13 мин.

The Sharapova drug story: What’s the evidence? Part 2

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David Nunan, Senior Research Fellow

In my previous blog I looked at the evidence for the use of Mildronate/Meldonium to *treat* a 17-year-old female with abnormal ECG, indicators for diabetes and magnesium deficiency. The evidence didn’t stack up well.

Here I consider the evidence for Meldonium/Mildronate for enhancing performance. However, my investigations have led me to conclude there’s an important discussion to be had around the processes WADA uses for determining what substances make it on to the Prohibited List; ‘Part 3’ to follow.

Why was Meldonium banned?

WADA initially stated that Meldonium was placed on its banned substances list “because of its use by athletes with the intention of enhancing performance” (there’s an important and much-needed debate around the evidence of athletes’ “intentions” but that can wait). More importantly, this reason does not fit entirely with WADA’s own criteria for banning a substance.

Before its ban on January 1, 2016, Meldonium was previously on WADA’s list of drugs to be monitored. Like others, I’m sure, I have learnt that WADA’s website is frustratingly obscure and as a result I’ve been unable to obtain full details of the methods and results of this monitoring period (I feel an FOI coming!).

Thankfully the Sports Integrity Initiative have produced a nice schematic that summarises the processes (and evidence) behind Meldonium being placed on the Prohibited List:

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Source: https://photobooth.cdn.sports.ru/preset/post/e/a0/ebff1021d4292b6439b6df0ee65f9.jpeg

So it appears WADA’s review of the literature found evidence of a mechanistic action linking an improved supply of oxygen to [skeletal – this distinction is important] muscle that in turn COULD lead to improved endurance properties and physical work capabilities. Investigations also revealed a high number of positive tests in elite athletes. WADA therefore concluded that two of the three criteria for banning a substance had been met, namely “potential to enhance or enhances sport performance” and “violates the spirit of sport”. Let’s leave aside the latter and focus here on the “evidence” for the former.

Does Meldonium enhance performance?

In conversations I’ve had with colleagues, some have argued “So what? Why does the evidence matter? If an athlete is taking something because they think it’s performance-enhancing then that’s cheating. So it (the “something”) should be banned and the athlete penalised”.

Ok. On that notion then, if an athlete is convinced that by eating Smarties their performance will be enhanced then Smarties should be placed on the List and the athlete appropriately sanctioned. It’s a silly example but one that highlights the importance of additional evidence beyond just the athlete’s intentions for use.

In fact, WADA have acknowledged this in refusing to add thyroid medication to the List due to no conclusive proof thyroid hormones can enhance performance and the (non-medical) use of thyroid drugs is not harmful to health (more on this later).

On this basis the evidence that WADA have found should provide “conclusive proof” Meldonium enhances performance.

The WADA “review”?

Numerous blogs and articles highlight some of the purported performance-enhancing effects of Mildronate (very little research refers to Meldonium) including this one in the Telegraph: “WADA’s monitoring of the drug found that some of its medical benefits include enhanced athletic performance (especially in endurance athletes). Other benefits include increased endurance and aerobic capabilities of athletes and increased recovery rate.”

One publication in particular is consistently cited as the source of evidence that Meldonium is performance enhancing (some seem to think it is the WADA literature review, others think it is more than one study). In actual fact it is the same spectrometry accuracy study already discussed. In their introduction, the authors cite other studies as would be expected of any IMRAD paper. However, there is no “review”, systematic or otherwise, of the literature nor any appraisal of the studies cited.

On closer inspection, the authors state in their introduction that “Under sport-physiological aspects, reports on positive effects on the physical working capacity of elite athletes were published and dosages of Mildronate (per os between 0.25 and 1.0 g twice a day over 2–3 weeks during the training period and 10–14 days before competition) were discussed”. Apart from not making much sense no references are provided.

They then provide two sentences for the evidence of a performance enhancing effect, adding “Further studies demonstrate an increase in endurance performance athletes, improved rehabilitation after exercise, protection against stress, and enhanced activations of central nervous system [CNS] functions.” Here, two references are given. The final evidence of a performance-enhancing effect is that “Mildronate shows mood-improving effects as well as an increased learning and memory performance, which are properties athletes may also benefit from.” Three references for these effects are provided.

Let’s look at each of these more closely.

The 5 “studies”

The first study (no indication of design i.e. RCT, controlled trial, before-after study) reports on the effects of Mildronate in Russian Judokas published in the journal Annals of Biomedical Research and Education [Georgia]. No results are presented and there’s no mention of the quality/validity of the data. Perhaps like me the authors were unable to find the article online. Or maybe they also cannot read Russian?

The second is a 2012 conference abstract co-authored by the drug’s inventor, Ivars Kalvins. A quick search of PubMed and Google Scholar suggests it has never been published in a peer-reviewed journal.

The abstract states the aim was “to review literature data about recent studies on Mildronate especially in fields associated with physical work capabilities and sport. Abstract limitations make it tricky to review methods and quality, but it appears a search of PubMed found 158 reports on Mildronate, 25 of which related to effects on physical capabilities; there’s no distinction between animal or human studies.

Additionally it states inclusion of six review articles not cited in PubMed but gives no indication of how these were identified. Half the results section describes the biochemical and pharmacological effects of Mildronate before two studies both authored by Kalvins (or Kalvinsh, he uses both interchangeably) are cited as evidence “Mildronate prepares cellular metabolism and membrane structures to survive the ischemic stress conditions”.

One of the two cited studies is a detailed narrative review of 99 selected studies on the pharmacological and mechanisms of action of Mildronate published in 2006 in Pharmacologyonline. It’s quite a read – no really! Covering no less than 9 pathological conditions (infectious and non-infectious including most cardiovascular diseases, diabetes and pulmonary disorders), for all of which Mildronate has a “benevolent” effect. And no harms. Not one!

The authors go to great detail to extol the benefits of Mildronate and point to a selection of their own, or colleagues’, research as evidence of this. However, they present NO actual data, unless “good results”, “effective”, and “improved” count.

This is a wonder drug. I cannot understand why it’s not approved for use in Europe, North America or any other major western country. You don’t have to have been in this game long or perhaps at all to see there might be a problem here.

Studies cited used animal models including guinea-pigs (1%), rabbits (2%), dogs (3%), “animals” [unspecified] (3%) and rats (20%); ~20% of citations are authored by the review authors; 0% of cited studies are RCTs, ~32% appear to be additional narrative reviews or editorials/essays; only 12% involve human clinical trials.

“Nowhere in any of what I have seen or read is there anything about assessing bias and the quality of the evidence and how this underpins decision-making. I wonder if WADA have ever heard of GRADE?”

In relation specifically to these clinical studies, all 12 cited are in patients with cardiovascular disease. Collectively the authors state these “trials” show:

“mildronate produced a positive effect on the hemodynamics and gaseous composition of the blood”;

“patients also showed normalization of the nitrogen metabolism and activity of the membrane-bound erythrocytic enzymes.”;

“monotherapy with mildronate is accompanied by an antianginal effect and an increase of the physical work capacity of [angina] patients.”;

“antiarrhythmic action of Mildronate and its] the ability to prevent ventricular extrasystoles, to reduce asthenia, to enhance physical performance and adaptive reactions.”;

“Improvement of coronary circulation in patients with atherosclerotic lesions of heart blood vessels were reported in several clinical trials”

“Mildronate manifested marked anti-ischemic effect in patients with postinfarction left ventricular dysfunction”

[In patients with chronic hypoxemia] “Mildronate was shown to improve the parameters of the acid-base state and gases in blood of examinees.”;

“Mildronate treatment improves the oxygen circulation parameters in erythrocytes of patients with heart failure.”;

“It decreases the level of methemoglobin in the patients’ blood and improves the phosphate balance, especially that of 2,3-diphosphoglycerate to control oxygen transport by hemoglobin, which is of paramount importance in hypoxia caused by coronary heart disease”

“Daily mildronate administration (1 g/day) improves quality of life of patients with chronic heart failure”

“Recent clinical trials performed in Russia [29], Ukraine [30] and Georgia [31] confirm efficiency of Mildronate in treatment of chronic heart failure and angina pectoris.” [sic]

No data is presented. Again all cited studies are in Russian or Ukranian, so no critical appraisal I’m afraid. But taking it on face value, Mildronate would appear to have positive anti-ischaemic and anti-arrhythmic effects in patients with select cardiovascular disease(s). Only two of the claimed benefits (3rd, 4th) relate to physical work capacity or performance.

What about the other 3 studies cited in the WADA paper in relation to mood-enhancing effects? Well the first is the same “99 studies” review already mentioned. Within this there is reference to one Russian narrative paper apparently showing “mood improving effects in patients: they become more active, motor dysfunction decreases, asthenia, dizziness and nausea are less pronounced”.

The second is a laboratory-based study in mice looking at the role of the glycoprotein “NCAM” in central and peripheral nervous system and cellular function and synaptic plasticity. This looks to be evidence of NCAM’s potential role in the development of areas of the brain responsible for learning and memory.

It’s cited in relation to a third study – another narrative review authored by the inventor of Mildronate including 82 studies, a large proportion of which are co-authored by the authors of the review, 1 of which relates to Mildronate’s effects on NCAM in rat models. This 1 study showed “that Mildronate per se did not influence NCAM expression in the striatum, while in the substantia nigra at a dose of 20 mg/kg, it caused a statistically significant increase in NCAM expression as compared with control (12±2 vs. 7±2 cells/mm2, P=0.049)”. The review was funded by Grindex, the manufacturer of Mildronate.

So these 5 papers would appear to represent the key evidence the WADA List Expert Panel group and Executive Committee have judged to provide “conclusive proof” for the performance-enhancing effects of Meldonium.

Interestingly, and again telling of their methods, the WADA paper did not cite the study on the manufacturers’ website that I previously reviewed claiming a 55 second (no confidence intervals I’m afraid) improvement in cycle ergometry exercise time in patients with stable angina and randomised to Mildronate.

Hang-on: big breath in! A study assessing the validity of a new mass spectrometry test citing in its introduction five studies, three of which are authored by the inventor of Mildronate, including a conference-abstract that cites four studies, of which three of these are authored by the inventor of Mildronate, one of these being a narrative review of 99 studies, of which 22 of these 99 studies are authored by the inventor of Mildronate, 29 are in animal models, only in 12 is it clear humans were included, none of which were in healthy adults, let alone athletes, and all showing the drug to have a positive effect across 9 different pathological conditions (including infectious and non-infectious disease), is WADA’s evidence that Mildronate enhances performance?

Mmmm. They set the bar high then. I’m sure I’ve heard somewhere that trials from drug manufacturers are overly positive in favour of their products. If only I could find evidence of this.

Nowhere in any of what I have seen or read is there anything about assessing bias and the quality of the evidence and how this underpins decision-making. I wonder if WADA have ever heard of GRADE? I see only high risk of bias both in the evidence cited and in the way WADA obtains and evaluates scientific evidence to underpin recommendations for inclusion on its prohibited list.

This is evidenced by looking back at WADA’s decision not to ban Thyroid Hormone based on “no conclusive proof thyroid hormones can enhance performance”. A quick scan of PubMed and you come across numerous studies (like this, this, and this) that show a “potential” – and this is enough according to the WADA Code – performance-enhancing effect including glucose metabolism, fat loss and improved recovery. The level and quality of this evidence would appear at least on a par with that for Meldonium.

Also, whilst clearly not extensive and the quality may be suspect, there may be harm with taking Thyroid hormone as evidenced here, here, here, and incredibly by Muhammad Ali back in 1981 here.

The majority of athletes that are taking Thyroid hormone most likely do so in the belief that it improves performance and not for medical reasons – around 2%-5% of the UK and U.S. population have hypothyroidism. Of interest is that some 9% of runners coached by Alberto Salazar have been diagnosed with hyperthyroidism; the diagnosis often coming from “alternative” endocrinologists known to use more liberal thresholds.

“I’m sure I’ve heard somewhere that trials from drug manufacturers are overly positive in favour of their products. If only I could find evidence of this.”

I make that 3/3 of WADA’s criteria being met (at least as well met as for Meldonium). So why is Thyroid hormone not banned?

Ascertaining the prevalence of Thyroid hormone is difficult as athletes are not required to report nor are they tested for its use. However, U.S. and UK doping agencies believe it is a big problem with their own athletes hence their call for a ban.

But it’s interesting that for two drugs which on the face of it appear to have similar “evidence” to support a ban, the one that is banned happens to be implicated in athletes predominantly competing for what would traditionally be called “Eastern bloc” countries, where as the one implicated largely in athletes competing for “Western” countries is not.

“In summary, your honour…”

Based on the information presented here I see very weak evidence for a performance-enhancing effect in athletes taking Meldonium/Mildronate.

Comically it would appear the manufacturer, and inventor of the drug, share this view, going directly against their own “research findings” when posting on it’s website on March 9th:

“Meldonium is a cytoprotective substance, which is used to prevent death of ischemic cells, and not increase performance of normal cells. It means Meldonium cannot improve athletic performance, but it can stop tissue damage in case of ischemia. That is why this therapeutic drug is not a doping agent.”

I’m all for clean sport, although I think it’s an unachievable goal. But I’m even more for good evidence-based practice. WADA claims it’s decisions for placing a substance on its prohibited list are evidence-based. What’s become more apparent is their definition of what counts as “evidenced-based” differs to mine and also apparently for different substances.

http://www.cebm.net/sharapova-drug-story-whats-evidence-part-2-2/

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