Trials Headlining ACC Session 'Promise to Be Practice Changing'

March 06, 2018

ORLANDO — Two of the highest-profile studies slated for presentation at the American College of Cardiology (ACC) 2018 Scientific Session are to be unveiled at the meeting's launch the morning of Saturday, March 10. 

Both "truly promise to be practice-changing," Andrew Kates, MD, Washington University, St Louis, Missouri, vice-chair of the ACC 2018 sessions, said at a briefing for the media on the upcoming presentation of the ODYSSEY Outcomes  and Vest Prevention of Early Sudden Death (VEST) trials. The results of both investigations are, as is customary, formally under wraps until their live presentation at the meeting. 

ODYSSEY Outcomes tested the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab (Praluent, Sanofi/Regeneron) in patients with a recent hospitalization for acute coronary syndromes and followed them for cardiovascular events.

Positive or negative, the results "will really influence practice — change practice to potentially change guidelines," Kates said. "Just how it influences our practices and how it affects guidelines really depend upon the data that's presented and the strength of the data."

The VEST trial is exploring whether a defibrillator system worn in a light harness (LifeVest; ZOLL Medical) can safely protect patients from arrhythmic death during the first 3 months after a myocardial infarction (MI).

The trial "certainly will influence clinical practice also," Kates said. Implantable defibrillators aren't an option for patients such as those in VEST, in whom guidelines have long recommended the devices be off-limits at least 40 days after an MI, and at least 90 days if the MI was treated with percutaneous coronary intervention (PCI).

The 35 other late-breaking trials and feature research presentations, out of 125 that had been submitted for consideration, include a new slant on the barbershop-based outreach for blood pressure control in African American; a wireless atrial fibrillation (AF) monitor worn as an adhesive patch; and updates on the groundbreaking CANTOS trial and the controversial POISE trial, as well as on several drugs primarily seen as diabetes agents but increasingly shown to prevent some cardiovascular events.

All the late-breaking trials sessions are scheduled for the Main Tent, that is, Hall C of the Orange County Convention Center. The "featured clinical research" sessions are slated for room 311E on Saturday and Monday of the meeting and for room 202C on Sunday.

Other new research not to be overlooked at the meeting: 2719 abstracts for standard oral presentations and posters, including moderated posters, out of a total 4886 submitted for consideration, according to the ACC.

Saturday, March 10, 9:00 am to 10:00 am: Joint ACC/JACC Late-Breaking Clinical Trials

The ODYSSEY Outcomes trial randomly assigned more than 18,000 patients with a recent hospitalization for MI or unstable angina to alirocumab or placebo on top of statins and followed them for cardiac events or stroke. Entry required a low-density lipoprotein cholesterol (LDL-C) level of at least 70 mg/dL, non–high-density lipoprotein cholesterol level of at least 100 mg/dL, or an apolipoprotein B level of at least 80 mg/dL during statin therapy and other evidence-based treatments.

It's the second major randomized outcomes trial for the class of drugs that can reduce LDL-C to almost unprecedented levels, even in patients already receiving statins. ODYSSEY Outcomes follows presentation of the groundbreaking, randomized FOURIER outcomes trial of another PCSK9 inhibitor, evolocumab (Repatha, Amgen) at last year's ACC session.

In FOURIER, which will be important to interpreting the new trial, evolocumab was associated with significant, modest reductions in nonfatal cardiovascular events but not mortality over nearly 2 years in its statin-treated patients with a history of cardiovascular events. But uptake of the drug into clinical practice has been weak because of its immense cost compared with generic statins.

If alirocumab turns out to have a survival benefit in ODYSSEY Outcomes, "I think that's going to give this class of drugs a lot more interest in terms of what the clinicians have to provide to their patients," Jeffrey Kuvin, MD, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, said at the briefing.

But, he added, "I think if the data are quite similar to FOURIER, in that we see significant reductions in LDL and we see a decreased number of events, but not necessarily impacting mortality, I think again that's going to reinforce a lipid-lowering pathway that some of our patients will benefit from."

The other randomized trial in the session, VEST, follows previous observational experience suggesting that the LifeVest successfully delivered appropriate shocks to 1.4% of more than 8000 patients who wore the device during the early post-MI period in which implantable defibrillators are avoided.

That proscription stems primarily from two trials, DINAMIT from 2004 and IRIS from 2009, that found no survival benefit or even an increase in all-cause mortality when implantable defibrillators were used in the early post-MI period.  

To determine whether a wearable defibrillator might safely overcome that limitation of implanted devices, VEST randomly assigned an estimated 2300 patients with a left ventricular ejection fraction no higher than 35% to start using the LifeVest during an acute MI hospitalization or within 7 days of discharge. The primary endpoint is sudden-death mortality within 3 months of the acute event.

Saturday, March 10, 12:15 pm to 1:45 pm: Featured Clinical Research I

First up in this session is a cost-effectiveness analysis from the DEFINE-FLAIR study, a follow-up to its primary outcomes reported last year, showing no difference in clinical outcomes for PCI guided by fractional flow reserve determinations or adenosine-free instantaneous wave-free ratio index.

The findings of DEFINE-FLAIR and the corroborating iFR-Swedeheart study had pointed to a practical advantage for the latter technique, which is less invasive than conventional fractional flow reserve guidance.

Scheduled next is the Assessment of Prospective CYP2C19 Genotype Guided Dosing of Anti-Platelet Therapy in Percutaneous Coronary Intervention  (ADAPT) study, a 504-patient cost-effectiveness exploration of ticagrelor (Brilinta/Brilique, AstraZeneca) after stent PCI guided by the presence of a gene variant that affects the antiplatelet potency of clopidogrel.

Afterward, the COMBO Collaboration 1-year outcomes analysis based on patients in two registries, MASCOT and REMEDEE, who were treated with the novel COMBO stent (OrbusNeich). The sirolimus-eluting stent features an abluminal coating that contains antibodies designed to attract circulating endothelial progenitor cells.

The subsequent presentation will look at 5-year outcomes of patients in the NOTION trial, which compared transcatheter aortic valve replacement with surgical aortic valve replacement in 280 older patients with severe aortic valve stenosis deemed low risk for surgery. Results at 1 year had shown no significant differences between the strategies in the composite outcome of death from any cause, stroke, or MI. 

Next on the bill is an analysis based on the Geisinger His Bundle Pacing Registry that compared patients undergoing permanent His-bundle pacing at a major medical center to those who received conventional right ventricular pacing at another hospital in the same health system. The approximately 760 patients were treated at the two centers from 2013 to 2016.

The presentation's title is "Permanent His Bundle Pacing Is Associated With Reduction in Mortality and Morbidity Compared to Right Ventricular Pacing."

His-bundle pacing, which doesn't require a left ventricular lead, is increasingly viewed as a potential alternative to biventricular pacing for heart failure and is under evaluation for that use in a small randomized trial.

Rounding out the session are the primary outcomes of the mHealth Screening to Prevent Strokes  (mSToPS) trial, which randomly assigned 2274 high-risk cardiovascular patients without AF to wear or not wear a Zio XT (iRhythm Technologies) sensor, an AF monitor in an adhesive patch. The primary endpoint is new-onset AF over the study's 4-month monitoring period; patients will be followed over 3 years for stroke, systemic emboli, or MI.

Sunday, March 11, 8:00 am to 9:15 am: Joint ACC/JAMA Late-Breaking Clinical Trials

Another exploration of genotype-guided antiplatelet therapy, the Pharmacogenetics of Clopidogrel in Acute Coronary Syndromes (PHARMCLO) study, randomly assigned 889 patients with acute coronary syndromes (ACS), including ST-segment-elevation MI (STEMI), to treatment with clopidogrel, ticagrelor, or prasugrel (Effient, Efient, Lilly/Daiichi-Sankyo). They were followed for MI, stroke, or major bleeding over 1 year.

Next on the schedule, the Affordability and Real-world Antiplatelet Treatment Effectiveness after Myocardial Infarction Study (ARTEMIS) followed about 11,000 patients after randomization to receive or not receive vouchers that covered their third-party payer copayment costs for prescriptions of clopidogrel or ticagrelor.

It's to be followed by the Ticagrelor in Patients With ST Elevation Myocardial Infarction Treated With Pharmacological Thrombolysis (TREAT) comparison of ticagrelor or clopidogrel initiated in about 3800 patients with acute STEMI who had received thrombolytic therapy within the previous 12  hours. Treatment was continued for a year; patients were followed for major bleeding at 30 days and 1 year and clinical events at 1 year.

TREAT is to be followed by the Management of Myocardial Injury After Noncardiac Surgery (MANAGE) trial, which assigned 1754 patients with MI associated with noncardiac surgery to dabigatran, 110 mg twice daily, with vs without omeprazole. The two agents are compared to their placebos in the trial with a four-by-four randomization.

Scheduled next is the Statins Evaluation in Coronary Procedures and Revascularization (SECURE-PCI) trial, which randomly assigned 4192 patients undergoing PCI in the setting of ACS to receive placebo or an 80-mg loading dose of atorvastatin immediately before and 24 hours after the procedure, followed by atorvastatin, 40 mg for a month. They were followed for death, MI, stroke, or revascularization at 30 days.

Sunday, March 11, 10:45 am to 11:45 am: Late-Breaking Clinical Trials

This session includes long-term outcomes from the MOMENTUM-3 trial, which compared treatment with the recently introduced HeartMate 3 left ventricular assist system and the long-available HeartMate 2 (both pumps from St Jude Medical) in more than 1000 patients with advanced New York Heart Association (NYHA) 3-4 systolic heart failure.

In a 2016 interim report, the rate of disabling stroke was similar for the two devices, but the HeartMate 3 showed a lower rate of thrombosis and device malfunction.

Next is the Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure with Preserved Ejection Fraction (INDIE-HFpEF) trial, which randomly assigned about 100 patients with NYHA class 2-4 heart failure and LVEF of at least 50% to receive nebulized sodium nitrite or placebo as outpatients while wearing an accelerometer. The were followed for changes in exercise capacity, hemodynamics by echocardiography, biomarkers, and quality of life for up to 12 weeks.

The rest of the session is to be devoted to the Carvedilol for Prevention of Chemotherapy-Induced Cardiotoxicity (Ceccy) trial with about 200 patients and the 468-patient Lisinopril or Carvedilol for Prevention of Trastuzumab Induced Cardiotoxicity trial. Both look at the use of standard cardiovascular medications for the prevention of systolic dysfunction secondary to chemotherapy with anthracyclines and trastuzumab, respectively, for breast cancer.

Sunday, March 11, 4:45 pm to 6:00 pm: Featured Interventional Clinical Research II

The session starts with two studies looking at cardiovascular outcomes in patients taking antidiabetic sodium-glucose co-transporter 2 (SGLT-2) inhibitors, such as canagliflozin (Invokana, Janssen), dapagliflozin (Farxiga/Forxiga, AstraZeneca), or empagliflozin (Jardiance, Boehringer Ingelheim).

They include the CVD-REAL 2 study, billed as tracking "real-world" outcomes in more than 400,000 patients in different parts of the world, and conducted by the group behind the slightly smaller CVD-REAL retrospective study reported last year.

In that earlier study, treatment with an SGLT-2 inhibitor, compared with another diabetes drug class, was associated with significantly reduced heart failure hospitalization and mortality over 4 years.

The other SGLT-2 inhibitor presentation is an update from the CANVAS program of a diabetes trial, focusing on the endpoint of heart failure. It had been previously reported from the studies that canagliflozin therapy was associated with significant reductions in a composite endpoint that included death, nonfatal MI, or nonfatal stroke.

Then, a follow-up from the CANTOS trial focusing on its patients with chronic kidney disease. The trial had randomly assigned more than 10,000 patients with a history of MI and elevated C-reactive protein levels to receive or not receive the novel anti-inflammatory drug canakinumab (Ilaris, Novartis).

As previously reported for the overall trial population, the patients taking the monoclonal antibody had shown significant reductions in risk for new cardiovascular events, need for revascularization, and, surprisingly, new lung cancer.

Concluding the session is an analysis from the COMPASS trial, partly titled "High Mortality After Major Adverse Limb Events in Peripheral Artery Disease." Previously in the randomized trial, rivaroxaban (Xarelto, Bayer/Janssen Pharmaceuticals) given at 2.5 mg twice daily on top of low-dose aspirin was associated with significantly reduced risk for major cardiovascular and limb events in patients with peripheral arterial disease (PAD).

Monday, March 12, 8:00 am to 9:15 am: Joint ACC/NEJM Late-Breaking Clinical Trials

This session will lead off with the full primary results of the Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Comorbidities (CARES) trial comparing the gout medication febuxostat (Uloric, Takeda Pharmaceuticals) against allopurinol in more than 6000 patients with gout.

Cursory results are already known: In November 2017, the US Food and Drug Administration (FDA), which had mandated the trial, announced in a safety communication that febuxostat was associated with an excess of "heart-related deaths and death from all causes."

However, according to the preliminary results, there was no such increase in risk for the primary endpoint, which was a composite of cardiac mortality, nonfatal MI, nonfatal stroke, and cardiac ischemia requiring urgent surgery.

On the schedule next is another CANTOS analysis, this one focusing on the rates of new diabetes in the canakinumab and placebo groups. It's to be followed by Cut Your Pressure Too: The Los Angeles Barbershop Blood Pressure Study.

The study is another in a line of trials exploring the usefulness of community-based outreach programs for blood pressure (BP) control aimed at African American men in neighborhood barbershops. It compared a pharmacologic therapy approach to a lifestyle modification approach centered at two respective groups of barbershops in the Los Angeles area.

The 320 male customers of the barbershops were followed primarily for change in systolic blood pressure over 6 months and secondarily for, in part, proportion of patients achieving BP goals and change in number and type of BP medications used.

The next presentation, Triple Pill vs Usual Care Management for Patients with Mild-to-Moderate Hypertension (TRIUMPH), randomly assigned about 700 patients with recalcitrant mild-to-moderate hypertension at 20 centers in India to receive a daily single-pill combination of telmisartan 20 mg, amlodipine 2.5 mg, and hydrochlorothiazide 6.25 mg, with attempted titration upward to twice those levels, or to "continued usual care." The primary endpoint is the proportion achieving BP target by 6 months.

The session concludes with a 1-year follow-up report on a trial that reported 30-day results about a decade ago: the Perioperative Ischemic Evaluation (POISE), which had seen a marginally significant benefit for extended-release metoprolol in 8351 patients at high atherosclerotic risk undergoing noncardiac surgery who were randomly assigned to a β-blocker or placebo. That was despite increased mortality and risk for stroke in the metoprolol group.

The findings became caught up in a long-standing controversy about the role of β-blockade in noncardiac surgery, as reflected in slow-to-change guidelines and discredited data from a different, related trial.

Why did it take 10 years to release the POISE 1-year results? "Unfortunately, due to a requirement of our funding we were forced to do the long-term follow-up in Canada through our administrative databases," principal investigator, Philip J Devereaux, MD, McMaster University, Hamilton, Ontario, Canada, told theheart.org | Medscape Cardiology.

"These databases run a few years behind and then it took years of negotiating and pleading to get the data," he said. "It was a lesson in real challenges in using national administrative data in Canada to follow patients in trials."

Monday, March 12, 10:45 am to 11:45 am: Late-Breaking Clinical Trials: Interventional Cardiology

On the bill first is the phase 2 SDF1 Plasmid Treatment for Patients With Peripheral Artery Disease (STOP-PAD) study, a randomized test of gene transfer via intramuscular injections of the DNA-expressing plasmid JVS-100 (Juventas Therapeutics) for promoting wound healing and preventing limb loss in patients with severe PAD.

Next is the Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients With High-Risk Patent Foramen Ovale (DEFENSE-PFO) study, featuring an estimated 210 patients with a recent history of cryptogenic stroke and a PFO considered high risk for promoting recurrent stroke.

They were randomly assigned to receive standard medical therapy with vs without catheter placement of a PFO occluder (Amplatzer, St Jude Medical) and followed for 2 years for a composite endpoint of recurrent nonfatal stroke, vascular death, or major bleeding by TIMI criteria.

The FDA approved the Amplatzer device for the indication in 2016 based on 10-year results of the pivotal that at long last showed it can confer a significant protective effect against recurrent stroke.

DEFENSE-PFO is to be followed by the single-center Safety of 6-month Duration of Dual Antiplatelet Therapy After Acute Coronary Syndromes (SMART-DATE) study, which compared 6 months vs 12 months of antiplatelet therapy with clopidogrel, ticagrelor, or prasugrel after PCI in 2712 patients with any form of ACS.

Concluding the session is an interim report from the ANNEXA-4 study. The open-label study will include a projected 350 patients who have acute major bleeding while receiving anticoagulation with factor Xa inhibitors that is treated with andexanet alfa (AndexXa, Portola Pharmaceuticals). The agent is a bioengineered decoy receptor that intercepts molecules of the inhibiting agents.

Previously reported interim results in 77 patients suggested that the antidote does its intended job, reversing the anticoagulant effects of factor Xa inhibitors, such as apixaban (Eliquis, Bristol-Myers Squibb), rivaroxaban (Xarelto), edoxaban (Savaysa, Lixiana, Daiichi-Sankyo), and even enoxaparin.

Monday, March 12, 2:00 pm to 3:30 pm: Featured Interventional Clinical Research III

Leading off the session is a Get With The Guidelines-Heart Failure Registry analysis called "Hospital Performance Based on 30-Day Risk Standardized Mortality and Long-Term Survival after Heart Failure Hospitalization."

The new presentation may expand on findings from the registry published in November 2017 that controversially suggested that efforts to reduce heart failure readmission rates in line with the Centers for Medicare & Medicaid Services Hospital Readmission Reduction Program may have been associated with increased mortality at 30-days and one year.

Next is the second Ferric Iron in Heart Failure (FERRIC-HF 2) study, which explored the effects of iron(III) isomaltoside 1000 (Diafer, Pharmacosmos) administration on skeletal muscles and functional capacity in anemic patients who have stable heart failure with reduced ejection fraction (HFrEF).  

Following FERRIC-HF 2 are two studies under the umbrella Modalities to Assist with Guiding Therapy and the Evaluation of Patients with Heart Failure (IMAGE-HF) Projects, which is described as a multidisciplinary initiative across centers in Argentina, Brazil, Canada, Finland, and the United States.

The first of the two, the Computed Tomographic Coronary Angiography for Heart Failure Patients (CTA-HF) trial, looked at the effect of management guided by CT angiography on resource utilization and care costs in patients with heart failure in whom the presence of coronary disease had not been determined. The study randomly assigned 253 patients, with a planned follow-up of up to a year.

It is to be followed by the IMAGE-HF trial called OUTSMART-HF, which randomly assigned 518 patients with nonischemic heart failure to undergo cardiac MRI or standard management for identification of the cause of cardiomyopathy. It's following patients for any effects of management strategy on clinical outcomes, symptoms, quality of life, and costs.

Next on the schedule is a "real-world comparative effectiveness study" showing "lower mortality and heart failure hospitalization rates" for patients implanted with the CardioMEMS (St Jude Medical) pulmonary artery pressure monitor. It follows the previous randomized CHAMPION trial, in which use of the tiny monitor to help guide medical management of heart failure was associated with reduced rates of heart failure hospitalization over both 6 months and 18 months

Concluding the session are late outcomes from the first-in-human experience with the V-Wave Interatrial Shunt System (V-Wave Medical), a left-to-right shunt system for alleviation of HFrEF symptoms. Functional and symptomatic results at 3 months had been reported 2 years ago for the study's 10 patients. The device is similar to the IASD System II (Corvia Medical) tested in the recently reported REDUCE LAP-HF I trial.

Kates and Kuvin report they have "nothing to disclose."

Follow Steve Stiles on Twitter: @SteveStiles2. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.

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