New Orleans on the Map With Mardi Gras, the Saints, and AHA 2016

November 08, 2016

NEW ORLEANS, LA — No one should be gettin' the blues next week as the American Heart Association (AHA) Scientific Sessions returns to the Crescent City,     with a menu that includes a diverse slate of late-breaking clinical-trial (LBCT) offerings to go with the evenings' étouffée, jambalaya, and mud bugs.

They include trials on the relative safety of different nonsteroidal anti-inflammatory drugs (NSAIDs) in high-CV-risk patients; inhibition of proprotein     convertase subtilisin/kexin type 9 (PCSK9) synthesis as a new twist for LDL lowering; direct oral anticoagulants (DOAC) for atrial fibrillation (AF) in     patients getting antiplatelets with their PCI; iron-repletion therapy for heart failure; fractional-flow-reserve (FFR) guidance of PCI for multivessel     disease; and two explorations of whether HDL-mimicking agents can bend cholesterol transport to improve outcomes in patients with ACS.

LBCT 1: Sunday, November 13, 2016, 3:45 pm

The session includes the             Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen         (PRECISION) trial aimed at finding the best of three NSAIDs in patients with indications for the drugs who are high risk for CV disease.

With a planned enrollment of about 24,000 patients with rheumatoid arthritis or osteoarthritis, PRECISION compared celecoxib, naproxen, and ibuprofen at     more than a 1000 centers for the primary end point of first occurrence of cardiovascular or hemorrhagic death, nonfatal MI, or nonfatal stroke.

Also, the Heart Outcomes Prevention Evaluation-3 (HOPE-3) trial keeps on giving with an ancillary     analysis looking at the effects of treatments that lower LDL cholesterol and control blood pressure on cognitive function. The presentation follows the     primary analyses presented at a splashy session at ACC 2016 that looked at clinical outcomes in     a low- to intermediate-risk population and produced largely confirmatory findings for statin therapy and controversial ones for antihypertensive therapy.

Also scheduled at AHA 2016, the randomized efficacy and safety    Trial of Ularitide Efficacy and Safety in Acute Heart Failure     (TRUE-AHF) looked at the use of intravenous ularitide (Cardiorentis), a synthetic natriuretic peptide, in >2000 patients at almost 200 centers in North     America, South America, and Europe. Previously scheduled for presentation at ACC 2016, TRUE-AHF looked at the co–primary end points of all-cause mortality and     clinical events at 48 hours.

The LBCT lineup includes the Examining Use of Ticagrelor in Peripheral Artery Disease     (EUCLID) trial, which explored ticagrelor (Brilinta, Brilique, AstraZeneca) vs clopidogrel 75 mg for preventing CV death, heart attack, or stroke.     EUCLID tipped its hand last month as superficial top-line results suggested that it didn't meet     its primary end point of time to first occurrence of CV death, MI, or ischemic stroke. As reported at the time, EUCLID included 13,885 patients in 28     countries and was claimed to be the largest cardiovascular trial exclusively of patients with symptomatic peripheral artery disease (PAD).

LBCT 2: Monday, November 14, 2016, 10:45 am

The Arterial Revascularisation Trial (ART) randomized 3102 patients at 28 centers in seven     countries to coronary bypass surgery with single or bilateral internal mammary artery (IMA) grafts. With a primary end point of survival at 10 years, ART     is scheduled to complete its follow-up in 2017. Outcomes at 1 year were comparable.

The Functional Testing Underlying Coronary Revascularization (FUTURE) is billed as a     "real-world" comparison of need for PCI guided by standard angiography or FFR in patients with multivessel disease. The study conducted in France looked at     >900 patients for the primary end points of major cardiovascular events at 1 year.

Also, the PIONEER AF-PCI trial with >2000 patients is a     randomized comparison of rivaroxaban (Xarelto, Bayer/Johnson & Johnson) at two separate dosage levels vs a dose-adjusted vitamin-K antagonist in     patients with AF who undergo PCI. As previously reported by heartwire from Medscape,     the trial's primary end points focus on bleeding, but it isn't powered for stroke outcomes.

Wrapping up the LBCT session is a comparison of patients with severe symptomatic aortic stenosis undergoing transcatheter aortic-valve replacement (TAVR) vs surgical aortic-valve implantation in the    German Aortic Valve Registry, looking at     1-year mortality outcomes. The study had an estimated enrollment of 100,000 patients.

LBCT 3: Tuesday, November 15, 2016, 10:45 am

Even with its mid-October announcement that treatment with an investigational drug called ALN-PCSsc (the Medicines Company) has been followed by "robust and durable" drops in LDL-C at 90 days in an interim analysis, the    ORION study still intrigues in its pursuit of a novel pathway     to reduction of PCSK9 levels. The drug targets PCSK9 synthesis in the liver via RNA interference, rather than by competitive inhibition of PCSK9 in the     bloodstream in the fashion of evolocumab (Repatha, Amgen) and alirocumab (Praluent, Sanofi/ Regeneron).

It turns out that treatment with at least one of those already-approved PCSK9 inhibitors may modify coronary lesion progression when added to statins,     suggested recently announced top line findings from the             Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound         (GLAGOV) trial.

In GLAGOV, treatment with evolocumab "met" its primary end point of change in percent atheroma volume (PAV) vs placebo, as measured by intravascular     ultrasound, from baseline to week 78. Sponsor Amgen has said the trial, included in LBCT 3, randomized 968 patients.

Also in the session: two trials of different formulations of apolipoprotein A1 (apoA1), which in endogenous form is thought to do the heavy lifting for     reverse cholesterol transport by HDL, of which it is a major component.

The phase 2b ApoA-1 Event Reduction in Ischemic Syndromes I     (AEGIS-I) trial explored safety and tolerability of the apoA1 formulation CSL112 (CSL Behring) in >1200 patients with acute MI. Its primary end points     look at changes in liver function and renal status. CSL112 is given in an IV infusion once a week for 4 weeks. Ultimately, it's hoped that the strategy     will enhance reverse cholesterol transport and shrink coronary plaques.

It's scheduled to be followed by the MILANO-PILOT study of an agent described as a     recombinant version of the HDL apoA1 Milano protein variant in HDL, which is under development as MDCO-216 (the Medicines Company). With a planned     enrollment of "up to" 120 patients, the randomized, double-blind trial is following them with IVUS.

Also in the session is a randomized trial of about 60 "healthy" subjects with raised     triglycerides and patients with familial hypercholesterolemia, looking at the safety and pharmacokinetics of IONIS ANGPTL3-LRx (Ionis Pharmaceuticals), an     antisense inhibitor of angiopoietinlike protein 3 (ANGPTL3). Hopes are that inhibition of ANGPTL3, itself an inhibitor of lipoprotein lipase and     endothelial lipase, will reduce LDL-C and triglycerides.

LBCT 4: Wednesday, November 16, 2016, 10:45 am

Heart failure is the feature of the last LBCT session, which starts with the    REDUCE LAP Heart Failure (REDUCE LAP-HF) trial of a     novel HF device therapy, a catheter-delivered interatrial shunt (IASD System II, Corvia Medical) in patients with heart failure and preserved ejection     fraction (HFpEF).

The REDUCE LAP-HF 6-month results in 64 patients suggested that implantation of the device may reduce left atrial pressure without untoward complications;     the AHA 2016 presentation will provide 1-year outcomes.

Two trials of iron-repletion therapy in patients with heart failure are on the schedule, both looking at intravenous forms of iron for correction of iron     deficiency, which is seen in about half of HF patients. Some studies have suggested that such     correction of iron deficiency can improve symptoms and functional capacity in patients with heart failure.

The randomized, double-blind    Oral Iron Repletion effects on Oxygen Uptake in Heart Failure     (IRONOUT HF) trial enrolled a projected 225 patients with chronic HF with reduced EF (HFrEF) who took placebo or polysaccharide iron complex and has     followed them for the primary end point of change in peak VO2 over 16 weeks.

Also, the             Effect of Ferric Carboxymaltose on Exercise Capacity in Patients With Iron Deficiency and Chronic Heart Failure         (EFFECT-HF) trial was to assess about 170 patients with heart failure for changes in peak VO2 over 24 weeks; they had been randomized open-label     to receive either IV ferric carboxymaltose (Ferinject, Vifor) or usual care.

Afterward, the MOMENTUM 3 trial primary results are expected; the trial compared the HeartMate 3 (Thoratec/St Jude Medical) left ventricular assist device (LVAD) against an earlier incarnation, the    HeartMate 2, in a projected population of >1000 patients with NYHA class 4 heart failure or in severely symptomatic NYHA class 3.

The devices' names are similar but the newer pump's design is fundamentally different from the older one, featuring a rotor that is magnetically levitated and propelled, making the rotor essentially the only moving part. In the HeartMate 3 CE Mark Trial, the device    seemed to perform better in terms of resisting thrombosis and infection compared with benchmarks     set by the HeartMate 2, which has an axial-flow pump and a driveline.

Concluding the final LBCT session is the observational             Evaluation of Multisensor Data in Heart Failure Patients With Implanted Devices         (MultiSENSE) study, which has a projected enrollment of almost 1000 patients with planned or past implantation of COGNIS CRT-D systems (Boston     Scientific).

The devices received investigational software that allowed them to monitor metrics that change with worsening heart failure, including intrathoracic     impedance and physiologic-exercise responses, without interfering with their capacity to pace or deliver shocks. The study doesn't have conventional end     points; rather, it's designed to collect data to be used in developing algorithms that can pick up on worsening heart failure.

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