GERIATRIC ISSUES

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Questioning Statins
Questioning Statins

Statins health benefit is the lowering of thrombi the same way aspirin does.  Lowering cholesterol doesn’t get at the root cause—oxidative damage of VLDL.   

 

Last year I looked into the Statin issue because a former wife and her husband are taking them and they were too lazy to investigate—even thought they are retired, and she has sufficient education, high IQ (member of MENSA), and had worked in the medical field for a decade.  I struggled with incomplete studies, sketchy pharmacology textbooks, and market-motivated production of information.  I came to the conclusion that lowering LDL is not the cause for the lower mortality rates for those on statins, but it was rather its ability to lower thrombi (the cause of 70% of myocardial infractions).  Statins in addition to lowering the various cholesterol components also in the same way as aspirin lower the incidence of thrombi.  I posted this other statin mechanism, which I feel is the primary reason for favorable results for statins.  Evidence suggest that for most cases, an aspirin a day is just as effective, and without the serious side effects (one coated 325 mg aspirin per day with meals is quite safe).    This conclusion was shared by the public-watch dog Worst Pill—which bases its conclusions on medical science using reasoned and balanced analysis of the evidence.  Now I have come across confirmation in a big PhARMA website, and they obligingly listed the studies which cast doubts over the value of statins. 

 

Big PhARMA has been pushing the stick lower as to when statins ought to be taken. The pitch of big PhARMA has been that improving the cholesterol profile slows the development of atherosclerosis—ignoring the oxidative evidence.  The role of oxidative damage and reactive chemicals has been known for over 30 years.   The reduction in mortality found is based not on their sales pitch of an improved cholesterol profile, but on the aspirin-like mechanism where by the statins effect clotting and thereby lower the risk of an MI.   

 

WHAT I WOULD RECOMMEND FOR THOSE WHOSE CHOLESTROL PROFILE IS TO TAKE 325 MGS OF ASPIRIN DAILY, AND THEREBY REDUCE BOTH THE RISK OF THROMBI AND CANCER

FiercePharma at

http://us.f817.mail.yahoo.com/ym/ShowLetter?Search=&Idx=4&YY=23810&y5beta=yes&y5beta=yes&order=down&sort=date&pos=0&view=a&head=b#3

In what may become the most far-reaching effects of the failed Vytorin trial, experts are questioning the sacred link between cholesterol and heart disease. After all, Vytorin did do a better job of lowering LDL in the Enhance trial. So why did it utterly fail at holding off atherosclerosis? Why did Pfizer's experimental torcetrapib lower "bad" cholesterol and raise "good" cholesterol--and yet cause heart attacks and strokes, rather than prevent them? Why did AstraZeneca's Crestor fail to beat placebo at preventing heart attacks in the Corona study released last fall?

The ramifications of these questions are huge. The "lower LDL is good" is such a core belief in cardiology that drug makers have only had to prove that their meds lower the offending substance--not that the products actually prevented heart attack or stroke--to get FDA approval. And pharma sells billions of dollars worth of cholesterol-lowering drugs every year. If the link between LDL and disease were to be severed, or even weakened, companies would suffer.1

Now, a couple of statins--namely Lipitor and Zocor--have proven to reduce heart attacks and strokes in post-marketing trials. But is it the LDL-lowering itself that cut the risk? Or some other unknown action of those drugs?

Outcomes trials of Zetia, the med added to Zocor to make Vytorin, and Vytorin itself are ongoing. Tuesday, the American Heart Association called for the Zetia events trial to be finished as quickly as possible. But in another bit of Enhance fallout, patients in at least one of the outcomes trials have panicking, calling up clinical investigators to ask whether they should stay in the study.

   1 The answer is that LDL and VLDL are missing one reaction, oxidative damage.  Oxidative damage is necessary for plaque formation within an artery wall. The second part of the process is the trigger mechanism whereby the damaged VLDL is deposited.  Plaque formation is a controlled by a feedback mechanism (only partially understood) whereby the muscle cells which make up the artery walls respond to reactive chemical such as carbon monoxide or possible a blood born signals from certain white blood cells.  An association with coronary artery disease has been also found with chronic infections. When conditions improve, a certain type of white blood cell can release a polypeptide which shuts down the plaque-formation process.  Thus taking a drug which lowers LDL and VLDL doesn’t stop the process.  However, those with very high levels of VLDL would have the formation of plaque proceeds at a higher rate than those with a low level of VLDL.  Even those with very low VLDL, triglycerides, LDL, and cholesterol still can develop hardening of the arteries.  That is why even those who eat an ideal diet and those with an excellent cholesterol profile can nevertheless have coronary artery disease—jk.

Pfizer halts Torcetrapib development

December 3, 2006

 

In a huge blow to the world's largest drug maker, Pfizer announced that it will halt development of its cholesterol drug Torcetrapib, one of the biggest drugs in Pfizer's pipeline. The decision came after an independent Data Safety Monitoring Board recommended terminating the study because of an imbalance of mortality and cardiovascular events. "Based on all the evidence we have seen regarding Torcetrapib and in light of prior study results, we were very surprised by the information received from the DSMB, the only body with access to the unblinded safety data. We believed that the study was coming along as expected, and this new information was totally unexpected and disappointing, given the potential benefits of this drug," said Dr. Philip Barter, Director of the Heart Research Institute in Australia and Chairman of the Steering Committee overseeing the Torcetrapib study.

Tapped by many as a future blockbuster, the drug was expected to take the place of Lipitor--a $12 billion-a-year blockbuster--before that drug loses patent protection in 2010. Pfizer spent more than $800 million developing Torcetrapib and now says it will refocus its efforts on other opportunities and "continue to invest in a wide range of pipeline opportunities across a diverse range of therapeutic areas." Potential Pfizer collaborators will, no doubt, take advantage of Pfizer's tough situation and demand premium prices for new pacts. Just last week the company reassured analysts that the company's pipeline was healthy, pointing to Torcetrapib as a promising new blockbuster. 

- check out Pfizer's press release on the decision to halt Torcetrapib development
- see the FDA's statement on Pfizer's decision

PLUS: Pfizer isn't the only company dealing with cholesterol drug woes. Shares of Forbes Medi-Tech lost half their value this morning when the drug developer announced FM-VP4 did not lower bad cholesterol by 15 percent. However, the drug did hit its primary endpoint. Release.

 

AZ's Crestor flubs key heart failure trial

November 5, 2007

AstraZeneca didn't get its coveted results from the long-awaited CORONA trial. Crestor failed to show any statistically significant benefit in heart failure patients. So Crestor lacks a competitive edge enjoyed by rival Lipitor and generic statins: Trials that show a clear reduction in deaths and heart disease.

It was a long shot, really; heart failure isn't generally considered to be relieved by statins like Crestor. But AZ wanted something different from the old, tried-and-true data that shows the drugs stave off complications from heart disease. A head-to-head trial against Lipitor would have cost beaucoups, and it would have been risky to boot. What if Lipitor had come out ahead?

 

 

Statins show in major study a 20-25% reduction in MI, however, aspirin does as well.  Moreover those on statins are more likely to have earlier intervention if experience a heart attack.  This is a confounding variable when comparing mortality rates—jk.

Association of Statin Therapy with Outcomes of Acute Coronary Syndromes: The GRACE Study

Frederick A. Spencer, MD; Jeanna Allegrone, BA; Robert J. Goldberg, PhD; Joel M. Gore, MD; Keith A.A. Fox, MB, ChB, FRCP; Christopher B. Granger, MD; Rajendra H. Mehta, MD; David Brieger, MD, the GRACE Investigators*

1 June 2004 | Volume 140 Issue 11 | Pages 857-866

Background: Statins administered early in patients with acute coronary syndromes may lead to modest reductions in recurrent ischemic events.

Objective: To examine the association between previous and early in-hospital statin therapy and the presentation and outcomes of an acute coronary syndrome.

Design: Cohort study.

Setting: 94 hospitals in 14 countries participating in the Global Registry of Acute Coronary Events (GRACE).

Patients: 19 537 patients with an acute coronary syndrome who were enrolled from April 1999 to September 2002.

Measurements: Statin use before and after presentation with an acute coronary syndrome and associated rates of myocardial infarction, hospital complications, and hospital mortality. The composite end point included death, in-hospital myocardial infarction, and stroke.

Results: Patients who were already taking statins when they presented to the hospital were less likely to have ST-segment elevation (odds ratio [OR], 0.79 [95% CI, 0.71 to 0.88]) or myocardial infarction (OR, 0.78 [CI, 0.70 to 0.86]). Patients who continued to take statins in the hospital were less likely to experience complications or die than patients who never received statins (OR, 0.66 [CI, 0.56 to 0.77]). Patients not previously taking statins who began statin therapy in the hospital were less likely to die than patients who never received statin therapy (OR, 0.38 [CI, 0.30 to 0.48]). However, adjustment for the hospital of admission attenuated the association between initiation of statin therapy and the composite end point (OR, 0.84 [CI, 0.65 to 1.10]).

Limitations: This observational study cannot exclude confounding by clinical and hospital factors.

Conclusions: These data support the hypothesis that statin therapy can modulate early pathophysiologic processes in patients with acute coronary syndromes. A randomized trial of statin therapy in acute myocardial infarction is warranted.

 

American Heart Association at http://www.americanheart.org/presenter.jhtml?identifier=3035946

Another major study shows statins are at best no better than aspirin. 

After Myocardial Infarction: The IDEAL Study: A Randomized Controlled Trial

Date: November 16, 2005

Summary: Aggressively reducing the levels of “bad cholesterol” or low density lipoprotein (LDL) in patients who had already had a heart attack did not reduce the percentage of deaths from heart disease, the occurrence of heart attacks or sudden heart stoppages in patients who had had to be resuscitated.

This is particularly telling, for if as big PhARMA maintains the more you lower LDL the slower is the development of atherosclerosis.  However when comparing high dose statins to low dose usage, there was a negative result.  This conclusion supports the conclusion which I—and others maintain—that statins benefits is rather through the same mechanism as aspirin, that of reducing thrombus; and like aspirin, there is little if any reduction in the rate of  thrombus with a higher does of either aspirin or statins, nor is their combination superior--jk.

The Grace Study Results

The very choice of two different statins rather than two doses of the same statin is suspect, since for to test the benefits of a higher does, normally it is compared directly to a lower does, rather than a lower dose of a another drug of the same family of drugs.  Given the big PhARMA bias, the reasonable conclusion is that they have stacked the test protocol so as to favor the high dose treatment.  However, the results showed a very minor benefit. There were 8,888 subject followed for approximately 2 years.  The low dose group had 4% coronary deaths and the high dose a 3.9%.  For nonfatal myocardial infractions the difference was 6% versus 7.2%.  Given the greater expense and side effects there is scant reason for taking the higher does statin.  Moreover is one factors in the difference in deaths from cancer (a know risk of statins), it turns out that the higher dose had a higher death rate.  There were 112 death from cancer in the high does and 99 in the low does group, or a difference of 13.  Subtract the coronary deaths difference of 3 (178 versus 175 for the high does) and there is a net loss of life of 10 for the higher dose group.        

The entire study is available on the internet at http://jama.ama-assn.org/cgi/content/full/294/19/2437  or in the JAMA at Vol. 294 No. 18, November 16, 2005

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