A recent article on the British newspaper The Guardian, (The Guardian, Monday 22 December, 2014) reported several groundless conjectures, lies and unverified information about Emergency’s work in the fight against Ebola in Sierra Leone. Some of these unsubstantiated accusations have also been written by the same group of NHS doctors as a response to a BMJ article (http://www.bmj.com/content/349/bmj.g7198/rapid-responses) and have been reported in an article on Aljazeera website.
It is false that “mortality rate in the Lakka Centre is around 67%”. The Lakka Centre has been operational as both isolation and treatment unit from 18th September until 10th December 2014. The overall Case Fatality Rate (CFR) of the Centre, where 122 patients with a confirmed EVD diagnosis have been treated, is 57.4%, with 52 survivors and 70 dead (13 of these patients arrived in very critical conditions and died within 24 hours from admission ). CFR from other Ebola Treatment Centres are not always available and not very reliable as stated also by WHO experts. Recent WHO reports estimate the CFR in treatment centres to be around 60% (WHO Situation report, 24 December 2014).
It is false that amiodarone is an untested drug in humans. It is used in clinical cardiology since 40 years, prescribed to millions of people, even in critical conditions and in patients in need of intensive care. In fact, very few drugs have a well know safety profile as amiodarone, confirmed by such a long term use: aspirin, metformin and a few others. It is true that amiodarone has not been tested yet in the treatment of EVD (but for the acceptability of this use see below). Nevertheless it is widely acknowledged in clinical research the “off label” use of already known drugs for new purposes. In the “Ethical considerations for use of unregistered interventions for Ebola viral disease” a WHO panel stated that it is ethically acceptable to offer unproven interventions that have shown promising results in the laboratory and in animal models but have not yet been evaluated for safety and efficacy in humans as potential treatment or prevention. We don’t see why this principle should not be applied to such a safe drug as amiodarone.
It is false and highly offensive stating that Emergency used amiodarone in a “reckless” way outside “carefully controlled conditions”. On the contrary, amiodarone has been used with an intensive ICU patients’ monitoring: non-invasive arterial pressure, ECG (including Q-T interval determination), heart rate, oxygen saturation, electrolytes.
It is false that EMERGENCY stopped to administer amiodarone upon request from DFID. DFID is not involved in technical assessing nor determining patients therapies or clinical procedures.
Emergency acknowledged since the very beginning that it was necessary to design a proper randomized clinical trial to promote scientific knowledge in the Ebola context. The study named EASE (Emergency Amiodarone Study against Ebola) has been registered on ClinicaTrials.gov and already approved by the ethical committees of the IRCCS of Reggio Emilia, Italy, and by the ethical committee of the Italian National Institute of infectious diseases, L. Spallanzani, Rome. Emergency decided to stop the “case by case” use of amiodarone when the EASE trial has been submitted to the Ethical and Scientific Committee of Sierra Leone.
It is false that DFID withdrew NHS staff from Emergency’s facility. Emergency has been always very open and transparent in discussing its clinical approach with every member of its team. After more than one week of repeated discussions with the NHS team, Emergency agreed with those who were not feeling comfortable that they could stop their cooperation with the organization. An approach endorsed by DFID, too. On the contrary, some of the NHS team who wanted to continue to work with us were put under pressure and threatened by colleagues until eventually all the team left. Nevertheless some members of that same team have already expressed their willingness to come back to work again with Emergency in the future.
Emergency has been very surprised by this behaviour because our work had been previously very positively evaluated by a Quality Assessment survey performed by UK Med , shared both with DFID and NHS. In addition, Emergency’s clinical practices have been officially endorsed by the Chief Medical Officer of Sierra Leone and the organization has provided important inputs in the development of the newly published WHO Sierra Leone adaptation VHF pocket guide.
It is false that “the main focus of the Emergency staff was to ensure the patients received these drugs instead of ensuring they were adequately hydrated, clean and comfortable”. As stated in WHO and Emergency clinical guidelines, patients’ rehydration is one of the most important components of the supportive treatment. Patients have been aggressively rehydrated with several liters of infusions per day to restore volume and electrolytes balance. Rosters in Lakka were organized to guarantee an optimal patients attendance: approximately 350 min per patient per day of medical attention, allowing accurate monitoring to provide the best possible standard of care, and to ensure high standards of hygiene. If the NHS team had spent time looking after patients in the hospital rather than staying at home to exercise criticism, they would have had a much clearer picture of our patients management. Out of the 122 Ebola confirmed patients treated in Lakka, they have actually observed very few patients and for a very limited period of time. EMERGENCY has formally shared with DFID an official complaint report about the behaviour of some NHS staff and the management of the team by UK-Med.
It is false and slanderous to state that Emergency does not ask for patients’ consent. Since 20 years in all Emergency’s facilities worldwide patients, or relatives when appropriate, are requested to provide their informed consent for any medical or surgical procedures.
On the contrary, we wonder why no one is asking the African patients their “consent” to be treated in a very different way (“a second class way”, one could say) compared to the “western patients”.
A somehow disturbing drug
Following an in-depth discussion with international experts and scientists, Emergency decided to administer the drug called amiodarone to some patients affected by Ebola Virus Disease (EVD) in Sierra Leone. The drug has been used “off label”, i.e. outside the normal therapeutic indications.
Emergency believes that this decision is scientifically and ethically appropriate, since many tests performed in vitro proved that amiodarone has a specific anti-viral action against Ebola virus. (J Antimicrob Chemother. 2014 Aug;69(8):2123-31. doi: 10.1093/jac/dku091. Epub 2014 Apr 7.), at the dosage commonly prescribed in clinical cardiology.
All patients who received it (upon a medical “case by case” decision, outside a clinical protocol or trial) have been very carefully monitored throughout the treatment.
Confronting a disease that is still registering a very high mortality rate and for which no specific treatment is available, we believe that the use of drugs with a potentially beneficial effect against Ebola is ethical and appropriate, provided that the drugs are safe and their side effects known.
The decision to use amiodarone in Lakka on a case by case basis was shared with the Health Authorities of Sierra Leone, and authorised by a Memorandum of Understanding, signed on 22nd September 2014 with the Ministry of Health.
Unfortunately amiodarone has a major defect, unbearable for many of the “experts” involved in different ways in the “fight against Ebola”: amiodarone does not produce any profit for anyone. It simply cannot produce profit, being a generic drug, out of patent since many years, easy to be produced at a very low cost, a few cents per tablet, everywhere in the word.
Obviously, Emergency is not stating that amiodarone is working against Ebola. To say so it should be tested with a randomized clinical trial, as we proposed. Nevertheless, we believe that it is foolish from a scientific perspective to deny approval for testing amiodarone while focusing exclusively on new drugs (really “untested”) available only in Europe or in the USA in very limited quantity and at a very high cost (hundreds of thousands of USD each dose). This could be a lost chance to contribute to the defeat of Ebola.
Our experience in Lakka
Observational data on patients who have received amiodarone at the Lakka Ebola Treatment Unit managed by Emergency can be summarised as follows:
48 patients received the drug in dosages aiming at obtaining a serum plasma concentration up to 10 uM, in order to develop a significant anti-viral action, without exceeding 20 mg/kg/die which is the maximum suggested dosage in clinical cardiology.
Amiodarone has been administered I.V. in the first 3 days and orally in the following 7 days of treatment.
We recorded 24 deaths in patients who were receiving amiodarone (6 of them presented in very critical conditions and died within 24 hours from admission). The mortality rate within this group has been 50%. ( 42,8% if we exclude those 6 early deaths, 18 dead over 42 patients).
As previously stated, the overall CFR of the Lakka Centre was 57.4%, over 122 patients, and 52.3% if we exclude the 13 patients who died within 24 hours from admission.
As far as drug safety is concerned, we have observed minor side effects in 2 patients only : in one case, systolic pressure dropped by 20%, in the other we registered bradycardia (Heart Rate 60 beats/min). Despite the fact that both patients remained asymptomatic, our clinicians decided to stop administering amiodarone.
These preliminary observations provide, in our opinion, a solid ethical and scientific ground to state that amiodarone is not “harmful” for the patients and might even be beneficial, reinforcing the rationale for a clinical trial.