Consensus statement from The Ehlers-Danlos Society and professional members of the vEDS community

Posted August 9, 2019

Celiprolol and vEDS: facts, limitations and recommendations

In the context of the recent press about celiprolol and the FDA announcement not to license Celiprolol in the US for use limited to treatment of people with vEDS, we thought that it was time to bring together the global vascular EDS community from within the consortium, to update our community on where we stand. 

Summary of statement

There is not enough evidence to know for sure whether people with vEDS should take celiprolol or another medication to manage blood pressure to try to change the rate of arterial complications. Some medical centers with expertise in vEDS use celiprolol for their patients. Other medical centers with expertise in vEDS use other blood pressure medications. Since there is not one clear best option right now, people with vEDS should talk with their health care provider to create a plan based on their personal medical history.

Statement

Vascular EDS (vEDS) is a rare genetic condition caused by defects in the COL3A1 gene, which encodes type III procollagen, an important protein in vessel walls and hollow organs. The resulting defects of type III procollagen production lead to tissue fragility, particularly in arteries and hollow organs. This fragility causes clinical complications, such as arterial dissections, aneurysms, and rupture of hollow organs such as the bowel. These complications can start during childhood, and can occur unpredictably throughout the entire adult life. In addition, because of tissue fragility, endovascular procedures and surgical repair pose a high risk, especially in the emergency setting. Thus there is an urgent need for therapy that could prevent or delay arterial complications and, perhaps, those in other tissues. 

To date, the only published attempts to assess the benefit of a pharmacological treatment in vEDS are (1) the BBest study, a multi center, international, randomized open-label clinical trial that was published in 2010 and (2) the observational cohort study of 144 patients with molecularly confirmed vEDS that was published in June 2019. Both studies suggested that treatment with celiprolol might reduce the frequency of arterial events and was a safe and well-tolerated drug. There were several study limitations that were recognized by the investigators.  In the BBest study, sequence analysis identified COL3A1 mutations in about 2/3rds of the participants who were not equally represented in the study arms. The observational study did not have an adequate control group. As a result it was concluded that any changes in arterial event rates could not be attributed solely to celiprolol in patients with vEDS.

Celiprolol, a blood pressure lowering agent (β-blocker) was first commercialized in the mid 80’s in many countries, but not in the United States. β-blockers are used for the treatment of arterial hypertension, angina pectoris, and are a standard of care therapy in individuals with aortic dissections. Celiprolol is available to physicians in many countries, and may be used in vEDS as an off-label prescription. Following the publication of the BBest trial, celiprolol has become the primary treatment for vEDS patients in several European countries. An application to license celiprolol for use in people with vEDS in the United States by Acer Therapeutics, based on the data from the BBest trial, was denied in June 2019 by the Food and Drug Administration, which considered that there is not enough evidence to approve exclusive use of celiprolol as an effective drug in vEDS in the United States and called for an adequate and well-controlled trial.

Since the publication of the BBEST trial in 2010, the only ongoing interventional clinical trial in vEDS is the ARCADE trial (NCT02597361), a randomized, double-blind, placebo-controlled multicenter trial which compares the effect of the addition of the angiotensin II type receptor blocker, irbesartan, or placebo to celiprolol over a 2-year period. 

The Ehlers-Danlos Society, the vascular EDS Committee of the International EDS Consortium and the medium-sized arteries working group of VASCERN (The European Reference Network on rare multisystemic vascular disease) advocate that rigorously designed prospective, randomized, double-blinded clinical trials, in individuals with genetically confirmed vEDS are of key importance to guide future therapy in vEDS. The Ehlers-Danlos Society commits to working with the global vEDS medical community to set up these studies. In the meantime, it is deemed safe for individuals with vEDS currently under treatment with celiprolol, to continue this medication. Whether the suggested beneficial effect of celiprolol in vEDS can be extrapolated to other β-blockers remains unknown. Similarly, we do not know yet if other blood pressure-reducing drugs, such as angiotensin receptor blockers, have beneficial effects. 

In summary, it is recommended that each patient discuss an individual treatment plan with his/her health care provider with access to their complete medical history. A careful personal and familial evaluation, the establishment of a multidisciplinary care team, and, if feasible, follow-up in a dedicated reference centre should be proposed to all molecularly-proven patients with this rare condition.

The Ehlers-Danlos Society remains committed to supporting and educating the vascular EDS community and will continue to work closely with the global network of professionals in the EDS Consortium to develop a global registry, raise funding required for research and provide a platform for continued international collaboration.  


The Ehlers Danlos Society

The Ehlers-Danlos Society facilitates the work of the EDS and HSD International Consortium, which was created following the efforts that resulted in the 2017 diagnostic criteria and management and care guidelines. Clinicians, scientists, and patient experts are organized into committees based on medical specialty and research interests, and coordinated by a Steering Committee.

The International Consortium is an independent group of medical professionals and experts with the administrative and event-planning needs facilitated by The Ehlers-Danlos Society, but all work and opinions are independent and come solely from the consortium members.

Written by members of the Vascular EDS Committee and Steering Committee in the EDS International Consortium:

Dr. Peter H. Byers, MD (USA), 

Dr. Harry C. Dietz, MD (USA), 

Dr. Fleur van Dijk, MD, PhD (UK), 

Dr. Clair A. Francomano, MD (USA), 

Dr. Michael Frank, MD (France), 

Dr. Alan Hakim, MB BChir MA FRCP (UK), 

Professor Xavier Jeunemaitre, MD, PhD (France), 

Dr. Diana Johnson BM BSc MD (UK), 

Professor Fransiska Malfait MD, PhD (Belgium), 

Dr. Lauren Puryear, MS, CGC (USA), 

Dr. Leema Robert MRCPCH (UK), 

Dr. Sherene Shalhub, MD, MPH, FACS (USA)

Professor Nigel Wheeldon MB ChB MD FRCP FESC (UK)

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