Wednesday, March 15, 2006

Findings from Crestor [Statin] Study

While the headlines are screaming out for your attention to highlight all the 'benefits' of taking a statin cholesterol medication for reducing the risk of a heart attack, let's step back a moment and take a closer look!

The very convincing headline on MSNBC yesterday - Statin drug shown to reverse heart disease - might lead you to believe taking a statin may be a good preventative step to reduce your risk of heart disease. The actual study remains unpublished as it is scheduled for release in JAMA in the April 5, 2006 edition.

From the March 13, 2006 JAMA press release about the study, we learn that the trial included participants with coronary artery disease, specifically atherosclerosis. The study was designed to determine the effects of high-intensity statin therapy on IVUS-derived measures of coronary atherosclerosis regression. This is the first critical item in the study - patients in the study already had established coronary disease. If you read through the MSNBC article however, this tidbit is missing - nowhere in the article are readers informed the study was conducted on those with established coronary artery disease.

The findings are quite impressive - the therapy, which included high doses of Crestor (rosuvastatin) reduced LDL, increased HDL and also resulted in a slight demonstrated regression of their atherosclerosis. On average, LDL fell from 130mg/dL to 60.8mg/dL; HDL rose from 43.1mg/dL to 49mg/DL; and "[f]or the primary efficacy parameter of change in PAV, the average decrease was -0.98 percent and 63.6 percent of patients showed regression of atherosclerosis. For the second primary efficacy parameter, change in atheroma volume in the 10-mm subsegment with the greatest disease severity, there was a median (midpoint) reduction of 9.1 percent in atheroma volume, and 78.1 percent of patients demonstrated regression of atherosclerosis. The secondary efficacy parameter, change in total atheroma volume, showed a 6.8 percent median reduction."

Did you catch those numbers? I hope you did - the study subjects already had pretty good cholesterol levels. While 130mg/dL is the level at which the American Heart Association recommends one consider drug therapy for those with existing coronary heart disease, the participants in this study did not have an alarming LDL level - they were, on average, just at the level to consider a drug intervention. More important, the participants' HDL level was well within the "normal" range of 40-50mg/dL with an average of 43mg/dL.

This leaves me with a question - I wonder if cholesterol really is the end-all-be-all measure in the process of coronary disease as we're repeatedly told? I've wondered this for quite some time actually - and this study just reinforces my doubts. Had the average patient in this study walked into their doctor's office, alarm bells would not have been sounding all that loudly about their cholesterol levels. Even if their clinician was a bit concerned about their LDL, a level of comfort would have come from the HDL readings. Add to that our knowledge that 50% of people who have heart attacks have a normal level of cholesterol.

Hmm...might be easy to say our target levels are still too high. But, to answer that, we also must consider that our target levels truly are accurate and cholesterol isn't really the issue - something else is and we're still missing what that is.With this study we are still missing critical pieces of data - we have no idea what their total cholesterol was, nor do we have any clue what their triglycerides were. We're left in the dark about other known risk factors - like blood pressure, inflammatory markers, weight and activity levels.

Until the publication of the paper, we'll just have to be patient - this additional information is critical to effectively analyze the total effect on cholesterol - did the therapy result in an improved cholesterol ratio? Did it improve triglycerides? Did it have an effect on blood pressure? Did it reduce inflammation? Did participants actively seek to normalize their weight? Were these folks active?

Without the additional data, we simply cannot make a judgement about whether this therapy provided real improvements and/or if there were confounding variables to consider. Yes, the therapy improved LDL and HDL and led to a small regression - but what does that mean for the long-term? At this point, I'm fairly certain that in the long-term, this therapy is not going to be as effective as the headlines want us to believe - it's notable that the press release stated that "[a]dverse events were infrequent and similar to other statin trials."

So, during the term of this study, adverse events [read: deaths and/or other complications or compromises in health] were similar to other studies. At the end of the day, this means that the therapy had little effect on quality of life or whether one would die without the therapy when compared with those using the therapy. Hey, they did improve some measures of their cholesterol and had a regression - but they didn't live longer or better, did they?

I'm not surprised the numerous articles in the media aren't including this information though - it might make someone think twice about whether the positives of the therapy outweigh the negatives. I'm also not surprised that the media isn't highlighting that this was designed as a "secondary prevention" trial - that is to evaluate if a therapy can cut your risk of having another "adverse event" when you've already had one.

This type of study is very different from those designed to evaluate a therapy for "primary prevention" - that is to answer the question of whether a therapy will be effective to reduce the risk of having the first-time "adverse event."

Basically, if a study is not designed to measure primary prevention, its data should not be extrapolated as evidence of efficacy for a healthy population or even a population with a few risk factors who have not yet experienced an adverse event. But, I can almost guarantee that's what's going to happen with this study - we're going to start to see the recommendations call for more aggressive drug intervention in the near future. Just pay no mind to the fact that "[a]dverse events were infrequent and similar to other statin trials."

At least one of the study co-authors did issue a caution in another press release from JAMA regarding the study - Editorial co-author Navin K. Kapur, M.D., a clinical research fellow at Hopkins, adds that, “Researchers’ next steps have to determine whether these very promising results translate into greater reductions in future heart attacks and strokes.”

6 comments:

  1. As a bypass recipient I've known quite a few other people in the same shape...but the MAJORITY of them eventually have problems with statins. I took them (Lipitor) for a couple of years at 10 mg but as soon as they doubled my dose I started to get liver reactions and muscle aches. I switched to ezetemibe (Zetia) and it worked OK but nothing to write home about. I've since stopped all prescription cholesterol meds and began taking Sytrinol, Policosinol, Guggul, and Niacin. My TC is < 200, LDL < 130, TG < 120 and HDL > 50 (for the first time in my life of checking it). I hope to live long enough to see that you're suspicions are correct Regina...that cholesterol has little to do with it. I think that our societal switch from saturated fats to polyunsaturates and the associated risks of free radicals that they help spawn will be the final answer.

    Drache

    ReplyDelete
  2. A few comment concerning the Statin study showing showed regression of atherosclerosis by increased increased blood flow to the heart, at least if I'm understanding the terminology.

    One, is that this a surrogate endpoint, i.e. it does not in and of itself prove that these will not have another heart attack or that a recurrence will be delayed or that they will die of something else.

    Two is that I recall reading somewhere, possibly in the The International Network of Cholesterol Skeptics website THINCS, discussions section although I have not been able to find the reference that it is common to have increased blood flow to the heart after a coronary event. There could be several reasons for this including exercise program, increase mineral and vitamin intake, other medications prescribed, in addition to natural healing processes. This criticism has been directed at Dr. Dean Ornish for his Lifestyle Prevention Study which also increased lumen diameters.

    Having said all that, there is certainly some evidence that statins are of some value for secondary prevention of heart attacks, although it is unclear if the side effects and the fact that they have not been shown to reduce the overall mortality rate in clinical trial still make their use at best problematic.

    (Please note that the primary purpose of the comment was that improvements in atheroma volume may not be of value in treating CHD. Love your BLOG as one of the few that deals with diet and nutrition in a scientific way.)

    ReplyDelete
  3. Having said all that, there is certainly some evidence that statins are of some value for secondary prevention of heart attacks, although it is unclear if the side effects and the fact that they have not been shown to reduce the overall mortality rate in clinical trial still make their use at best problematic.

    I agree...what troubles me is the media's representation of the study - basically a failure to clearly state this was a secondary prevention trial and its data shouldn't extend out to create a model for primary prevention, ya know?

    I also think there are effective ways to improve cholesterol if one believes cholesterol values are of high importance. Dietary measures can be especially effective to lower triglycerides significantly, raise HDL, perhaps lower LDL - but most importantly, at least in my mind, improve the ratios overall.

    The simple elimination of added sugars alone goes a long way to improve triglycerides - is that because of the reduction in overall carbohydrate or because of the restriction on processed foods or because of something else, like foods that are eaten are higher in a particular essential nutrient? Perhaps it's a bit of all of these, perhaps it none of them!

    Personally I see high cholesterol values as more a symptom than a cause - something else is going on and that's what we need to address...taking a statin may bring the cholesterol down, but is it addressing the underlying cause of the elevation? Who knows? There is something to statins - we just don't quite know what that something is and I think it is prudent to continue focused trials to better understand their mechanisms in the body and be sure we're not doing more harm than good in the long-term, especially since we're slowly seeing recommendation creep, where individuals who may not have met guidelines previously are now targeted as potential users as the levels at which intervention is recommended slowly inches its way down!

    ReplyDelete
  4. Tintin6:11 PM

    I discovered that I have high level of LDL since 1983. I was 35 years old. It reached a level of 380. I started fighting it by reducing fat consumption and sports. In 1989 I started treatment on Mevacor. Since 1993 I tried all kinds of Statins at the highest dose: 80mg zocor, lipitor ... I could never get results better than total cholesterol 250.
    I used zetia in association with statins. I got no better results. I had an open heart surgery in 2004. They by-passed three veins.
    However, in 2005 I started using crestor 20 in association with 20mg of zetia. I obtained a progressive improvement of total cholesterol levels that reached 200. the LDL level went down to 140-145.
    I have less muscle pain, the SGPT and SGOT levels as well as the createnin level became normal

    ReplyDelete
  5. Anonymous6:02 AM

    Hi
    My GP precribed SIMVASTATIN 40MG to help reduce my cholesterol which was 6+. He said that Cardiologists recommend this high dose. I took the drugs for a month and then started to have severe pains in my arm and leg muscles, and general weakness in these limbs, together with a fealing of exhaustion which I had not experienced before.
    I returned to see him and he said stop the drug ;b but maybe a weaker dose would be OK. I was in so much pain that i have not taken them again at all. Now I see that CRESTOR have introduced a new statin drug. Will the ingredient of the new drug have the same effect on me; or is the product improved to help prevent these side effects.
    I would be very grateful for your views Regards Robert

    ReplyDelete
  6. Robert, I am not a doctor but I do read up on statin therapy regularly. The Medical letter states two main reasons for side effects 1. The higher the dose the more side effects you will probably have (makes sense), 2. Drug to drug interaction. Someone who is on multiple medications should pay attention to how the drug is metabolized and if the drug in monotherapy(one drug) or combination therapy (two drugs combined). If a person is on multiple meds- adding a combination drug adds two more chemicals in your body on top of all the drugs you are currently taking. Some drugs are metabolized in different pathways and this is important. You should find a statin that will bring your cholesterol levels down the most at the lowest dose possible (dosing is key for side effects). Robert, everyone is different but all statins have the ability to cause myalgias (muscle pains). This does not mean every statin will cause you muscle pain. Try different statins until you find one that causes little or no pain. Either way if you do not change your diet and exercise in conjunction with a statin you will not get the full effect of statin therapy. People are living longer today then ever before Robert and it's because of great scientists who create great medicines. I wish you and your family the best of luck. GOD BLESS

    ReplyDelete