The clinical and cost effectiveness of long-term ventricular assist devices (VADs) as a bridge-to-transplant in adults Health technology description

Transcription

1 In response to an enquiry from the NHS National Services Division Number 39 July 2011 The clinical and cost effectiveness of long-term ventricular assist devices (VADs) as a bridge-to-transplant in adults Health technology description Ventricular assist devices (VADs) are mechanical pumps that provide circulatory support to the failing heart by helping the ventricles to pump blood around the body. 1,2 There are short-term use and long-term use VAD technologies. 3,4 VADs for longterm use have a pump that is implanted inside the body and connected by percutaneous leads to a portable control system and battery pack outside the body. 3,4 The national health service (NHS) currently funds the use of long-term VADs as bridge-to-transplant (BTT) 5 to support heart transplant candidates who are too unwell to undergo the procedure or are unlikely to survive in a good clinical state until a suitable donor heart becomes available. 1-3,6-8 Long-term VADs are not intended for transplant candidates who are well enough to wait for a donor heart. 8 Some countries (not the United Kingdom (UK)) have also approved long-term VADs to provide permanent support, or destination therapy (DT), to patients who are not eligible for transplantation. 1,3,7 Once a VAD is implanted as BTT the heart may recover sufficient function to enable explantation (removal) of the device and removal of the patient from the transplant list. Similarly, some patients who receive a VAD as DT may become eligible for transplantation as a result of VAD support. 1,7 Key points Long-term ventricular assist devices can act as a bridge-to-transplant to allow heart transplant candidates who would otherwise become transplant-ineligible or die on the waiting list to survive to transplantation. There are no published randomised controlled trials of ventricular assist devices as bridge-totransplant. There is evidence from observational studies of improvement in functional status and quality of life during ventricular assist device support as bridge-to-transplant, and improved survival to transplant with second generation compared with first generation devices. Implantation of contemporary ventricular assist devices remains associated with serious adverse events. Ventricular assist device support as bridgeto-transplant is not cost effective at currently accepted thresholds in the United Kingdom. Technological development of VADs is ongoing. 3,4,9 Currently available long-term devices vary in design, pump type, and configuration. Contemporary second generation devices (eg HeartMate II, Jarvik 2000, DeBakey ) and emerging third generation VADs (eg HVAD, VentrAssist ) have smaller, lighter and technically simpler continuous-flow pumps designed to overcome some of the problems with the earlier pulsatile-flow first generation devices (eg HeartMate XVE, Thoratec IVAD). 3,4,9 Larger VAD pumps are implanted in the abdomen (eg HeartMate XVE, HeartMate II, Thoratec IVAD, VentrAssist ) whereas smaller devices can be positioned in the pericardial space (HVAD, DeBakey ) or the apex of the left ventricle (Jarvik 2000 ). Most long-term VADs are left ventricular assist devices (LVAD) configured to support the left ventricle, whereas some (Thoratec IVAD) can also be used for right ventricular (RVAD) and biventricular (BiVAD) support. Long-term VADs require systemic anticoagulation therapy to prevent thromboembolism because the mechanical nature of the pumps carries the risk of blood clotting. 4,10 In Scotland, long-term VADs are currently being used as BTT at the Scottish National Advanced Heart Failure Service (SNAHFS) at the Golden Jubilee Hospital in Glasgow. 8

2 Epidemiology Heart failure (HF) affects around 750,000 people in the UK. 11 Estimates based on General Practice Research Database data for 2009 indicate that there are over 27,000 new cases of HF in the UK each year 12, including 2,732 cases (95% Confidence Interval (CI) 2,017 to 3,685) in Scotland (P Scarborough, Senior Researcher, University of Oxford. Personal Communication, 5 July 2011). The prevalence of HF in Scotland was estimated at 15.6 per 1,000 population in 2004 using national general practice administration data. 13 Estimates of the number of people currently living with HF in Scotland range from 60, up to 100, The rate of first hospitalisation for HF per 100,000 population in Scotland in 2003 was 105 (95% CI 101 to 109) for men and 101 (95% CI 97 to 105) for women. 16 Estimates of the UK incidence and prevalence of advanced HF have not been based on recent data. The prevalence of advanced HF was estimated for England and Wales at approximately 7,000 8,000 cases based on studies published in HF has a poor prognosis with mortality rates at 1-year of up to 30 40%, 16,18,19 rising to 50% or more for advanced disease. 17,20,21 A heart transplant is the last treatment option when advanced HF becomes refractory to all other means of medical management. 5,8,20 Transplant candidates are mostly younger patients under the age of 65 years with no serious co-morbidities. 8,22,23 Heart transplantation increases survival in these patients to around 80% at 1-year and 50% at 10-years, with a return to near normal quality of life (QOL). 7,23-25 Heart transplantation in the UK is, however, in decline 5,8,17,25,26 for reasons that include decreasing availability of donor hearts. 5,26 The shortage of donor hearts increases waiting times for transplantation, and up to 20 40% of transplant candidates may die before a suitable donor heart becomes available. 17 The median waiting time for a heart transplant in the UK is currently 184 days. 27 Fifty-three percent (55/103) of UK non-urgent adult heart transplant candidates registered in had received a transplant within 6 months, 35% were still waiting and 7% had died waiting; after 3 years, 69% were transplanted, 4% were still waiting and 16% had died on the waiting list. 26 As UK funding for long-term VADs is restricted to BTT every recipient has to be either a transplant candidate or a potential transplant candidate after a period of VAD support. 28 The SNAHFS typically has 5 10 adult patients on the non-urgent waiting list. 8 While many more patients in Scotland could be referred for heart transplantation, or BTT with a VAD, the actual number who would meet the eligibility criteria has not been determined. 8 Clinical effectiveness * 2 There are no published randomised controlled trials (RCTs) of VADs as BTT. 17,23 Two RCTs conducted in the United States of America (USA) evaluated LVADs as DT. 29,30 The REMATCH trial showed a statistically significant reduction in all-cause mortality comparing the first generation HeartMate VE LVAD with medical management (Relative Risk (RR)=0.52; 95% CI 0.34 to 0.78; p=0.001). 29 The subsequent RCT compared the second generation HeartMate II LVAD with the first generation HeartMate XVE. 30 The median duration of LVAD support was 1.7 years (range 0 to 3.7) and 0.6 years (range 0 to 2.1), respectively. The primary outcome was a composite of survival free from disabling stroke and re-operation to repair or replace the VAD at 2-years follow-up. The trial showed a statistically significant difference in favour of the HeartMate II (Hazard Ratio (HR)=0.38; 95% CI 0.27 to 0.54; p<0.001). 30 Survival rates at 1 and 2-years were 68% (95% CI 60 to 76) and 58% (95% CI 49 to 67), respectively, with the HeartMate II compared with 55% (95% CI 42 to 69) and 24% (95% CI 1 to 46) with the first generation device. 30 Similar improvements in functional capacity and QOL were seen with both devices. 30 As both RCTs enrolled patients who were ineligible for transplantation, the findings cannot be extrapolated to BTT patients who are younger and have less co-morbidity. 7,30 The EVAD UK study prospectively evaluated adult transplant candidates who received first or second generation long-term LVAD (n=46) or BiVAD (n=24) support as BTT in England in ,31 The median duration of support overall was 82 days (95% CI 46 to 125). Overall, 44% (31/70) survived to transplantation, 43% (30/70) died during VAD support, 6% (4/70) recovered and 7% (5/70) remained on support at the time of reporting. 23,31 Overall survival at 1 year was 50% for first generation devices and 59% in patients (n=13) who received a second generation device (Jarvick 2000 ). 23 In the same centres, 74% (184/250) of non-vad transplant candidates underwent transplantation, and 9% died on the waiting list. 23,31 The Interagency Registry for Mechanical Circulatory Support (INTERMACS) has also reported low medium-term mortality among 496 patients who received first or second generation long-term LVADs as BTT in the USA. 32 At 1 year 52% had undergone transplantation, 35% were still alive on VAD

3 3 support, 12% died before transplantation, and 1% had recovered. 33 The INTERMACS data indicated a statistically significant survival advantage with second generation VADs compared with first generation devices among BTT patients. 33 Two health technology assessments (HTAs) summarised the findings from 26 observational studies, mostly small, retrospective uncontrolled case series, of first and second generation VADs as BTT published to March ,23,34 In the largest study (n=150) of a long-term second generation LVAD (DeBakey ) (mean duration of support 75 days, standard deviation (SD) 81), 41% were successfully bridged to transplantation, 45% died during VAD support, 13% remained on VAD support and one patient recovered. 23 Two subsequently published multicentre studies of the HeartMate II in Europe and the USA reported rates of survival to transplantation, recovery or ongoing LVAD support of 71.5% at 1 year 35 and 79% at 18 months 36, respectively. Recently published case series of third generation VADs as BTT reported survival rates of 81% at 6 months and 77% at 1 year (DuraHeart, mean duration of support 242 days, range 19 to 1148; n=68) 37 ; and 91% at 6 months and 86% at 1 year (HVAD, mean duration of support 167 days, range 13 to 425; n=23). 38 A prospective uncontrolled trial of the VentrAssist (n=33) reported 82% survival to transplant or transplant eligibility 154 days after implantation. 39 LVAD implantation as BTT has been shown to improve functional status and QOL among evaluable participants in observational studies. 17,23,36,37,39,40 In the EVAD UK study, QOL was poor in the month following VAD implantation but improved over time. 33 The aforementioned HTAs identified few data on post-transplant survival. 17,23 A later large cohort study that controlled for selection bias found no significant difference in post-transplant survival between patients who received a first generation LVAD and those who did not. 41 An observational study that compared patients supported with first (n=80) or second generation (n=50) LVADs with matched patients without LVAD support found no significant difference in 30-day or long-term survival after transplantation. 42 In the EVAD UK study, survival 1 year after transplantation was 84% for VADs recipients similar to inotropedependent (85%) and inotrope non-dependent (84%) non-vad supported transplant candidates at the same centres. 23,31 There was little difference in QOL between the VAD and non-vad supported groups after transplantation with both showing improvement in physical and psychosocial function. 23 * The findings in this section are based on the results of a literature search undertaken in November Safety The HeartMate II RCT showed statistically significant reductions in major adverse events including infection, sepsis and right heart failure compared with the first generation HeartMate XVE; but no significant difference in bleeding, stroke or other neurological events. 30 Haemorrhagic stroke and right heart failure remained major causes of death in both groups. 30 Observational studies published to March 2005 indicated that BTT with first and second generation LVADs carried a significant risk of serious adverse events including infection, bleeding, thromboembolic events and device malfunction. 17,23,34 Infection/sepsis and bleeding were also among the most common adverse events reported to the INTERMACS registry 33 and in the EVAD UK study. 23,31 INTERMACS data showed significant reductions in adverse events comparing second generation with first generation devices 33, although multicentre studies of the HeartMate II in Europe and the USA continue to report high rates of infection, bleeding, stroke and right heart failure 35,36 ; and these remain the most commonly reported major adverse events with third generation LVADs Data on the long-term durability of second and third generation long-term VADs are limited. INTERMACS recorded 0.82 second generation LVAD malfunction events per 100 patient months in the 6 months following implantation as BTT or bridge-to-transplant-candidacy, based on limited follow up (mean 4.6 months). 33 In the HeartMate II RCT, 12/133 recipients of the second generation LVAD required 13 pump replacements over the 2-year study period. 30 A subsequent observational study of the HeartMate II in transplant candidates with at least 18 months follow up reported no mechanical pump failures, although 11/281 patients required 12 pump replacements and 7 deaths were attributed to implanted component malfunction or external component failure. 36 Small studies of early experience with third generation LVADs report low rates of device malfunction Cost effectiveness * Two UK HTAs conducted economic evaluations of the cost effectiveness of VADs as BTT with an NHS perspective 17,23,34,43 after reviewing the literature and finding few published evaluations, typically of poor methodological quality and with limited applicability to the UK. 17,23,34,43,44

4 4 Clegg et al. constructed a 5-year decision analytic model for a first generation HeartMate LVAD compared with medical management. 17,34 The cost per quality adjusted life year (QALY) for LVAD support as BTT was 65,242 (95% CI 34,194 to 364,564). The total combined one-off cost associated with the LVAD (ie assessment, operation and device costs) was a key cost driver. The baseline total one-off LVAD cost in the model was 87,877 per patient (driven by the LVAD device cost ( 48,000) and operation cost ( 36,986)) and a threshold analysis indicated that this had to fall below 50,000 to achieve a cost per QALY below 40, ,34 Sharples et al. modelled the cost effectiveness of VADs as BTT using inputs from the EVAD UK study (first and second generation devices, LVAD and BiVAD support), other UK data and expert opinion. 23,43 The mean implantation cost, including the device and theatre costs, was estimated to be 63, ,43 The non-vad comparator groups were inotrope-dependent, non-inotrope-dependent, and a hypothetical worst case scenario that assumed all potential VAD patients would die in an intensive care unit (ICU) within 1 month if unable to access VAD technology. Across all time horizons, both non-vad groups dominated the VAD group as they cost less and survived longer. 23,43 At the 50-year lifetime horizon, the mean cost for VAD patients was 173,841 (95% CI 156,000 to 192,200) with mean survival 5.63 years (95% CI 4.35 to 7.05) and 3.27 QALYs (95% CI 2.56 to 4.01). 23,43 For inotropedependent non-vad patients the corresponding mean cost was 130,905 (95% CI 118,170 to 143,630) with mean survival 8.62 years (95% CI 7.49 to 10.29) and 4.99 QALYs (95% CI 4.41 to 5.58). For the non-inotrope-dependent group the mean cost was 114,400 (95% CI 104,000 to 125,000) with mean survival 8.96 years (95% CI 7.96 to 10.52) and 5.10 QALYs (95% CI 4.61 to 5.63). 23,43 The mean cost per QALY for VADs compared with the worst case scenario was 49,384 (95% CI 44,451 to 55,896). 23,43 The main cost drivers in the model were the VAD device, staff costs, ICU and hospital stay, and adverse events including bleeding, stroke and infection. 23,43 The key findings from the model were unchanged under a range of assumptions that included reducing the cost of the VAD device by half, and then to zero; reducing both hospital and ICU length of stay; reducing mortality with VADs to a best case scenario similar to other cardiothoracic procedures; and applying different utility scores in the model. 23,43 The existing economic models have several limitations. They are based largely on clinical effectiveness estimates from early experience with first generation devices, and the lack of adequate control group data to compare with VADs patients is problematic. Although more recent evidence, primarily from uncontrolled observational studies, suggests improved survival and a reduction in adverse event rates with second and third generation devices 30,33,35-39 the existing economic evaluations indicate that more substantial reductions in the costs associated with VADs and/or improvements in survival and QOL would be necessary to achieve costs per QALY within currently acceptable UK thresholds ( 20,000 to 30,000 per QALY). 17,23,34,43 * The findings in this section are based on the results of a literature search undertaken in November Equality and Diversity Healthcare Improvement Scotland is committed to equality and diversity in respect of the six equality groups defined by age, disability, gender, race, religion/belief and sexual orientation. The Evidence Note process has been assessed and no adverse impact across any of these groups is expected. The completed equality and diversity checklist is available on About Evidence Notes For further information about the Evidence Note process, see To propose a topic for an Evidence Note, Evidencenotes.HCIS@nhs.net References can be accessed via the internet (where addresses are provided), via the NHS Knowledge Network or by contacting your local library and information service.

5 5 Acknowledgements Healthcare Improvement Scotland would like to acknowledge the helpful contribution of the following, who gave advice on the content of this Evidence Note: Dr Mark Petrie, Consultant Cardiologist and Director of the Scottish National Advanced Heart Failure Service, Golden Jubilee National Hospital, NHS Greater Glasgow and Clyde Dr Guy MacGowan, Consultant Cardiologist with Major Interest in Heart Failure, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust Healthcare Improvement Scotland Development Team Heather McIntosh, Lead Author/Health Services Researcher Susan Myles, Author/ Lead Health Economist Jenny Harbour, Information Scientist Susan Downie, Medical Writer Doreen Pedlar, Project Co-ordinator Marina Logan, Team Support Administrator Healthcare Improvement Scotland 2011 ISBN References 1. Shams OF, Ventura HO. Device therapy for heart failure: when and for whom? Am J Cardiovasc Drugs. 2008;8(3): Baughman KL, Jarcho JA. Bridge to life - cardiac mechanical support. N Engl J Med. 2007;357(9): Jeevanandam V, Eisen HJ. Intermediate- and long-term mechanical cardiac support. [online] [cited 2010 Nov 23]; Available from: intermediate-and-long-term-mechanical-cardiac-support?source=search result&selectedtitle=2%7e9. 4. Alba AC, Delgado DH. The future is here: ventricular assist devices for the failing heart. Expert Rev Cardiovasc Ther. 2009;7(9): MacGowan GA, Parry G, Schueler S, Hasan A. The decline in heart transplantation in the UK (editorial). BMJ. 2011;342:d Gronda E, Bourge RC, Costanzo MD, Deng M, Mancini D, Martinelli L, et al. Heart rhythm considerations in heart transplant candidates and considerations for ventricular assist devices: International Society for Heart and Lung Transplantation Guidelines for the care of cardiac transplant candidates J Heart Lung Transplant. 2006;25(9): Stevenson LW, Rose EA. Left ventricular assist devices. Bridges to transplantation, recovery, and destination for whom? Circulation. 2003;108: NHS National Waiting Times centre. The Scottish National Advanced Heart Failure Service - the way forward. NHS National Waiting Times Centre; Krishnamani R, DeNofrio D, Konstam MA. Emerging ventricular assist devices for long-term cardiac support. Nat Rev Cardiol. 2010;7(2): Slaughter MS, Pagani FD, Rogers JG, Miller LW, Sun B, Russell SD, et al. Clinical management of continuous-flow left ventricular assist devices in advanced heart failure. J Heart Lung Transplant. 2010;29(4:Suppl):S1-S39.

6 6 References continued 11. British Heart Foundation. Incidence of Heart Failure [online] Oct 18 [cited 2011 Jun 15]; Available from: Scarborough P, Bhatnagar P, Wickramasinghe K, Smolina K, Mitchell C, Rayner M. Coronary heart disease statistics. British Heart Foundation; Hawkins NM, Jhund PS, Simpson CR, Petrie MC, MacDonald MR, Dunn FG, et al. Primary care burden and treatment of patients with heart failure and chronic obstructive pulmonary disease in Scotland. Eur J Heart Fail. 2010;12: British Heart Foundation. Scotland coronary heart disease statistics [online] [cited 2011 Jun 30]; Available from: idoc.ashx?docid=ea0d5fc4-745c-412e-8bfe-64e71f4d1d4c&version= The Scottish Government. Better heart disease and stroke care action plan. Edinburgh: The Scottish Government; Jhund PS, MacIntyre K, Simpson CR, Lewsey JD, Stewart S, Redpath A, et al. Long-term trends in first hospitalization for heart failure and subsequent survival between 1986 and Circulation. 2009;119: Clegg AJ, Scott DA, Loveman E, Colquitt J, Hutchinson J, Royle P, et al. The clinical and costeffectiveness of left ventricular assist devices for end-stage heart failure: a systematic review and economic evaluation. [online] [cited 2010 Nov 22]; Available from: National Clinical Guideline Centre. Chronic heart failure: the management of chronic heart failure in adults in primary and secondary care. National Clinical Guideline Centre; Available from: Hobbs F, Roalfe, AK., Davis RC, Davies MK, Hare R, et al. Prognosis of all-cause heart failure and borderline left ventricular systolic dysfunction: 5 year mortality follow-up of the Echocardiographic Heart of England Screening Study (ECHOES). Eur Heart J. 2007;28: Dickstein K, Cohen-Solal A, Filippatos G, McMurry JJ, Ponikowski P, Poole-Wilson P, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure Eur Heart J. 2008;29: Sharpe N, Doughty R. Epidemiology of heart failure and ventricular dysfunction. Lancet. 1998;352(Suppl 1):S13-S Port FK, Merion RM, Roys EC, Wolfe RA. Trends in organ donation and transplantation in the United States, Am J Transplant. 2008;8(2): Sharples LD, Buxton M, Caine N, Cafferty F, Demitis N, Dyer M, et al. Evaluation of the ventricular assist device programme in the UK [online] Nov [cited 2010 Nov 22]; Available from: Scottish Intercollegiate Guidelines Network. Management of chronic heart failure: a national clinical guideline. SIGN guideline no. 95 [online] Feb [cited 2010 Nov 22]; Available from: Rogers C, Emin A, Thomas H, van der Meulen J, Parameshwar J, Bonser RS, et al. UK cardiothoracic transplant audit. The Royal College of Surgeons of England Clinical Effectiveness Unit and NHS Blood and Transplant; NHS Blood and Transplant. Transplant activity in the UK. Activity report 2009/10. NHS Blood and Transplant; NHS Blood and Transplant. Waiting time to transplant [online] [cited 2011 Feb 24]; Available from: transplant/waiting_time_to_transplant.jsp. 28. Birks EJ. The comparative use of ventricular assist devices: differences between Europe and the United States. Tex Heart Inst J. 2010;37(5):565-7.

7 7 References continued 29. Rose EA, Gelijns A, Moskowitz AJ, Heitjan DF, Stevenson LW, Dembitsky W, et al. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med. 2001;345(20): 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(23): Sharples LD, Cafferty F, Demitis N, Freeman C, Dyer M, Banner N, et al. Evaluation of the clinical effectiveness of the ventricular assist device program in the United Kingdom (EVAD UK). J Heart Lung Transplant. 2007;26(1): Kirklin JK, Naftel DC. Mechanical circulatory support. Circ Heart fail. 2008;1: Kirklin JK, Naftel DC, Kormos RL, Stevenson LW, Pagani FD, Miller MA, et al. Second INTERMACS annual report: More than 1,000 primary left ventricular assist device implants. J Heart Lung Transplant. 2010;29(1): Clegg AJ, Scott DA, Loveman E, Colquitt JL, Royle P, Bryant J. Clinical and cost-effectiveness of left ventricular assist devices as a bridge to heart transplantation for people with end-stage heart failure: a systematic review and economic evaluation. Eur Heart J. 2005;27(24): Lahpor J, Khaghani A, Hetzer R, Pavie A, Friedrich I, Sander K, et al. European results with a continuous-flow ventricular assist device for advanced heart-failure patients. Eur J Cardiothorac Surg. 2010;37(2): Pagani FD, Miller LW, Russell SD, Aaronson KD, John R, Boyle AJ, et al. Extended mechanical circulatory support with a continuous-flow rotary left ventricular assist device. J Am Coll Cardiol. 2009;54(4): Morshuis M, El-Banayosy A, Arusoglu L, Koerfer R, Hetzer R, Wieselthaler G, et al. European experience of DuraHeart magnetically levitated centrifugal left ventricular assist system. Eur J Cardiothorac Surg. 2009;35(6): Wieselthaler GM, O'Driscoll G, Jansz P, Khaghani A, Strueber M. Initial clinical experience with a novel left ventricular assist device with a magnetically levitated rotor in a multi-institutional trial. J Heart Lung Transplant. 2010;29(11): Esmore D, Kaye D, Spratt P, Larbalestier R, Ruygrok P, Tsui S, et al. A prospective, multicenter trial of the VentrAssist left ventricular assist device for bridge to transplant: safety and efficacy. J Heart Lung Transplant. 2008;27(6): Rogers JG, Aaronson KD, Boyle AJ, Russell SD, Milano CA, Pagani FD, et al. Continuous flow left ventricular assist device improves functional capacity and quality of life of advanced heart failure patients. J Am Coll Cardiol. 2010;55(17): Shuhaiber JH, Hur K, Gibbons R. The influence of preoperative use of ventricular assist devices on survival after heart transplantation: propensity score matched analysis. BMJ. 2010;340:c Klotz S, Stypmann J, Welp H, Schmid C, Drees G, Rukosujew A, et al. Does continuous flow left ventricular assist device technology have a positive impact on outcome pretransplant and posttransplant? Ann Thorac Surg. 2006;82(5): Sharples LD, Dyer M, Cafferty F, Demiris N, Freeman C, Banner NR, et al. Cost-effectiveness of ventricular assist device use in the United Kingdom: results from the evaluation of ventricular assist device programme in the UK (EVAD-UK). J Heart Lung Transplant. 2006;25(11): Hutchinson J, Scott DA, Clegg AJ, Loveman E, Royle P, Bryant J, et al. Cost-effectiveness of left ventricular-assist devices in end-stage heart failure. Expert Rev Cardiovasc Ther. 2008;6: