The Crestor Study Tells Us…? Mark Zucker Explains
12 CommentsBy Ed Silverman // November 10th, 2008 // 4:53 pm
The hoopla over the Jupiter study, which measured levels of a protein called CRP that can indicate arteries are inflamed and point toward heart disease, is prompting debate over a number of points - the extent to which CRP should be used as a guidepost for treating cholsterol, the wisdom in prescribing AstraZeneca’s Crestor and other statins to people with low cholesterol, and the study results themselves. An online survey run by The New England Journal of Medicine, so far, shows that 52 percent of respondents say the results will not likely have a significant impact on prescribing, 26 percent say it will likely have a significant impact, and 22 percent appear uncertain, according to Sanford Bernstein analyst Tim Anderson. We chatted with Mark Zucker, a heart treatment specialist at the St. Barnabas Health Care System and president of the American College of Cardiology’s New Jersey chapter, for some perspective. This is an excerpt…
Pharmalot: What did the study tell you?
Zucker: It’s not unknown in the medical community that statins decrease inflammation. Therefore, the idea that statins might lower CRP isn’t at all surprising…What is surprising and reassuring is that we saw an effect in a relatively short period of time…It also suggests that our general sense, in the past, the the benefits of statins extend beyond their cholesterol-lowering effects is probably correct…In the short run the impact may be hard to asses, but in the long run, the study may have a profound impact on how we treat patients and shifts the paradigm from treatment to prevention.
Pharmalot: Well, should everyone be tested for CRP?
Zucker: CRP is certainly a strong predictor of additional risk above and beyond cholesterol and LDL. For that reason, it is not unreasonable to screen patients for CRP elevations at least once during their 40’s or early 50’s.
Pharmalot: Should statins now be given to people with high CRP and low LDL?
Zucker: That’s the crux of the study - what to do with patients with elevated CRP and acceptable LDL? Let’s first keep in mind that the target level of total cholesterol and LDL is somewhat arbitrary. We accept 70 mg/dl as the target, but in agrarian societies and in newborns, the LDL is generally less than 50 to 60 mg/dl. So, in reality it is unclear if the LDL in these patients was optimal. It probably wasn’t. It was just not particularly elevated by our standard. If you do choose to prescribe statins more liberally, this study provides at least some preliminary data to support your position. Nevertheless, putting patients on a statin to lower the CRP is certainly not an approved indication and does place the physician at some risk. At a minimum, one ought to recheck the CRP after three to six months of treatment just to ensure that the desired effect was achieved, otherwise, you might as well discontinue it until more data is available.
Pharmalot: Should Crestor be widely prescribed? And what about other statins?
Zucker: A few points need to be considered. First, Crestor was the only drug studied. Second, it is the single most potent statin on the market. Third, Crestor it is expensive and it is not available as a generic. The cost treating the over 7 million Americans who might fall into the Jupiter cohort would be measured in the billions of dollars. Admittedly, upfront costs may save costs downstream by preventing CAD, CHF and CVA’s. Unfortunately, it’s a very hard analysis to perform. Certainly, the costs would be less if generically available statins had the same effect. This is not known and it is not good science or medicine to assume that all members of the class of statins will likewise decrease CRP. It may be true, but this is as yet unproven. From my point of view, additional studies will need to be done with other statins before recommending widespread use of Crestor or any of the sister statins
Pharmalot: What are the caveats?
Zucker: The study ran less than two years and there has been chatter among physicians over the past year or two that there might be an association between low LDL and the risk of cancer. While most of us are not convinced by the data, it would probably have been more prudent to not stop the study early and to instead follow all of the patients out for a longer period of time to make certain that no untoward or unexpected problems develop.
Pharmalot: What about the higher incidence of diabetes?
Zucker: The absolute percentage difference between the cohorts was fairly small, although admittedly statistically significant. However, if you do enough analyses in any given study you always run the risk of finding something that looks statistically significant when it really isn’t. Let’s wait for additional data. Also, one would have expected that with all of the other statin trials done over the past 20 years, this ’signal’ would have already been noted.
Doug Bremner
Indeed. One should not prescribe a statin to lower CRP, and one should not prescribe a statin to lower LDL cholesterol either.
One should prescribe a statin to prevent death, and possibly heart attacks (although not if that risk is offset by increased mortality from other causes, like liver damage).
Here are some other comments on the Jupiter study some stimulated from comments I have gotten from others.
The study excluded subjects with diabetes or hypertension and there was a four week “placebo” run in phase and subjects who were not compliant during that phase were dropped. 80% of the patients were excluded and many more were excluded during the placebo run in phase. What this means for the regular patient is unknown.
Interesting that women benefited to the same extent as men.
The reduction in total mortality was 1.0 per 100 patient years versus 1.25 in the placebo group, a difference of 25% in relative risk, but of 0.25% in absolute risk (i.e. not that great). I think one thing this study highlights is that maybe LDL reduction is not the “cause” of risk reduction, or at least exclusively.
The other issue is what the clinical implications of this study are. Are doctors going to check CRP and LDL in everyone and treat whoever fits either profile? That means everyone will be on this stuff. Crazy.
The relative risk v absolute risk distinction is critical. The story I use is for primary prevention in men with risk factors. Out of 100 men, 4 men on placebo will have a heart attack in five years v 3 on a statin. If you told someone that a drug would reduce his risk of having a heart attack by 25% (and told him none of the risks, he would take it! If you went into a room of 100 men and said I want you all to take a drug and it will prevent only one of you from having a heart attack, but three of you will have some liver damage or muscle pain, and maybe it causes cancer but we are not sure, they wouldn’t take it. Both describe the same situation (going from 3 to 4 is a 25% change (relative risk) but 4%-3%=1%). Crucial distinction. Most doctors don’t understand, but the pharma detail people do. And they always use the one that suits them best. Also, NNT is the number needed to treat. Means that (in this case) 31 patients need to be treated for four years to save one from a cardiovascular event or procedure (their primary outcome). Which isn’t all that great. The authors pointed out that this is similar to prior studies of those with high LDL, but all that says is that LDL is not the be all and end all (the cardiology research community has been moving toward the inflammatory pathways area for several years now; elevated CRP is probably associated with the metabolic syndrome, etc).
Doug Bremner
I shouldn’t say stimulated, some are quotes of comments that people from the AHA meeting and others sent to me.
Jim
Doug
Thanks for the explanation, it appeared to me at least that the numbers presented in the Crestor Study did not demonstrate the need for increased statin therapy and your explanation validates my initial impression.
Also the study included individuals who smoked, suffered from metabolic disorder, came from families with a history of cardiovascular disorder, or were over the age of 65 and I was curious as to how many individuals from those groups suffered a CVE. I believe a closer look at these individuals will invalidate the study in its entirety and demonstrate that the risk associated with increased statin use definitely outweighs its benefits, but I won’t hold my breath waiting for that announcement.
In my opinion the study only demonstrates that the pharmaceutical industry will go to any lengths to expand their customer base.
Brian
Jim said…”In my opinion…” I could not agree with you more.
PaulGGG
Problem is that CRP is totally non-specific. It goes up with anything and everything. You have a cold, CRP goes up. You exercise, CRP goes up. Many foods drive CRP up.
So how is anyone going to tell is someone has true vascular CRP elevation or just artificial?
Nathan
Doug,
You like to harp on “relative vrs absolute risk”. But I’ll remind you that the absolute risk of many many things is quite low. Auto accidents, air crashes, drownings, food poisoning. The “absolute risk” of death and injury from all those events is very, very low. Yet, as a society we spends LOTS of money and effort in order to lower the “absolute risk” of those tragedies by very small amounts.
Nathan
To clarify what I mean: By your logic, we shouldn’t bother wearing seatbelts because the absolute risk of dying by a car crash over a given 5 year period is very, very low.
Doug Bremner
But wearing a seat belt has no side effects, Nathan. The question is true risk versus benefit. Interesting example though. Did you know that in the 1960s General Motors hired a hooker to try and entrap Ralph Nader because they were upset that he was trying to get them to put seat belts in cars? And look where they are now, getting ready for a tax payer bail out. How the mighty have fallen.
S M
Nathan wrote: “To clarify what I mean: By your logic, we shouldn’t bother wearing seatbelts because the absolute risk of dying by a car crash over a given 5 year period is very, very low.”
That’s not an equivalent analogy to increased statin use. Statins can have significant side effects, whereas wearing a seatbelt is by all measurements benign.
Nathan
Seat belts have no side effects. Air bags would be a better example. They clearly have risk (child head trauma) and cost (~$300/car?) associated with them. Yet we clearly accept the “risk” in order to receive the benefit. Note that the vast majority of cars go to their grave without ever having deployed their air-bag. Was all that cost a waste?
Back to the topic at hand: I agree, it’s all a risk-benefit calculation. However, in your posts, you frequently allude to the low (absolute) benefit without noting the absolute risk is also very, very low. (however, I agree, there ARE risks)
Shareen Adams
My husband has a 4.1 CRP. He is 30 years old with a family history of high blood pressure and cholesterol. He just developed this in the past 2 years. Many men in the family have had heart attacks but also did not treat their health conditions. My husbands dr. wants to put him on this new medication, Crestor but says it is very strong with many side effects. I am not sure it is worth it. This is a new drug with not much history. I am very worried for my husband. Would you recommend he takes this drug? Is it worth it?
Jim
Ms. Adams
I am not sure you will read this but if you I will first qualify my statements by advising you that I am not in the medical field.
The Jupitor studies have shown some benefit in reducing the number of Cardiovascular Events (CVE’s) during it clinical trials but at this time the use of Crestor has not been approved for use as a preventative of CVE’s. If your husband’s LDL chosterol levels are now under control, the number was 130 but now the medical profession is stating it should be at 70, then there is no current valid reason to prescribe any Statins.
As far as the CRP measurement is concerned, CRP levels have not yet been approved as a measure to determine the liklihood of a CVE, elevated CRP levels can occur for a variety of reasons.
You write that your husband’s family has a history of heart attacks and in my opinion, that is extremely important. However before starting on a life long regime of statin therapy at the age of thirty, I would seek a second opinion and also seek additional testing to determine if your husband is currently showing additional risk factors that would induce his physician to recommend that he begin statin therapy. If your husband’s doctor is recommending Crestor and Crestor only I believe he is jumping the gun and prescribing Crestor for an as of yet unapproved off label use of this drug.
However in defense of your husband’s doctor he did advise your husband that the drug has serious side effects so I am assuming he has looked at all of the factors I described above and he only mentioned the CRP readings because of the recent study but that is not his primary reason for prescribing the statin therapy.