dealing_with_zika_virus_in_pregnancy_ 5_feb.pdf 45 Public Health England, Royal College of Obstetricians and Gynaecologists, Royal College of Midwives, Health Protection Scotland, NHS Scotland. Zika Virus: Interim Algorithm for Assessing Pregnant Women with a History of Travel During Pregnancy. London: United Kingdom Government; 2016 [cited 2016 Feb 1]. Available from
URL: https://www.gov.uk/government/ uploads/system/uploads/ attachment_data/file/496817/ Interim_Zika_testing_algorithm_for_ assessing_pregnant_women_ with_a_history_of_travel_ v2_010216_Gateway.pdf 46 Queensland Government Department of Health. Zika Virus: Queensland Health Guidelines for Public Health Units. Queensland: The
Department; 2014 [cited 2016 Jan 31]. Available from URL: https://www. health.qld.gov.au/cdcg/index/zika.asp 47 Hoffmann AA, Montgomery BL, Popovici J, Iturbe-Ormaetxe I, Johnson PH, Muzzi F et al. Successful establishment of Wolbachia in Aedes populations to suppress dengue transmission. Nature 2011; 476: 454–7.
Supporting information Additional supporting information may be found in the online version of this article at the publisher’s web-site: Table S1 Diagnostic tests for Zika virus.
REVIEW
Role of long‐term mechanical circulatory support in patients with advanced heart failure M. B. Stokes, P. Bergin and D. McGiffin Department of Advanced Heart Failure/Transplantation, The Alfred Hospital, Melbourne, Victoria, Australia
Key words advanced heart failure, mechanical circulatory support, left ventricular assist device, bridge to transplantation, destination therapy, bridge to recovery. Correspondence Michael B. Stokes, Heart Centre, Department of Advanced Heart Failure/Transplantation, The Alfred Hospital, Commercial Road, Melbourne, Vic. 3004, Australia. Email: [email protected] Received 19 March 2015; accepted 12 May 2015.
Abstract Advanced heart failure represents a small proportion of patients with heart failure that possess high‐risk features associated with high hospital readmission rates, significant functional impairment and mortality. Identification of those who have progressed to, or are near a state of advanced heart failure should prompt referral to a service that offers therapies in mechanical circulatory support (MCS) and cardiac transplantation. MCS has grown as a management strategy in the care of these patients, most commonly as a bridge to cardiac transplantation. The predominant utilisation of MCS is implantation of left ventricular assist devices (LVAD), which have evolved significantly in their technology and application over the past 15–20 years. The technology has evolved to such an extent that Destination Therapy is now being utilised as a strategy in management of advanced heart failure in appropriately selected patients. Complication rates have decreased with VAD implantation, but remain a significant consideration in the decision to implant a device, and in the follow up of these patients.
doi:10.1111/imj.12817
Introduction An awareness of the management options and patient selection for therapies in management of advanced heart failure is essential for physicians managing patients with
Funding: None. Conflict of interest: None.
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heart failure. A significant proportion of patients with heart failure will progress to a state of advanced heart failure. While many are not candidates for mechanical circulatory support (MCS) and cardiac transplantation, there has been a significant change in this field in the past 15–20 years. The population burden of heart failure is estimated to grow significantly as a result of the ageing population, improved management of acute
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cardiovascular disease (such as acute myocardial infarction), and from improved management and availability of treatments for heart failure with resultant increased survival. MCS is an important consideration in advanced heart failure management both in the acute (e.g. extra‐ corporeal membrane oxygenation or short‐term percutaneous devices) and long‐term (e.g. ventricular assist devices (VAD)). The focus of this review will be on the discussion of long‐term MCS with advanced heart failure, predominantly focusing on the role of left VAD therapy.
Table 2 Clinical progression suggestive of failure of medical therapy and progression to advanced heart failure Hypotension limiting use of ACE inhibitors or angiotensin receptor blockers Diuretic resistance requiring IV diuretics to relieve congestion Recurrent AICD discharges/failure of CRT therapy (i.e. non‐ responders) Need for pleural +/or ascitic taps Hospital admissions requiring inotropes Persistent symptoms despite optimal medical therapy Development of cardiac cachexia ACE, angiotensin-converting enzyme; AICD, automated internal cardiac defibrillator; CRT, cardiac re-synchronisation therapy; IV, intravenous.
Advanced heart failure Heart failure represents a significant burden to the Australian healthcare budget as well as patient morbidity and mortality. It is estimated that 300 000 people in Australia have a diagnosis of heart failure with approximately 30 000 new diagnoses annually.1 The annual cost of heart failure to the Australian health budget is estimated at over $1 billion per year, which is largely due to the expense of hospitalisations. Readmission rates at 30 days are estimated at up to 30% locally and internationally, and mortality at 1 year and 5 years is worse than many forms of common cancer. It is estimated that 5% of admissions to hospital with decompensated heart failure die in hospital, and approximately 25% have died at 1 year and 50% at 5 years following diagnosis.1–3 Advanced heart failure represents a proportion of those patients with heart failure who possess the following features (Table 1). In those with advanced heart failure, failure of medical therapy is clinically apparent by the following (Table 2). Patients with the above features represent a group of patients with progressive pump failure who carry a poor prognosis. Referral to a unit that manages advanced heart failure, MCS and cardiac transplantation allows patients to be considered for therapies that may
Table 1 Features consistent with advanced heart failure4 Persistent New York Heart Association (NYHA) Class III or IV symptoms Episodes of fluid retention +/− reduced cardiac output at rest Evidence of cardiac dysfunction (LVEF < 30%; pseudonormal or restrictive Doppler mitral inflow pattern on echocardiography; elevated haemodynamic LV pressure (PCWP >16 mmHg +/or RAP >12 mmHg; High BNP or NT‐ProBNP plasma levels) Impairment of functional capacity (inability to exercise, 6‐min walk test < 300 m, peak VO2max < 12–14 mL/kg/min) History of ≥1 heart failure hospitalisation in the past 6 months. BNP, brain natriuretic peptide; NT‐ProBNP, N‐terminal pro‐hormone of brain natriuretic peptide; LVEF, left ventricular ejection fraction; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure.
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significantly improve their quality of life and prognosis. Prompt referral of these patients once it is apparent that they have progressed to advanced heart failure is crucial to their outcomes. Development of end‐organ damage, such as progressive renal or hepatic impairment, ascites and worsening cachexia may limit treatment options if they have progressed beyond a level where MCS can be considered. Frailty is an important consideration and carries increased risk of adverse outcomes, including higher rates of readmission and death.5 Right ventricular failure and ‘fixed’ pulmonary hypertension are also common features in late‐stage advanced heart failure and present difficult management challenges when considering MCS and transplantation.
VAD therapy Over the past 30 years, significant advances have been made in the field of MCS. This progression in technology and patient selection has been associated with improved outcomes and reduction in complications. VAD implantation has evolved as by far the most common utility of MCS. Significant growth in the number of VAD implants internationally has occurred over the past 10–15 years. Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) is an international registry of MCS which provides informative data on international trends in utilisation of MCS, indications for implantation and clinical outcomes (Fig. 1). The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial published in 2001 demonstrated improvement in mortality in patients who underwent LVAD implantation compared with medical therapy alone in patients who were not candidates for cardiac transplantation. Sixty‐eight subjects randomised to LVAD were compared with 61 controls. Implantation of the Heartmate XVE LVAD was associated with a reduction in all‐cause mortality with 41 deaths in the LVAD group compared with 54 deaths in the control group. Median survival was 531
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Figure 1 These data from INTERMACS demonstrate the growth internationally in ventricular assist devices utilisation since 2006. The transition to continuous flow intra‐corporeal devices along with the low rates of utilisation of the total artificial heart (TAH) is demonstrated6 (Reproduced with permission of the Copyright owner.) ( ), Continuous flow intracorporeal left ventricular assist devices (LVAD) pump; ( ), pulsatile flow intracorporeal TAH; ( ), pulsatile flow intracorporeal LVAD pump; ( ), pulsatile flow paracorporeal LVAD pump.
408 days in the LVAD group compared with 150 days in the control group (relative risk 0.52 (95% CI 0.34–0.78), P = 0.001). This trial was the first major randomised trial evaluating the use of VAD and provided the impetus for further device development and wider clinical use.7 The advent of continuous‐flow VAD provided an important step in the reduction of complications compared with pulsatile devices. Continuous‐flow devices are smaller, more durable, have smaller drivelines and one internal moving part. The HeartMate II trial published in 2009 clearly demonstrated the superiority of axial continuous flow pump technology over pulsatile LVAD in patients who were not eligible for transplantation. Two‐year survival in those patients who received a HeartMate II was 58% compared with 24% in those who received a HeartMate XVE.8 The ADVANCE trial evaluated the HVAD (HeartWare ventricular assist device) which is a centrifugal continuous flow pump. One hundred and forty patients implanted with the HVAD had survival rates comparable to a control group of 499 patients derived from the INTERMACS registry that predominantly included continuous flow pumps, including the HeartMate II. Patients in both groups underwent VAD implantation as a bridge 532
to transplantation (BTT) intent. The HVAD was found to have comparable outcomes, with 92% of the patients who received the HVAD surviving 180 days with the pump, or had received a transplant or recovered ventricular function enough to have the device removed.9 The ADVANCE and HeartMate II Trial resulted in significant change in practice in the utilisation of continuous‐flow devices rather than pulsatile devices (Fig. 1). VAD therapy allows those with advanced heart failure to be supported with a device that provides significant assistance or essentially full replacement for their intrinsic cardiac output. This provides improved organ perfusion, improvement in symptoms of congestion and New York Heart Association (NYHA) Class. Constant ventricular unloading provides reduction in left atrial pressure which may allow significant pulmonary vascular remodelling and reduction in pulmonary vascular resistance. In patients who are candidates for cardiac transplantation, VAD therapy may result in significantly improved quality of life and reduced mortality while awaiting transplantation. The two most commonly used devices presently in Australia are the HeartMate II and the HeartWare (Figs 2, 3). © 2016 Royal Australasian College of Physicians
Role of MCS in advanced heart failure
Indications for VAD therapy VAD insertion as a BTT is the only utility of the therapy within Australia. However, it is important to recognise that an individual's designation for MCS can change over time as clinical factors may dictate. In an analysis of INTERMACS data, 43% of those implanted with a device as BTT intent were not on the transplant list within
2 years and 15% of patients implanted with a destination therapy (DT) intent were on the transplant list within 2 years. This illustrates the dynamic nature of heart failure and MCS and that the indication for MCS may change depending on the clinical scenario.12 Table 3 summarises the different indications for VAD therapy. As demonstrated in Figure 4, the proportion of patients undergoing transplantation who are bridged with a LVAD has grown significantly in Australia. In 2013 in Australia, 40% of patients who underwent cardiac transplantation were bridged to transplantation with a ventricular assist device.13 VAD insertion as a bridge to recovery is an uncommon event, occurring in approximately 2–5% of device insertions. Cardiomyopathic processes, such as peri‐partum and post‐myocarditis may be associated with a greater chance of recovery. Novel strategies that may promote myocardial recovery (and possibly allow device removal), including drugs that promote myocardial hypertrophy (with the Beta‐2 agonist Clenbuterol), myocardial stem cell placement and genetic enzyme replacement therapy targeting SERCA2a gene expression in myocytes that promote inotropy, lusitropy and calcium cycling,14,15 remain under investigation.
Selection of patients for VAD
Figure 2 The HeartMate II Device. A second generation axial flow pump that requires creation of a pump pocket at the time of implantation. The external controller connects to the pump through the external driveline. The inflow and outflow cannula connect to the left ventricular apex and ascending aorta respectively as demonstrated. The battery packs are also displayed. (Image courtesy of Thoratec.)10
In Australia, VAD implantation occurs in hospitals appropriately staffed with cardiologists, cardiac surgeons and intensive care specialists experienced in advanced heart failure and transplantation. Trained skilled nursing support is also essential. In Australia, there are four of these units presently in adult medicine and one in the paediatric population. There is one such centre in New Zealand. Consideration of VAD implantation is warranted in patients with the following profile (Table 4).
Figure 3 The HeartWare Device. The smaller centrifugal small contains a single moving impellar part. The pump is implanted in the pericardial space without need for creation of a pump pocket. The driveline connects the pump to a power source externally. (Images courtesy of HeartWare.)11
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It is important to recognise that implantation of a VAD is a significant undertaking for a patient and their caregivers with significant lifestyle changes. An in‐depth discussion with the patient and their family is required to ensure that they are informed as to the risks of the implant, the requirement for anticoagulation, the need for education and awareness of the device function and the need for regular medical follow up.
Contraindications to VAD insertion are summarised below. It is important to recognise also that many patients being assessed and listed for transplantation may not be suitable candidates for VAD implantation. This includes patients with restrictive cardiomyopathies, hypertrophic cardiomyopathy (due to reduced LV cavity size) and some patients with complex congenital heart disease (Table 5).
Table 3 The different indications for ventricular assist devices (VAD) implantation Bridge to transplantation • Patients actively listed at the time of VAD implantation. Due to limited donor availability, the average wait times may be (BTT) well over 1 year. • Usual practice is to remove temporarily from transplant waiting list following VAD implant to allow for sternotomy healing, improvement of physical status and organ function prior to transplantation. Bridge to candidacy (BTC) • VAD implanted to clarify or improve an aspect of patients’ candidacy prior to transplantation. Examples include: 1 Pulmonary hypertension to a degree that precludes cardiac transplantation (which may improve with pulmonary vascular remodelling following VAD implant). 2 To assist with weight loss and improvement in muscle mass. 3 Improvement of organ function (e.g. improvement in renal function with improved cardiac output). 4 To provide haemodynamic support in patients who have quit smoking, but are less than 6 months smoking cessation to allow listing for transplantation. Bridge to recovery (BTR) • Uncommon, occurring in 2–5% of VAD implants. Is rarely a set strategy. Destination therapy (DT) • Patients whom are not considered candidates for cardiac transplantation (e.g. Comorbidities, prior malignancy, age). • Device is implanted as a long‐term strategy. Ideally have relatively preserved end‐organ function, good ability to self‐care and reasonably preserved end‐organ function otherwise.
Figure 4 Significant growth in use of ventricular assist devices as a bridge to transplantation in Australia over the past 20 years.13 (Reproduced with permission.) ( ), New York Heart Association III %; ( ), New York Heart Association IV %; ( ), inotropic support %; ( ), intra‐aortic balloon pump %; ( ), ventricular assist device %; ( ), total artificial heart %.
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Timing of implantation of MCS Following the development of advanced heart failure along with one or more of the ‘failures’ listed in Table 2, serious consideration should be given to assessment for candidacy for MCS. A variety of clinical scenarios may present clinical challenges with regard to the optimal timing of VAD implantation. In the early years of VAD as a BTT intent, patients were largely INTERMACS 1 or 2 (Table 6) at the time of Table 4 ESC Heart Failure Guidelines (2012) – current indications for ventricular assist devices (VAD) implantation16 >2 months of severe symptoms despite optimal medical and device therapy and more than one of the following LVEF < 25%, and if measured, peak VO2 < 12 mL/kg/min ≥ 3 hospitalisation in the previous 12 months without an obvious precipitating cause Dependence on IV inotropic therapy Progressive end‐organ dysfunction (worsening renal and/or hepatic function) due to reduced perfusion and not to inadequate ventricular filling pressure (PCWP ≥ 20 mmHg and SBP ≤ 80–90 mmHg or CI ≤ 2 L/min/m2) Deteriorating right ventricular function ESC, European Society of Cardiology; LVEF, left ventricular ejection fraction; PCWP, pulmonary capillary wedge pressure; SBP, systolic blood pressure.
Table 5 Contraindication's to ventricular assist devices (VAD) insertion Absolute and relative contraindications to VAD insertion • Irreversible major end organ failure (e.g. hepatic/renal) not due to poor cardiac output • Metastatic cancer • Cerebral damage/neurological deficit/uncertain neurological status • Major coagulopathy • Active infection • Mechanical heart valves (may replace with bio‐prosthetic valve) • Severe aortic valve regurgitation (although can be managed by closing or replacing aortic valve at time of VAD insertion) • Inability to tolerate anticoagulation • Unresolved significant psychosocial issues
Table 6 Seven INTERMACS levels of clinical severity of end‐stage heart failure INTERMACS level 1 2 3 4 5 6 7
Clinical definition Critical cardiogenic shock Progressive decline Stable but inotrope dependent Resting symptoms Exertion intolerant Exertion limited Advanced NYHA Class‐III
NYHA, New York Heart Association.
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implantation. However, as technology has improved and the beneficial effects of VAD therapy on patients’ end organ function, NYHA Class and pulmonary vasculature have become more apparent, ‘earlier implantation’ of VAD is being considered and implemented in many centres. In the latest INTERMACS report, a greater proportion of patients were INTERMACS 3–4 at the time of implantation.6 Whether this translates to reduced operative mortality and provides better long‐term outcomes remains to be proven. Implanting VAD ‘early’ (i.e. in patients who are INTERMACS 4–7) is hypothesised to be associated with less adverse surgical outcomes because of less critical clinical profiles, but does expose patients to risks of the significant complications of VAD implantation. Specific clinical scenarios may mandate early VAD insertion at the time of diagnosis of a cardiomyopathy. This may include an inability to wean patients from extracorporeal membrane oxygenation (ECMO), which has been inserted following cardiac surgery or in severe acute decompensated heart failure with inotrope dependence.
Biventricular advanced heart failure Many patients who are referred for consideration of MCS have significant right ventricular dysfunction. Implantation of an LVAD alone in these patients can be associated with development of severe right heart failure postoperatively. Up to 30% of patients who develop right ventricular failure after an LVAD require either short or long‐term right ventricular support.17 Predicting the likelihood of developing right heart failure is challenging; however, a number of clinical factors can predict risk (Table 7). The Total Artificial Heart (TAH) device was the initial form of long‐term MCS which was developed in the early 1980s. The Syncardia TAH is at present the most commonly used and approved form. This consists of two pneumatically driven polyurethane ventricles, each with two unidirectional mechanical valves that displace blood in a pulsatile manner. The device also consists of an external driveline, which connects to the console that Table 7 Risk factors for right ventricular failure postoperatively18,19 • RVSWI < 300 (=Stroke Volume index x(mean PAP‐mean RAP) • CVP/PCWP > 0.63 • CVP > 15 mmHg • Severe tricuspid regurgitation • Preoperative intubation • Severe RV dysfunction identified pre‐VAD implantation CVP/PCWP, central venous pressure/pulmonary capillary wedge pressure; RVSWI, right ventricular stroke work index; VAD, ventricular assist devices.
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contains the pneumatic drivers. Challenges with the TAH include sizing difficulties as the device is quite large and the fact that patients are completely dependent on the TAH for cardiac output, which puts patients at risk of disastrous complications if device disruptions were to occur (Fig. 5). The use of TAH represents a small proportion of MCS in advanced heart failure. However, since the advent of continuous flow VAD, bi-ventricular assist device (BiVAD) implantation has evolved as a means of successfully supporting patients with severe bi‐ventricular failure. Right ventricular support can be provided by use of a VAD implanted in a variety of anatomical positions of the inflow cannula. Cannula configuration from right atrium to pulmonary artery has been successfully performed.21 Ideally, postoperative right ventricular failure following an LVAD implantation could be predicted preoperatively and the decision made to implant a BiVAD. For patients who clearly do not require a BiVAD, but may require temporary right‐sided support, a centrifugal device can be employed in the para‐corporeal position with inflow from a cannula in the femoral vein and an outflow through a Dacron graft anastomosed to the main pulmonary artery. Following right ventricular recovery, the device can be weaned and removed without reopening the chest. Support may occur using this method for up to 14 days.22
Figure 5 The Syncardia TAH. (Courtesy of Syncardia.)20
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General aspects of management and complications following VAD insertion There are several important aspects of management of VAD patients in the short and long‐term period following implantation. The main principles of management are to optimise VAD output, to avoid complications and to manage anti‐thrombotic therapy appropriately. Some of the key aspects of management are summarised in Table 8. A number of important complications can occur both early and late following a VAD insertion. These include the following: 1 Early postoperative pericardial bleeding – secondary to the early introduction of systemic anticoagulation postoperatively to avoid pump thrombus. This can frequently result in the need to return to the operating theatre for control of bleeding. 2 Systemic embolisation/CVA – embolisation of thrombus from within the device. 3 Intracerebral haemorrhage (ICH) – due to the requirement of anticoagulation combined with antiplatelet therapy, patients with VAD are at increased risk of spontaneous and traumatic ICH. If this occurs, multi‐speciality input is required. Neurosurgical intervention may be required and anticoagulant and/or antiplatelet therapy will likely need to be temporary interrupted. The period of time of anticoagulant therapy is minimised to avoid the risk of development of pump thrombus. The long‐term strategy for anti‐platelet and anticoagulant therapy is reassessed with consideration of reducing the anti‐platelet agents from two to one, and also revising the international normalised ratio (INR) target range (i.e. 2.5–3.0, may be revised to 2–2.5). If significant neurological insult has occurred, rehabilitation may be required. 4 Infection – driveline infections are common in those with long‐term VAD and approach 40% in those who carry a device for 3 years (Fig. 6). This is a significant source of morbidity and mortality. Meticulous driveline care and early recognition and treatment with antibiotics are imperative. The most effective way of clearing a driveline or pocket infection is cardiac transplantation. 5 Pump thrombus – presence of thrombus within the rotor, inflow or outflow cannula. This may present with device power surges, intravascular haemolysis and evidence of left ventricular failure due to failure of ventricular unloading. Risks for thrombus include active infection, sub‐therapeutic anticoagulation, obstruction of inflow or outflow cannula, bleeding episodes where permissive sub‐ therapeutic anticoagulation has occurred with low pump speed. Pump thrombus commonly necessitates a pump exchange; however, thrombolysis has also been used.
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Table 8 General aspects in clinical assessment and routine follow up of ventricular assist devices (VAD) Clinical parameter
Aspects of review and optimisation
LVAD pump speed setting Assessment for clinical evidence of heart failure symptoms and signs. Review of VAD data regarding incidence of low flow alarms, suction alarms and pulsatility index events. Integration of echocardiographic data into speed optimisation, including ventricular size, aortic valve opening, interventricular septal position and right heart function. Monitoring for Clinical evidence of intravascular haemolysis (e.g. dark urine) or congestive symptoms due to heart failure. development of pump Incidence of high power alarms or spikes in pump power (may be an early sign indicative of pump thrombus). thrombus Blood parameters: elevation or a rise in trend of levels of lactate dehydrogenase, plasma free haemoglobin, bilirubin. If suspicion or confirmation of pump thrombus – needs urgent assessment regarding requirement for pump exchange or thrombolytic therapy. Driveline care Patient and/or carer diligence to the routine of driveline dressing care. Presence of fevers, discharge or erythema from driveline site. If discharge present, taking swab for microscopy, culture and sensitivity and early commencement of antibiotics is strongly considered. Measurement of Targeting mean arterial pressure of 70–80 mmHg as measured with Doppler and standard blood pressure cuff. meanarterial pressure This target reduces the afterload strain on the VAD and reduces the risk of intra‐cerebral haemorrhage. Low flow alarms May occur due to dehydration, postural changes, right ventricular failure or high afterload. Clinical assessment involves fluid review, measurement and optimisation of mean arterial pressure; consider altering pump speed and addressingright ventricular failure where present. Suction alarms If pump speed too high relative to blood volume in the ventricles – ventricular walls may ‘suck down’ or collapse across the inflow cannula. May be indicative of intravascular depletion, inadequate right ventricular contractility or too high VAD pump speed. Management includes administration of volume (orally or intravenously if required), postural manoeuvres to increase venous return and reducing VAD pump speed if appropriate. If persistent low flow alarms and/or suction alarms with evidence of right ventricular failure, inotropic therapy is considered to augment right ventricular function, and occasionally temporary or permanent mechanical RV support may be used. LVAD, left ventricular assist devices.
Figure 6 External driveline infection with evidence of erythema and discharge.
6 Gastrointestinal bleeding and epistaxis – patients with VAD may develop a characteristic acquired von Willebrand syndrome. This is secondary to the shearing forces of the pump that result in structural defects in von Willebrand's factor. Continuous flow VAD are also believed to result in neovascularisation of blood vessels (angiodysplasia) within the gastrointestinal tract that may be a © 2016 Royal Australasian College of Physicians
source of bleeding. Epistaxis may occur due to this acquired von Willebrand syndrome and also due to the effects of anti‐platelet and anticoagulant medication. Relief can sometimes be achieved through cauterisation of the culprit intra‐nasal vessel. If persisting and recurrent episodes of gastrointestinal bleeding and epistaxis occur, reduction in the anti‐platelet medications from two to one and reducing the INR target level may be considered. However, the risks of development of pump thrombus against recurrent bleeding have to be considered. 7 Right ventricular failure – increased cardiac output from the LVAD can overload the myopathic right ventricle. Clinically, this may present with clinical evidence of right heart failure and low LVAD flows secondary to poor LV filling. Optimisation of volume state and VAD flow rates with echocardiographic assistance may provide some improvement. Persistent right heart failure may require conversion to a BiVAD device. 8 Aortic valve regurgitation – the presence of greater than mild aortic regurgitation requires valve repair, replacement or valve closure at the time of LVAD implantation to prevent the progression of aortic regurgitation. The development of severe aortic regurgitation results in a circulatory loop from regurgitant blood, reducing forward flow. Progressive aortic regurgitation or de novo aortic regurgitation following implantation may 537
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develop due to a combination of factors, including lack of aortic valve opening, altered valve haemodynamics and aortic valve commissural fusion. 9 Pump malfunction/pump stop – these are very uncommon events with modern devices and may reflect pump thrombosis, driveline fracture or disconnection, controller failure, pump malfunction or both power sources being disconnected. Patients are supplied with a ‘back‐up’ controller in the event of controller failure. 10 Increased rates of allo‐sensitisation (to human leucocyte antigens) – this may increase rates of positive cross‐ matching, increase waiting list times and put patients at risk of higher rates of rejection episodes following transplantation. This appears to be less prevalent with continuous flow devices compared with pulsatile devices.
MCS in patients with congenital heart disease Patients with end‐stage heart failure due to congenital heart disease represent a growing and challenging group of patients requiring MCS in the setting of uncorrectable or previously corrected or palliated congenital heart disease. This is a group of patients that are challenging candidates for MCS due to their unique physiology and anatomy. Significant pulmonary hypertension that may preclude isolated orthotopic cardiac transplantation may also provide challenges with MCS. VAD have been successfully implanted for systemic support (right ventricular morphology) in patients with congenitally corrected transposition of the great arteries as well as patients with d‐transposition of the great arteries who may present with late systemic ventricular failure after a previous atrial switch operation.23 Small numbers of case reports have also described the use of mechanical devices to support congenital lesions with single ventricle physiology and the failing Fontan circulations.24,25
DT While not widely available within Australian advanced heart failure centres, DT therapy offers appropriately selected patients with advanced heart failure who are not candidates for cardiac transplantation to have significantly improved quality of life and reduced mortality. DT is an increasingly used indication for VAD use internationally. Along with technological improvements in VAD, the results of the REMATCH and HeartMate II DT trial, and the fact that a significant proportion of patients with advanced heart failure possess comorbidities that may preclude cardiac transplantation have driven this increase. In the sixth INTERMAC, 41% of all MCS implants were inserted for DT.6 Patients selected for DT 538
usually have contraindications for cardiac transplantation, such as malignancy within the previous 5 years, chronic renal failure, severe obesity or elevated pulmonary vascular disease that precludes listing for transplantation (e.g. trans-pulmonary gradient >15 mmHg +/or pulmonary vascular resistance >6 Wood Units). Use of DT therapy may increase the management options for specific patients following VAD implant. As mentioned previously, 15% of patients in an analysis of INTERMACS data of patients who were assigned DT were eventually listed for transplantation.12 Changes in patients' nutrition, frailty, end‐organ function and comorbidities may affect transplant candidacy and thus may provide some patients with an eventual option for BTT. Potential for short and long‐term adverse outcomes following VAD placement for DT cannot be underestimated when considering potential candidates, particularly given the potential for greater comorbidities in this group.26 However, wider availability of DT within Australia would provide appropriately selected patients significantly improved quality of life and would reduce the rate of their admissions to hospital with acute decompensated heart failure. The international growth rates in DT utilisation highlight the need for this indication to be widely accepted in Australia.
Future directions in MCS Advances in device design, the use of continuous flow VAD, improvements in technology, as well as clinical experience in patient selection, have resulted in a significant fall in complications from VAD use. However, the morbidity from complications such cerebrovascular events, bleeding and driveline‐related infections remains substantial. Two devices currently undergoing development include the HeartWare MVAD pump and the HeartMate III. The MVAD is approximately one third the size of the HVAD allowing for potential minimally invasive surgery through the apical approach. The MVAD utilises axial flow pump technology and contains a magnetic and hydro-dynamic impeller system with wide helical flow channels designed to minimise shear stress on blood components. A novel cannula configuration allowing placement of the outflow cannula across the aortic valve that would potentially allow trans‐apical implantation is also under evaluation.27 The device has been successfully implanted in an ovine model and human trials are anticipated in the future.28 The HeartMate III is presently undergoing clinical trials in humans. The favourable improvements compared with the HeartMate II are designed to improve blood compatibility with reduction in clinical adverse events. It contains textured blood‐contacting surfaces, has a fully © 2016 Royal Australasian College of Physicians
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magnetically levitated single moving part with less potential for friction. It also contains a component of artificial pulse technology that is postulated to reduce the risk of thrombus formation within the pump and the potential bleeding complications associated with continuous flow VAD, which include acquired von Willebrand disease, angiodysplasia of the gastrointestinal tract and impaired platelet aggregation.29 The HeartMate III also provides a smaller pocket controller for easier patient use. An eagerly awaited advance in MCS is elimination of the need for an external power source (and hence drivelines). Transcutaneous energy transfer (TET) allows transmission of energy non‐invasively inside the body through an induction‐heating system where an electromagnetic charge between two sets of coils located inside and outside body. Use of TET has been performed in small numbers with previously available devices in small
References 1 Page K, Marwick TH, Lee R, Grenfell R, Abhayaratna WP, Aggarwal A et al. A systematic approach to chronic heart failure care: a consensus statement. Med J Aust 2014; 201: 146–50. 2 Stewart S, Ekman I, Ekman T, Oden A, Rosengren A. Population impact of heart failure and the most common forms of cancer: a study of 1 162 309 hospital cases in Sweden (1988 to 2004). Circ Cardiovasc Qual Outcomes 2010; 3: 573–80. 3 Ponikowski P, Anker S, AlHabib K, Cowie M, Force TL, Hu S et al. Heart failure preventing disease and death worldwide. Nice: European Society of Cardiology; 2014. White Paper. 4 Metra M, Ponikowski P, Dickstein K, McMurray J, Gavazzi A, Berg CH et al. Advanced chronic heart failure: a position statement from the Study Group on Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2007; 9: 684–94. 5 Dunlay SM, Park SJ, Joyce LD, Daly RC, Stulak JM, McNallan SM et al. Frailty and outcomes after implantation of left ventricular assist device as destination therapy. J Heart Lung Transplant 2014; 33: 359–65. 6 Kirklin JK, Naftel DC, Pagani FD, Kormos RL, Stevenson LW, Blume ED et al. Sixth INTERMACS annual report: a 10,000 patient database. J Heart Lung Transplant 2014; 33: 555–64. 7 Rose EA, Gelijns AC, Moskowitz AJ, Heitjan DF, Stevenson LW,
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published series.30 If incorporated into modern devices, the use of TET could significantly reduce complications, particularly infections.
Conclusion MCS is a growing and important aspect of management of advanced heart failure. Significant improvements in device design, patient selection, management of complications and outcomes have occurred over the past 15– 20 years. Long‐term use of VAD support has successfully occurred and, as a result, DT is now considered an appropriate step in many patients with advanced heart failure. Early recognition and referral to centres that manage advanced heart failure allow appropriate patients to be considered for MCS in a timely manner before the complications of disease progression preclude this option.
Dembitsky W et al. Long term use of a ventricular assist device for end‐stage heart failure. N Engl J Med 2001; 345: 1435–43. Slaughter MS, Rogers JG, Milano CA, Russell SD, Conte JV, Feldman D et al. Advanced heart failure treated with continuous‐flow left ventricular assist device. N Engl J Med 2009; 361: 2241–51. Aaronson KD. Evaluation of the HeartWare HVAD left ventricular assist device system for bridge to transplant in advanced heart failure: the ADVANCE trial. American Heart Association 2010 Scientific Sessions; November 15, Chicago, IL. (Late Breaking Clinical Trials I); 2010. Thoratec Corporation (Homepage on the Internet). San Francisco (CA): Thoratec [cited 2016 Apr 10]. Available from URL: http://www.thoratec.com HeartWare (Homepage on the Internet) [cited 2016 Apr 10]. Available from URL: http://www.heartware.com Teuteberg JJ, Stewart GC, Jessup M, Kormos RL, Sun B, Frazier OH et al. Implant strategies change over time and impact outcomes: insights from the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). JACC Heart Fail 2013; 1: 369–78. Keogh A, Williams T, Pettersson R, eds. Australia and New Zealand Cardiothoracic Organ Transplant Registry: 2013 report. Sydney: Australia and New Zealand Cardiothoracic Organ Transplant Registry; 2013.
14 Birks EJ, Tansley PD, Hardy J, George RS, Bowles CT, Burke M et al. Left ventricular assist device and drug therapy for the reversal of heart failure. N Engl J Med 2006; 355: 1873–84. 15 Jessup M, Greenburg B, Mancini D, Cappola T, Pauly DF, Jaski B et al. Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+‐ATPase in patients with advanced heart failure. Circulation 2011; 124: 304–13. 16 McMurray J, Adamopoulos S, Anker S, Auricchio A, Bohm M, Dickstein K et al. European Society of Cardiology Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur Heart J 2012; 33: 1787–847. 17 Potapov EV, Loforte A, Weng Y, Jurmann M, Pasic M, Drews T et al. Experience with over 1000 implanted ventricular assist devices. J Card Surg 2008; 23: 185–94. 18 Atluri P, Goldstone AB, Fairman AS, MacArthur JW, Shudo Y, Cohen JE et al. Predicting right ventricular failure in the modern, continuous flow left ventricular assist device era. Ann Thorac Surg 2013; 96: 857–64. 19 Kormos RL, Teuteberg JJ, Pagani PD, Russell SD, John R, Miller LW et al. Right ventricular failure in patients with the HeartMate II: incidence, risk factors, and effect on outcomes. J Thorac Cardiovasc Surg 2010; 139: 1316–24.
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20 Syncardia (Homepage on the Internet). Tuscon (AZ): Syncardia [cited 2016 Apr 10]. Available from URL: http://www. syncardia.com 21 Marasco SF, Stornebrink RK, Murphy DA, Bergin PJ, Lo C, McGiffin DC. Long‐term right ventricular support with a centrifugal ventricular assist device placed in the right atrium. J Card Surg 2014; 29: 839–42. 22 Haneya A, Philip A, Puehler T, Rupprecht L, Kobuch R, Hilker M et al. Temporary percutaneous right ventricular support using a centrifugal pump in patients with postoperative acute refractory right ventricular failure after left ventricular assist device implantation. Eur J Cardiothorac Surg 2012; 41: 219–3. 23 Joyce DL, Crow SS, John R, St Louis JD, Braunlin EA, Pyles LA et al. Mechanical
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circulatory support in patients with heart failure secondary to transposition of the great arteries. J Heart Lung Transplant 2010; 29: 1302–15. Rossano JW, Goldberg DJ, Fuller S, Ravishankar C, Montenegro LM, Gaynor JW. Successful use of the total artificial heart in the failing Fontan circulation. Ann Thorac Surg 2014; 97: 1438–40. Nathan M, Baird C. Successful implantation of a Berlin heart biventricular assist device in a failing single ventricle. J Thorac Cardiovasc Surg 2006; 131: 1407–18. Porepa LF, Starling RC. Destination therapy for left ventricular assist devices: for whom and when? Can J Cardiol 2014; 30: 296–303. Tamez D, LaRose JA, Shambaugh C, Chorpenning K, Soucy KG, Sobieski MA et al. Early feasibility
testing and engineering development of the transapical approach for the HeartWare MVAD ventricular assist system. ASAIO J 2014; 60: 170–7. 28 McGee EJ, Chorpenning K, Brown MC, Breznock E, Larose JA, Tamez D. In vivo evaluation of the HeartWare MVAD pump. J Heart Lung Transplant 2014; 33: 366–71. 29 Suarez J, Patel CB, Felker M, Becker R, Hermandez AF, Rogers JG. Mechanisms of bleeding and approach to patients with axial‐flow left ventricular assist devices. Circ Heart Fail 2011; 4: 779–84. 30 Slaughter MS, Myers TJ. Transcutaneous energy transmission for mechanical circulatory support systems: history, current status, and future prospects. J Card Surg 2010; 25: 485–9.
CLINICAL PERSPECTIVES
Novel approaches to the treatment of hyperglycaemia in type 2 diabetes mellitus A. Galligan1 and T. M. Greenaway1,2 1 Department of Endocrinology, The Royal Hobart Hospital, and 2The School of Medicine, Faculty of Health Science, University of Tasmania, Hobart, Tasmania, Australia
Key words type 2 diabetes, anti-hyperglycaemic agents, cardiovascular safety, novel and emerging therapies. Correspondence Anna Galligan, Department of Endocrinology and Diabetes Services, The Royal Hobart Hospital, 48 Liverpool Street, Hobart, Tas. 7000, Australia. Email: [email protected] Received 4 August 2015; accepted 3 December 2015.
Abstract Control of hyperglycaemia is a fundamental therapeutic goal in patients with type 2 diabetes. The progressive nature of β-cell dysfunction in type 2 diabetes leads to the need for escalating anti-hyperglycaemic treatment, including insulin, in most patients. Given the prevalence of complications such as weight gain and hypoglycaemia associated with traditional anti-hyperglycaemic agents (AHA), including sulphonylureas and insulin, it is unsurprising that recent years have seen the development of novel agents to treat hyperglycaemia. With increasing evidence supporting the need for a multi-faceted approach to the prevention of adverse cardiovascular events in people with type 2 diabetes, a patient-centred and individualised management strategy addressing lifestyle, cardiovascular risk factor modification and glycaemic control remains critical in improving outcomes in these patients.
doi:10.1111/imj.13070
Funding: Since 2010, T. M. Greenaway has received lecture fees from Novo Nordisk, Novartis, Astra Zeneca, Lilly, Merck, BristolMyers Squibb and Glaxo Smith Kline and research and travel support from Novo Nordisk, Novartis and Sanofi Aventis. He is an investigator on the LEADER trial. Conflict of interest: None. 540
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URL: https://www.gov.uk/government/ uploads/system/uploads/ attachment_data/file/496817/ Interim_Zika_testing_algorithm_for_ assessing_pregnant_women_ with_a_history_of_travel_ v2_010216_Gateway.pdf 46 Queensland Government Department of Health. Zika Virus: Queensland Health Guidelines for Public Health Units. Queensland: The
Department; 2014 [cited 2016 Jan 31]. Available from URL: https://www. health.qld.gov.au/cdcg/index/zika.asp 47 Hoffmann AA, Montgomery BL, Popovici J, Iturbe-Ormaetxe I, Johnson PH, Muzzi F et al. Successful establishment of Wolbachia in Aedes populations to suppress dengue transmission. Nature 2011; 476: 454–7.
Supporting information Additional supporting information may be found in the online version of this article at the publisher’s web-site: Table S1 Diagnostic tests for Zika virus.
REVIEW
Role of long‐term mechanical circulatory support in patients with advanced heart failure M. B. Stokes, P. Bergin and D. McGiffin Department of Advanced Heart Failure/Transplantation, The Alfred Hospital, Melbourne, Victoria, Australia
Key words advanced heart failure, mechanical circulatory support, left ventricular assist device, bridge to transplantation, destination therapy, bridge to recovery. Correspondence Michael B. Stokes, Heart Centre, Department of Advanced Heart Failure/Transplantation, The Alfred Hospital, Commercial Road, Melbourne, Vic. 3004, Australia. Email: [email protected] Received 19 March 2015; accepted 12 May 2015.
Abstract Advanced heart failure represents a small proportion of patients with heart failure that possess high‐risk features associated with high hospital readmission rates, significant functional impairment and mortality. Identification of those who have progressed to, or are near a state of advanced heart failure should prompt referral to a service that offers therapies in mechanical circulatory support (MCS) and cardiac transplantation. MCS has grown as a management strategy in the care of these patients, most commonly as a bridge to cardiac transplantation. The predominant utilisation of MCS is implantation of left ventricular assist devices (LVAD), which have evolved significantly in their technology and application over the past 15–20 years. The technology has evolved to such an extent that Destination Therapy is now being utilised as a strategy in management of advanced heart failure in appropriately selected patients. Complication rates have decreased with VAD implantation, but remain a significant consideration in the decision to implant a device, and in the follow up of these patients.
doi:10.1111/imj.12817
Introduction An awareness of the management options and patient selection for therapies in management of advanced heart failure is essential for physicians managing patients with
Funding: None. Conflict of interest: None.
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heart failure. A significant proportion of patients with heart failure will progress to a state of advanced heart failure. While many are not candidates for mechanical circulatory support (MCS) and cardiac transplantation, there has been a significant change in this field in the past 15–20 years. The population burden of heart failure is estimated to grow significantly as a result of the ageing population, improved management of acute
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cardiovascular disease (such as acute myocardial infarction), and from improved management and availability of treatments for heart failure with resultant increased survival. MCS is an important consideration in advanced heart failure management both in the acute (e.g. extra‐ corporeal membrane oxygenation or short‐term percutaneous devices) and long‐term (e.g. ventricular assist devices (VAD)). The focus of this review will be on the discussion of long‐term MCS with advanced heart failure, predominantly focusing on the role of left VAD therapy.
Table 2 Clinical progression suggestive of failure of medical therapy and progression to advanced heart failure Hypotension limiting use of ACE inhibitors or angiotensin receptor blockers Diuretic resistance requiring IV diuretics to relieve congestion Recurrent AICD discharges/failure of CRT therapy (i.e. non‐ responders) Need for pleural +/or ascitic taps Hospital admissions requiring inotropes Persistent symptoms despite optimal medical therapy Development of cardiac cachexia ACE, angiotensin-converting enzyme; AICD, automated internal cardiac defibrillator; CRT, cardiac re-synchronisation therapy; IV, intravenous.
Advanced heart failure Heart failure represents a significant burden to the Australian healthcare budget as well as patient morbidity and mortality. It is estimated that 300 000 people in Australia have a diagnosis of heart failure with approximately 30 000 new diagnoses annually.1 The annual cost of heart failure to the Australian health budget is estimated at over $1 billion per year, which is largely due to the expense of hospitalisations. Readmission rates at 30 days are estimated at up to 30% locally and internationally, and mortality at 1 year and 5 years is worse than many forms of common cancer. It is estimated that 5% of admissions to hospital with decompensated heart failure die in hospital, and approximately 25% have died at 1 year and 50% at 5 years following diagnosis.1–3 Advanced heart failure represents a proportion of those patients with heart failure who possess the following features (Table 1). In those with advanced heart failure, failure of medical therapy is clinically apparent by the following (Table 2). Patients with the above features represent a group of patients with progressive pump failure who carry a poor prognosis. Referral to a unit that manages advanced heart failure, MCS and cardiac transplantation allows patients to be considered for therapies that may
Table 1 Features consistent with advanced heart failure4 Persistent New York Heart Association (NYHA) Class III or IV symptoms Episodes of fluid retention +/− reduced cardiac output at rest Evidence of cardiac dysfunction (LVEF < 30%; pseudonormal or restrictive Doppler mitral inflow pattern on echocardiography; elevated haemodynamic LV pressure (PCWP >16 mmHg +/or RAP >12 mmHg; High BNP or NT‐ProBNP plasma levels) Impairment of functional capacity (inability to exercise, 6‐min walk test < 300 m, peak VO2max < 12–14 mL/kg/min) History of ≥1 heart failure hospitalisation in the past 6 months. BNP, brain natriuretic peptide; NT‐ProBNP, N‐terminal pro‐hormone of brain natriuretic peptide; LVEF, left ventricular ejection fraction; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure.
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significantly improve their quality of life and prognosis. Prompt referral of these patients once it is apparent that they have progressed to advanced heart failure is crucial to their outcomes. Development of end‐organ damage, such as progressive renal or hepatic impairment, ascites and worsening cachexia may limit treatment options if they have progressed beyond a level where MCS can be considered. Frailty is an important consideration and carries increased risk of adverse outcomes, including higher rates of readmission and death.5 Right ventricular failure and ‘fixed’ pulmonary hypertension are also common features in late‐stage advanced heart failure and present difficult management challenges when considering MCS and transplantation.
VAD therapy Over the past 30 years, significant advances have been made in the field of MCS. This progression in technology and patient selection has been associated with improved outcomes and reduction in complications. VAD implantation has evolved as by far the most common utility of MCS. Significant growth in the number of VAD implants internationally has occurred over the past 10–15 years. Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) is an international registry of MCS which provides informative data on international trends in utilisation of MCS, indications for implantation and clinical outcomes (Fig. 1). The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial published in 2001 demonstrated improvement in mortality in patients who underwent LVAD implantation compared with medical therapy alone in patients who were not candidates for cardiac transplantation. Sixty‐eight subjects randomised to LVAD were compared with 61 controls. Implantation of the Heartmate XVE LVAD was associated with a reduction in all‐cause mortality with 41 deaths in the LVAD group compared with 54 deaths in the control group. Median survival was 531
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Figure 1 These data from INTERMACS demonstrate the growth internationally in ventricular assist devices utilisation since 2006. The transition to continuous flow intra‐corporeal devices along with the low rates of utilisation of the total artificial heart (TAH) is demonstrated6 (Reproduced with permission of the Copyright owner.) ( ), Continuous flow intracorporeal left ventricular assist devices (LVAD) pump; ( ), pulsatile flow intracorporeal TAH; ( ), pulsatile flow intracorporeal LVAD pump; ( ), pulsatile flow paracorporeal LVAD pump.
408 days in the LVAD group compared with 150 days in the control group (relative risk 0.52 (95% CI 0.34–0.78), P = 0.001). This trial was the first major randomised trial evaluating the use of VAD and provided the impetus for further device development and wider clinical use.7 The advent of continuous‐flow VAD provided an important step in the reduction of complications compared with pulsatile devices. Continuous‐flow devices are smaller, more durable, have smaller drivelines and one internal moving part. The HeartMate II trial published in 2009 clearly demonstrated the superiority of axial continuous flow pump technology over pulsatile LVAD in patients who were not eligible for transplantation. Two‐year survival in those patients who received a HeartMate II was 58% compared with 24% in those who received a HeartMate XVE.8 The ADVANCE trial evaluated the HVAD (HeartWare ventricular assist device) which is a centrifugal continuous flow pump. One hundred and forty patients implanted with the HVAD had survival rates comparable to a control group of 499 patients derived from the INTERMACS registry that predominantly included continuous flow pumps, including the HeartMate II. Patients in both groups underwent VAD implantation as a bridge 532
to transplantation (BTT) intent. The HVAD was found to have comparable outcomes, with 92% of the patients who received the HVAD surviving 180 days with the pump, or had received a transplant or recovered ventricular function enough to have the device removed.9 The ADVANCE and HeartMate II Trial resulted in significant change in practice in the utilisation of continuous‐flow devices rather than pulsatile devices (Fig. 1). VAD therapy allows those with advanced heart failure to be supported with a device that provides significant assistance or essentially full replacement for their intrinsic cardiac output. This provides improved organ perfusion, improvement in symptoms of congestion and New York Heart Association (NYHA) Class. Constant ventricular unloading provides reduction in left atrial pressure which may allow significant pulmonary vascular remodelling and reduction in pulmonary vascular resistance. In patients who are candidates for cardiac transplantation, VAD therapy may result in significantly improved quality of life and reduced mortality while awaiting transplantation. The two most commonly used devices presently in Australia are the HeartMate II and the HeartWare (Figs 2, 3). © 2016 Royal Australasian College of Physicians
Role of MCS in advanced heart failure
Indications for VAD therapy VAD insertion as a BTT is the only utility of the therapy within Australia. However, it is important to recognise that an individual's designation for MCS can change over time as clinical factors may dictate. In an analysis of INTERMACS data, 43% of those implanted with a device as BTT intent were not on the transplant list within
2 years and 15% of patients implanted with a destination therapy (DT) intent were on the transplant list within 2 years. This illustrates the dynamic nature of heart failure and MCS and that the indication for MCS may change depending on the clinical scenario.12 Table 3 summarises the different indications for VAD therapy. As demonstrated in Figure 4, the proportion of patients undergoing transplantation who are bridged with a LVAD has grown significantly in Australia. In 2013 in Australia, 40% of patients who underwent cardiac transplantation were bridged to transplantation with a ventricular assist device.13 VAD insertion as a bridge to recovery is an uncommon event, occurring in approximately 2–5% of device insertions. Cardiomyopathic processes, such as peri‐partum and post‐myocarditis may be associated with a greater chance of recovery. Novel strategies that may promote myocardial recovery (and possibly allow device removal), including drugs that promote myocardial hypertrophy (with the Beta‐2 agonist Clenbuterol), myocardial stem cell placement and genetic enzyme replacement therapy targeting SERCA2a gene expression in myocytes that promote inotropy, lusitropy and calcium cycling,14,15 remain under investigation.
Selection of patients for VAD
Figure 2 The HeartMate II Device. A second generation axial flow pump that requires creation of a pump pocket at the time of implantation. The external controller connects to the pump through the external driveline. The inflow and outflow cannula connect to the left ventricular apex and ascending aorta respectively as demonstrated. The battery packs are also displayed. (Image courtesy of Thoratec.)10
In Australia, VAD implantation occurs in hospitals appropriately staffed with cardiologists, cardiac surgeons and intensive care specialists experienced in advanced heart failure and transplantation. Trained skilled nursing support is also essential. In Australia, there are four of these units presently in adult medicine and one in the paediatric population. There is one such centre in New Zealand. Consideration of VAD implantation is warranted in patients with the following profile (Table 4).
Figure 3 The HeartWare Device. The smaller centrifugal small contains a single moving impellar part. The pump is implanted in the pericardial space without need for creation of a pump pocket. The driveline connects the pump to a power source externally. (Images courtesy of HeartWare.)11
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It is important to recognise that implantation of a VAD is a significant undertaking for a patient and their caregivers with significant lifestyle changes. An in‐depth discussion with the patient and their family is required to ensure that they are informed as to the risks of the implant, the requirement for anticoagulation, the need for education and awareness of the device function and the need for regular medical follow up.
Contraindications to VAD insertion are summarised below. It is important to recognise also that many patients being assessed and listed for transplantation may not be suitable candidates for VAD implantation. This includes patients with restrictive cardiomyopathies, hypertrophic cardiomyopathy (due to reduced LV cavity size) and some patients with complex congenital heart disease (Table 5).
Table 3 The different indications for ventricular assist devices (VAD) implantation Bridge to transplantation • Patients actively listed at the time of VAD implantation. Due to limited donor availability, the average wait times may be (BTT) well over 1 year. • Usual practice is to remove temporarily from transplant waiting list following VAD implant to allow for sternotomy healing, improvement of physical status and organ function prior to transplantation. Bridge to candidacy (BTC) • VAD implanted to clarify or improve an aspect of patients’ candidacy prior to transplantation. Examples include: 1 Pulmonary hypertension to a degree that precludes cardiac transplantation (which may improve with pulmonary vascular remodelling following VAD implant). 2 To assist with weight loss and improvement in muscle mass. 3 Improvement of organ function (e.g. improvement in renal function with improved cardiac output). 4 To provide haemodynamic support in patients who have quit smoking, but are less than 6 months smoking cessation to allow listing for transplantation. Bridge to recovery (BTR) • Uncommon, occurring in 2–5% of VAD implants. Is rarely a set strategy. Destination therapy (DT) • Patients whom are not considered candidates for cardiac transplantation (e.g. Comorbidities, prior malignancy, age). • Device is implanted as a long‐term strategy. Ideally have relatively preserved end‐organ function, good ability to self‐care and reasonably preserved end‐organ function otherwise.
Figure 4 Significant growth in use of ventricular assist devices as a bridge to transplantation in Australia over the past 20 years.13 (Reproduced with permission.) ( ), New York Heart Association III %; ( ), New York Heart Association IV %; ( ), inotropic support %; ( ), intra‐aortic balloon pump %; ( ), ventricular assist device %; ( ), total artificial heart %.
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Timing of implantation of MCS Following the development of advanced heart failure along with one or more of the ‘failures’ listed in Table 2, serious consideration should be given to assessment for candidacy for MCS. A variety of clinical scenarios may present clinical challenges with regard to the optimal timing of VAD implantation. In the early years of VAD as a BTT intent, patients were largely INTERMACS 1 or 2 (Table 6) at the time of Table 4 ESC Heart Failure Guidelines (2012) – current indications for ventricular assist devices (VAD) implantation16 >2 months of severe symptoms despite optimal medical and device therapy and more than one of the following LVEF < 25%, and if measured, peak VO2 < 12 mL/kg/min ≥ 3 hospitalisation in the previous 12 months without an obvious precipitating cause Dependence on IV inotropic therapy Progressive end‐organ dysfunction (worsening renal and/or hepatic function) due to reduced perfusion and not to inadequate ventricular filling pressure (PCWP ≥ 20 mmHg and SBP ≤ 80–90 mmHg or CI ≤ 2 L/min/m2) Deteriorating right ventricular function ESC, European Society of Cardiology; LVEF, left ventricular ejection fraction; PCWP, pulmonary capillary wedge pressure; SBP, systolic blood pressure.
Table 5 Contraindication's to ventricular assist devices (VAD) insertion Absolute and relative contraindications to VAD insertion • Irreversible major end organ failure (e.g. hepatic/renal) not due to poor cardiac output • Metastatic cancer • Cerebral damage/neurological deficit/uncertain neurological status • Major coagulopathy • Active infection • Mechanical heart valves (may replace with bio‐prosthetic valve) • Severe aortic valve regurgitation (although can be managed by closing or replacing aortic valve at time of VAD insertion) • Inability to tolerate anticoagulation • Unresolved significant psychosocial issues
Table 6 Seven INTERMACS levels of clinical severity of end‐stage heart failure INTERMACS level 1 2 3 4 5 6 7
Clinical definition Critical cardiogenic shock Progressive decline Stable but inotrope dependent Resting symptoms Exertion intolerant Exertion limited Advanced NYHA Class‐III
NYHA, New York Heart Association.
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implantation. However, as technology has improved and the beneficial effects of VAD therapy on patients’ end organ function, NYHA Class and pulmonary vasculature have become more apparent, ‘earlier implantation’ of VAD is being considered and implemented in many centres. In the latest INTERMACS report, a greater proportion of patients were INTERMACS 3–4 at the time of implantation.6 Whether this translates to reduced operative mortality and provides better long‐term outcomes remains to be proven. Implanting VAD ‘early’ (i.e. in patients who are INTERMACS 4–7) is hypothesised to be associated with less adverse surgical outcomes because of less critical clinical profiles, but does expose patients to risks of the significant complications of VAD implantation. Specific clinical scenarios may mandate early VAD insertion at the time of diagnosis of a cardiomyopathy. This may include an inability to wean patients from extracorporeal membrane oxygenation (ECMO), which has been inserted following cardiac surgery or in severe acute decompensated heart failure with inotrope dependence.
Biventricular advanced heart failure Many patients who are referred for consideration of MCS have significant right ventricular dysfunction. Implantation of an LVAD alone in these patients can be associated with development of severe right heart failure postoperatively. Up to 30% of patients who develop right ventricular failure after an LVAD require either short or long‐term right ventricular support.17 Predicting the likelihood of developing right heart failure is challenging; however, a number of clinical factors can predict risk (Table 7). The Total Artificial Heart (TAH) device was the initial form of long‐term MCS which was developed in the early 1980s. The Syncardia TAH is at present the most commonly used and approved form. This consists of two pneumatically driven polyurethane ventricles, each with two unidirectional mechanical valves that displace blood in a pulsatile manner. The device also consists of an external driveline, which connects to the console that Table 7 Risk factors for right ventricular failure postoperatively18,19 • RVSWI < 300 (=Stroke Volume index x(mean PAP‐mean RAP) • CVP/PCWP > 0.63 • CVP > 15 mmHg • Severe tricuspid regurgitation • Preoperative intubation • Severe RV dysfunction identified pre‐VAD implantation CVP/PCWP, central venous pressure/pulmonary capillary wedge pressure; RVSWI, right ventricular stroke work index; VAD, ventricular assist devices.
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contains the pneumatic drivers. Challenges with the TAH include sizing difficulties as the device is quite large and the fact that patients are completely dependent on the TAH for cardiac output, which puts patients at risk of disastrous complications if device disruptions were to occur (Fig. 5). The use of TAH represents a small proportion of MCS in advanced heart failure. However, since the advent of continuous flow VAD, bi-ventricular assist device (BiVAD) implantation has evolved as a means of successfully supporting patients with severe bi‐ventricular failure. Right ventricular support can be provided by use of a VAD implanted in a variety of anatomical positions of the inflow cannula. Cannula configuration from right atrium to pulmonary artery has been successfully performed.21 Ideally, postoperative right ventricular failure following an LVAD implantation could be predicted preoperatively and the decision made to implant a BiVAD. For patients who clearly do not require a BiVAD, but may require temporary right‐sided support, a centrifugal device can be employed in the para‐corporeal position with inflow from a cannula in the femoral vein and an outflow through a Dacron graft anastomosed to the main pulmonary artery. Following right ventricular recovery, the device can be weaned and removed without reopening the chest. Support may occur using this method for up to 14 days.22
Figure 5 The Syncardia TAH. (Courtesy of Syncardia.)20
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General aspects of management and complications following VAD insertion There are several important aspects of management of VAD patients in the short and long‐term period following implantation. The main principles of management are to optimise VAD output, to avoid complications and to manage anti‐thrombotic therapy appropriately. Some of the key aspects of management are summarised in Table 8. A number of important complications can occur both early and late following a VAD insertion. These include the following: 1 Early postoperative pericardial bleeding – secondary to the early introduction of systemic anticoagulation postoperatively to avoid pump thrombus. This can frequently result in the need to return to the operating theatre for control of bleeding. 2 Systemic embolisation/CVA – embolisation of thrombus from within the device. 3 Intracerebral haemorrhage (ICH) – due to the requirement of anticoagulation combined with antiplatelet therapy, patients with VAD are at increased risk of spontaneous and traumatic ICH. If this occurs, multi‐speciality input is required. Neurosurgical intervention may be required and anticoagulant and/or antiplatelet therapy will likely need to be temporary interrupted. The period of time of anticoagulant therapy is minimised to avoid the risk of development of pump thrombus. The long‐term strategy for anti‐platelet and anticoagulant therapy is reassessed with consideration of reducing the anti‐platelet agents from two to one, and also revising the international normalised ratio (INR) target range (i.e. 2.5–3.0, may be revised to 2–2.5). If significant neurological insult has occurred, rehabilitation may be required. 4 Infection – driveline infections are common in those with long‐term VAD and approach 40% in those who carry a device for 3 years (Fig. 6). This is a significant source of morbidity and mortality. Meticulous driveline care and early recognition and treatment with antibiotics are imperative. The most effective way of clearing a driveline or pocket infection is cardiac transplantation. 5 Pump thrombus – presence of thrombus within the rotor, inflow or outflow cannula. This may present with device power surges, intravascular haemolysis and evidence of left ventricular failure due to failure of ventricular unloading. Risks for thrombus include active infection, sub‐therapeutic anticoagulation, obstruction of inflow or outflow cannula, bleeding episodes where permissive sub‐ therapeutic anticoagulation has occurred with low pump speed. Pump thrombus commonly necessitates a pump exchange; however, thrombolysis has also been used.
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Table 8 General aspects in clinical assessment and routine follow up of ventricular assist devices (VAD) Clinical parameter
Aspects of review and optimisation
LVAD pump speed setting Assessment for clinical evidence of heart failure symptoms and signs. Review of VAD data regarding incidence of low flow alarms, suction alarms and pulsatility index events. Integration of echocardiographic data into speed optimisation, including ventricular size, aortic valve opening, interventricular septal position and right heart function. Monitoring for Clinical evidence of intravascular haemolysis (e.g. dark urine) or congestive symptoms due to heart failure. development of pump Incidence of high power alarms or spikes in pump power (may be an early sign indicative of pump thrombus). thrombus Blood parameters: elevation or a rise in trend of levels of lactate dehydrogenase, plasma free haemoglobin, bilirubin. If suspicion or confirmation of pump thrombus – needs urgent assessment regarding requirement for pump exchange or thrombolytic therapy. Driveline care Patient and/or carer diligence to the routine of driveline dressing care. Presence of fevers, discharge or erythema from driveline site. If discharge present, taking swab for microscopy, culture and sensitivity and early commencement of antibiotics is strongly considered. Measurement of Targeting mean arterial pressure of 70–80 mmHg as measured with Doppler and standard blood pressure cuff. meanarterial pressure This target reduces the afterload strain on the VAD and reduces the risk of intra‐cerebral haemorrhage. Low flow alarms May occur due to dehydration, postural changes, right ventricular failure or high afterload. Clinical assessment involves fluid review, measurement and optimisation of mean arterial pressure; consider altering pump speed and addressingright ventricular failure where present. Suction alarms If pump speed too high relative to blood volume in the ventricles – ventricular walls may ‘suck down’ or collapse across the inflow cannula. May be indicative of intravascular depletion, inadequate right ventricular contractility or too high VAD pump speed. Management includes administration of volume (orally or intravenously if required), postural manoeuvres to increase venous return and reducing VAD pump speed if appropriate. If persistent low flow alarms and/or suction alarms with evidence of right ventricular failure, inotropic therapy is considered to augment right ventricular function, and occasionally temporary or permanent mechanical RV support may be used. LVAD, left ventricular assist devices.
Figure 6 External driveline infection with evidence of erythema and discharge.
6 Gastrointestinal bleeding and epistaxis – patients with VAD may develop a characteristic acquired von Willebrand syndrome. This is secondary to the shearing forces of the pump that result in structural defects in von Willebrand's factor. Continuous flow VAD are also believed to result in neovascularisation of blood vessels (angiodysplasia) within the gastrointestinal tract that may be a © 2016 Royal Australasian College of Physicians
source of bleeding. Epistaxis may occur due to this acquired von Willebrand syndrome and also due to the effects of anti‐platelet and anticoagulant medication. Relief can sometimes be achieved through cauterisation of the culprit intra‐nasal vessel. If persisting and recurrent episodes of gastrointestinal bleeding and epistaxis occur, reduction in the anti‐platelet medications from two to one and reducing the INR target level may be considered. However, the risks of development of pump thrombus against recurrent bleeding have to be considered. 7 Right ventricular failure – increased cardiac output from the LVAD can overload the myopathic right ventricle. Clinically, this may present with clinical evidence of right heart failure and low LVAD flows secondary to poor LV filling. Optimisation of volume state and VAD flow rates with echocardiographic assistance may provide some improvement. Persistent right heart failure may require conversion to a BiVAD device. 8 Aortic valve regurgitation – the presence of greater than mild aortic regurgitation requires valve repair, replacement or valve closure at the time of LVAD implantation to prevent the progression of aortic regurgitation. The development of severe aortic regurgitation results in a circulatory loop from regurgitant blood, reducing forward flow. Progressive aortic regurgitation or de novo aortic regurgitation following implantation may 537
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develop due to a combination of factors, including lack of aortic valve opening, altered valve haemodynamics and aortic valve commissural fusion. 9 Pump malfunction/pump stop – these are very uncommon events with modern devices and may reflect pump thrombosis, driveline fracture or disconnection, controller failure, pump malfunction or both power sources being disconnected. Patients are supplied with a ‘back‐up’ controller in the event of controller failure. 10 Increased rates of allo‐sensitisation (to human leucocyte antigens) – this may increase rates of positive cross‐ matching, increase waiting list times and put patients at risk of higher rates of rejection episodes following transplantation. This appears to be less prevalent with continuous flow devices compared with pulsatile devices.
MCS in patients with congenital heart disease Patients with end‐stage heart failure due to congenital heart disease represent a growing and challenging group of patients requiring MCS in the setting of uncorrectable or previously corrected or palliated congenital heart disease. This is a group of patients that are challenging candidates for MCS due to their unique physiology and anatomy. Significant pulmonary hypertension that may preclude isolated orthotopic cardiac transplantation may also provide challenges with MCS. VAD have been successfully implanted for systemic support (right ventricular morphology) in patients with congenitally corrected transposition of the great arteries as well as patients with d‐transposition of the great arteries who may present with late systemic ventricular failure after a previous atrial switch operation.23 Small numbers of case reports have also described the use of mechanical devices to support congenital lesions with single ventricle physiology and the failing Fontan circulations.24,25
DT While not widely available within Australian advanced heart failure centres, DT therapy offers appropriately selected patients with advanced heart failure who are not candidates for cardiac transplantation to have significantly improved quality of life and reduced mortality. DT is an increasingly used indication for VAD use internationally. Along with technological improvements in VAD, the results of the REMATCH and HeartMate II DT trial, and the fact that a significant proportion of patients with advanced heart failure possess comorbidities that may preclude cardiac transplantation have driven this increase. In the sixth INTERMAC, 41% of all MCS implants were inserted for DT.6 Patients selected for DT 538
usually have contraindications for cardiac transplantation, such as malignancy within the previous 5 years, chronic renal failure, severe obesity or elevated pulmonary vascular disease that precludes listing for transplantation (e.g. trans-pulmonary gradient >15 mmHg +/or pulmonary vascular resistance >6 Wood Units). Use of DT therapy may increase the management options for specific patients following VAD implant. As mentioned previously, 15% of patients in an analysis of INTERMACS data of patients who were assigned DT were eventually listed for transplantation.12 Changes in patients' nutrition, frailty, end‐organ function and comorbidities may affect transplant candidacy and thus may provide some patients with an eventual option for BTT. Potential for short and long‐term adverse outcomes following VAD placement for DT cannot be underestimated when considering potential candidates, particularly given the potential for greater comorbidities in this group.26 However, wider availability of DT within Australia would provide appropriately selected patients significantly improved quality of life and would reduce the rate of their admissions to hospital with acute decompensated heart failure. The international growth rates in DT utilisation highlight the need for this indication to be widely accepted in Australia.
Future directions in MCS Advances in device design, the use of continuous flow VAD, improvements in technology, as well as clinical experience in patient selection, have resulted in a significant fall in complications from VAD use. However, the morbidity from complications such cerebrovascular events, bleeding and driveline‐related infections remains substantial. Two devices currently undergoing development include the HeartWare MVAD pump and the HeartMate III. The MVAD is approximately one third the size of the HVAD allowing for potential minimally invasive surgery through the apical approach. The MVAD utilises axial flow pump technology and contains a magnetic and hydro-dynamic impeller system with wide helical flow channels designed to minimise shear stress on blood components. A novel cannula configuration allowing placement of the outflow cannula across the aortic valve that would potentially allow trans‐apical implantation is also under evaluation.27 The device has been successfully implanted in an ovine model and human trials are anticipated in the future.28 The HeartMate III is presently undergoing clinical trials in humans. The favourable improvements compared with the HeartMate II are designed to improve blood compatibility with reduction in clinical adverse events. It contains textured blood‐contacting surfaces, has a fully © 2016 Royal Australasian College of Physicians
Role of MCS in advanced heart failure
magnetically levitated single moving part with less potential for friction. It also contains a component of artificial pulse technology that is postulated to reduce the risk of thrombus formation within the pump and the potential bleeding complications associated with continuous flow VAD, which include acquired von Willebrand disease, angiodysplasia of the gastrointestinal tract and impaired platelet aggregation.29 The HeartMate III also provides a smaller pocket controller for easier patient use. An eagerly awaited advance in MCS is elimination of the need for an external power source (and hence drivelines). Transcutaneous energy transfer (TET) allows transmission of energy non‐invasively inside the body through an induction‐heating system where an electromagnetic charge between two sets of coils located inside and outside body. Use of TET has been performed in small numbers with previously available devices in small
References 1 Page K, Marwick TH, Lee R, Grenfell R, Abhayaratna WP, Aggarwal A et al. A systematic approach to chronic heart failure care: a consensus statement. Med J Aust 2014; 201: 146–50. 2 Stewart S, Ekman I, Ekman T, Oden A, Rosengren A. Population impact of heart failure and the most common forms of cancer: a study of 1 162 309 hospital cases in Sweden (1988 to 2004). Circ Cardiovasc Qual Outcomes 2010; 3: 573–80. 3 Ponikowski P, Anker S, AlHabib K, Cowie M, Force TL, Hu S et al. Heart failure preventing disease and death worldwide. Nice: European Society of Cardiology; 2014. White Paper. 4 Metra M, Ponikowski P, Dickstein K, McMurray J, Gavazzi A, Berg CH et al. Advanced chronic heart failure: a position statement from the Study Group on Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2007; 9: 684–94. 5 Dunlay SM, Park SJ, Joyce LD, Daly RC, Stulak JM, McNallan SM et al. Frailty and outcomes after implantation of left ventricular assist device as destination therapy. J Heart Lung Transplant 2014; 33: 359–65. 6 Kirklin JK, Naftel DC, Pagani FD, Kormos RL, Stevenson LW, Blume ED et al. Sixth INTERMACS annual report: a 10,000 patient database. J Heart Lung Transplant 2014; 33: 555–64. 7 Rose EA, Gelijns AC, Moskowitz AJ, Heitjan DF, Stevenson LW,
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published series.30 If incorporated into modern devices, the use of TET could significantly reduce complications, particularly infections.
Conclusion MCS is a growing and important aspect of management of advanced heart failure. Significant improvements in device design, patient selection, management of complications and outcomes have occurred over the past 15– 20 years. Long‐term use of VAD support has successfully occurred and, as a result, DT is now considered an appropriate step in many patients with advanced heart failure. Early recognition and referral to centres that manage advanced heart failure allow appropriate patients to be considered for MCS in a timely manner before the complications of disease progression preclude this option.
Dembitsky W et al. Long term use of a ventricular assist device for end‐stage heart failure. N Engl J Med 2001; 345: 1435–43. Slaughter MS, Rogers JG, Milano CA, Russell SD, Conte JV, Feldman D et al. Advanced heart failure treated with continuous‐flow left ventricular assist device. N Engl J Med 2009; 361: 2241–51. Aaronson KD. Evaluation of the HeartWare HVAD left ventricular assist device system for bridge to transplant in advanced heart failure: the ADVANCE trial. American Heart Association 2010 Scientific Sessions; November 15, Chicago, IL. (Late Breaking Clinical Trials I); 2010. Thoratec Corporation (Homepage on the Internet). San Francisco (CA): Thoratec [cited 2016 Apr 10]. Available from URL: http://www.thoratec.com HeartWare (Homepage on the Internet) [cited 2016 Apr 10]. Available from URL: http://www.heartware.com Teuteberg JJ, Stewart GC, Jessup M, Kormos RL, Sun B, Frazier OH et al. Implant strategies change over time and impact outcomes: insights from the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). JACC Heart Fail 2013; 1: 369–78. Keogh A, Williams T, Pettersson R, eds. Australia and New Zealand Cardiothoracic Organ Transplant Registry: 2013 report. Sydney: Australia and New Zealand Cardiothoracic Organ Transplant Registry; 2013.
14 Birks EJ, Tansley PD, Hardy J, George RS, Bowles CT, Burke M et al. Left ventricular assist device and drug therapy for the reversal of heart failure. N Engl J Med 2006; 355: 1873–84. 15 Jessup M, Greenburg B, Mancini D, Cappola T, Pauly DF, Jaski B et al. Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+‐ATPase in patients with advanced heart failure. Circulation 2011; 124: 304–13. 16 McMurray J, Adamopoulos S, Anker S, Auricchio A, Bohm M, Dickstein K et al. European Society of Cardiology Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur Heart J 2012; 33: 1787–847. 17 Potapov EV, Loforte A, Weng Y, Jurmann M, Pasic M, Drews T et al. Experience with over 1000 implanted ventricular assist devices. J Card Surg 2008; 23: 185–94. 18 Atluri P, Goldstone AB, Fairman AS, MacArthur JW, Shudo Y, Cohen JE et al. Predicting right ventricular failure in the modern, continuous flow left ventricular assist device era. Ann Thorac Surg 2013; 96: 857–64. 19 Kormos RL, Teuteberg JJ, Pagani PD, Russell SD, John R, Miller LW et al. Right ventricular failure in patients with the HeartMate II: incidence, risk factors, and effect on outcomes. J Thorac Cardiovasc Surg 2010; 139: 1316–24.
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20 Syncardia (Homepage on the Internet). Tuscon (AZ): Syncardia [cited 2016 Apr 10]. Available from URL: http://www. syncardia.com 21 Marasco SF, Stornebrink RK, Murphy DA, Bergin PJ, Lo C, McGiffin DC. Long‐term right ventricular support with a centrifugal ventricular assist device placed in the right atrium. J Card Surg 2014; 29: 839–42. 22 Haneya A, Philip A, Puehler T, Rupprecht L, Kobuch R, Hilker M et al. Temporary percutaneous right ventricular support using a centrifugal pump in patients with postoperative acute refractory right ventricular failure after left ventricular assist device implantation. Eur J Cardiothorac Surg 2012; 41: 219–3. 23 Joyce DL, Crow SS, John R, St Louis JD, Braunlin EA, Pyles LA et al. Mechanical
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circulatory support in patients with heart failure secondary to transposition of the great arteries. J Heart Lung Transplant 2010; 29: 1302–15. Rossano JW, Goldberg DJ, Fuller S, Ravishankar C, Montenegro LM, Gaynor JW. Successful use of the total artificial heart in the failing Fontan circulation. Ann Thorac Surg 2014; 97: 1438–40. Nathan M, Baird C. Successful implantation of a Berlin heart biventricular assist device in a failing single ventricle. J Thorac Cardiovasc Surg 2006; 131: 1407–18. Porepa LF, Starling RC. Destination therapy for left ventricular assist devices: for whom and when? Can J Cardiol 2014; 30: 296–303. Tamez D, LaRose JA, Shambaugh C, Chorpenning K, Soucy KG, Sobieski MA et al. Early feasibility
testing and engineering development of the transapical approach for the HeartWare MVAD ventricular assist system. ASAIO J 2014; 60: 170–7. 28 McGee EJ, Chorpenning K, Brown MC, Breznock E, Larose JA, Tamez D. In vivo evaluation of the HeartWare MVAD pump. J Heart Lung Transplant 2014; 33: 366–71. 29 Suarez J, Patel CB, Felker M, Becker R, Hermandez AF, Rogers JG. Mechanisms of bleeding and approach to patients with axial‐flow left ventricular assist devices. Circ Heart Fail 2011; 4: 779–84. 30 Slaughter MS, Myers TJ. Transcutaneous energy transmission for mechanical circulatory support systems: history, current status, and future prospects. J Card Surg 2010; 25: 485–9.
CLINICAL PERSPECTIVES
Novel approaches to the treatment of hyperglycaemia in type 2 diabetes mellitus A. Galligan1 and T. M. Greenaway1,2 1 Department of Endocrinology, The Royal Hobart Hospital, and 2The School of Medicine, Faculty of Health Science, University of Tasmania, Hobart, Tasmania, Australia
Key words type 2 diabetes, anti-hyperglycaemic agents, cardiovascular safety, novel and emerging therapies. Correspondence Anna Galligan, Department of Endocrinology and Diabetes Services, The Royal Hobart Hospital, 48 Liverpool Street, Hobart, Tas. 7000, Australia. Email: [email protected] Received 4 August 2015; accepted 3 December 2015.
Abstract Control of hyperglycaemia is a fundamental therapeutic goal in patients with type 2 diabetes. The progressive nature of β-cell dysfunction in type 2 diabetes leads to the need for escalating anti-hyperglycaemic treatment, including insulin, in most patients. Given the prevalence of complications such as weight gain and hypoglycaemia associated with traditional anti-hyperglycaemic agents (AHA), including sulphonylureas and insulin, it is unsurprising that recent years have seen the development of novel agents to treat hyperglycaemia. With increasing evidence supporting the need for a multi-faceted approach to the prevention of adverse cardiovascular events in people with type 2 diabetes, a patient-centred and individualised management strategy addressing lifestyle, cardiovascular risk factor modification and glycaemic control remains critical in improving outcomes in these patients.
doi:10.1111/imj.13070
Funding: Since 2010, T. M. Greenaway has received lecture fees from Novo Nordisk, Novartis, Astra Zeneca, Lilly, Merck, BristolMyers Squibb and Glaxo Smith Kline and research and travel support from Novo Nordisk, Novartis and Sanofi Aventis. He is an investigator on the LEADER trial. Conflict of interest: None. 540
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