Last Thursday, Dutch researchers made a bold claim: that erythropoietin (EPO), a hemoglobin-boosting drug prominent in doping cases across a wide variety of sports, has no performance-enhancing effect.
“This review shows that only very weak scientific evidence exists about the effects of rHuEPO on cycling performance in professional or even well-trained cyclists,” Dr. Adam Cohen of Leiden and his team wrote in a paper to be published in the British Journal of Clinical Pharmacology.
The study has already gotten a lot of press, including from Outside magazine, and the authors are using the media attention to press their case. But backlash against the study has also already begun. Dr. Arne Ljungqvist, Vice President of the World Anti-Doping Agency (WADA) and a recent FasterSkier interview subject, has warned that the authors may be overselling their point.
“There is biological evidence that EPO in adequate doses increases the number of red blood cells and it is therefore crucial in endurance tests,” Ljungqvist told Eurosport.se. “There are parallels in the 80’s. There were no scientific studies that prove that anabolic steroids were performance enhancing. Today we know that it is so.”
So, can the study – available here, which has been accepted by the journal, but has yet to go through final edits and formatting – be trusted? FasterSkier dove in to see what the fuss was all about.
Framing the Question
As in any study, scientific or otherwise, one of the most important steps is at the very start: choosing a question to ask. In this case, the authors did not perform any new experimental research. Instead, they wrote a review pulling together all existing research, a technique that is incredibly useful to examine important issues at regular intervals. They wanted to know whether recombinant human EPO (rhEPO or rHuEPO) had a positive effect on performance of elite cyclists.
Just as important, however, is who is asking the question and how they choose to answer it. In this case, the researchers do not come from an exercise physiology background. Cohen, the leader of the project, lectures in clinical pharmacology at the University of Leiden and is also the CEO of the Centre for Human Drug Research. In another recent paper, Cohen described the organization as one that “provides consultancy and research to pharmaceutical industries.”
Before joining CHDR, Cohen worked in drug development at Wellcome, which has since been acquired by pharmaceutical giant GlaxoSmithKline. That conglomerate in turn entered into a licencing agreement in 2009 with Japanese company JCR Pharmaceuticals to gain global rights to market their erythropoietin products. (Cohen has no affiliation with either company at this time.)
Although Cohen has published several hundred papers, the last to focus on exercise appears to be from 1992, when he wrote about the anticoagulant Heparin, not apparently for a sports application but to assess its effect on regular patients when they exercised. He is joined on the current paper by an internist, a pulmonologist, a professor of translational pharmacology, and several pharmacology students.
Cohen is also the executive editor of the journal in which this paper is to be published.
The team approaches the issue of EPO from a pharmacological viewpoint: “Imagine a medicine that is expected to have very limited effects based upon knowledge of pharmacology and (patho)physiology,” the team writes in the very first sentence of the abstract. With that in mind, they set out to review whether performance-enhancing effects have ever actually been found in cyclists.
Tearing Down VO2Max
The team then reviewed both the biochemistry of EPO (worth a read) and the determinants of endurance performance: VO2Max, lactate threshold, and working economy.
In discussing VO2Max, the authors stated something that FasterSkier has tried to emphasize in previous coverage: that VO2Max is not the sole determinant of performance, and often factors such as efficiency can prevent an athlete with the highest VO2Max from actually becoming the best in the world at their given sport. They also noted that typically, mid-level athletes can improve their VO2Max at a much higher rate than elite athletes, who reach some sort of plateau.
They also point out that elite athletes, by training, increase their lactate threshold and experience physiological changes like metabolic adaptations in their muscles. Compared to the general population, these changes lead to increased performance. (Other factors used by the authors to explain why athletes can continue improving while maintaining the same VO2Max were accurate yet also comically simple: heart rate and breathing patterns.)
After this conclusion the authors state that VO2Max must not be an important factor in elite athletics, since all athletes are highly trained and keep improving once they reach their plateau. “This also demonstrates that in world-class athletes, an increase in VO2max will have only limited effect on performance,” they write.
This is a logical fallacy, and the studies they cite don’t actually address this question – they look in the opposite direction, showing that elite athletes perform higher than models would predict given their VO2Max, not whether increasing VO2Max actually leads to a performance benefit.
What the authors miss is that if the athletes have reached the highest VO2Max they can achieve given their genetics and personal physiology, then yes, they are at a plateau – but if a drug gave them the chance to overcome these natural limitations, why wouldn’t it help to have a higher VO2Max? This, of course, has not been studied, because research that involves actual doping by elite athletes is limited.
That lack of studies is purportedly exactly what the authors want to examine, but they have given their biases away in the run-up to their actual research. They found 13 studies examining cycling and EPO, and set about a systematic, qualitative review.
Immediately, the researchers ran into problems: none of the subjects in any of the studies could be considered competitive cyclists.
“It cannot be assumed that effects found in these rHuEPO studies on healthy untrained or trained individuals automatically apply to well-trained, elite and world-class cyclists,” they wrote.
There were other problems with the quality of the studies. For example, five of the 13 were not placebo-controlled – and as such, it would be impossible to determine how much of the result was due to EPO use, versus simply training. Of the studies that were placebo-controlled, only five were double-blind, which is the gold standard in clinical study design.
Nevertheless, the authors were able to draw some conclusions. Reticulocytes, the precursors of red blood cells, doubled with a low dose of EPO and tripled with a high dose. Hemoglobin increased roughly five to 15 percent in subjects using EPO, and hematocrit eight to 20 percent. (EPO also seemed to reduce plasma volume, which, as FasterSkier has reviewed before, affects these measurements.)
In the non-elite test subjects, VO2Max increased by seven to nine percent. Power output also increased, as did performance on a time-to-exhaustion test – by 20 to 50 percent in subjects using EPO.
The authors make very valid points about the studies performed to date: that results in untrained athletes can’t be applied to elite cyclists; that a time-to-exhaustion test is not the same as a five-hour stage of the Tour de France; that team tactics may lead to a up-and-down effort rather than a steady one.
They also point out that of the factors contributing to performance, only VO2Max could be directly effected by EPO. They postulate that the drug has little effect on lactate threshold, for instance, and also bring up the interesting point that increasing the oxygen carrying capacity of the blood may be of limited use if factors in the muscles can’t use it.
But they go on to cite things contrary to their own argument. For instance, the explain that power output is one of the most important determinants of cycling performance, but do not revisit the fact that power output had actually increased with EPO use. They also note that in one study, long-term use of EPO actually cause changes in skeletal muscle tissue which allowed cyclists to improve their efficiency.
These findings not only contradict the team’s assertion that EPO only affects VO2Max and therefore can’t lead to significant increases in performance, but also supports the tenet held by anti-doping organizations: that in-competition use of drugs is not the only danger, because out-of-competition use may allow better training. If used over the long term by elite cyclists, something like EPO could lead to improvements in efficiency and power output in addition to the direct, more immediate increase in VO2Max.
One of the most confusing aspects of the paper is the authors’ refusal to acknowledge that VO2Max may increase with EPO use. When they write, “it cannot be concluded that rHuEPO use enhances performance in professional or elite cyclists,” they aren’t wrong; the studies available to the scientific community today do not prove any such claim about either performance or VO2Max.
Importantly, however, the studies also do not show that EPO does not enhance performance or VO2Max. And if one was forced to make an extrapolation – which the team is loathe to do – it would certainly be easier to conclude that based on evidence in recreational athletes, the drug may enhance elite performance, rather than that it might not.
And yet that’s what the authors seize on, again and again.
“This review shows that only very weak scientific evidence exists about the effects of rHuEPO on cycling performance in professional or even well-trained cyclists,” they write later in the paper. “Neither a scientific basis for performance-enhancing properties, nor possible harmful side-effects have been provided for athletes or trainees.”
In the final pages of the paper, Cohen and his fellow authors go on to show a complete lack of understanding of the doping situation. The authors assert that athletes should be better educated about the adverse health risks of EPO; while that is certainly true, many stories from admitted dopers have shown that they were aware of and considered the health risks of EPO and other drugs, then took them anyway. If an athlete is willing to do something illegal and potentially career-ending to win, then shaking a finger and warning of shadowy health consequences is unlikely to be much of a deterrent.
They also advocate that team doctors be made aware of EPO’s lack of performance benefits and its adverse health consequences, asserting that this would keep doctors from giving it to athletes. This ignores both the history of state-sponsored doping in places like East Germany and the more recent depositions from the Lance Armstrong case and the recent case against Italian doctor Michele Ferrari which show that “team doctors” can in some cases be in on the cheating and don’t, necessarily, have the athlete’s long-term health in mind.
FasterSkier’s conclusion is that while the authors make a good point that no research currently exists on the effects of EPO on elite athletes, the message they leave for readers – that EPO therefore is not performance enhancing – is not supported by their own analysis and would be dangerous to put into practice. Removing EPO from the banned list based on such weak evidence, for example, would be frankly ridiculous.