated. The COMET study is currently comparing carvedilol and metoprolol in a double-blind study of over 3000 patients [11]. The outcome is keenly awaited.
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3. MUSTIC (MUlti-site STimulation In Cardiomyopathy) |
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TopAbstract1. The IMPROVEMENT of...2. COPERNICUS (Carvedilol...3. MUSTIC (MUlti-site...4. APRICOT II and...References |
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Ventricular dyssynchrony is not uncommon in heart failure. Broad QRS complexes on the ECG (e.g. >120 ms) are a simple marker of patients likely to have this problem. Cardiac resynchronisation through atrio-ventricular and multi-site ventricular pacing is an evolving technology showing some promise for the treatment of severe heart failure. The MUSTIC study investigated the role of resynchronisation for the improvement of symptoms and exercise capacity for patients with severe heart failure.
3.1. Design
Single-blind, cross-over study with 3-month treatment periods comparing resynchronisation therapy vs. control. All patients had devices implanted (93% success rate) with pacing leads in the right ventricular apex and coronary sinus (for left ventricular pacing). Patients in sinus rhythm had an atrial sensing lead to allow pacing with short atrio-ventricular delay. Patients in atrial fibrillation (AF) were recruited only if they had slow ventricular rate or had an atrio-ventricular node ablation. These patients had rate-responsive pacemakers implanted. The control mode in sinus rhythm was back-up pacing at 40 b.p.m. The control mode in the AF group was pacing at 70 b.p.m. with the rate response algorithm set to 85% of predicted maximum heart rate.
3.2. Inclusion/exclusion
Patients had to have NYHA III heart failure, dilated left ventricles with ejection fraction <35% and QRS width >150 ms for those in sinus rhythm or 200 ms during ventricular pacing for those in AF.
3.3. Population
Sixty-seven patients in sinus rhythm and 64 in AF had devices implanted. 58 and 46, respectively, were randomised, while 48 and 41, respectively, completed all phases of the study. Their mean age was 64 years and approximately 80% were men.
3.4. Outcome
The primary endpoint was a 6-min walk distance. The study was powered to detect a 10% increase with 95% CI. Secondary endpoints were quality of life (Minnesota scale), peak exercise oxygen consumption, admissions and all cause mortality.
3.5. Results
Ninety-four percent of successfully implanted systems (i.e. 87% of attempted cases) were functional at the end of the relevant double-blind phase. Those patients in sinus rhythm had a significant increase in the 6-min walk distance, increase in peak exercise oxygen consumption, improvement in quality of life score and had significantly fewer hospitalisations. Patients in AF showed similar but non-significant trends on an intention-to-treat analysis but once protocol violators were removed benefits seemed similar to those observed in sinus rhythm. Over 80% of patients in both groups preferred resynchronisation to control (P<0.001, Table 3). Mortality was low (4 in the cross-over phase) but more often occurred during resynchronisation.
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3.6. Discussion
The MUSTIC study lends further support for a role for cardiac resynchronisation in the management of symptoms in patients with severe heart failure and left ventricular dyssynchrony. *** It is now important to establish whether resynchronisation is safe or can even reduced morbidity and mortality. A summary of ongoing trials of cardiac resynchronisation in heart failure is given in Tables 4 and 5.
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4. APRICOT II and ASPECT II (Antithrombotics in the Prevention of Reocclusion in COronary Thrombolysis and Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis) |
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TopAbstract1. The IMPROVEMENT of...2. COPERNICUS (Carvedilol...3. MUSTIC (MUlti-site...4. APRICOT II and...References |
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Most heart failure is secondary to ischaemic heart disease and is often the result of myocardial infarction. There are few data to support the use of chronic anti-coagulation and even less to support chronic anti-platelet therapy after myocardial infarction, despite some flawed meta-analyses [12,13]. No substantial, long-term, post-infarction study has compared placebo with aspirin at a dose of <300 mg/day [13]. It is remarkable how cardiology has adopted the fashion and ignored the evidence on this topic. There are even fewer data to support the use of chronic anti-thrombotic therapy in heart failure, despite the high athero-thrombotic event rate in this patient population [13]. A preliminary report in patients with heart failure suggested that compared to warfarin or no anti-thrombotic therapy, aspirin increased the risk of hospitalisation with worsening heart failure [14]. A large mortality study (n=4500) is currently being conducted in the US, Canada and the UK under the auspices of the US Veterans’ Administration [14] (Fig. 1). Further studies to clarify current misconceptions are welcome and two studies reported at the ESC help.
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4.1. APRICOT II
APRICOT II randomised 308 patients in the acute post-infarction setting after successful thrombolysis to aspirin alone or aspirin plus heparin followed by anti-coagulation to an INR of 2.6. The study suggested that combination therapy was superior to aspirin alone, but could not address the question of whether anti-coagulation alone might have been as or more effective than combination therapy. ASPECT-II provides some intriguing data on precisely this topic. This study randomised, open-label, 993 patients who had had a myocardinal infarction within the last 2 months to aspirin 80 mg/day, warfarin to a target INR range of 3–4 (mean 3.2) or a combination of aspirin 80 mg/day and warfarin to a target INR range of 2–2.5 (mean 2.4). The primary outcome was a combination of death, myocardial infarction or stroke. The study was terminated prematurely for administrative reasons. Over a mean follow-up of 1 year, significantly fewer patients in both warfarin groups reached the primary end-point, with the warfarin-only arm being associated with the lowest mortality and a complete absence of stroke (Table 6). The ratio of death to non-fatal myocardial infarction was much higher in the aspirin group suggesting that aspirin may be associated with an increased propensity to sudden death, as in all previous secondary prevention trials (Table 7). This may be due to the concealing of myocardial infarctions through inducing dyspepsia or increasing the rate of ‘silent’ myocardial infarction [15]. Combination therapy was associated with the highest rate of side effects and withdrawals. These data not only provide powerful reasons for avoiding aspirin/warfarin combinations but also re-open the issue not only of the efficacy but also the safety of aspirin in chronic vascular disease.
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4.2. HEART-UK
Whether patients with heart failure should undergo investigation to detect subclinical ischaemia and or viable but dysfunctional myocardium is a hot topic currently being partially addressed by the CHRISTMAS study [16]. Such investigations can only be recommended as part of the routine work-up of patients if it can be shown that the investigation will alter patient management. It is uncertain whether revascularisation is a safe and effective treatment for patients with heart failure and a myocardial viability problem [17]. The HEART-UK study, comparing revascularisation in addition to optimal medical therapy vs. optimal medical therapy only, was announced during the highlights session. The study aims to recruit 800 patients with a minimum follow-up of 5 years with mortality as the primary endpoint. Currently, participation of European centres other than the UK is being discussed which may lead to an even more substantial study.
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