Phosphodiesterase-5 Inhibitor Therapy and Post–Left Ventricular Assist Device Outcomes

HomeCirculation: Heart FailureVol. 12, No. 6Phosphodiesterase-5 Inhibitor Therapy and Post–Left Ventricular Assist Device Outcomes Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBPhosphodiesterase-5 Inhibitor Therapy and Post–Left Ventricular Assist Device OutcomesThe Significance of Uncertainty Brian A. Houston, MD Brian A. HoustonBrian A. Houston Brian Houston, MD, Assistant Professor of Medicine, Director of Mechanical Circulatory Support, 114 Doughty St, MSC 592, BM222, Charleston, SC 29425. Email E-mail Address: [email protected] Division of Cardiology, Medical University of South Carolina, Charleston. Originally published11 Jun 2019https://doi.org/10.1161/CIRCHEARTFAILURE.119.006162Circulation: Heart Failure. 2019;12:e006162This article is a commentary on the followingPreimplant Phosphodiesterase-5 Inhibitor Use Is Associated With Higher Rates of Severe Early Right Heart Failure After Left Ventricular Assist Device ImplantationSee Article by Gulati et alWe demand rigidly defined areas of doubt and uncertainty!—Douglas Adams, The Hitchhiker's Guide to the GalaxyIn Douglas Adams' The Hitchhiker's Guide to the Galaxy, a group of "hyperintelligent pan-dimensional beings" create an omniscient computer (dubbed Deep Thought) as the ultimate arbiter of truth.1 The creation of this computer greatly discomfits a pair of philosophers, Vroomfondel and Majikthise, who worry that it will put them "straight out of a job." As the pair's vexation grows, Vroomfondel makes his demand to Deep Thought for "rigidly defined areas of doubt and uncertainty" (with the obvious and ridiculous corollary demand for rigidly defined areas of certainty). As physicians, we often feel the same discomfiture—particularly when a study calls into question a concept we had previously assigned as certain or a clinical practice ingrained by biological plausibility. In their important study about the association of preimplant PDE5i (phosphodiesterase-5 inhibitor) use with post-left ventricular assist device (LVAD) outcomes, Gulati et al2 have further advanced the boundary of doubt and uncertainty surrounding the use of these medications in patients undergoing LVAD implantation and indeed in any patient with underlying left heart disease (LHD).2In this issue of Circulation: Heart Failure, Gulati et al retrospectively queried the Interagency Registry for Mechanically Assisted Circulatory Support registry to investigate the association of pre-LVAD PDE5i use and post-LVAD severe early right heart failure (RHF). The primary outcome was defined largely per the current Interagency Registry for Mechanically Assisted Circulatory Support definition: death from RHF or multiorgan system failure within 30 days, need for right ventricular assist device within 30 days, or use of inotropes beyond 14 days.3 The authors excluded patients who received durable right ventricular assist devices during the index procedure from the primary outcome, as it was thought this likely represented a preventive instead of reactive operative strategy. Given the retrospective and nonrandomized nature of the study, selection bias was addressed via a robust propensity matching system using 22 variables in the assigned propensity score to model the likelihood of receiving PDE5i therapy. Importantly, the authors also took pains to perform quality control on the registry-reported hemodynamic data by ensuring pulmonary arterial wedge pressure did not exceed pulmonary arterial diastolic pressure, carefully selecting between right atrial and central venous pressures based on plausibility, and not accepting pulmonary arterial wedge pressures <1 mm Hg.Ultimately, the study compared 1177 propensity-matched PDE5i and control patients. Even with the extensive propensity matching model, severe early RHF remained more common in the PDE5i group versus controls (odds ratio, 1.31; 95% CI, 1.09–1.57). Interestingly, this was driven solely by prolonged inotrope duration, with no significant difference in right ventricular assist device use or death from RHF. Furthermore, although total hospital length of stay was 3 days longer in the PDE5i group, at 6 months the groups had similar survival, quality of life scores, and 6-minute walk distance. The authors astutely investigated the association of PDE5i use and major bleeding events, finding a significantly higher incidence of major bleeding within the first 7 postoperative days in the PDE5i group (hazards ratio, 1.52; 95% CI, 1.15–2.0).The incautious interpretation of the study is that preoperative PDE5i use increases the risk for post-LVAD severe early RHF. However, several aspects of the study counsel caution in reaching this conclusion. First, despite extensive propensity matching endeavors, it is possible that residual selection bias exists in this retrospective study—it may still be that patients receiving preoperative PDE5i therapy were sicker in unknown unknown ways than the matched control cohort. Notably, of the 22 variables used in the propensity scoring system, pulmonary arterial wedge pressure was missing in 30% of cases. The authors report that pulmonary vascular resistance was higher in the PDE5i group (2.6 versus 2.3 WU, P<0.001), but the high proportion of missing pulmonary arterial wedge pressure values may lead us to underestimate the true difference in pulmonary vascular load between the groups. Second, it is noteworthy that though the authors report a higher incidence of severe early RHF in the PDE5i group, this was driven entirely by prolonged inotrope use. The PDE5i group did not suffer higher early mortality, need for early right ventricular assist device implantation, or even higher morbidity or mortality at 6 months. Many prior studies have found an association between severe early RHF and mortality,4–6 and so its absence here is conspicuous and leads us to question exactly what specific outcome we are capturing—true hemodynamic failure of the right heart system, covariation of preoperative PDE5i use and postoperative provider decision making regarding inotrope use, or association of PDE5i use with a postoperative event necessitating prolonged inotrope use but not representing causative hemodynamic failure of the right heart? The finding of a higher risk of early postoperative bleeding in the PDE5i group points a tentative finger at the latter explanation. However, we must note that the propensity scoring system did not account for important bleeding risk factors, such as platelet count and international normalized ratio. It is possible that the noted bleeding risk was itself confounded by unaccounted for selection bias.Despite these caveats, this study adds an important voice to others which together push the use of PDE5i therapy in patients with pulmonary hypertension due to LHD into an increasingly "rigidly defined area of doubt and uncertainty." It is notable that, of the patients meeting the inclusion criteria in this study, 10.4% were on preoperative PDE5i therapy—a striking proportion in a patient population selected for the most severe degree of LV failure and ostensibly in whom preoperative right ventricular embarrassment is selectively avoided. Prior studies have indicated that the majority of real-world PDE5i use is in patients without WHO Group 1 precapillary pulmonary arterial hypertension.7,8 In one study of veterans treated with PDE5i, over half did not even have a verifiable right heart catheterization.7 We might be forgiven to a degree for this prescribing pattern; we know that patients with pulmonary hypertension due to LHD do worse, and as clinicians we are desperate for helpful therapies in this scenario. The afterload sensitive nature of the right ventricle,9 the ability of PDE5i therapy to reduce pulmonary vascular load,10 and early small studies with promising surrogate end points11 all present an enticing, biologically plausible argument for their use in these patients. However, together with the recently published SIOVAC study (Sildenafil for Improving Outcomes After Valvular Correction) showing worse outcomes with PDE5i therapy in patients with persistent pulmonary hypertension after valvular intervention,12 the current study weakens the arguments of biological plausibility for the utility of these agents in patients with LHD.Importantly, this study begs the important next question of the role of PDE5i therapy initiated as a treatment for RHF after LVAD implantation. Other important areas of doubt and uncertainty urgently requiring answer include whether any patient phenotype with pulmonary hypertension due to LHD benefits from PDE5i therapy and whether other pulmonary arterial hypertension–specific therapy may be more effective for these patients. The currently enrolling SOPRANO study may shed light on the utility of endothelin receptor antagonist therapy post-LVAD,13 although doubtless questions will remain. In the current study, Gulati et al are to be congratulated not for providing an answer to these questions but for more rigidly defining the area of doubt and uncertainty. In doing so, they have provided what Lewandowsky et al14 describe as uncertainty as actionable knowledge. The call to action as presented by this study is increasingly pressing—if pulmonary arterial hypertension–specific therapy is indeed shown to increase the risk of harm to our patients with LVAD or LHD, guidelines and practice patterns should expeditiously abandon the arguments of biological plausibility and surrogate end points just as they did with antiarrhythmic agents for premature ventricular contractions and inotropic medications for LV failure.Ultimately, the philosophers in The Hitchhiker's Guide are placated when Deep Thought assures them that it will take 7.5 million years to reach "the answer to the Ultimate Question of Life, the Universe, and Everything," giving them plenty of time to ply their trade. Hopefully, we will not have to wait that long to answer these important questions regarding pulmonary arterial hypertension–specific therapy in patients with LVAD or LHD.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Guest Editor for this article was Kenneth B. Margulies, MD.Brian Houston, MD, Assistant Professor of Medicine, Director of Mechanical Circulatory Support, 114 Doughty St, MSC 592, BM222, Charleston, SC 29425. Email [email protected]eduReferences1. Adams, Douglas, 1952–2001. The Hitchhiker's Guide to the Galaxy. New York: Harmony Books; 1980.Google Scholar2. Gulati G, Grandin EW, Kennedy K, Cabezas F, DeNofrio D, Kociol R, Rame JE, Pagani F, Kirklin J, Kormos RL, Teuteberg J, Kiernan MS. Preimplant phosphodiesterase-5 inhibitor use is associated with higher rates of severe early right heart failure after left ventricular assist device implantation: an INTERMACS analysis.Circ Heart Fail. 2019; 12:e005537. doi: 10.1161/CIRCHEARTFAILURE.118.005537LinkGoogle Scholar3. Interagency Registry for Mechanically Assisted Circulatory Support. Appendix A - adverse event definitions. UAB School of Medicine. http://www.uab.edu/medicine/intermacs/Appendix_A_INTERMAC_AE_Definitions_05152013. Accessed April 25, 2019.Google Scholar4. Kormos RL, Teuteberg JJ, Pagani FD, Russell SD, John R, Miller LW, Massey T, Milano CA, Moazami N, Sundareswaran KS, Farrar DJ; HeartMate II Clinical Investigators. Right ventricular failure in patients with the HeartMate II continuous-flow left ventricular assist device: incidence, risk factors, and effect on outcomes.J Thorac Cardiovasc Surg. 2010; 139:1316–1324. doi: 10.1016/j.jtcvs.2009.11.020CrossrefMedlineGoogle Scholar5. Grandin EW, Zamani P, Mazurek JA, Troutman GS, Birati EY, Vorovich E, Chirinos JA, Tedford RJ, Margulies KB, Atluri P, Rame JE. Right ventricular response to pulsatile load is associated with early right heart failure and mortality after left ventricular assist device.J Heart Lung Transplant. 2017; 36:97–105. doi: 10.1016/j.healun.2016.06.015CrossrefMedlineGoogle Scholar6. Drakos SG, Janicki L, Horne BD, Kfoury AG, Reid BB, Clayson S, Horton K, Haddad F, Li DY, Renlund DG, Fisher PW. Risk factors predictive of right ventricular failure after left ventricular assist device implantation.Am J Cardiol. 2010; 105:1030–1035. doi: 10.1016/j.amjcard.2009.11.026CrossrefMedlineGoogle Scholar7. Kim D, Lee KM, Freiman MR, Powell WR, Klings ES, Rinne ST, Miller DR, Rose AJ, Wiener RS. Phosphodiesterase-5 inhibitor therapy for pulmonary hypertension in the United States. Actual versus recommended use.Ann Am Thorac Soc. 2018; 15:693–701. doi: 10.1513/AnnalsATS.201710-762OCCrossrefMedlineGoogle Scholar8. Wijeratne DT, Lajkosz K, Brogly SB, Lougheed MD, Jiang L, Housin A, Barber D, Johnson A, Doliszny KM, Archer SL. Increasing incidence and prevalence of world health organization groups 1 to 4 pulmonary hypertension: a population-based cohort study in Ontario, Canada.Circ Cardiovasc Qual Outcomes. 2018; 11:e003973. doi: 10.1161/CIRCOUTCOMES.117.003973LinkGoogle Scholar9. Abel FL, Waldhausen JA. Effects of alterations in pulmonary vascular resistance on right ventricular function.J Thorac Cardiovasc Surg. 1967; 54:886–894.CrossrefMedlineGoogle Scholar10. Tedford RJ, Hemnes AR, Russell SD, Wittstein IS, Mahmud M, Zaiman AL, Mathai SC, Thiemann DR, Hassoun PM, Girgis RE, Orens JB, Shah AS, Yuh D, Conte JV, Champion HC. PDE5A inhibitor treatment of persistent pulmonary hypertension after mechanical circulatory support.Circ Heart Fail. 2008; 1:213–219. doi: 10.1161/CIRCHEARTFAILURE.108.796789LinkGoogle Scholar11. Guazzi M, Vicenzi M, Arena R, Guazzi MD. PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebo-controlled study.Circ Heart Fail. 2011; 4:8–17. doi: 10.1161/CIRCHEARTFAILURE.110.944694LinkGoogle Scholar12. Bermejo J, Yotti R, García-Orta R, Sánchez-Fernández PL, Castaño M, Segovia-Cubero J, Escribano-Subías P, San Román JA, Borrás X, Alonso-Gómez A, Botas J, Crespo-Leiro MG, Velasco S, Bayés-Genís A, López A, Muñoz-Aguilera R, de Teresa E, González-Juanatey JR, Evangelista A, Mombiela T, González-Mansilla A, Elízaga J, Martín-Moreiras J, González-Santos JM, Moreno-Escobar E, Fernández-Avilés F; Sildenafil for Improving Outcomes after VAlvular Correction (SIOVAC) investigators. Sildenafil for improving outcomes in patients with corrected valvular heart disease and persistent pulmonary hypertension: a multicenter, double-blind, randomized clinical trial.Eur Heart J. 2018; 39:1255–1264. doi: 10.1093/eurheartj/ehx700CrossrefMedlineGoogle Scholar13. Clinical Study to Assess the Efficacy and Safety of Macitentan in Patients With Pulmonary Hypertension After Left Ventricular Assist Device Implantation (SOPRANO). ClinicalTrials.gov Identifier: NCT02554903. https://clinicaltrials.gov/ct2/show/NCT02554903. Accessed April 25, 2019.Google Scholar14. Lewandowsky S, Ballard T, Pancost RD. Uncertainty as knowledge.Philos Trans A Math Phys Eng Sci. 2015; 373: pii: 20140462. doi: 10.1098/rsta.2014.0462.CrossrefGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Jakstaite A, Luedike P, Schmack B, Pizanis N, Riebisch M, Weymann A, Kamler M, Ruhparwar A, Rassaf T and Papathanasiou M (2021) Increased bleeding risk with phosphodiesterase‐5 inhibitors after left ventricular assist device implantation, ESC Heart Failure, 10.1002/ehf2.13322, 8:4, (2419-2427), Online publication date: 1-Aug-2021. Related articlesPreimplant Phosphodiesterase-5 Inhibitor Use Is Associated With Higher Rates of Severe Early Right Heart Failure After Left Ventricular Assist Device ImplantationGaurav Gulati, et al. Circulation: Heart Failure. 2019;12 June 2019Vol 12, Issue 6 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.119.006162PMID: 31181954 Originally publishedJune 11, 2019 Keywordsmortalitysurvivalheart diseasesquality of lifeEditorialsvascular resistancePDF download Advertisement SubjectsCardiomyopathyHeart Failure

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