© 2002 European Society of Cardiology
Clinical trials update: The Heart Protection Study, IONA, CARISA, ENRICHD, ACUTE, ALIVE, MADIT II and REMATCH
Department of Academic Cardiology, Castle Hill Hospital Cottingham, Kingston upon Hull, HU16 5JQ, UK
* Correspondence author. Tel.: +44-1482-622613; fax: +44-1482-624085. E-mail address: a.p.coletta{at}hull.ac.uk
 |
Abstract |
|---|
 Top Abstract 1. Angina and coronary...2. Depression3. Arrhythmias4. End-stage heart failureReferences |
|---|
This article continues a series of reports summarising recent research developments of particular interest to those involved in the management of patients with heart failure. A number of relevant presentations were made at the American Heart Association Scientific Sessions in Anaheim, California, between 11–14 November 2001. Summaries of the following Clinical Trials are included: The Heart Protection Study, IONA, CARISA, ENRICHD, ACUTE, ALIVE, MADIT II and REMATCH.
Key Words: Heart failure • Cardiology • The heart protection study • IONA • CARISA • ENRICHD • ACUTE • ALIVE • MADIT II • REMATCH
Received November 19, 2001; Accepted December 3, 2001
|
1. Angina and coronary heart disease |
|---|
|
TopAbstract1. Angina and coronary...2. Depression3. Arrhythmias4. End-stage heart failureReferences |
|---|
1.1. Heart Protection Study
Although coronary artery disease causes or complicates most cases of heart failure, there are several reasons to be cautious about extending the use of lipid lowering interventions in general, and statins in particular, to such patients. In patients with heart failure, a high cholesterol and obesity indicate a better prognosis, possibly because they are markers of less severe disease, but a causal relationship cannot be discounted [1,2]. Hyperlipidaemia may help prevent endotoxin-induced activation of inflammatory cytokine pathways. Obesity, although it does not preclude a diagnosis of cardiac cachexia, makes it less likely. Thus, obesity may also be a marker of less neuroendocrine and cytokine activation. Statins may also reduce the synthesis of co-enzyme Q10, a powerful endogenous antioxidant. In patients with heart failure, who are subject to intense oxidant stress, dietary supplements of co-enzyme Q10 have improved symptoms and reduced hospitalisation with worsening heart failure in some double-blind, placebo-controlled studies, although smaller studies have generally failed to show a difference [2].
Trials of statins have generally been very successful in excluding patients with heart failure so far, which may account for the relatively low mortality observed (Table 1). It is likely that patients with heart failure were excluded because it was considered futile to treat patients with heart failure rather than because of fear of harm. The small amount of data that do exist from the 4S trial suggested possible benefit [3]. Recent clinical trials indicate that a substantial proportion of patients with heart failure already receive a statin [1,4]. Observational data from ELITE-II suggest that statin use is a marker for better outcome but this could just indicate that statin use is a marker for better quality care. The effect of statins on prognosis cannot be addressed by this sort of data [1,2]. Interestingly, patients receiving a statin who remain hyperlipidaemic appear to have the best prognosis. Clearly, data on the safety and efficacy of statins from randomised studies in patients with heart failure are urgently required.
|
The Heart Protection Study enrolled 20 536 patients with or at high-risk of vascular disease and a blood total cholesterol
3.5 mmol/l [5]. Patients with heart failure were, for once, not completely excluded. Patients were randomised, in a factorial design, to simvastatin 40 mg/day or multi-vitamins (A [beta-carotene 20 mg/day], C [250 mg/day] and E [600 mg/day]) or matching placebo. The study showed no benefit or risk from the vitamin preparation. Simvastatin was associated with a 1.5% absolute (12% relative; P<0.001) reduction in mortality over 5 years of follow-up; an absolute risk reduction of three per thousand patients treated per year. Unfortunately, no subgroup data amongst patients with heart failure has been reported so far. However, patients receiving ACE inhibitors, a possible marker for heart failure, had a trend to less benefit. There were slightly fewer deaths from heart failure in the simvastatin group but this did not approach significance. So far, the Heart Protection Study does not provide any additional comfort about the safety or efficacy of statins amongst patients with heart failure. Concern exists about the large number of patients requiring treatment in order to reduce morbid and fatal events in these studies; 1000 patients treated for 5 years in the heart protection study would have prevented only 55 serious events and 17 deaths. Whether greater benefits would accrue with even longer term treatment is unclear.
1.2. IONA: (Impact Of Nicorandil on Angina)
The design and purpose of this study have been published previously [6]. The objective of the IONA study was to establish whether treatment with the potassium channel activator nicorandil could reduce the incidence of severe and life threatening coronary events in patients with stable angina who were receiving treatment with standard therapies. IONA was a randomised double blind, placebo controlled study, performed in centres in the UK. A total of 5126 patients was randomised to treatment with either placebo or nicorandil administered as 10 mg bd for 2 weeks, then up-titrated to 20 mg bd for the remainder of the study. Study treatment was administered in addition to standard therapy, and patients were followed-up for between 1 and 3 years (average 1.6 years).
The primary endpoint for this study was death from coronary heart disease, non-fatal MI and unplanned hospitalisation for cardiac chest pain. 15.5% of patients in the placebo group reached the primary endpoint compared with 13.1% in the nicorandil group. Nicorandil reduced the risk of primary endpoints by 17% (P=0.014). There was a reduction in the secondary endpoint (CHD death and non-fatal MI) but this did not reach significance (Table 2).
|
This is the first long-term follow up study in angina to show that a single agent might reduce clinically important outcomes. Previous work with potassium channel activators has suggested that a possible mode of action is to induce a state similar to ischemic pre-conditioning. However, the IONA results are driven mainly by a reduction in hospitalisations for angina, rather than a fall in MI or death, suggesting that the underlying disease process itself may not have been affected.
1.3. CARISA: (Combination Assessment of Ranolazine In Stable Angina)
Ranolazine is a partial fatty acid oxidation inhibitor, which suppresses fatty acid oxidation and facilitates carbohydrate oxidation, thereby reducing the demand for oxygen, as more oxygen is required for ATP phosphorylation during fatty acid oxidation. This results in less tissue oxygen demand without reducing its functional capacity.
The CARISA study was a randomised, double blind, controlled trial to assess the safety and efficacy of two dosage regimens of ranolazine administered in combination with one of three other commonly used anti-anginal medications (atenolol 50 mg/day, amlodipine 5 mg/day or diltiazem 180 mg/day). 820 patients with angina, on medication, who had exercise induced chest pain and ST segment depression on treadmill exercise testing, with an exercise duration greater than 3 min and less than 9 min on a Modified Bruce protocol, were randomised to placebo or ranolazine (750 or 1000 mg) twice a day. The study duration was 12 weeks and the enrolled patients had exercise tests at 2, 6 and 12 weeks.
The number of angina episodes per week was reduced in the ranolazine groups compared to placebo (3.4 vs. 2.7 vs. 2.3 in placebo, 750 mg bd ranolazine and 1000 mg bd ranolazine groups respectively, P<0.001). The time to onset of angina, exercise duration and time to development of ischemia on exercise ECG at peak drug levels was significantly increased in both ranolazine groups at 2 weeks (P=0.01) and was maintained at 6 and 12 weeks. Ranolazine had minimal effects on blood pressure and heart rate. There was no added benefit at 1000 mg bd of ranolazine.
Therefore, addition of ranolazine to beta-blockers or calcium antagonists in patients with angina reduces symptoms and improves exercise tolerance. In addition, it has a minimal heart rate and blood pressure lowering effect, which could be an advantage in treatment of angina complicated by hypotension or bradycardia.
|
2. Depression |
|---|
|
TopAbstract1. Angina and coronary...2. Depression3. Arrhythmias4. End-stage heart failureReferences |
|---|
2.1. ENRICHD (ENhancing Recovery In Coronary Heart Disease patients)
Depression and low social support have been associated with increased risk of mortality and morbidity in post-MI individuals [7,8].
The aim of the ENRICHD study was to reduce depression and to increase social support with Cognitive Behaviour Therapy (CBT) and adjunctive pharmacotherapy, and so subsequently have an impact on mortality and morbidity on post acute MI patients [9].
ENRICHD was a multicenter, randomised controlled clinical trial. A total of 2481 patients, average age 61 years, were recruited from eight clinical centres across the United States [10]. Participants in the study had to be in a recovery state after an acute MI (screened during the first 28 days since the MI). They also had to fulfil the criteria of major depression, minor depression with a history of major depression, or dysthymia as defined by the DSM-IV (screened with various tests, including the Depression Interview and Structured Hamilton (DISH)) and/or the ENRICHD criteria for Low Perceived Social Support (LPSS) [10].
The study included a large number of women (44%) and minorities (34%). 1238 patients were randomly allocated to CBT intervention with adjunctive pharmacotherapy if needed, and 1243 to usual medical care.
CBT, which aims to modify thought patterns that are associated with patients’ symptoms and facilitate change in patients’ habits, was given for 6 months.
The primary end-points of the study were reduction in all cause mortality or recurring non-fatal MI. The mean follow-up was 41 months.
Although the intervention treatment program significantly reduced depression and significantly increased the level of social support in comparison to the usual care group, it didn't manage to lower mortality or the recurrence of MI. Death was recorded in 303 (24.4%) of the intervention treatment group and 299 (24.2%) of the usual care group.
The lack of prognostic benefits, despite the successful treatment of depression, is attributed to various factors: the inherent difficulties that a depressed and socially isolated population entails; the diversity of the study cohort; the delayed onset of treatment after the occurrence of original MI (17 days), and finally; the small (although significant) difference in depression between the usual medical care group and the intervention treatment group. Speculation was made on why a smaller than expected difference in depression score was observed between the groups. Individuals in the usual treatment group may have been seeking outside help for their depression; participation in the study itself may have reduced depression; the usual treatment group may have had only short-term depression in the first place, and spontaneously recovered.
Further, analysis of the results may explain why, although depression was reduced and social support was increased, there was no change in deaths or re-occurrence of MI.
Similar outcomes were also found in the SADHART trial. Here, treatment with sertraline reduced depression but had no effect on cardiac symptoms such as left ventricular ejection fraction, ventricular arrhythmias, or ECG.
Although the results of the above studies were disappointing the fact that depression has an adverse effect in relation to cardiovascular diseases remains a well supported finding reconfirmed by recent studies. A study on depression in relation to post-CABG showed that major depression is related to adverse cardiac events [11], and a study on optimism in relation to CAD linked pessimism to an increased heart-disease risk [12].
Further research is needed to shed some light on the treatment of depression in relation to cardiovascular disease.
|
3. Arrhythmias |
|---|
|
TopAbstract1. Angina and coronary...2. Depression3. Arrhythmias4. End-stage heart failureReferences |
|---|
3.1. ACUTE: (Assessment of Cardioversion Using Transoesophageal Echocardiography)
This study was designed to compare a transoesophageal echocardiography (TOE) guided approach with the conventional approach to electrical cardioversion in patients with atrial fibrillation of at least 2 days duration. A total of 1222 patients who required electrical cardioversion were randomised to either the TOE guided approach or the conventional approach. Patients in the TOE group received therapeutic anticoagulation before undergoing TOE. If no thrombus was detected patients underwent cardioversion followed by 4 weeks anticoagulation therapy. In patients with a thrombus imaged by TOE, cardioversion was postponed and anticoagulation continued for 3 weeks, the TOE was then repeated. Cardioversion was only performed if no thrombus was detected, warfarin was continued for 4 weeks in all patients. Patients in the conventional therapy group received anticoagulation for 3 weeks prior to cardioversion and for 4 weeks afterwards. Patients were followed-up after 8 weeks and 6 months. The study design has been published previously [13].
At eight weeks there was no significant difference in the embolic events between the TOE approach and the conventional approach, however, the incidence of haemorrhagic events was reduced in the TOE group (2.9% vs. 5.5%, P=0.03). More patients in the TOE group achieved sinus rhythm (71.1% vs. 65.2%, P=0.03) at eight weeks. These results have already been published [14].
Data from the six-month follow-up of these patients were presented at this meeting. At six months there was no significant difference in the rate of embolic events between the two groups. The composite haemorrhagic rates were reduced in the TOE guided approach (4.4% vs. 7.5%, P=0.04) however, the reduction in major and minor haemorrhagic complications did not reach statistical significance individually.
The TOE guided approach allows early and safe cardioversion but does not reduce embolisation rates. There is less haemorrhagic risk associated with the TOE guided approach. Thus, TOE guided strategy can be considered as an alternative strategy for management of patients with atrial fibrillation undergoing cardioversion.
3.2. ALIVE: (AzimiLide post-Infarct surVival Evaluation)
Azimilide is a Class III antiarrhythmic agent, which blocks the slowly conducting, and rapidly conducting components of the delayed rectifier potassium channel.
This study was designed to assess the effect of azimilide on all-cause mortality in post-infarct patients at risk of sudden death characterised by a low ejection fraction (15–25%). The total study population consisted of 3717 patients, of which 1264 were considered high risk based on a low heart rate variability index (<20 units). The patients were randomised to azimilide 100 mg or placebo and monitored for up to 365 days after randomisation.
There was no difference in all-cause mortality between the two groups. Intention to treat analysis showed no beneficial or adverse effect from using azimilide in all randomised patients including patients at high risk for sudden death. Withdrawal rates were similar in both groups. Five patients in the azimilide group experienced torsades de pointes compared to one in the placebo group. The incidence of neutropenia in the azimilide group was 0.9%. The incidence of atrial fibrillation/flutter was low in the azimilide group (HR=0.43, P=0.04). Low heart rate variability was associated with high mortality rate at 1 year (14.5% vs. 9.5%, P=0.0005) and heart rate variability proved to be effective in identifying high-risk patients regardless of other baseline characteristics.
Thus, azimilide has no beneficial or adverse effect on all-cause mortality, post myocardial infarction. Azimilide is associated with a low incidence of torsades de pointes and severe neutropenia. Low heart rate variability identified post-infarct patients at high mortality risk.
3.3. MADIT-II: (Multicenter Automatic Defibrillator Implantation Trial)
The MADIT-II study randomised patients at least one month after a myocardial infarction, who had a left ventricular ejection fraction 
30% and 10 ventricular extrasystoles per hour on ambulatory monitoring, on standard medical therapy alone (presumably including an ACE inhibitor and beta-blocker) to a control group or an implantable defibrillator. Patients at high risk of arrhythmias were excluded, as the investigators believed all of these patients should receive a device. No further stratification for arrhythmic risk was required. Approximately 1200 patients were randomised. Shortly after the American Heart Association meeting, it was announced that the MADIT-II study had been stopped because of a highly statistically significant 30% reduction in all-cause mortality. We still do not know what the absolute risk of death was in the control group and it is the absolute reduction in risk that is the important determinant of effectiveness and cost-effectiveness. Assuming that the absolute as well as relative reduction in risk is substantial this result has enormous implications for the management of heart failure, as two-thirds of patients with heart failure and left ventricular systolic dysfunction have coronary disease. If the results of MADIT-II are confirmed by further ongoing studies [15,16], most notably the SCD-HeFT trial then a major public debate will ensue about how to implement these findings. At least four outcomes are possible:-
- A lottery will develop with some patients arbitrarily receiving or being denied an ICD. This is the most likely initial response and one of the least satisfactory.
- Some health providers may refuse to pay for the intervention entirely if cost-effectiveness proves marginal. This could be a major issue caused by the short study duration as rigorous health-economic analysis may only take into account the costs within the study period. If that is the case, ICDs could appear expensive due to the high initial costs of the device. This might mean that only patients who can afford them would receive one. This may seem unfair but it would also be unfair for a health system with a restricted budget to deny effective therapy to the few that can afford to pay for life saving treatment just because most cannot.
- The price of ICDs will fall dramatically as the number of devices implanted grows so that health services can afford to implant more.
- Health services and doctors will demand further studies to target patients who will benefit more effectively
Ultimately, a mixed response is likely. It is extremely unlikely that the MADIT-II results will be applied in full for many years to come, if ever.
|
4. End-stage heart failure |
|---|
|
TopAbstract1. Angina and coronary...2. Depression3. Arrhythmias4. End-stage heart failureReferences |
|---|
4.1. REMATCH (Randomised Evaluation of Mechanical Assistance for Treatment of Chronic Heart failure)
This study has already been reported in full [17]. Briefly, 129 patients with severe heart failure (NYHA class IV, LVEF
25%) were randomised to a control group or implantation of a left ventricular assist device (LVAD), in addition to optimal medical therapy, between 1998 and 2001. All patients in the study were unsuitable for cardiac transplantation. Baseline medical therapy included digoxin, loop diuretics, spironolactone, ACE inhibitors, angiotensin II antagonists, amiodarone, beta-blockers and intravenous inotopic agents. Mortality data are presented in Table 3. At the time of the final analysis 54 patients in the control group had died compared with 41 patients in the active group. The average extension of life was 8 months, of which 3 months was spent in hospital. Although the study result is positive, it has to be questioned whether the benefits to patients is cost-effective, given the expense of the device and the continuing patient care, or worthwhile, given the high morbidity and poor quality of life during the extra months of life conferred. The outcome of other trials in progress are keenly awaited [18]. However, considering the dramatic advances in the science and technology of LVADs since the inception of the REMATCH trial it is almost certain that the next trial, for there must surely be several others, will show a dramatically lower morbidity with device therapy. On the other hand, there will be a temptation to recruit lower risk patients so it is likely that the outcome in the control group will also improve, even without taking recent advances in health care into account. It will be some years, if not decades, before it is clear how to select appropriate patients for an LVAD. Selecting patients who are nearly dead is probably too late to be optimal, selecting patients who are too mild exposes patients to unnecessary morbidity and risk. However, as LVADs become less expensive, easier to implant and less prone to complications it is likely that they will be used in patients with milder and milder disease. It is difficult to predict where the limit of this approach lies [19]. Cost and, especially amongst older patients, comorbidity may be the final determinants of how this technology is used [20].
|
|
References |
|---|
|
TopAbstract1. Angina and coronary...2. Depression3. Arrhythmias4. End-stage heart failureReferences |
|---|
- Anker, SD, Davos, CH, Francis, D, Segal, R, Santoro, E, Poole-Wilson, PA, Pitt, B, Coats, AJS. Body mass index, obesity, and cachexia vs. survival in chronic heart failure: results from the ELITE-II study. JACC 37 (suppl A):203A, 2001. (Abstract).
- Louis A., Cleland J.G.F., Crabbe S., et al. Clinical trials update: CAPRICORN, COPERNICUS, MIRACLE, STAF, RITZ-2, RECOVER and RENAISSANCE and cachexia and cholesterol in heart failure. Highlights of the Scientific Sessions of the American College of Cardiology, 2001. Eur J Heart Failure (2001) 3:381–387.
[Abstract/Free Full Text] - Kjekshus J., Pedersen T.R., Olsson A.G., Faergeman O., Pyorala K. The effects of simvastatin on the incidence of heart failure in patients with coronary disease. J Cardiac Failure (1997) 3:249–254.[CrossRef][Medline]
- The beta-blocker evaluation of survival trial investigators A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. New Engl J Med 2001; 344: 1659–67.
- MRC/BHF Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience. Eur Heart J 1999; 20:725–41.
- The IONA Study Group. Trial to show the impact of nicorandil in angina (IONA): design, methodology and management. Heart 2001; 85 (6): E9.
- Frasure-Smith N., Lesperance F., Talajic M. Depression following myocardial infarction: impact on 6-months survival. JAMA (1993) 270:1819–1825.
[Abstract/Free Full Text] - Gorkin L., Schron E.B., Brooks M.M., et al. for the CAST Investigators. Psychosocial predictors of mortality in the Cardiac Arrhythmia Suppression Trial-1 (CAST-1). Am J Cardiol (1993) 71:263–267.[CrossRef][Web of Science][Medline]
- The ENRICHD Investigators. Enhancing recovery in coronary heart disease patients (ENRICHD): Study design and methods. Am Heart J 2000; 139: 1–9.
- The ENRICHD Investigators. Enhancing Recovery in Coronary Heart Disease (ENRICHD) Study Intervention: Rationale and Design. Psychosom Med 2001; 63:747–55.
- Connerney I., Shapiro P.A., McLaughlin J.S., Bagiella E., Sloan R.P. Relation between depression after coronary bypass surgery and 12-month outcome: a prospective study. Lancet (2001) 358:1766–1771.[CrossRef][Web of Science][Medline]
- Kubzansky L.D., Sparrow D., Vokonas P., Kawachi I. Is the glass half empty or half full? A prospective study of optimism and coronary heart disease in the normative ageing study. Psychosom Med (2001) 63:910–916.
[Abstract/Free Full Text] - The Steering and Publication Committee of the ACUTE Study: Design of a clinical trial; for the assessment of cardioversion during transesophageal echocardiography (The ACUTE multicentre study). Am J Cardiol 1998; 81: 877–83.
- Klein A.L., Grimm R.A., Murray R.D., et al. Use of transoesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med (2001) 344:1411–1420.
[Abstract/Free Full Text] - Cleland, JGF, Thackray, S, Goodge, L, Kaye, GC, Cooklin, M. Outcome studies with device therapy in patients with heart failure. J Clin Pacing, 2001. In press.
- Klein H., Auricchio A., Reek S., Geller C. New primary prevention trials of sudden cardiac death in patients with left ventricular dysfunction: SCD-HEFT and MADIT-II. Am J Cardiol (1999) 83:91D–97D.[CrossRef][Web of Science][Medline]
- Rose E.A., Gelijns A.C., Moskowitz A.J., et al. for the REMATCH study group. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med (2001) 345:1435–1443.
[Abstract/Free Full Text] - Cleland J.G.F., Mohacsi P., Murphy R.L.W. Implantable left ventricular assist systems: clinical trials. Eur J Heart Failure (2000) 2(1):19–21.
[Free Full Text] - Mohacsi P., Deng M., Murphy R., et al. Implantable left ventricular assist systems (LVAS): Recent results. A report from a series of meetings sponsored by the Study Group on Advanced Heart Failure of the Working Group on Heart Failure. Eur J Heart Failure (2000) 2(1):13–18.
[Abstract/Free Full Text] - Moskowitz A.J., Weinberg A.D., Oz M.C., Williams D.L. Quality of life with an implanted left ventricular assist device. Ann Thorac.Surg (1997) 64:1764–1769.
[Abstract/Free Full Text]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A.P. Coletta, N. Nikitin, A.L. Clark, and J.G.F. Cleland Clinical trials update from the American Heart Association meeting: PROSPER, DIAL, home care monitoring trials, immune modulation therapy, COMPANION and anaemia in heart failure Eur J Heart Fail, January 1, 2003; 5(1): 95 - 99. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||