Barry A Borlaug1, John Blair2, Martin W Bergmann3, Heiko Bugger4, Dan Burkhoff5, Leonhard Bruch6, David S Celermajer7, Brian Claggett8, John G F Cleland9,10, Donald E Cutlip11, Ira Dauber12, Jean-Christophe Eicher13, Qi Gao11, Thomas M Gorter14, Finn Gustafsson15, Chris Hayward16, Jan van der Heyden17, Gerd Hasenfuß18, Scott L Hummel19,20, David M Kaye21, Jan Komtebedde22, Joseph M Massaro23, Jeremy A Mazurek24, Scott McKenzie25, Shamir R Mehta26, Mark C Petrie27, Marco C Post28, Ajith Nair29, Andreas Rieth30, Frank E Silvestry24, Scott D Solomon8, Jean-Noël Trochu31, Dirk J Van Veldhuisen14, Ralf Westenfeld32, Martin B Leon5, Sanjiv J Shah33. 1. Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN (B.A.B.). 2. University of Chicago (J.B.). 3. Cardiologicum Hamburg, Germany (M.W.B.). 4. Medical University of Graz, Austria (H.B.). 5. Cardiovascular Research Foundation, New York, NY (D.B., M.B.L.). 6. BG Klinikum Unfallkrankenhaus, Berlin, Germany (L.B.). 7. Royal Prince Alfred Hospital, The University of Sydney, Australia (D.S.C.). 8. Brigham and Women's Hospital, Boston, MA (B.C., S.D.S.). 9. Robertson Centre for Biostatistics and Glasgow Clinical Trials Unit, Institute of Health and Wellbeing, United Kingdom (J.G.F.C.). 10. National Heart & Lung Institute, Imperial College London, United Kingdom (J.G.F.C.). 11. Baim Clinical Research Institute, Boston, MA (D.E.C., Q.G.). 12. South Denver Cardiology Associates/Centura Health, CO (I.D.). 13. CHU de Dijon-Hôpital Bocage Central, Dijon, France (J.-C.E.). 14. University of Groningen, University Medical Center Groningen, The Netherlands (T.M.G., D.J.V.V.). 15. Rigshospitalet, University of Copenhagen, Denmark (F.G.). 16. St Vincents Hospital Sydney, Australia (C.H.). 17. AZ Sint-Jan Brugge-Oostende, Bruges, Belgium (J.v.d.H.). 18. Heart Center, University Medical Center, Göttingen, Germany (G.H.). 19. University of Michigan, Ann Harbor (S.L.H.). 20. VA Ann Arbor Health System, MI (S.L.H.). 21. Alfred Hospital, Melbourne, Australia (D.M.K.). 22. Corvia Medical Inc, Tewksbury, MA (J.K.). 23. Boston University School of Public Health, MA (J.M.M.). 24. Hospital of the University of Pennsylvania, Philadelphia (J.A.M., F.E.S.). 25. Prince Charles Hospital, Brisbane, Australia (S.M.). 26. McMaster University and Hamilton Health Sciences, Hamilton, Canada (S.R.M.). 27. University of Glasgow, Scotland (M.C. Petrie). 28. Departments of Cardiology, St Antonius Hospital Nieuwegein and University Medical Center Utrecht, the Netherlands (M.C. Post). 29. Baylor College of Medicine, Houston, TX (A.N.). 30. Kerckhoff Heart and Thoraxcenter, Bad Nauheim, Germany (A.R.). 31. l'Institut du Thorax, CHU Nantes, Nantes Université, CNRS, INSERM, Nantes, France (J.-N.T.). 32. Division of Cardiology, Pulmonology, and Vascular Medicine Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany (R.W.). 33. Northwestern University Feinberg School of Medicine, Chicago, IL (S.J.S.).
Abstract
BACKGROUND: In REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure), implantation of an atrial shunt device did not provide overall clinical benefit for patients with heart failure with preserved or mildly reduced ejection fraction. However, prespecified analyses identified differences in response in subgroups defined by pulmonary artery systolic pressure during submaximal exercise, right atrial volume, and sex. Shunt implantation reduces left atrial pressures but increases pulmonary blood flow, which may be poorly tolerated in patients with pulmonary vascular disease (PVD). On the basis of these results, we hypothesized that patients with latent PVD, defined as elevated pulmonary vascular resistance during exercise, might be harmed by shunt implantation, and conversely that patients without PVD might benefit. METHODS: REDUCE LAP-HF II enrolled 626 patients with heart failure, ejection fraction ≥40%, exercise pulmonary capillary wedge pressure ≥25 mm Hg, and resting pulmonary vascular resistance <3.5 Wood units who were randomized 1:1 to atrial shunt device or sham control. The primary outcome-a hierarchical composite of cardiovascular death, nonfatal ischemic stroke, recurrent HF events, and change in health status-was analyzed using the win ratio. Latent PVD was defined as pulmonary vascular resistance ≥1.74 Wood units (highest tertile) at peak exercise, measured before randomization. RESULTS: Compared with patients without PVD (n=382), those with latent PVD (n=188) were older, had more atrial fibrillation and right heart dysfunction, and were more likely to have elevated left atrial pressure at rest. Shunt treatment was associated with worse outcomes in patients with PVD (win ratio, 0.60 [95% CI, 0.42, 0.86]; P=0.005) and signal of clinical benefit in patients without PVD (win ratio, 1.31 [95% CI, 1.02, 1.68]; P=0.038). Patients with larger right atrial volumes and men had worse outcomes with the device and both groups were more likely to have pacemakers, heart failure with mildly reduced ejection fraction, and increased left atrial volume. For patients without latent PVD or pacemaker (n=313; 50% of randomized patients), shunt treatment resulted in more robust signal of clinical benefit (win ratio, 1.51 [95% CI, 1.14, 2.00]; P=0.004). CONCLUSIONS: In patients with heart failure with preserved or mildly reduced ejection fraction, the presence of latent PVD uncovered by invasive hemodynamic exercise testing identifies patients who may worsen with atrial shunt therapy, whereas those without latent PVD may benefit.
BACKGROUND: In REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure), implantation of an atrial shunt device did not provide overall clinical benefit for patients with heart failure with preserved or mildly reduced ejection fraction. However, prespecified analyses identified differences in response in subgroups defined by pulmonary artery systolic pressure during submaximal exercise, right atrial volume, and sex. Shunt implantation reduces left atrial pressures but increases pulmonary blood flow, which may be poorly tolerated in patients with pulmonary vascular disease (PVD). On the basis of these results, we hypothesized that patients with latent PVD, defined as elevated pulmonary vascular resistance during exercise, might be harmed by shunt implantation, and conversely that patients without PVD might benefit. METHODS: REDUCE LAP-HF II enrolled 626 patients with heart failure, ejection fraction ≥40%, exercise pulmonary capillary wedge pressure ≥25 mm Hg, and resting pulmonary vascular resistance <3.5 Wood units who were randomized 1:1 to atrial shunt device or sham control. The primary outcome-a hierarchical composite of cardiovascular death, nonfatal ischemic stroke, recurrent HF events, and change in health status-was analyzed using the win ratio. Latent PVD was defined as pulmonary vascular resistance ≥1.74 Wood units (highest tertile) at peak exercise, measured before randomization. RESULTS: Compared with patients without PVD (n=382), those with latent PVD (n=188) were older, had more atrial fibrillation and right heart dysfunction, and were more likely to have elevated left atrial pressure at rest. Shunt treatment was associated with worse outcomes in patients with PVD (win ratio, 0.60 [95% CI, 0.42, 0.86]; P=0.005) and signal of clinical benefit in patients without PVD (win ratio, 1.31 [95% CI, 1.02, 1.68]; P=0.038). Patients with larger right atrial volumes and men had worse outcomes with the device and both groups were more likely to have pacemakers, heart failure with mildly reduced ejection fraction, and increased left atrial volume. For patients without latent PVD or pacemaker (n=313; 50% of randomized patients), shunt treatment resulted in more robust signal of clinical benefit (win ratio, 1.51 [95% CI, 1.14, 2.00]; P=0.004). CONCLUSIONS: In patients with heart failure with preserved or mildly reduced ejection fraction, the presence of latent PVD uncovered by invasive hemodynamic exercise testing identifies patients who may worsen with atrial shunt therapy, whereas those without latent PVD may benefit.
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