Fraudulent CCSVI study? Self-interests against negative data?

Endovascular treatment of chronic cerebro-spinal venous insufficiency in multiple sclerosis: a retrospective study
R. Alroughani, S. Lamdhade (Kuwait, KW)

Background: Chronic Cerebro-Spinal Venous Insufficiency (CCSVI) has been proposed to be associated with Multiple Sclerosis (MS). Zamboni et al reported significant improvement in neurological outcomes in MS patients who underwent Percutaneous Transluminal Angioplasty (PTA).

Objectives: This retrospective observation study evaluated the neurological outcomes in MS patients who underwent PTA.

Method: Patients with clinically definite MS who underwent PTA in the last 2 years were assessed. Patients chose to undergo the PTA outside Kuwait voluntarily and not under any study protocol. Patients aged between 18 and 60 years who have relapsing remitting (RR) course and completed at least one-year post-PTA were included. Adherence and discontinuation of disease modifying Therapies (DMTs) were assessed. Patients with clinically isolated syndrome or progressive forms of MS and those with incomplete data were excluded. The primary endpoint was the proportion of relapse-free patients at one year. Secondary endpoints were change in mean EDSS score and proportion of patients with new MRI activity (defined as either Gadolinium-enhancing or new T2 lesions) at one year.

Results: Forty-two patients satisfied the study inclusion criteria and their pre- and post- PTA clinical and radiological data were analyzed. Females constituted 73.8% of the cohort. The mean age and mean disease duration were 34.02 and 7.31 years respectively. At one year post-PTA, the proportion of relapse-free patients decreased from 85.71% to 66.67% (p = 0.071) whereas the mean EDSS score increased from 2.90 SD±1.64 to 3.24 SD±1.86 (p =0.377). The proportion of patients with new MRI activity increased significantly from 16.67% to 42.86% (p = 0.016). 35.71% of patients stopped their DMTs. There was no difference among the patients who stopped or continued their DMTs with respect to relapses (p=0.734) or new MRI activity (p=0.517).

Conclusion: The study revealed that PTA in relapsing remitting MS patients was not associated with any neurological improvement. However, there was an increase in disease activity evident by MRI parameters irrespective of the adherence to DMTs. Given the safety concern of this small observation study, further evidence of the association between CCSVI and MS is required prior to the institution of PTA in clinical trials.

Based on this it is clear that there is no evidence of efficacy and worse still it suggests that disease activity is worsened. If the procedure was that great as some people say then it should not be hard to see benefit. The prospective trials will shed light on this but the future would not look bright. This is however only n=42 what happens when we increase this 10 times. 

However, in the interests of balance I thought I would see what our Mate Joan from CCSVI central 🙂 made of this. It bothered me what I read as there was a implied suggestion that this was fraud and this is coming from CCSVI-supporting Doctors.
 
So first was a post linked to comments from the Hubbard Foundation .

This was set up by a protagonist of CCSVI, David Hubbard who also has a BLOG and was reporting on CCSVI at ECTRIMS 2012

Reviewed by David Hubbard MD, Hubbard Foundation
Very brief summaries of each abstract are presented below. First we summarize the highlights:
There is an abstract from a doctor in Kuwait reporting that patients were actually worse 1 year after treatment. Here is an email to me from Tariq Sinan MD, the lead author of the work referred to in this abstract.

Oct 1, 2012
Dear David,
Absolutely. you can forward my emails to anybody you want.
Furthermore his poster is not just repudiated. its illegal. he did not get permission neither from all investigators nor from the Kuwait research authorities. All papers and results have to be approved by them. same paper was rejected from ANM after we wrote to them. The author in his poster is not even part of the study team. Dr. Alrougani met less than 30 % of patients once only. the rest of the patients refused to go to him because they thought he was biased. We used another Neurologist. its now more than 2 years since we started the study. 70% of patients feel they have benefited from the procedure. 1 patient got worse, he got thrombosis in one vein and the neurologist thought he got worse because he stopped Tysabri suddenly. We hope our 2 yrs follow up prospective study will be out soon.
Best regards,
Tariq Sinan. MD Kuwait

Hubbard Site said

Thirteen of the 21 abstracts were ultrasound studies and predictably were negative, inconclusive, and/or repetitive. I think we have all learned that ultrasound is not able to provide diagnostic criteria for the hypothesis of chronic cerebro-spinal venous insufficiency, and internal jugular ultrasound will not help us understand what is happening in the small veins of the CNS white matter where MS lesions occur.
Alroughani and Lamdhade. Kuwait (not Sinan’s group)
42 MS patients had venoplasty and were signicantly worse at 1 year by relapse rate, EDSS score and MRI .

The inference is clear that the data in the ECTRIMS abstract is fraudulent. Then it appeared that an abstract had been submitted previously by the Same Authors at American Association of Neurology meeting and withdrawn. This time the letter was from a different person

Regarding

http://www.abstracts2view.com/aan/view.php?nu=AAN12L_S10_007&terms

We would like to bring to your attention that the abstract above was submitted by Dr. Raed Alroughani from Kuwait and is fraudulant and not legal due to the following reasons:-

·Dr. Raed Alroughani submitted the paper without approval of the national research committee from ministry of health of Kuwait. Also without approval of the primary investigator Dr Tareq Sinan. Dr. Raed Alroughani was invited the study late and not the main neurologist involved but Dr. Sulaiman Al-Khashan is the main neurologist involved in the study. Dr. Raed Alroughani did not follow up all patients because was biased toward not having the procedure and was in favor of medical therapy of MS.  He only saw 25 % of patients in his clinic for follow up. Dr. Raed Alroughani never met with the group investigators (Dr. Tariq Sinan, Dr. Hussain Safar, Dr. Muzaini and Dr. Sluiman alkhashan, and the ethical and the research committee from the ministry of health) to discuss any results. Dr. Raed Alroughani send the abstract without even receiving approval of his colleague neurologist Dr. Sulaiman Al-Khashan. Dr. Raed Alroughani was objecting from the start regarding the CCSVI procedure from the beginning and he had in his mind a plan to stop the procedure early and to write against it
This abstract is fraudulant and immoral .

For your information, all the committee agreed that we should continue to follow the patients for 2 years due to the fact this neurologist was not willing to follow up these patients properly.

I think this matter should be raised to the higher committee of the American Academy of Neurology.

Thank you,
Dr. Hussein Safar
Consultant Vascular surgeon
Kuwait

 Alarm Bells were ringing and again it appeared that Fraud was being claimed. Should I alert ECTRIMS organisers?, as this publication is clearly going to be controversial. I thought that I would investigate this and here are my letters to the Author of the Abstract and the alleged person claiming fraud and their responses 


Dear Dr Sinan
I write to you regarding a letter attributed to you on the Hubbard Foundation website, concerning an abstract R. Alroughani, S. Lamdhade (Kuwait, KW).

I can see you are not an author on the manuscript, but are you alleging that the data as presented is incorrect and fraudlent? That it was not presented by the Kuwaiti authorities I think is a separate issue about whether the information as presented is correct.

Any light you can shed on this is important as the data have interest to the MS community and your concerns about it are also public.

The response is
“This poster presented is illegal because it does not have Kuwait Authority approval which is a pre condition by Kuwait Authority who originally approved the study with (similar name) with me as the principal author. Dr. Alroughani was one of 6 investigators involved. Non of the other 5 Investigators involved in the study are aware of his poster or the Data that it includes. So I don’t know if the Data is correct. But to this date I regularly follow up 90% of patients enrolled in the original study by Ultrasound and MRI. and the impression I have from the patients and Imaging toltally contardict Dr. AlRoughani conclusion. We have to see the final results when the official Kuwait study is published. so, what is your point ? The fact that he choosed to not include my name and use some one elses name from outside the study group is an unaccepatable action which was challnged before and now he has to answer to Kuwait research Authority.
Best regards,
Dr. Tariq Sinan”

Therefore, whilst it is suggested to me that Dr Sinan believes that protocol has not been followed in Kuwait and that he believes that he should have been included on the report in the study, he does not know what the actual data is. There is clearly a clash of personality and perhaps sour grapes. The impression is that the conclusion may not be right but does not go as far a explicitly stating that the data is falsified but not far off. This is a serious thing for health care professionals to be making in public. Likewise Dr.Sinan had time to prepare data that would clearly counter the claims being made. The studies are not blinded, so ideally opinion should be more than an impression.

We all get left off papers that we think we may be on. That’s life. However, you take it on the chin or deal with the author. When you find out and if it pisses you off, then it only happens once as you do not work with the offending person again. You send the paper out to all authors to comment before you submit, If a potential author disagrees with the content then they can remove their name from the paper. If they do not give approval their name should be removed from the study. Sometimes you get on papers you may not have expected. Whining in public is not the best way to deal with it.
Maybe these are allegations that deserve action and appear to be occurring. It seems interesting that you have to ask your National Government to present data, it certainly does not occur in UK and could be anti-academic if the results were political and Governments tried to stop you publishing, which in this case I doubt it. As this is the second time this type of story is being aired, surely the Government would have had time to address this issue if it was of importance. It seems as if investigation is underway

Anyway now on the the other party.
 

I have read on the internet a letter attributed to Dr Sinan on the Hubbard website and there is another attributed to Dr. Hussein Safar (CCSVI faceook) which imply your results are fraudulent. I wonder if you would care to comment on this as the issue.

The validity of CCSVI is of immense public interest and the public critisism of this work and and contents clear deserves some reply.

So now for the reply the attachments were sent

Thank you for your email.

I will explain the whole situation in order to clarify any points that could be raised.

I have submitted a different abstract to the AAN that included patients that were assessed by the study team in Kuwait. Dr Safar and Dr Tariq sent an a letter to the AAN with the concerns raised in the facebook website.The AAN placed a suspension till i clarified the concerns (my letter to AAN is attached). I responded to the AAN letter and finally the suspension was removed (AAN email is attached). In summary, i responded in that letter and clarified all points in a systematic manner and the AAN council acknowledged that. However, i withdrew the abstract in April since i have asked for an independent investigations in Kuwait to investigate the results after i submitted a letter to the minister of Health in Kuwait to preserve my rights after the unethical accusation to the neurology team.

The abstract submitted to the ECTRIMS is different than that submitted to the AAN. It did not include any patients who were enrolled in the original study. I have clearly indicated in the abstract that one of the major inclusion criteria was patients who underwent angioplasty outside any other study protocol. So, we included patients who underwent the procedure voluntarily outside Kuwait and these were not assessed by either Dr Sinan or Dr Safar. At least 300 Kuwaiti patients underwent the procedure inside and outside Kuwait. Dr Sinan and Dr Safar did not assess these patients because they did the study on only 100 patients in Kuwait.

We retrospectively evaluated the neurological and MRI outcomes (and not the angiographic outcomes). So, the cohort and the analysis were completely different and those doctors Sinan and Safar were not part of out study team. I think they are confused and they did not read the abstract submitted to the ECTRIMS that clearly indicated that we only included patients who did the angioplasty outside Kuwait but in fact they were my patients and i have been following them for the last years. We as a neurology team are following patients on the long term and we see the repeated relapses and attacks along with the increase in MRI activities in our patients that placed them in a great danger. We have an ethical obligation to report these safety concerns in an unbiased scientific
manner.

At the end, Dr Sinan and his team are trying to obstruct any data that may raise any concerns about the safety or efficacy of the angioplasty. The reason can be easily explained. Despite that the ethics committee in Kuwait had clearly indicated to Dr Sinan that they should not do any of these procedures, they are still doing the procedure in Kuwait illegally and privately in their clinics (patients are paying between $5000-8000). They do not want any safety or efficacy results that could impact on their illegal procedure even though the patients we included in our ECTRIMS abstract were never been assessed by them.

I hope i have clarified any issues. Thank you again for your email.
Best regards,

Raed Alroughani, MD, FRCPC
 
I think this seems a rational response and therefore it would appear that the Hubbard Foundation and elsewhere should have done a lot more due diligence before making accusations and asks questions about their impartiality and professionalism. Maybe we should write to David Hubbard?. If you look on his webpage on Hubbard.org website, we can see the research interest of David Hubbard is in lie detection and truth verification. Maybe a self fMRI scan would be in order.

Maybe we should investigate potential conflict of interests?.

However, there are often two sides to a story and the reality may lie somewhere in between. As to whether CCSVI worsens MS, there are other reports you could dig up that may argue otherwise. As Mouse Doctor2 has pointed out 35% of people stopped taking their DMT, because they presumably thought that venoplasty ws the cure. So the fact that some people start to relapse after stopping DMT therapy may not be surprising and could this largely account for the observation of worsening. The trials are starting the data will be out one way or another, but my concerns are that those with a vested interests may not want to hear as CCSVI is a profitable industry to some.
 
In regard to the first AAN abstract it appeared that Dr Sinan was the principal applicant and Dr Alroughhani was a co-applicant. There were two teams one interventional radiology/vascular surgery and the other lead by Dr Alroughani was the neurology team. The Neurology team had safety concerns about increased disease activity and because of failure of the other team to engage, safety concerns were raised. The AAN appear to accept the explanation.

This is work is clearly a Hot Potato, I will leave you to deliberate what you think is and who you think was reasonable. Claiming fraud is a very big issue, just because you do not like the results or the people. Being blinkered to the reality is likewise a problem and so one has to be careful what you read and believe. This is the moral of the story