Left ventricular assist devices: bridges to transplantation, recovery, and destination for whom?

Abstract

HomeCirculationVol. 108, No. 25Left Ventricular Assist Devices Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBLeft Ventricular Assist DevicesBridges to Transplantation, Recovery, and Destination for Whom? Lynne Warner Stevenson, MD and Eric A. Rose, MD Lynne Warner StevensonLynne Warner Stevenson From the Cardiovascular Division, Brigham and Women’s Hospital, Boston, Mass (L.W.S.); and the Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, NY (E.A.R.). Search for more papers by this author and Eric A. RoseEric A. Rose From the Cardiovascular Division, Brigham and Women’s Hospital, Boston, Mass (L.W.S.); and the Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, NY (E.A.R.). Search for more papers by this author Originally published23 Dec 2003https://doi.org/10.1161/01.CIR.0000090961.53902.99Circulation. 2003;108:3059–3063Application of mechanical cardiac support now requires consideration of a wider range of goals beyond bridging to transplantation to include destination therapy and perhaps bridging to recovery.1,2 Responsible dissemination of the technology requires identification of patient populations from which to select candidates most likely to benefit. At this early stage, benefit is most apparent against a high background mortality from end-stage heart failure.Populations of Advanced Heart FailureHeart failure affects an estimated 5 million patients in the United States. Of those, ≈60% have heart failure with left ventricular dilation and reduced ejection fraction. Trials demonstrating benefit of therapies for heart failure have focused primarily on mild–moderate heart failure with reduced ejection fraction, generally with annual mortality in the range of 8% to 18%.3Advanced heart failure has been defined as symptoms limiting daily activity (New York Heart Association class III and IV) despite attempted therapy with angiotensin-converting enzyme inhibitors, β-blockers, digoxin, and diuretics,4 a description that applies to ≈300 000 to 800 000 patients in the United States. Although often labeled as “refractory,” many patients enjoy improved quality of life and decreased hospitalizations after referral to experienced heart failure centers, where aggressive medical strategies focus on relief of congestion. Surgical approaches include complex revascularization, valvular repair/replacement, or ventricular reconstruction. When technically successful, biventricular pacing can improve functional status for many of the 25% to 40% of patients with marked ventricular asynchrony.5 If early stabilization allows institution of β-adrenergic–blocking agents, prognosis is further improved.6 Dedicated heart failure management programs that facilitate patient education, compliance, and fluid balance have been integral to benefits observed with these therapies.The highest-risk heart failure populations are best identified after optimization of current therapies. Low left ventricular ejection fraction is not sufficient description of either function or prognosis once heart failure has become advanced. Neither does development of class IV symptoms necessarily condemn patients to continued disability or imminent mortality. For those patients who can achieve and maintain freedom from congestion at 1 month, 2-year survival approaches 80%.7 Peak oxygen consumption integrates cardiac reserve, peripheral conditioning, and general status, predicting mortality when <10 to 12 mL · kg−1 · min−1 and survival when >16 to 18 mL · kg−1 · min−1,8 and may also improve within 3 to 6 months after referral.9 Cachexia is another integrated measure associated with poor outcome but has not been consistently defined. Laboratory indices of failing homeostasis, such as hyponatremia and worsening renal function, predict poor outcome in populations but are less useful in individuals. Within an experienced group with uniform strategies, ambulatory patients with persistent class IV symptoms can be further identified as high risk by the development of circulatory or renal limitations to angiotensin-converting enzyme inhibitors10 and inability to wean from inotropic infusions (Figure). Download figureDownload PowerPointDefinition of heart failure populations with decreasing estimated mortality. As cardiac transplantation is associated with <20% 1-year mortality and ≈50% 10-year survival, survival benefit is anticipated even in the absence of imminent mortality. Benefit of LVAD for bridging to transplantation is accepted. Initial data on LVAD as permanent “destination” therapy demonstrate survival benefit in patients with 6-month mortality in the range of 50%. Improving results with assist devices will expand the population in whom benefit is expected.Populations for Cardiac TransplantationFor the individual patient, further intervention is considered by comparing expected outcomes with and without the intervention. Most experience with advanced heart failure has derived from evaluation for transplantation. Without a controlled trial, this therapy was established after a rigorous observational study federally funded at expert centers, where patients were deemed to have had “less than 6 months to live.”11 Subsequent improvements in both transplantation and medical therapy led to a downward shift of population risk, such that patients now have better outcomes than initially, both with and without transplantation. Although earlier risk analyses encompassed both sudden and hemodynamic deaths, the decreasing prevalence of unexpected sudden death now allows focus on symptoms and death related to hemodynamic deterioration. Absolute indications for transplantation include refractory cardiogenic shock, dependence on intravenous inotropic support (both Status I), or persistent class IV symptoms with peak oxygen consumption <10 mL · kg−1 · min−1.3 Anticipated benefit for transplantation in this group is the difference between 1-year survival of <50% without transplantation and 83% after transplantation, with almost 50% alive at 10 years. Most patients awaiting transplantation are ambulatory on oral therapy (Status II), fulfilling relative indications of major daily limitation with peak oxygen consumption 11 to 14.3 Their anticipated benefits are less dramatic but still highly favorable. Although of major importance for the individual recipient, cardiac transplantation is epidemiologically trivial inasmuch as donor heart supply is limited to 2200 yearly in the United States, where an estimated 100 000 patients might meet criteria without major contraindications.12Populations for Destination Left Ventricular Assist DevicePatients With Proven BenefitPermanent therapy with mechanical cardiac output was originally envisioned for patients with end-stage heart failure for whom donor hearts were not available. In the recent Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart failure (REMATCH) trial, inclusion criteria resembled those for transplantation: class IV heart failure, left ventricular ejection fraction <25%, and either peak oxygen consumption <12 to 14 mL · kg−1 · min−1 or dependence on intravenous inotropic infusion.13 Extrapolation from transplant evaluation led to underestimation of disease severity14 in patients signing up for randomization to mechanical cardiac support, who were considered ineligible for transplantation. The enrolled patients represented the most severe profile randomized in a heart failure trial, both in terms of the robust factors of blood pressure, sodium, and creatinine and in terms of the mortality2 (Table 1). The population was intermediate in severity between Status I (urgent) and Status II transplantation candidates, but significantly older. TABLE 1. Profiles of Severe Heart FailureCONSENSUS22RALES15PROMISE20COPERNICUS6FIRST21Tx IITx IREMATCH MedicalCONSENSUS indicates COoperative North Scandinavian ENalapril SUrvival Study; RALES, Randomized ALdactone Evaluation Study; COPERNICUS, CarvedilOl ProspEctive RaNdomIzed CUmulative Survival; PROMISE, Prospective RandOmized MIlrinone Survival Evaluation; FIRST, Flolan International Randomized Survival Trial; and REMATCH, Randomized Evaluation of Mechanical Assistance for Treatment of Congestive Heart Failure.Mortality from control survival curves, on ACE inhibitors as tolerated (active for CONSENSUS). LVEF indicates left ventricular ejection fraction; SBP, systolic blood pressure; Tx II, transplantation candidates listed as status II (of whom 44% had transplantation by 6 mo and 30% had either died or deteriorated to urgent status*);Tx I, candidates listed as status I (on intravenous inotropic agents or assist devices) for whom blood pressures not comparable (76% of patients had undergone transplantation by 6 mo). †Data derived from the Pre-Transplant Research Database (courtesy of R. Bourge and D. Kirklin).Age, y7065646365515168SBP, mm Hg119122115125107100†103LVEF, %…25212019201717Sodium, meq/L138…139137137137135135Creatinine, mg/dL1.51.21.51.5…1.41.41.8Mortality at 6 mo, %292528103730*40†48Although REMATCH randomized patients to left ventricular assist device (LVAD) versus “optimal medical management,”13 most patients randomized were already beyond current medical therapy. Hypotension and progressive renal dysfunction had led to discontinuation of renin–angiotensin system inhibitors in 32% of patients. Development of circulatory-renal limitation preventing angiotensin-converting enzyme inhibitor use has been associated elsewhere with 6-month mortality over 50%.10 Few of these patients could be considered for β-adrenergic–blocking agents, presenting a worse profile than the recent CarvedilOl ProspEctive RaNdomIzed CUmulative Survival (COPERNICUS) trial,6 where 6-month control mortality was 10%, compared with 48% in REMATCH. For 71% of patients, continuous intravenous inotropic agents were given at enrollment, consistent with the indication for palliation of refractory heart failure in recent American College of Cardiology/American Heart Association guidelines.3 Mortality for patients on multiple experiences of chronic inotropic infusions has been close to 50% at 6 months.In this uniquely compromised study population of 129 patients, assist devices decreased mortality by 48% over 2 years.2 The improvement in survival was greatest for patients receiving intravenous inotropic therapy at randomization, in whom 1-year mortality was reduced by the LVAD from 76% to 51%. It is sobering that the benefit of the device would not have been appreciated without the control arm, which had a mortality rate twice that projected.In trials of patients likely to survive anyway, calculation of relative decreases in mortality emphasizes the positive impact of interventions (Table 2). Relative mortality reduction with the LVAD was similar to that for spironolactone and carvedilol in moderate-to-severe heart failure.6,15 When the natural history predicts mortality during the trial, however, it may be more relevant to calculate the increase in survival (Table 2). For patients on intravenous inotropic therapy at the time of randomization, implantation of the LVAD increased 1-year survival by 104%. TABLE 2. What Is Meaningful Benefit in End-Stage Disease?Study (Therapy)Control vs Therapy, % of patientsRelative Benefit, %Absolute Benefit (Year 1 = No. Patients/100)SOLVD indicates Studies Of Left Ventricular Dysfunction. Other abbreviations as in Table 1.SOLVD (ACE inhibitor)23 Mortality at 1 y14 vs 11213 Survival at 1 y86 vs 893CONSENSUS (ACE inhibitor)22 Mortality at 1 y62 vs 452717 Survival at 1 y38 vs 5545COPERNICUS (β-blocker)6 Mortality at 1 y18.5 vs 11417.5 Survival at 1 y81.5 vs 8910RALES (spironolactone)15 Mortality at 1 y25 vs 17328 Survival at 1 y75 vs 8311REMATCH-inotropic (LVAD) Mortality at 1 y76 vs 513725 Survival at 1 y24 vs 49104Many patients rate the quality of survival to be of equal or greater importance than the duration.16 The initial heart failure symptom score of 75 indicates more severe limitation than any previous trial.2 Improvement to below 50 confirms a major symptomatic improvement, to a level expected for NYHA class III. These results are apparent despite a high complication rate, with median 88 hospital days after LVAD compared with 24 days on continued medical therapy. The LVAD patients experienced 340 days alive out of the hospital, compared with 106 for patients on medical therapy.2The majority of the morbidity and mortality resulted from device infections and failures. The REMATCH surgical experience strongly suggests that infectious morbidity could be markedly reduced by meticulous attention to driveline immobilization by specifically designed garments, use of more pliable materials in driveline fabrication, and vigorous nutritional supplementation in cachectic patients. Modifications of the device inflow valve, device controller software, and motor design are also likely to afford improved future durability.Preliminary cost data from the investigation reflects early experience in this population and the investigational protocol. Of the average cost of $202 000 (range $76 000 to $732 000, median $141 000), one third was for the device itself and one quarter was for intensive care unit days.17 It is anticipated that the initial cost of this new technology application will decline with wider acceptance and experience but is comparable to cardiac transplantation and lower than liver transplantation. The current target population for this device is estimated at 5000 to 10 000 but is likely to increase as the outcomes improve. Preparing for equitable access to this technology presents multiple societal challenges different from those created by the limited organ supply for transplantation.Bridge and RecoveryBridgeLVADs have been used in over 3500 patients as a bridge to transplantation, with over 50% of recent implantable device recipients discharged home. As transplantation offers good-quality survival of almost 50% at 10 years, patients requiring chronic LVADs for the near future will continue to proceed to transplantation if eligible.1 However, increasing time on the waiting list has allowed progressively longer experiences with these devices. As some candidates choose to defer transplantation while enjoying device support, the distinction between bridging and destination is blurring, although transplantation candidates still present a more favorable comorbidity profile than primary “destination” LVAD patients.RecoverySome patients have demonstrated sufficient recovery of ventricular function to allow successful device weaning. This is most apparent for acute-onset fulminant myocarditis, with which spontaneous recovery is common if circulation is maintained acutely. Patients presenting less dramatically with ≤6 months of cardiomyopathy have almost 50% chance of major spontaneous improvement, rarely requiring mechanical support. Major recovery after a year of symptomatic heart failure has been less often observed, although a degree of improvement is common. Left ventricular size contracts, fetal gene expression diminishes, fibrosis regresses, and myocyte architecture often improves after a month of support. Although the experience has been variable, fewer than 10% of patients have demonstrated sufficient recovery of left ventricular function within 3 to 6 months to undergo device explantation.18 Recovery is most often seen in dilated cardiomyopathy and may be influenced by multiple factors, including the degree of unloading, neurohormonal inhibition, and the underlying myocardial injury. Early use of neurohormonal antagonists and timed therapy with clenbuterol have been suggested to enhance hypertrophy and recovery of skeletal and cardiac muscle during prolonged mechanical support. There is currently a collaborative working group to assess whether recovery can occur more consistently.Successful introduction of skeletal myoblasts and stem cells into infarcted myocardium raises new possibilities for reengineered recovery.19 Multiple challenges are presented, however, for individual cell survival and function, and the formation of effective syncytia without the creation of substrates for limiting ventricular arrhythmias.Next DestinationsNew DevicesAlthough REMATCH proved the survival and quality-of-life benefit of the Thoratec HeartMate device for patients with end-stage heart failure not considered appropriate for transplantation, similar pulsatile implantable devices (eg, Worldheart Novacor, Arrow Lionheart) and newer modifications may prove equal or superior. A new generation of smaller, more efficient, nonpulsatile devices may offer a less surgically traumatic approach, though hemodynamic effectiveness and durability remain unproven in large patient populations. Early experience with the Abiocor total artificial heart confirms hemodynamic effectiveness for this more complex class of devices, which may be particularly well suited for severe biventricular failure. Substantial morbidity and concerns about the quality of life for patients in recent trials mandate continued caution. Hindsight will likely reveal the current era to be an early stage in the evolution of device therapy for heart failure. As the technology improves, use of devices for end-stage heart failure will likely increasingly mirror the use of hemodialysis for end-stage renal failure.New PopulationsWho will form the new populations for clinical evaluation of devices? End-stage disease and immediate impact of current devices defy precedents set by pharmacological trials.1 At this time, it does not seem ethical to randomize a population similar to REMATCH to a medical therapy arm unless physical constraints prevent implantation of currently available devices. Subsequent trials will likely include provision for compassionate device placement in patients reaching preestablished criteria for imminent mortality. Comparison of 2 active device interventions can be done when the newer device offers potential advantage for either quality of life or survival. The international mechanical cardiac support device registry currently being implemented will be vital to provide benchmarks of performance as the experience with destination therapy expands beyond the 68 device patients from REMATCH.As devices and the techniques for infection prophylaxis continue to improve, the benefits for both survival and function will be easier to identify. New trials may then include patients with lesser immediate compromise and risk of death (Figure). As device reliability improves, trials will likely focus more on composite end points of quality of life and survival and may eventually be designed to demonstrate decreased disease progression. The complexity of resources required restricts the trial population to a fraction of that required to demonstrate small absolute benefits in pharmaceutical trials. To streamline identification of target populations before device approval and refine their definition afterward, a high priority for further progress in this field is the development of independent registries of patients with advanced heart failure.1 Implantable circulatory support devices represent one of several expensive technologies, such as coated stents and implantable defibrillators, that warrant close surveillance to maximize benefit within the context of the total resources available for health care.SummaryWe are entering an era in which long-term mechanical circulatory support will likely play an increasing role in the approach to end-stage heart disease. The extension of mechanical circulatory support devices into destination therapy has revealed the limitations of our understanding of these populations. Current candidates for benefit from these devices demonstrate progression of disease beyond the scope of current medical therapy as provided in experienced centers, with estimated 50% mortality at 6 months. The recent REMATCH trial doubled 1-year survival to that of ambulatory class IV patients on oral therapy, providing a benchmark for future progress. Trials of devices for end-stage disease require innovative design. As devices and techniques continue to improve, benefit for both survival and function may be demonstrated in patients with decreasing severity of disease. Acceptance of devices presents societal challenges for equitable health resource allocation.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Dr Rose is a research investigator for Thoratec, Micromed, and Arrow. Dr Stevenson is a research investigator for the REMATCH trial, which was sponsored by the National Heart, Lung, and Blood Institute, in conjunction with Thoratec.FootnotesCorrespondence to Lynne Warner Stevenson, MD, Brigham and Women’s Hospital, Cardiovascular Division, 75 Francis St, Boston, MA 02115. References 1 Stevenson LW, Kormos RL. Mechanical cardiac support 2000: current applications and future trial design. J Am Coll Cardiol. 2001; 37: 340–370.CrossrefMedlineGoogle Scholar2 Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med. 2001; 345: 1435–1443.CrossrefMedlineGoogle Scholar3 Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2001; 38: 2101–2113.CrossrefMedlineGoogle Scholar4 Adams KF, Zannad F. Clinical definition and epidemiology of advanced heart failure. Am Heart J. 1998; 135: S204–S215.CrossrefMedlineGoogle Scholar5 Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002; 346: 1845–1853.CrossrefMedlineGoogle Scholar6 Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001; 344: 1651–1658.CrossrefMedlineGoogle Scholar7 Lucas C, Johnson W, Hamilton MA, et al. Freedom from congestion predicts good survival despite previous class IV symptoms of heart failure. Am Heart J. 2000; 140: 840–847.CrossrefMedlineGoogle Scholar8 Mancini DM, Eisen H, Kussmaul W, et al. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation. 1991; 83: 778–786.CrossrefMedlineGoogle Scholar9 Stevenson LW, Steimle AE, Fonarow G, et al. Improvement in exercise capacity of candidates awaiting heart transplantation. J Am Coll Cardiol. 1995; 25: 163–170.CrossrefMedlineGoogle Scholar10 Kittleson M, Stevenson LW, Hurwitz S, et al. Development of circulatory-renal limitations to ACE inhibitors identifies patients with severe heart failure and early mortality. J Am Coll Cardiol. 2003; 41: 2029–2035.CrossrefMedlineGoogle Scholar11 Evans RW, Broida JH. National Heart Transplantation Study. Seattle, Wash: Battelle Human Affairs Research Centers, 1985.Google Scholar12 Willman V. Expert panel review of NHLBI Total Artificial Heart Program. 1999. Available at: http://www.nhlbi.nih.gov/resources/docs/tah-rpt.htm. Accessed November 17, 2003.Google Scholar13 Rose EA, Moskowitz AJ, Packer M, et al. The REMATCH trial: rationale, design, and end points. Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure. Ann Thorac Surg. 1999; 67: 723–730.CrossrefMedlineGoogle Scholar14 Stevenson LW, Couper G, Natterson B, et al. Target heart failure populations for newer therapies. Circulation. 1995; 92 (suppl II): II-174–II-181.LinkGoogle Scholar15 Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999; 341: 709–717.CrossrefMedlineGoogle Scholar16 Lewis EF, Johnson PA, Johnson W, et al. Preferences for quality of life or survival expressed by patients with heart failure. J Heart Lung Transplant. 2001; 20: 1016–1024.CrossrefMedlineGoogle Scholar17 Oz M, Gelijns AC, Moskowitz AJ, et al. Costs of LVAD implantation: lessons from the REMATCH trial. Circulation. 2002; 106 (suppl II): II–606.Abstract.Google Scholar18 Mancini DM, Beniaminovitz A, Levin H, et al. Low incidence of myocardial recovery after left ventricular assist device implantation in patients with chronic heart failure. Circulation. 1998; 98: 2383–2389.CrossrefMedlineGoogle Scholar19 Menasche P, Hagege AA, Scorsin M, et al. Myoblast transplantation for heart failure. Lancet. 2001; 357: 279–280.CrossrefMedlineGoogle Scholar20 Packer M, Carver JR, Rodeheffer RJ, et al. The PROMISE Study Research Group. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med. 1991; 325: 1468–1475.CrossrefMedlineGoogle Scholar21 Califf RM, Adams KF, McKenna WJ, et al. A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: The Flolan International Randomized Survival Trial (FIRST). Am Heart J. 1997; 134: 44–54.CrossrefMedlineGoogle Scholar22 The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987; 316: 1429–1435.CrossrefMedlineGoogle Scholar23 The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991; 325: 293–302.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Vishram-Nielsen J, Deis T, Rossing K, Wolsk E, Alba A and Gustafsson F (2020) Clinical presentation and outcomes in women and men with advanced heart failure, Scandinavian Cardiovascular Journal, 10.1080/14017431.2020.1792972, 54:6, (361-368), Online publication date: 1-Nov-2020. 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