Heart failure and mechanical circulatory support

Best Practice & Research Clinical Anaesthesiology 26 (2012) 91–104

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Heart failure and mechanical circulatory support Stephen Andrew Esper, MD a, Kathirvel Subramaniam, MD b, * a b

Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA Department of Anesthesiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

Keywords: heart failure mechanical circulatory support ventricular assist devices anaesthesia

Cardiovascular disease (CVD) is defined as one of the following: hypertension, congestive heart failure (HF), stroke, coronary heart disease and congenital heart defects. CVD is the main cause of the disease burden (illness and death) in Europe (23% of all the disease burdens) and the second main cause of the disease burden in those European Union (EU) countries with very low child and adult mortality (17%).1 Heart disease is a common health problem worldwide. According to the most recent Heart Disease and Stroke Statistics-2011 update,2 greater than 82 000 000 adults living in the United States of America (USA) have one or more types of CVD. Many resources have been invested in attempting to understand and curtail the progression of congestive HF. This article attempts to address the growing concern over HF by looking at the epidemiology, pathophysiology and available therapies as anaesthesiologists encounter these patients more often nowadays in the operating room and intensive care units. Mechanical circulatory assistance and heart transplantation are two established treatment methods for end-stage HF. In this review, we also address the indications and contraindications for mechanical circulatory assistance, types and spectrum of available ventricular assist devices, efficacy, safety and cost analysis of circulatory support therapy. Ó 2012 Elsevier Ltd. All rights reserved.

Epidemiology of heart failure Cardiovascular disease (CVD) is the number one cause of death among women and men in Europe. It accounts for nearly half of all deaths in Europe, causing over 4.3 million deaths in Europe every year. In

* Corresponding author. Department of Anesthesiology, University of Pittsburgh Medical Center-Presbyterian Hospital, 200 Lothrop Street, C-Wing, Pittsburgh, PA 15213, USA. Tel.: þ1 4126475635/1 7247995852; Fax: þ1 4126476290. E-mail address: [email protected] (K. Subramaniam). 1521-6896/$ – see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpa.2012.03.003

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the European Union (EU) alone, CVD causes over 2 million deaths every year. CVD is estimated to cost the EU economy more than V192 billion each year.3 More than 2200 people living in the United States of America (USA) die from CVD each day, which is an average of one death every 39 s4 The number of medical visits for heart failure (HF) in 2007 exceeded 3.4 million.5 Of individuals in the USA who suffer from CVD, 5.7 million above the age of 20 years have been diagnosed with diastolic and/or systolic HF. Of those individuals, 3.1 million are male and 2.6 million are female. The incidence for both sexes combined is greater than 600 000 and all mortality is greater than 56 000 people. Furthermore, Rogers et al. reported that HF was mentioned on 277 193 death certificates in 2007 (one in nine deaths).2 This is similar to the data reported from the National Heart Lung and Blood Institute (NHLBI) and the National Center of Health Statistics (NCHS) from 1995 to 2006, with mortality numbers of 287 000 and 283 000, respectively. Levy et al., using the data from the Framingham Study, evaluated the incidence of HF and the survival after its onset during four defined time periods.6 Although the incidence of HF has declined among women, there has been no change among men. They also found that the survival after the onset of HF has improved in both sexes over time. A similar conclusion was reached by Rogers et al.7 However, both studies report a high death rate of approximately 50% within 5 years of HF diagnosis. Between the years 1970 and 1993, HF, as the contributing factor for death, increased by an average of 10 000 patients per year. The incidence of HF approaches 10 per 1000 population after 65 years of age and hypertension precedes this syndrome in 75% of cases. As individuals age, there is a greater risk of developing HF symptoms. New HF events have been reported in 15.2/1000 population at age 65 years. In population older than 85 years, HF rates are in excess of 65 per 1000. After studying a cohort of greater than 6000 patients, Bahrami et al. showed that there is a greater risk of HF among African Americans and Hispanics in USA, generally related to a higher prevalence of diabetes mellitus, hypertension and differences in socioeconomic status. In addition, it was noted that myocardial infarction (MI) was least likely to be the cause of HF in the African American population, while an increase in left ventricular mass had a significant effect on Hispanics and Caucasians.8 It should be noted that in the Atherosclerosis Risk in Communities (ARIC) study of NHLBI, Loehr et al. described a higher incidence of atherosclerotic risk factors in African Americans as compared with Caucasians.9 Pathophysiology of HF Congestive heart failure (CHF) does not have one cause. There are multiple structural, mechanical and biologic mechanisms that work in tandem to precipitate HF. HF can be designated as systolic or diastolic. The characteristics of the two types of HF are described in Table 1. The current clinical definition of systolic HF taken from a paper published by Davis et al. (2006) is “a clinical syndrome associated with congestive symptoms and/or symptoms of low cardiac output due to impaired ventricular pump function or reduced ejection fraction.”10 Diastolic HF is more controversial in its definition. Satpathy et al. used the following definition: Diastolic HF occurs when signs and symptoms of HF are present but left ventricular systolic function is preserved with an ejection fraction of greater than 45%.11 Left ventricular systolic dysfunction is the most common cause of HF, occurring in about 60% of patients, the majority of whom have coronary artery disease (CAD), with or without a history of MI. There are different types of cardiomyopathies that can cause HF. Dilated cardiomyopathy is defined as ‘a diminution in the contractile force of the left ventricle (LV) in the absence of pressure overload, volume overload or CAD. The loss of cardiac muscle function results in HF’. Hypertrophic obstructive cardiomyopathy, also referred to as ‘idiopathic hypertrophic subaortic stenosis or asymmetric septal hypertrophy’ is a disorder in which there is excessive hypertrophy of the interventricular septum. As a result, the septum and the anterior leaflet of the mitral valve can produce LV outflow obstruction, called ‘systolic anterior motion of the mitral valve’ which can cause a decrease in ejection from the LV, leading to HF. Dilated cardiomyopathies are more common. HF can occur acutely or chronically. In some cases, an acute exacerbation can be superimposed on chronic HF. The normal heart operates based on the Frank–Starling curve, which was elucidated by Otto Frank and Earnest Henry Starling.12–15 The Frank–Starling mechanism is ‘the ability of the heart to

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Table 1 Characteristics of patients with systolic and diastolic heart failure. (Reprinted with permission from Jessup medical Progress: Heart Failure. N Engl J Med. 2003; 348:2007–2019). Characteristic

Systolic heart failure

Diastolic heart failure

Age Sex Left ventricular ejection fraction Left ventricular cavity size

All ages typically 50–70 years More often male Depressed (<40%)

Frequently elderly Frequently female Preserved (>40%)

Usually dilated

Usually normal, often concentric hypertrophy Usually present

Left ventricular hypertrophy on echocardiography Chest radiography

Sometimes present

Gallop rhythm Co-existing conditions Hypertension Diabetes mellitus Previous myocardial infarction Obesity Chronic lung disease Sleep apnoea Long-term dialysis Atrial fibrillation

Third heart sound

Congestion with or without cardiomegaly Fourth heart sound

þþ þþ þþþ

þþþ þþþ þ

þ 0 þþ 0 þ (usually persistent)

þþþ þþ þþ þþ þ (usually paroxysmal)

Congestion and cardiomegaly

change its force of contraction and stroke volume in response to changes in venous return’. As venous return increases, sarcomere length increases, myocyte stretching occurs, increasing the active tension of the muscle fibre. Resultantly, there is an increase in velocity and generation of force by the ventricle. Stroke volume is increased and, in many cases, so too is cardiac output. In HF, the LV has sustained physiologic embarrassment and dilation occurs. Unlike a normal ventricle, the ventricle in HF is no longer able to match the increases in venous return and cannot generate the pressure required for the rest of the body, leading to end-organ dysfunction. End-organ dysfunction can manifest as chronic renal insufficiency with an elevated creatinine and blood urea nitrogen (BUN), hepatic insufficiency leading to elevated liver transaminases and neurologic dysfunction including syncopal episodes. The body sees these insults as a decrease in intravascular volume. A cascade of neurohormonal responses ensues which attempt to compensate for the hypoperfusion, despite a normal fluid status. The sympathetic nervous system increases the amount of circulating catecholamines to increase cardiac output by increasing contractility and heart rate. In addition, this causes arteriolar vasoconstriction which stimulates the secretion of renin from the juxtaglomerular apparatus of the kidney. Activation of the renin–angiotensin system results in arteriolar vasoconstriction and the release of aldosterone, which is responsible for salt and water retention. Furthermore, the hypothalamus releases vasopressin which also causes renal water reabsorption.16 The increase in intravascular volume causes the heart to become further dilated, and as end diastolic and systolic volume increase, as shown by the pressure–volume curves and the Frank–Starling curve, the LV may no longer be able to deal with this amount of fluid secondary to its diseased state. The pulmonary system becomes congested and oxygen exchange across the pulmonary vasculature does not occur with any efficiency. The atrium experiences a type of stretch because there is such a large amount of fluid from the reabsorption of salt and water. As a result, natriuretic peptides (hormones released by secretory granules in cardiac myocytes in response to myocardial stretching) are released. These peptides are able to enhance the excretion of sodium and water, dilate the systemic and pulmonary vascular beds and suppress the neurohormonal response.16 In addition to the physiologic response by the body, the heart, in an effort to compensate for the increased amount of fluid, attempts to remodel. Several experts discuss this remodelling in their papers.17,18 After an initial embarrassment to the myocardial muscle (or in the case of a cardiopathy without a clear initial insult), a waterfall of events transpires to alter the function, shape and size of the heart. There is subsequent myocardial cell apoptosis, interstitial fibrosis, hypertrophy, trabeculation

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and dilatation. The heart loses its synchronisation, and its capacity to keep up with the metabolic demands of the body is diminished. Dilatation of the LV can also lead to annular dilatation of the mitral valvular apparatus. The circumference of the heart actually increases and the papillary muscles are further separated, as a result. Because of this, there is an increase in tension on the chordae tendinae of the mitral valve, tethering of the valvular leaflets occurs, the valvular point of coaptation is no longer precise and mitral regurgitation (MR) occurs.19,20 The electrical system is not immune to the effects of HF and dilatation of the ventricle. Benjamin et al. described supraventricular arrhythmias, especially atrial fibrillation, as that which can announce the onset of HF.21 As discussed earlier, an increase in LV end diastolic volume will increase LV end diastolic pressure. As a result, the atrium will experience a higher pressure gradient and will stretch. As it stretches, electrical instability results, and atrial fibrillation is the outcome. Furthermore, patients with HF are at a higher risk for left bundle branch block, ventricular dysrhythmias and sudden cardiac death (SCD).22 In 1994, the New York Heart Association (NYHA) attempted to classify HF based on the functional status of the patients.23 The American College of Cardiology and the American Heart Association (AHA/ ACC) have developed and adopted a new classification system that further attempted to define the stages of HF.24 In the new classification system, as opposed to the NYHA system, movement between classes is not allowed, and the patient carries the diagnosis until progression of disease occurs (Table 2). Therapy of HF is based on the stage of HF defined by AHA/ACC16 (Fig. 1). Available therapies for HF Pharmacotherapy Multiple studies have shown that angiotensin convertase enzyme inhibitors (ACE-I) are associated with a reduction in mortality for HF patients, symptom abatement and improvement in clinical status.25–28 As already described, when the kidneys experience decreased perfusion and hypotension, the juxtaglomerular apparatus (JGA) releases renin, which is responsible for the conversion of angiotensinogen to angiotensin I (AT I), which is converted to AT II by ACE. As a powerful vasoconstrictor, AT II leads to an increase in systemic vascular resistance (SVR) and afterload. This is, in part, responsible for the remodelling of the LV. ACE-inhibitors inhibit the conversion of AT I to AT II. The LV no longer experiences an increased afterload. Consequently, there is a decrease in oxygen demand with improved cardiac function possibly leading to reverse remodelling. Angiotensin II receptor blockers (ARBs) are also quite beneficial for HF patients, especially if those patients are unable to take ACE-I secondary to an allergy. The clinical efficacy is similar to ACE-I as this type of drug class is also associated with a reduction in mortality in patients with HF.29,30 Beta-blockers are responsible for reduction of heart rate and blood pressure, thereby reducing the stress to which the LV is exposed. Chronic intake of beta-blockers has also been shown to be associated with improvement in HF symptoms, decreased incidence of arrhythmias, reduced mortality and pathologically reverse remodelling.31

Table 2 Classification of heart failure. American college of cardiology/American heart association classification

New York heart association classification

Stage A – Risk factors present (Diabetes, hyperlipidaemia, hypertension), Not in heart failure Stage B – Structural heart disease without signs and symptoms of heart failure Stage C – Structural heart disease with prior or current symptoms of heart failure and left ventricular dysfunction Stage D – Refractory end-stage heart disease

Class I – No symptoms Class II – No symptoms at rest, symptoms with normal activity Class III – No symptoms at rest, symptoms with less than normal activity Class IV – Symptoms at rest despite maximal medical therapy

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Fig. 1. American heart association and American college of cardiology stages of heart failure and therapy based on the stage of disease. (Reprinted with permission from Jessup Medical Progress: Heart Failure. N Engl J Med. 2003; 348:2007–2019).

Aldosterone antagonists reduce mortality and morbidity in selected patients with systolic HF.32,33 While there are no clear data that demonstrate diuretics such as acetazolamide, thiazides and loop diuretics are associated with an enhancement of survival in patients with HF, they continue to be the mainstay of therapy in acute exacerbations of chronic HF. They relieve pulmonary congestion and peripheral oedema and are absolutely necessary in the management of volume status. Cardiac glycosides such as digoxin improves contractility and LV ejection fraction (LVEF), and they are still used in some patients with systolic HF. These drugs enhance vagal tone, which reduces heart rate and slows conduction through the atrio-ventricular node. The use of glycosides to decrease mortality in patients with HF has not been clearly shown in the literature. The use of vasodilators, such as hydralazine and isosorbide dinitrate, appears to be associated with reduced mortality but not hospitalisations in patients with HF who are not taking ACE-I or betablockers.34 When the combination of these vasodilators was compared with ACE-I, ACE-I was superior with regard to the enhancement of survival.35 The use of milrinone and other inotropes (including dobutamine and vesnarinone) for the treatment of HF has not been associated with a decrease in mortality. In fact, there may be an association with increased mortality, especially in patients with CAD.36,37

Cardiac resynchronisation therapy Silverman and others discovered that there is a prolonged QRS complex in EKG of patients with HF.38,39 ACC/AHA update on HF (2009) indicated that there is no ‘consensus definition of cardiac dyssynchrony’. Echocardiographic findings such as suboptimal ventricular filling, prolonged MR and paradoxical septal wall motion may be useful to define dyssynchrony. To counteract this dyssynchrony, a biventricular pacemaker can be placed, activating the left and right ventricles in a synchronous

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fashion. This cardiac resynchronisation therapy (CRT) has been associated with decreased MR and enhanced ventricular contraction.40,41 There have been attempts to examine the role of amiodarone and implantable cardioverterdefibrillator (ICD) to prevent the occurrence of dysrhythmias and SCD in patients with HF.42,43 Bardy et al. compared amiodarone and AICD treatment in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT).44 It was concluded that in patients with NYHA class II or III HF and LVEF 35%, amiodarone had no favourable effect on survival, whereas single-lead, shock-only ICD therapy reduced overall mortality by 23%. It was further demonstrated in other studies that all-cause mortality was significantly reduced with ICD therapy, providing further validation to the SCD-HeFT study results.45,46 Role of mechanical circulatory support in HF Goldstein et al. described ventricular assist devices (VADs) as those devices that are ‘mechanical pumps that take over the function of the damaged ventricle and restore normal haemodynamics and end-organ blood flow’.47 The year 1964 marked the beginning of the search for mechanical cardiac support, which included the artificial heart. As time passed, a small, pneumatically activated device did not seem feasible to maintain a good quality of life, and electrically powered devices were developed. In the 1980s, DeVries et al.48 described the implantation of the first pneumatically activated artificial heart, Jarvik-7-100, and subsequently, Dr. Copeland and his group published a report of a long-term survivor who received this therapy.49 These were discontinued secondary to thrombotic events and infectious complications. Improvements in technology produced safer VADs with much improved efficacy in the recent years. VADs also have taken on a smaller size in more recent years, allowing for a better quality of life. INTERMACS Interagency registry for mechanically assisted circulatory support (INTERMACS) is a United States Registry on mechanical circulatory support (MCS) devised by the joint effort of NHLBI, Center for Medicare and Medicaid Services (CMS), Food and Drug Administration (FDA), clinicians, scientists and industry representatives. INTERMACS collect and analyse the patient data from 126 participating institutions and publish a report on the efficacy and outcomes after MCS every year. According to INTERMACS fourth annual report (2012), more than 4000 VAD implantations have been performed in the last 5 years (June 2006–June 2011).50 Indications NYHA classification and American College of Cardiology/American Heart Association classify HF into four categories with grade IV representing severe end-stage HF despite maximal medical therapy. To further characterise the patients within end-stage HF, INTERMACS classified them into seven patient profiles depending on the severity of symptoms and trajectory of decline over time51 (Table 3). Indications of short-term and long-term MCS are given in Table 4. Long-term support is indicated in patients with end-stage HF not responding to medical therapy (Stage D, NYHA IV and INTERMACS patient profiles 1–5). There are three factors which can modify the indication of VAD in different patient profiles. The presence of sustained ventricular arrhythmias requiring repeated defibrillation or shocks require immediate attention irrespective of the patient profile. Insertion of a VAD and haemodynamic stabilisation has been shown to improve patient’s arrhythmias in such situations. Temporary circulatory support (TCS) modifier includes patients on temporary circulatory support and frequent flyer (FF) modifier includes patients who require two emergency visits in 3 months or three visits in 6 months for IV diuretics, inotropes and vasodilators or for thoracocentesis and ultrafiltration (Table 3). Patients with incurable malignancy, active infection, irreversible end-organ dysfunction (renal, pulmonary, hepatic and neurologic), psychiatric disease and noncompliant patients should not be considered for VAD insertion. Patients with severe bleeding diathesis, hypercoagulable syndromes,

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Table 3 INTERMACS patient profiles for end-stage heart failure. Profile

Clinical picture

Shorthand

NYHA

Time to MCS

Modifier TCS

1

Critical cardiogenic shock Progressive decline on inotropes Clinical stability on moderate dose of inotropes or temporary circulatory support, Can be hospitalized or at home Recurrent advanced heart failure-Resting symptoms on oral therapy Exertion intolerantComfortable at rest but ADL limited by symptoms Exertion limited – ADL not limited but all meaningful exertion limited History of decompensation but currently stable at reasonable level of activity,

Crashing and burning Sliding fast

IV

Hours

X

X

IV

Days

X

X

Stable but inotrope dependent

IV

Weeks

X (if hospitalized)

Recurrent rather than refractory

IV

Housebound

2 3

4

5

6

7

Modifier FF

Modifier A

X (only at home)

X

Weeks to months

X

X

IV

Variable

X

X

Walking wounded

IIIB

Variable

X

X

Advanced NYHA III

III

Not indicated

X

X

ADL – Activity of Daily Living; TCS – Temporary circulatory support modifier; FF – Frequent fliers to the hospital modifier; A – Arrhythmia modifier; MCS – Mechanical Circulatory support.

severe aortic and peripheral vascular disease, morbid obesity and poor nutritional status are also not candidates for VAD therapy. Patients with high pulmonary vascular resistance and right ventricular (RV) dysfunction should not be considered for destination VADs. Destination therapy clinical trials recruited patients in NYHA IIIB but did not clearly indicate the outcome differences of those patients compared to NYHA IV patients. It is controversial whether NYHA III sub-classification is accurate enough to be accepted for clinical decision making regarding VAD therapy. Whether VAD therapy will be beneficial for moderately advanced HF population (NYHA III Table 4 Indications for short-term mechanical circulatory Support and assist device therapy. Short-term therapy with mechanical circulatory assistance Post-cardiotomy shock Post heart transplantation early graft failure Cardiogenic shock during noncardiac surgery or catheter intervention Post Myocardial infarction cardiogenic shock Acute Myocarditis and Cardiomyopathies (e.g., peripartum) Haemodynamic support during high-risk interventional or surgical procedures Destination therapy Patients with New York Heart Association (NYHA) Class IV end-stage ventricular heart failure, who are not candidates for heart transplant and who meet all of the following conditions: a Have failed to respond to optimal medical management (including beta-blockers, and ACE-inhibitors if tolerated) for at least 45 of the last 60 days, or have been balloon pump dependent for 7 days, or IV inotrope dependent for 14 days; and, b Have a left ventricular ejection fraction (LVEF) <25%; and, c Have demonstrated functional limitation with a peak oxygen consumption of 14 ml/kg/min unless balloon pump or inotrope dependent or physically unable to perform the test. Bridge to transplantation Transplant candidate with Cardiac index <2 L min1 m2, Systolic blood pressure <80 mmHg and Pulmonary capillary wedge pressure >20 mmHg

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class, EF < 35%, no end-organ damage and not on inotropes) is being investigated by REVIVE-IT clinical trial.52 Classification of VADs VADs are classified based on the duration of support, purpose of support, ventricles supported, drive mechanism, flow characteristics and generation of the devices (Table 5). Duration of support At the University of Pittsburgh, extracorporeal membrane oxygenation (ECMO), Centrimag (Levotronix, Waltham, MA, USA) or a paracorporeal VAD (PVAD, Thoratec Corp., Pleasanton, CA, USA) are used for short-term support. Short-term circulatory support devices are described in detail in a separate chapter. Heartmate II (Thoratec Corp., Pleasanton, CA, USA) is Food and Drug Administration (FDA) approved for bridge to transplantation (BTT) and destination therapy (DT) and is the most commonly used LVAD for long-term support. Heartware HVAD (Heartware Inc, Framingham, MA) is also being implanted nowadays for long-term support (investigational use). Characteristics of these commonly used VADs are given in Table 6. Purpose of support There are several purposes of implanting VADs in patients with HF. Bridge to recovery (BTR) These patients require assist devices to allow the heart to recover its function. The ventricular volume must be unloaded; the myocardial work must be diminished so that subendocardial perfusion is maintained. BTT The second group consists of patients who are not expected to recover adequate cardiac function and require mechanical support as a BTT. Recent studies have shown that there is an improved survival with the use of LVADs for BTT therapy. In fact, John et al. showed a 96% survival at 30 days and an 86% survival at 6 months.53

Table 5 Classification of mechanical circulatory devices. Duration of support Short-term (6 h–7 days) Intermediate term (7 days–1 year) Long-term (forever) Ventricular support Right ventricular (RVAD) Left ventricular (LVAD) Biventricular (BiVAD) Purpose of support Bridge to recovery Bridge to Transplant Bridge to Candidacy Bridge to decision Bridge to bridge Generation of device First, second and third-generation devices

Location of the device in relation to the body Paracorporeal Extracorporeal Intracorporeal Drive mechanism Pneumatically driven Electrically driven Pump mechanism Axial Centrifugal Flow characteristics Continuous flow devices Pulsatile flow devices Total artificial hearts Cardiowest Abiocor

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Table 6 Commonly used ventricular assist devices. Device

Duration of support

Ventricle Purpose of Generation Location of supported support the device

Thoratec PVAD

Short to intermediate

RV, LV, BV BTT, BTR

First

RV, LV, BV BTR, BTD, BTB

Second

Levotronix Short Centrimag Heartmate II Heartware

Intermediate, LV Long Intermediate, LV Long

Drive

Pump

Flow

Paracorporeal

BTT, DT

Second

Pneumatic Vacuum assisted filling and pneumatic compression of blood chamber pumping blood producing pulsatile flow Extracorporeal Electric Centrifugal Continuous Magnetically levitated Intracorporeal Electric Axial Continuous

BTT, DT

Third

Intracorporeal

Electric

Centrifugal, Continuous Magnetically levitated

DT In the current medical climate that exists today, intense study has been directed towards destination VAD implantation for end-stage HF patients who are not candidates for heart transplantation (HT). The Randomised Evaluation of Mechanical Assistance for Treatment of Congestive Heart Failure (REMATCH)54 clinical trial studied 129 patients with end-stage HF, who were not candidates for HT, to optima medical management or implantation of an LVAD. The study found that there was a ‘clinically meaningful survival benefit and an improved quality of life’ associated with the use of an LVAD. A study from Duke University compared baseline characteristics and outcomes between the extended criteria HT and DT patients. They found that 1-year mortality was similar for both groups, the 3-year survival was better for the extended criteria group. The DT survival was better than the survival achieved with VADs from the REMATCH study possibly related to the use of newer generation continuous flow LVADs.55 Apart from organ shortage as the main limitation, HT can also be associated with significant morbidity (hypertension, renal dysfunction, malignancy, coronary artery vasculopathy, infections and hyperlipaemia), which affects the quality of life. As VAD technology is showing promise in improving the survival and quality of life in patients with HF, VADs can be seen as the alternate form of therapy to HT for patients with HF in future. DT VAD implantations increased from 3.8% in 2009 to 34% in 2011 after FDA approval of Heartmate II for DT.50 Though the incidence of adverse events has decreased with the current-generation VAD (e.g., HeartMate II) implantation, improvement in areas such as gastrointestinal bleeding, mediastinal bleeding, driveline infections and adverse neurological events is necessary to provide a ‘real long-term alternative to HT’.53,56 Bridge to decision, bridge to bridge and bridge to candidacy The number of patients in profile 1 (critical cardiogenic shock) requiring durable VADs has decreased from 42% in 2006 to 14% in 2011. This is because the patients presenting with acute cardiogenic shock undergo insertion of a short-term VAD (Impella, Levotronix, Abiomed BVS, Thoratec PVAD and Tandem Heart) or ECMO for stabilisation before a decision can be made on further plans on therapy. Short-term devices are useful when the neurological status of the patient is unknown. Device

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therapy is terminated when there is no neurological recovery. While few patients recover for the device to be explanted, others may need a long-term device either for BTT or as bridging to candidacy (BTC). This subset of patients constitutes bridge to bridge. BTT patients are already in the HT list while BTC patients cannot be listed at the time of VAD implantation because they are critically ill, have a contraindication for HT or they have not been evaluated for HT. They are further divided into three subcategories; listing likely, listing moderate and listing unlikely. There is a proliferation of bridge to candidacy device strategy over the years (40% of all implants in 2011).50 Ventricle supported Though there are several devices available in the market for LV support, the options for RV support are limited. Temporary RV support is usually provided with Centrimag, thoratec PVAD or Abiomed BVS 5000. Bhama et al. from our institution reported successful weaning from Centrimag short-term RV support (mean duration of support 8  8 days) in 52% of 29 patients with RV failure due to various reasons (post-cardiotomy, primary graft dysfunction after HT and post-LVAD implantation).57 Patients with end-stage HF experience biventricular failure and require planned biventricular assist device (BiVAD) therapy, whereas others develop RV dysfunction after LVAD implantation severe enough to require right ventricular assist device (RVAD). BiVAD insertion is associated with significantly higher morbidity and mortality compared to univentricular device implantation. One-year survival was 80% with LVADs and 55% with BiVADs.50 The available options for mid-term and long-term biventricular support are also limited. Thoratec PVAD, Thoratec implantable VAD (IVAD) and BerlinHeart Excor are three devices used for this purpose.58 All of these devices have a large pneumatic console and restrict the mobility to impair the quality of life significantly. Total artificial heart (TAH) can also be used for biventricular support but requires that the native heart be excised with no back-up in case of device failure. TAH is described in a separate chapter in detail. Krabatsch et al. reported the use of continuous flow Heartware HVAD as BiVAD in 17 patients.59 Heartware HVAD is designed for use with systemic ventricle and the flows delivered may be too high to cause pulmonary oedema at the recommended pump speed for LV. Modifications such as reducing the pump speed, lowering the outflow graft diameter and shortening the inflow cannula were done to make this pump adapt to the lower afterload of pulmonary circulation in their study. Thirty-day survival was 82% and 59% of patients were discharged home. Since RV support is an area of intense research, several investigational and percutaneous devices are being tried for this purpose (Tandem Heart, Impella RD and DexAide).57 Three generations of VADs First-generation devices provided pulsatile flow from positive displacement pumps driven pneumatically or electromechanically. They contained valves and many other components, which came in contact with blood. They were large, noisy with low portability and durability.58 Heartmate I, Thoratec PVAD and Abiomed BVS 5000 are examples. Second-generation devices, such as the Heartmate II, provided continuous flow using electrically driven, rotary pump. They were compact, reliable and lasted longer. Third-generation devices use magnetic levitated centrifugal pumps with only one moving part (impellar) and produce less damage to the blood components.60 They are very small, less thrombogenic and some of them are easily implanted in the chest with no abdominal components (Heartware HVAD).59 Their reliability and longevity are being investigated and hold a lot of promise to the future. These devices are described in detail in Chapter 3. Overall, the trend is to produce the devices that are smaller, easily implantable and do not further hinder the quality of life. Pulsatile versus continuous flow The environment of assist devices is a dynamic one. The first major change is the use of continuous flow LVADs (CF-LVADs) for all forms of bridge therapy and DT. Slaughter et al. (The HeartMate II investigators) showed that treatment with a CF-LVAD “in patients with advanced failure significantly

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improved the probability of survival free from stroke and device failure at two years, compared to the pulsatile flow-LVADs (PF-LVAD) device, while both devices significantly improved the quality of life and functional capacity”.61 INTERMACS latest annual report confirmed the paradigm shift of PF-LVADs to CF-LVADs over the past 5 years (June 2006–June 2011).50 Between January 2011 and June 2011, only 33 PF-LVADs were implanted compared to 692 CF-LVAD insertions. Survival at 2 years was significantly better for CF-LVADs (74%) compared to PF-LVADs (43%). Pulsatile versus continuous flow is described in detail in Chapter 2. Percutaneous minimally invasive technology Another area of development in VAD technology is percutaneous implantation for short-term use. Adequate flow can be provided and survival in patients with low-output syndromes improved with these devices. Kar et al. evaluated the efficacy and safety of the percutaneous VAD in patients in severe refractory cardiogenic shock despite intra-aortic balloon pump (IABP) and/or high-dose vasopressor support.62 It was determined that the VAD reversed the terminal haemodynamic compromise in these patients, and gave a further validation that percutaneous VADs can be used with good results. Sjauw et al. published a retrospective, multicentre study to evaluate the safety and feasibility of LVAD support in 144 patients with the Impella 2.5 TM.63 Patients underwent high-risk percutaneous intervention, and end points included 30-day adverse events and successful device function. The data from the study supported the usefulness of haemodynamic support with this device during these interventions. Clearly, as in most surgical interventions, there is a continuing trend to minimally invasive and less cumbersome devices that will function safely yet maintain the appropriate efficacy and comply with the standard of care that has come to be expected by the medical community at large. Financial aspects of assist device therapy In the Executive Summary published by the AHA, Lloyd-Jones et al. indicate that inpatient cardiovascular operations increased in the 10 years from 1996 to 2006 by 33%.64 In addition, the cost of CVD in the USA for 2010 is estimated at $503.2 billion, which includes direct costs (physicians, professionals, hospital and nursing homes) and lost productivity from morbidity and mortality. The cost of HF in the USA was $39.2 billion, which represented 1–2% of all health-care expenditures. Mechanical assist therapy cost has been studied extensively. Moskowitz et al. indicated that for a long-term LVAD implantation, the first year cost would exceed $222 000, and further went on to indicate that if the organ shortage continues, these devices will ‘only be cost-effective if they offer similar efficacy to HT’.65 Clegg et al., in their review, did look favourably upon the cost-effectiveness of LVAD therapy, either as a BTT or DT, indicating that there would have to be a ‘60% improvement in survival’ before costeffectiveness improved.66 Oz et al. from Columbia University indicated that the initial hospitalisation related to the implant was in excess of $210 000 and the annual readmission cost per patient was around $105 326, though this study indicated that this was fairly comparable to the cost of transplantation.67 Girling et al. indicated that in order for the DT to be effective, the cost would have to be reduced to 40 000 pounds.68 A study by Miller et al. compared costs from the REMATCH era to the post-REMATCH era.69 In the post-REMATCH era, the cost was around $100 000 less than during the REMATCH era. There was also a similar difference between survivors and non-survivors. This would indicate that there may have been a greater improvement in efficacy of the device, treating associated disease and longer survival after implantation. Most recently, Rogers et al. indicated that the cost-effectiveness has improved significantly over time, explained by “significant improvements in survival, functional status, and reduction of implant costs”, and by the use of continuous flow devices.70 It would appear from the literature that, while initial studies indicated that LVADs were of high cost and cost-effectiveness was limited, over time with better survival rates and newer developments in VAD technology, financial aspects have improved.

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Practical points  MCS and HT are the two main stays of therapy for patients with end-stage HF refractory to medical therapy.  MCS can be provided with IABP, extracorporeal membrane oxygenators and various shortterm and long-term VADs.  VAD therapy has undergone significant changes with continuous flow device therapy replacing pulsatile flow devices in the recent years.  Survival has improved with use of continuous flow devices for all forms of VAD therapy including DT.  Heartmate II is the commonly used long-term LVAD whereas ECMO, Levotronix Centrimag, Impella and Tandom Heart are being used for short-term support.  DT VADs are used more often in patients who are not heart transplant candidates.  Cost-effectiveness of VAD therapy should be established and adverse events such as neurological dysfunction, bleeding and infection should be reduced to acceptable levels before VAD therapy can be recommended as an alternate therapy to HT.

Research agenda  RV failure requiring mechanical assistance is being recognised as a significant problem after LVAD implantation. Research is directed towards preventive strategies and improved treatment methods.  Strategy for patients presenting with critical cardiogenic shock is not clear at present. Profile 1 patients are now treated by a period of stabilisation with short-term circulatory support before durable devices are considered. Whether this strategy had improved outcomes is not known at present.  Whether to consider LVAD in less sick NYHA class III patients is undergoing active research.  The early and mid-term outcomes with newer generation VADs are comparable with HT outcomes in HF subjects. While availability is not a concern for VAD, organ shortage is a continuing problem for HT. Comparisons of VAD technology with HT as the real alternate therapy for end-stage HF are appropriate.

Conflicts of interest None.

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