Editor’s note: The following is the second in a two-part series in which sports medicine physician Michael Puchowicz disputes claims made by Dr. Michele Ferrari in January that Lance Armstrong would have seen comparable benefits from altitude training without the use of EPO and other performance enhancing drugs. In part 1, Dr. Puchowicz detailed literature that disputed Ferrari’s claims that altitude training could produce five-to-10-percent gains in hemoglobin mass. Today, he details Ferrari’s claims regarding PED use.

When Dr. Michele Ferrari made the claim that Lance Armstrong could have won all seven of his Tour de France titles without doping, he based his argument on the assertion that altitude would produce an increase in hemoglobin (Hgb) mass on the order of five-to-10 percent, and that the effect of Armstrong’s doping would not exceed this same magnitude. In part 1 of this analysis, a closer look at the literature revealed that Ferrari misrepresented the data he cited. Rather than five-to-10-percent improvements, the data realistically suggests that at time points relevant to grand tour performance, the elevation in Hgb mass would be about one-to-five percent.

Part 2 of this analysis considers whether Dr Ferrari’s statements on the effect of doping are misleading as well.

Please note that the actual values for EPO dosages have been replaced with the qualitative terms “Sub Micro Dose,” “Micro Dose,” and “Standard Dose” so that this article does not provide specific dosing information. For the same reason, we have removed the author and title information for one source used in this analysis.

Ferrari stated that “EPO and auto-transfusions, always in the manner reported by teammates (micro-doses of EPO and one-to-two units of blood) correspond to an increase of (Hgb) mass by five-to-10 percent for an endurance athlete weighing 75kg, who has nine-to-10 liters of blood.” He did not cite any studies to support this side of his argument. Presumably, the doctor banned from the sport due to doping violations relied on his own expert opinion.

Regardless, if we take Armstrong’s admission that he used EPO, “but just a little,” at face value, then data suggest his EPO “micro-dose” regimen would likely increase his Hgb mass by about 10 percent (Ashenden 2011a). So, on EPO alone, the increase from doping is already at the high end of Ferrari’s five-to-10-percent range. As such, the EPO effect is well above the one-to-five-percent increase that would be expected from altitude. More importantly, the EPO effect could be sustained for the full three weeks of a grand tour. Also, an additional 3.8-percent increase per blood bag (see notes below) would be expected from blood transfusions. Together, the total doping effect would be a sustained 10-percent increase with as much as an 18-percent increase in Hgb mass for key stages of the Tour de France.

To visualize the difference between the effect of altitude and doping, we added simulated EPO and blood doping data (squares) to the altitude figure from Part 1. Although, some of the altitude data points (circles) taken at or immediately after altitude may be close, the gap quickly widens at time points relevant to a grand tour. For key stages, adding blood transfusions on top of EPO could reasonably produce an effect that would be more than three times the effect of altitude training.

When questioned about the discrepancy, Ferrari replied, “Regarding the study of Ashenden (2011a), the ‘micro-doses’ of EPO administered for a period of 12 weeks ranged from (‘Micro Dose’ to ‘Standard Dose’). Even the lowest dose is detectable in urine up to 16 hours after IV administration (#### 1990, fig X). Therefore, these ‘micro-doses’ can not be used by cyclists, who as we know can be tested from 6:00 a.m. to 11:00 p.m.”

To visualize Ferrari’s point, we created this representation of figure X from #### (1990). The actual data was intentionally not used as it would be useful to would-be dopers.

In our figure, three different IV doses of EPO are represented. The level of EPO “detectable” in the serum is then plotted out over time. The blue arrow is inserted to show the earliest time that an anti-doping EPO test could be conducted. As Dr Ferrari pointed out, even with the micro-dose regimen, EPO would still be “detectable” at this time.

However, Ferrari’s rebuttal is, to put it kindly, flawed. The most obvious issue is a complete disregard for the timeframe of events. Armstrong’s first Tour de France wins in came in 1999 and 2000. The EPO test was introduced in 2001. For at least these two years there was simply no EPO test in place. Therefore, arguing what might or might not be detectable is completely irrelevant for these years. Armstrong was free to use any EPO dose necessary. The retrospectively tested samples from 1999 confirm that Armstrong did just that. His samples were not “just a little” positive for EPO, but “flaming positive, the highest we’ve ever seen,” according to U.S. Anti-Doping Agency CEO Travis Tygart in his 60 Minutes interview.

The window of detection that Ferrari focused on is not a concern at all until 2001 and only truly relevant when out-of-competition testing was later put in place in 2004.

The second major issue is Ferrari’s chain of logic. He implies that theoretically “detectable” equals positive test result and therefore theoretically “detectable” also equals “cannot be used by cyclists.”

To illustrate this flaw in Ferrari’s statement, we added a dashed line to represent the level of EPO necessary to trigger a positive test. The purpose is to illustrate that although the “Micro Dose” may result in a “detectable” level of EPO at the time of the anti-doping test it would not necessarily be high enough to trigger a positive result.

This concept proves to be true in Armstrong’s own anti-doping tests. Armstrong produced a sample with detectable levels of EPO at the 2001 Tour of Switzerland after the EPO test had been put in place. While the sample was judged to be “suspect” according to Martial Saugy, the director of the Lausanne laboratory, he also pointed out to the AFP that, “there was no positive test on the Tour of Switzerland in 2001.”

Similarly, according to Saugy, “Armstrong had another suspect result during the 2002 Dauphiné Libéré.” Armstrong’s own results show that the introduction of the EPO test did not stop him from continuing to use detectable doses of EPO, nor did the “detectable” levels of EPO result in positive tests.

Just like he did in the altitude discussion, Ferrari began his doping-related argument with legitimate science. But to fit the “Armstrong could have won clean” narrative, Ferrari stretched the implications of the data well beyond any reasonable conclusion.

Continuing this pattern, Ferrari suggested that from 1999-2005 Armstrong never used doses high enough to produce any benefit beyond a placebo effect. “In fact, the natural production of EPO at sea level is about ‘Sub Micro Dose’ (Klausen 1992): therefore a natural production of EPO of approximately ‘Sub Micro Dose’ keeps Hgb mass constant. As a consequence, there is a no ‘micro-dose’ that is effective on Hgb mass which is not detectable within a period of seven-to-eight hours after administration, also via IV.” Again, Dr Ferrari begins on solid ground but ends up some place far removed from reality.

Armstrong doped, he doped well, and no amount of scientific sleight of hand will change that. During this period, a large number of riders in the peloton used EPO. The doses used were not at all insignificant. Armstrong himself stated that anyone on the podium would fall into this doping group.

In an email, former Armstrong teammate and current Garmin-Sharp boss Jonathan Vaughters was kind enough lay out in detail the doping practices of the time:

For post 50-percent rule, the standard [dose] … gets a guy from 39 percent to 48 percent in four weeks or so and will stabilize it there in a three-week [grand tour].

Now, once the EPO test came into play, initially, the dosage… didn’t change, just the method, from subcutaneous to IV. In a 70kg rider, [this dose] will clear in 24 hours. So, take the shot straight after the stage, it’s out by the time you could get tested the next day.

Once OOC [out-of-competition] testing was introduced and they could come anytime other than between 10:00 p.m. and 7 a.m., a quicker clearance was needed, hence the ‘Micro Dose’ intravenous method.

A quick calculation confirms that the EPO dosing described for the Armstrong era was equal to or greater than the dosing in the Ashenden (2011a) study. Therefore, a 10-percent increase in Hgb mass derived from the Ashenden (2011a) study stands as a safe estimate for the effect of EPO.

In a final attempt to redirect Ferrari in a meaningful debate, I asked directly, “Are you confident that Armstrong never used doses of EPO greater than or equal to ‘Micro Dose’?”

He replied, “I can not exclude it with certainty, but ‘Micro Dose’ is detectable in the urine and blood for more than 10 hours; therefore, I think it unlikely that Armstrong made use of it.”

This statement leaves no room for credibility. When we shared these comments with Vaughters, he responded: “Ferrari is the one who invented the [micro-dose] system!!! … That’s funny.”

Less funny is the depth of cynicism revealed by revisiting Ferrari’s rebuttal in the context of his having developed the micro-dose IV regimen. His argument is built on data contained in #### (1990) figure X, which is now over 20 years old. The age of the data is notable because it precedes the introduction of any test for EPO. The design of the study is also notable because, unlike later studies, which shifted focus to higher subcutaneous doses, it looked at relatively small IV doses. In fact, at the time the EPO test was introduced, this study would have been the go-to article for anyone interested in finding a faster way to get EPO to clear the system. Turning to figure X (#### 1990) would have been like turning to a perfect roadmap to beat the EPO test. Map in hand, designing the micro-dose IV regimen would have been no harder than checking figure X and lifting the IV micro-dose straight from the paper. It’s almost as though his rebuttal above was intended to be an inside joke made at the expense of anyone who didn’t catch his meaning.

Maybe in all of this discussion, the most relevant question asked was not about the science itself, but about Ferrari’s opinion. I put to him whether he had the same opinion, that the altitude was as effective as EPO/blood doping, back in 1999-2005. Unfortunately, this is a question Ferrari declined to answer. Although, in the context of his other replies, maybe his non-answer was about as honest as he could get.

For the sake of thoroughness and closure for the fans of the sport, one final way to address the question at hand is to look as directly as possible at the effect of doping on Armstrong’s blood data. Because only biological passport data from 2008-2009 onward is available, an assumption has to be made that Armstrong’s level of doping in 2009 would have been less than from 1999-2005, though Armstrong maintains he did not cheat during his 2009-2010 comeback.

Similarly, because the bio passport does not contain direct measurements of Hgb mass, increases in Hgb mass have to be inferred from suppressions of the reticulocyte count. With these assumptions made, the data points from June 16, 2009 through the end of the Tour de France stand out.

It is clearly visible here that the reticulocyte count during this period is consistently suppressed, indicating a sustained increase in Hgb mass. In USADA’s reasoned decision, it concluded that “the approximate likelihood of Armstrong’s seven suppressed reticulocyte values during the 2009 and 2010 Tours de France occurring naturally was less than one in a million.” If we rephrased this statement in terms of altitude and doping, it would read: “The approximate likelihood that the effect of Armstrong’s 2009 doping could have been equaled by altitude training is less than one in a million.” So, Armstrong’s own blood data suggests that there was no way that altitude could produce the same magnitude of effect seen with even his 2009 doping, let alone his 1999-2005 doping.

To summarize, a realistic look at the scientific data allows a reasonable estimation that Hgb mass would be increased by 10-18 percent from the combination of EPO and blood transfusions used by Lance Armstrong. Even well-timed altitude training is unlikely to produce a sustained effect greater than five percent. Based on the literature reviewed, Dr. Michele Ferrari’s claim that Armstrong could have won all seven of his Tour de France titles clean is not credible.

Michael Puchowicz is a former lab rat turned sports medicine physician. After the last two years of laying waste to grammar, farce, and pretense in the shadowy world of anonymous cycling blogs and Twitter rants, he’s finally caved and gone legit. Please don’t mistake his views for those of his employer, his friends, or anyone else linked by real or perceived affiliations through the medical and science communities. To do so, would surely end his uncompromising pursuit of all things true and glorious in cycling.

Author’s note: To calculate the effect of blood doping, we can use Dr. Ferrari’s estimated nine-too-10 liters of blood volume and Armstrong’s average Hgb gm/dL of 14.5. 145 gm/L x 9.5 L = 1377 gm of Hgb. One 0.5L blood bag withdrawn at 14.5 gm/dL would contain 72.5 gm of Hgb. Transfusing a fresh, stored bag with a yield of 72 percent (Ashenden 2011) would increase Hgb mass by 52.2 gm or 3.8 percent per bag.

Works cited
#### 1990 [Title, author withheld]

a Ashenden M, Gough CE, Garnham A, Gore CJ, Sharpe K. Current markers of the Athlete Blood Passport do not flag microdose EPO doping. European Journal of Applied Physiology. 2011 Sep;111(9):2307-14.

Ashenden M, Mørkeberg J. Net haemoglobin increase from reinfusion of refrigerated vs. frozen red blood cells after autologous blood transfusions. Vox Sang. 2011 Nov;101(4):320-6.

Berglund B. High-altitude training. Aspects of haematological adaptation. Sports Medicine. 1992 Nov;14(5):289-303. Review.

Chapman RF, Stray-Gundersen J, Levine BD. Individual variation in response to altitude training. Journal of Applied Physiology. 1998 Oct;85(4):1448-56.

Clark SA, Quod MJ, Clark MA, Martin DT, Saunders PU, Gore CJ. Time course of haemoglobin mass during 21 days live high:train low simulated altitude. European Journal of Applied Physiology. 2009 Jun;106(3):399-406.

Friedmann B, Frese F, Menold E, Kauper F, Jost J, Bärtsch P. Individual variation in the erythropoietic response to altitude training in elite junior swimmers. British Journal of Sports Medicine. 2005 Mar;39(3):148-53.

Garvican L, Martin D, Quod M, Stephens B, Sassi A, Gore C. Time course of the hemoglobin mass response to natural altitude training in elite endurance cyclists. Scandinavian Journal of Medicine and Science in Sports. 2012 Feb;22(1):95-103.

Gore CJ, Hahn A, Rice A, Bourdon P, Lawrence S, Walsh C, Stanef T, Barnes P, Parisotto R, Martin D, Pyne D. Altitude training at 2690m does not increase total haemoglobin mass or sea level VO2max in world champion track cyclists. Journal of Science and Medicine in Sport. 1998 Sep;1(3):156-70.

Gough CE, Saunders PU, Fowlie J, Savage B, Pyne DB, Anson JM, Wachsmuth N, Prommer N, Gore CJ. Influence of altitude training modality on performance and total haemoglobin mass in elite swimmers. European Journal of Applied Physiology. 2012 Sep;112(9):3275-85.

Heinicke K, Heinicke I, Schmidt W, Wolfarth B. A three-week traditional altitude training increases hemoglobin mass and red cell volume in elite biathlon athletes. International Journal of Sports Medicine. 2005 Jun;26(5):350-5.

Klausen T, Ghisler U, Mohr T, Fogh-Andersen N, Erythropoietin, 2,3 diphosphoglycerate and plasma volume during moderate-altitude training. Scandinavian Journal of Medicine and Science in Sports. 1992; 2:16-20.

Pottgiesser T, Garvican LA, Martin DT, Featonby JM, Gore CJ, Schumacher YO. Short-term hematological effects upon completion of a four-week simulated altitude camp. International Journal of Sports Physiology and Performance. 2012 Mar;7(1):79-83

Rice L, Ruiz W, Driscoll T, Whitley CE, Tapia R, Hachey DL, Gonzales GF, Alfrey CP. Neocytolysis on descent from altitude: a newly recognized mechanism for the control of red cell mass. Annals of Internal Medicine. 2001 Apr 17;134(8):652-6.

a Robertson EY, Saunders PU, Pyne DB, Aughey RJ, Anson JM, Gore CJ. Reproducibility of performance changes to simulated live high/train low altitude. Medical Science of Sports and Exercise. 2010 Feb;42(2):394-401.

b Robertson EY, Saunders PU, Pyne DB, Gore CJ, Anson JM. Effectiveness of intermittent training in hypoxia combined with live high/train low. European Journal of Applied Physiology. 2010 Sep;110(2):379-87.

c Robertson EY, Aughey RJ, Anson JM, Hopkins WG, Pyne DB. Effects of simulated and real altitude exposure in elite swimmers. Journal of Strength and Conditioning Research. 2010 Feb;24(2):487-93.

Saunders PU, Ahlgrim C, Vallance B, Green DJ, Robertson EY, Clark SA, Schumacher YO, Gore CJ. An attempt to quantify the placebo effect from a three-week simulated altitude training camp in elite race walkers. International Journal of Sports Physiology and Performance. 2010 Dec;5(4):521-34.

Wachsmuth NB, Völzke C, Prommer N, Schmidt-Trucksäss A, Frese F, Spahl O, Eastwood A, Stray-Gundersen J, Schmidt W. The effects of classic altitude training on hemoglobin mass in swimmers. European Journal of Applied Physiology. 2012 Nov 9

Wehrlin JP, Zuest P, Hallén J, Marti B. Live high-train low for 24 days increases hemoglobin mass and red cell volume in elite endurance athletes. Journal of Applied Physiology. 2006 Jun;100(6):1938-45.