I was reading Dr. Cinque's blog this morning. He gave it over to the comments of a Dr. Uffe Ravnskov on the results of the recent SATURN trial:
Effect of Two Intensive Statin Regimens On Progression Of Coronary Disease (SATURN), New England Journal of Medicine, November 15, 2011
This trial pitted Lipitor against Crestor, both statins, both very high doses. It had no placebo arm. It gauged the effectiveness of these drugs by measuring changes in the cross-sectional area of an artery wall (a surrogate measure of atherosclerosis).
In the end, there was no difference between the two. The doses of Lipitor (80 mg) and Crestor (40 mg) used were found to be equally effective at "regressing atherosclerosis."
Dr. Ravnskov (who I know only from reading his Amazon entry) had some criticisms. Take statins? Not if you value your kidneys and liver, and not if you're loathe to slap down $ on a drug that has "an uncertain effect on a surrogate end-point, which may or may not mean anything." He has a point, many points in fact.
"A more detailed review of adverse events reveals that “new proteinuria”, defined as an excretion of more than twice the amount of protein in the urine during the follow-up, in 1.7 [Lipitor] and 3.8% [Crestor], respectively in the two groups. An increase in proteinuria is a measure of progressive damage to the kidneys. This trial only lasted two years, so we don´t know what would have happened in the longer term."Protein in the urine indicates kidney damage. What was happening to the kidneys of patients who were experiencing protein in urine twice that of normal? How many were? That wasn't even recorded! Healthy kidneys are adept at preventing protein from leaking into urine at all.
"Equally it was stated that less than two per cent had laboratory signs of liver damage. However, liver damage was only recorded if the laboratory signs were at least three times higher than the upper limit of the normal range."Table 4 shows the number of patients who experienced elevated liver enzymes at 3 times normal. Again you have to ask, what was happening to the livers of patients whose enzymes were up to 3 times normal? How many were there? No data.
"And whilst less than two per cent had muscular damage, this was only reported if the laboratory signs were at least five times higher than the upper limit of the normal value."5 times! What was happening to the muscles of patients whose lab values were up to 5 times normal (and even 10 times! as Table 4 shows)? You could assume there were a significant number of patients with abnormal values. It's entirely possible that 100% of patients experienced muscle abnormalities; you don't know. Choosing this high cut-off precluded the authors from having to address statins' effect on muscles.
Imagine if you had a placebo group and could compare kidney, liver, and muscle function of those not on statins to those on Lipitor and Crestor.
Regression Of Coronary Atherosclerosis?
The goal of this study was to measure regression of atherosclerosis, via a marker: the change in PAV (Percent Atheroma Volume), which I understood as the change in cross-sectional area of an artery wall. One coronary artery in each patient was measured twice, once at the start of the study and once after 104 weeks of treatment. There was a statistically significant reduction in PAV of less than 1% for Lipitor and 1.2% for Crestor. They had a secondary endpoint, TAV, which also showed a statistically significant reduction from baseline. (I originally said that these reductions were statistically insignificant. But in the Results section it does say that "P<0.001 for the change from baseline in each group." I was incorrectly looking at the between group P values in Table 3.)
Not only were these changes tiny, but whether they indicate regression of coronary atherosclerosis is debatable. Dr. Ravnskov says they may well have been explained by non-drug effects, such as "mental stress, anxiety, exposure to cold, and even a sustained handgrip." Bear in mind there were only two measurements two years apart, making it difficult to account for these non-drug effects.
"In short, the degree of arterial dilation is a massive and uncontrolled variable in the SATURN study. This problem could have been solved if the investigators had included a placebo group."The study also had a high drop-out rate (29%!), which Dr. Ravnskov attributed to patients' poor tolerance of the high-dose drugs. High drop-out rates reduce the internal validity of a study.
Can The Ability Of Statins To Stave Off Heart Attack Be Ascertained by Ultrasound?
The primary endpoint of the SATURN trial above, PAV (Percent Atheroma Volume) gained via ultrasound, has limited ability to determine plaque's risk. This editorial addresses that:
Seeking Alternatives to Hard End Points, Is Imaging the Best APPROACH?, Circulation, March 2010
Here's a slide from it, and the caption:
"Measures of total atheroma burden may not accurately estimate cardiovascular risk because they do not take into account coronary plaque morphology."The percentage of plaque is about the same in Figures A and C. However, the plaque in Figure C has less dead tissue (necrotic core), a thicker cap, less evident inflammation, and is considered more stable that the plaque in figure A. PAV alone does not tell you this.
As Dave noted in Comments, the authors of SATURN say as much:
"Yet intravascular ultrasonography remains a surrogate end point, and a reduction in plaque volume should not be interpreted as equivalent to a clinical benefit in terms of preventing cardiovascular events."
I try not to be too cynical but I was taken aback at the extent of these authors' conflicts of interest (AstraZeneca makes Crestor, Pfizer makes Lipitor). How in the world are we going to get at the heart of drug effectiveness when there's so much money to be made?
Dr. Nicholls reports receiving consulting fees from Roche, Esperion, Merck, Omthera, Sanofi-Aventis, and Boehringer Ingelheim, serving as an unpaid consultant for Abbott, Pfizer, LipoScience, Novo Nordisk, AtheroNova, and CSL Behring, receiving grant support from Eli Lilly, AstraZeneca, Novartis, Anthera, LipoScience, Roche, and Resverlogix and lecture fees from AstraZeneca and Roche;If my physician wanted to put me on a statin to reduce the chance of a heart attack, I may agree (assuming diet, exercise, adequate sleep, stress management, smoking cessation, etc. all failed to reduce my risk, however that risk was measured), but I would request a copy of my lab values and compare them to my values prior to taking the drug. Not saying statins are solely responsible for lab changes, but at least I'd be informed. Damaged kidneys, liver, and muscles may very well be an acceptable cost for lessening heart attack risk, as these authors said, "Both agents had acceptable side-effect profiles."
Dr. Ballantyne, receiving grant support from Abbott, Astra-Zeneca, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Kowa, Merck, Novartis, Roche, Sanofi-Synthelabo, and Takeda, consulting fees and honoraria from Abbott, Adnexus, Amarin, Amylin, AstraZeneca, Bristol-Myers Squibb, Esperion, Genentech, GlaxoSmithKline, Idera, Kowa, Merck, Novartis, Omthera, Resverlogix, Roche, Sanofi-Synthelabo, and Takeda and lecture fees from Abbott, AstraZeneca, GlaxoSmithKline, and Merck;
Dr. Barter, holding an advisory board position for AstraZeneca, Merck, Roche, CSL Behring, and Pfizer, receiving grant support from Merck, consulting fees from CSL Behring, and lecture fees from AstraZeneca, Kowa, Merck, Pfizer, and Roche;
Dr. Chapman, receiving grant support from Merck and Kowa, consulting fees from Merck and Pfizer, and lectures fees from Merck and Kowa;
Dr. Erbel, receiving grant support from the Heinz Nixdorf Foundation and the German Research Foundation and support for travel, accommodations, or meeting expenses from Biotronik, Sanofi, and Novartis;
Dr. Libby, serving as an unpaid consultant for Novartis, Johnson & Johnson, Amgen, and Roche, serving in unpaid leadership roles for clinical trials sponsored by AstraZeneca, GlaxoSmithKline, Novartis, Pfizer, Pronova, and Sigma Tau, and having previously received royalties from Roche for the patent on CD40L in cardiovascular risk stratification;
Dr. Raichlen, being an employee of and owning stock in AstraZeneca;
Dr. Nissen, receiving consulting fees from Eli Lilly, grant funding from AstraZeneca, Pfizer, Novartis, Karo Bio, Novo Nordisk, Takeda, Resverlogix, and Omthera, and support for travel, accommodations, or meeting expenses from Novo Nordisk, Takeda, Karo Bio, Eli Lilly, Pfizer, Novartis, and Amgen.