STUDY OF LONG-TERM OUTCOMES IN vEDS (2019)

A 17-year study analyzing the impact of celiprolol and other factors on vEDS

Overview

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:

The study
The results
The conclusion
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
Periodic imaging
Medical management
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.