Sunday, November 9, 2008

Jupiter, Statins, C-reactive Protein and Cardiovascular Disease: An Explanation from the DMCB

Every once in awhile, an important study on the prevention of a chronic illness appears. News outlets have a deservedly lousy reputation for accurate healthcare reporting. You don’t have time to read the original research either.

The Disease Management Blog at your service!

A study acronymed 'Jupiter' has come out showing that cholesterol drugs (statins) can reduce the occurrence of heart attacks among persons without a prior history of disease and who otherwise seem to be at low risk. Most experts recommend that statins be used among persons who’ve already had a heart attack (to prevent a repeat attack) as well as among persons multiple risks factors, such as tobacco use, diabetes or a very high blood cholesterol level. Lowering the threshold of use for statins among healthier persons could dramatically increase the use of this class of drug.

But first you need to know about ‘C-Reactive Protein’ (or 'CRP' which is picture above and to the right). This is made by liver cells in response to inflammation of any cause. It binds to a bacterial cell wall component called ‘Fraction C’ (hence the name ‘C’ reactive). Scientists are unsure just what CRP does, but its ability to bind to foreign proteins suggests it is a part of the immune system. When this protein was discovered back in the 1930s, it was hoped that a ‘positive CRP test’ would confirm infection by S. pneumonia. It was eventually found this protein is made in response to other inflammatory conditions such as tuberculosis, lupus and many types of cancer. If there is severe inflammatory disease, blood levels can go as high as 500 mg/L. While the protein is easy to detect when levels are elevated, a ‘high sensitivity’ lab assay (accounting for the name ‘high sensitivity CRP’) is needed to measure low levels of CRP.

CRP remained an historical curiosity until researchers began to find an association between slightly elevated CRP levels (more than 2 mg/L) and heart attacks. Scientists began to wonder if aspirin not only thinned blood but treated some sort of inflammation involving the vascular system. It’s also been known for a long time that statins reduce heart attack rates more than can be explained by just the lowered cholesterol levels; there are other drugs that lower cholesterol just as much but don’t have the same survival rates. What’s more, statins have been shown to lower CRP levels. The American Heart Association even noted that CRP testing could be used to help decide whether statin treatment was warranted in borderline high risk cases.

Enter the New England Journal of Medicine, which has just released the AstraZeneca funded 'Jupiter' study by Dr. Ridker and colleagues involving a whopping 1315 clinics in 26 countries involving 17,802 persons aged 50 or more (men) or 60 or more (women) years with no history of heart disease (making this primary prevention), a cholesterol level of 130 or less (not very high) but who had an elevated ‘C-Reactive Protein’ of 2 mg./L or greater. Persons were randomly assigned to either daily placebo or 20 mg of rosuvastatin (Crestor – which is manufactured by AstraZeneca). After an average of 1.9 years, it was apparent that the persons taking the drug were having fewer cardiovascular events (including heart attack, stroke, heart surgery or cardiovascular death).

The overall rate in the drug group was .77 per 100 person-years (mathematically, think of this as 77 persons among 10,000 taking the drug per year) versus 1.36 per 100 person-years (or 136 among 10,000 persons on the placebo). You can see what happened to the rates of individual types of cardiovascular events here. The authors calculated the all important number needed to treat with a daily dose of rosuvastatin to prevent one event was 95 persons for 2 years. To give you a sense of comparison, about 25 persons with a history of heart attack have to be treated with a beta blocker for only one year to save a life.

Adverse events? Death from cancer was statistically significantly lower in the rosuvastatin group (35 vs. 58). Physician-reported new cases of diabetes was more statistically significantly more frequent in the rosuvastatin group (270 reports of diabetes, vs. 216 in the placebo group. Neither should be a surprise. The DMCB doesn't think the data supports a link between cancer and statins and statins have been shown to be rarely associated with the development of diabetes. While not in Crestor's package insert, it only lists the more common side effects.

Take-aways from the DMCB:

Depending on how much attention this study gets in the media and how little information is given on the magnitude of the benefit, physicians, managed care organizations (MCOs) and their pharmacy benefit managers may need to prepare increased demand for all statin drugs among persons with an elevated CRP that would not have otherwise qualified for treatment. Even though this study involved AstraZeneca’s drug Crestor, the DMCB suspects that all statins will work among persons with elevated levels of CRP.

You’d think that MCOs would be happy to economically trade increased use of statins for reduced heart attacks, but a) the budget for pharmacy is usually disconnected from medical cost savings in most settings and b) the absolute reduction in heart attacks (just over .5%) is relatively small.

An accompanying editorial in the Journal points out that long term studies are needed to assess whether having very low blood cholesterol levels is dangerous. The DMCB agrees, but it thinks that should have declared itself by now.

Disease management organizations need to monitor the evolving science of CRP-statin-primary prevention and be prepared to incorporate consumer friendly information about this in their patient coaching protocols and prevention programs. The sooner the better.


Chus said...

Cholesterol pills may become as ubiquitous as a daily dose of aspirin for middle-aged men and women who have normal levels of artery-clogging fat after a study found the medicine cut their risks of heart attacks, strokes and death by almost half.

Anonymous said...

In the study, the treatment cost $464,000 per life saved in the two year study period. (1300 yr for crestor x 2 yrs x 8925 pts in the treatment group) / 50 (the reduction in all cause mortality). Aspirin costs $4 per month, Crestor costs $115 per month (from ePocrates). I don't think the cost is clearly worth the benefit compared to other interventions and other problems and urge careful analysis of cost per quality-adjusted life year at different ages. IF generic atorvastatin could be substituted (not proven) then the cost would come down to $139,000 per life saved in the two year period. Again, this is just arithmetic, not QALY analysis, which needs to be done before this approach is recommended for the general public.

Jaan Sidorov said...

Well said Peter. The only caution is that the price of pharmaceuticals in many pharmacy benefit plans vary considerably (their purchasing power helps them avoid retail), which would bring the price per life saved even lower. For an example of what happens with a shift in the cost of a medicine, see

I hope an enterprising researcher is working on a CRP-lipid-statin-QALY manuscript right now. Furthermore, I suggest he or she assume that this is a class effect and include the pricing of generic statins.

Anonymous said...

Peter, totally agree about the cost as well.

Even statins for higher risk people aren't cost-saving, at least not in all subgroups. Cost-effective -yes, for high risk, but not cost saving. So why would MPOs want to trade the cost of treating one heart attacks in exchange for treating 95 people for 2 years? Not to mention the additional cost of doctors visits and tests.

In fact, if I were a patient whose doctor recommended statins, I doubt I'd want to go on a prescription drug for life for such a small absolute benefit. Are the risks of side effects really smaller than this possible benefit?