© 2004 European Society of Cardiology
Clinical trials update and cumulative meta-analyses from the American College of Cardiology: WATCH, SCD-HeFT, DINAMIT, CASINO, INSPIRE, STRATUS-US, RIO-Lipids and cardiac resynchronisation therapy in heart failure
a Department of Cardiology, University of Hull, Castle Hill Hospital Cottingham, Kingston-upon-Hull HU16 5JQ, UK
b Department of Primary Care and General Practice, University of Birmingham Edgbaston, Birmingham B15 2TT, UK
* Corresponding author. Tel.: +44-1482-624086; fax: +44-1482-624085. E-mail address: a.p.coletta{at}hull.ac.uk
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 Top Abstract 1. WATCH: warfarin and...2. SCD-HeFT: sudden cardiac...3. DINAMIT: defibrillator in...4. CASINO: calcium sensitiser...5. INSPIRE: adenosine sestamibi...6. STRATUS-US: studies with...7. New information on...References |
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This article continues a series of reports on recent research developments in the field of heart failure. Key presentations made at the American College of Cardiology meeting, held in New Orleans, Louisiana, USA in March 2004 are reported. These new data have been added to existing data in cumulative meta-analyses. The WATCH study randomised 1587 patients with heart failure and left ventricular systolic dysfunction to warfarin, aspirin or clopidogrel. The study showed no difference between the effects of these agents on mortality or myocardial infarction, but hospitalisations for heart failure were higher on aspirin (22.2%) compared to warfarin (16.1%). The SCD-HeFT study showed that ICD therapy reduced all-cause mortality at 5 years by 23% in patients with predominantly NYHA class II heart failure and left ventricular systolic dysfunction, but amiodarone was ineffective. The DINAMIT study showed that ICD therapy was not beneficial in patients with left ventricular dysfunction after a recent MI, even in those with risk factors for arrhythmic death. In CASINO, levosimendan improved survival compared with dobutamine or placebo in patients with decompensated heart failure. INSPIRE showed that SPECT imaging can be used to assess risk early after acute MI safely and accurately. Rimonabant was shown to be safe and effective in treating the combined cardiovascular risk factors of smoking and obesity. An overview of new developments in cardiac resynchronisation therapy (CRT) in heart failure is also reported.
Key Words: WATCH • SCD-HeFT • DINAMIT • CASINO • INSPIRE • STRATUS-US • RIO-Lipids and CRT in heart failure
Received April 13, 2004; Accepted April 26, 2004
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1. WATCH: warfarin and antiplatelet therapy in chronic heart failure |
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TopAbstract1. WATCH: warfarin and...2. SCD-HeFT: sudden cardiac...3. DINAMIT: defibrillator in...4. CASINO: calcium sensitiser...5. INSPIRE: adenosine sestamibi...6. STRATUS-US: studies with...7. New information on...References |
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Evidence that anti-thrombotic therapy is effective or safe in patients with chronic heart failure is lacking, even for patients with underlying coronary disease. There is particular concern about the use of aspirin, due to possible adverse effects on the endogenous pathophysiology of heart failure or because aspirin detracts from the benefits of treatments for heart failure, including ACE inhibitors, beta-blockers and possibly aldosterone antagonists. These adverse effects are thought to be mediated by inhibition of cyclo-oxygenase [1,2].
The WASH pilot study randomised 279 heart failure patients to treatment with either aspirin, warfarin or no antithrombotic therapy and showed no difference in mortality between these interventions [3]. However, compared to the other two groups, more patients randomised to aspirin were hospitalised for worsening heart failure [3,4]. The WATCH trial assumed that patients with heart failure should receive some form of anti-thrombotic therapy and sought to identify whether aspirin, clopidogrel (an anti-platelet agent that does not block cyclo-oxygenase) or warfarin should be preferred [5]. Patients in New York Heart Association class II–IV, with a left ventricular ejection fraction (LVEF) 
35% were included. Patients were randomised to treatment with, open-label warfarin (titrated to an INR of 2.5–3), double-blind aspirin 162 mg/day or double blind clopidogrel 75 mg/day. The study was conducted in 142 centres in North America and the UK. The study aimed to recruit 4500 patients. Recruitment was stopped by the sponsor (Department of Veterans’ Affairs) due to poor recruitment rates when only 1587 patients had been randomised. Patients were followed-up for an average of 23 months. Their mean age was 63 years, 85% were male, 34% were diabetic and their mean ejection fraction was 24%. Baseline medication included ACE inhibitors (88%), beta-blockers (70%), ARBs (11%) and loop diuretics (99%).
There was no difference between the three treatment groups for the primary endpoint (all cause mortality, non-fatal MI or non-fatal stroke) (Table 1). However, 27% fewer patients had a hospitalisation for heart failure in the warfarin group compared with aspirin (P=0.01) leading to 31% fewer episodes of hospitalisation for heart failure, which is consistent with the findings of the WASH study [3,4] (Fig. 1). Deaths and vascular events were similar on aspirin and clopidogrel. There were fewer hospitalisations for heart failure in the clopidogrel group. The safety data showed, as would be expected, a greater incidence of bleeding complications in the warfarin group.
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Meta-analysis of the two largest studies of anti-thrombotic therapy conducted so far in chronic heart failure suggests a weak trend in favour of a lower mortality with warfarin compared to aspirin (at least on an intention to treat analysis) but also suggests that a substantial difference in mortality or vascular events cannot be excluded (Figs. 1 and 2). The data are consistent with a substantial difference in the rate of hospitalisation between aspirin and warfarin and suggest that up to one third of all hospitalisations for heart failure could be attributed to the use of aspirin (Fig. 3). One further large trial continues. The WARCEF (warfarin vs. aspirin in reduced cardiac ejection fraction) study may provide further evidence for the optimal use of antithrombotic therapy in heart failure. The studies that have reported so far provide fuel for debate and can be used to support the use of aspirin, warfarin, clopidogrel or no anti-thrombotic treatment. The last option might be cheapest but, perhaps surprisingly in view of complaints about polypharmacy by both patients and physicians, may prove the least acceptable. Further analyses are required to determine which of the options is most cost-effective.
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2. SCD-HeFT: sudden cardiac death in heart failure trial |
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TopAbstract1. WATCH: warfarin and...2. SCD-HeFT: sudden cardiac...3. DINAMIT: defibrillator in...4. CASINO: calcium sensitiser...5. INSPIRE: adenosine sestamibi...6. STRATUS-US: studies with...7. New information on...References |
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The reduction in mortality with implantable cardiac defibrillator (ICD) therapy in patients with reduced ejection fraction with and without ischaemic heart disease has been reported previously [6–10]. The use of amiodarone, which could be an effective method of preventing sudden death, was discouraged in these trials.
The SCD-HeFT study sought to determine whether amiodarone or a conservatively programmed shock-only ICD reduced all-cause mortality compared with placebo in patients with heart failure in NYHA class II–III, with either ischaemic or non-ischaemic aetiology and an LVEF35% [11]. Back-up pacing was not triggered until heart rate dropped to 34 bpm and was set to pace at only 50 bpm. In this way, the potential desynchronising effect of pacing on cardiac function was avoided [12,13]. The median age of the 2521 patients was 60 years, 23% were female, the average duration of heart failure was 24 months and the mean LVEF was 25%. 70% of patients were in NYHA class II and the remainder were in class III. 52% of patients had ischaemic heart disease and the mean QRS duration was 112 ms. Patients were generally well medicated at baseline, with 96% receiving an ACE inhibitor or ARB, 69% beta blockers, 19% spironalactone, 82% loop diuretics, 56% aspirin and 38% statins. The median duration of follow-up was 45.5 months.
The mortality rate in the placebo group was 36.1% at 5 years or 7.2% per year. All-cause mortality at 5 years was reduced by 23% in the ICD group compared with placebo. There was no effect observed for amiodarone compared with placebo (Table 2) even in the subgroup taking beta-blockers. Sub-group analysis of mortality data for ICD vs. placebo showed that a similar effect was achieved in patients with both ischaemic and non-ischaemic aetiology. The relative benefits of ICD therapy appeared greater in patients with NYHA II heart failure, the group in which sudden death is expected to predominate. There appeared to be no benefit in patients with NYHA III heart failure. The interpretation of this subgroup analysis remains unclear especially as patients with lower ejection fraction tended to get greater benefit from the ICD. The shape of the mortality curves in each NYHA subgroup, mode of death and correction for confounding variables are all required. One interpretation of these data is that patients with more severe heart failure could be considered for resynchronisation therapy as well as an ICD. Confirmation that this strategy is appropriate awaits the results of the ongoing CARE-HF study [14]. Younger patients, men, those with QRS >120 ms, those receiving beta-blockers, non-diabetics and patients with ‘non-ischaemic’ heart failure tended to have greater benefit, although none of these trends was significant. The effect of the ICD in the 164 patients from Canada and New Zealand was striking (63% reduction in mortality) although not significantly different from the 18% reduction observed in US patients. It is possible that treatment differences, such as more aggressive revascularisation in the US, could diminish the benefits of the ICD by reducing the risk of ICD-treatable events. However, revascularisation has not been shown to be an effective or safe treatment for heart failure [15].
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The direction and magnitude of benefit in SCD-HeFT is consistent with the data from previous, unconfounded studies [9] (Fig. 4). It confirms that ICDs reduce mortality in patients with heart failure. However, curiously, these trials tell us that they should probably not be copied in clinical practice. The trials suggest that only about one patient in 10 will benefit from an ICD over 3–5 years. The morbidity and expense associated with implantation, box changes and inappropriate shocks in the 90% of patients who do not benefit must be weighed carefully against the 10% who do benefit. The new question facing patients and physicians is no longer whether devices are effective, but in whom. Novel strategies for risk stratification need to be evolved.
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3. DINAMIT: defibrillator in acute myocardial infarction trial |
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TopAbstract1. WATCH: warfarin and...2. SCD-HeFT: sudden cardiac...3. DINAMIT: defibrillator in...4. CASINO: calcium sensitiser...5. INSPIRE: adenosine sestamibi...6. STRATUS-US: studies with...7. New information on...References |
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In patients who survive acute myocardial infarction (MI), mortality at 1 year is high, and approximately 40% of these deaths are arrhythmic. The MADIT and MUSTT [16,17] trials have both suggested a beneficial effect of implanting an ICD in patients with ‘healed’ myocardial infarction, although the MUSTT trial design was confounded making it difficult to interpret. The aim of the DINAMIT study was to evaluate the use of ICD therapy initiated within 40 days of the index MI, compared to optimal medical therapy alone, in patients at high risk of death. In order to select a high risk group, patients with an ejection fraction (EF)
35% and impaired cardiac autonomic function (depressed heart rate variability (standard deviation of normal–normal R–R interval <70 ms) or elevated heart rate (mean 24 h RR interval 750 ms)), were included. The study was a randomised, open comparison of ICD therapy vs. no ICD [18] performed in 73 centres in 10 countries. The mean duration of follow-up was 30 months. Due to a lower than expected mortality rate, the number of patients was increased to 674 during the study. 332 patients were randomised to ICD therapy and 342 to control. Patients in both groups received optimal medical therapy, including beta-blockers (87%), ACE inhibitors (95%), lipid lowering therapy (78%) and antiplatelet agents (92%). 76% of patients were male, the mean age was 62 years, 72% of patients had an anterior infarct and 52% had heart failure with the index MI. The mean LVEF was 28%.
The primary endpoint of all-cause mortality showed no difference between the groups. Further analysis of the data showed a highly significant reduction in arrhythmic death in the ICD group compared with the control, however, this was offset by an increase in non-arrhythmic deaths in these patients (Table 3). The results of this study show that ICD therapy is not beneficial in patients with a recent MI, even in those with risk factors for arrhythmic death. It was concluded that further research is required to identify appropriate therapeutic strategies in this high risk patient cohort. It is possible that device implantation or discharge during the healing phase of myocardial infarction has an adverse effect on ventricular remodelling and therefore the development of heart failure.
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4. CASINO: calcium sensitiser or inotrope or none in low output heart failure study |
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TopAbstract1. WATCH: warfarin and...2. SCD-HeFT: sudden cardiac...3. DINAMIT: defibrillator in...4. CASINO: calcium sensitiser...5. INSPIRE: adenosine sestamibi...6. STRATUS-US: studies with...7. New information on...References |
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There is insufficient data on the efficacy or safety of inotropic agents in the management of decompensated heart failure. The calcium sensitiser levosimendan, which improves myocardial performance without increasing myocardial oxygen consumption or provoking arrhythmias, has been shown in one study to improve medium-term prognosis compared to dobutamine in patients with severe heart failure [19]. However, the LIDO study did not include a placebo arm, and it is possible that the difference may have been due to an adverse effect of dobutamine. A recent meta-analysis of the use of intravenous dobutamine in heart failure showed little evidence of benefit and suggested it may not be safe [20] (Fig. 5). The RUSSLAN [21] and REVIVE-pilot [22] studies showed trends in favour of levosimendan compared to placebo. The CASINO study was designed to compare the safety and efficacy of levosimendan, dobutamine and placebo in patients with decompensated heart failure.
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Hospitalised patients with New York Heart Association class IV heart failure and LVEF
35% were randomised to treatment with levosimendan, dobutamine or placebo, infused intravenously over 24 h. The study was originally designed to recruit 600 patients, however, was stopped prematurely after 299 patients had been enrolled, due to a clear mortality benefit in favour of levosimendan. The mean age of patients was 71 years, 71% were male and 54% had a previous MI. The mortality data at 1 month and 6 months are shown in Table 4. Levosimendan showed a significant survival benefit in these decompensated heart failure patients, whereas dobutamine appeared to increase mortality. However, it should be noted that these data are incomplete. Eight patients were withdrawn from the study and are not included in the analysis, which may have some impact on the data.
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The ESC guidelines on the treatment of chronic heart failure [23] state that levosimendan appears to be safer than dobutamine in these patients. The results of the CASINO study support this assertion (Fig. 6), but the results of further trials are required. There are currently two studies ongoing with levosimendan, SURVIVE and REVIVE, which may provide more conclusive evidence for the use of levosimendan in patients with low-output heart failure (Fig. 7).
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5. INSPIRE: adenosine sestamibi post-infarction evaluation |
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TopAbstract1. WATCH: warfarin and...2. SCD-HeFT: sudden cardiac...3. DINAMIT: defibrillator in...4. CASINO: calcium sensitiser...5. INSPIRE: adenosine sestamibi...6. STRATUS-US: studies with...7. New information on...References |
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Coronary angiography is the investigation currently used to assess risk in patients following acute myocardial infarction. The aim of this study was to determine whether adenosine Tc-99 m sestamibi single photon tomography (SPECT) performed early following acute MI could stratify patients into low and high risk groups and track subsequent risk. A secondary aim was to use SPECT imaging to monitor the relative effects of intensive medical therapy vs. coronary revascularisation in these high risk patients.
A maximum of 10 days following acute MI, 728 patients underwent baseline adenosine-sestamibi SPECT and were classified as having a low (n=242), intermediate (n=213) or high (n=273) risk of further cardiac events. Patients in the high risk group were then classified according to left ventricular function. Patients with an ejection fraction (EF) <35% underwent coronary angiography. Patients with an EF
35% were randomised to either intensive medical therapy or coronary revascularisation by PTCA or CABG plus intensive medical therapy. A second imaging test was then performed and patients were followed-up for 1 year.
The mean age of patients was 63 years, 69% were male, 28% had a previous history of CAD and 17% had a prior MI. Seventy percent of patients underwent SPECT imaging within 4 days of the MI.
The incidences of death or recurrent MI (P=0.009) and total cardiac events (P=0.007) at 1 year were more frequent in the intermediate and high risk groups compared with the low risk group. In the high risk patients randomised to either intensive medical therapy alone or revascularisation plus medical therapy, both therapies produced a comparable reduction in scintigraphic ischemia [24].
SPECT imaging can thus safely and accurately be used to assess risk early after acute MI and improves risk stratification beyond that of the TIMI risk score. SPECT imaging could therefore be used to identify low risk patients in whom more aggressive investigation and therapy could be avoided, improving the cost-effectiveness of post-infarct management. It is unfortunate that the investigators did not extend the randomised part of their study to patients with low ejection fraction, a group in whom the safety and efficacy of revascularisation is largely unexplored [15].
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6. STRATUS-US: studies with rimonabant and tobacco use and RIO-lipids: rimonabant in obesity |
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TopAbstract1. WATCH: warfarin and...2. SCD-HeFT: sudden cardiac...3. DINAMIT: defibrillator in...4. CASINO: calcium sensitiser...5. INSPIRE: adenosine sestamibi...6. STRATUS-US: studies with...7. New information on...References |
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The endocannabinoid system has a role in maintaining energy balance by regulating food intake and energy expenditure. It may also have a role in controlling tobacco dependence. Rimonabant, a selective cannabinoid type 1 (CB1) receptor antagonist was evaluated in two phase III studies of obesity and tobacco use, both of which are major risk factors for cardiovascular disease.
In the RIO-lipid study, 1036 obese patients with dyslipidaemia and a BMI of 27–40 kg/m2 were randomised to double-blind treatment with either rimonabant (5 or 20 mg per day) or placebo for 1 year. In addition all patients were required to follow a reduced calorie diet.
Patients in the high dose rimonabant group lost an average of 20 lbs compared with only 5 lbs in the placebo group (P<0.001). The percentage of patients who lost more than 10% of their body weight was 44.3% (P<0.001 vs. placebo), 16.3% and 10.3% in the rimonabant 20 mg, 5 mg and placebo groups, respectively. The number of patients in the rimonabant 20 mg group classified as having metabolic syndrome was reduced from 52.9% at baseline to 25.8% at one year (P<0.0001 vs. placebo). Rimonabant 20 mg was associated with a significant reduction in waist circumference, triglycerides and C reactive protein and an increase in HDL-cholesterol (all P<0.01 vs. placebo).
The STRATUS-US study enrolled 787 smokers, who were randomised to double-blind treatment with either rimonabant (5 or 20 mg per day) or placebo for 10 weeks. Patients smoked an average of 23 cigarettes per day, were motivated to stop, but had failed on an average of four previous attempts. Abstinence from smoking was assessed during the last 4 weeks of treatment, by patient self-reporting, carbon monoxide levels in expired air and plasma cotinine levels.
The percentage of patients who stopped smoking was 36.2% in the rimonabant 20 mg group compared with 20.6% on placebo (P<0.002) and 20.2% for rimonabant 5 mg. Those patients taking rimonabant 20 mg who were overweight or obese lost weight, however, normal weight patients did not.
Rimonabant was generally well tolerated in both studies; the most frequently reported side-effects were nausea, dizziness and upper respiratory tract infections. There were no cardiovascular safety concerns and depression and anxiety scores were similar in the three treatment groups.
Canabinoid receptor antagonists may be useful for managing smoking and obesity in heart failure patients, assuming that it can be shown that weight reduction in this setting is not associated with an adverse prognosis [25].
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7. New information on cardiac resynchronisation therapy (CRT) in heart failure |
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TopAbstract1. WATCH: warfarin and...2. SCD-HeFT: sudden cardiac...3. DINAMIT: defibrillator in...4. CASINO: calcium sensitiser...5. INSPIRE: adenosine sestamibi...6. STRATUS-US: studies with...7. New information on...References |
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7.1. Selection for CRT
Clinical trials indicate that about one third of patients who receive CRT will not gain benefit [26] and this may reflect the inadequacy of the selection criteria used. The most widely used indicator of ventricular dyssynchrony is QRS duration but there is increasing evidence that it is a rather crude marker with only moderate sensitivity (even if a QRS cut-off of 120 ms is chosen) and specificity (although fairly high if QRS is >150 ms). If CRT is to be deployed effectively it is important not to miss patients with a narrow QRS who may benefit [29] and those with a broad QRS who may not. Imaging techniques may be a more accurate way of identifying patients with dyssynchrony but require more skill in the generation and interpretation of the result [27–31]. Tissue Doppler mapping techniques appear a promising approach that may be simple to interpret, although it depends on movement in the longitudinal axis of the heart [30,31]. Although three-dimensional echocardiography suffers from decreased temporal resolution when compared with tissue Doppler imaging, it has the advantage of being able to assess multiple myocardial segments in both the short axis and the long axis at the same time [32,33].
Indicators of the likelihood of a beneficial response at the time of implantation could help in lead positioning. Analysis of 106 patients undergoing CRT showed greater improvement in ejection fraction, QOL, 6 min walk distance, functional class and mortality for patients with the left ventricular lead placed laterally rather than anterior or septally [34]. Whether QRS shortening with bi-ventricular pacing predicts clinical response is uncertain. The MIRACLE study did not show a relationship between QRS shortening and response if the same ECG lead was used for assessment before and after CRT. However, Burkhardt et al. [35] found that if the widest QRS in any lead was used, then QRS shortening did predict improvement in NYHA class, LVEDD and severity of mitral regurgitation. However, these data should be interpreted with caution as all that has been demonstrated is association, not cause and effect.
7.2. CRT and LV function
Trials of CRT have focussed on improving symptoms and have therefore recruited patients in NYHA class III–IV. CRT could potentially be used to improve cardiac function and therefore prevent the progression of heart failure and perhaps sudden death. One trial of 20 patients with NYHA II symptoms suggested that CRT was as or more effective in improving cardiac function than in patients with more severe symptoms [36].
7.3. Permanent pacing
Requirement for a permanent pacemaker for bradyarrhythmia was an exclusion criterion from the major trials of CRT. Patients who are dependent upon ventricular pacing are paced from the right ventricular apex: this will usually cause dyssynchrony and may provoke heart failure [13]. Prophylactic CRT may be appropriate in patients requiring a pacemaker who are at risk of developing heart failure. Non-randomised trials suggest an improvement in symptoms and cardiac function from upgrading standard pacing to CRT [13,36,37].
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TopAbstract1. WATCH: warfarin and...2. SCD-HeFT: sudden cardiac...3. DINAMIT: defibrillator in...4. CASINO: calcium sensitiser...5. INSPIRE: adenosine sestamibi...6. STRATUS-US: studies with...7. New information on...References |
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