© 2003 European Society of Cardiology
Update of clinical trials from the American College of Cardiology 2003. EPHESUS, SPORTIF-III, ASCOT, COMPANION, UK-PACE and T-wave alternans
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: a.p.coletta{at}hull.ac.uk
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Abstract |
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 Top Abstract 1. EPHESUS [Eplerenone Post-AMI...2. SPORTIF-III [Stroke...3. ASCOT [Anglo-Scandinavian...4. COMPANION [Comparison of...5. UK-PACE6. T-wave alternansReferences |
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The American College of Cardiology provided much useful new information to inform those who care for patients with heart failure about what they should and should not adopt into current clinical practice. The EPHESUS trial suggests a much wider role for aldosterone antagonists for the management of heart failure and left ventricular systolic dysfunction. SPORTIF-III indicates we may have a safer, simpler warfarin substitute soon. ASCOT reinforces the potential futility of statin therapy unless it is well targeted. The results of the COMPANION study investigating cardiac resynchronisation devices and implantable defibrillators were encouraging but inconclusive and/or hard to interpret. UK-PACE again questions the use of dual chamber pacing. T-wave alternans is an interesting experimental technique that may be useful in selecting which patients need an implantable defibrillator, although the technology needs testing in an appropriate patient population.
Key Words: EPHESUS • SPORTIF-III • ASCOT • COMPANION • UK-PACE • T-Wave Alternans
Received April 9, 2003; Accepted April 16, 2003
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1. EPHESUS [Eplerenone Post-AMI Heart Failure Efficacy and SUrvival Study] |
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TopAbstract1. EPHESUS [Eplerenone Post-AMI...2. SPORTIF-III [Stroke...3. ASCOT [Anglo-Scandinavian...4. COMPANION [Comparison of...5. UK-PACE6. T-wave alternansReferences |
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The principal results of this study have been published [1,2]. The main results and some observations are presented here.
1.1. Rationale
Plasma aldosterone falls acutely with the introduction of an ACE inhibitor but returns towards pre-treatment levels with chronic therapy. This may reflect potassium retention in response to ACE inhibition and, therefore, be a useful safety valve to prevent hyperkalaemia. Potassium retention is a very potent stimulus for aldosterone secretion and occurs even before plasma potassium concentration occurs. Reduced hepatic degradation of aldosterone or increased sensitivity to angiotensin II, albeit to lower plasma concentrations, are alternative explanations for the modest long-term effect of ACE inhibitors on plasma aldosterone concentration. Aldosterone has a broad range of cardiovascular effects, including effects on electrolyte metabolism, sympathetic activity, endothelial function and collagen turnover [3]. The RALES study showed that spironolactone could reduce mortality when added to ACE inhibitors in patients with severe heart failure [4]. The EPHESUS study sought to extend these data to patients with post-infarction left ventricular systolic dysfunction who exhibited at least transient signs of heart failure or who had diabetes, most of whom were treated with ACE inhibitors and beta-blockers [1].
1.2. Design
This was a randomised, double-blind trial comparing eplerenone (initially 25 mg/day titrated to 50 mg/day after 4 weeks) and placebo in patients who had sustained a myocardial infarction in the previous 3–14 days (mean 7.3 days) and who had a left ventricular ejection fraction <40% (mean 33%) and who had at least transient evidence of heart failure (90%) or diabetes mellitus (32%), two markers of increased risk. Treatment was in addition to optimal medical therapy for post-infarction heart failure and generally included an ACE inhibitor (87%), beta-blocker (75%), diuretic (61%), aspirin (89%) and statins (47%). However, 55% of patients did not undergo reperfusion therapy, perhaps reflecting their late presentation after the onset of symptoms. Exclusion criteria included use of potassium sparing diuretics, a serum creatinine >220 µmol/l (mean was 97 µmol/l) or serum potassium >5 mmol/l (mean was 4.3 mmol/l). The trial was designed to enrol 6200 patients and to continue until 1012 deaths had occurred.
1.3. Monitoring
Serum potassium was monitored at 48 h, 1, 4 and 5 weeks and at 3-monthly study visits thereafter and within 1 week of any dose change.
1.4. Primary endpoints
All-cause mortality and the composite of cardiovascular death or hospitalisations were the co-primary endpoints. Analysis was by intention-to-treat, the most rigorous test but one that underestimates the true effects of therapy, whether benefits or side effects.
1.5. Results
The mean age of the patients was 64 years and 29% were women. Baseline biochemistry and therapy is shown above. There was a relatively high early mortality (10% by 6 months) but, thereafter, a relatively low annual mortality of approximately 6% in the placebo group (Table 1). Discounting the early mortality, the population prognosis appears similar to that of the SOLVD-prevention trial, which showed an annual mortality of 5%. However, this low mortality was only achieved in EPHESUS with the combined use of ACE inhibitors and beta-blockers, so the population risk was probably intrinsically higher than in SOLVD-prevention [5]. The mean left ventricular ejection fraction was 33% similar to that in previous studies of heart failure and post-infarction LV dysfunction. Despite the relatively benign prognosis of the population, addition of eplerenone to fairly optimal background therapy reduced mortality by a further 15% and cardiovascular death or hospitalisation by 13%. The number of patients who died or were hospitalised for any reason was also reduced, as was the total number of heart failure hospitalisations. Sudden death was the most common mode of death and this is where eplerenone exerted its greatest relative and absolute impact. Indeed, if death due to acute myocardial infarction, a common cause of sudden death, is included in this outcome then more than 70% of lives saved were saved in this way [6]. In patients with LVEF <30% (the MADIT-II population) eplerenone reduced sudden death by 33%.
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Subgroup analysis showed little heterogeneity but patients already receiving ACE inhibitors and beta-blockers had greater benefit from eplerenone (20% reduction in mortality; P=0.04). Patients with a pulse pressure
45 mmHg (P=0.01) and a past history of hypertension (P=0.05) had significantly greater mortality benefits. Patients with LVEF <35% and those undergoing reperfusion also tended to obtain greater mortality benefit. Differences in outcome for the second co-primary endpoint were less convincing. There was no adverse interaction with baseline aspirin use. Patients randomised to eplerenone were less likely to get respiratory infections, presumably due to a reduction in pulmonary congestion, were at somewhat increased risk of serious hyperkalaemia (>6 mmol/l) but lower risk of hypokalaemia (<3.5 mmol/l). Eplerenone appeared free of feminising side effects such as gynaecomastia.
1.6. Conclusion
The EPHESUS study confirms that anti-aldosterone antagonists should be used for a broad range of patients with left ventricular systolic dysfunction perhaps even those who are asymptomatic. In patients with a severely depressed left ventricular ejection fraction the benefits of eplerenone appear similar to those observed with spironolactone in RALES. Whether it is better to choose eplerenone or spironolactone will revolve around the debate on cost vs. side effects. The combination of ACE inhibitor, beta-blocker and aldosterone antagonist should now be the standard ‘triple’ therapy for a broad range of patients with heart failure and left ventricular systolic dysfunction. The cumulative effects of this therapy are shown in Fig. 1.
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2. SPORTIF-III [Stroke Prophylaxis Using an Oral Thrombin Inhibitor in Atrial Fibrillation] |
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TopAbstract1. EPHESUS [Eplerenone Post-AMI...2. SPORTIF-III [Stroke...3. ASCOT [Anglo-Scandinavian...4. COMPANION [Comparison of...5. UK-PACE6. T-wave alternansReferences |
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2.1. Rationale
Coumadin anti-coagulants, unlike aspirin, reduce the risk of stroke markedly and death significantly in patients with atrial fibrillation [7]. However, anticoagulation requires careful monitoring in order to render it safe. Possibly more than 50% of all patients with atrial fibrillation have heart failure and more than 40% of patients with heart failure may suffer chronic or paroxysmal atrial fibrillation [7,8]. Patients with heart failure have variable hepatic congestion, multiple potential drug interactions and possibly an increased propensity to gastro-intestinal bleeding that render them more prone to complications and in need of even more monitoring than other patients with heart failure [9,10]. New anti-coagulant agents that have a predictable relationship between dose and effects could be safer and easier to administer. Ximelagatran is the first of a new class of direct thrombin inhibitors, the anticoagulant effects of which are predictable and are thought not to require monitoring. SPORTIF-III sought to determine whether ximelagatran could offer similar protection against stroke compared to warfarin.
2.2. Study design
This was a randomised, open-label study comparing ximelagatran (36 mg bd) compared to warfarin (INR range 2–3 checked monthly). Possible stroke end-points were evaluated by neurologists blind to treatment allocation and adjudicated by a blinded end-points committee.
2.3. Inclusion/exclusion
Patients had to have non-valvular AF and at least one additional risk factor for stroke, including previous stroke, hypertension or heart failure.
2.4. Primary endpoint
The primary endpoint was all strokes (ischaemic and haemorrhagic) and systemic thromboembolic events. The objective was to show that ximelagatran was no worse than warfarin. A secondary endpoint was the combined endpoint of death, stroke or major haemorrhage.
2.5. Results
Three thousand four hundred and seven patients were randomised and followed for a mean of 17 months. Patients were mainly men, 25% were aged >75 years and 30% had heart failure or major left ventricular systolic dysfunction.
The effect of ximelagatran on the primary end-point confirmed equivalence and approached statistical superiority compared to warfarin. No data were provided on stroke disability so far, an important issue as it is now clear that many strokes reported in trials resolve without significant disability. For the even more highly clinically relevant secondary endpoint of death, major haemorrhage or stroke, ximelagatran was superior to warfarin (Table 2).
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Liver enzyme abnormalities were observed in 6.5% of patients compared to 0.7% on warfarin (P<0.001). These resolved spontaneously or after cessation of therapy. Whether these abnormalities reflect important liver damage or not is uncertain (biopsy is contra-indicated!).
2.6. Conclusion
Ximelagatran is potentially a major advance in anti-thrombotic therapy and arguably the first significant new compound for over 50 years. Demonstration of greater safety in patients in whom anti-coagulation is difficult (such as those with heart failure) combined with the lack of need for monitoring, means that ximelagatran could rapidly displace treatment with coumadins and also expand the population for whom anti-coagulant rather than anti-platelet therapy is indicated.
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3. ASCOT [Anglo-Scandinavian Cardiac Outcomes Trial] |
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TopAbstract1. EPHESUS [Eplerenone Post-AMI...2. SPORTIF-III [Stroke...3. ASCOT [Anglo-Scandinavian...4. COMPANION [Comparison of...5. UK-PACE6. T-wave alternansReferences |
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3.1. Rationale
It is not clear if lipid-lowering therapy can reduce cardiovascular events in patients with hypertension.
3.2. Study design
The ASCOT study randomised 19 342 patients aged 40–79 years with previously treated or untreated hypertension and at least three other cardiovascular risk factors, to a combination of ‘old’ (beta-blocker and diuretic) or new (ACE inhibitor and calcium antagonist) therapies [11]. 10 305 Patients who were not on cholesterol lowering therapy and who had cholesterol <6.5 mmol/l were then re-randomised, double-blind to placebo or atorvastatin.
3.3. Primary endpoint
The primary end-point was myocardial infarction or coronary heart disease death.
3.4. Results
The lipid-lowering component of the study was stopped prematurely after a mean follow-up of 3.3 years by the data safety and monitoring committee because of perceived benefit. It is not clear that this was a wise decision, as there is no evidence from ASCOT that the reduction in non-fatal events observed on atorvastatin translated into a reduction in death or disability (Table 3). Despite >15 000 patient-years of follow-up in each arm of the study, there were only 54 fewer primary end-points on atorvastatin, a reduction of only three for every thousand patients treated per year. However, this did not translate into a reduction in death (there were only eight fewer cardiovascular deaths overall on atorvastatin) or disability (there were slightly more cases of heart failure on atorvastatin). There were 32 fewer strokes on atorvastatin (approx. one less for every thousand treated per year) but stroke deaths were not reduced and no data on stroke disability were provided, an important aspect of therapy evaluation.
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3.5. Conclusions
ASCOT is another example of a statistically positive but clinically neutral outcome study, somewhat similar to PROSPER [12] and MADIT-II [13], that tells clinicians what NOT to do. These studies all indicate that more selective treatment is required.
The clinical neutrality of the statin in this population is similar to that observed in PROSPER and ALL-HAT [14]. These neutral results further reinforce the need to demonstrate both the safety and the efficacy of statin therapy in heart failure. Two large trials are ongoing, GISSI-CHF and CORONA [15–17].
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4. COMPANION [Comparison of Medical Therapy, Pacing and Defibrillation in Chronic Heart Failure] |
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TopAbstract1. EPHESUS [Eplerenone Post-AMI...2. SPORTIF-III [Stroke...3. ASCOT [Anglo-Scandinavian...4. COMPANION [Comparison of...5. UK-PACE6. T-wave alternansReferences |
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The preliminary results of the COMPANION study were presented [18]. Follow-up of all patients is not yet complete.
4.1. Rationale
Studies suggest that 25% of patients with heart failure due to left ventricular systolic dysfunction will have a broad QRS (>120 ms), a surface ECG marker for cardiac dyssynchrony [19,20]. Studies completed so far show that atrio-biventricular pacing (cardiac resynchronisation/CRT) can improve symptoms in patients with advanced heart failure but the design of these studies precluded a true assessment of the safety or ability of CRT to reduce the long-term morbidity and mortality associated with heart failure [19,20]. The COMPANION study sought to address these questions. A more robustly designed study addressing the effects of CRT in a similar population, CARE-HF [21] is continuing.
4.2. Design
This was a randomised, open-label study comparing the safety and efficacy of implanting a CRT device, a CRT device with a defibrillator function (CRT–ICD) or no device, in addition to optimal medical therapy. Twice as many patients were randomised to each intervention compared to control. Analysis was by intention to treat.
4.3. Inclusion/exclusion
Patients had to have NYHA class III/IV heart failure, QRS width >120 ms and PR >150 ms on the surface ECG, hospitalisation for heart failure in the preceding year and left ventricular ejection fraction 
35% and end-diastolic dimension 60 mm despite optimal medical therapy with ACE inhibitors, beta-blockers and spironolactone.
4.4. Primary endpoint
The primary endpoint was a time-to-first-event analysis of all-cause mortality or all-cause hospitalisation comparing each intervention with control. A comparison of CRT alone vs. CRT–ICD was not part of the primary endpoint. Clearly, few deaths will occur in the absence of a preceding hospitalisation in this population and, therefore, >80% of the primary endpoints were for hospitalisation. This is dangerous in the setting of an open label study as hospitalisation is open to patient and investigator bias. Also, hospitalisation for device implantation was not counted (very sensible) but this biases the study in favour of devices since during the implantation period only the control group can reach an end-point.
4.5. Withdrawals and lost to follow-up
Approximately 13% of patients in the control group (approx. 40 patients) withdrew consent before reaching a primary endpoint and are currently lost to follow-up. Efforts are being made to correct this situation. Only investigator-reported, cause-specific hospitalisation was presented, as the end-points committee has not yet completed adjudication of outcomes.
4.6. Results
The mean age of patients was 66 years and 67% were men. Eighty-nine percent of patients were treated with an ACE inhibitor or angiotensin receptor blocker, 68% a beta-blocker and 54% spironolactone. Fifty-five percent had ischaemic heart disease. The mean left ventricular ejection fraction was 23% and QRS width 159 ms. The success rate for device implantation was 90% which is similar to that reported in other studies. There were only two deaths related to device implantation in each of the intervention groups. The study was stopped early by its data safety and monitoring board, because of perceived benefit, although this decision now seems controversial in the light of the results presented. Mean follow-up was 16 months. Compared to control, CRT alone reduced the primary endpoint but not mortality whilst CRT–ICD reduced both the primary endpoint and mortality (Table 4). There was no difference between CRT and CRT–ICD for either outcome (not a pre-planned analysis).
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4.7. Conclusions
The COMPANION result is very encouraging but should be interpreted with caution, as the study was unblinded. The high withdrawal rate from the OMT group prior to the patient encountering a primary end-point suggests that there may well have been a patient/investigator bias. Investigators or patients may also have had a lower threshold for hospital admission in the OMT group in order to facilitate cross-over, suggested by the high rate of withdrawal. These potential biases may well have diluted the effects on mortality but may have exaggerated differences in non-fatal events.
The reduction in mortality with CRT-ICD is consistent with data on ICD-only devices, although without an increase in heart failure hospitalisation, which could reflect an additional benefit from CRT [13]. The COMPANION study suggests, for the first time, that there is a benefit from ICDs in patients without ischaemic heart disease [20]. In terms of mortality, the outcome with CRT was not significantly superior to OMT but not significantly inferior to CRT-ICD (although this was not a pre-defined comparison). Given the difference in cost between CRT and CRT-ICD this could be an important finding. In MADIT-II [13], patients with QRS >150 ms received greater benefit than other patients (one in three patients rather than one in 20 in those with QRS <120 ms benefiting over 2 years). It is possible that CRT reduces the benefit of ICD therapy as a function of shortening QRS duration. Moreover, there was still substantial room for improvement in pharmacological therapy which could have reduced sudden death further (see Section 1 above). The results of other ongoing studies of ICDs and CRT in progress, particularly SCD-HeFT and CARE-HF are awaited before making strong recommendations on management [20].
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5. UK-PACE |
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TopAbstract1. EPHESUS [Eplerenone Post-AMI...2. SPORTIF-III [Stroke...3. ASCOT [Anglo-Scandinavian...4. COMPANION [Comparison of...5. UK-PACE6. T-wave alternansReferences |
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5.1. Rationale
Dual chamber atrio-right-ventricular (DDD) pacing is generally considered physiologically superior to right-ventricular chamber (VVI[R]) pacing. Recent studies have suggested this may not translate into superior outcomes [22,23]. UK-PACE was designed to further address this issue.
5.2. Study design
This was a randomised, controlled trial comparing DDD and VVI/VVIR pacing. The study was open label.
5.3. Inclusion/exclusion
Patients had to be aged 70 years, with high-grade atrio-ventricular block undergoing a first pacemaker implant. Patients with atrial fibrillation, severe heart failure or other debilitating illness were excluded.
5.4. Primary endpoint
The primary outcome was all-cause mortality. Secondary outcomes included the development of stroke, atrial fibrillation or heart failure. Symptoms and quality of life were also secondary outcomes but these data were not presented.
5.5. Results
Mortality data were available for a follow-up of 4.6 years and for non-fatal events (which were monitored in a different way) for 3 years. The average age of the patients was 80 years and 57% were men. Sixteen percent had a diagnosis of heart failure but 71% had heart failure symptoms and 48% were taking a diuretic. Forty-one percent were taking aspirin and 3% warfarin.
There was no difference in mortality, which was approximately 25% over 3 years and 40% over 4.6 years. Patients with DDD pacing were at increased early risk of developing atrial fibrillation, although by 3 years 10% in each group had developed this arrhythmia. There was a non-significant trend to fewer strokes with DDD pacing (5% vs. 6% over 3 years). Ninty-nine of 1012 (9.8%) patients developed new-onset heart failure over 3 years with DDD pacing vs. 86 of 1009 (8.5%) with VVI/VVIR pacing. Therefore, approximately 25% of the population eventually received a diagnosis of heart failure. It is likely that the diagnosis was frequently missed given the symptoms and use of diuretic in this study.
5.6. Conclusions
UK-PACE indicates that DDD and VVI/VVIR pacing appear equivalent. This may be equivalently good or equivalently bad depending on your viewpoint. Heart failure is common in this population. This may reflect the desynchronising effect of right ventricular pacing, indicating that DDD and VVI[R] pacing are both un-physiological [19,24]. It remains to be seen if high septal or left ventricular pacing is more physiological. The high mortality in this population should be noted, although this probably reflects the great age of the patients. However, patients with severe chronic disability were excluded from this study, so the patients included do represent the fitter end of the population at risk.
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6. T-wave alternans |
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TopAbstract1. EPHESUS [Eplerenone Post-AMI...2. SPORTIF-III [Stroke...3. ASCOT [Anglo-Scandinavian...4. COMPANION [Comparison of...5. UK-PACE6. T-wave alternansReferences |
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6.1. Rationale
Studies of ICDs indicate that these devices can reduce mortality in patients with heart failure but also that a more selective approach is required since most patients who had an ICD implanted in the trials did not benefit, there is a morbidity and mortality associated with the device itself and the potential costs are prohibitive. T-wave alternans during an exercise test has been suggested as a useful marker of sudden death and need for ICD implantation [25].
6.2. Study design
This was a nine-centre observational study. Patients had a (mainly treadmill) exercise test with assessment of T-wave alternans at baseline and were then followed up.
6.3. Inclusion/exclusion
Patients had to be in sinus rhythm, left ventricular ejection fraction <40% and in NYHA class I–III. Patients with recent unstable angina or myocardial infarction were excluded.
6.4. Primary endpoint
Sudden, presumed arrhythmic, death.
6.5. Results
590 Patients were recruited. Seventy-one percent were men, 47% had ischaemic heart disease, 30% were diabetic, 52% were NYHA class II and mean left ventricular ejection fraction was 25%. Seventy-eight percent were treated with a beta-blocker and 82% with an ACE inhibitor.
Thirty percent tested positive for T-wave alternans, 34% tested negative and artefact prevented interpretation in 36%.
There were only 20 deaths over 2 years—a remarkable achievement but suggesting that this was a population at unrepresentatively low risk. Of 186 patients who tested negative, only 1% died, vs. 11% of 161 who tested positive and 9% in whom the test could not be interpreted. Thus, the test has the possibility of identifying one third of patients who may not benefit from a device.
6.6. Conclusion
Of 100 patients who might qualify for an ICD on MADIT-II criteria, this test would identify 34 low-risk patients, six would benefit from device implantation and 52 would still be implanted but not benefit over 2 years. Clearly, risk-stratification has a long way to go. Also, given the unrepresentative nature of the populations studied so far this technique remains experimental and cannot yet be relied on in clinical practice.
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J. G.F. Cleland, N. Freemantle, G. Kaye, M. Nasir, P. Velavan, K. Lalukota, T. Mudawi, R. Shelton, A. L. Clark, and A. P. Coletta Clinical trials update from the American Heart Association meeting: {Omega}-3 fatty acids and arrhythmia risk in patients with an implantable defibrillator, ACTIV in CHF, VALIANT, the Hanover autologous bone marrow transplantation study, SPORTIF V, ORBIT and PAD and DEFINITE Eur J Heart Fail, January 1, 2004; 6(1): 109 - 115. [Abstract] [Full Text] [PDF]
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J. G. F. Cleland and A. L. Clark Delivering the cumulative benefits of triple therapy to improve outcomes in heart failure: Too many cooks will spoil the broth J. Am. Coll. Cardiol., October 1, 2003; 42(7): 1234 - 1237. [Full Text] [PDF]
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A. P. Coletta, A. L. Clark, A.-M. L. Seymour, and J. G.F. Cleland Clinical trials update from the European Society of Cardiology Heart Failure meeting: COMET, COMPANION, Tezosentan and SHAPE Eur J Heart Fail, August 1, 2003; 5(4): 545 - 548. [Abstract] [Full Text] [PDF]
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