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The Enabling Potential of Device Therapy for Heart Failure

Published:February 13, 2022DOI:https://doi.org/10.1016/j.cardfail.2022.02.005
      Patients with heart failure (HF) have poor prognoses despite substantial advances in therapeutic development. Comprehensive guideline-directed medical therapy (GDMT) is infrequently achieved in practice, especially at target doses.
      • Greene SJ
      • Fonarow GC
      • DeVore AD
      • Sharma PP
      • Vaduganathan M
      • Albert NM
      • et al.
      Titration of medical therapy for heart failure with reduced ejection fraction.
      The effects of GDMT on hemodynamic, electrolyte and renal parameters limit clinicians’ eagerness to initiate and titrate these drugs. Indeed, the most common reason for the inability to achieve target GDMT is that a patient is on “maximally tolerated” therapy.
      • Fiuzat M
      • Ezekowitz J
      • Alemayehu W
      • Westerhout CM
      • Sbolli M
      • Cani D
      • et al.
      Assessment of limitations to optimization of guideline-directed medical therapy in heart failure from the GUIDE-IT Trial: a secondary analysis of a randomized clinical trial.
      GDMT intolerance is associated with particularly unfavorable outcomes.
      • Morris AA
      • Khazanie P
      • Drazner MH
      • Albert NM
      • Breathett K
      • Cooper LB
      • et al.
      Guidance for timely and appropriate referral of patients with advanced heart failure: a scientific statement from the American Heart Association.
      Whether this is related to fragile hemodynamic status, lack of exposure to beneficial therapies, or some combination of the 2 has not been fully elucidated. Some patients who have this clinical profile are eligible for advanced therapies, but the vast majority will not undergo cardiac replacement.
      • Truby LK
      • Rogers JG.
      Advanced heart failure: epidemiology, diagnosis, and therapeutic approaches.
      ,
      • Birks EJ
      • Drakos SG
      • Patel SR
      • Lowes BD
      • Selzman CH
      • Starling RC
      • et al.
      Prospective multicenter study of myocardial recovery using left ventricular assist devices (RESTAGE-HF [Remission from Stage D Heart Failure]): medium-term and primary end point results.
      Thus, there is an ongoing need for strategies that can facilitate GDMT tolerance. Drug therapies have long been used to facilitate tolerance of beneficial devices (eg, dual antiplatelet therapy after percutaneous coronary intervention) and other drugs (eg, potassium binders to facilitate renin-angiotensin-aldosterone system inhibitor use), but most cardiac devices have not been intentionally applied to facilitate tolerance of beneficial drugs (Fig. 1), some notable exceptions being myocardial recovery in patients with durable mechanical circulatory support (MCS)5 and pacemaker implantation to facilitate beta-blocker tolerance for arrhythmia management.
      Fig 1
      Fig. 1Status of enabling strategies for patients with heart failure with reduced ejection fraction. BAT, baroreflex activation therapy; CCM, cardiac contractility modulation; CRT, cardiac resynchronization therapy; GDMT, guideline-directed medical therapy; HFrEF, heart failure with reduced ejection fraction; MCS, mechanical circulatory support; OAC, oral anticoagulation; RAASi, renin-angiotensin-aldosterone system inhibitors; TEER, transcatheter edge-to-edge repair. Created with BioRender.com.
      Several device therapies have recently been shown to improve hemodynamics and outcomes in HF. Currently approved options include transcatheter edge-to-edge repair of the mitral valve, cardiac resynchronization therapy, cardiac contractility modulation, and baroreflex activation therapy. Moreover, multiple devices including percutaneous endo-aortic MCS, venous MCS, interatrial shunts, and ventricular reshaping technologies are in clinical development. However, the development paths of HF drugs and devices have not intersected in a meaningful way. Therefore, there has been limited understanding of the interactions between, and optimal sequencing of, drug and device therapies in HF. Given the invasive and costly nature of device therapies, their use has generally been relegated to patients who are on maximally tolerated GDMT.
      Patients who exhibit intolerance of pharmacotherapy are an exceptionally high-risk cohort, so early use of devices that improve hemodynamic status may enable GDMT tolerance, improve clinical outcomes, and potentially obviate the need for more costly therapies (ie, heart transplantation or durable MCS). From a systems perspective, early use of a potentially expensive device to facilitate downstream medical therapy will have to be carefully studied for cost-effectiveness. From a patient perspective, using devices as a “bridge” to comprehensive GDMT is realistic only if the index device and subsequent drug therapies are accessible and affordable; thus, this comprehensive strategy may not be within reach of all patients. Value-based constructs may incentivize this approach if reductions in hospitalization rates offset the incremental costs of early device therapy. Furthermore, whether patients with HF prefer upfront device therapy or an extended trial of GDMT titration will also have to be evaluated on a case-by-case basis and with structured, population-level preference studies.
      The HF community should advance strategic priorities to define ideal comprehensive care strategies for patients with HF. These include an understanding of which devices facilitate tolerance of GDMT from both retrospective analyses and by including postintervention GDMT use as an endpoint in device trials. Additionally, although current HF device trials often include GDMT optimization committees that oversee pharmacotherapy prior to device intervention, little GDMT optimization is stipulated if hemodynamics improve after device intervention. This is, in part, related to concerns about unequal “drop-in” of medical therapies selectively in the control arm (as drugs are preferentially optimized in patients with progressive symptoms). Incorporating GDMT titration protocols that specify drug titrations to be made after device interventions could identify which devices are more likely to facilitate drug tolerance. Until such strategies are implemented, a multidisciplinary Heart Team approach should be extended to the period after device implantation, with the twin goals of optimization of device parameters and pharmacotherapy. Prospective, randomized evaluations of the effect of devices on GDMT tolerance are needed and may support the overall value of a device.
      Remarkable advancements in drug and device therapies for patients with HF have occurred largely in parallel. Lack of GDMT optimization is frequently attributed to GDMT intolerance, and in practice little GDMT titration is attempted after intolerance manifests. Even though we routinely use drugs to facilitate tolerance of devices, the converse approach—using devices to enable tolerance of drugs—has generally not been pursued. With the advent of less invasive, safer device therapies, it is now time to prioritize the development of comprehensive care strategies that employ drug and device therapies in a synergistic, rather than incremental, manner.

      Disclosures

      Dr. Varshney serves on an advisory board for Broadview Ventures, has received consulting fees from Buoy Health and has received support from the National Heart, Lung, and Blood Institute T32 postdoctoral training grant T32HL007604 and the Daniel Pierce Family Fellowship in Advanced Heart Disease. Dr. Butler has received personal fees as a consultant from Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Berlin Cures, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceuticals, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, SC Pharma, V-Wave Limited, and Vifor outside the submitted work. Dr. Vaduganathan has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Pharmacosmos, Relypsa, Roche Diagnostics, and Sanofi, speaker engagements with Novartis and Roche Diagnostics, and participates on clinical trial committees for studies sponsored by Galmed, Impulse Dynamics, Novartis, and Occlutech.

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