Medical therapy

Optimizing medical therapy before clip repair for MR? ‘It’s hard’

Ensuring that patients receive maximum doses of heart failure treatments within guidelines is important, but also challenging, experts say.

MIAMI, FL—A debate at TVT 2021 last week was supposed to focus on whether guideline-directed medical treatment should be tried at maximum tolerated doses before patients undergo transcatheter edge-to-edge repair (TEER ) for functional mitral regurgitation (MR), but he ended up focusing on the difficulty of getting patients on to basic therapies for heart failure in the first place.

JoAnn Lindenfeld, MD (Vanderbilt Heart and Vascular Institute, Nashville, TN), started out by saying that drug therapy should be maximized first, but her ostensible opponent didn’t disagree.

“I want to concede the debate to JoAnn. I think she made a compelling point, and I really don’t have much to add to what she said,” said Milton Packer, MD (Baylor Heart and Vascular Institute, Houston, TX).

Instead, Packer spent his time advocating for a more practical approach to launching proven heart failure drugs like ACE/ARA inhibitors, sacubitril-valsartan (Entresto; Novartis), beta-blockers , mineralocorticoid receptor antagonists (MRAs) and the sodium-glucose cotransporter. 2 (SGLT2), a time-consuming process that rarely allows patients to receive target doses of all core therapies.

Speaking of conventional drug initiation sequencing, Packer said, “If you do it reasonably compulsively, it will take 6 months. And people don’t do that. Fewer than 5% of patients receive four foundational drugs at therapeutic doses, he added, underscoring a point Lindenfeld made: Significant delays in starting these therapies lead to hospitalizations and deaths.

Clyde Yancy, MD (Northwestern Medicine, Chicago, IL), succinctly summarized the problem after Lindenfeld and Packer’s intervention: “In clinical practice, it’s really hard to do, and we need more science of implementation to discover a new way of doing it and better titration goals.

Benefits of medical therapy

Lindenfeld laid the groundwork for his argument that medical therapy should be tried before edge-to-edge repair, but pointed to the benefits of having patients on all major drug classes. She pointed 2020 study in the Lancet estimating that adding new drugs like sacubitril/valsartan and SGLT2 inhibitors to ACE/ARB inhibitors and beta-blockers would increase the life expectancy of patients with heart failure by 8 years and a reduced ejection fraction.

The best option, I would conclude, is what was done in COAPT: medical therapy directed by maximum tolerated guidelines first. JoAnn Lindenfeld

“So I don’t want us to underestimate here the benefits of guideline-directed medical therapy,” she said, noting that benefits have been shown to occur very early in pivotal trials. . “If you delay this, for example, to do a procedure, [then] you are delaying substantial benefits. TEER is excellent, but the medical therapy is also very good, even at the beginning. »

Unfortunately, most patients never see the full benefits of these medications. A 2018 analysis of the CHAMP-HF Register, Lindenfeld pointed out, showed that many – and sometimes most – patients without contraindications were not treated with the fundamental therapies and that less than 1% received target doses of all. “If you’re referred to an undertreated patient, you do a procedure and you send them back, chances are they’re still undertreated and you lose maybe 8 years of life,” she pointed out. .

Even within the COPT trial, which established the benefit of TEER with the MitraClip (Abbott) for patients with functional MR, those whose MR was reduced to 2+ or less achieved similar benefits whether obtained with the device or optimal medical treatment alone, says Lindenfeld. And another analysis of 63 patients referred for a MitraClip procedure, most of whom had 3-4+ functional MRs, showed that 57% no longer had such severe MRs after receiving foundational treatments for heart failure and therefore “no longer had indications for TEER” , she said.

Lindenfeld also highlighted data indicating how difficult it can be to select individual patients who might benefit the most from medical treatment. “So the best option, I would conclude, is what was done in COAPT: maximally tolerated guideline-directed medical treatment first,” she said.

Start treatment quickly

Recognizing the importance of fundamental treatments for heart failure, Packer discussed the rationale for a rapid sequencing approach it is offered with John McMurray, MD (University of Glasgow, Scotland). Instead of the process taking 6 months, it would take 4 weeks: start with beta-blockers and SGLT2 inhibitors, add sacubitril/valsartan 2 weeks later, then add ARM 2 weeks later.

This strategy takes into account data showing that the order in which these drugs are started does not affect their clinical benefit, although it may affect their safety. Hypotension and azotemia linked to ACE inhibitors, for example, can be alleviated by diuretics, which are also important in preventing the early worsening of heart failure seen with beta-blockers, Packer pointed out. . And there is evidence that ARM-related hyperkalemia can be reduced by a neprilysin or SGLT2 inhibitor.

Rapid sequencing is also supported by data from the pivotal trials themselves, which show that in the early stages – when treatments are increased to target doses – active treatment still has substantial advantages over placebo.

“Low initial doses of foundational drugs have very significant effects, so broad coverage should be prioritized before uptitration,” Packer concluded. “People should take all four drug classes within 4 weeks of starting treatment. I agree with JoAnn. Time is running out.”

“75% of the time, there is a big failure”

In his comments, Yancy said the “more telling” data point from the CHAMP-HF registry was that only 25% of patients were taking any dose of any drug from each of the foundational drug classes. “It tells us that in sophisticated practices, 75% of the time, there is a big miss. In my own practice, I have to be super diligent for that to happen. It takes a lot of time and effort, and I’m not sure [it] can be applied outside of a large academic medical center with the care team involved. So the most important thing to remember is that it is difficult.

I think sometimes people get distracted by MR and forget that there is a patient with ventricular disease who benefits from these drugs. Paul Grayburn

One problem is that the approaches to starting patients on these therapies are based on empiricism, without any guidance from biological studies, according to Yancy. Plus, “it’s a very drastic approach,” he said. “You titrate and titrate until you reach the maximum tolerable dose. Let’s be clear: this means that the patient’s mental function changes or their blood pressure changes. There should be a more sophisticated method. Maybe this biomarkers are the answer, but we should have a better surrogate marker of the adequacy of these therapies.” Expecting all patients to respond the same, regardless of age, height, and demographic background, “gives me some time to pause,” Yancy added.

Gregg Stone, MD (Icahn School of Medicine at Mount Sinai, New York, NY), raised a provocative question during a roundtable, acknowledging the difficulty of getting patients to maximum tolerated doses of major kidney failure drugs cardiac: consider TEER to treat MR?

“I’m not so sure, no,” said Mayra Guerrero, MD (Mayo Clinic, Rochester, MN). “I think we have to start with the drugs.” If patients are referred for TEER and not even on basic medications, they will be referred first to a heart failure specialist, Guerrero noted.

Paul Grayburn, MD (Baylor Scott & White Health, Dallas, TX), said it’s a mistake to oversimplify functional MRI because it’s a “very different range of diseases.” .

But, he continued, “having said that, I think JoAnn made that key point. . . that you can add 8 years of life to people by treating them with appropriate drugs in heart failure. So to some extent we should forget about the MR for a minute and say are we treating heart failure, the patient’s left ventricle, right? And if there is MR, where does MitraClip fit into that? But I think sometimes people get distracted by MR and forget that there’s a patient with ventricular disease who benefits from these drugs.