Meeting NewsPerspective

TRED-HF: HF therapy withdrawal after cardiomyopathy recovery increases relapse risk

Brian Halliday
Brian Halliday

CHICAGO — Nearly half of patients who withdrew from pharmacological HF therapy and were considered as being recovered from dilated cardiomyopathy relapsed, according to data presented at the American Heart Association Scientific Sessions.

“Withdrawal of therapy should not usually be advised to our patients at least until we can predict who is going to relapse and who is not and we have a better understanding of therapies that may be able to be reduced and the importance of the different therapies,” Brian Halliday, MBChB, PhD, clinical lecturer in cardiology at Imperial College in London, said during a press conference.

Researchers analyzed data from 51 patients with a prior diagnosis of dilated cardiomyopathy and subsequent recovery and who were taking at least one medication. A screening visit was conducted prior to randomization for clinical assessment, symptom questionnaires, cardiac MRI, N-terminal pro-B-type natriuretic peptide measurement and cardiopulmonary exercise test.

Patients were assigned either therapy withdrawal (n = 25; median age, 54 years; 64% men) or continued therapy (n = 26; median age, 56 years; 69% men). Medications including loop diuretics (12%), mineralocorticoid receptor antagonists (47%), beta-blockers (88%) and angiotensin converting enzyme inhibitors or angiotensin receptor blockers (100%) were reduced and then stopped in patients in the withdrawal group.

Patients in the withdrawal group underwent clinic review every 4 weeks, and those in the continued therapy group underwent a clinic visit every 8 weeks. Follow-up visits were also performed at 16 weeks and 6 months. At 6 months, patients in the control arm underwent therapy withdrawal with the same protocol as the patients who were originally assigned withdrawal.

The primary endpoint was relapse of dilated cardiomyopathy, defined as either reduction in left ventricular ejection fraction by greater than 10% and below 50%, increase in LV end-diastolic volume by greater than 10% and to above normal range, twofold increase in NT pro-BNP and to greater than 400 ng/L or clinical evidence of HF. Therapy was immediately reintroduced once the primary endpoint was met.

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Nearly half of patients who withdrew from pharmacological HF therapy and were considered as being recovered from dilated cardiomyopathy relapsed, according to data presented at the American Heart Association Scientific Sessions.
Source: Adobe Stock

The primary endpoint was met in 44% of patients in the therapy-withdrawal group compared with none in the control group. During the crossover phase, the primary endpoint was seen in 36% of patients. In all patients who began withdrawal (n = 50), the primary endpoint was seen in 40%, and 50% of patients completed follow-up without treatment re-initiation. LVEF did not deteriorate in 32% of patients who completed withdrawal.

The safety endpoint was major adverse CV events, CV mortality and unplanned CV hospitalization. During follow-up, there were no unplanned HF hospitalizations, deaths or major adverse CV events. Three serious adverse events occurred in patients assigned withdrawal and included hospitalizations for noncardiac chest pain, urinary sepsis and an elective procedure. There were also no sustained ventricular arrhythmias or device therapies. Atrial fibrillation occurred in three patients. All patients who met the primary endpoint were asymptomatic during follow-up.

“Improvement in function represents remission rather than permanent recovery for many patients,” Halliday said during the press conference.

Jane E. Wilcox
Jane E. Wilcox

“This trial does not squelch the idea of myocardial recovery,” Jane E. Wilcox, MD, MSc, assistant professor of medicine (cardiology) at Northwestern University Feinberg School of Medicine, said during the discussant portion of the press conference. “In fact, I think this will invigorate the field to dig deeper and consider the genomics, proteomics and metabolomics of recovery. Assessment of the myocardial substrate is key, and the signals in cardiac mechanics as measured on cardiac MRI that suggest durability of recovery are real, but require rigorous standardization.”

Clyde W. Yancy

This study was simultaneously published in The Lancet and included an editorial.

“Going forward, in response to a patient’s question: ‘Now that my heart failure has improved, am I able to stop my heart failure drugs?’, the answer should be, ‘No, not at this time,’” Wilcox and Clyde W. Yancy, MD, MSc, vice dean for diversity and inclusion, chief of cardiology in the department of medicine, Magerstadt Professor and professor of medicine and medical social sciences at Northwestern University Feinberg School of Medicine, and past president of the AHA, wrote in the related editorial. “In those patients fortunate enough to have an improvement in ventricular function and amelioration of the clinical syndrome of heart failure, we should continue effective treatments indefinitely.” – by Darlene Dobkowski

References:

Halliday B, et al. LBS.05 – Hot News in HF. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.

Halliday B, et al. Lancet. 2018;doi:10.1016/S0140-6736(18)32484-X.

Wilcox JE, et al. Lancet. 2018;doi:10.1016/S0140-6736(18)32825-3.

Disclosures: Halliday, Wilcox and Yancy report no relevant financial disclosures.

Brian Halliday
Brian Halliday

CHICAGO — Nearly half of patients who withdrew from pharmacological HF therapy and were considered as being recovered from dilated cardiomyopathy relapsed, according to data presented at the American Heart Association Scientific Sessions.

“Withdrawal of therapy should not usually be advised to our patients at least until we can predict who is going to relapse and who is not and we have a better understanding of therapies that may be able to be reduced and the importance of the different therapies,” Brian Halliday, MBChB, PhD, clinical lecturer in cardiology at Imperial College in London, said during a press conference.

Researchers analyzed data from 51 patients with a prior diagnosis of dilated cardiomyopathy and subsequent recovery and who were taking at least one medication. A screening visit was conducted prior to randomization for clinical assessment, symptom questionnaires, cardiac MRI, N-terminal pro-B-type natriuretic peptide measurement and cardiopulmonary exercise test.

Patients were assigned either therapy withdrawal (n = 25; median age, 54 years; 64% men) or continued therapy (n = 26; median age, 56 years; 69% men). Medications including loop diuretics (12%), mineralocorticoid receptor antagonists (47%), beta-blockers (88%) and angiotensin converting enzyme inhibitors or angiotensin receptor blockers (100%) were reduced and then stopped in patients in the withdrawal group.

Patients in the withdrawal group underwent clinic review every 4 weeks, and those in the continued therapy group underwent a clinic visit every 8 weeks. Follow-up visits were also performed at 16 weeks and 6 months. At 6 months, patients in the control arm underwent therapy withdrawal with the same protocol as the patients who were originally assigned withdrawal.

The primary endpoint was relapse of dilated cardiomyopathy, defined as either reduction in left ventricular ejection fraction by greater than 10% and below 50%, increase in LV end-diastolic volume by greater than 10% and to above normal range, twofold increase in NT pro-BNP and to greater than 400 ng/L or clinical evidence of HF. Therapy was immediately reintroduced once the primary endpoint was met.

#
Nearly half of patients who withdrew from pharmacological HF therapy and were considered as being recovered from dilated cardiomyopathy relapsed, according to data presented at the American Heart Association Scientific Sessions.
Source: Adobe Stock

The primary endpoint was met in 44% of patients in the therapy-withdrawal group compared with none in the control group. During the crossover phase, the primary endpoint was seen in 36% of patients. In all patients who began withdrawal (n = 50), the primary endpoint was seen in 40%, and 50% of patients completed follow-up without treatment re-initiation. LVEF did not deteriorate in 32% of patients who completed withdrawal.

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The safety endpoint was major adverse CV events, CV mortality and unplanned CV hospitalization. During follow-up, there were no unplanned HF hospitalizations, deaths or major adverse CV events. Three serious adverse events occurred in patients assigned withdrawal and included hospitalizations for noncardiac chest pain, urinary sepsis and an elective procedure. There were also no sustained ventricular arrhythmias or device therapies. Atrial fibrillation occurred in three patients. All patients who met the primary endpoint were asymptomatic during follow-up.

“Improvement in function represents remission rather than permanent recovery for many patients,” Halliday said during the press conference.

Jane E. Wilcox
Jane E. Wilcox

“This trial does not squelch the idea of myocardial recovery,” Jane E. Wilcox, MD, MSc, assistant professor of medicine (cardiology) at Northwestern University Feinberg School of Medicine, said during the discussant portion of the press conference. “In fact, I think this will invigorate the field to dig deeper and consider the genomics, proteomics and metabolomics of recovery. Assessment of the myocardial substrate is key, and the signals in cardiac mechanics as measured on cardiac MRI that suggest durability of recovery are real, but require rigorous standardization.”

Clyde W. Yancy

This study was simultaneously published in The Lancet and included an editorial.

“Going forward, in response to a patient’s question: ‘Now that my heart failure has improved, am I able to stop my heart failure drugs?’, the answer should be, ‘No, not at this time,’” Wilcox and Clyde W. Yancy, MD, MSc, vice dean for diversity and inclusion, chief of cardiology in the department of medicine, Magerstadt Professor and professor of medicine and medical social sciences at Northwestern University Feinberg School of Medicine, and past president of the AHA, wrote in the related editorial. “In those patients fortunate enough to have an improvement in ventricular function and amelioration of the clinical syndrome of heart failure, we should continue effective treatments indefinitely.” – by Darlene Dobkowski

References:

Halliday B, et al. LBS.05 – Hot News in HF. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.

Halliday B, et al. Lancet. 2018;doi:10.1016/S0140-6736(18)32484-X.

Wilcox JE, et al. Lancet. 2018;doi:10.1016/S0140-6736(18)32825-3.

Disclosures: Halliday, Wilcox and Yancy report no relevant financial disclosures.

    Perspective
    James L. Januzzi Jr.

    James L. Januzzi Jr.

    TRED-HF looked at a population of patients with dilated cardiomyopathy, wherein a robust improvement in their EF had occurred during medical therapy. We see this in clinical practice. Certain patients initiated and titrated on their guideline-directed therapies have a miraculous improvement in their LV function.

    My patients ask me, “Well, doctor, do I have to take these medicines for my entire life?” The answer was found pretty definitively in the TRED-HF study, which was a small study in which patients with a previous miraculous improvement in EF had their medications downtitrated and/or removed. Forty percent of the patients studied had a downturn in their EF, indicating the fact that despite the improvement in their EF, the medications that fostered that reverse remodeling and improvement in their heart function were absolutely necessary in order to preserve their cardiac function and longevity. This is a very important study, providing much-needed information to clinicians and patients alike.

    • James L. Januzzi Jr., MD
    • Hutter Family Professor of Medicine
      Harvard Medical School
      Director, Dennis and Marilyn Barry Fellowship in Cardiology Research
      Massachusetts General Hospital

    Disclosures: Januzzi reports no relevant financial disclosures.

    Perspective
    Paul Mather

    Paul Mather

    This is a difficult trial because all HF is not similar. Is it remission or recovery? Remission is a worthy endpoint; recovery is a more hoped-for but usually elusive endpoint.

    When you look at the previous trials with peripartum cardiomyopathies, we know that starting at approximately 7 weeks after delivery of the baby, the hormonal milieu of the woman changes back to her baseline. You can argue that after 7 weeks, you could have a chance of recovery in peripartum cardiomyopathy, but the TRED-HF trial is not restricted to the peripartum group. It takes all comers with dilated cardiomyopathy. Remission is probably occurring because of therapy, so why would you want to take that therapy away? Forty percent of people had a worsening after their therapy was stopped. It must be noted that this study had a small enrollment.

    My take-home point is not all HF is the same. HF is a final common pathway of multiple diseases. It is hard to imagine that one approach to multiple different diseases will have a unified answer.

    This study should have an impact in the sense that people should be very cautious about withdrawing reverse remodeling therapy in the setting of a dilated cardiomyopathy. As a HF specialist, I would feel more comfortable in analyzing my peripartum cardiomyopathy patients for recovery and subsequent withdrawal of therapy, based on the IMAC trials of the past decade. It will not change my practice, but hopefully the message out there will be to be very cautious in withdrawing reverse remodeling therapy in the dilated cardiomyopathy patient.

    • Paul Mather, MD, FACC, FAHA, FHFSA, FESC, FACP
    • Professor of Clinical Medicine
      Perelman School of Medicine
      University of Pennsylvania

    Disclosures: Mather reports no relevant financial disclosures.

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