Barcelona, Still Healing, Welcomes ESC Congress

August 21, 2017

BARCELONA, SPAIN — Cardiologists from across the globe will soon descend on the Fira Gran Via for nearly 5 days of networking, the latest insights on their craft, and a show of solidarity with this city, ever the proud host to the world's students, tourists, and other celebrants of civilization but now healing from wounds inflicted by a violent, hateful few.

Among Barcelona's many gifts to science and culture are Pablo Casals and José Carreras, Gaudi's La Sagrada Familia and Miro's El Carnaval de Arlequín , and Dr Joan Massagué and Dr Valentin Fuster, and starting August 26 it will present the European Society of Cardiology (ESC) 2017 Congress.

Several studies featured in the late-breaking clinical-trials series of presentations have tipped their hands with announcements that they've "met their primary end point," but such sketchy top-line data usually replace questions with more questions.

Those presentations, all slated for the cavernous main auditorium (Barcelona Room), feature a factor Xa inhibitor potentially as a supplement or replacement for aspirin in chronic CAD, yet another novel approach to lipid modification, and potentially an entirely new way to intervene on the inflammatory process for secondary MI prevention.

Selected highlights of the late-breaking clinical trials and other featured presentations:

Hotline: Late-Breaking Clinical Trials 1, Sunday, August 27, 11:00–12:35

Statins still reign, but efforts to find novel pathways for stemming CAD progression and preventing ACS events, having largely succeeded with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, may have scored again with an agent that targets inflammatory cytokines.

LBCT 1 will feature primary results of the phase 3 Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS), which randomized about 10,000 survivors of acute MI and elevated inflammatory biomarkers to treatment with canakinumab (Ilaris, ACZ885; Novartis) or placebo on top of standard care.

Two months ago, Novartis turned heads by announcing that the trial met its primary end point of major adverse cardiovascular events (MACE), a composite of CV death, nonfatal MI, and stroke at 3 years.

In a twist on the usual regulatory pathway for a new potential CV drug, canakinumab, a monoclonal-antibody inhibitor of interleukin-1beta, is already approved on both sides of the Atlantic for several indications with autoinflammatory components that are far less prevalent than secondary CVD prevention.

For all the excitement about its use in cardiovascular disease, canakinumab, an immunosuppressant, hasn't been without controversy. In 2011 the US Food and Drug Administration refused to approve canakinumab for acute gout episodes due to a poor safety profile, leading a public-interest group to ask the agency to halt all current trials using the drug.

The same LBCT 1 session will feature results from the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial, which won't be entirely a surprise. In February the sponsoring company announced that the study, which compared antithrombotic regimens containing rivaroxaban (Xarelto, Bayer/Janssen) with aspirin alone in 27,395 patients with stable CAD or peripheral artery disease (PAD) was halted a year before its planned end date.

The primary end point of MI, stroke, or cardiovascular death "reached its prespecified criteria for superiority," it was said, but there was no word as to which of the randomization arms with rivaroxaban—alone or paired with aspirin—proved superior.

Three years ago, the US FDA refused to approve rivaroxaban for secondary prevention in patients with ACS, following the recommendation of its advisory panel.

Following those trials at the LBCT 1 session, the RACE 3 trial randomized about 250 patients with "early" symptomatic persistent atrial fibrillation (AF) and mild to moderate heart failure to guidelines-recommended rhythm control or to an "aggressive upstream rhythm-control" approach that included aldosterone antagonists and statins, dietary changes, counseling, and cardiac rehabilitation.

The study, with a primary end point of maintenance of sinus rhythm while on assigned therapy at 1 year after electrical cardioversion, reflects a number of recent studies pointing to a benefit from exercise, other lifestyle changes, and weight loss in managing AF.

Next on the schedule, the CASTLE-AF trial had a planned enrollment of about 420 patients with AF, an LVEF ≤35%, and heart failure of NYHA functional class 2 or higher, who had been implanted with dual-chamber defibrillators (ICDs) with remote monitoring.

The unblinded trial randomized patients to receive standard therapy with or without RF ablation for pulmonary-vein isolation of their arrhythmia. Patients were followed at least 3 years.

A tiny 2014 study provided a hint that AF ablation in similar patients may greatly improve ventricular function, showing a mean LVEF rise of about 18 points and mean NYHA class improvement from 3.2 to 1.8 over more than 2 years.

Hotline: Late-Breaking Clinical Trials 2, Monday, August 28, 11:00–12:48

Another factor Xa inhibitor has been evaluated as a substitute for vitamin K antagonists (VKAs) or parenteral anticoagulants in patients slated for electrical AF cardioversion. In the EMANATE trial, with a projected enrollment of about 1500, patients were randomized to start on either apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) or an oral VKA or heparin as a prelude to AF cardioversion and followed for the 30-day primary end points of stroke or systemic embolism, major or clinically relevant bleeding, or all-cause death.

Other direct oral anticoagulants (DOACs) that have been studied for the same indication include rivaroxaban and edoxaban (Savaysa/Lixiana, Daiichi Sankyo), and both  were judged as safe and effective as their VKA comparator in their respective studies.

Knowledge may be power, but will it encourage patients with AF to take their oral anticoagulants as prescribed? The Improve Treatment With Oral Anticoagulants in Atrial Fibrillation (IMPACT-AF) trial randomized >2300 patients with documented paroxysmal, persistent, or permanent atrial fibrillation to standard care with or without an "interventional education" component designed to promote adherence to their anticoagulation regimen over 1 year.

The educational part of the study is tailored to "the specific needs of each country." The trial is looking at change in the percentage of patients on oral anticoagulation as the primary end point.

In 2014, when the AVOID trial, with about 440 patients, found that giving supplemental oxygen to patients with acute STEMI seemed to worsen myocardial damage and increase the risk of reinfarction and arrhythmias, it hit against a practice used worldwide for about a century. There had already been observational evidence and published viewpoints questioning the practice, at least in patients who aren't hypoxic. With some dismay, it seemed, observers urged larger trials with harder end points.

Apparently filling that need, the Determination of the Role of Oxygen in Suspected Acute Myocardial Infarction (DETO2X-AMI) trial randomized >6600 patients with symptomatic, troponin, or ECG evidence of acute STEMI, NSTEMI, or unstable angina to receive or not receive supplemental oxygen. The patients, taken from the SWEDEHEART registry, have been followed for a primary end point of 1-year all-cause mortality.

Hotline: Late-Breaking Clinical Trials 3, Monday, August 28, 14:00–15:30

On its publication and meeting presentation in November 2016, the PRECISION trial made a splash by showing celecoxib (Celebrex, Pfizer) as noninferior to ibuprofen and naproxen for CV safety in patients with osteoarthritis or rheumatoid arthritis.

Although the results were met with caution and doubts that the trial would be the final word on celecoxib and safety, PRECISION had more to tell. The LBCT-3 sessions include the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen-Ambulatory Blood Pressure Measurement (PRECISION-ABPM) substudy, which has compared the BP effects of the three NSAIDs.

Also at LBCT-3: The Left Atrial Appendage Closure During Open-Heart Surgery (LAACS) study, with its approximately 200 randomized patients, is looking at whether surgical LAA closure added to another planned cardiac surgery will lower the risk of stroke or number of cerebral microinfarcts by MR imaging. An analysis from the STS Registry recently saw that adding LAA closure in such cases could reduce the risk of thromboembolism and mortality, but randomized trials have been lacking.

Hotline: Late-Breaking Clinical Trials 4, Tuesday, August 29, 08:30–10:00

LBCT-4 features the Randomized Evaluation of the Effects of Anacetrapib Through Lipid Modification (REVEAL) outcomes study of anacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, which was given to high-risk CAD patients already on a statin.

Other CETP inhibitors have had a disappointing history, but things may be looking up for anacetrapib. Two months ago Merck announced that REVEAL had met its primary end point, meaning treatment with the drug on top of statins reduced the risk of a composite of coronary death, MI, and coronary revascularization.

The trial's >30,000 randomized patients were considered high risk in that they had to have a history of MI or clinically manifest cerebrovascular or peripheral artery disease or diabetes with symptomatic CAD.

In the EMPATHY study planned for the same session, >5000 patients with dyslipidemia and diabetic retinopathy but no CAD were randomized to either standard-intensity or high-intensity statin therapy, to LDL-C targets of >100 and <120 mg/dL or <70 mg/dL, respectively. Patients were followed for the primary end point of a composite of CV disease or CV death.

On the oft-noted idea that symptom relief is of paramount importance to patients with AF, the randomized Catheter Ablation Compared With Pharmacological Therapy for Atrial Fibrillation (CAPTAF) trial is noteworthy for its primary end point, health-related quality of life at 12 months. It randomized more than 100 patients without heart failure to undergo catheter ablation of AF or to receive drug therapy for rate or rhythm control; they received an implanted rhythm monitor 2 months before randomization. AF burden, clinical outcomes, functional capacity, resource utilization, and other secondary end points are being followed for 4 years.

Would more cases of AF be identified in the community if people with risk factors for AF screened themselves with a smartphone-based ECG monitor, and would it make a difference to stroke risk or other clinical outcomes?

The randomized Remote Heart Rhythm Sampling Using the AliveCor Heart Monitor to Screen for Atrial Fibrillation (REHEARSE-AF) pursued those questions in patients who regularly used such a device and phone app (AliveCor, now Kardia Mobile; AliveCor) and sent their ECG readings to clinicians twice a week for 12 months.

Hotline: Late-Breaking Registry Results 1, Tuesday, August 29, 11:00–12:30

Research based on ongoing registries also get their time in the Barcelona sun, including the first of two "late-breaking registry-results" sessions that will open with two analyses from the massive Prospective Urban Rural Epidemiology Study (PURE) study.

The first presentation, as described by the ESC, "will reveal dose-response effect of fruit, vegetable, and legume intake on cardiovascular disease and mortality" in the PURE cohort of about 135,000 people without CV disease from 18 countries worldwide.

The subsequent presentation, from the PURE nutrition study, is billed as showing that "dietary fats are protective but carbohydrates are harmful." Both PURE analyses are follow-ups of sorts to a meeting presentation by the same group a year ago suggesting that efforts to reduce saturated fat in the diet won't improve lipid CV-risk markers if those fats are largely replaced in the diet by carbohydrates.

A following presentation asks, how much did it matter when guidelines shifted from clopidogrel to ticagrelor (Brilinta/Brilique, AstraZeneca) as the preferred P2Y12 inhibitor to accompany aspirin in dual antiplatelet therapy (DAPT) in the setting of PCI for ACS?

The switch was made on the basis of clinical trials (including PLATO in 2009) giving the newer P2Y12 inhibitor the edge in patients receiving bare-metal or early-generation drug-eluting stents (DES), note investigators from the Change of Dual Antiplatelet Therapy in Patients With Acute Coronary Syndrome (CHANGE DAPT), scheduled for the this registry session.

They're slated to report their prospective single-center registry looking at a similar issue in 2062 ACS patients who received contemporary drug-eluting stents (DES) either before or after the guidelines made ticagrelor preferred for their DAPT. The two cohorts were followed for a year for the composite primary end point of all-cause death, any MI, stroke, or major bleeding.

Clinical Trial Update 2, Tuesday, August 29, 16:30–18:00

The second of the meeting's two "clinical-trial update" sessions (both to be held at the Dali location at the Hub) will feature a revisit of the PRECISION trial, the safety comparison of celecoxib, naproxen, and ibuprofen whose primary results emerged last year.

Following PRECISION is a subanalysis from the previously reported GLAGOV trial, which saw significant overall regression of atheromatous lesions in patients taking the PCSK9 inhibitor evolocumab (Repatha, Amgen) in addition to statins, accompanied by steep drops in LDL-cholesterol levels.

Whereas that primary analysis looked at changes in atheroma volume, the new analysis in Barcelona is described as looking at atheroma composition. How evolocumab might change the constituents of the lesions it shrinks could say a lot about the drug's potential effect on risk of plaque rupture.

Afterward, there is a subanalysis from EMPA-REG OUTCOME empagliflozin (Jardiance, Boehringer Ingelheim) trial, which 2 years ago—along with the more recent LEADER study of liraglutide (Victoza, Novo Nordisk)—helped launch an era of cardiovascular indications for agents that had been primarily for diabetes. The new EMPA-REG OUTCOME analysis promises to show that empagliflozin was associated with significantly reduced mortality in diabetic patients with a history of CABG surgery.

Las Ramblas, Barcelona

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