LVAD Plus Drug Therapy May Reverse Heart Failure

November 01, 2006

November 1, 2006 (Harefield, UK) - A group of British researchers have shown in a prospective study that sustained reversal of severe heart failure is possible in selected patients with the use of a left ventricular assist device (LVAD) and a specific drug regimen [1]. Of the 15 patients they treated in this way, 11 had sufficient myocardial recovery to undergo explantation of the LVAD, and eight of these are still alive, with no heart failure, five years later.

Dr Emma J Birks (Royal Brompton and Harefield National Health Service Trust, UK) and colleagues report their findings in the November 2, 2006 issue of the New England Journal of Medicine. Birks told heartwire that it had been "a fantastic feeling, to take these dying patients and salvage them. It is so rewarding, especially because many of them are young people." She said that her team had refrained from publishing the data until now, because they wanted to ensure that the positive outcomes were sustained.

In an editorial accompanying the paper [2], Drs Dale G Renlund and Abdallah G Kfoury (LDS Hospital, Salt Lake City, UT) say Birks et al "have tantalizingly provided more than just a series of anecdotes regarding recovery from end-stage heart failure. Their report is reasonably convincing that support with a LVAD may serve as a platform from which to administer promising therapies."

Birks revealed to heartwire that other centers around the world that implant LVADs had initially been quite skeptical of their work: "They thought it was almost too good to be true." But they have changed their minds now, with the help of the peer-review process of the New England Journal of Medicine, "and many centers are going to join us in further studies in larger numbers of patients."

Benefit of two-stage drug regimen not proven

The team at Harefield Hospital has developed a form of combination therapy consisting of a HeartMate (Thoratec, Pleasanton, CA) LVAD and drugs known to enhance reverse modeling, followed by the use of the beta-2 adrenergic receptor agonist clenbuterol. This drug is approved for clinical use in the UK for asthma and is also licensed in Canada and some European countries, but not in the US.

They recruited 27 patients with stage D nonischemic heart failure (excluding myocarditis) who received LVADs. Three patients were ruled out because they had coronary artery disease, four because they were in cardiogenic shock at the time of implantation, and five because they did not complete the pharmacologic regimen. The remaining 15 received the first stage of the pharmacologic regimen consisting of four drugs intended to enhance reverse remodeling—lisinopril to 40 mg daily, carvedilol to 50 mg twice daily, spironolactone to 25 mg daily, and losartan to 100 mg daily.

The second stage of therapy was started after maximal regression in the left ventricular end-diastolic diameter had been achieved and a constant left ventricular size had been maintained for at least two weeks. Clenbuterol was given at an initial dose of 40 µg twice daily, then 40 µg three times daily, and gradually titrated up to a dose of 700 µg three times daily. The dose was adjusted to maintain the resting heart rate at a level below 100 beats per minute. Before clenbuterol was started, the selective beta-1 blocker bisoprolol, at doses of up to 10 mg/day, replaced carvedilol.

Birks et al say that extensive data from clinical trials support the initial phase of mechanical and pharmacologic therapy to promote left ventricular remodeling but that the benefit of the second stage (clenbuterol) "is less firmly established." While beta-2 agonists have been shown to have various positive effects in this setting, they may also have adverse effects on the myocardium and/or skeletal muscle, as has been reported in animal models, they explain.

In their patients, however, there were no severe adverse effects of clenbuterol. Some experienced mild tremor and muscle cramp, which disappeared after a few doses, but all remained on the drug, Birks said.

Rate and duration of recovery "significantly higher than previously reported"

After an average of 320 days of support, 11 of the remaining 15 patients recovered sufficiently for the LVAD to be removed, at which point the clenbuterol therapy was stopped. One of these died early, from intractable arrhythmias 24 hours after explantation, but the others survived for more than two years. One of these died from lung cancer 27 months after the LVAD was taken out, while another had to have a transplant 18 months after explantation, probably due to a bout of alcohol abuse, Birks said.

The remaining eight patients are all still alive five years later, with no signs of heart failure and a good quality of life, she said. "We have kept them on the four-drug regimen, however, because we were too nervous too stop it." But one woman did stop taking the drugs because of adverse effects "and is still fine," she noted.

Birks says the rate and duration of recovery seen in their series of patients was "significantly higher than previously reported after implantation of LVADs. The rates in previously published studies were 5%, 24%, and 11% in a larger series that included patients with acute myocarditis."

In their editorial, Renlund and Kfoury say: "To use legal parlance, Birks et al have achieved 'a preponderance of evidence' but are not convincing 'beyond a reasonable doubt,' " but, they add, "maybe, in some patients, the failing heart is not end stage after all."

Confirmatory studies will be done in US and Europe

Birks told heartwire that they have now successfully removed 23 LVADs at Harefield, and the next stage of the plan is to repeat the same procedure and drug regimen in about 50 or 60 patients, at a number of centers in the US and Europe. US centers involved include the Texas Heart Institute in Houston, Georgetown University in Washington, DC, and Montefiore Hospital in New York, she said.

If these data are robust, a larger randomized study will begin, with one group given clenbuterol and another not, to try to nail down the role that this drug plays in events, she says.

"If this works, it will be great for everyone. For the patients, it's incredible, and they get a really good quality of life. For those awaiting transplant but not eligible for this therapy, it frees up more donor hearts for them."

  1. Birks EJ, Tansley PD, Hardy J et al. left ventricular assist device and drug therapy for the reversal of heart failure. New Engl J Med 2006; 355: 1873-1884.

  2. Renlund DG and Kfoury AG. When the failing, end-stage heart is not end-stage. New Engl J Med 2006; 355: 1922-1925.

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