Stopping medication for heart failure with improved ejection fraction
Authors: Jane Wilcox, Clyde W Yancy
Journal: The Lancet (2018)

Current clinical practice guidelines have identified a new category of heart failure: heart failure with improved ejection fraction.1Writing Committee Members2016 ACC/AHA/HFSA Focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.Circulation. 2016; 134: e282-e293Crossref PubMed Scopus (321) Google Scholar, 2Ponikowski P Voors AA Anker SD et al.2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.Eur Heart J. 2016; 37: 2129-2200Crossref PubMed Scopus (8726) Google Scholar Multiple observational series on heart failure show improved measures of ventricular function after initial presentation of heart failure with reduced ejection fraction3Basuray A French B Ky B et al.Heart failure with recovered ejection fraction: clinical description, biomarkers, and outcomes.Circulation. 2014; 129: 2380-2387Crossref PubMed Scopus (192) Google Scholar, 4Florea VG Rector TS Anand IS Cohn JN Heart failure with improved ejection fraction: clinical characteristics, correlates of recovery, and survival: results from the valsartan heart failure trial.Circ Heart Fail. 2016; 9: e003123Crossref PubMed Scopus (65) Google Scholar, 5Kalogeropoulos AP Fonarow GC Georgiopoulou V et al.Characteristics and outcomes of adult outpatients with heart failure and improved or recovered ejection fraction.JAMA Cardiol. 2016; 1: 510-518Crossref PubMed Scopus (138) Google Scholar, 6Punnoose LR Givertz MM Lewis EF Pratibhu P Stevenson LW Desai AS Heart failure with recovered ejection fraction: a distinct clinical entity.J Card Fail. 2011; 17: 527-532Summary Full Text Full Text PDF PubMed Scopus (107) Google Scholar and improvement in clinical outcomes. What drives ventricular recovery is largely unknown; is it removal of insult (eg, tachycardia or toxins) or a fortuitous response to medical or device therapy? Moreover, the biology of true ventricular recovery, if such an effect occurs, is unknown. Pragmatically, a salient question emerges: in patients with improved heart failure, is ongoing exposure to multidrug medical treatment still required? In The Lancet, Brian P Halliday and colleagues7Halliday BP Wassall R Lota AS et al.Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial.Lancet. 2018; (published online Nov 11.)http://dx.doi.org/10.1016/S0140-6736(18)32484-XSummary Full Text Full Text PDF Scopus (252) Google Scholar report the results of the TRED-HF trial, an open-label, pilot, randomised study of evidence-based medical treatment withdrawal for reduced ejection fraction heart failure due to dilated cardiomyopathy in patients with complete restoration of ventricular function (left ventricular ejection fraction [LVEF] >50%), normalisation of biomarker profiles (N-terminal pro-B-type natriuretic peptide [NT-pro-BNP] <250 ng/L), and New York Heart Association Class class I symptoms. By use of an empirically derived protocol for medication withdrawal over 16 weeks, the investigators7Halliday BP Wassall R Lota AS et al.Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial.Lancet. 2018; (published online Nov 11.)http://dx.doi.org/10.1016/S0140-6736(18)32484-XSummary Full Text Full Text PDF Scopus (252) Google Scholar identified a compelling 44% rate of recrudescent ventricular dysfunction represented by a drop in ejection fraction (in 11 of 25 patients randomly assigned to treatment withdrawal who met the primary endpoint of relapse compared with none of 26 assigned to continue treatment; Kaplan-Meier estimate of event rate 45·7% [95% CI 28·5–67·2]; p=0·0001) and a rise in biomarkers over a follow-up period of 6 months. However, evidence of recrudescent heart failure—defined as a drop in LVEF of 10% to less than 50%, increase in left ventricular end diastolic volume by more than 10% or a two-fold increase in NT-pro-BNP to more than 400 ng/L, or clinical symptoms—became apparent within just 8 weeks. A similar incidence of recrudescent heart failure (in nine [36·0%] of 25 patients) was noted in the control group at the time of the single-arm crossover; and the independent data safety monitor was alerted early in the study to a high occurrence of recurrent heart failure. The authors are acknowledged for addressing a provocative question, for acting expeditiously to resume medical treatments before overt clinical decompensation, and for a priori creating a process to adjudicate events and terminate the trial as needed. The key commentary, however, is the scientific implication of these results. First, we are reminded that mechanisms of improvement after exposure to evidence-based medical treatments, although well informed, have not been fully resolved. Other than LVEF, there are no biomarkers or clinical profiles that align with treatment responses. We have no signal or barometer to suggest that a previously indicated treatment for reduced ejection fraction is no longer necessary and can be safely discontinued. Second, we should be more precise with our nomenclature. Those patients who have restoration of ventricular function are less likely to have recovered ventricular function and more appropriately should be described as having ventricular dysfunction in remission. The parallels with oncology are appropriate. This distinction has been previously described in the literature8Mann DL Barger PM Burkhoff D Myocardial recovery and the failing heart: myth, magic, or molecular target?.J Am Coll Cardiol. 2012; 60: 2465-2472Crossref PubMed Scopus (174) Google Scholar but the results of the TRED-HF study now endorse the view that most patients with restoration of ventricular function as measured by an improved LVEF are in remission and have an indefinite indication for evidence-based medical treatment without interruption. Third, recovery would necessarily suggest that intrinsic contractility and especially cardiac mechanics, as assessed more precisely by Lagrangian strain, have been restored; protein expression has been normalised; and the neurohormonal milieu has returned to normal and is no longer activated. In fact, recent data show that many patients with restored ejection fraction still have underlying abnormal cardiac mechanics (ie, impaired longitudinal strain) and are at risk for clinical events and heart failure relapse, even with continued medical treatment.9Adamo L Perry A Novak E Makan M Lindman BR Mann DL Abnormal global longitudinal strain predicts future deterioration of left ventricular function in heart failure patients with a recovered left ventricular ejection fraction.Circ Heart Fail. 2017; 10: e003788Crossref PubMed Scopus (46) Google Scholar Thus, we would expect that those who had recrudescent heart failure (44%) might have had abnormal strain and those who did not relapse (n=30) should have had intact strain measures. However, the reported strain measures as obtained by deformation-tracking cardiovascular magnetic resonance (CMR) were in the normal range for most patients in TRED-HF. Importantly, measurement of strain is not yet standardised. As a case in point, feature-tracking CMR methods have much higher reported normal values (–0·19).10Puntmann VO Valbuena S Hinojar R et al.Society for Cardiovascular Magnetic Resonance (SCMR) expert consensus for CMR imaging endpoints in clinical research: part I—analytical validation and clinical qualification.J Cardiovasc Magn Reson. 2018; 20: 67Crossref PubMed Scopus (78) Google Scholar This uncertainty around restoration of cardiac mechanics in patients with restored ejection fraction emphasises the need for validated sequence-specific normal ranges for CMR-derived strain methods and highlights the notion that true recovery of normal ventricular function is likely an infrequent occurrence.9Adamo L Perry A Novak E Makan M Lindman BR Mann DL Abnormal global longitudinal strain predicts future deterioration of left ventricular function in heart failure patients with a recovered left ventricular ejection fraction.Circ Heart Fail. 2017; 10: e003788Crossref PubMed Scopus (46) Google Scholar Molecular pathways involved in fibrosis,11Bruckner BA Razeghi P Stetson S et al.Degree of cardiac fibrosis and hypertrophy at time of implantation predicts myocardial improvement during left ventricular assist device support.J Heart Lung Transplant. 2004; 23: 36-42Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar excitation–contraction coupling and calcium handling,12Latif N Yacoub MH George R Barton PJ Birks EJ Changes in sarcomeric and non-sarcomeric cytoskeletal proteins and focal adhesion molecules during clinical myocardial recovery after left ventricular assist device support.J Heart Lung Transplant. 2007; 26: 230-235Summary Full Text Full Text PDF PubMed Scopus (48) Google Scholar and T-tubule systems13Seidel T Navankasattusas S Ahmad A et al.Sheet-like remodeling of the transverse tubular system in human heart failure impairs excitation-contraction coupling and functional recovery by mechanical unloading.Circulation. 2017; 135: 1632-1645Crossref PubMed Scopus (63) Google Scholar might further define the extent of ventricular recovery. Certain genomics in dilated cardiomyopathy predict prognosis, risk of sudden death, and response to treatments. It is not surprising that almost a quarter of patients in this study had truncating variants in TTN, which tends to have a more benign course than other genetic cardiomyopathies (eg, LMNA).14Jansweijer JA Nieuwhof K Russo F et al.Truncating titin mutations are associated with a mild and treatable form of dilated cardiomyopathy.Eur J Heart Fail. 2017; 19: 512-521Crossref PubMed Scopus (95) Google Scholar The results of TRED-HF are not definitive as this was a highly selected, open-label pilot study with small numbers of patients with dilated cardiomyopathy; all of these aspects were necessary to ensure safety and restrict exposure to an uncertain intervention. Further studies to identify ventricular recovery are warranted, but we should tread lightly. In addition to the clinical findings from this study—the effects of advanced age, higher NT-pro-BNP concentration, the need for a multidrug heart failure regimen, and reduced global radial strain—future explorations should include a broader profile of omics (eg, proteomics, genomics, and metabolomics) and rigorously standardised measures of cardiac mechanics. For those in whom recovery has occurred, avoidance of morbidity and costs associated with lifelong medical treatment can and should matter. For those in remission, identifying the minimal exposure to evidence-based medical treatment required for stability should be a similar pursuit. 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.” 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. We declare no competing interests. Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trialMany patients deemed to have recovered from dilated cardiomyopathy will relapse following treatment withdrawal. Until robust predictors of relapse are defined, treatment should continue indefinitely. Full-Text PDF Open Access