The clinical perspective: news from the American College of Cardiology 2016

ixCELL-DCM Study

In this study bone-marrow cells were extracted and expanded over 2 weeks to increase two key types of mononuclear cells: CD90+ mesenchymal stem cells and CD45+ and CD14+ macrophages (ixmyelocel-T product). The ixmyelocel-T product or placebo were then randomly assigned to 126 patients with NYHA class 3/4 symptomatic heart failure due to ischemic cardiomyopathy with an aLVEF of 35% or less and an ICD in place. Patients were also required to have one of three high-risk characteristics: heart-failure hospitalization within 6 months, elevated brain natriuretic peptide (BNP) or N-terminal proBNP, or a 6-minute-walk <400 m. At 1 year, patients treated with ixmyelocel-T had a 37% relative reduction in the risk of all-cause mortality, cardiovascular-related hospital admissions, and unplanned clinic visits to treat acute decompensated heart failure. However, the multicellular therapy had no effect on the secondary end points of LVEF or left ventricular volumes,
Patel AN, Henry TD, Quyyumi AA, et al. Ixmyelocel-T for patients with ischemic heart failure: A prospective, randomized double-blind trial.

Lancet 2016; DOI:10.1016/S0140-6736(16)30137-4.  

FIRE AND ICE trial

The FIRE AND ICE trial randomized 762 of paroxysmal atrial fibrillation (AF) patients in eight European countries to pulmonary-vein isolation by cryoballoon (Arctic Front catheter) ablation with phrenic nerve pacing or radiofrequency (ThermoCool catheter) ablation with 3D electroanatomical mapping. The primary efficacy end point of time to first recurrence of AF >30 s, atrial flutter, or atrial tachycardia, use of antiarrhythmic drugs, or reablation occurred in 34.6% of the cryoablation group and 35.9% of RFC patients. The trial demonstrated that efficacy and safety of cryoballoon ablation was on a par with radiofrequency catheter ablation for the treatment of paroxysmal atrial fibrillation. Importantly, about 40% of patients were women, well beyond the typical 20% enrollment for ablation trials, which makes the results generalizable across sexes.
Kuck, KH, Brugada J, Fürnkranz A, et al. Cryoballoon or radiofrequency ablation for paroxysmal atrial fibrillation.

N Engl J Med 2016. DOI:10.1056/NEJMoa1602014.

DANAMI 3

The third Danish Study of Optimal Acute Treatment of Patients with ST-segment Elevation Myocardial Infarction . This trial assessed whether deferred stent implementation reduces the risk of jeopardized myocardial vascular flow and improves the clinical course of STEMI patients compared with conventional PCI. The two strategies were evaluated in 1215 patients presenting with chest pain for less than 12 hours and ST-segment elevation >0.1 mV in at least two contiguous leads in whom a stabilized TIMI 2–3 flow could be achieved after minimal acute manipulation. Their mean age was 62 years, and three-quarters were men. After a median of 42 months, deferred stenting did not improve the composite primary end point of all-cause death, hospitalization for heart failure, reinfarction, or TVR compared with immediate stenting (hazard ratio [HR] 0.99; P=0.92).
Kelbæk H, Høfsten DE, Køber L, et al. Deferred versus conventional stent implantation in patients with ST-segment elevation myocardial infarction (DANAMI 3-DEFER): An open-label, randomized controlled trial.

Lancet 2016. DOI.org/10.1016/S0140-6736 (16)30072

Very High LDL Seldom Caused By FH Gene Variants

In this study, the researchers aimed to first assess the diagnostic yield of genetic testing for Familial Hypercholesterolemia (FH) genes in this population of subjects selected only on the basis of severe hypercholesterolemia, and second to determine whether the CAD risk varies according to FH mutation status within a given stratum of LDL cholesterol. Three genes causative for FH—LDL receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9)— were sequenced in 26,025 participants from seven CAD case-control studies (5540 CAD cases and 8577 controls free of CAD) and five prospective cohort studies including 11,908 participants. The researchers found that only 1.7% have a known FH mutation, a low diagnostic yield.

Khera AV, Won HH, Peloso GM, et al. Diagnostic yield of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia.

J Am Coll Cardiol 2016; DOI:10.1016/j.jacc.2016.03.520. 

GAUSS-3

The third Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects.  Within this study, participants were randomized to either receive atorvastatin 20 mg or placebo for 10 weeks and then, after a 2-week washout, switched treatment for an additional 10 weeks to determine whether they really did have statin intolerance. A total of 43% reported having intolerably painful muscle symptoms while taking the statin but not the placebo. However, 27% reported symptoms with the placebo but not atorvastatin, and 10% reported symptoms with both treatments. Next, 218 of the participants who reported adverse muscle symptoms while taking atorvastatin during phase 1 moved on to the study's 24-week phase 2 and were randomized 2:1 to injectable evolocumab (PCSK9 inhibitor) 420 mg/month plus oral placebo vs oral ezetimibe 10 mg/day plus injectable placebo. The evolocumab group had a more than 50% mean reduction in LDL-C levels from baseline to the average of weeks 22 and 24 and from baseline to week 24 (co–primary end points) vs the ezetimibe group. During this second phase of the trial, muscle-related events were reported by 21% and 29% of the evolocumab and ezetimibe groups, respectively, but only 0.7% vs 7% discontinued use of the treatment because of muscle symptoms. This trial suggests that six-month treatment with PCSK9 inhibitor evolocumab can dramatically reduce LDL-cholesterol levels in patients with both uncontrolled LDL-C levels and statin intolerance.
Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance.

JAMA 2016; DOI:10.1001/jama.2016.3608

HOPE-3 trial

Heart Outcomes Prevention Evaluation.  HOPE-3 included 12,705 intermediate-risk patients (without CVD) from 21 countries that were randomized to statin therapy and blood-pressure-lowering therapy in a 2x2 factorial design. In HOPE-3's first arm, those who received BP-lowering treatment, consisting of 16 mg/day candesartan and 12.5 mg/day hydrochlorothiazide, did not significantly reduce occurrences of a composite of CV-related death, nonfatal MI, or nonfatal stroke (the first co-primary outcome) a mean of 5.6 years later compared with those who received placebo (4.1% vs 4.4%, respectively). The second co–primary outcome, which added heart failure, cardiac arrest, or revascularization to the composite, was also not significantly different between the groups (4.9%  vs 5.2%).However, pre-specified subgroup analysis, which divided baseline systolic BP into thirds, showed that the participants with upper-third measurements (>143.5 mm Hg) receiving candesartan/hydrochlorothiazide did meet the co–primary outcomes.

In the second arm, the participants who were randomized to 10 mg/day rosuvastatin also met both primary outcomes vs placebo (P=0.002 and P<0.001 for both group comparisons, respectively) and had a 24% lower risk for CV events.

In conclusion, in a large group of intermediate-risk patients without CVD, treatment with a low-dose statin plus an angiotensin receptor blocker and thiazide diuretic significantly reduced the risk of cardiovascular events when compared with placebo.

Lonn EM, Bosch J, Lopez-Jaramillo P, et al. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease.

N Engl J Med 2016; DOI:10.1056/NEJMoa1600175

ALPS trial

Amiodarone, Lidocaine or Placebo Study. The ALPS trial assessed more than 3000 patients who had an out-of-hospital arrest caused by pulseless ventricular tachycardia or shock-refractory ventricular fibrillation (VF). It showed that those who received a modified formulation of amiodarone that reduces hypotensive effects (Nexterone, Baxter Healthcare) had a statistically nonsignificant 3.2% higher rate of survival than those who received saline placebo (primary outcome, P=0.08); and those receiving lidocaine had a 2.6% higher rate vs placebo (P=0.16). The difference between the amiodarone vs lidocaine groups was only 0.7%. In addition, rates of favourable neurologic function at discharge were similar between the treatment groups: 19% of those receiving amiodarone, 18% of those receiving lidocaine, and 17% of those receiving placebo. However, in pre-specified subgroup analysis of the participants who had a bystander-witnessed cardiac arrest, survival to discharge was significantly higher in those receiving amiodarone vs placebo (P=0.04) and those receiving lidocaine vs placebo (P=0.03). There were no between-treatment differences for those with unwitnessed arrests.. In conclusion, the use of either of two antiarrhythmic medications does not significantly improve survival to discharge or neurologic outcomes over placebo in patients who have an out-of-hospital cardiac arrest.
Kudenchuk PJ, Brown SP, Daya M, et al. Amiodarone, lidocaine, or placebo in out-of-hospital cardiac arrest.

N Engl J Med 2016; DOI:10.1056/NEJMoa1514204.

PARTNER 2 trial

The second Placement of Aortic Transcatheter Valves trial. Within this trail 2032 patients with severe symptomatic aortic stenosis underwent transcatheter aortic-valve replacement (TAVR) or surgical aortic-valve replacement (AVR) between December 2011 and November 2013. The mean age was 81 years at the time of implantation. Patients were considered to be at intermediate risk after clinical assessment by a multidisciplinary heart team at 57 centres. The mean Society of Thoracic Surgeons score was 5.8%, with 81.3% having a score between 4% and 8%. At 2 years, the primary composite end point of all-cause death or disabling stroke occurred in 19.3% with TAVR and 21.1% with surgery in the intention-to-treat population (hazard ratio [HR] 0.89; P=0.25).The results of this trial suggest that TAVR is a reasonable alternative to AVR in intermediate-risk patients.
Leon M, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients.

N Engl J Med 2016. DOI: 10.1056/NEJMoa151461

Early-BAMI trial

This trial randomized 638 patients with STEMI to receive metoprolol 5 mg or placebo in the ambulance en route and a second such bolus on arrival at a PCI-equipped hospital. The original primary goal was infarct size reduction, as defined by peak troponin at 12 hours; but the primary end point's measure of infarct size was changed in the trial's second year to magnetic-resonance imaging (MRI). Ultimately only 342 of the randomized patients, or 54%, underwent MRI. The trial also looked at treatment effects on malignant ventricular arrhythmias, bradycardia, hypotension and shock, along with major adverse cardiac events at 30 days, as secondary end points. The authors concluded that, in a non-restricted STEMI population, early intravenous metoprolol before PCI was not associated with a reduction in infarct size. Metoprolol reduced the incidence of malignant arrhythmias in the acute phase and was not associated with an increase in adverse events.

Roolvink V, Ibanez B, et al; EARLY BAMI investigators. J Am Coll Cardiol. 2016 Mar 29. pii: S0735-1097(16)32401-9. doi: 10.1016/j.jacc.2016.03.522