An Apple a Day? And Other Questions Answered at ACC.19

March 11, 2019

New Orleans was forced to wait until March 5 for its Mardi Gras blow-out this year, its appetite for revelry having grown so intense that another big celebration was called for right away.

Just over a week later, the American College of Cardiology (ACC) 2019 Scientific Session (ACC.19) will do its part à laisser les bons temps rouler. The society's latest stopover in the Crescent City starts Saturday, March 16.

The Apple Heart Study (AHS) has been given an entire Late-Breaking Clinical Trials (LBCT) session all to itself, in a showcase time slot (Saturday, 9:00–10:00 AM, Main Tent, Great Hall) atop the 3-day meeting.

Was it a nod to its colossal population sample of up to one-half million people? Or its potential for dramatically altering the nature, and reach, of screening for atrial fibrillation (AF)? Or, perhaps, it honors the trial's attempt to leverage one of the great addictions of the modern age, personal electronics, for good rather than evil.

For the observational study, adults armed with an Apple Watch and an iPhone model 5s or later were invited to download the AHS app and to wear the iconic smartwatch as a heart-rhythm monitor. If the watch senses possible AF, the participant might wear an electrocardiography (ECG) patch for up to week to confirm any arrhythmia. The trial aims to see how effective and reliable the AHS app is at detecting AF, and how it might possibly affect overall care by providers.

A consumer-oriented Apple ECG App that functions similarly — it can monitor pulse rate, take essentially a single-lead electrocardiogram, and deliver notifications of heart-rhythm abnormalities — became available to the public in December 2018.

"We're approached by patients on a regular basis who are using these devices and are asking for our feedback as to whether or not they are helpful. We don't know if they're helpful for screening or not," Andrew Kates, MD, Washington University, St. Louis, and chair of ACC.19, said at a recent media briefing.

Importantly, he said, the Apple Heart Study should "help us decide as clinicians how to use digital or wearable devices in screening patients."

The technology might prove especially useful for people with asymptomatic AF who could not otherwise be referred for oral anticoagulation (OAC), Pamela B. Morris, MD, Medical University of South Carolina, Charleston, and vice-chair of ACC.19, pointed out at the press conference.

"If this study shows that there's good accuracy in detecting afib, then it could encourage patients to get medical attention early and begin therapy before they have a catastrophic event," she said.

"On the other hand, if the devices don't accurately detect the rhythm, and possibly create artefacts, then it could result in unnecessary concern on the part of consumers and unnecessary healthcare visits or diagnostic testing."

Later the same day, the first Featured Clinical Research session (Saturday, 12:15–1:45 PM, La Nouvelle C) is to feature the Home Treatment of Pulmonary Embolism (HoT-PE) cohort study of factor Xa inhibitor rivaroxaban (Xarelto, Bayer/Janssen Pharmaceuticals) in patients with low-risk pulmonary embolism (PE).

The study's 1050 patients were started on OAC in the hospital, discharged within 2 days, and followed for 3 months for the primary end point of symptomatic recurrent venous thromboembolism (VTE) or PE-related mortality.

Other presentations slated for the session include:

  • The phase 2 PANACHE placebo-controlled safety and efficacy study of the partial adenosine A1 receptor agonist neladenoson bialanate in patients with heart failure and preserved ejection fraction (HFpEF).

  • The open-label extension phase of PIONEER-HF , which had seen natriuretic peptide levels decline more after predischarge initiation of sacubitril/valsartan (Entresto, Novartis), compared with enalapril, in patients stabilized after a bout of decompensated heart failure with reduced ejection fraction (HFrEF).

  • One-year primary outcomes from the Hopeful Heart Trial , which explored a collaborative-care model for comanagement of depression and heart failure.

  • The CODIACS-QoL evaluation of whether screening for depression in patients with acute coronary syndrome (ACS) makes a difference to quality-of-life and cost-effectiveness measures.

The next day's ACC/NEJM Late-Breaking Clinical Trials II session (Sunday, 8:00–9:15 AM, Main Tent, Great Hall) will feature two studies comparing transcatheter aortic-valve replacement (TAVR) and surgical aortic-valve replacement (SAVR) in patients judged to be at low surgical risk.

The PARTNER 3 trial has compared TAVR using the Edwards Lifesciences SAPIEN 3 valve and SAVR in patients at least 19 years of age with severe calcific aortic stenosis, following them for mortality, stroke, or rehospitalization.

A similar trial using Medtronic's Evolut transcatheter aortic valve will also be presented; it has enrolled both children and adults, its primary results not due for another 2 years.

"These trials are potentially practice changing and will give us meaningful insights into the relative value of the transcatheter vs the surgical approach, particularly in younger patients who might be good candidates for conventional surgery," Morris said.

A key issue is whether TAVR valves can compete with surgical implants for longevity "as we begin to use these valves in younger, lower-risk patients."

TAVR trials typically have had limited follow-up times, as will these two studies looking at short-term outcomes with the Edwards and Medtronic valves. "I think one of the really important issues that will be discussed with these two trials is, what will be the lifelong, long-term durability?" Morris added.

Other presentations in the session:

  • Two follow-up analyses from the COAPT trial, which saw a significant decline in heart failure hospitalizations in patients with secondary mitral regurgitation who received the transcatheter Abbott MitraClip on top of guideline-directed meds. On tap at ACC.19 are echocardiographic and quality-of-life substudies.

  • An analysis from the STS/TVT Registry on TAVR using the Sapien 3 in patients with bicuspid aortic stenosis.

Later, the ACC/JAMA Late-Breaking Clinical Trials III session (Sunday, 10:45 AM–12:00, Main Tent, Great Hall) leads off with the AUGUSTUS trial, which explored the thorny question of whether to add OAC or another antiplatelet to single-agent antiplatelet therapy in patients with nonvalvular AF and a history of MI or percutaneous coronary intervention (PCI).

The open-label trial's 2×2 randomization scheme placed patients into four groups by treatment — apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), warfarin, aspirin, or an aspirin placebo — all on top of a P2Y12 inhibitor such as clopidogrel.

Recently introduced guidelines recommend against "triple therapy" with aspirin, a P2Y12 inhibitor, and OAC in most such cases, but give a IIa recommendation to the kind of "double therapy" that AUGUSTUS is putting to the test.

Scheduled for the same time session:

  • The World-Wide Randomized Antibiotic Envelope Infection Prevention Trial (WRAP-IT ), a test of whether surrounding de novo or replacement implantable pacemakers or defibrillators with the TYRX Absorbable Antibacterial Envelope (Medtronic) can cut the risk for device-related infection. Observational data suggest it can, but WRAP-IT is the device's more definitive large, randomized trial.

  • Longer-term follow-up results from the POET trial, which saw no important downsides, whether for safety or efficacy, over 6 months to switching stabilized patients with left-sided endocarditis from intravenous to oral antibiotic therapy within days of entering the hospital.

  • The "final analysis" from MOMENTUM-3 , which had compared Abbott's HeartMate 3 continuous-flow ventricular support pump with a magnetically levitated impeller to the company's long-established continuous-axial-flow pump, the HeartMate II. HeartMate 3 was approved for destination therapy in end-stage heart failure largely on the basis of the trial's 6-month results.

  • One-year outcomes from the CardioMEMS Post-Approval Study, which is scheduled to run until 2020. The CardioMEMS (Abbott/St. Jude Medical) implantable pulmonary artery pressure monitor had previously been associated with 30% fewer deaths when used to guide medical management of chronic heart failure, compared with a historic control group. Its use was followed by significantly fewer heart failure hospitalizations in the randomized CHAMPION trial.

Sunday afternoon in the Featured Clinical Research II: Interventional session (2:00–3:30 PM, Room 206):

  • The DEFINE PCI Trial, a prospective cohort study of patients with successful PCI exploring how testing for residual ischemia by the instantaneous wave-free ratio (iFR) index compares to structural outcomes by quantitative coronary angiography.

  • One-year outcomes from the ADVANCE Registry , which explored the effect of fractional flow reserve (FFR) derived from coronary computed tomographic angiography (CTA) on downstream management, including use of invasive angiography and PCI.

  • The "First Randomized Human Experience with a Ticagrelor Reversal Agent," which tested 10 dosage levels of the agent, PB2452 (PhaseBio Pharmaceuticals) in 64 healthy subjects, with and without pretreatment with ticagrelor (Brilinta/Brilique, AstraZeneca).

  • The Microvascular Reperfusion Utilizing Sonothrombolysis in Acute Myocardial Infarction (MRUSMI ) trial, which randomized patients with acute ST-segment-elevation MI (STEMI) to receive standard management, including PCI, with or without application of an ultrasound catheter and injection of microbubble contrast agent.

  • The GLOBAL LEADERS Adjudication Sub-Study (GLASSY) comparing investigator-reported outcomes in the main trial with those adjudicated by an independent Clinical Event Committee.

With the new day Monday and the Late-Breaking Clinical Trials IV session (8:00–9:15 AM, Main Tent, Great Hall) comes the CLEAR Wisdom trial, which enrolled people with elevated LDL cholesterol and established coronary disease or familial hypercholesterolemia despite maximal standard lipid-modifying therapy.

It assigned them to either bempedoic acid at 180 mg/day or placebo on top of the existing regimen. The drug inhibits the HMG-coenzymeA-reductase cholesterol biosynthesis pathway upstream of the segment that is the target of statin therapy.

The primary end point is simply change in levels of LDL-C over 12 weeks.

"In view of the expense of the newer injectable PCSK9 inhibitors, there is a gap in affordable oral agents that can help to further lower LDL cholesterol in high-risk patients," Morris observed.

"If this medication does prove in the CLEAR Wisdom trial to be both safe and effective, then there will certainly be a need in the future for cardiovascular outcomes trials with this agent."

Also in the session:

  • The CREOLE Study, a "comparison of three combination therapies in lowering blood pressure in black Africans" in which adults with hypertension in six African nations were randomly assigned to one of three dual-agent regimens that included an ACE inhibitor, a calcium-channel blocker, and/or a diuretic.

  • The INFINITY trial, which assigned people at least 75 years of age with hypertension and other risk factors for cerebrovascular disease (including telltale signs on MRI) to either a standard or intensive antihypertensive regimen. The systolic blood pressure targets were 145 mm Hg or less and 130 mm Hg or less, respectively. The primary end points consist of change in mobility and cognitive-functional assessments over 36 months.

  • An analysis from the DECLARE-TIMI 58 trial that expands on a recent finding in its published primary analysis, a reduction in cardiovascular death or heart failure hospitalizations in patients with type 2 diabetes who received dapagliflozin (Farxiga/Forxiga, AstraZeneca) compared with placebo. The new analysis looks at ejection fraction response in the trial.

  • A follow-up analysis to the REDUCE-IT randomized trial of icosapent ethyl (Vascepa, Amarin) in people with hypertriglyceridemia and other cardiovascular risk factors or diabetes, looking at ischemia end points. The drug is a highly purified form of eicosapentaenoic acid (EPA), an omega-3 fatty acid.

Later that morning, the Late-Breaking Clinical Trials V session (10:45 AM–12:00, Main Tent, Great Hall) starts with the SAFARI STEMI trial, a randomized comparison of PCI using femoral- or radial-artery catheter access in patients with acute STEMI. The primary end point: all-cause mortality at 30 days.

It's to be followed by:

  • The Coronary Angiography after Cardiac Arrest (COACT ) trial, which compares the strategies of immediate and delayed coronary angiography, with PCI as needed, in adults presenting to the hospital after cardiac arrest but no evidence of STEMI. The primary end point is survival at 90 days.

  • A follow-up analysis from the TREAT trial, which had previously showed noninferiority for delayed administration of ticagrelor compared with clopidogrel for major bleeding at 30 days in patients who had received thrombolytic therapy for STEMI.

  • The Short and Optimal Duration of Dual Antiplatelet Therapy 2 (STOPDAPT-2) study, a randomized comparison of 1 month of dual-antiplatelet therapy (DAPT) followed by clopidogrel monotherapy vs 12 months of DAPT followed by aspirin monotherapy after PCI with an everolimus-eluting stent.

  • The SMART-CHOICE randomized comparison of clopidogrel as the sole antiplatelet agent vs DAPT after a 3-month course of DAPT after drug-eluting-stent PCI.

Following up in the afternoon, the Featured Clinical Research III session (2:00–3:30 PM, La Nouvelle C) leads off with the Alcohol-AF trial, also known as ETOH-AF. It has assigned patients with moderate alcohol intake, defined as 120 g (or about 10 drinks) per week, and paroxysmal AF to either abstinence or maintenance of usual consumption levels.

The groups are followed for the primary end points of AF/atrial flutter burden and of time to first recurrence over 6 months, both documented with periodic 7-day Holter, loop recorder, or dual-chamber pacemaker monitoring.

"This will be important for getting the data we need to reinforce how we approach lifestyle changes for patients with afib, and overall in the context of cardiovascular risk reduction," Kates said to reporters.

Then in that session:

  • Genetic aspects of patient responses to the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib in the previously published REVEAL trial.

  • Lipoprotein(a) responses as a possible mechanism of the previously demonstrated benefit from treatment with the PCSK9 inhibitor alirocumab (Praluent, Sanofi/Regeneron) in the ODYSSEY OUTCOMES trial.

  • Another analysis from DECLARE-TIMI 58 evaluating dapagliflozin in its diabetic patients with peripheral artery disease, of interest after signals of an increased amputation risk in previous trials with other drugs in the same class.

  • "Lessons learned from 9000 patients" in the International Registry of Acute Aortic Dissections (IRAD).

Finally, returning to Sunday at ACC.19, the 2019 ACC/American Heart Association Primary Prevention guideline is scheduled to make its debut at an afternoon session called "All You Needed to Know About Cardiovascular Disease Prevention Guidelines, Well — Almost All" (2:00–3:30 PM, La Nouvelle B).

The new document will "represent a consolidated source for a clear and evidence-based approach to prevention of cardiovascular disease," said Morris. It will rope together parts of the society's 2013 Cardiovascular Risk Assessment guideline, 2013 Lifestyle guideline, and 2013 overweight and obesity guideline, "and then include information from the 2017 hypertension and 2018 cholesterol guideline, particularly where they relate to primary prevention."

Kates reports he has nothing to disclose. Morris discloses receiving consultant fees or honoraria from Amgen, Esperion, and Sanofi Regeneron.

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