News highlights from the American College of Cardiology, European Atherosclerosis Society and American Diabetes Association.
American College of Cardiology
FIRE AND ICE: to freeze or fry the atrium?
Cryoballoon atrial ablation was found to be non-inferior to radiofrequency (RF) ablation with respect to efficacy for the treatment of patients with drug-refractory paroxysmal atrial fibrillation (AF). There was also no significant difference between the two procedures in regard to patient safety, according to late-breaking clinical trial research presented at ACC and simultaneously published in the New England Journal of Medicine (doi: 10.1056/NEJMoa160201).
The FIRE AND ICE trial, conducted by Dr Karl-Heinz Kuck (Department of Cardiology, Asklepios Klinik, St Georg, Hamburg, Germany) and co-investigators, is the largest randomised trial of its kind, and included participants from 16 centres in eight European countries. “The FIRE AND ICE trial demonstrated that the cryoballoon, a newer, easier-to-use ablation catheter, worked as well as the established technology, which ultimately means that more patients can be treated for AF without having [to go to a] specialised cardiac centre,” said Dr Kuck. “In addition there was, in general, a low risk of procedural complications in both groups, demonstrating that catheter ablation has become much safer over the years.”
The authors compared the effectiveness of point-by-point mode applied RF ablation to that of cryoballoon ablation applied in a single step mode, a newer and less complex technique. The primary efficacy end point of the trial was time to first documented recurrence of AF/atrial tachycardia/atrial flutter, prescription of antiarrhythmic drugs, or repeat ablation.
The multi-centre, randomised, non-inferior open-label trial analysed data gathered from patients ranging from 18 to 75 years old, with symptomatic paroxysmal AF and prior antiarrhythmic drug failure. After exclusions for previous left atrial (LA) ablation, percutaneous coronary intervention (PCI) or myocardial infarction within three months of enrollment, and other clinical issues, 693 patients undergoing pulmonary vein isolation were randomly assigned in a 1:1 ratio: 352 underwent RF ablation and 341 underwent cryoballoon ablation.
In-office visits were scheduled at three, six, and 12 months and every six months after. The primary efficacy end point occurred in 138 patients in the cryoballoon group and in 143 patients in the RF group. A pre-specified superiority test performed for the primary efficacy end point did not indicate a significant difference between the treatment groups. The most common treatment-related serious adverse events were groin site complication and atrial flutter or atrial tachycardia.
The authors observed significant procedural differences between the two groups. RF ablation required less fluoroscopy time (17 vs. 22 minutes). Procedure time was shorter in the cryoballoon group (124 minutes vs. 141 minutes). LA dwell time in the cryoballoon group was shorter as well (92 vs. 109 minutes). A favourable safety profile was observed in both groups.
One limitation of the study is that it did not investigate ablation for treating patients with more advanced stages of AF. A separate trial would be needed to assess the ablation technique’s effectiveness and safety for that patient population, he said.
Deferred stenting shows no clinical benefit
Delayed or deferred stent implantation in patients experiencing ST-segment elevation myocardial infarction (STEMI) failed to reduce death from any cause, hospitalisation for heart failure, subsequent heart attacks or the need for a repeat procedure to restore blood flow to the heart, according to findings from DANAMI 3-DEFER (Third Danish Study of Optimal Acute Treatment of Patients with ST-segment Elevation Myocardial Infarction: DEFERred stent implantation in connection with primary PCI).
“The take-home message from this study is that deferred stent implantation cannot be recommended as a routine procedure for STEMI patients treated with primary PCI,” said Dr Henning Kelbaek (Roskilde Hospital, University of Copenhagen, Denmark), lead author of the study. “Our results completely rebut the promising findings of preliminary studies that suggested deferred stenting should translate to clinical benefit.”
Contradicting findings of promising preliminary studies, DANAMI-3-DEFER was the largest trial yet conducted to evaluate whether delaying stent implantation would improve patients’ survival and reduce their risk of heart failure or another heart attack.
In the study, 1,234 patients (average age 61 years; 75 % male) with acute STEMI symptoms of less than 12 hours’ duration were randomly assigned to receive standard angioplasty with immediate stent implantation or angioplasty followed by deferred stent implantation after a re-examination 24 to 48 hours later.
After an average follow-up time of 43 months, 109 (18 %) in the standard treatment group and 105 patients (17%) in the deferred group met the primary end point, a composite of death from any cause, hospitalisation for heart failure, a second heart attack, and unplanned repeat angioplasty – a non-significant difference.
Although the trial was the largest so far to address the issue of deferred stent implantation, it may not have been large enough to detect a difference between the two treatment groups, Dr Kelbaek said. Another limitation is that the trial did not select patients who were at the highest risk for developing another arterial blockage, such as those over age 65 years, those who have had more than one heart attack or those known to have a large number of blood clots.
“We cannot rule out that a fraction of our patients who met these criteria might have benefitted from delayed stent placement, especially because we found a small improvement in heart-muscle function 18 months after treatment among patients who underwent deferred stenting,” Dr Kelbaek said.
The study was not powered to detect this improvement, but Dr Kelbaek said he and his team would now look carefully for possible “hypothesis-generating” findings in subsets of patients – both those who might have benefitted from the deferred-treatment strategy and, equally important, those in whom this strategy might have worsened their condition.
Stem cell therapy improves outcomes in severe heart failure
A new therapy using stem cells significantly improved long-term health outcomes in patients with severe and end-stage heart failure, who normally have few other treatment options.
The regenerative therapy study, a phase 2 clinical trial for a new stem cell therapy known as ixmyelocel-T, enrolled 109 ischaemic cardiomyopathy patients, who were randomised to receive ixmyelocel-T, which involved extracting stem cells from a patient’s own bone marrow, or placebo (n=58 and n=51, respectively). The composite primary end point (a composite of deaths, cardiovascular hospitalisations and clinic visits for sudden worsening of heart failure symptoms over a 12-month period) was reached by 38% of patients in the stem cell therapy group and 49% of patients in the placebo group, a reduction of 37%.
“To date, this is the largest double-blind, placebo-controlled stem cell trial for treatment of heart failure to be presented,” said Dr Timothy Henry (Cedars-Sinai Heart Institute, Los Angeles, USA), one of the study’s lead authors. “Based on these positive results, we are encouraged that this is an attractive potential therapy for patients with class III and class III and IV heart failure…who currently have limited options.”
The trial builds upon lessons learned from previous smaller-scale stem cell studies, which have mostly shown modest improvements in outcomes for heart failure. Past trials with ixmyelocel-T have shown better results in patients with ischaemic cardiomyopathy than in those with non-ischaemic cardiomyopathy. In addition, previous studies have shown greater success with procedures in which the stem cells are injected percutaneously via the groin compared with open-heart surgery, so the new trial used a percutaneous approach.
A key limitation of the new trial is its modest size. Dr Henry said the next step is to expand the investigation of percutaneous, intramyocardial ixmyelocel-T treatment in a larger sample of heart failure patients with ischemic cardiomyopathy.
This study was published online in The Lancet at the time of presentation (doi: 10.1016/S0140-6736(16)30137-4).
European Atherosclerosis Society
The 84th Congress of the European Atherosclerosis Society (EAS) took place in Innsbruck, Austria from 29th May–1st June 2016.
New guidelines on CVD prevention
The recently published Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice was reviewed by EAS President, Professor Alberico Catapano (University of Milan, Italy) in a special Congress session. He focused on key areas including risk assessment, goals and targets for important cardiovascular risk factors, recommendations for imaging, and lipid control, as well as intervention strategies.
Risk assessment is recommended in individuals at increased risk i.e. with a family history of premature cardiovascular disease (CVD) or major risk factors, and this should be repeated at least every five years, and more often in those with risk factors at levels close to targets for management. Systematic risk assessment may be considered in men aged >40 years or women >50 years or post-menopausal women with no known cardiovascular risk factors. Global risk estimation is based on the SCORE approach, with charts providing the 10-year risk of fatal CVD, according to age, sex, smoking, systolic blood pressure and total cholesterol. In addition, relative risk charts, adapted from SCORE, may offer additional value in young individuals with risk factors.
Much of the focus of discussion was on lipids. While low-density lipoprotein cholesterol (LDL-C) goals remain unchanged across the spectrum of cardiovascular risk, the alternative goal of at least 50% reduction from baseline LDL-C levels for high-risk and very high-risk patients has been refined. This can be considered in very high-risk patients with baseline LDL-C levels between 1.8 and 3.5 mmol/L (70 and 135 mg/dL), and high-risk patients with baseline LDL-C levels between 2.6 and 5.1 mmol/L (100 and 200 mg/dL).
While the Societies have recognised emerging evidence for high fasting triglycerides (>1.7 mmol/L or >~150 mg/dL) as a CVD risk factor, there is still no support for targets. Similarly, beyond recognition of low high-density lipoprotein cholesterol (HDL-C) being a CVD risk factor (i.e. <1.0 mmol/L or 40 mg/dL in men and <1.2 mmol/L or <45 mg/dL in women), there is no good evidence for targets for HDL-C.
Imaging and treatment
The guidelines consider coronary artery calcium scoring, atherosclerotic plaque detection by carotid artery scanning, and ankle brachial index as risk modifiers in cardiovascular risk assessment. Carotid intima-media thickness screening is not recommended for cardiovascular risk assessment.
As with all guidelines, the Sixth Joint Task Force guidelines place diet at the heart of prevention of CVD. Lifestyle advice is recommended even for people at very low risk (SCORE <1%), with LDL-C levels <2.6 mmol/L or 100 mg/dL.
For lipid control, statins remain the first choice for treating elevated LDL-C. In patients at high or very high-risk of cardiovascular events, who require further LDL-C lowering to reach goal, ezetimibe is the treatment of choice for combination with a statin. With respect to new therapies, the guidelines recognise that there is consistent support from clinical trials for up to 60% lowering of LDL-C with the new proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.
Results of ongoing outcomes studies are needed before any definitive recommendations on their use can be made. Overall, these Sixth Joint Task Force guidelines have provided alignment with the 2011 Joint European Society of Cardiology/European Atherosclerosis Society guidelines; updates to these guidelines are expected at this year’s European Society of Cardiology Congress in Rome, Italy.
The guidelines have highlighted the importance of adherence, and have provided specific recommendations for attaining and improving adherence. These include simplifying the treatment regimen, assessment of medication adherence, as well as reasons for non-adherence by clinicians, and considering combination therapies strategies – a polypill – to improve adherence.
The guidelines are published in the European Heart Journal (doi: 10.1093/eurheartj/ehw106).
American Diabetes Association
The 76th Scientific Sessions of the American Diabetes Association (ADA 2016) took place in New Orleans, 10th–14th June 2016.
Diabetes drug, liraglutide shows CV benefits in LEADER trial
The main results of the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation) trial were presented at the ADA meeting and also published in the New England Journal of Medicine (doi: 10.1056/NEJMoa1603827). The diabetes drug, liraglutide significantly reduced the risk of the composite primary end point of cardiovascular (CV) death, non-fatal myocardial infarction or non-fatal stroke by 13% versus placebo (95% confidence interval [CI]: 0.78; 0.97, p=0.01), when added to standard of care in 9,340 adults with type 2 diabetes at high CV risk.
Liraglutide is the only approved glucagon-like peptide-1 (GLP-1) receptor agonist to demonstrate a superior reduction of major CV events versus placebo, both on top of standard of care, in a cardiovascular outcomes trial.
There was a significant 22% reduction in CV death with liraglutide treatment versus placebo (95% CI: 0.66; 0.93, p=0.007) and non-significant reductions in non-fatal myocardial infarction (HR=0.88, 95% CI: 0.75; 1.03, p=0.11) and non-fatal stroke (HR=0.89, 95% CI: 0.72; 1.11, p=0.30).
“These findings are exciting, as it demonstrates that Victoza® (liraglutide) can improve outcomes beyond glucose reduction and weight loss by helping to avoid cardiovascular complications and death in people with type 2 diabetes,” said Dr John Buse, (Director of the Diabetes Care Centre at the University of North Carolina School of Medicine, Chapel Hill, USA) chairman of the LEADER Steering Committee.
All-cause death was significantly reduced by 15% with liraglutide compared to placebo (95% CI: 0.74; 0.97, p=0.02). The expanded CV end point (which included the three components of the primary end point in addition to unstable angina leading to hospitalisation, coronary revascularisation and hospitalisation for heart failure) was significantly reduced by 12% with this treatment compared to placebo (95% CI: 0.81; 0.96, p=0.005).
From a mean baseline of 8.7% (both groups), there was a greater reduction in HbA1c with liraglutide versus placebo, both on top of standard of care, at three years (estimated treatment difference [ETD]: -0.40%, 95% CI: -0.45; -0.34). Weight loss was also sustained over three years with the drug treatment versus placebo (ETD: -2.3 kg, 95% CI: -2.5; -2.0). Mean baseline weight was 91.9 kg and 91.6 kg, respectively.
Systolic blood pressure was 1.2 mmHg lower and diastolic pressure 0.6 mmHg lower with liraglutide versus placebo although heart rate was 3 beats per minute higher with liraglutide treatment. The proportion of adults experiencing adverse events was similar between the treatment and placebo groups (62.3% versus 60.8%, respectively). The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was non-significantly lower in the treatment group than in the placebo group.