KeywordsTwo decades ago, the nascent field of left ventricular assist devices (LVADs) encountered a paradigm shift. The older, bulkier devices which provided suitable circulatory support for short-term life prolongation in severe heart failure were plagued by poor device durability and a high burden of morbidity. Bioengineers developed continuous flow devices which were small in profile, had few moving parts and, as a consequence, exhibited greater durability. Clinical trials demonstrated a marked improvement in survival compared with older generation pumps, and patients approaching refractoriness to neurohormonal therapy with advanced heart failure now had an off the shelf option in contradistinction to the limited availability of heart transplantation, the only two treatments demonstrated to offer a gain in quality adjusted life years (1A history of devices as an alternative to heart transplantation.,2Evolving trends in mechanical circulatory support: Clinical development of a fully magnetically levitated durable ventricular assist device.). As adoption advanced steadily and experience with bridge to transplantation matured, the notion of lifelong therapy in those individuals who were ineligible for transplantation was established, particularly within the United States (3Pinney SP Anyanwu AC Lala A Teuteberg JJ Uriel N Mehra MR. Left Ventricular Assist Devices for Lifelong Support.). Across the world, use of LVADs grew but some countries were slower to embrace this technology and restricted its use to bridge to transplantation due to reasons of cost-effectiveness (4Clegg AJ Scott DA Loveman E Colquitt J Hutchinson J Royle P Bryant J. The clinical and cost-effectiveness of left ventricular assist devices for end-stage heart failure: a systematic review and economic evaluation.).A constellation of adverse events, reflecting an imbalance in hemocompatibility, began to be noted during the patient journey on a continuous flow LVAD (5The burden of haemocompatibility with left ventricular assist systems: a complex weave.). Of the two principal pumps, the HeartMate II LVAD (Abbott Labs, US) suffered from a high incidence of pump thrombosis leading to pump malfunction and need for replacement (6Mehra MR Stewart GC Uber PA. The vexing problem of thrombosis in long-term mechanical circulatory support.). This axial flow device was built with a mechanical bearing which often facilitated development of thrombus upon the rotor. The second device was the HeartWare HVAD (Medtronic, US) which was centrifugal in design, implanted intrapericardially and suitable for those with smaller body surface area including children or smaller women, or when a device was required in a biventricular support configuration. However, this pump was beset by a higher than usual rate of neurological adverse events and required very close attention to precise blood pressure control and use of optimal antiplatelet and anticoagulant regimens (7Teuteberg JJ Slaughter MS Rogers JG McGee EC Pagani FD Gordon R Rame E Acker M Kormos RL Salerno C Schleeter TP Goldstein DJ Shin J Starling RC Wozniak T Malik AS Silvestry S Ewald GA Jorde UP Naka Y Birks E Najarian KB Hathaway DR Aaronson KD; ADVANCE Trial Investigators. The HVAD Left Ventricular Assist Device: Risk Factors for Neurological Events and Risk Mitigation Strategies.,8Milano CA Rogers JG Tatooles AJ Bhat G Slaughter MS Birks EJ Mokadam NA Mahr C Miller JS Markham DW Jeevanandam V Uriel N Aaronson KD Vassiliades TA Pagani FD ENDURANCE Investigators. HVAD: The ENDURANCE Supplemental Trial.). Both pumps suffered from non-surgical bleeding, especially in the gastrointestinal tract, a peculiar adverse event related to the unnatural low pulsatile flow imposed due to continuous flow characteristics. A novel device, the HeartMate 3 LVAD (Abbott labs, US) was introduced which was centrifugal in configuration, intrapericardial in position, and engineered with wide flow pathways to avoid excess red blood cell destruction. Importantly, this LVAD was engineered using a frictionless fully magnetically levitated rotor with an asynchronous pulsatility algorithm (by fixed rotor speed changes) to prevent blood stasis (9Mehra MR Naka Y Uriel N Goldstein DJ Cleveland Jr, JC Colombo PC Walsh MN Milano CA Patel CB Jorde UP Pagani FD Aaronson KD Dean DA McCants K Itoh A Ewald GA Horstmanshof D Long JW Salerno C MOMENTUM 3 Investigators. A Fully Magnetically Levitated Circulatory Pump for Advanced Heart Failure.). These attributes were tested in clinical trials and shown to be associated with a marked reduction in hemocompatibility related adverse events including near elimination of pump thrombosis, a marked decrease in stroke rates and a reduction in bleeding events and associated with a 80% 2 year survival (in a group of patients with a dismal survival without such therapy) (10Mehra MR Uriel N Naka Y Cleveland Jr, JC Yuzefpolskaya M Salerno CT Walsh MN Milano CA Patel CB Hutchins SW Ransom J Ewald GA Itoh A Raval NY Silvestry SC Cogswell R John R Bhimaraj A Bruckner BA Lowes BD Um JY Jeevanandam V Sayer G Mangi AA Molina EJ Sheikh F Aaronson K Pagani FD Cotts WG Tatooles AJ Babu A Chomsky D Katz JN Tessmann PB Dean D Krishnamoorthy A Chuang J Topuria I Sood P Goldstein DJ MOMENTUM 3 Investigators. A Fully Magnetically Levitated Left Ventricular Assist Device - Final Report.). Quickly, this LVAD was embraced as the most commonly implanted LVAD world-wide.On June 3rd, 2021, the manufacturer of the Heartware HVAD announced that it had decided to stop sales and distribution of its device due to concerns with the fidelity of the device stop and start mechanisms which were associated with fatalities, as well as in light of the data with the rival device, the HeartMate 3 LVAD, demonstrating a better overall survival and reduced incidence of neurological events (). This action has now left a single commercial LVAD in the market, an event which raises unique challenges, concerns and considerations for the field of advanced heart failure, which we now discuss (figure 1).

Figure 1Challenges, Concerns and Considerations with LVAD Therapy: Outcomes, Innovation and Need for Timely Referral

An accidental MonopolyIn the case of LVADs, lack of a competitive market creates concern for complacency in continued research and development, the potential for dictating pricing without attention to demand, and inefficiencies in support. This is of particular concern for a technology that is still awaiting demonstration of cost effectiveness for lifelong therapy. It is incumbent upon the manufacturer to vividly reassure clinicians that they will maintain relentless attention on engineering innovation while ensuring adequate supply and infrastructural support for centers to remain proficient in the optimal use of the remaining device, the HeartMate 3 LVAD. A key innovation that is awaited includes freedom from an externally exiting driveline that powers the pump through external sources (12Evolving disruption in left ventricular assist systems: forgiving but not yet forgettable.).Clinical confidence in the therapyLVAD therapy remains enigmatic to many practitioners not engaged in day-to-day management of such patients and they are often uncertain about the risk-benefit ratio and clinical outcomes. Withdrawal of a widely used device in part as a consequence of technical challenges may lead to skepticism in physicians less familiar with mechanical circulatory support. In the largest experience of 2200 HeartMate 3 LVADs implanted, the 2-year survival reached or exceed 80%, even in those designated as transplant ineligible (13Mehra MR Cleveland Jr, JC Primary results of long-term outcomes in the MOMENTUM 3 pivotal trial and continued access protocol study phase: a study of 2200 HeartMate 3 left ventricular assist device implants.). This experience also demonstrated that the net burden of hemocompatibility related adverse events was lower with a consequent decrease in hospitalization as proficiency has grown compared to the early outcomes in the pivotal trial that confirmed the superior efficacy of the HeartMate 3 LVAD. These clinical outcomes have been mirrored in real world by evaluations performed in a United States public payer environment (Medicare or Medicaid) as well as in registry series, which also point to a decrease in cost of care compared with the other devices (14Pagani FD Mehra MR Cowger JA Horstmanshof DA Silvestry SC Atluri P Cleveland Jr, JC Lindenfeld J Roberts GJ Bharmi R Dalal N Kormos RL Rogers JG. Clinical outcomes and healthcare expenditures in the real world with left ventricular assist devices - The CLEAR-LVAD study., 15Pagani FD Cantor R Cowger J Goldstein D Teuteberg J Mahr C Atluri P Kilic A Maozami N Habib R Naftel D Kirklin JK. Concordance of Treatment Effect: An Analysis of The Society of Thoracic Surgeons Intermacs Database.). Thus, it is incumbent upon us to instill confidence in the use of LVAD therapy in appropriately selected patients with advanced heart failure by targeted educational efforts to frontline clinicians who are engaged in diagnosing and caring for heart failure patients.Timely referral for advanced therapies in heart failureLate referral of patients with symptoms of advanced heart failure remains a critical challenge. When patients are received in an unstable condition, LVAD therapy is life-saving but at a price of an increase in morbidity, prolonged hospitalization, consequent higher cost of care and a modest decrease in survival when compared to patients implanted in more stable conditions (13Mehra MR Cleveland Jr, JC Primary results of long-term outcomes in the MOMENTUM 3 pivotal trial and continued access protocol study phase: a study of 2200 HeartMate 3 left ventricular assist device implants.). Thus, not only is it important to instill confidence in the life-saving benefits of this technology but to ensure that front-line heart failure clinicians identify the optimal timing for referral. While several algorithms have been proposed, such as “I NEED HELP”, we believe that these too may identify patients a bit late in the clinical course of their illness (16I Need Help"-A mnemonic to aid timely referral in advanced heart failure., 17Left ventricular assist device therapy in advanced heart failure: patient selection and outcomes.). We propose a simple rule of 3 which includes a) repetitive hospitalizations for heart failure (e.g. 2 or more events in a year), b) staircase diuretic requirements over time (e.g., an increase of oral loop diuretics therapy by 50% in the preceding 6 months) to maintain clinical stability, and c) intolerance to neurohormonal therapy with onset of cardio-renal perturbation (17Left ventricular assist device therapy in advanced heart failure: patient selection and outcomes.). Clinicians must also recognize the particularly poor prognosis in two specific patient groups which include those with moderate-severe secondary mitral regurgitation ineligible for a percutaneous mitral valve transcatheter edge to edge repair (or those implanted with a MitraClip who remain ill without improvement in heart failure) and non-responders to cardiac resynchronization therapy (17Left ventricular assist device therapy in advanced heart failure: patient selection and outcomes.,18Transcatheter mitral valve intervention in advanced heart failure.). All such patients should ideally be referred for management at centers specializing in advanced heart failure therapeutics.Vulnerable patients implanted with a phased-out LVADPatients implanted with the HeartWare HVAD pump must be managed in collaboration with expertise and experience in implantation of the HeartMate 3 LVAD. Although the manufacturer of the HeartMate 3 pump has assured clinicians that there will be sufficient supply of the device to fulfil the needs of de-novo patients, it is important to not ignore the needs of those implanted with ongoing device support, since it is likely some will need repair or replacement for complications. We suggest that special consideration be given for transplant eligible patients with a HVAD pump to prioritize organ offers (which will require regulatory dialogue) since a device exchange to a HeartMate 3 is not simple and systematic surgical procedures have not been adequately outlined except in anecdotal cases (19Hanke JS Rojas SV Dogan G Feldmann C Beckmann E Deniz E Wiegmann B Michaelis JE Napp LC Berliner D Shrestha M Bauersachs J Haverich A Schmitto JD. First series of left ventricular assist device exchanges to HeartMate 3.). In those unable to be bridged to transplantation, it is important to develop strategies to ensure timely referral to surgical centers experienced and able to exchange malfunctioning pumps with a HM 3 LVAD.Need for continued innovation in LVAD therapyThe academic community must demand and support innovation in the field. We need to facilitate the development of newer technology that can be used as an early phase pump to promote recovery, provide freedom from external cables, use biocompatible surfaces to reduce need for anticoagulation, and develop smart-pump capability to meet the physiological demands of an active lifestyle (20Schmid Daners M Kaufmann F Amacher R Ochsner G Wilhelm MJ Ferrari A Mazza E Poulikakos D Meboldt M Falk V. Left Ventricular Assist Devices: Challenges Toward Sustaining Long-Term Patient Care.). While a David and Goliath situation may confront the field, academic leaders must search for ways to partner with early phase technology to ensure its viability and eventual sustainability.

In summary, we believe that just as heart transplantation represents an important single option for well selected patients, those with advanced heart failure who fail appropriate medical therapy should be considered for timely referral to an advanced heart failure center as a life-saving therapy, even as efforts to continuously support and enhance innovation in LVAD therapy are facilitated in earnest pursuit.

Disclosures

Mandeep R. Mehra reports payments made to my institution from Abbott for consulting; Consultant fees from Medtronic, Janssen, Mesoblast, Portola, Bayer, Triple Gene, and Baim Institute for Clinical Research. Scientific Advisory Board Member for NuPulseCV, Leviticus and FineHeart; Finn Gustafsson reports consulting honoraria from Abbott, Bayer, Pfizer, Alnylam, Boehringer-Ingelheim Amgen, Pharmacosmos and Idorisa for consulting and speaker fees from Novartis, Astra-Zeneca, Orion Pharma, Vifor

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Ann Biomed Eng. 45: 1836-1851https://doi.org/10.1007/s10439-017-1858-9Article InfoPublication History

Accepted: June 9, 2021

Received: June 9, 2021

Publication stageIn Press Journal Pre-ProofIdentification

DOI: https://doi.org/10.1016/j.cardfail.2021.06.003

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