© 2004 European Society of Cardiology
Clinical trials update from the American Heart Association meeting: 
-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
a Department of Cardiology University of Hull, Castle Hill Hospital, Cottingham, Kingston-upon-Hull, HU15 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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Abstract |
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 Top Abstract 1. {Omega}-3 Fatty acids...2. ACTIV in CHF:...3. VALIANT: Valsartan in...4. The Hanover Autologous...5. SPORTIF-V: Stroke Prophylaxis...6. ORBIT and PAD7. DEFINITE: DEFbrillator In...References |
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The American Heart Association meeting reported the results of several clinical trials of particular interest to those who care for patients with heart failure.
-3 fatty acids were associated with a trend to increased recurrence of ventricular arrhythmias but not mortality in patients with an implantable debrillator. The ACTIV in CHF study provides more evidence of a therapeutic role for arginine vasopressin antagonists in the treatment of heart failure. The VALIANT study provides further evidence to suggest that a combination of angiotensin receptor antagonist and ACE inhibitor does not reduce mortality but may reduce morbidity in post-MI patients with heart failure or major LV systolic dysfunction. A study of autologous bone marrow cell transplantation into myocardial scar give gave encouraging results. SPORTIF V showed ximelagation to be as effective as warfarin but with improved safety. ORBIT and PAD showed public access defibrillators saved lives but questioned their cost effectiveness. DEFINITE supported a role for ICDs in patients with non-ischemic cardiomyopathy, although cost-effectiveness remains in doubt.
Key Words: -3 fatty acids • ACTIV in CHF • VALIANT • The Hanover Autologous Bone Marrow Transplantation Study • SPORTIF V • ORBIT • PAD • DEFINITE
Received November 30, 2003; Accepted December 5, 2003
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1. -3 Fatty acids and arrhythmia risk in patients with an implantable defibrillator
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TopAbstract1. {Omega}-3 Fatty acids...2. ACTIV in CHF:...3. VALIANT: Valsartan in...4. The Hanover Autologous...5. SPORTIF-V: Stroke Prophylaxis...6. ORBIT and PAD7. DEFINITE: DEFbrillator In...References |
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The GISSI-Prevenzione trial suggested that administration of
-3 fatty acids to patients with a recent myocardial infarction reduced the risk of death, particularly sudden death. The reduction in sudden death was generally attributed to a reduction in arrhythmias [1] rather than vascular events because trials of -3 fatty acids have not generally shown a reduction in re-infarction [1,2]. The GISSI-CHF trial evaluated the effects of -3 fatty acids and statins in a factorial design in patients with heart failure. One other relevant population that might clarify the effects of -3 fatty acids on arrhythmias is patients with ICDs. These patients often have ventricular dysfunction and heart failure and have their arrhythmias recorded and treated. This trial compared the effects of 1.8 g fish oil per day with placebo (olive oil in this case!) on time to first appropriate device discharge in 200 patients either with a recently implanted ICD for an episode of sustained ventricular tachycardia (VT) or fibrillation (VF) or with an ICD that had discharged appropriately within the previous 3 months. Patients on Class I or III anti-arrhythmic drugs were excluded. Blood samples showed good compliance with randomised therapy.
Over a follow-up of 2 years, there was a non-significant trend to an increased risk of ventricular arrhythmia. Subgroup analysis suggested that patients who had received an ICD for sustained VT had significantly more arrhythmias on fish-oil, whilst patients enrolled with VF tended to have a reduction. There were only two sudden deaths, both on fish oil. There were fewer deaths overall in the fish oil group, but this was not significant.
This trial suggests that if -3 fatty acids do reduce mortality, they may do so by a mechanism other than reduction in ventricular arrhythmias. However, as the substrate for the induction of VT and VF may be different, a specific effect on VF suppression cannot be excluded.
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2. ACTIV in CHF: Acute and Chronic Therapeutic Impact of a Vasopressin 2 antagonist in Congestive Heart Failure |
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TopAbstract1. {Omega}-3 Fatty acids...2. ACTIV in CHF:...3. VALIANT: Valsartan in...4. The Hanover Autologous...5. SPORTIF-V: Stroke Prophylaxis...6. ORBIT and PAD7. DEFINITE: DEFbrillator In...References |
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Agents to suppress the effects of arginine vasopressin (AVP) have been in development for over a decade. Recently, the ‘vasopressin antagonist’ class of agent has shown its ability to cause an aquaresis and reduce cardiac filling pressures [3]. Large-scale trials are beginning to report their short-term clinical effects and the first long-term mortality trial (EVEREST; (Efficacy of Vasopressin antagonism in hEart failuRE: outcome Study with Tolvaptan)) has recently started. Agents that selectively block the V2-receptor or additionally block the V1A-receptor are available. The V2-receptor is responsible for mediating the effects of AVP on water reabsorption and is also a clearance receptor for the hormone. Consequently, V2-receptor antagonists cause plasma concentrations of AVP to rise, which may stimulate V1-receptors. The V1A-receptor is responsible for mediating the vasoconstrictor and platelet aggregating effects of AVP. The V1-receptor is also important for the induction of thirst. V3-receptors and oxytocin receptors also bind vasopressin. Less selective agents might have a benefit by blocking the theoretically adverse effects of V1-receptor stimulation.
The ACTIV in CHF trial enrolled patients within 72 hours of a hospital admission for an exacerbation of heart failure, a left ventricular ejection <40% and signs of either pulmonary or peripheral congestion. Patients were randomised to placebo or tolvaptan, a selective V2-receptor antagonist, at one of three doses (30 mg, 60 mg or 90 mg/day) for 60 days. The primary acute outcome measure was weight reduction. The primary 60-day outcome measure was the composite of death, re-hospitalisation for heart failure or an unscheduled out-patient visit for worsening heart failure.
319 patients were randomised. All patients were taking conventional diuretics, 85% an ACE inhibitor, 70% digoxin, 40% a beta-blocker and 40% spironolactone at baseline. At discharge, weight had decreased by 4 kg on tolvaptan versus 2.5 kg on placebo (P<0.01). Signs, symptoms and hyponatraemia improved more on tolvaptan and furosemide dose was reduced by a mean of 40 mg/day. During the 60-day follow-up there was a high discontinuation rate with tolvaptan, possibly due to intolerable thirst. Blood pressure, serum creatinine and potassium were unchanged. At 60 days there was a trend to better outcome (Table 1) including a reduction in mortality with tolvaptan, which was significant in the subgroup with hyponatraemia renal dysfunction or peripheral oedema.
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It is not clear whether treatment with AVP antagonists should be targeted at specific subgroups (eg:- hyponatraemic patients, diuretic-resistant patients, patients with renal dysfunction) or whether they should be used intermittently. Intolerable thirst appears to be a problem and it is not yet clear whether this can be managed by reducing the doses of conventional diuretics, whether this will require periodic discontinuation or the development of agents that block vasopressin receptors in the brain's ‘thirst’ centre. ‘AVP antagonists are unlikely to be‘prescribe-and-forget’ drugs.
AVP is one of the earliest neuroendocrine systems to be activated during the evolution of cardiac dysfunction and it is possible that ‘AVP antagonists’ could be effective first-line agents for patients developing cardiac dysfunction [4]. Development of non-selective V2 & V1A receptor antagonists have stalled for no obvious good reason despite their theoretical advantages.
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3. VALIANT: Valsartan in acute myocardial infarction trial |
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TopAbstract1. {Omega}-3 Fatty acids...2. ACTIV in CHF:...3. VALIANT: Valsartan in...4. The Hanover Autologous...5. SPORTIF-V: Stroke Prophylaxis...6. ORBIT and PAD7. DEFINITE: DEFbrillator In...References |
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The objective of this very large double-blind trial was to determine whether valsartan (160 mg bd) alone or in combination with an ACE inhibitor (80 mg bd of valsartan plus 50 mg tid of captopril) exerted a superior or at least equivalent effect to captopril (50 mg tid) on all-cause mortality in patients who had suffered a recent myocardial infarction and developed evidence of heart failure or major left ventricular systolic dysfunction. This is the only large post-infarction trial to assess the effects of combined ARB/ACE inhibitor therapy.
The population recruited was a somewhat higher risk population, as evidenced by a worse Killip class, than in the OPTIMAAL trial [5] that had previously failed to show that losartan, at a relatively low dose of 50 mg/day, was as effective as captopril 50 mg tid. The dose of valsartan used in VALIANT was much higher than the dose of losartan in OPTIMAAL. In the combination arm, fear of side-effects such as hypotension led to the use of a lower target dose of valsartan. The study design, baseline patient characteristics [6] and initial results have been published [7].
Comparing captopril to valsartan, mortality and other pre-specified cardiovascular outcomes including the composite of death from cardiovascular causes or non-fatal myocardial infarction or hospitalisation for heart failure were almost identical. The results are clearly consistent with those of OPTIMAAL although the narrower confidence interval was able to exclude non-inferiority unlike the OPTIMAAL study (Fig. 1a,b). The total number of hospitalisations for myocardial infarction was also similar. Tests for heterogeneity in subgroups revealed no convincing subgroup effect. Only 56% of patients were taking target doses of each drug at one year, whilst 15.3% of valsartan patients and 16.8% of captopril patients (P=0.07) had stopped therapy. Eighty three (1.7%) fewer patients discontinued valsartan (P<0.05) because of adverse events, mainly driven by such events as cough, skin rash and taste disturbance. This trial shows, for the first time, that an ARB was not inferior to an ACE inhibitor, although care should be taken in extrapolating these data to other target doses or other agents. As valsartan was associated with somewhat fewer withdrawals due to side-effects and was as effective as an ACE inhibitor, a case could be made for using it in preference to an ACE inhibitor, provided the likely increase in cost can be met.
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).Comparing captopril to the combination, mortality and other pre-specified outcomes were again almost identical. However, the total number of hospitalisations for myocardial infarction or heart failure was reduced (1437 to 1297; P=0.007) in a post-hoc analysis. A reduction in heart failure hospitalisations, but not a reduction in all-cause mortality, was also observed in the Val-HeFT [8] and CHARM-Added [9] studies, that also compared combination treatment with an ACE inhibitor and ARB versus ACE inhibitor alone (Fig. 2). However, the size of the effect may be smaller in VALIANT. Tests for heterogeneity suggested possible (P=0.11) greater benefit with combination therapy in patients in Killip class III or IV. Only 47% of patients were taking target doses of combination therapy at one year (P<0.001 versus captopril alone), whilst 19.0% (P=0.007) had stopped therapy. Combination therapy was associated with all the side effects of captopril and slightly more hypotension and renal dysfunction than captopril alone. However, the overall discontinuation rate for adverse events or for any reason were only 1.3% higher and 2.9% higher respectively. As with the previous add-on studies, there does appear to be a modest benefit with combination therapy on hospitalisation events, although more data are required before this can be properly assessed.
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4. The Hanover Autologous Bone Marrow Transplantation Study |
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TopAbstract1. {Omega}-3 Fatty acids...2. ACTIV in CHF:...3. VALIANT: Valsartan in...4. The Hanover Autologous...5. SPORTIF-V: Stroke Prophylaxis...6. ORBIT and PAD7. DEFINITE: DEFbrillator In...References |
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There has recently been an explosion of interest in the possibility of transplantation of bone marrow stem cells into the failing heart and myocardial scar [10–14].
This study enrolled 60 patients with an acute myocardial infarction and extensive wall motion defect who had undergone reperfusion by angioplasty and stent. 90% or more of patients were treated with a beta-blocker and an ACE inhibitor or angiotensin receptor blocker. Patients were randomised to receive either optimal medical therapy plus autologous intra-coronary bone marrow or optimal medical therapy alone (placebo). Cardiac function was evaluated using cine magnetic resonance imaging at baseline and at 6 months. Holter monitoring was also conducted. Patients underwent general anaesthesia and 128 ml of marrow was aspirated from the iliac crest (presumably in both the placebo and bone marrow cell transplantation group) a mean of 4.8 days after the infarction. On the same day the cells were infused into a coronary artery occluded by an angioplasty balloon to increase the time of contact of transplanted cells with the myocardium/scar.
Left ventricular ejection fraction increased more in the transplant group (50.0% to 56.7%) than on placebo (51.3% to 52.0%; P=0.0026 for the difference between groups). There was no difference in Holter findings.
This study suggests that cell transplantation may improve cardiac function after myocardial infarction but provides limited insights into the mechanism. It is possible that cells are transforming into cardiac myocytes, alternatively it is possible that the procedure provokes neo-angiogenesis or populates the myocardium with cells that block the adverse inotropic effects of cytokines. No doubt future research will provide answers to many of these questions and find out whether this is a simple, relatively inexpensive therapy for heart failure.
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5. SPORTIF-V: Stroke Prophylaxis using an ORal Thrombin Inhibitor in atrial Fibrillation |
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TopAbstract1. {Omega}-3 Fatty acids...2. ACTIV in CHF:...3. VALIANT: Valsartan in...4. The Hanover Autologous...5. SPORTIF-V: Stroke Prophylaxis...6. ORBIT and PAD7. DEFINITE: DEFbrillator In...References |
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An agent that was more effective, safer or simpler to use than warfarin (preferably all three) in patients with atrial fibrillation, about 50% of whom will have heart failure [15], would be a major therapeutic advance. The SPORTIF-III trial [16,17] suggested that ximelagatran was at least as effective as warfarin and did not require anti-coagulant monitoring. However, it was an open-label study, which might have biased the results, although due to the use of ‘hard’ endpoints this seems unlikely. SPORTIF-V attempted to replicate SPORTIF-III in a double-blind fashion.
Patients were eligible for SPORTIF-V if they had non-valvular atrial fibrillation and one other risk factor for stroke including age >75 years, prior stroke, or history of heart failure or hypertension. The primary endpoint was all strokes and systemic thromboembolic events. An important secondary endpoint added all-cause mortality to the primary composite. 3922 patients were randomised to 36 mg bd of ximelagatran or warfarin (titrated to an INR of 2–3) and followed for 20 months. Both warfarin and its corresponding placebo in those patients randomised to ximelagatran were titrated double-blind. The mean age of the patients was 72 years and 40% were aged >75 years. 25% had had a previous neurological event, 40% had left ventricular systolic dysfunction or heart failure and 80% had a history of hypertension. The mean INR in the warfarin group was 2.4 and 83% of the time INR was in the range 1.8–2.3.
The rate for the primary outcome was 1.6% pa for ximelagatran and 1.2% for warfarin. The risk of a major bleed was similar on ximelagatran (2.4%) and warfarin (3.1%) but minor bleeds occurred less often with ximelagatran (37% vs. 47%) (Table 2). For the secondary outcome, using data from both SPORTIF-III and V, there was a trend in favour of ximelagatran. Ximelagatran provoked increases in liver enzymes in about 6% of patients. These generally occurred within 2–6 months of starting therapy and usually resolved despite continued therapy.
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These data suggest that from a clinical efficacy viewpoint, ximelagatran is as effective as warfarin and somewhat safer. The next major debate will revolve around cost-effectiveness, pitting higher acquisition costs against reduced monitoring costs. Patient and physician convenience will also play a role in decision making.
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6. ORBIT and PAD |
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TopAbstract1. {Omega}-3 Fatty acids...2. ACTIV in CHF:...3. VALIANT: Valsartan in...4. The Hanover Autologous...5. SPORTIF-V: Stroke Prophylaxis...6. ORBIT and PAD7. DEFINITE: DEFbrillator In...References |
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These two studies investigated the impact of public-access defibrillator programmes. ORBIT compared conventional versus biphasic recti-linear cardioversion. Of 380 attempted resuscitations, only 29 patients survived until discharge (8%). PAD trained 20 000 members in 1200 ‘communities’ to call for ambulance assistance and initiate resuscitation alone or to defibrillate in addition. The study ran over 25.1 months during which 232 definite arrests were recorded. Only 15 (
13%) patients in whom resuscitation only was attempted before the ambulance arrived survived until hospital discharge, compared to 29 (25%) patients randomised to defibrillator therapy (P=0.042). It appears that public access defibrillators backed by an appropriate training programme can save lives but it is not clear that this is cost-effective. Resources might be better directed at prevention. |
7. DEFINITE: DEFbrillator In Non-Ischemic Cardiomyopathy Treatment Evaluation |
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TopAbstract1. {Omega}-3 Fatty acids...2. ACTIV in CHF:...3. VALIANT: Valsartan in...4. The Hanover Autologous...5. SPORTIF-V: Stroke Prophylaxis...6. ORBIT and PAD7. DEFINITE: DEFbrillator In...References |
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The MADIT [18,19] and CABG-Patch trial [20] suggested that ICDs reduced mortality in patients with left ventricular systolic dysfunction due to coronary heart disease even in the absence of a previous life-threatening arrhythmia. In MADIT-II, the best designed and most relevant study, benefits were observed even when patients were treated with ACE inhibitors and beta-blockers. These trials have led many to conclude that ICDs should be used widely in patients with a depressed ejection fraction and ischaemic heart disease. However, it was not clear from these studies whether ICDs should also be advocated in patients with dilated cardiomyopathy. Two small trials [21,22] suggested no benefit from ICDs in this population but COMPANION suggested that adding an ICD function to a resynchronisation device could reduce mortality regardless of the aetiology of disease [16] (Table 3).
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The DEFINITE trial was designed to determine if an ICD reduced mortality in patients with symptomatic heart failure due to non-ischemic cardiomyopathy. Patients had to have a low ejection fraction (
35%) and non-sustained ventricular tachycardia or >10 ventricular ectopics/hour NSVT/PVC's on Holter monitoring within the previous 6 months and to be receiving optimal medical therapy. Patients with syncope, prior history of life threatening arrhythmia, NYHA class IV heart failure or age >80 years were excluded. Importantly, amiodarone use was discouraged. Amiodarone was allowed when used for atrial fibrillation but not when given for ventricular tachycardia. ICDs were programmed to a VVI back-up pacing mode, which has been shown superior to DDD back-up [23]. 458 patients were randomised equally to ICD or medical therapy alone. The mean age of the patients was 58 years, 70% were men, 23% had diabetes, 24% atrial fibrillation and 80% were in NYHA I or II. 20% had left bundle branch block and the mean QRS width was 115 msec. 90% had non-sustained ventricular tachycardia on Holter monitoring. The mean 6-minute walk test was 320 meters. 85% were on ACE inhibitors and beta-blockers, 87% on diuretics and 42% digoxin but few received aldosterone antagonists.
Two-year mortality was reduced from 13.8% to 8.1% (P=0.06) by the ICD. There was a trend for greater benefit if QRS >120 msec. All of the observed benefit appeared to be in NYHA class III patients (hazard ratio 0.33; P=0.009). 24 of the 56 observed deaths were non-cardiovascular. There were 11 sudden deaths in the medical group versus 3 in the ICD group (hazard ratio 0.26; P=0.01).
Although DEFINITE by itself is not a convincing result, viewed in the wider context of MADIT-II and COMPANION, it provides a strong case for a benefit from ICDs in patients with left ventricular systolic dysfunction even in the absence of ischaemic heart disease (Fig. 3). However, two important issues remain. The absolute benefit is small, only 4 lives saved in DEFINITE and only 7 in MADIT-II over two years for every 100 devices implanted. This suggests that better targeting of therapy is required before ICD therapy can be deployed cost-effectively (and therefore widely) in patients with heart failure. Secondly, these studies have discouraged the use of amiodarone. Amiodarone may be more effective in reducing sudden death in the modern era of beta-blockade [24]. SCD-HeFT is comparing placebo, amiodarone and ICDs in patients with left ventricular ejection fraction 35% treated with ACE inhibitors and beta-blockers in approximately 2500 patients. The study will report in 2004. The study has not been stopped prematurely. We should wait for the results of this trial before deciding on how to deploy ICDs for patients with heart failure.
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References |
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TopAbstract1. {Omega}-3 Fatty acids...2. ACTIV in CHF:...3. VALIANT: Valsartan in...4. The Hanover Autologous...5. SPORTIF-V: Stroke Prophylaxis...6. ORBIT and PAD7. DEFINITE: DEFbrillator In...References |
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- Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione. Circulation (2002) 105(16):1897–1903.
[Abstract/Free Full Text] - Cleland J.G.F, Massie B.M, Packer M. Sudden death in heart failure: vascular of electrical? Eur J Heart Fail (1999) 1:41–45.
[Free Full Text] - Udelson J.E, Smith W.B, Hendrix G.H, et al. Acute haemodynamic effects of conivaptan, a dual V1A and V2 vasopressin receptor antagonist, in patients with advanced heart failure. Circulation (2001) 104:2417–2423.
[Abstract/Free Full Text] - Francis G.S, Benedict C, Johnstone D.E, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A sub-study of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation (1990) 82:1724–1729.
[Abstract/Free Full Text] - Dickstein K, Kjekshus J and the OPTIMAAL Steering Committee for the OPTIMAAL Study Group. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Lancet 2002;360(9335):752–60.
- Velazquez EJ, Pfeffer MA, McMurray JV, et al. VALsartan in Acute myocardial iNfarcTion (VALIANT) trial: baseline characteristics in context. Eur J Heart Fail 2003;(4):537–544.
- Pfeffer M.A, McMurray J.J.V, Velazquez E.J, et al. Valsartan, Captopril or both in myocardial infarction complicated by heart failure, left ventricular dysfunction or both. N Engl J Med (2003) 349:1893–1906.
[Abstract/Free Full Text] - Cohn JN, Tognoni G, for the Valsartan Heart Failure Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345(23):1667–1675.
- McMurray J.J.V, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet (2003) 362(9386):767–771.[CrossRef][Web of Science][Medline]
- Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium. Nature (2001) 410(6829):701–705.[CrossRef][Medline]
- Kamihata H, Matsubara H, Nishiue T, et al. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation (2001) 104(9):1046–1052.
[Abstract/Free Full Text] - Strauer B.E, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation (2002) 106(15):1913–1918.
[Abstract/Free Full Text] - Assmus B, Schachinger V, Teupe C, et al. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation (2002) 106(24):3009–3017.
[Abstract/Free Full Text] - Britten M.B, Abolmaali N.D, Assmus B, et al. Infarct remodeling after intracoronary progenitor cell treatment in patients with acute myocardial infarction (TOPCARE-AMI): mechanistic insights from serial contrast-enhanced magnetic resonance imaging. Circulation (2003) 108(18):2212–2218.
[Abstract/Free Full Text] - Petersen P, Boysen G, Godtfredsen J, Andersen E.D, Andersen B. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Lancet (1989) 1(8631):175–179.[Web of Science][Medline]
- Cleland J.G, Coletta A.P, Nikitin N, Louis A, Clark A. Update of clinical trials from the American College of Cardiology . EPHESUS, SPORTIF-III, ASCOT, COMPANION, UK-PACE and T-wave alternans. Eur J Heart Fail (2003) 5(3):391–398.
[Abstract/Free Full Text] - Halperin JL, Executive Steering Committee, SPORTIF III and V Study Investigators. Ximelagatran compared with warfarin for prevention of thromboembolism in patients with nonvalvular atrial fibrillation: Rationale, objectives, and design of a pair of clinical studies and baseline patient characteristics (SPORTIF III and V). Am Heart J 2003;146(3):431–8.
- Moss A.H.J, Hall W.J, Cannom D.S, et al. Improved survival with an implantable defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. N Engl J Med (1996) 335:1933–1940.
[Abstract/Free Full Text] - Moss A.J, Zareba W, Hall W.J, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med (2002) 346:877–883.
[Abstract/Free Full Text] - Bigger JTJ, for the Coronary Artery Bypass Graft (CABG) Patch trial investigators. Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronary-artery bypass graft surgery. Coronary Artery Bypass Graft (CABG) Patch Trial Investigators. N Engl J Med 1997;337(22):1569–75.
- Strickberger SA, Hummel JD, Bartlett TG, et al, for the AMIOVIRT Investigators. Amiodarone versus implantable cardioverter-defibrillator: randomized trial in patients with nonischemic dilated cardiomyopathy and asymptomatic nonsustained ventricular tachycardia-AMIOVIRT. J Am Coll Cardiol 2003;41(10):1707–12.
- Bansch D, Antz M, Boczor S, et al, for the CAT investigators. Primary prevention of sudden cardiac death in idiopathic dilated cardiomyopathy. The Cardiomyopathy trial (CAT). Circulation 2002;105:1453–8.
- The DAVID trial Investigators. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator. The dual chamber and VVI implantable defibrillator (DAVID) trial. J Am Med Assoc (2002) 288:3115–3123.
[Abstract/Free Full Text] - Boutite F, Boissel J.-P, Connolly S.J, et al. Amiodarone interaction with beta-blockers. Analysis of the merged EMIAT and CAMIAT databases. Circulation (1999) 99:2268–2275.
[Abstract/Free Full Text]
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