Highlights of the Latest Clinical Trials From the 2010 Scientific Sessions of the American Heart Association

Keywords:

• anticoagulation
• atrial fibrillation
• contrast agents
• heart failure
• patent foramen ovale
• telemonitoring

The 2010 Annual Scientific Sessions of the American Heart Association (AHA) are still considered one of the world‘s premier cardiovascular (CV) research meetings. In November 2010 the scientific sessions were held in Chicago, IL, USA and attracted more than 20,000 participants from more than 50 countries around the globe. The scientific program consisted of over 4000 abstracts of original research, invited lectures, how-to sessions and CV seminars, all clustered into seven distinct cores, with particular special focus on specific areas from ‘Cardiovascular Imgaing‘ (core one) to ‘Vascular Disease: Biology and Clinical Science‘ (core seven). Furthermore, the main program included four plenary sessions focusing on the latest trials, as well as three sessions entitled ‘Clinical Science: Special Reports‘ [101]. In the following article, a selection of large randomized trials reported during these sessions will be presented and their potential impact for clinical practice discussed.

ROCKET-AF

Atrial fibrillation is the most common rhythm disease worldwide, affecting approximately 2.3 million patients in the USA alone. Anticoagulation with vitamin K antagonists, such as warfarin, prevents ischemic strokes in patients with valvular and nonvalvular atrial fibrillation. However, the necessity of routine coagulation monitoring and the interference of a variety of agents, as well as the influence of dietary changes, requiring dose adjustments limit their overall use and benefit. In general, in less than 70% of the patients treated with vitamin K antagonists the international normalized ratio values are within the therapeutic range of 2.0–3.0, thereby reducing their therapeutic benefit and increasing their bleeding risk [1]. Recently, in a large randomized trial, the Randomized Evaluation of Long Term Anticoagulant Therapy (RELY) study, which enrolled patients with nonvalvular atrial fibrillation, the oral thrombin inhibitor dabigatran at lower doses (110 mg twice daily) was observed to reduce the bleeding risk, although at this dose dabigatran was as effective as warfarin in preventing ischemic strokes [2]. At a higher dose (150 mg twice daily) dabigatran was even superior to warfarin in preventing ischemic strokes without increasing the bleeding risk above that of warfarin. The oral factor Xa inhibitor rivaroxaban represents a potential alternative anticoagulant. It was the aim of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) study to establish whether rivaroxaban (20 mg once daily) is noninferior to warfarin in preventing cardiac embolic events. ROCKET AF included 14,269 patients (mean age 73 years) with nonvalvular atrial fibrillation who had previously experienced a stroke or patients who possessed at least two risk factor for stroke. Reflecting a high-risk population, the Congestive Heart Failure, Hypertension, Age, Diabetes and Stroke (CHADS₂) score was more than 3 in 85% of the patients enrolled. After a mean follow-up of 42 months the primary end point (ischemic and hemorrhagic stroke and systemic embolization) was reached in 2.12% of the patient population receiving rivaroxaban and in 2.42% receiving warfarin, indicating noninferiority of rivaroxaban. Focusing the analysis to the ‘on-treatment population‘, that is those patients who received the study drug over the entire study period, rivaroxaban reduced the primary end point rate from 2.15 to 1.70% (p = 0.015), which corresponds to a 21% relative risk reduction. The risk of minor and major bleeding was comparable between rivaroxaban and warfarin. In conclusion, rivaroxaban appears to be a future alternative to anticoagulation with vitamin K antagonists in the treatment of patients with nonvalvular atrial fibrillation.

P-OM3

ω-3 fatty acids are claimed to have some antiarrhythmic properties, especially in the failing heart. However, the data of large randomized trials in heart failure (HF) patients are so far inconsistent [3]. Furthermore, the OMEGA trial recently demonstrated no beneficial effect of ω-3 fatty acids in postmyocardial infarct patients [4]. So far the effect of ω-3 fatty acids on atrial fibrillation was not specifically addressed in low-risk patients. Therefore, it was the aim of the Efficacy and Safety of Prescription ω-3 Acid Ethyl Esters (P-OM3) for the Prevention of Recurrent Symptomatic Atrial Fibrillation trial to prospectively investigate in 663 patients with recurrent atrial fibrillation (paroxysmal atrial fibrillation in 542 and persistent atrial fibrillation in 121 patients) not receiving an antiarrhythmic agent, whether P-OM3 reduced the risk of recurrent atrial fibrillation. Patients were randomly assigned to P-OM3 (4 mg per day) or placebo over a study period of 24 weeks. P-OM3 had no major side effects and it was well tolerated by the patients. However, the time to first recurrence of atrial fibrillation was not affected by P-OM3 in patients with paroxysmal or in patients with persistent atrial fibrillation. Thus, P-OM3 failed to have a secondary preventive effect on recurrence of atrial fibrillation in non-HF patients. Whether it may be beneficial in HF patients with atrial fibrillation requires a separate study. Of course, the results of this study do not rule out that P-OM3 might have worked in primary prevention. However, thus far there is no precedence for a drug to be used in primary prevention if it had failed in secondary prevention.

EMPHASIS-HF

Despite recent advances in HF therapy the annual mortality is still rather high, reaching up to 50% in those patients who had been hospitalized for cardiac decompensation [5]. Relatively low doses of aldosterone antagonists (25–50 mg once daily) have been demonstrated to reduce the risk of CV death and HF hospitalization, in addition to β-blockers and ACE inhibitors in the New York Heart Association (NYHA) class III–IV patients in the Randomized Aldactone Evaluation Study (RALES) and in patients with a myocardial infarction complicated by a reduction in left ventricular ejection fraction (LVEF) less than 40% and signs and symptoms of HF in the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) [6,7]. It was the aim of The Effect of Eplerenone vs Placebo on Cardiovascular Mortality or Heart Failure Hospitalization in Subjects with NYHA Class II Chronic Systolic Heart Failure (EMPHASIS-HF) trial to investigate the potential prognostic benefit of the aldosterone antagonist eplerenone (25–50 mg daily) on CV mortality and HF hospitalization (i.e., combined primary end point) in 2737 NYHA class II patients (LVEF <35%) already on standard HF medication. The study was terminated prematurely as eplerenone demonstrated such superiority compared with placebo that continuation of the study was no longer ethically acceptable [8]. After a mean follow-up of 21 months the primary end point was reached by 25.9% of the patients in the placebo group and by only 18.3% receiving eplerenone. This corresponds to a 37% (p < 0.001) reduction of the primary end point or a number needed to treat of 19 patients per year in order to prevent one CV death or one HF hospitalization with eplerenone. Total mortality was reduced by eplerenone from 15.5 to 12.5%, corresponding to a 24% relative risk reduction (p = 0.008). Serum potassium exceeding 5.5 mmol/l was observed in 11.8% of the patients receiving eplerenone and in 7.2% of the patients receiving placebo (p < 0.001) [8]. Thus, the aldosterone antagonist eplerenone should become standard therapy (in addition to β-blockers and ACE inhibitors) in systolic HF patients with only mild-to-moderate symptoms as long as their renal function is normal or only moderately impaired (glomerular filtration rate >30 ml/min/1.73 m²) and their serum potassium is within the normal range and regularly controlled. Spironolactone may have a similar effectiveness as eplerenone in NYHA class II patients; however, this was not tested in the EMPHASIS-HF trial. Whether, aldosterone antagonists are also prognostically beneficial in patients with HF and preserved EF is currently under investigation.

RAFT

In patients with advanced HF, cardiac resynchronization therapy (CRT) has been demonstrated to improve prognosis either alone (in the Cardiac Resynchronization in Heart Failure [CARE-HF] study) or in combination with an implantable cardioverter–defibrillator (ICD) in addition to optimized medical HF therapy [9,10]. Recently, a reduction in HF events, but not in mortality, was observed with the use of ICD with CRT (ICD–CRT) as compared with ICD alone in patients with mild HF, that is NYHA class I and II, in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) [11]. Therefore, the prognostic role of CRT in patients with mild-to-moderate HF symptoms requiring an ICD remained under discussion. The Resynchronization/Defibrillation for Ambulatory Heart Failure Trial (RAFT) is a prospective multicenter trial, which included 1798 HF patients (mostly NYHA class II, some NYHA class III) with a LVEF less than 30% and a wide QRS duration (>120 ms) [12]. At baseline, mean age of the patient population was 66 years, mean LVEF 23% and mean QRS duration 158 ms. In addition to standard HF therapy, patients were randomly assigned either to ICD or ICD–CRT. After a mean follow-up of 40 months, the primary end point (i.e., death or HF hospitalization) was reduced by 25% in patients with an ICD–CRT (event rate: 33.2 vs 40.3%; p < 0.001). ICD–CRT also reduced total mortality, CV lethality and HF hospitalization significantly. However, the mortality was much higher in RAFT than in MADIT-CRT (26.1 vs 7.3%). The number needed to treat to prevent one death by the additional CRT feature was 70 patients per year and to prevent one HF hospitalization 55 patients per year in the RAFT trial [12]. Thus, in NYHA class II and III patients with a left bundle branch block and a QRS duration of more than 120 ms requiring an ICD, an ICD–CRT therapy should be considered. However, it should be noted that in RAFT, the implantation of an ICD–CRT was accompanied by a higher adverse event rate at 30 days attributed to the implantation procedure and device-associated problems (adverse events in 124 patients vs in only 58 patients with ICD alone; p < 0.001), a feature also observed in other trials involving CRT.

Telemonitoring in heart failure & telemedical interventional monitoring in heart failure

Healthcare systems worldwide are under increasing pressure to cut costs by reducing hospital readmissions. HF hospitalizations are the leading cause of short-term readmissions [5]. Telemonitoring is a promising strategy for early detection of clinical worsening in HF [13]. Whether telemonitoring is able to prevent readmissions and to improve prognosis of patients with advanced HF was investigated in two large controlled trials, the Telemonitoring in Heart Failure (TELE-HF) trial and the Telemedical Interventional Monitoring in Heart Failure (TIM-HF) study [14,15].

The TELE-HF trial enrolled a total of 1653 patients (mean age 61 years, in 70% LVEF <40%) on optimal medical therapy (∼80% on β-blocker, 67% on ACE-inhibitor, 78% on loop diuretic, and ∼33% on ARB) who had been hospitalized for HF within the past 30 days. These patients were either randomly assigned to a commercially available telemonitoring system, which consisted of a telephone-based interactive voice control system that collected daily information regarding symptoms and bodyweight (reviewed by specially trained nurses and supported by clinicians) or to usual care. The patient adherence (making >three calls a week) to this system dropped from 90% in the first week to 55% at week 26. The primary end point (all-cause readmission or death within 6 months after enrollment) was reached by 52% of the patients in both groups (p = 0.75). Furthermore, there was no difference between both groups in mortality (11% in each group; p = 0.88) or readmission rate (49.3% in the telemonitoring and 47.4% in the usual care group; p = 0.45).

The TIM-HF study enrolled a total of 710 stable ambulatory HF patients (mean age 67 years, mean LVEF 27%, 50% NYHA class II and 50% NYHA class III) on optimal medical therapy (92% on β-blocker, approximately 95% on ACE-inhibitor and/or ARB, 94% on diuretic), who had been hospitalized for cardiac decompensation within 24 months prior to enrollment. The patients were either randomized to remote telemedical management, collecting information on blood pressure, heart rate and bodyweight as well as the ECG, all connected to a telemedical center or to usual care and followed for at least 12 months (man follow-up 26 months). To avoid any bias in the assessment of end points, in all patients a systemic cross-check with health insurance hospitalization records was performed. In TIM-HF the primary end point, all-cause mortality (reached by ∼17% of the patients), was not different between the two groups (p = 0.87), and neither was the secondary composite end point, CV death and HF hospitalization (reached by ∼26% of the patients; p = 0.44). Subgroups with possible benefit appeared to be patients without a severely reduced LVEF (<25%) and patients without depression.

The neutral results of TELE-HF and TIM-HF indicate the importance of a thorough, independent evaluation of disease-management strategies before adoption [14]. Further studies in selected patient groups may help to identify those HF patients who may benefit from telemonitoring either as ‘bridge to stability‘ or as a long-term assistance in their HF management.

CLOSURE I

So far the prognostic benefit of an interventional, catheter-based closure of a patent foramen ovale (PFO) over medical therapy in patients who suffered from a presumed paradoxical cerebral embolization leading to a transient ischemic attack (TIA) or a stroke was unknown. However, nonrandomized analyses of large registries from experienced centers indicated only low rates of recurrent stroke or TIA after a device-based PFO closure [16]. The CLOSURE I trial is the first published prospective, multicenter, randomized controlled trial comparing percutaneous PFO closure utilizing the StarFlex^® (NMT Medical, Inc., MA, USA) Septal Closure System (a ‘clamshell‘ device to patch the PFO) versus best medical therapy in 909 patients (age <60 years, mean age 46 years) with a PFO (<40% with an additional atrial septal aneurysm) and a cryptogenic stroke or a TIA within 6 months of randomization. The primary end point was a composite of the two-year incidence of stroke or TIA, all-cause mortality within the first 30 days and neurological mortality within 31 days and 2 years after randomization. This primary end point was not significantly different between catheter-based closure (including aspirin 325 mg daily for 2 years and clopidogrel 75 mg for 6 months) and best medical therapy (aspirin 325 mg daily or warfarin with a target international normalized ratio of 2.0–3.0 or both): 5.9 vs 7.7% (p = 0.30). The recurrent stroke rate was approximately 3% in both arms (p = 0.77). However, in the device arm the rate of secondary end points such as major vascular complications (3.2 vs 0%; p < 0.001) and atrial fibrillation (5.7 vs 0.7%; p < 0.001) were higher than in the medical arm. Therefore, the StarFlex Septal Closure System appeared to be somewhat inferior to medical therapy in preventing CV end points in the rather heterogeneous study population of CLOSURE I. The efficacy of PFO device closure in well-defined patient populations, such as those with a repeat TIA and stroke under ‘best‘ medical therapy, warrants further study. Furthermore, the results of CLOSURE I are based on the StarFlex Septal Closure System and may not be extrapolated to other device systems for PFO closure. Finally, with a relatively high rate of periprocedural complications and a closure rate of less than 90% it may be speculated that the event rate may be lower and the success rate higher in high volume centers.

GRAVITAS

The antithrombotic effect of clopidogrel is known to be variable within individuals. This is thought to be the main reason why clopidogrel is inferior to two other antiplatelet agents, namely prasugrel and ticagrelor, in patients with an acute coronary syndrome receiving a coronary stent [17,18]. The aim of the Gauging Responsiveness with a VerifyNow Assay – Impact on Thrombosis and Safety (GRAVITAS) trial was to test the hypothesis that doubling the dose of clopidogrel to 150 mg daily may overcome the reduced antithrombotic effect in patients with a high residual platelet activity after receiving the standard clopidogrel dose (loading dose 300 mg and followed by 75 mg once daily). In 41% of 5429 patients undergoing a percutaneous coronary intervention with a drug-eluting stent a high residual platelet activity was found. These 2214 patients were randomized to either the standard dose of clopidogrel (75 mg daily) or a ‘double‘ dose of clopidogrel (i.e., 150 mg daily). During a follow-up of 6 months a similar CV event rate (death, myocardial infarction or stent thrombosis) was observed in both groups. Although the event rate of 2.3% in both groups was rather low, one might still have expected at least a trend towards a lower event rate in the high-dose group. Thus, a high residual platelet activity may not be simply overcome by doubling the dose of clopidgrel. It may be speculated that in these patients prasugrel or ticagrelor may be the better choice. However, this assumption still needs to be supported by randomized studies.

ACT

Contrast-induced nephropathy is associated with an increased mortality and prolonged hospitalization. Furthermore, it bares the risk of inducing irreversible renal failure requiring life-long dialysis. Previously, it has been demonstrated that prophylactic administration of acetylcysteine significantly reduces the increase in serum creatinine after exposure to contrast agents [19]. However, so far, a large controlled trial with focus on clinically relevant end points was missing. It was the aim of the Acetylcysteine for the Prevention of Contrast-Induced Nephropathy (ACT) trial to prospectively compare the effect of acetylcysteine (1200 mg orally twice daily before and two doses after contrast agent exposure) with placebo in 2308 patients (mean age 68 years) with at least one risk factor, that is age 70 years or older, chronic renal failure (∼16%), diabetes mellitus (∼60%), HF or LVEF less than 45% (∼10%) or shock. The mean glomerular filtration rate was 60.2 ml/min/1.74 m² in the acetylcysteine arm and 61.4 ml/min/1.74 m² in the placebo arm. Approximately two thirds of the patients underwent a diagnostic coronary angiography and about one third a percutaneous coronary intervention. The mean contrast volume administered was 100 ml per patient. The primary end point, contrast-induced nephropathy (>25% increase in serum creatinine above baseline 48–96 h after angiography), was reached in 12.7% of the patients in both groups (p = 0.97). Furthermore, secondary end points such as total or CV mortality and need for dialysis within 30 days were not affected by acetylcysteine. Therefore, acetylcysteine failed to reduce the short-term risk of contrast-induced nephropathy in patients with an increased risk. Thus, the best prophylaxis of contrast-induced nephropathy in patients with an increased risk appears to be – besides careful patient selection and use of low- or iso-osmolar contrast agents – an adequate hydration and temporary pausing of medications with potential negative influence on renal function (e.g., ACE inhibitors and diuretics) prior to, during and after contrast agent exposure.

Financial & competing interests disclosure

The author has received speaker honoraria as well as honoraria for participation in clinical end point committees from several pharmaceutical companies, but has no conflict of interest to disclose for this article. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.