Correspondence Article Type Response to Letters Regarding Article, “Anticoagulation and Survival in Pulmonary Arterial Hypertension: Results From the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA)” Drs Suissa and Galié postulate that the 21% reduction in mortality observed in patients with idiopathic (IPAH) pulmonary arterial hypertension (PAH) who received anticoagulants was mainly the result of immortal time bias rather than a true drug effect. We can assure them that this was not the case. Anticoagulation was started within 3 months after diagnosis in 92.4% of all patients (94.8% after 6 months and 97.4% after 12 months).1 In addition, we included only incident cases. Hence, it is highly unlikely that immortal time bias had a major impact on our findings. In fact, it is possible that the lack of sustained exposure to anticoagulants in the group of everusers resulted in an underestimation of the therapeutic potential of anticoagulants. Finally, if immortal time bias were truly a driver of our results, it would have shifted the survival of patients with other forms of PAH in the same direction as in patients with IPAH. The opposite was the case, which leaves us confident that our results and their interpretation are robust. Dr Bertoletti and colleagues raise the issue that comorbidities may have affected our results. This point has been addressed already in our Discussion, where we stated as 1 of the limitations of our study that comorbidities were not systematically assessed in the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) and that the presence of comorbidities might have affected the decision to use or not to use anticoagulants, as well as survival. The COMPERA population with its relatively advanced average age reflects the changing PAH phenotype in the Western world. Our findings suggest that anticoagulation may be useful in patients with a contemporary phenotype of IPAH but probably not in patients with other forms of PAH. The decision to start or to withhold anticoagulants in an individual patient is always based on an individual risk–benefit assessment, for which our data add relevant evidence. Drs Ogawa and Matsubara take the opportunity to issue a note of caution about the concomitant use of epoprostenol and anticoagulants, although this issue was not addressed in our article. The COMPERA registry does not help us support their caution, but we tend to disagree with this statement. Although it is correct that anticoagulants and prostacyclin analogs may synergistically increase bleedings risks, there is no such evidence from randomized, controlled trials or large case series, respectively.2–5 Most expert centers continue to use anticoagulants in IPAH patients receiving prostacyclin analogs. Registries provide important information on real-life patients, treatment patterns, and outcomes, but biases cannot be fully controlled for, which is why registry data must be interpreted with caution. We agree with our colleagues that we need to find ways to generate more robust evidence, in particular when it comes to the long-term use of potentially dangerous treatments such as anticoagulants. Uncertainties remain, but the body of evidence still favors the use of anticoagulants in patients with IPAH, as recommended by current guidelines.6 Of equal importance is the lack of a beneficial effect in patients with other forms of PAH, and we believe that future guidelines should issue a note of caution about the use of anticoagulants in these patients.

Disclosures Dr Olsson has received speaker fees from Actelion, Bayer, and Lilly. Dr Delcroix has received investigator, speaker, consultant, or steering

committee member fees from Actelion, Aventis Pharmaceuticals, Bayer, Eli Lilly, Encysive, Gilead (Myogen), GlaxoSmithKline, Nippon Shyniaku, Novartis, Pfizer, Schering, and United Therapeutics; educational grants from Actelion, GlaxoSmithKline, Pfizer, and Therabel; and research grants from Actelion, Pfizer, and GlaxoSmithKline. Dr Delcroix is holder of the Actelion Chair for Pulmonary Hypertension and of the GSK chair for research and education in pulmonary vascular pathology at the Catholic University of Leuven. Dr Tiede has received honoraria for consultations or speaking at conferences or travel grants from Bayer HealthCare AG, Actelion, Encysive, GSK, Lilly, Pfizer, and AstraZeneca. Dr Ghofrani has received honorariums for consultations or speaking at conferences from Bayer HealthCare AG, Actelion, Encysive, Pfizer, Ergonex, Lilly, and Novartis. He is a member of advisory boards for Bayer HealthCare AG, Pfizer, GSK, Actelion, Lilly, Merck, Encysive, and Ergonex. He has also received governmental grants from the German Research Foundation (DFG), Excellence Cluster Cardiopulmonary Research (ECCPS), State Government of Hessen (LOEWE), and the German Ministry for Education and Research (BMBF). Dr Speich has received investigator, speaker, consultant, or steering committee member fees from Actelion, Bayer, and United Therapeutics; educational grants from Actelion, Bayer, and OrPha Swiss; and a research grant from Actelion. E Grunig has received honorariums for consultations or speaking at conferences from Actelion, Bayer, Gilead, GSK, Lilly, Milteney, Novartis, Pfizer, and Rotex Medica and funding for clinical trials by Actelion, Bayer, GSK, Encysive, Lilly, and Pfizer. Dr Staehler has received honoraria for lectures or consultancy from Actelion, Bayer, GSK, and Pfizer. Dr Rosenkranz has received honoraria for lectures or consultancy from Actavis, Actelion, Bayer, GSK, Lilly, Novartis, Pfizer, and United Therapeutics. Dr Halank has received speaker fees and honoraria for consultations from Actelion, Bayer, GSK, Lilly, OMT, Novartis, Pfizer, and United Therapeutics. Dr Held has received speaker fees and honoraria for consultations from Actelion, Bayer, Boehringer Ingelheim Pharma, Encysive, Glaxo Smith Kline, Lilly, Janssen, Novartis, Pfizer, Nycomed, Roche, and Servier. Dr Lange has received speaker fees, honoraria for consultations, and research funding from Actelion, AOP Orphan Pharmaceuticals, Encysive, GSK, Lilly, Novartis, and Pfizer. Dr Behr has received honoraria for lectures or consultancy from Actelion, Bayer, Boehringer, Gilead, GSK, InterMune, Lilly, MSD, Novartis, and Pfizer. Dr Klose has received speaker fees and honoraria for consultations from Actelion, Bayer, GSK, Lilly, Novartis, Pfizer, and United Therapeutics and research grants from Actelion. Dr Claussen has received speaker fees from Actelion, Bayer, and Pfizer. Dr Ewert has received speaker fees and honoraria for consultations from Actelion, Bayer, GSK, Lilly, Novartis, Pfizer, and United Therapeutics. Dr Opitz has received speaker fees and honoraria for consultations from Actelion, Bayer, GSK, Lilly, Novartis and Pfizer. Dr Vizza has received fees for serving as a speaker, consultant, and an advisory board member from Actelion, Dompè, GSK, Italfarmaco, Lilly, Pfizer, and United Therapeutics. Dr Scelsi has received fees for serving as speaker and an advisory board member from Actelion, Dompè, GSK, Lilly, and Pfizer. Dr Vonk-Noordegraaf reports receiving lecture fees from Actelion, Bayer, GlaxoSmithKline, Lilly, and Pfizer, industry advisory board from Actelion and Bayer, and serving on steering committees for Actelion, Bayer, GlaxoSmithKline, and Pfizer. Dr Kaemmerer has received honoraria for lectures or consultancy from Actelion, Boehringer Ingelheim, and Pfizer. Dr Gibbs has received speaker fees and honoraria for consultations from Actelion, Bayer, Gilead, GSK, Lilly, Novartis, and Pfizer. Dr Coghlan has received fees for consultancies lectures from Actelion, Bayer, GSK, United Therapeutics, and Pfizer, as well as equipment and educational grants from Actelion. Dr Pepke-Zaba has participated to advisory boards for Actelion, United Therapeutics, Bayer, Pfizer, Lilly, and Novartis; has received funds for research and education from

(Circulation. 2014;130:e110-e112.) © 2014 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org

DOI: 10.1161/CIRCULATIONAHA.114.010921

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Correspondence  e111 Actelion, Pfizer, GSK, and Bayer; and has received reimbursements of travel expenses to congresses and speakers’ fees from Actelion, Pfizer, GSK, Bayer, LungRx, and United Therapeutics. Dr Schulz has received unrestricted research grants from Bayer and Actelion; honoraria for consultations from XDX, Gilead, and Novartis; and speaker fees from Novartis, Actelion, Bayer, Gilead, and MSD. Dr Gorenflo has participated to advisory board for Pfizer and has received reimbursements of travel expenses to congresses and speaker fees from Actelion, Pfizer, and Bayer. Dr Pittrow has received speaker fees or honoraria for consultations from Actelion, Bayer, Boehringer Encysive, Ingelheim, Encysive, Novartis, and Pfizer. Dr Hoeper has received speaker fees and honoraria for consultations from Actelion, Bayer, Gilead, GSK, Lilly, Novartis, and Pfizer. The other authors report no conflicts. Karen M. Olsson, MD Department of Respiratory Medicine and German Center of Lung Research (DZL) Hannover Medical School Hannover, Germany Marion Delcroix, MD Department of Pneumology University Hospitals of Leuven Leuven, Belgium H. Ardeschir Ghofrani, MD Henning Tiede, MD MSc University of Giessen and Marburg Lung Center (UGMLC) Member of the German Center for Lung Research (DZL) Hannover Medical School Hannover, Germany Doerte Huscher, MSc Department of Rheumatology and Clinical Immunology Charité University Hospital Berlin, Germany Epidemiology Unit German Rheumatism Research Centre Berlin, Germany Rudolf Speich, MD Clinic of Internal Medicine University Hospital Zurich, Switzerland Ekkehard Grünig, MD Thoraxclinic University Hospital Heidelberg Heidelberg, Germany Gerd Staehler, MD Medical Clinic I Clinic Loewenstein Loewenstein, Germany

Tobias J. Lange, MD Department of Internal Medicine II Division of Pneumology University Medical Center Regensburg Regensburg, Germany Juergen Behr, MD Department of Internal Medicine V University of Munich Germany Member of the German Center for Lung Research (DZL) Hannover, Germany Hans Klose, MD University Medical Center Hamburg-Eppendorf Center of Oncology Department of Respiratory Medicine Hamburg, Germany Martin Claussen, MD LungenClinic Grosshansdorf, Germany Ralf Ewert, MD Clinic of Internal Medicine Department of Respiratory Medicine Ernst Moritz Arndt University of Greifswald Greifswald, Germany Christian F. Opitz, MD Department of Cardiology DRK Kliniken Berlin Köpenick Berlin, Germany C. Dario Vizza, MD Department of Cardiovascular and Respiratory Diseases Sapienza University of Rome Rome, Italy Laura Scelsi, MD Fondazione IRCCS Policlinico San Matteo University of Pavia Pavia, Italy Anton Vonk-Noordegraaf, MD Department of Pulmonary Diseases VU University Medical Center Amsterdam, The Netherlands Harald Kaemmerer, MD Department of Pediatric Cardiology and Congenital Cardiac Defects German Heart Centre Munich Technical University Munich Munich, Germany J. Simon R. Gibbs, MD Department of Cardiology National Heart & Lung Institute Imperial College London London, UK

Stephan Rosenkranz, MD Clinic III for Internal Medicine (Cardiology) and Center for Molecular Medicine Cologne (CMMC) University of Cologne Cologne, Germany Michael Halank, MD Internal Medicine I University Hospital Carl Gustav Carus Technical University Dresden Dresden, Germany Matthias Held, MD Department of Internal Medicine Respiratory Medicine and Cardiology Mission Medical Hospital Würzburg, Germany

Gerry Coghlan, MD Department of Cardiology Royal Free Hospital London London, UK Joanna Pepke-Zaba, MD Pulmonary Vascular Diseases Unit Papworth Hospital NHS Foundation Trust Cambridge, UK

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Uwe Schulz, MD Herzzentrum Bad Oeynhausen Bad Oeynhausen, Germany

e112  Circulation  September 16, 2014 Matthias Gorenflo, MD Department of Pediatric Cardiology University Hospital Heidelberg Heidelberg, Germany David Pittrow, MD Institute for Clinical Pharmacology Medical Faculty Technical University Dresden Dresden, Germany Marius M. Hoeper, MD Department of Respiratory Medicine and German Center of Lung Research (DZL) Hannover Medical School Hannover, Germany

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2. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, Bourge RC, Brundage BH, Koerner SK, Langleben D, Keller CA, Murali S, Uretsky BF, Clayton LM, Jöbsis MM, Blackburn SD, Shortino D, Crow JW; Primary Pulmonary Hypertension Study Group. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334:296–302. 3. Simonneau G, Rubin LJ, Galiè N, Barst RJ, Fleming TR, Frost AE, Engel PJ, Kramer MR, Burgess G, Collings L, Cossons N, Sitbon O, Badesch DB; PACES Study Group. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med. 2008;149:521–530. 4. Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Hervé P, Rainisio M, Simonneau G. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;40:780–788. 5. McLaughlin VV. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002;106:1477–1482. 6. Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M and Simonneau G. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Respir J. 2009;34:1219–1263.

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Response to Letters Regarding Article, ''Anticoagulation and Survival in Pulmonary Arterial Hypertension: Results From the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA)'' Karen M. Olsson, Marion Delcroix, H. Ardeschir Ghofrani, Henning Tiede, Doerte Huscher, Rudolf Speich, Ekkehard Grünig, Gerd Staehler, Stephan Rosenkranz, Michael Halank, Matthias Held, Tobias J. Lange, Juergen Behr, Hans Klose, Martin Claussen, Ralf Ewert, Christian F. Opitz, C. Dario Vizza, Laura Scelsi, Anton Vonk-Noordegraaf, Harald Kaemmerer, J. Simon R. Gibbs, Gerry Coghlan, Joanna Pepke-Zaba, Uwe Schulz, Matthias Gorenflo, David Pittrow and Marius M. Hoeper Circulation. 2014;130:e110-e112 doi: 10.1161/CIRCULATIONAHA.114.010921 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539

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