Associate editor: Yiannis Chatzizisis
Ventricular assist devices: Pharmacological aspects of a mechanical therapy

https://doi.org/10.1016/j.pharmthera.2012.01.003Get rights and content

Abstract

Heart failure (HF) is a global epidemic that continues to cause significant morbidity and mortality despite advances in medical therapy. Ventricular assist device technology has emerged as a therapeutic option to bridge patients with end-stage HF to heart transplantation or as an alternative to transplantation in selected patients. In some patients, mechanical unloading induced by ventricular assist devices leads to improvement of myocardial function and a possibility of device removal. The implementation of this advanced technology requires multiple pharmacological interventions, both in the perioperative and long-term periods, in order to minimize potential complications and improve patient outcomes. We herein review the latest available evidence supporting the use of specific pharmacological interventions and current practices in the care of these patients: anticoagulation, bleeding management, pump thrombosis, infections, arrhythmias, right ventricular failure, hypertension, desensitization protocols, among others. Areas of uncertainty and ground for future research are also highlighted.

Introduction

Heart failure (HF) is a global epidemic that despite remarkable advances in medical therapy remains a significant cause of morbidity and mortality (Roger et al., 2011). Heart transplantation, considered to be the most effective therapy for patients with end-stage HF, is limited by donor availability. Furthermore, older patients (typically > 65 years of age) are less likely to be considered appropriate candidates for heart transplantation (Mehra et al., 2006). As a result, and in conjunction with improvements in left ventricular assist device (LVAD) technology that have dramatically improved outcomes, the number of implanted LVADs has grown exponentially (Kirklin et al., 2011).

In current clinical practice, LVADs are used either to provide short-term hemodynamic support during high-risk cardiac surgery or percutaneous coronary interventions (paracorporeal and percutaneous LVADs), or to provide long-term mechanical circulatory support (implantable durable LVADs). Durable LVADs are currently used as a bridge to transplant, as permanent or destination therapy, and in selected patients as a temporizing measure until native myocardial function improvement occurs, allowing explantation of the device (bridge to recovery). Favorable results of clinical trials of the continuous-flow HeartMate II LVAD led to the approval by the Food and Drug Administration of this device for clinical use, first as a bridge to transplant in 2008 and later as destination therapy in 2010 (Miller et al., 2007, Slaughter et al., 2009). Currently, more than 98% of the durable LVADs implanted are continuous-flow devices (Kirklin et al., 2011) and we will therefore focus on continuous-flow durable LVADs in this review.

Even though LVADs are a standalone therapy, their effects on the hemodynamics of both the unsupported right ventricle and the supported left ventricle, on the vascular, hematologic and immune systems and the complications associated with their use require multiple and complex pharmacologic interventions to ensure the continued and proper function of these devices while improving patient outcomes. Herein, we review recent clinical studies, pharmacological advances and current practices in the care of LVAD supported patients.

Section snippets

Anticoagulation management

  • a.

    Standard anticoagulation strategies

Anticoagulation strategies in the mechanical circulatory support field have represented a considerable challenge for decades. The invaluable experience acquired from the first-in-human chronic application of the total artificial heart in Barney Clark at the University of Utah (De Vries et al., NEJM 1984), prophetically indicated both in terms of clinical outcomes and in post-mortem pathology studies, that thromboembolic complications are probably the most

Management of bleeding

  • a.

    Perioperative management

Bleeding is the most common perioperative complication after LVAD implantation (Haj-Yahia et al., 2007, Miller et al., 2007, Slaughter et al., 2009). Therefore, a thorough preoperative evaluation is essential for minimizing bleeding and transfusion requirements. Patients with advanced HF frequently present with multiple comorbidities, poor nutritional status, anemia, and deficiency of coagulation factors, all of which may predispose them to an increase in the risk of

Management of LVAD thrombosis

Device thrombosis is a complication of circulatory support with continuous-flow LVADs that is associated with significant morbidity and mortality, often requiring exchange of the LVAD. The incidence of LVAD thrombosis in the HeartMate II bridge to transplant and destination therapy trials was 1.5% and 3.76%, respectively (Miller et al., 2007, Slaughter et al., 2009) . Thrombosis can occur at different levels, including the inflow and outflow cannula, or in the pump itself, a scenario frequently

Right ventricular failure: prevention and management

The right and left ventricle are connected in series and interact with each other hemodynamically due to the anatomic coupling provided by the shared interventricular septum and common muscle fibers. The impact of LV support by a LVAD on the geometry of the right ventricle, hemodynamics and function can be complex. The reduction of left ventricular filling pressures by the LVAD can substantially decrease the pulmonary vascular resistance, right ventricle afterload and in that way improve right

Management of infections

LVAD infections are classified as VAD-specific infections (related to the hardware, do not occur in non-VAD patients), VAD-related infections (can also occur in non-VAD patients, e.g. infective endocarditis) and non-VAD infections (unrelated to the VAD presence, e.g. urinary tract infection) (Hannan et al., 2011). Infections represent a significant cause of morbidity and mortality in patients supported with LVADs (Monkowski et al., 2007, Kirklin et al., 2010, Kirklin et al., 2011). Percutaneous

Management of arrhythmias

  • a.

    Ventricular arrhythmias

Ventricular arrhythmias are common among patients with end-stage HF supported by LVADs, and their incidence during circulatory support appears to be higher in patients with ischemic heart disease (Arai et al., 1991, Oz et al., 1994, Ziv et al., 2005, Drakos et al., 2011b). Although there are reports that these potentially lethal arrhythmias can be tolerated surprisingly well by patients on LVAD support (Busch et al., 2011, Patel et al., 2011b, Sims et al., 2011), their

Management of systemic hypertension

Hypertension is highly prevalent in patients with HF with as many as 75% having antecedent hypertension (Roger et al., 2011). While hypertension may be masked in advanced stages of the disease due to reduced cardiac output/cardiac function, hypertension may resurface after LVAD placement. Results from an animal study also suggest that the renin–angiotensin system may be upregulated in the setting of circulatory support with a continuous-flow device (Ootaki et al., 2008). Central arterial-wave

HLA-allosensitization: prevention and treatment strategies

Development of antibodies to HLA is a common complication associated with the use of LVADs that deserves special consideration in patients awaiting heart transplantation. HLA-allosensitization in LVAD supported patients is thought to be caused by the continuous contact of nonbiological material with the patient's blood. In order to detect allosensitization, transplant candidates undergo testing that exposes recipient serum to HLA antigens through different techniques, with a result being

Myocardial reverse remodeling: combining mechanical and pharmacological interventions

Myocardial injury (i.e. myocardial infarction, cardiotoxic chemotherapy, etc.) can lead to a series of molecular, structural and functional changes referred to as myocardial remodeling. Ventricular volume and pressure overload are thought to be responsible for perpetuating the vicious cycle of myocardial dysfunction and worsening HF (Katz, 2002). The use of LVAD support effectively unloads the LV and could potentially disrupt the vicious cycle, thus allowing reversal of the maladaptive changes

Conclusions

We expect that the use of LVADs will continue to increase steadily in the near future, a result of the increasing prevalence of HF in the aging population and the advances in LVAD technology combined with continued limited donor availability (Stehlik et al. 2011 ISHLT Registry report) and potential changes in donor organ allocation policies (Moazami et al., 2011). Consequently, a better understanding of the different pharmacological interventions, their efficacy and safety profile in this

Acknowledgments

The authors are indebted to John N. Nanas for his enormous clinical and academic support over the years

References (120)

  • Z.T. Demirozu et al.

    Arteriovenous malformation and gastrointestinal bleeding in patients with the HeartMate II left ventricular assist device

    J Heart Lung Transplant

    (2011)
  • R.D. Dowling et al.

    Use of intravenous immunoglobulin in sensitized LVAD recipients

    Transplant Proc

    (1998)
  • S.G. Drakos et al.

    Risk factors predictive of right ventricular failure after left ventricular assist device implantation

    Am J Cardiol

    (2010)
  • S.G. Drakos et al.

    Impact of mechanical unloading on microvasculature and associated central remodeling features of the failing human heart

    J Am Coll Cardiol

    (2010)
  • S.G. Drakos et al.

    Prior human leukocyte antigen-allosensitization and left ventricular assist device type affect degree of post-implantation human leukocyte antigen-allosensitization

    J Heart Lung Transplant

    (2009)
  • S.G. Drakos et al.

    Low-dose prophylactic intravenous immunoglobulin does not prevent HLA sensitization in left ventricular assist device recipients

    Ann Thorac Surg

    (2006)
  • S.G. Drakos et al.

    Prevalence and risks of allosensitization in HeartMate left ventricular assist device recipients: The impact of leukofiltered cellular blood product transfusions

    J Thorac Cardiovasc Surg

    (2007)
  • S.G. Drakos et al.

    Reverse remodeling during long-term mechanical unloading of the left ventricle

    J Mol Cell Cardiol

    (2007)
  • S.G. Drakos et al.

    Reverse electrophysiologic remodeling after cardiac mechanical unloading for end-stage nonischemic cardiomyopathy

    Ann Thorac Surg

    (2011)
  • A. Emaminia et al.

    Concomitant left ventricular assist device placement and cryoablation for treatment of ventricular tachyarrhythmias associated with heart failure

    Ann Thorac Surg

    (2011)
  • D.J. Farrar et al.

    Long-term follow-up of Thoratec ventricular assist device bridge-to-recovery patients successfully removed from support after recovery of ventricular function

    J Heart Lung Transplant

    (2002)
  • M. Findler et al.

    Dental treatment of a patient with an implanted left ventricular assist device: Expanding the frontiers

    Oral Surg Oral Med Oral Pathol Oral Radiol Endod

    (2011)
  • J.R. Fitzpatrick et al.

    Risk score derived from pre-operative data analysis predicts the need for biventricular mechanical circulatory support

    J Heart Lung Transplant

    (2008)
  • S. Haj-Yahia et al.

    Midterm experience with the Jarvik 2000 axial flow left ventricular assist device

    J Thorac Cardiovasc Surg

    (2007)
  • M.M. Hannan et al.

    Working formulation for the standardization of definitions of infections in patients using ventricular assist devices

    J Heart Lung Transplant

    (2011)
  • K. Holdy et al.

    Nutrition assessment and management of left ventricular assist device patients

    J Heart Lung Transplant

    (2005)
  • W.L. Holman et al.

    Infection in permanent circulatory support: Experience from the REMATCH trial

    J Heart Lung Transplant

    (2004)
  • J. Jahanyar et al.

    Increased expression of stem cell factor and its receptor after left ventricular assist device support: A potential novel target for therapeutic interventions in heart failure

    J Heart Lung Transplant

    (2008)
  • D.L. Joyce et al.

    Impact of left ventricular assist device (LVAD)-mediated humoral sensitization on post-transplant outcomes

    J Heart Lung Transplant

    (2005)
  • R.J. Kaplon et al.

    Vitamin K reduces bleeding in left ventricular assist device recipients

    J Heart Lung Transplant

    (1999)
  • A.G. Kfoury et al.

    Cardiovascular mortality among heart transplant recipients with asymptomatic antibody-mediated or stable mixed cellular and antibody-mediated rejection

    J Heart Lung Transplant

    (2009)
  • A.G. Kfoury et al.

    A clinical correlation study of severity of antibody-mediated rejection and cardiovascular mortality in heart transplantation

    J Heart Lung Transplant

    (2009)
  • J.K. Kirklin et al.

    Second INTERMACS annual report: more than 1,000 primary left ventricular assist device implants

    J Heart Lung Transplant

    (2010)
  • J.K. Kirklin et al.

    Third INTERMACS Annual Report: The evolution of destination therapy in the United States

    J Heart Lung Transplant

    (2011)
  • C.T. Klodell et al.

    Effect of sildenafil on pulmonary artery pressure, systemic pressure, and nitric oxide utilization in patients with left ventricular assist devices

    Ann Thorac Surg

    (2007)
  • R.L. Kormos et al.

    Right ventricular failure in patients with the HeartMate II continuous-flow left ventricular assist device: Incidence, risk factors, and effect on outcomes

    J Thorac Cardiovasc Surg

    (2010)
  • A. Koster et al.

    Impact of heparin-induced thrombocytopenia on outcome in patients with ventricular assist device support: Single-institution experience in 358 consecutive patients

    Ann Thorac Surg

    (2007)
  • M. Kukucka et al.

    Acute impact of left ventricular unloading by left ventricular assist device on the right ventricle geometry and function: Effect of nitric oxide inhalation

    J Thorac Cardiovasc Surg

    (2011)
  • G.V. Letsou et al.

    Gastrointestinal bleeding from arteriovenous malformations in patients supported by the Jarvik 2000 axial-flow left ventricular assist device

    J Heart Lung Transplant

    (2005)
  • S.D. Lick et al.

    Transplantation of high panel-reactive antibody left ventricular assist device patients without crossmatch using on-bypass pheresis and alemtuzumab

    Ann Thorac Surg

    (2011)
  • M.G. Massad et al.

    Factors influencing HLA sensitization in implantable LVAD recipients

    Ann Thorac Surg

    (1997)
  • J.C. Matthews et al.

    The right ventricular failure risk score a pre-operative tool for assessing the risk of right ventricular failure in left ventricular assist device candidates

    J Am Coll Cardiol

    (2008)
  • S.H. McKellar et al.

    Treatment of infected left ventricular assist device using antibiotic-impregnated beads

    Ann Thorac Surg

    (1999)
  • M.R. Mehra et al.

    Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates—2006

    J Heart Lung Transplant

    (2006)
  • A.L. Meyer et al.

    HeartMate II implantation in patients with heparin-induced thrombocytopenia type II

    Ann Thorac Surg

    (2009)
  • N. Moazami et al.

    Stable patients on left ventricular assist device support have a disproportionate advantage: Time to re-evaluate the current UNOS policy

    J Heart Lung Transplant

    (2011)
  • M. Movsesian et al.

    PDE3 inhibition in dilated cardiomyopathy

    Curr Opin Pharmacol

    (2011)
  • C. Ootaki et al.

    Reduced pulsatility induces periarteritis in kidney: Role of the local renin–angiotensin system

    J Thorac Cardiovasc Surg

    (2008)
  • M.C. Oz et al.

    Malignant ventricular arrhythmias are well tolerated in patients receiving long-term left ventricular assist devices

    J Am Coll Cardiol

    (1994)
  • F.D. Pagani et al.

    Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans. Histological analysis of cell survival and differentiation

    J Am Coll Cardiol

    (2003)
  • Cited by (14)

    • Arrhythmias after left ventricular assist device implantation: Incidence and management

      2018, Trends in Cardiovascular Medicine
      Citation Excerpt :

      Digoxin slows ventricular response to AF through enhancement of parasympathetic tone, and while generally ineffective as sole therapy, may be a useful adjunct to β-blocker therapy [17,18]. Calcium channel blockers are another class of drugs that may be used to achieve rate control in LVAD recipients, though are not generally used in patients with systolic heart failure [19]. Rate control may also be achieved non-pharmacologically via ablation of the AV node, though this does necessitate ventricular pacing following ablation.

    • Team-based Care for Advanced Heart Failure

      2015, Heart Failure Clinics
      Citation Excerpt :

      LVAD-related infections represent a significant cause of morbidity and mortality in patients supported with LVADs. Multidisciplinary approaches directed at preventing and treating infectious complications during LVAD support have been previously described,36 which in the authors' experience has resulted in improved outcomes. As the number of patients on LVAD support continues to grow, multidisciplinary teams are now facing an increasing number of non-LVAD-related adverse events.

    • Postoperative Management Strategies in Mechanical Circulatory Support Patients

      2020, Mechanical Support for Heart Failure: Current Solutions and New Technologies
    View all citing articles on Scopus
    View full text