Monday, 27 January 2014

ACE inhibitors are not so ACE

Doerner M, Beckmann K, Knappertz V, Kappos L, Hartung HP, Filippi M, O'Connor PW, Arnason B, Cook S, Jeffery D, Comi G, Limmroth V Effects of Inhibitors of the Renin-Angiotensin System on the Efficacy of Interferon beta-1b: A post hoc Analysis of the BEYOND Study. Eur Neurol. 2014 Jan;71(3-4):173-179. [Epub ahead of print]

Background: In experimental autoimmune encephalomyelitis, inhibition of the renin-angiotensin system with angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors resulted in a significantly ameliorated disease course. We evaluated the effects of ARBs and ACE inhibitors on the efficacy of interferon beta-1b in patients with relapsing-remitting multiple sclerosis (RRMS). 

Methods: In this post hoc analysis of the BEYOND (Betaferon Efficacy Yielding Outcomes of a New Dose) study, clinical and MRI end points were compared between patients treated with interferon beta-1b 250 or 500 µg and concomitant ARBs or ACE inhibitors and patients treated with interferon beta-1b 250 or 500 µg only (reference group). 
Results: Patients in the ARB group (n = 22) tended to have a higher relapse rate (0.48 vs. 0.23, p = 0.051) and a higher number of new gadolinium-enhancing lesions (0.6 vs. 0.3, p = 0.057) than patients in the reference group. Patients in the ACE inhibitor group (n = 49) also tended to have a higher relapse rate (0.29 vs. 0.22, p = 0.357). No differences were observed for the other end points. Conclusion: In the BEYOND study cohort, a concomitant medication with ARBs or ACE inhibitors did not have a beneficial effect in patients with RRMS treated with interferon beta-1b. As patients appeared to have a higher relapse rate, our results warrant further investigation.

Animal studies may have suggested some use of ACE/ARB inhibitors that are used to control blood pressure can affect EAE. A different set of people, wonder if professional trialists ever talk to the people who made the discovery:-) looked at what happened on a clinical trial to assess the effects of beta interferon, where people were also taking ACE/ARB inhibitors and found no effect. 

The authors suggest there may have been a worsening but let's remember P (probability value) greater than 0.05 means there was no difference. The conclusion should be no affect on relapse rate (P=0.051)  or MRI lesion (P=0.057) for ACR inhibitor and no effect of ARB inhibitors P= (0.357).  So there was no beneficial effect..or significant worsening. 

So time for another meta analysis, but if pharma don't make their trial data open how can we do these retrospective analysis to see if there are drug-drug interactions maybe with access to large data sets you could see a benefit (or not) to aspirin. The authors have made the suggestion of worsening and therefore they need to follow this up get access to all beta interferon trial data and interrogate it. 

However, I hear you say it is that rubbishy animal model (EAE) again, as there was no inhibition of disease in MS. 

So another case of failure to translate from animals to humans!

Em, maybe we need to look at the animal studies and see how this was translated into the human studies. So the animal studies used 10mg/kg lisinopril (and 1mg/kg before disease induction) or enalapril  (ACE inhibitors) and 120mg/kg of Losartan (ARB) and they inhibited the development of EAE. 

However, 10mg dose of lisinopril (about 0.15mg/kg) and 5 mg human dose of enalapril (0.07mg/kg) or 50mg of Losartan (less than 1mg/kg) so about 100 times lower dose and way above the ten times scaling for mice, so what would a comparable does have done in the human, well maybe caused too many side effects because of effects on blood pressure. So maybe a comparable animal and human does would do nothing, because when we look at what 100 times dose did? Well maybe not much, with probably most animals developing EAE with a minor diminution of disease. One would expect Gilenya to flat line the score at about 0 with essentially no disease at all in the same type of experiment. This tells us that you need to look at the data and not just the headline as so often happens in media circles. This is why you hear "Cure of the Week" every week. However, the question has to be put what was the effect of a human dose equivalent as the animal studies were performed along time after the human dosing schedule was known. Guideline 19 of ARRIVE guidelines asks for a report on the relevance to human biology, without proper dose-responses the answer may be "none".

So it may perhaps be a case of overestimation of the drug effect in the EAE papers, on behalf of the neuros. Humans have as much to do in the failure as the animal models.


  1. Just curious -- did the authors control for potential confounders related to the use of ARBs/ACE inhibitors? Perhaps the ARB/ACE subjects' underlying condition(s) were responsible for the higher relapse rate. The abstract doesn't discuss this but maybe the paper does?

  2. Good point but statistically there was no higher relapse rate sothere isnt need to look for confounders.

  3. In Platten et al in Fig 6 1mg/kg per day was used with efficacy comparable to 10mg/kg. The response is robust. 1mg/kg is an acceptable human dose of lisinopril. I know a neuroimmunologist who takes a such a dose for mild hypertension. I see him in the mirror. The Doerner study is interesting, but the group win ARBs and ACE's may have had the confound of being 'at risk' due to their hypertension.

    Finally there is a lot of talk about 0.05 in the blog. Everyone ought to read the recent commentary in Nature about statistics. I doubt that Fisher meant to imply that 0.05 was a harsh boundary. C'mon folks, animal models point the way to human trials. A prospective human trial would answer the question. And trialists and mouse doctors often talk to each other, and sometimes they straddle both sides of the 'divide'.

    1. Good to see you hear Prof Steinman!

  4. Lies; dam lies and ststistics

  5. Side effects of ACE inhibitors are not good for MS patients; and Calcium Channel Blockers are dire (never prescribe them for MS patients). But, uncontrolled hypertension is too dangerous to ignore, so best to go with low doses of ACE inhibitors(from 2 to 2.5mg Lisinopril or Perindopril). As for the mice experiments.. how many times have we seen the failure of such tests to translate into anything helpful? (99.99%). Anyone with any experience of ACE inhibitors would understand that giving humans the same dose as was given to mice would cripple them with side effects or simply kill them. Multiple Sclerosis is not an immune system disorder per se (although researchers have conditioned themselves to believe this and have consequently wasted millions of pounds and years of valuable time; and continue to do so); it is a failure of the blood brain barrier to keep unwanted T cells out of the CNS; where such T cells will naturally attack myelin. Until researchers discover why the blood brain barrier is permeable in MS patients, we will never cure MS.


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