Ve n t r i c u l a r A s s i s t a n c e D e v i c e s a s B r i d g e t o Tra n s p l a n t a t i o n Mario Gaudino, MDa,*, Piero Farina, MDa, Sonia Bernazzali, MDb, Piergiorgio Bruno, MDa, Christian Colizzi, MDa, Guido Sani, MDb, Massimo Massetti, MDa KEYWORDS Ventricular assistance devices Heart transplantation Therapeutic strategies Posttransplant outcomes
KEY POINTS
BACKGROUND Almost 50 years after the first procedure performed in 1967, heart transplantation still remains the gold standard for the treatment of advanced and refractory heart failure (HF) because of its excellent long-term outcomes. The number of procedures carried out worldwide dramatically increased in the early 1980s following the clinical employment of cyclosporine to prevent graft rejection. Since the 1990s, the total number of transplants slowly started to decrease, until reaching (since the 2000s) a stable number of about 4500 procedures per year.1 Although transplants have remained stable, the number of patients waiting for a heart continues to increase and actually largely exceeds the available organs; in North America, 13.6% of patients die while on the waiting list for transplantation.2 Mechanical circulatory support (MCS) is an umbrella term that encompasses various devices that sustain or even replace cardiac function. The first
clinical applications of MCS date back to the 1960s, mostly in the setting of postcardiotomy cardiogenic shock.3 The development of durable, implantable MCS devices was initially conceived for indefinite support (destination therapy) in patients who were not eligible for heart transplantation. Concerns about the long-term performance and safety, however, led regulatory agencies to restrict the initial use of such devices to patients who were eligible for a transplant. This bias set the early stage for what has become the bridge to transplantation (BTT) indication.4 The devices typically used for BTT are ventricular assistance devices (VADs). These devices are pumps connected to the patients’ circulation that partially or completely replace the function of the left or right side of the heart (or both). Both percutaneously and surgically implanted VADs are available. The first type (intravascular or extracorporeal) is intended for temporary, short-term use, whereas surgically implanted (intracorporeal or paracorporeal, axial or centrifugal) VADs are for
Disclosures, Conflicts of Interest, Funding: None. a Division of Cardiac Surgery, Department of Cardiovascular Sciences, Catholic University, L.go Gemelli 8, 00168 Rome, Italy; b Cardiac Surgery, Department of Medical-Surgical Critical Care, University of Firenze, Florence, Italy * Corresponding author. E-mail address: [emailprotected] Heart Failure Clin 10 (2014) S39–S45 http://dx.doi.org/10.1016/j.hfc.2013.08.006 1551-7136/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
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Bridge to transplantation is a major indication for ventricular assistance device (VAD) implantation both as a life-saving measure and in the elective setting. VAD implantation improves patients’ status and can reduce operative risk. VAD implantation does not seem to adversely affect posttransplant outcomes, at least in selected patients. Bridge to transplantation by VAD can potentially be cost-effective in some patients groups.
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Gaudino et al midterm or long-term use. The first VADs were paracorporeal, bulky pulsatile pumps (mostly pneumatically driven) requiring hospitalization and allowing very poor patient mobilization. The development of continuous-flow, axial pumps (secondgeneration VADs) eliminated the reservoir chamber and valves needed for the first-generation pulsatile pump. This development has led to more reliable, smaller, and totally implantable devices, thereby allowing a quality of life that is comparable with normal. The magnetic and/or hydrodynamic levitation of the impeller without any contact bearings with the pump is the major advancement of the third-generation VAD.5
INDICATIONS FOR BTT To date, there is no universal consensus on the indications for MCS as a BTT. The Heart Failure Society of America’s comprehensive HF practice guidelines6 state that patients awaiting heart transplantation who have become refractory to all means of medical circulatory support should be considered for an MCS device as a BTT (level of evidence B). Also, patients with refractory HF and hemodynamic instability and/or compromised end-organ function with relative contraindications to cardiac transplantation or permanent MCS expected to improve with time or restoration of an improved hemodynamic profile should be considered for urgent MCS as a bridge to decision (ie, in order to gain time for a further evaluation over the most appropriate strategy) (level of evidence C). The European Society of Cardiology’s 2012 guidelines for the diagnosis and treatment of acute and chronic HF recommend left VAD (LVAD) or biventricular assistance device support as BTT in selected patients with end-stage HF despite optimal pharmacologic and device treatment and who are otherwise suitable for heart transplantation to improve symptoms and reduce the risk of HF hospitalization for worsening HF and to reduce the risk of premature death while awaiting transplantation (class I, level of evidence B).7 Establishing the time frame for implantation of MCS is crucial to maximize the benefit and minimize the risk of MCS. The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) is a US registry that acquires data on patients supported with Food and Drug Administration–approved MCS devices. In the registry, patients in the New York Heart Association III to IV class are further classified into 7 clinical profiles according to their signs and symptoms (7 being the least and 1 the most severe profile) (Table 1). The prognostic implications of the INTERMACS profiles provide guidance for the indication for
MCS; for the optimal timing of implantation; and ultimately, for the selection of the appropriate device.8 INTERMACS 1 patients need MCS within hours; rapidly implantable devices, like intraaortic balloon counterpulsation, percutaneously implanted VADs, or extracorporeal membrane oxygenation (ECMO) will bridge the patients to durable MCS devices or transplantation. Patients in the INTERMACS 2 profile require enrollment in the emergent transplantation list or, alternatively, MCS support to be provided within days; both short-term and surgically implanted VADs can be considered. INTERMACS 3 and 4 patients are in end-stage HF and are waiting for elective MCS implantation; surgically implantable devices are the devices of choice.
VAD AS BTT: SETTINGS AND CURRENT STATUS In the current clinical practice, BTT is a major indication for VAD implantation. In the most recent publication from the INTERMACS registry, 54.1% of the primary VAD implantations were for BTT (with about half of the implanted patients listed for transplantation at the time of the device implantation).9 Similarly, the 2010 International Society of Heart and Lung Transplantations’ report shows that the incidence of VAD-supported cases at the time of transplantation increased from 11% in 1999 to 36% in 20111; most of the cases (89%) are supported with LVAD, almost 10% require biventricular assistance, and only a small minority (1%) need right ventricular support. Patients receive VAD as a BTT in 2 different settings. A consistent number of cases receive VAD in the setting of acute, unresponsive cardiogenic shock as a life-saving measure (INTERMACS 1 and 2 patients). In this setting, VAD implantation as a BTT seems associated with improved outcomes when compared with emergency transplantation.10 In others circ*mstances, patients who are already on the waiting list undergo device implantation in a more elective setting with the aim of preventing progressive hemodynamic deterioration and improving physical and nutritional status before transplantation.11 A distinctive advantage of device implantation is the possibility to decrease pulmonary pressures leading to possible improvements in posttransplant outcomes and even to listing patients who were previously not listable (bridge to candidacy).12 VAD implantation ameliorates end-organ perfusion and function and consents optimization of patients’ fitness and nutritional status, but these advantages must be weighed against the potential risk of surgery
Ventricular Assistance Devices
Table 1 INTERMACS Clinical profiles
Level
Description
Hemodynamic Status
1
Critical cardiogenic shock, crash and burn
2
Progressive decline on inotropic support, sliding on inotropes
3
Stable but inotrope dependent, dependent stability
4
Resting symptoms, frequent flyer
5
Exertion intolerant, housebound
6
Exertion limited, walking wounded
7
Advanced NYHA III symptoms, placeholder
Persistent hypotension despite rapidly escalating inotropic support and eventually IABP, and critical organ hypoperfusion Intravenous inotropic support with acceptable values of blood pressure and continuing deterioration in nutrition, renal function, or fluid retention Stability reached with mild to moderate doses of inotropes but demonstrating failure to wean from them because of hypotension, worsening symptoms, or progressive renal dysfunction Possible weaning of inotropes but experiencing recurrent relapses, usually fluid retention Severe limited tolerance for activity, comfortable at rest with some volume overload, and often with some renal dysfunction Less severe limited tolerance for activity and lack of volume overload, fatigued easily Patients without current or recent unstable fluid balance, NYHA class II or III
Time Frame for Intervention Within hours
Within days
Elective over weeks to months
Elective over weeks to months Variable urgency, depends on nutrition and organ function Variable urgency, depends on nutrition and organ function Not currently indicated
Abbreviations: IABP, intra-aortic balloon pump; NYHA, New York Heart Association. Adapted from Boyle AJ, Ascheim DD, Russo MJ, et al. Clinical outcomes for continuous-flow left ventricular assist device patients stratified by pre-operative INTERMACS classification. J Heart Lung Transplant 2011;30:403; with permission.
and of VAD complications like bleeding, infection, and neurologic events. A still-open issue is the time of relisting heart transplantation candidates who receive a VAD as a BTT. An interval of at least 6 months after implantation is recommended by most investigators in cases of pulmonary hypertension13,14; no general consensus exists for patients who receive BTTVAD for other reasons. Although it has been consistently shown that VAD reduce mortality while on the transplant waiting list,15,16 whether device implantation as a BTT affects posttransplantation outcomes is still controversial. Single studies have given conflicting results, demonstrating no difference, decreased, or even improved survival between patients with VAD versus patients without VAD.17–24 In contrast, reports from large registries, such as the International Society of Heart and Lung Transplantation and the Organ Procurement and Transplantation Network, have shown increased posttransplant
mortality for VAD-supported patients.1,25 In a comprehensive systematic review of 31 studies including almost 20,000 patients, Alba and colleagues26 found that the use of paracorporeal VAD as a BTT was associated with significantly higher mortality at 1, 3, and 5 years after transplantation; but these data were not replicated for intracorporeal devices, whose postoperative outcomes were similar to nonsupported patients. In the same study, even the risk of rejection and the development of chronic renal dysfunction and coronary allograft vasculopathy were not affected by VAD implantation as a BTT. Similarly, in a bestevidence review of the current literature including more than 400 articles, Urban and coauthors27 found that VAD implantation before transplantation does not affect posttransplant outcomes in selected patients. Patients who require biventricular assistance are a particularly complex and sick population with poor early and long-term outcomes.28 Evidence exists that the type of VAD
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Gaudino et al implanted can influence posttransplant outcome; Ono and colleagues29 reported how continuousflow VAD used as a BTT achieve better clinical outcomes when compared with paracorporeal devices, and this finding is consistent with those previously reported by Kamdar and associates30 and by Alba and colleagues.26 Recently, an economic model based on outcome probabilities from published studies and costs from a cohort of patients with HF seen at a single institution estimated that BTT by VAD is likely to be cost-effective relative to nonbridged transplantation in specific circ*mstances.31 BTT VAD therapy is likely to be more cost-effective in patients at high to medium risk, with an expected long waiting time before transplantation, with renal dysfunction, and of a young age. The excellent results achieved by continuousflow VADs (both as a BTT and as destination therapy), the increased mortality rate for heart transplantation caused by the more liberal donor criteria actually adopted, and the considerable mortality on the waiting list of nonsupported patients have led some investigators to hypothesize that VAD implantation should be viewed as the primary treatment of terminal HF, followed by transplantation only in carefully selected patients.32 Although this proposal is actually provocative and discussion stimulating more than really applicable, it is undeniable that the progress in terms of reliability, safety, and availability of new-generation devices coupled with the chronic shortage of transplantable hearts have the potential to lead to a reassessment of the current therapeutic approaches for patients with end-stage HF.
valve competence and the left ventricular compliance. In any case, detrimental effects on the subendocardial perfusion, myocardial oxygen consumption, pulmonary performance, and blood-gas exchanges are usually observed. To avoid this, left ventricular drainage must be achieved; methods for ventricular unloading range from the use of the intra-aortic balloon counterpulsation, the Impella centrifugal pump (Abiomed, Danvers, MA, USA), or direct ventricular venting percutaneously or surgically inserted.33–36 Recently, a method of minimally invasive apical left ventricular drainage that allows a switch from peripheral ECMO to a midterm paracorporeal VAD has been described.37 After hemodynamic stabilization or in less acute settings, a left, right or biventricular paracorporeal VAD can be implanted. When a long period of assistance is foreseen, an intracorporeal device can replace the paracorporeal ones. Fig. 1 shows an example of a long-term
VAD AS BTT: STRATEGY AND SEQUENCE In the acute setting, the first-line treatment of patients with decompensated HF is the percutaneous placement of a venoarterial ECMO to improve (or restore in emergency cases) endorgan perfusion. Although ECMO offers an excellent support to circulation, its effect on the heart is by far less favorable. In fact, the institution of peripheral ECMO usually worsens ventricular performance and, in a sizable proportion of cases, leads to left ventricular distension and pulmonary congestion. Although the pathophysiology of this phenomenon is complex and probably not fully understood, residual return to the left atrium via the pulmonary and bronchial circulation and increased afterload from the ECMO arterial cannula certainly play a major role. The increased ventricular pressure can affect, more or less, the pulmonary bed depending on the degree of mitral
Fig. 1. Macroscopic view of the heart excised at transplantation from a patient with dilated cardiomyopathy who received an LVAD as bridge to transplant; the interval between LVAD implant and transplantation was 317 days. Then heart transplantation was successfully performed. The upper panel shows the low-power view of the heart, and the lower panel shows a higher-magnification view of the apical conduit; a thin fibrous peel covers the internal surface of the conduit and progresses smoothly to the trabecular endocardium. HTx, heart transplantation.
Ventricular Assistance Devices
Fig. 2. Proposed algorithm for MCS support as a bridge to heart transplant. HTx, heart transplantation; icVAD, intracorporeal ventricular assistance device; LV, left ventricle; pcVAD, paracorporeal ventricular assistance device; pVAD, percutaneous ventricular assistance device; PVR, pulmonary vascular resistance; vaECMO, venoarterial extracorporeal membrane oxygenation. The arrow colors reflect the urgency of the setting. White, elective; grey, urgent; black, emergent.
intracorporeal device at the time of explantation. Other possible indications for the implantation of an intracorporeal VAD are as a bridge to candidacy and destination therapy. An algorithm for VAD as a BTT in either the acute setting or the chronic setting is presented in Fig. 2.
SUMMARY BTT is actually a major indication for VAD use. Device implantation increases survival while on the waiting list, improves patients’ fitness and nutritional status, and can possibly reduce operative risk. Although there is no general consensus on the effect of VAD as a BTT on posttransplant outcomes, it seems that VAD implantation before transplantation does not affect posttransplant outcomes, at least in selected patients, and using last-generation devices. In these instances, VAD as a BTT can even be cost-effective. The continuous improvement in the safety and availability of new VAD coupled with the chronic shortage of transplantable hearts and the increased operative risk of heart transplantation can potentially lead to a reassessment of the current therapeutic approach to patients with endstage HF.
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