vEDS Research Studies
The studies and trials conducted in vascular EDS
The 2019 Study of Long-Term Outcomes in Vascular Ehlers-Danlos Syndrome
In April 2019 a study was published in the Journal of American College of Cardiology which reviewed management and outcomes of Vascular Ehlers-Danlos Syndrome (vEDS) patients at a single national referral center in Paris, France. This study is significant because it is the only study since the BBEST trial to report on a group of vEDS patients that were systematically followed and documented as part of a vEDS specific research project.
FIGHT vEDS reviewed the publication and discussed it with leading researchers in the field of vEDS in the United States. This overview has 4 sections that detail the important elements of the research:
Evaluation of the effects of celiprolol by the study
We are incredibly thankful for the efforts of the team in France caring for vEDS patients. The study design does not allow for concrete conclusions regarding the benefit of celiprolol, but there are many tremendously valuable lessons within the publication. The main message is that patients with vEDS benefit significantly from a structured multi-disciplinary approach with follow up at a strong referral center with experience in the disorder. Although we don’t know what impact celiprolol or the other factors have on outcomes, the combination of factors is improving outcomes for patients in France and some of these approaches could be adopted in the US and elsewhere.
1. The Study
In April 2019 a study was published in the Journal of American College of Cardiology which reviewed outcomes of vEDS patients at a single national referral center in Paris, France. This hospital (Hôpital Européen Georges Pompidou) contains the French National Referral Center for Rare Vascular Diseases, where all patients with vEDS in France are sent, when possible. The study was a long-term observational study, which means they followed vEDS patients and during this time recorded certain vEDS-related events (such as arterial events, hospitalizations, and deaths). In total, 144 patients were enrolled between January 2000 and March 2017, with a median length of time the patients were followed of 5.3 years. All of these patients had genetic testing with a molecularly confirmed diagnosis of vEDS.
Collection of data
The French researchers created a database of vEDS patients in 2011. For all patients enrolled before 2011 (from 2000-2011), they went back and manually entered all the data they could find regarding patients enrolled in the study (data was entered retrospectively). From 2011 to 2017, all information was entered as it occurred (at the time of follow up visits, after hospitalizations, etc).
The database contained all available medical histories for each vEDS patient. This included all information from their initial workup, any information from follow up visits and any information regarding hospitalizations or new clinical events—such as a dissection or bowel rupture that would require clinical attention. They also documented within their database any deaths and the cause of death.
Follow Up and Treatment
Follow Up: Patients were seen for follow up visits every 6 to 9 months, and by the end of the study, the majority of patients (90.3%) were placed on celiprolol (the beta-blocker used as the primary medication in the study). If the patient was increasing their dose of celiprolol they were seen more often to assess how they were handling the increased dose. The most common side effect that would determine if they could keep increasing the dose to the goal of 400mg/day was fatigue on the medicine.
Imaging: Imaging was performed at the time of diagnosis to establish a baseline view of the blood vessels for all vEDS patients in the study. This was done either by ultrasound, magnetic resonance angiography (MRA) or computed tomography angiogram (CTA). If patients remained asymptomatic, they received repeat scans every 12 to 18 months. Any time patients had an arterial event (such as a dissection), the researchers obtained any imaging and hospital notes they could and added this information into their database.
Treatment: The researchers primarily used celiprolol to treat vEDS patients in the study. Celiprolol is a beta-blocker that had previously been studied in vEDS patients on the BBEST trial, which you can learn about (here). After the publication of the BBEST trial, it was made standard practice in France to offer every patient celiprolol (if they were taking a different beta-blocker, they were offered to switch to celiprolol). The goal dose was a maximum of 400mg/day—taken as 200mg twice daily. At the start of the study, only 50% of patients were on any type of regular treatment, and the other 50% were ‘not treated regularly’. Additionally, 33.3% of the patients were taking celiprolol. By the end of the study, 90.3% of patients were taking celiprolol, either alone or in combination with other blood pressure medicines.
Emergencies: Whenever possible, vEDS patients were seen at the primary facility in Paris. However, to prepare for emergency situations when patients were at home and being treated by local physicians and hospitals, the study organizers provided their patients with contact information to reach the team in Paris when emergency situations arose. This way the experts in Paris could communicate with local providers and provide advice on management to help improve care and outcomes. The study does not go into detail on how the emergency hotline functioned so it is unclear whether this was a resource for patients to communicate with the team in Paris or if it was used by local physicians to connect with the experts in Paris.
2. The Results
vEDS survival on the study: Overall, this study showed that it is possible to have good outcomes and survival in vEDS!
1-Year Overall Survival: 99.3%
5-year Overall Survival: 89.9%
10-year Overall Survival: 83.4%
Causes of death during the study: 17 patients out of 144 passed away by the end of the study (14 due to vEDS). Causes of death included:
Arterial Rupture: this was the most common cause of death (12 patients, 70.6% of deaths)
Bowel perforation: was the second most common cause of death (2 patients, 11.8% of deaths)
Unrelated: the remaining 3 patients died of issues unrelated to vEDS
Management of Arterial Events: The French group favors medical management of acute arterial events whenever possible (blood pressure control, medications, etc.). In total, there were 80 hospitalizations for acute arterial events. Only 17 of these arterial events required an intervention. These were treated by:
Embolization Procedures: in 10 cases
Open Repairs: in 3 cases
Other Endovascular Procedures: in 4 cases
3. The conclusion
The vEDS patients followed in the study had a low annual occurrence of arterial complications and a high survival rate. The researchers attribute this to the overall medical care these patients received -- a combination of treatment at a single center with vEDS experts, medical management, regular follow up and surveillance, and intervention for medical events as needed.
As discussed earlier, the French group took a multi-pronged approach to treat vEDS patients:
Regular follow-up with knowledgeable physicians
Conservative surgical management
Emergency contact information
It appears clear that this combination is helping to have a positive impact on vEDS care. However, it is impossible to determine from this study is how much each of those elements is helping, if at all.
4. Evaluation of the effects of celiprolol by the study
The potential benefits of celiprolol for vEDS could not be concluded by this study. The authors themselves conclude that:
“It is difficult to formally assess this beneficial effect (the benefit of celiprolol on survival) in the absence of a placebo-controlled prospective trial, because other confounders might have influenced this observation.”
In other words, the French researchers that did this study acknowledge that the only way to tell how beneficial celiprolol truly is in vEDS is through a clinical trial that compares celiprolol directly to another treatment (or a ‘no treatment arm’), and controls for other variables (differences in patient age, health status, etc,) which could affect the outcome.
Below are some of the main takeaways regarding celiprolol and this study:
Celiprolol’s effect on hospitalizations: the study compared the number of hospitalizations for acute arterial events before and after 2011 when the French group introduced organized follow up and treatment protocols. This comparison showed a significant decrease in the number of hospitalizations for arterial events after 2011. However, the exact role of celiprolol in these findings could not be determined. After 2011, there were many changes that could have affected hospitalization rates including regular follow up, surveillance and imaging.
Celiprolol’s effect on mortality: Conclusions regarding celiprolol’s effect on mortality could not be made from this study. In total, 17 patients died; 8 of them were in the ‘no treatment’ group (47.1% of deaths) and 9 were in the celiprolol group (52.9% of deaths). We can note that a higher percentage of patients died in the ‘no treatment’ group (8 out of 24, or 33.3%) versus those treated with celiprolol (9 out of 111, or 8.1%). However, these groups cannot be directly compared to confirm that celiprolol was the cause of this difference. The ‘no treatment’ group was much smaller and had a mixture of different patients and treatments. Patients were grouped into this category if they could not tolerate celiprolol, if they were on no treatment at all, or if they were non-compliant to treatments (did not take the medicine regularly as directed). As such, this group was not randomly selected and it is possible that the patients included in the ‘no treatment’ category had other factors which put them at higher risk of mortality and negative outcomes.
Celiprolol’s effect on improving survival: there was a significant difference in survival between the group treated with celiprolol and those who were not. However, the study design does not allow us to conclude that celiprolol influenced this outcome or how much of a role it played compared to other beneficial factors.
Dose response with celiprolol: Celiprolol’s effectiveness seems to have a dose dependence, where patients taking 400mg per day do better than those taking <400mg per day. Further study is necessary, but this is something worth potentially evaluating in the future.
ARCADE Clinical Trial
Angiotensin II Receptor Blockade in Vascular Ehlers-Danlos Syndrome (ARCADE) research study:
Summary: This is an ongoing research trial in France. All patients on the study are taking the beta-blocker Celiprolol. The doctors leading this study are looking into how adding another medication, called Irbesartan, effects patients with vascular EDS. Will it help lessen stress on our blood vessels and decrease the number of 'bad' events (dissections, aneurysms, etc.)?
What is Irbesartan?
Irbesartan is a type of drug called an Angiotensin II Receptor Blocker (ARB). Angiotensin is a chemical made in our body. One of its jobs is to 'constrict' (narrow) your blood vessels. Angiotensin II Receptor Blockers work like their name implies. They block the chemical Angiotensin II. The result is that your blood vessels stay more dilated (open), your blood pressure is lowered, and there is less strain on your blood vessels.
Why is Irbesartan being studied?
Reducing blood pressure in patients with vascular EDS is thought to be beneficial. Irbesartan accomplishes this. It also decreases a particular cell signaling pathway which is increased (abnormally elevated) in vascular EDS. With the thought being that reduction in the 'expression' of these pathways might help reduce the symptoms of the disease. We will have to wait for the results of the study to know if Irbesartan does (or does not) have a positive impact on vascular EDS patients and their symptoms.
The Beta-Blockers in Ehlers-Danlos Syndrome Treatment (BBEST) Trial
The BBEST Trial was published in 2010 in The Lancet, a medical journal from the United Kingdom. The study took patients with vascular EDS and split them into two groups:
Group 1: The ‘No Treatment’ group. This is known as a control group. These patients received no treatment during the study, including the use of any other beta-blockers(2).
Group 2: The ‘Celiprolol’ group. This is known as an experimental group. These patients all received celiprolol as a treatment.
The researchers then followed all of these patients for several years. All the while, they were keeping track of adverse events. This included events such as artery rupture, artery dissection (artery tears), intestinal perforations and death. In the end, the study was stopped early after 64 months because of the benefit they saw with Celiprolol treatment(2). Only 5 of 25 patients in the celiprolol group had a ‘primary endpoint’ recorded, compared to 14 of 28 patients in the No Treatment group(2). Primary endpoints were the above mentioned adverse events (dissection, artery rupture etc.). In the end, this study suggests that treatment of vascular EDS with celiprolol ‘extends the time to vascular complications compared to those not treated’(1). It is because of this study that celiprolol is being used as the standard treatment for all patients with vEDS in France, as well as many other parts of Europe and the United Kingdom.
In the United States celiprolol is not an FDA approved drug and therefore cannot be purchased in local pharmacies. It can however be purchased through online pharmacies in Canada, which many patients in the United States currently do. For more information see our Celiprolol page.
Challenges to the BBEST Trial:
While this is an exciting study, it’s important to recognize that it does have some issues. The selection of patients to place on the study was based on clinical features. This means that not all patients on the study had a genetic diagnosis of vascular EDS. It was determined part way through that ~1/3 of all patients on the study did not have a COL3A1 gene mutation(1). Remember, COL3A1 mutations are the cause of vascular EDS. In total, 12 of the 25 patients on the ‘Celiprolol’ group did NOT have proven COL3A1 mutations and 8 out of 28 in the ‘No Treatment’ group did NOT have proven COL3A1 mutations(2).
Some researchers in the vascular EDS community feel that these facts muddy the results of the study. They argue that with so many patients not having a proven genetic diagnosis of vEDS, it makes it more difficult to interpret if celiprolol really delays or prevents vascular events in patients with vEDS. Other researchers (who support celiprolol) still point to the fact that patients with a COL3A1 mutation (and therefore vascular EDS) who were treated with celiprolol still appeared to benefit from a reduction in vascular events.
Byers PH, Belmont J, Black J, De Backer J, Frank M, Jeunemaitre X, Johnson D, Pepin MG, Robert L, Sanders L, Wheeldon N. 2017. Diagnosis, natural history and management in vascular Ehlers-Danlos syndrome. American Journal of Medical Genetics Part C (Seminars in Medical Genetics). 175C:40-47.
Ong KT, Perdu J, De Backer J, Bozec E, Collignon P, Emmerich J, Fauret AL, Fiessinger JN, Germain DP, Georgesco G, Hulot JS, De Paepe A, Plauchu H, Jeunemaitre X, Laurent S, Boutouyrie P. 2010. Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: A prospective randomized, open, blinded-endpoints trial. Lancet 376: 1476-1484.