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The Clinical Perspective: trials' selection from the ESC Congress 2014

11 trials highlighted

The studies mentioned below were presented during the Highlight Session at the ESC congress 2014 in Barcelona. Only those trials were chosen that might be of particular interest for the basic scientist. Of note, the ESC introduced five new practice guidelines, with a range of tools for everyday application: Non-Cardiac Surgery, Acute Pulmonary Embolism, Hypertrophic Cardiomyopathy, Aortic Diseases and Myocardial Revascularization.

Basic Science

The PARADIGM-HF trial is the most recognized trial presented at the ESC congress 2014 that will very likely have a potential impact on daily clinical practice. Beta blockers, aldosterone antagonists and in particular ACE-inhibitors have been the gold standard for the treatment of patients suffering from heart failure due to reduced ejection fraction for the last decades. PARADIGM-HF tested the hypothesis that a new compound (LCZ696 200 mg bid) was superior to a gold standard ACE inhibitor enalapril 10 mg bid in reducing mortality and morbidity in patients with heart failure and reduced ejection fraction.
LCZ696 consists of the well-known angiotensin receptor blocker Valsartan, but in combination with a so called neprilysin inhibitor (together called “ARNI”). This compound simultaneously blocks the renin-angiotensin-aldosterone system (RAAS) and in addition augments endogenous natriuretic peptides (and other endogenous vasoactive substances) by blocking the neprilysin or neutral endopeptidase enzyme that degrades these substances. The valsartan component of the drug primarily causes vasodilatation and increases excretion of Na and water via the kidneys, while the neprilysin inhibitory component leads to lowering of both, blood volume and blood pressure. Both agents have anti-remodeling capacities and prevent fibrosis.    

InPARADIGM-HF >8000 patients were randomised in a 1:1 ratio to double-blind treatment with Enalapril or LCZ696. The primary end point was a composite of time to either cardiovascular death or heart failure hospitalization. The study was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At this time treatment with LCZ696 lead to a 20% risk reduction on the primary endpoint, CV death or heart failure hospitalization (p=0.0000002). But the risks of death from cardiovascular causes (by 20%, p=0.00004) and heart failure hospitalizations (by 21%, p=0.00004) were also significantly reduced alone. Finally and most importantly, all-cause mortality was decreased by 16% (p=0.0005) in patients taking LCZ696. ). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group. Fewer patients on LCZ696 discontinued study medication for any adverse event compared to those on enalapril. The study was published simultaneously in the New England Journal of Medicine (2014. 371:993-1004).

Confirm HF. This trial was designed to evaluate the benefits and safety of long-term intravenous iron therapy using ferric carboxymaltose (FCM) in 304 iron-deficient (not anemia) patients with symptomatic heart failure. Iron deficiency was defined as a serum ferritin level of less than 100 ng/mL, or between 100 and 300 ng/mL if transferrin saturation was less than 20%. Treatment with FCM over a 1-year period resulted in sustainable improvement in functional capacity, symptoms, and quality of life. Moreover, FCM reduced the risk of recurrent hospitalisations due to worsening of heart failure (post hoc) by 61%. Of note, more than 75% of the patients required only a maximum of two injections of FCM to correct and maintain the iron parameters (Eur Heart J. 2014 Aug 31. pii: ehu385. [Epub ahead of print]).

NECTAR-HF. 96 patients were randomized in to receive an implanted active vagal nerve stimulation or control for a 6-month period in a sham-control design. Stimulating the vagus nerve failed to demonstrate a significant effect on the change in LV end systolic diameter (LVESD) at 6 months and cardiac remodeling and functional capacity in symptomatic heart failure patients, but improved quality-of-life. Given that preliminary studies suggested a benefit of vagal nerve stimulation and also some issues to trial design and function of the devices, vagal nerve stimulation should be investigated in further clinical studies (Eur Heart J. 2014 Aug 31. pii: ehu345. [Epub ahead of print]).

Wear-IT. 2000 Patients were enrolled in the WEARIT registry in order to wear a defibrillator "vest" for three months. This therapy is attractive for patients where a long term indication of an implantable cardioverter defibrillator (ICD) is not clear such as patients suffering from acute myocarditis or acute coronary syndromes. In this registry less than 50% of the patients received an ICD at the end of the vest use. The most frequent reason not to implant an ICD following the wearable defibrillator was improvement in left ventricular ejection fraction which is of particular interest for clinical practice. The use of this defibrillator "vest" seems to be safe and interestingly inappropriate therapy was very low.

A battery less cardiac pacemaker powered by cardiac motion was also introduced at the ESC meeting. A clockwork mechanism converts the motion of the beating heart into electrical energy. This prototype does not require battery replacement. The system was successfully tested in domestic pigs and demonstrates that it is possible to pace the heart using the power of its own motion.

CvLPRIT. 296 STEMI patients with coronary multivessel disease were randomized to infarct-related coronary artery PCI or to complete myocardial revascularization. The primary end point which is a composite of total mortality, recurrent myocardial infarction, heart failure and ischemie driven revascularization was reduced in the complete revascularization group. The results of this trial are in agreement with the findings of the PRAMI trial, which was presented during last year’s ESC Hot Line session.

TASTE. 7244 patients with STEMI were evaluated with respect to clinical outcomes at 1 year after coronary thrombus aspiration and PCI or PCI alone. Although the results of this trial at 30 days had been reported previously, the composite end point of death from any cause, rehospitalization for myocardial infarction, or stent thrombosis at 1 year were not significantly changed between both groups (N Engl J Med. 2014. 371(12):1111-20).

FAME 2. This trial investigated fractional flow reserve (FFR)-guided PCI plus medical therapy to medical therapy alone in patients with stable coronary artery disease. In 1220 patients with stable coronary artery disease, the FFR was assesed in all stenoses that were visible on angiography. Patients who had at least one stenosis with an FFR of 0.80 or less were randomized. In subjects with stable coronary artery disease, FFR-guided intervention compared with medical therapy, improved the outcome. Of note, patients without ischemia had a favorable outcome with medical therapy alone (N Engl J Med. 371(13):1208-17).

SIGNIFY. This big trial is probably the most disappointing study presented at the ESC congress 2014 because of its negative result. 19,102 patients with stable coronary artery disease and a heart rate of ≥70 beats per minute, but in the absence of heart failure were treated with the If inhibitor Ivabradine to lower heart rate. After a median follow-up of 27.8 months, there was no significant difference between the ivabradine group and the placebo group in the incidence of death from cardiovascular causes and nonfatal myocardial infarction (primary endpoint). Spectacular was the finding of an increase in the incidence of the primary end point among patients with activity-limiting angina but not among those without activity-limiting angina because of the fact that ivabradine is approved for the treatment of symptomatic coronary heart disease patients (N Engl J Med. 371(12):1091-9.).

SOLID-TIMI 52: 13,026 patients were randomized within 30 days of hospitalization with an acute coronary syndrome to Darapladib an selective inhibitor of the Lipoprotein-associated phospholipase A2 enzyme. Darapladib as an anti-inflammatory strategy did not reduce the risk of major coronary events after a median duration of 2.5 years (JAMA. 2014. 312(10):1006-15).

ODYSSEY LONG TERM: Alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin kexin type 9 (PCSK9) was evaluated as a treatment option for patients with hypercholesterolemia. A subcutaneously given dosage two times per week was well tolerated and resulted in a good compliance. A substantial and sustained LDL-C lowering in patients at high to very high risk of CVD, including those with heterozygous FH could be obtained in addition of a maximally tolerated statin dose. The LDL-C lowering response resulted in a 61% reduction for patients treated with alirocumab. Adjudicated major cardiovascular events (cardiac death, myocardial infarction, stroke, and unstable angina requiring hospitalisation) in the alirocumab arm compared to placebo were also significantly reduced.