March 28, 2016

CHICAGO, IL — It's an award-winning musical, a brassy 70s-era rock band, and for 3 eventful days starting April 2, Chicago is host to the American College of Cardiology 2016 Scientific Sessions, including >2400 original research presentations, culled from more than twice as many submissions, the college has said.

Rolling out the list of scheduled late-breaking clinical trials (LBCTs) for reporters a few weeks ago, ACC president Dr Kim A Williams (Rush University, Chicago, IL) also ardently noted a theme the college is showcasing this year, population health with emphasis on lifestyle and prevention. He pointed to the annual Simon Dack Lecture, this year named Population Health: Is It the Secret Sauce? and slated for April 2, 2016, 8:40 am by Dr David B Nash (Thomas Jefferson University, Philadelphia, PA), and a three-part, half-day session with the Madison-Avenue-meets-Hunter-Thompson title Lifestyle Medicine: A Little Less Drug, a Little More Sex, and a Lot More Rock and Roll, April 2 in the afternoon.

Also highlighted that day, Williams noted: Food and Drug Administration commish and cardiology native son Dr Robert Califf will present the Eugene Braunwald Lecture on Evidence and the Practice of Cardiovascular Medicine, a kind of triumphant return to his community after at least 5 months dangling on a senatorial string and about 1 month in his new role.

Then there are at least two-dozen LBCTs and featured-research presentations, selected from a pool of 115 applicants for the coveted spots on the 3-day agenda, awarded for what customarily seems like a range of reasons, from preeminent clinical relevance to promising new approaches to old problems.

Saturday, April 2, 9:05–10:00 am

A perfect fit for the population-health theme, one of the most ambitious study presentations at the sessions will be a three-parter on the expansive primary-prevention third Heart Outcomes Prevention Evaluation (HOPE-3) trial, an exploration of rosuvastatin, candesartan plus hydrochlorothiazide (HCT), and both regimens together in a cohort >12,000-strong.

The trial's women aged 60 or older and men at least 55 were initially without a history of cardiovascular disease or stroke and said to be at moderately increased risk with at least one additional CV risk factor such as current or recent smoking, low HDL cholesterol, poor glycemic control, renal dysfunction, or family history of coronary heart disease.

HOPE 3, which spanned >20 countries and a wide range of cultures, is noteworthy for a population that is nearly one-half women and "a majority" that is of non-European descent, according to program committee chair Dr Athena Poppas (Cardiovascular Institute at Rhode Island Hospital, East Providence, RI), addressing the media. HOPE-3, she said, "is expected to demonstrate that combined lipid-lowering and blood-pressure lowering will substantially lower the risk for cardiovascular diseases and may substantially change our approach to cardiovascular prevention."

If population health and lifestyle is a dominant theme at the ACC sessions, it's certainly rivaled by transcatheter aortic-valve replacement (TAVR) and its technique extended to other heart valves. Only the first of a number of TAVR sessions in the LBCT spotlight, the second Placement of Aortic Transcatheter Valves (PARTNER 2) trial randomized >5600 patients with symptomatic aortic stenosis stratified by risk status, inoperative or high surgical risk, and intermediate surgical risk. They underwent either surgical aortic-valve replacement (AVR) or TAVR using the Edwards Sapien XT or Sapien 3 transcatheter valve.

According to Dr Craig Smith (Columbia University, New York, NY), scheduled PARTNER 2 presenter speaking to heartwire from Medscape, "In the US and especially Europe, TAVR has already deeply penetrated the moderate- to intermediate-risk population, which was glaringly obvious when the CoreValve High-Risk Study here enrolled average [operative risk score] STS 7.3." And the STS/ACC TVT registry with its lower STS scores is "further proof" that the TAVR evidence base hasn't been exclusively the tougher patients. "Unless PARTNER 2 shows dramatic superiority for AVR, that trend will continue into low risk."

And at an LBCT session the following day, April 3 at 11:30 am, Dr Vinod H Thourani (Emory University, Atlanta, GA) is slated to present 1-year data from a propensity-matched analysis of intermediate-risk patients who underwent TAVR or standard aortic-valve surgery. This trial and PARTNER 2 are looking at both clinical and echocardiographic outcomes, said Poppas at the media presentation.

Sunday, April 3, 8:00–9:15 am

There's more in store in Chicago from a major PCSK9-inhibitor trial than merely the "positive" primary outcome reported last month.

The third Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects (GAUSS-3) trial "met its co–primary end points," which would mean that LDL-C levels fell significantly further on evolocumab (Repatha, Amgen) than on ezetimibe over 24 weeks in statin-intolerant patients.

But that's not the spoiler it might be, thanks to the trial's crossover run-in period. Because of that unusual feature, GAUSS 3 could go a long way toward answering one of cardiology's nagging questions about a mainstay therapy: just how common is statin intolerance, which typically means muscle pain or spasms.

"I would say that we encounter this in clinical practice more than the statin trials would lead us to believe," according to Dr Jeffrey Kuvin (Tufts University School of Medicine (Boston, MA). When patients on statins report muscle aches and pains, the practice is to try to rule out the drugs as the cause but "at the end of the day, it is often the statins," he said at the recent press-conference preview of the ACC session, for which Kuvin is scientific program vice chair.

The primary intent of GAUSS 3 was to compare two nonstatin lipid-modifying alternatives in patients judged statin-intolerant by the usual criteria, but the trial also prospectively explored the nature and true prevalence of statin intolerance itself, presenter Dr Steven E Nissen (Cleveland Clinic, OH) explained to heartwire . The trial's >500 patients started with a double-blind run-in period in which they received atorvastatin 20 mg/day or placebo for 10 weeks, followed by a 2-week washout period, followed by crossover to placebo or atorvastatin 20 mg/day, respectively.

The subsequent primary randomization to evolocumab vs ezetimibe, each accompanied by the other's placebo, was reserved only for those with symptoms of statin intolerance on atorvastatin during the run-in phase. And anyone with such symptoms on placebo, Nissen said, was excluded from the PCSK9-inhibitor part of the trial.

A study in the same LBCT session is trying to pin down a more functional clinical-practice definition for familial hypercholesterolemia (FH), thought to be caused by a single mutation in "any of at least three genes, LDLR, APOB, PCSK9," according to Dr Amit V Khera (Massachusetts General Hospital, Boston). Clinicians tend to assume that severely elevated LDL-C is due to FH, he told heartwire , but often it can instead stem from lifestyle, multiple common gene variants with small individual effects on LDL-C, or secondary causes like hypothyroidism.

"Few previous studies have used gene sequencing of relevant genes to determine the prevalence of an identifiable FH mutation in individuals selected only on the bases of an elevated LDL cholesterol," Khera said. The current study is not only looking at the prevalence of FH mutations in persons with severe hypercholesterolemia, it should "determine whether CAD differs according to mutation status beyond an observed LDL cholesterol." That could clarify the expected diagnostic yield and risk-stratification potential of gene sequencing "for any given observed LDL cholesterol."

Also in the LBCT bloc: findings from the Stepathlon Cardiovascular Health Study, based on the Stepathlon program, a "global mobile health, mass-participation physical-activity intervention" looking at the effects of exercise on chronic diseases, obesity, and mental health. As described by Poppas at the press briefing, the Stepathlon presentation will cover 70,000 participant in >60 countries that have been organized into teams by coordinating centers.

The LBCT session will also feature the Chest Pain Choice (CPC) trial, which randomized >900 patients presenting to the emergency department with chest pain and under consideration for further testing. They were assigned to usual care or to patient-physician shared decision making with the use of a "Chest Pain Choice Decision Aid" to explore whether the decision tool can promote patient engagement and satisfaction without worsening outcomes—or "to understand the implications of overtesting," as Poppas described it. "Patients in the study actually worked with the physicians to plan their testing for their chest discomfort."

Sunday, April 3, 10:45 am–12:00 noon

Two LBCT presentations, one study: the third Danish Study of Optimal Acute Treatment of Patients with ST-segment Elevation Myocardial Infarction (DANAMI 3) looked at two strategies for protecting the myocardium against reperfusion injury from primary PCI for their effects on clinical outcomes, including all-cause mortality, over 2 years. About 2000 patients with STEMI were randomized to conventional primary PCI with a drug-eluting stent (DES), to the same primary PCI plus ischemic postconditioning (four cycles of alternating reocclusion and reperfusion in the infarct-related artery [IRA] achieved with an angioplasty balloon), or to IRA recanalization achieved with a guidewire, thrombectomy catheter, or low-profile balloon followed 2 days later by DES stenting.

The postconditioning maneuver may protect the myocardium from the effects of abrupt reperfusion injury by "creating a smoother reperfusion profile," one of the presenters, Dr Thomas Engstrøm (Rigshospitalet University of Copenhagen, Denmark) told heartwire , whereas deferred stenting may attenuate distal embolization associated with the conventional procedure. Those possible benefits are supported by prior proof-of-concept studies, he said.

In the same myocardial-protection vein, the international Early-BAMI trial randomized 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. As lead investigator Dr Vincent Roolvink (Isala Klinieken, Zwolle, the Netherlands) described for heartwire , the trial randomized 638 patients with the original primary goal of 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), "to reduce sample size, and infarct size could be measured more precisely with MRI." Ultimately only 342 of the randomized patients, or 54%, underwent MRI, he said.

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, according to Roolvink.

Slated for the same LBCT session: a look at the effects of operator procedure volume on outcomes in the prospective STS/ACC TVT registry, which has a projected enrollment of 15,000 patients undergoing TAVR for what is described as severe aortic stenosis, looking primarily at major adverse cardiac and cerebrovascular events over 30 days.

Monday, April 4, 8:00-9:15 am

The name of the randomized Amiodarone, Lidocaine or Placebo Study (ALPS) refers to the question of antiarrhythmic adjuvant for nontraumatic out-of-hospital ventricular fibrillation or pulseless ventricular tachycardia that doesn't respond to a first shock. With an estimated enrollment of 3000, the trial compared the three interventions, including a novel amiodarone preparation, for any effects on survival to hospital discharge.

At the same session's presentation of the FIRE AND ICE trial, cardiac electrophysiologists will ponder a less existential question than that posed by Robert Frost. Some say that paroxysmal atrial fibrillation (PAF) should end by radiofrequency ablation, some say a cryoballoon. The issue is, for safety and efficacy, whether they should favor fire or whether ice would suffice.

Perhaps the choice will not be as stark, the design of the FIRE AND ICE trial calling only for noninferiority. It randomized about 770 patients with symptomatic, drug-refractory PAF to ablation using either hardware modality, following for the primary efficacy end point of clinical failure (including arrhythmia recurrence, a new prescription for antiarrhythmic therapy, or repeat ablation) and a primary safety end point encompassing death, stroke, and other events.

The rhythm-control vs rate-control debate has settled in more or less of a tie in the arena of nonvalvular AF not related to surgery, at least for now; but the same dilemma was put to the test for postoperative AF in trial with a projected enrollment of 520 patients undergoing CABG or surgical valve repair or both. The patients with AF lasting at least 60 minutes occurring within 7 days of surgery were randomized to rate control (amiodarone or direct-current cardioversion) vs rhythm control (beta-blockers, calcium-channel blockers, or digoxin) strategies. The trial is primarily assessing total in-hospital days but also looking at events related to the arrhythmia or the assigned treatment and time to conversion to a stable rhythm.

Rounding out the session is the Coronary Angiography at Risk of Radiocontrast Induced Nephropathy (CARIN) trial, a randomized, placebo-controlled test of CMX-2043 for myocardial and renal protection during coronary angiography. The 361 patients underwent catheterization in the setting of acute coronary syndromes or for suspected disease. CMX-2043 is an experimental modulator of an Akt signal-transduction pathway with antiapoptotic and other cytoprotective effects.

Monday, April 4, 10:45 am–12:00 noon

As the search for effective heart-failure drugs finds success in recent years outside the realm of renin-angiotensin-aldosterone-system (RAAS) inhibitors, the hunt continues within. The last LBCT session is scheduled to open with the randomized Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure (ATMOSPHERE), which compared both monotherapy with the direct renin inhibitor aliskiren (Tekturna, Novartis) and the combination of aliskiren and enalapril with enalapril monotherapy as the control comparator. The trial randomized >7000 patients NYHA class 2-4 heart failure and an LVEF <35% while on a stable dose of ACE inhibitor and followed them for cardiovascular death or heart-failure hospitalization over 4 years.

The trial is distinguished from earlier heart-failure trials with aliskiren, one of which was terminated early for futility, another that failed to show a significant benefit, and both of which showed possible harm from the drug, by featuring a run-in period "to eliminate patients with early intolerance to combination therapy," Dr John JV McMurray (University of Glasgow, Scotland) told heartwire .

In the arena of acute decompensated heart failure (ADHF), the Trial of Ularitide Efficacy and Safety in Acute Heart Failure (TRUE-AHF) is on the schedule, a randomized efficacy and safety evaluation of intravenous ularitide (Cardiorentis) vs placebo in a projected 2152 patients spanning close to 200 centers in North America, South America, and Europe.

Ularitide, according to its company, is a synthetic form of a human natriuretic peptide that promotes both diuresis and natriuresis and vasodilates. The trial is looking at the co–primary end points all-cause mortality and a clinical composite score out to 48 hours.

In an early-March teaser, the cell therapy under study for advanced ischemic heart failure in the ixCELL-DCM trial reportedly "met its primary end point," presumably meaning there was a benefit for shown for mortality, cardiovascular hospitalizations, or unplanned outpatient and emergency-department visits over 12 months. The LBCT agenda includes full results of the trial phase 2 trial, which—as described by the sponsoring company Vericel—tested the transendocardial-catheter injection of ixmyelocel-T, a treatment based on autologous bone-marrow–derived mesenchymal stromal cells and activated macrophages.

In the last of the Monday LBCTs, patients with NYHA class 2-4 systolic heart failure wore an external lung-impedance monitor, the Edema Guard (RS Medical Monitoring), designed to warn of impending pulmonary congestion and alert to the need for adjustment of medical therapy. The IMPEDANCE-HF trial randomized short of 300 patients to treatment guided by standard clinical assessment with vs without the noninvasive monitor and followed them for heart-failure hospitalizations over 12 months.

The two-center single-blind study saw significant reductions in incidence of acute heart failure and cardiovascular hospitalizations and in all-cause and cardiovascular mortality, according to a presentation of preliminary results by Dr Michael Shochat (Hillel Yaffe Medical Center, Hadera, Israel) at the December 2015 International Conference for Innovations in Tel-Aviv. He told heartwire that at the Chicago sessions he will present additional specifics on hospitalizations and mortality and focus more on the monitoring device and details on adjustments to medical therapy.


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