Sunday, November 27, 2011

The Statin Wars: Lipitor Vs. Crestor

A tie. But I'd probably agonize over the decision to take either one of them.

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.

Kidney Damage
"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.

Liver Damage
"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.

Muscle Damage
"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;
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.
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."


Dave said...

I think you raise some good points. No control group? Then this wasn't a real world test, was it?

However, you failed to address this:

"In previous studies of patients who...took lower doses of statins, 15 percent to 20 percent suffered a heart attack or stroke or required angioplasty to open a clogged artery over two years of follow-up.

"The rate of such events among patients in this new study was less than half of that."

That would mean 7.5 percent to 10 percent of patients had a heart attack, stroke, etc.

Doesn't that seem like the higher doses of the drug worked?

I have another question. You say the amount of regression of plaque - about 1 percent - was insignificant.

I don't understand this. If plaque in the average human coronary artery grows at x percent, isn't reduction of any amount a good thing? If the typical pattern is increased growth of plaque, then why is any regression insignificant?

If, for example, plaque is growing in my arteries at 3 percent per year, shouldn't I be happy with a 1 percent reduction over two years?

Or does plaque not grow the way I think it does?


Dave said...

Actually, I can't find the passage about the percentage of reduction of cardiovascular events in the study, comparing those on normal and high doses of statin. I only see those numbers in news articles.

Additionally, there is this. from the study:

"a reduction in plaque volume should not be interpreted as equivalent to a clinical benefit in terms of preventing cardio- vascular events."

So the value of taking higher doses of Crestor and Lipitor doesn't seem to be as amazing as reported in news articles.

Bix said...

Hi Dave, You're right. The 0.99% was significant, from baseline. I was looking at Table 3 and incorrectly thought the P values were for from baseline, not between group. I'm going to correct it.

I mean significant in a statistical way. Significance to me occurs when P is something less than 0.05.

I still think that 1% is low for 2 years of therapy. Especially when I compare it to Dr. Ravnskov's example where "a handgrip sustained for a few minutes was followed by a 35% decrease of the vessel diameter." How did they account for these confounders?

Also, not everyone benefitted: "About one third of patients in our study had disease progression despite maximally intensive statin therapy."

Dr. Ravnskov says about PAV, the primary endpoint in this study: "The critical measure was the difference between the inner and outer area of the artery. Unfortunately, there is no evidence that the figure from this calculation reflects atheroma volume. For example, vascular dilation will increase the inner diameter, without having any effect on the thickness of the arterial wall. But this would result in an apparent decrease in atheroma volume."

(I don't know the design of this former study you note. I was just looking at SATURN.)

Bix said...

While I have the study in hand, I want to say one more thing...

I said that a high drop-out rate reduces the internal validity of a study. The authors note this:

"Patients who did not complete the trial may have had rates of progression that were different from those among patients who completed the trial."

Say your drop-outs had progression of their plaque, instead of regression. If you factored them into your final number, it would have showed less overall benefit (something even lower than 0.99%) This is why I think it's important to note a study's drop-out rate.

Dave said...

"(I don't know the design of this former study you note. I was just looking at SATURN.)"

I was referring to the quote in a news article about this study that said the rate of heart attacks, strokes, and angioplasty was cut in half by those participants who were on the higher doses of statins, compared to people who have been on lower doses of statins.

This is such a confusing topic, at least for someone like me, with minimal scientific training in this field.

I note the people in the SATURN study all had elevated LDL, and high triglyceride levels, and prior issues with their hearts.

I have had a heart attack. However, my LDL level off of statins is normal - 128 - and my triglyceride level is super low (my HDL level is high normal). I know this because I recently stopped taking my statin to get my baseline numbers.

Were my numbers better when I was taking a statin? Yes, they were, at least the LDL level, which was down to about 80, while I was taking 40mg of Simvastatin. When my cardiologist bumped me up to 80mg, I started having muscle pain (and about the same time, the FDA directive about Simvastatin came out).

I'm about to have another blood test, so I can see if the 80mg of Lipitor I'm now taking will get my LDL level down below 70, which my cardiologist tells me I should be aiming for.

However, because I don't have the baseline numbers of the people in the SATURN study, I don't have any confidence that taking a statin is going to help me.

What I'd like to see is a study of people with absolutely normal cholesterol levels, including those who have never had a heart attack, who take statins. Because plenty of people who don't have high cholesterol numbers have heart attacks, anyway.

And I'd like to see a study of those people who have had a heart attack who have normal cholesterol levels - like me - to see if statins keep a second heart attack at bay.

All we ever get, though, are studies of people who have abnormal cholesterol readings to begin with. They are a minority of humans. And as you've pointed out, the conclusions about the benefits of statins, even to people with heart disease, are suspect.

Anyway, thanks for helping me interpret the SATURN study. I appreciate your efforts.

Dr. Mel said...

I keep thinking back to a few years ago when the editor-in--chief of--it was either NEJM or JAMA, can't remember which--at any rate he said he no longer trusts ANY peer-reviewed, published research b/c of the undue influence of lobbyists.

Bix said...

I blogged about that in 2009. It was Dr. Marcia Angell, the former editor-in-chief of The New England Journal of Medicine, who said:

"It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor of The New England Journal of Medicine."

I think I'm going to repost it:
Corrupted Research

Shreela said...

Less than a year after hubby started his most recent job (5'ish yrs ago), I made us both appointments for a general checkup, since neither of us had been to a dr in quite a few years, and we were starting to "get up there" in age (late 40s, mid 50s).

The dr ordered cholesterol, diabetes, testosterone and other age-appropriate tests for my hubby, but gave him a script for some kind of statin, BEFORE the labs had even been sent out!

During our follow up, I asked the dr why he ordered the statin without having lab results first, and he answered: "it was based on your husband's age"! I replied that I wasn't letting my husband take statins unless they were very much needed! Were they needed?

Obviously not, or else hopefully the dr would have argued for the statin.

I guess I haven't hit the magic age when statin scripts are handed out without labs. We're still waiting on my husband's recent labs in the mail (mine came last week, and they were drawn on the same day).

Bix said...

Shreela, you have the best stories. So, technically, older age is a risk factor for heart disease (women's risk goes up after menopause), but so is being human! I'd want to hear a few more justifications too. You're so detail-oriented; your husband is fortunate to have you as his consultant.