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ISCHEMIA Trial a Moment of Truth for PCI?

PHILADELPHIA — The American Heart Association (AHA) Scientific Sessions 2019 are headed to Philadelphia next week, with the white hot ISCHEMIA trial, several novel therapeutics, and society partnerships all looking for some brotherly love.

While the meeting will return for a second year in its pared-down, 3-day format, “one of the new things is that we are going to be in Philadelphia for the first time; we’re really excited about that,” program chair Donald Lloyd-Jones, MD, ScM, chair of preventive medicine, Northwestern Feinberg School of Medicine, Chicago, Illinois, told theheart.org | Medscape Cardiology.

“It’s a revamped venue for conventions that’s right downtown in the middle of where things are happening in Philadelphia and sits right on top of the Reading Terminal Market, which is an incredibly fun venue,” he said. “This is the first time that a large cardiovascular meeting has been there and we’re incredibly excited about AHA introducing Philadelphia to the world in this way.”

Apropos of the setting, the meeting will feature three actors from the smash musical “Hamilton” representing founding fathers Alexander Hamilton, Aaron Burr, and George Washington, who will perform six songs during Sunday’s Presidential Session. Don’t worry, two overflow rooms have been set aside.

“When found out I would be in this role as program chair and we would be in Philadelphia, I very much wanted to give a nod to the heritage that Philadelphia represents for this country, and what better way than to acknowledge the cultural phenomenon of ‘Hamilton’ but also the historical phenomenon of Hamilton,” Lloyd-Jones said. “It was a lot of work on the part of AHA to get it to the goal line,” but “I think that will be a real treat for our attendees, no question.”

The likely breakout star of the meeting, however, will be the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA), which takes center stage in its own 75-minute late-breaking science (LBS) session at 2 PM on the opening day, November 16. The LBS 2 will feature a primary report on the study‘s clinical outcomes and a health status analysis, as well as primary clinical outcomes in patients with chronic kidney disease from ISCHEMIA-CKD

More than 10 years and $100 million in the making, hopes are that the National Heart, Lung, and Blood Institute (NHLBI)-supported trial will establish whether a strategy of revascularization with percutaneous coronary intervention (PCI) or surgery, if feasible, results in fewer adverse cardiovascular events than optimal medical therapy alone in patients with stable moderate-to-severe ischemia.

“This is a really important trial and is probably the one that will generate the most buzz because it remains an unanswered question,” Lloyd-Jones observed. “Over the years, we’ve had AVERT, COURAGE, and the very interesting [ORBITA] data from the UK just a couple of years ago suggesting if you did sham procedures in people they really couldn’t tell if they’d got a stent or not. So I think this remains an incredibly important area where we have questions.”

Whether ISCHEMIA will be able to provide definitive answers has been hotly debated after slow accrual led the investigators to quietly change the primary endpoint of cardiovascular death and myocardial infarction (MI) to include resuscitated cardiac arrest, hospitalization for unstable angina, and hospitalization for heart failure.

The protocol was further amended — with the blessing of the independent data and safety monitoring board — to expand the definition of ischemia from 10% or more on nuclear perfusion imaging to patients with 5% ischemic burden at low levels of exertion and those with ECG changes during exercise tolerance testing without imaging.

The controversial changes prompted an editorial last year questioning the decisions, and proverbial tea leaf-readings on Twitter after baseline characteristics and risk profiles of ISCHEMIA participants were published earlier this year.

In September, an “Ischemia Trial Update” revealed that the protocol had been tweaked again to have the Seattle Angina Questionnaire (SAQ) Summary Score become the primary outcome of health status benefits instead of the SAQ Angina Frequency and Quality of Life scales, now to be reported as secondary outcomes. The changes were made prior to the planned database lock date of September 30, and before unblinding of the data, the trialists noted.

“I don’t know that we anticipate we’re going to get a clear, ‘this is the one winner’ answer,” Lloyd-Jones said. “I think it’s going to matter what the specific features are of patient subgroups as to what that answer looks like, and I think the quality-of-life data being layered right alongside that are an incredibly important aspect of this trial — and you can’t neglect that.

“I don’t honestly think it matters if this trial’s positive or not,” he added. “I think it’s generating the really important conversations about are we serving our patients best, are we asking the right questions, and are we really presenting the right outcome of these invasive procedures that we do, committing patients to a stent and dual antiplatelet therapy and the potential side effects? Are we getting the bang for our buck that we want to get and that patients want?”

While the discussion starts at AHA, it will not end there. “There’s just a lot of data that’s going to have to be unpacked around this,” Lloyd-Jones said. “So I for one am incredibly excited to see what the beginning of these answers are, but it’s going to be a hotly debated trial for years to come because it will provide really important information on so many different perspectives.”

Other Late-Breaking Science

For those looking beyond ISCHEMIA, there will be two other LBS sessions on Saturday, two on Sunday, and the final one on Monday morning. Lloyd-Jones described them as falling into two broad themes: novel approaches/therapeutics and deeper dives into some of the mega trials that have come out recently.

For example, Saturday morning’s LBS 1 will flesh out details from ORION-10, which recently announced positive top-line results for the small-interfering RNA agent inclisiran (The Medicines Company) in atherosclerotic CVD. Data from ORION-9 in heterozygous familial hypercholesterolemia are featured during Monday morning’s LBS 6: New Frontiers in Lipid Therapy.

At the ESC Congress 2019 in early September, a third phase 3 trial, ORION-11, reported a halving of LDL-cholesterol with twice-yearly injections of inclisiran, with regulatory filings planned for an LDL-lowering indication in the US later this year and worldwide early next year.

LBS 1 also features BETonMACE, examining selective bromodomain extraterminal domain (BET) inhibition with the investigational agent, RVX000222, plus high-dose statins in high-risk patients with type 2 diabetes and coronary artery disease, and COLCOT, which recasts the decade-old gout drug colchicine for use in patients after an acute MI. Periprocedural colchicine in patients undergoing percutaneous coronary intervention (PCI) will be taken up during LBS 4.

“I think that’s just really exciting, the repurposing and the novel mechanisms of drugs,” Lloyd-Jones said. “That sort of theme goes through a number of our different late-breaking sessions and, I think, is going to be one of the big stories of the meeting.”

Reflecting the deeper-dive theme, Lloyd-Jones highlighted an LBS 4 substudy of patients with acute coronary syndrome in TWILIGHT, which demonstrated at TCT 2019 that dropping aspirin after 3 months and continuing ticagrelor monotherapy reduced bleeding without an increase in overall ischemic events among high-risk patients undergoing PCI.

Similarly, an LBS 1 analysis will zero in on nondiabetic patients in DAPA-HF, which recently reported that the diabetes drug dapagliflozin (Farxiga, AstraZeneca) met its primary endpoint in patients with heart failure and reduced ejection fraction, either with or without diabetes.

“We already know that it works, but we don’t know how or why or any of the details about this. So I think the DAPA-HF in nondiabetics is going to be a really important story for people to focus on,” Lloyd-Jones said.

Beyond the LBS

Another theme of the meeting is extended programming, including two half-day sessions on Monday specifically addressing cardio-oncology as well as congenital heart disease and pediatric cardiology.

Cardio-oncology, or as I like to call it, onco-cardiology, is the most important new discipline within cardiology to emerge in the last decade,” Lloyd-Jones said. “And the reason for that is that we’ve had real successes in the oncology space in helping people survive cancer, but the therapies that that involves and, even just the disease processes of cancer itself, can have profound effects on the cardiovascular system.”

Similar successes in cardiovascular science have helped congenital heart patients survive to adulthood, but “too often, I think, the congenital heart story is just kind of passed over or gets one talk in a session only,” he said. “One of the things that’s critically important is the pass-off. As these patients age out of pediatric care, they need adult congenital expert care and too often that’s a slippery baton.”

Also similarly structured and equally important is a joint conference with the NHLBI scheduled for Monday morning called “Bethesda + 41,” which focuses on how to launch youths more successfully to maintain better cardiovascular health across the lifespan, he said. “That’s a really exciting session as well, and very interactive, with the participants helping to design the future research portfolio for NHLBI in that area.”

Several sessions are also devoted to a growing partnership between AHA and the World Economic Forum focusing on the fourth industrial revolution, including one at 4 PM Sunday on Big Data and deep learning and another on the use of blockchain in healthcare scheduled for 9:10 AM Monday.

Attendees may also notice structural changes to the meeting include the Heart Hub, which will be located in the middle of the Exhibition hall, connecting many of the oral sessions and poster presentations and featuring at its center a theatre-in-the-round.

At many meeting venues you have to walk half a mile down a long corridor but “this really creates a nexus and will enhance those chance networking encounters because everyone will be passing through here,” Lloyd-Jones said. “And it will also bring to the fore more awareness about some of the extra exciting programming that’s happening right there in the middle of the Hub.”

New for 2019 is the availability of on-site childcare (children aged 6 months to 12 years) for attendees. While some medical meetings have barred children from their venue, AHA went the other way in response to direct feedback from attendees and people who felt they couldn’t attend because of family responsibilities.

“We want to be as open to as many people as possible and particularly to our young investigators, who are the people who this will probably affect the most,” he said. It’s available for men and women attendees but “we hope this will be engaging for moms out there in particular.”

Like others organizing medical meetings, AHA is struggling to keep the Scientific Sessions accessible to attendees who may reside in countries currently under the US travel ban.

“I don’t think we’ve come up with any great solutions for it to be honest,” Lloyd-Jones acknowledged. “I think about 40% of our abstract presenters are abroad, based on the accepted abstracts we have. We love to have the engagement of the international community, but we recognize the challenges of travel to the United States these days and I think it’s an unfortunate side effect of our current situation.”

Finally, for those in need of some comfort after a long day of cardiovascular science, AHA is teaming up with a local animal shelter to offer some therapeutic time with puppies. Recent work suggests dog ownership may have a positive effect on cardiovascular health, even lengthening one’s life. And besides, who can resist a puppy?

Follow Patrice Wendling on Twitter: @pwendl. For more from theheart.org | Medscape Cardiology, join us on Twitter and Facebook




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