Drug Withdrawal Inadvisable in 'Recovered' Dilated Cardiomyopathy

November 11, 2018

CHICAGO —  Withdrawal of heart failure drug therapy from patients deemed to have "recovered" from dilated cardiomyopathy resulted in a relapse rate of 40% in the TRED-HF study.

"Our results suggest that improvement in function in patients with dilated cardiomyopathy represents remission rather than permanent recovery, and that withdrawal of therapy should not usually be attempted until predictors of relapse are defined, there is a better understanding of the importance of specific therapies and monitoring is in place," lead investigator, Brian Halliday, PhD, Imperial College London, United Kingdom, concluded.

He presented the results of the TRED-HF study today at the American Heart Association (AHA) Scientific Sessions 2018. The results were also published online November 11 in The Lancet.

"In answer to our question of whether we can withdraw therapy in these patients, our advice is 'don't do it'," Halliday commented to theheart.org | Medscape Cardiology.

Moderator of the AHA media briefing at which the study was discussed, Donald Lloyd-Jones, MD, Northwestern University Feinberg School of Medicine, Chicago, Illinois, said the study addressed an "incredibly important question which comes up all the time."

"I really want to commend the investigators for taking on what might seem to be an ethically challenging question, but they checked all the boxes so that it was done in a safe way," he said.

"It does push us down the path to do more studies try and understand better which patients we might want to select for withdrawal of therapy in the future because no patient wants to be on more medications than they need to be, but for the time being these patients are going to have to continue with their medication until we understand a little bit more," he added.

Designated discussant of the study, Jane Wilcox, MD, Northwestern University, Chicago, also congratulated Halliday and his team for trying to address this question.

"This is a really important study as return of heart failure signs occurred in 44% of patients within just 8 weeks of starting to withdraw therapy,' she said.

"This shows we should 'TRED' lightly as we currently have no clinical profile, including biomarkers that really aligns to response to therapy and identifies a patient who truly has recovered and can have medical therapy withdrawn," Wilcox concluded. "So these patients are in cardiac remission and have an indefinite indication for continuing their medical therapy without interruption, but I don't think this should discourage further research looking for a true signature of cardiac recovery."

Halliday explained that dilated cardiomyopathy is the second most common cause of heart failure but that about half of patients show recovery of function on medical therapy.

"There is no consensus on what to do about withdrawal of medication in these patients who have recovery and the practice at present is very variable. Many patients want to withdraw therapy, but we just don't know the risks of doing this."

His group therefore conducted a pilot study to look at this issue. The study included 51 patients with a prior diagnosis of nonischemic dilated cardiomyopathy with left ventricular ejection fraction (LVEF) of 40% or less, who were being treated with at least one heart failure medication and who had a current LVEF of 50% or greater and a left ventricular end diastolic volume (LVEDV) indexed to body surface area within normal range, no symptoms of heart failure, and plasma N-terminal pro B-type natriuretic peptide (NT-pro-BNP) concentration less than 250 ng/L.

They were randomly assigned to withdrawal or continuation of therapy over a 16-week period with follow-up to 6 months. There was then a single-arm crossover, and the original group who continued therapy underwent withdrawal.

One patient dropped out, so 50 patients underwent withdrawal. This was done very gradually over the 16 weeks, with one medication dosage being reduced every 2 weeks until completely stopped, and then the next medication was reduced in the same way.

Patients were contacted by phone every 2 weeks and seen every 4 weeks when they underwent blood tests. MRI was performed at baseline, 16 weeks, and 6 months.

The primary endpoint was a relapse of dilated cardiomyopathy, defined as any of the following: a reduction in LVEF of greater than 10% and to below 50%, an increase in LVEDV by greater than 10% and to above the normal range, a twofold rise in baseline NT-pro-BNP and to greater than 400 ng/L, or clinical evidence of heart failure. If a patient met any of these criteria, therapies were restarted.

Results showed that 20 of the 50 patients (40%) met the criteria for relapse. In addition, 4 patients restarted therapy without reaching the primary endpoint and 9 patients had a reduction in ejection fraction less than that needed to meet the primary endpoint but still considered to be possibly clinically significant.

"So there were only 16 out of 50 patients in whom the withdrawal of therapy was deemed to be successful," Halliday noted.  

The researchers actually recommended that these 16 patients restart therapy as well.

"Even though we haven't detected changes in 6 months given our high rate of relapses in the study, we felt there could be further relapses over the longer term and these patients need very close monitoring," he explained.

Halliday said they have tried to identify markers for patients who might be able to successfully withdraw from therapy, but this is difficult with such small numbers in this study and any data on this should be regarded as hypothesis generating.

But preliminary investigations suggest that normal NT-pro-BNP concentration is a good prognostic indicator and that results of strain imaging and fibrotic and inflammatory biomarkers may be useful, he reported.  

In addition, genetic analysis would be useful because it is unlikely that patients with a genetic basis for the condition would be able to come off therapy without relapsing, he added.

The researchers are now deciding how to address this issue further.

"We found a higher rate of relapse than we expected," Halliday said. "Maybe we should be trying to reduce medication rather than stopping it completely, and we are planning further studies to try this approach."

TRED-HF was an investigator-initiated study funded by the British Heart Foundation.

American Heart Association (AHA) Scientific Sessions 2018. Session LBS.05. Presented November 11, 2018.

Lancet. Published online November 11, 2018. Abstract

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