By JUPITER, Part II--A More Skeptical View

When I did my initial post on the JUPITER study (immediately preceding this post), I had not had the benefit of first talking with a true evidence-based-medicine mayvin. I have now just gotten off the phone with Jerry Hoffman of UCLA, who reviewed my post and the attached comments. I thought I had better hurry up and do a new post before my addled brain forgot all of his observations.

Jerry first of all defended Merrill Goozner against some of my skeptical comments about his blog post. Next, Jerry agreed with me that the basic result of JUPITER is to cast more doubt on the "lipid hypothesis" of how statins help in heart disease, and certainly undermine a strategy of widespread testing of cholesterol and trying to achieve a target level of cholesterol by adjusting statin dose.

Jerry concluded by saying that he put JUPITER together with earlier studies in this way. We know that there are basically three groups of folks--high, medium, and low risk for vascular disease. The really high risk people have already had a stroke or heart attack. For them it seems pretty clear that statins help, and that the number needed to treat (NNT), while still on the high side, at least seems to justify the three costs of statin therapy. (These costs are: the monetary cost of these pricey drugs; the known side effects of statins; and the as-yet-unknown side effects among people who may be on the drug for 30-40 years. One reason that the cost-benefit ratio is favorable in the high risk group is that if you already have had a stroke or heart attack, the chances of your hanging around long enough to develop those possible long term side effects becomes quite low.)

Then we have the low-risk people. For them, the NNT is extremely high. It seems hard to show that the costs, in their case, would be low enough to justify these slight benefits.

Finally we come to the moderate-risk group. JUPITER identified a bunch of these folks, who had the elevated C-reactive protein and also were on the older side. Surprise--their NNT turned out to be intermediate between the highest and lowest risk groups. So the question, first, is: does the intermediate NNT justify the still-substantial costs of statin therapy? (This was Goozner's main point.) If this was explained adequately to patients, some might say yes and others would say no.

The second question is trickier and ignoring it was the main defect in my first post. It is true that if you just looked at the people known to have a high CRP test, the NNT is 95 for 2 years. But that is not the best way to look at the data. If a patient comes to you, the doctor, you have a choice of two strategies. You can look at their existing risk factors, place them in a high-or low-risk category, and advise statins or not depending on that risk assessment, using if you want a tool like the Framingham score. Alternatively, you can order a CRP test and then alter your advice to the patient based on whether it is high or normal.

When you consider the true NNT, you cannot just look at those who are already known to have a high CRP. You have to look at the initial population and factor in the uncertainties associated with the test (such as false positives and negatives, etc.) The NNT for the entire strategy (first test, then treat if high) is going to be a higher number than 95 for 2 years to prevent one bad outcome. Jerry's final question is--how much extra value is added by doing the CRP test, compared to just using other knowledge of risk as we would do today? JUPITER did not give us enough data to answer this question. Specifically, it did not tell us how many patients might have been placed on statins anyway due to other risk factors even had the CRP not been done; nor did it tell us how many patients who did not have another reason to be on statins had to be screened with the CRP in order to yield the relatively small percentage of all comers who ended up in the trial.

I will turn Jerry's good observations into a hypothetical patient coming in the door who is perhaps moderate risk for heart disease, and wants to know if he should take a statin and if he should have that new blood test that he heard about on the news. It seems prudent to offer at least three options:

• Stay off statins and focus on lifestyle interventions to prevent heart disease--especially exercise--which for all we know have a lower (more favorable) NNT than statins do
• Don't do a CRP and prescribe statins, or not, based on other risk variables precisely as one would if the CRP did not exist
• Do the CRP and be guided by the results as to whether to give a statin, the cheapest possible one in the lowest reasonable dose (a modified JUPITER protocol)

My point is that all three options make sense to offer the patient. Jerry would add, that if the patient asked which one Jerry would recommend, he's not sure he'd recommend either statin option based on the totality of today's evidence, including JUPITER.

Finally, you might ask--as this blog is not about statins or heart disease prevention, but the pharmaceutical industry and its relationship with medicine, why have I gone off on this long JUPITER tangent? I might reply that we were forced onto this tangent because a major study that got a lot of media play was hampered by obvious conflicts of interest in its sponsorship and authorship (as again, Goozner accurately noted). This is at least the length that one needs to go to, in today's environment, to decide what to believe of what is published, so as to assure that drug company spin does not trump science. The mere fact that the study was discussed at the meeting of the American Heart Association, and published in the New England Journal, is a completely inadequate assurance of scientific reliability, as multiple examples provided in HOOKED attest.

By JUPITER: Slick Drug Marketing, Great Science, or Both?

The JUPITER study, which you have heard about on the news unless you have been in a deep coma this past week, is the sort of thing us Pharma skeptics would love to find fault with. My fellow blogger Merrill Goozner noted its two sins--first, the study was funded by AstraZeneca, maker of the study drug, rosuvastatin (Crestor); second, the first author, Paul Ridker of Harvard, owns a patent on the high-sensitivity test for C-reactive protein, the test that would be widely used if the study results are accepted. This led Goozner to twist himself into pretzels trying to find flaws in the study: http://www.gooznews.com/archives/001243.html

I studied JUPITER and the accompanying editorial in some detail and (while awaiting a better assessment from my friends who know study design and biostatistics better than I do) would offer the view that our pal Gooz went a bit overboard. Still, there is an important lesson here and it is not what the media claimed.

Basically, JUPITER screened about 89,000 patients and found 17,802 of them who met three major inclusion criteria--they had no existing heart disease; they had a normal cholesterol level; and they had an elevated high-sensitivity C-reactive protein test, a test for general bodily inflammation. The subjects were then randomized to the statin drug or a placebo daily. They were supposed to be followed for 4 years but the data monitoring board recommended cessation of the study after 1.9 years because of a significantly lower rate of all major outcomes (heart attack, stroke, unstable angina, need for coronary artery surgery) in the group that got the statin drug.

One point to note is that the JUPITER population was a relatively high-risk because older population, with the median age in each group being 66.

On one point, Gooz got it exactly right. The news media wildly reported that these bad outcomes had been "cut in half" by the statin. In actual fact, while the rate of bad stuff was generally half as much in the statin as in the placebo group, the more accurate statistic, absolute instead of relative risk reduction, was far less impressive. For example, if you added up all the bad outcomes as a composite endpoint, there would be 1.36 bad outcomes per 100 person-years of follow-up in the placebo group and 0.77 per 100 person-years in the statin group. This translates into a number needed to treat (NNT) of 95 over 2 years (that is, you would need to treat 95 patients for 2 years with statins to prevent one bad outcome). It is worth noting that this NNT is quite a bit more favorable than in most previous trials of primary prevention with statins, where it is not unusual to see NNT's in the range of 300 to 400. (A low NNT is good, a high one is bad.)

Another score for JUPITER--the death rate was reduced by statins but not by as much as the other bad outcomes. (There was only about a 20 percent relative risk reduction in deaths vs. the nearly 50 percent relative risk reduction for the other outcomes.) Still, this is very impressive because in many earlier primary prevention trials, while statins reduced the number of heart attacks or strokes, they could not be shown to reduce the overall death rate one bit. (This is partly what has led some to fear that statins increase the risk of other deadly diseases such as cancer at the same time that they reduce cardiac or vascular risks. In JUPITER there was no increase in cancers among the statin group, through the follow-up period was of course very short.)

There was also a very limited downside to taking statins for the duration of the study. The only adverse event that happened more often in the statin group was a new diagnosis of diabetes, and this was only a slight difference (3.0 vs. 2.4 percent). A lot of these subjects were diagnosed at the start with metabolic syndrome so their baseline risk of diabetes was very high.

So, bottom line-- it seem hard to argue that this study is a winner for using statins for primary prevention (before any vascular disease has arisen) in one high-risk population, those with elevated c-reactive protein; and that in turn implies the value of using the CRP test as a routine screening test. The NNT of 95 is quite respectable among primary prevention trials.

The JUPITER authors seem to have been fully aware of the skepticism that would greet their paper due to the obvious conflicts of interest. They went to great lengths to note that AstraZeneca did not even see the unblinded trial data until after the manuscript was submitted for publication. Two committees were said to be completely independent of both the company and the principal investigators--an endpoint adjudication committee and a data monitoring and safety committee. In short, if these statements are all true, the study was squeaky clean despite the commercial sponsorship.

Now I come to the point that the media seems completely to have missed. Skeptics of the widespread use of statins (like yours truly) have for a long time insisted that the bulk of the research literature to date does not support the "lipid hypothesis"--that statins work by lowering "bad cholesterol" levels; and that it is critically important to screen patients by testing their cholesterol, and then doing repeated tests to be sure that the response to statin treatment is a low enough level. We have insisted instead that the research indicates that whether or not statins are good for you depends almost completely on whether you have certain risk factors. The biggest risk factor, and the groups where statins have been shown most clearly to work, is already existing vascular disease (that is, secondary prevention). By contrast, very little benefit from statins has been seen in most primary prevention trials, except in men at high risk in the roughly 40-65 age group, and even there with a very high NNT. Since you don't need a cholesterol test to know if you have those risk factors, we have argued that the massive use of cholesterol screening leads to the inappropriate overuse of statins. Moreover, there is no evidence that hitting a lower target cholesterol level by increasing the statin dose lowers your risk to any significant degree.

One way to summarize all these data is to suggest that it is quite possible that statins prevent heart attacks and strokes, but not by lowering cholesterol. They are known to have an anti-inflammatory effect, and it is thought that inflammation plays a role in turning arterial plaque into a major blockage of a vessel that leads to bad disease. It may be their anti-inflammatory effect and not the lipid-lowering effect that explains why they work in the highest-risk groups.

Well, if this hypothesis was worthy of consideration yesterday, it has now received a huge boost with JUPITER. Based on lipid screening, these subjects did not need any statin. Yet they did better on a statin for primary prevention. They were a very high risk group (mainly due to age) and also had signs suggestive of an inflammatory process.

The media never picked up on this. All the coverage I heard simply took for granted that it was wise to treat elevated cholesterol with statins, so now we had yet another huge group of patients who needed a statin in addition to those with high cholesterol. On NPR (of all places) this morning, I heard a physician quoted that JUPITER showed that we need to reduce levels of cholesterol much lower than anyone had previously realized--when the real message is to test CRP and forget all about cholesterol. Even if the lipid hypothesis of statin treatment is all wet, we still seem completely hooked on it.

Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. New Engl J Med 359:2195-2207, Nov. 20, 2008.

Hlatky MA. Expanding the orbit of primary prevention--moving beyond JUPITER [editorial]. New Engl J Med 359:2280-2282, Nov. 20, 2008.