By Jay Cohen, M.D.
Associate Professor of Family and Preventative Medicine and Psychiatry at the University of California, San Diego.
It was originally reported that there were 31 deaths due to Baycol, but that number has increased to 52 deaths, and it is likely to be much higher. The drug's manufacturer, Bayer, confirmed a German government report on August 23 that Baycol was linked to 1,100 cases of muscle weakness.
It really appears that most of the statin drugs are an accident waiting to happen. Public Citizen is seeking a black box warning, which is the strongest labeling caution that can be mandated by the FDA. If you are taking Lipitor, Lescol, Zocor, Pravachol, or Mevacor you will want to seriously consider other options immediately.
Dr. Cohen's Article:
Although Bayer and the FDA have released few specifics, we know that 19/31 fatalities occurred with Baycol alone and 12/31 occurred with Baycol in combination with gemfibrozil (Lopid).
- occurred at the manufacturer's recommended initial dose (0.4 mg/day);
- and at the highest dose (0.8 mg/day)
- the majority of deaths occurred in elderly patients
- and, possibly, deaths occurred more often in women.
Why did these deaths occur? Why were they predictable -- and therefore avoidable?
Why Deaths Occurred At The Manufacturer's Recommended Initial Dose (0.4 Mg/Day)
Rational dosing is key with statins for not only achieving target low-density cholesterol (LDL-C) levels, but also for avoiding adverse effects. Most statin adverse effects, including the musculoskeletal (including rhabdomyolysis) and gastrointestinal systems are dose-related (1, 2).
That is, higher doses bring increased risks. Also dose-related are elevations in plasma fibrinogen levels (3) and liver enzyme indices (2, 4).
Each doubling of the statin dosage also doubles the incidence of liver enzyme elevations that exceed three times the upper limit of normal (4) -- a serious concern following the Food and Drug Administration's earlier report of 90 cases (63 confirmed) of liver failure and more than 30 deaths linked to statin drugs (5).
Thus, each person's dosage of any statin drug should be as low as possible to achieve the target LDL-C. How much LDL-C reduction do patients need? According to the Baycol package insert, the recommended initial dose for everyone young and old, big and small, male and female (except those with liver or kidney dysfunction) is 0.4 mg/day (7).
This dosage reduces LDL-C by 34% on average. But 0.3 mg -- 25% less medication -- reduces LDL-C by 31%, an amount sufficient for millions with elevated cholesterol to reach their target LDL-C (7).
Starting lower also makes sense because "Individual variation in LDL response to statin therapy is large (range 10% to 70%) (1)." In a 1998 study using the lower 0.3 mg dosage, 52% of patients achieved LDL-C reductions of 35%, and 30% of patients achieved LDL-C reductions of 40% (7).
In another study, 52% of patients achieved LDL-C reductions of 30% with just 0.2 mg/day of Baycol (8). These reductions are ample for millions of patients -- starting these patients at the manufacturer-recommended dose of 0.4 mg represents overmedication with unnecessary risks.
Deaths At The Highest Baycol Dosage (0.8 Mg/Day)
Why do some doctors start patients at even higher doses than manufacturers recommend? Because of poor information and the encouragement of some experts to use higher doses.
In the "Dosage & Administration" sections of most statin drugs (including Baycol), no guidelines are provided about starting people at the lowest effective doses.
Even more problematic, no distinction is made between treating patients with heart disease and without heart disease -- a key distinction in determining LDL-C goals and appropriate doses. Thus, patients with mild-to-moderate cholesterol elevations get the same aggressive doses as people with severe elevations and/or heart disease.
Experts have exhorted doctors to be aggressive with statin doses. In a 1997 article in the American Journal of Cardiology, editor-in-chief W.C. Roberts stated: "By knowing these average cholesterol reductions, it is relatively easy to predict which dose of which statin is necessary to reach the goal for any particular patient.... "
The "starting dose," in other words, should be the one necessary to achieve goal, not the lowest available dose (4). In other words, treat patients like statistical averages, not like individuals -- even if many individuals often get better than average responses and thus need only low doses.
And for patients requiring larger LDL-C reductions, don't bother with trying a lower or even standard dose -- start with a higher dose. Apparently, this is what some doctors did with Baycol and are doing with other statins.
Why the Majority of Deaths Occurred in Older Patients
Bayer recommended the same Baycol doses for older and younger patients. This was based apparently on Bayer's statement in the Baycol package insert: in the section labeled 'Geriatric' - "Plasma concentrations of cerivastatin are similar in healthy elderly male subjects (> 65 years) and in young males (< 40 years) (6)."
But as I stated in Geriatrics (Feb. 2000), studies of healthy elderly males tell us nothing about the majority of seniors, who are female, have several medical disorders, have reduced kidney and liver function, and are taking on average 2 prescription drugs and 1 over-the-counter medication (9).
Dosing with older patients should always be cautious, starting with low doses, as virtually all gerontologists recommend. Yet according to the manufacturers of Baycol and several other statins, seniors should be prescribed the same doses as young adults.
With Lipitor, no dosage adjustments are recommended despite the package insert's statement that "plasma concentrations of atorvastatin are higher in healthy elderly subjects," including a 40% greater maximum plasma level (6).
Higher plasma concentrations mean increased potency and risks.
With such methods (approved by the FDA), it is not surprising that although seniors comprise 17% of the U.S. population, they sustain 51% of the deaths from medication reactions. Or that 10%-17% of all hospitalizations of the seniors are related to medication reactions (9).
Baycol and Women
According to the Washington Post, the majority of Baycol fatalities may have occurred in women. This would not be surprising. In a 1999 study of Baycol at the standard starting dose (0.4 mg) and a one-half dose (0.2 mg), Baycol was substantially more potent in women (10).
With the standard dosage, women achieved average LDL-C reductions of 44.4%, whereas men achieved 37.0% average reductions. This reduction in men was nearly matched by women taking the one-half dosage, achieving 35.4% LDL-C reductions. Thus, many women need only one-half the dosage to obtain similar LDL-C reductions as men taking the full dosage.
Yet, Bayer's package insert made no recommendations for lower doses in women. If indeed women sustained more reactions with Baycol than men, then Baycol would become the 9th of 11 withdrawn medications that affected women the most. I discuss the reasons for this in my upcoming book, Over Dose: The Case Against the Drug Companies (11).
The AMA's Code of Medical Ethics require that patients receive informed consent about all reasonably effective treatments.
"The patient's right of self-decision can be effectively exercised only if the patient possesses enough information to enable an intelligent choice. The physician has an ethical obligation to help the patient make choices from among the therapeutic alternatives consistent with good medical practice (12)."
Therapeutic alternates include low, effective doses that reduce risks. Starting people at a manufacturer-recommended dose without informing patients about lower doses that might suffice violates ethical requirements.
Yet few patients are told about these possibilities.
Baycol Isn't The Only Offender
The lowest available dose of Lipitor, the best-selling statin in America (>48,000,000 prescriptions in 2000), is far stronger than millions of patients require to achieve their target LDL-C (13-16). Indeed, Pfizer doesn't include this low-dose data in the package insert, so doctors are not informed.
Overtreatment Produces Predictable, Avoidable Problems
With such methods, it is not surprising that a 2001 JAMA article noted: "Overuse of statin therapy was found among 69% of patients undergoing primary prevention and among 47% of patients undergoing secondary prevention (17)."
Overtreatment means increased, unnecessary risks.
Taking these risks often isn't necessary. When Merck and Bristol Myers Squibb petitioned the FDA for OTC versions of Mevacor and Pravachol, they provided substantial data demonstrating the effectiveness of very low statin doses in attaining target LDL-C for millions of patients (18, 19).
These excellent responses at very low doses require drug manufacturers and physicians to treat patients as individuals, not statistical averages. And to remember that the best dosage is the lowest effective dosage. Unfortunately, the trend within the drug industry and medical community has been in the opposite direction. Thus, serious problems were all but inevitable.
Months ago, I wrote in Over Dose: The Case Against the Drug Companies (end of Chapter 6) that the overly aggressive marketing and dosing of statin drugs was producing "a tide of concern is mounting. Balance needs to be established in the proper, individualized use of these very helpful drugs.
Otherwise, the excesses that are occurring will increase, reports of severe side effects and deaths will become more common, and another promising group of drugs will become feared by the public (11)." We are at this point now. It is unfortunate, because these problems were predictable -- and because they were predictable, they were avoidable.
About the Author:
Jay S. Cohen, M.D., is an associate professor of Family and Preventative Medicine and of Psychiatry at the University of California in San Diego. He is the author of 2 books and has has numerous papers published in peer-reviewed journals (see below). His latest book, Over Dose: The Case Against the Drug Companies, is due out in October.
Dr. Mercola's Comment:
Well here we have it, the makers of the famous Bayer aspirin voluntarily pulled its statin drug off the market.
The real tragedy is that virtually no one taking any of these statin drugs needs to take them at all if they were following a proper eating plan.
There are a rare group of individuals who have familial hypercholesterolemia. This genetic defect that occurs in about one in 500 people, does not seem to respond favorably to the grain and sugar restriction program.
However, this probably is less than 1% of the people taking the statin drugs.
If you were to believe the "experts," half of Americans should be placed on these drugs.
The European Medicines Evaluation Agency also announced on August 10 a safety review of other drugs in the same class as Baycol.
The review -- by the agency's pharmacovigilance working party -- would focus on the class of drugs known as statins, with a similar chemical make-up to Baycol.
Statins were introduced in 1987 and have quickly become blockbuster drugs with total annual sales now worth more than $14 billion. Leading products include Pfizer Inc.'s Lipitor, Merck and Co Inc.'s Zocor, and Bristol-Myers Squibb Co.'s Pravachol.
If you were on Baycol my suggestion would be to immediately switch over to an optimized eating plan and have your cholesterol level rechecked. Not only will the program control your cholesterol, but it will also reduce your insulin levels, decrease your rate of aging, lower your weight and reduce your risk of diabetes and cancer.
While I agree that overdosage is dangerous I disagree with the view that the goal of treatment is to optimize LDL-cholesterol. My view is that cholesterol has nothing to do with atherosclerosis or cardiovascular disease. A high cholesterol is a risk marker, nothing more, and the goal is not to treat high cholesterol but to prevent cardiovascular disease.
There is overwhelming evidence that the statins do not exert their effect by lowering cholesterol but by other mechanisms. Most important, the effect of statin treatment is independent of the dose - in the trials those whose cholesterol was lowered a little only had just as much benefit from the treatment as those whose cholesterol was lowered the most.
Therefore, there is no reason to check cholesterol at all or to govern the dose by looking at the effect on blood cholesterol. Prevention with statins should be performed with the lowest possible dose and because we don´t know the effect of 10 to 20 years of statin treatment, statins should only be given to patients with serious heart disease, which means a disease with an expected survival time of not more than 4-5 years, the length of the published statin trials.
1. Wierzbicki AS; Lumb PJ; Semra Y; Chik G; Christ ER; Crook MA. Atorvastatin compared with simvastatinbased therapies in the management of severe familial hyperlipidaemias. Qjm, 1999;92(7):38794.
2. Bradford RH; Shear CL; Chremos AN; Dujovne C; Downton M; Franklin FA; et al. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. I. Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia. Archives of Internal Medicine, 1991;151(1):439.
3. Sinzinger H; Rodrigues M. Atorvastatin and fibrinogena small subgroup shows extreme response [letter]. Atherosclerosis, 1999;145(2):4157.
4. Roberts, WC. The rule of 5 and the rule of 7 in lipid-lowering by statin drugs. American Journal of Cardiology, 1997;80:106-7.
5. Chang, J, Green, L. Food and Drug Administration Memorandum. United States Department of Human and Health Services, May 1, 2000.
6. Physicians' Desk Reference, 54th Edition. Montvale, N.J.: Medical Economics Company, 2000.
7. Stein EA. Extending therapy options in treating lipid disorders: a clinical review of cerivastatin, a novel HMGCoA reductase inhibitor. Drugs, 1998;56(Suppl 1):2531;
8. Betteridge DJ. International multicentre comparison of cerivastatin with placebo and simvastatin for the treatment of patients with primary hypercholesterolaemia. International Cerivastatin Study Group. International Journal of Clinical Practice, 1999; 53(4):24350.
9. Cohen, JS. Adverse Drug Reactions: Effective Low-Dose Therapies for Older Patients. Geriatrics, Feb. 2000; 55(2):54-64.
10. Ose L; Luurila O; Eriksson J; Olsson A; Lithell H; Widgren B. Efficacy and safety of cerivastatin, 0.2 mg and 0.4 mg, in patients with primary hypercholesterolaemia: a multinational, randomised, doubleblind study. Cerivastatin Study Group. Current Medical Research and Opinion, 1999, 15(3):22840.
11. Cohen, JS. Over Dose: The Case Against The Drug Companies. Tarcher/Putnam, New York: October 2001. Chapters cited include Chapter 5 "How the Drug Companies' Policies Harm Women;" Chapter 6 "Why 50-75% of People Quit Taking Their Cholesterol-Lowering Medications;" Chapter 8 "Why Seniors Are at the Greatest Risk;" Chapter 14 "How You Can Avoid Side Effects and Use Medications Safely;" as well as chapters on the FDA, drug companies, and many other top-selling drugs.
12. American Medical Association Council on Ethical and Judicial Affairs. Code of Medical Ethics, 1998-1999 Edition. American Medical Association, Chicago, IL.
13. BakkerArkema RG, Best J, Fayyad R, Heinonen TM, Marais AD, Nawrocki JW, et al. A brief review paper of the efficacy and safety of atorvastatin in early clinical trials. Atherosclerosis, 1997; 131(1):1723.
14. Nawrocki JW, Weiss SR, Davidson MH, Sprecher DL, Schwartz SL, Lupien PJ, et al. Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMGCoA reductase inhibitor. Arteriosclerosis, Thrombosis, and Vascular Biology, 1995; 15(5):67882.
15. Bertolini S, Bon GB, Campbell LM, Farnier M, Langan J, Mahla G, et al. Efficacy and safety of atorvastatin compared to pravastatin in patients with hypercholesterolemia. Atherosclerosis, 1997; 130(12):1917.
16. Cilla DD Jr, Whitfield LR, Gibson DM, Sedman AJ, Posvar EL. Multipledose pharmacokinetics, pharmacodynamics, and safety of atorvastatin, an inhibitor of HMGCoA reductase, in healthy subjects. Clinical Pharmacology and Therapeutics, 1996; 60(6):68795.
17. Abookire, SA, et al. Using and monitoring of statin lipid-lowering drugs.... Archives of Internal Medicine, Jan. 8, 2001; 161: 53-58.
18. Merck and Company. Nonprescription Mevacor. FDA Advisory Committee Background Information, FDA Website, June 2000.
19. Bristol-Myers Squibb. Advisory Committee Meeting Briefing Book for the Rx to OTC Switch of Pravachol (Pravastatin Sodium). Joint Meeting of Nonprescription Drugs Advisory Committee and Endocrinologic and Metabolic Drugs Advisory Committee, 2000: www.fda.gov/ohrms/dockets/ac/00/backgrd/3622b2a_part1.pdf.
ARTICLES BY DR COHEN ON PREVENTING ADVERSE REACTIONS WITH LOWER DOSES
Cohen, JS. Dose Discrepancies between the Physicians' Desk Reference and the Medical Literature, and Their Possible Role in the High Incidence of Dose-Related Adverse Drug Events. Archives of Internal Medicine, April 9, 2001:161:957-64.
Cohen, JS. Adverse drug effects, compliance, and the initial doses of antihypertensive drugs recommended by the Joint National Community vs. the Physicians' Desk Reference. Archives of Internal Medicine, March 26, 2001;161:880-85.
Cohen, JS. Preventing Adverse Drug Reactions Before They Occur. Expert Pharmacology Column. Medscape (www.Medscape.com), Dec., 1999.
Cohen, JS. The One-Size Dose Does Not Fit All: Look beyond the guidelines of drug manufacturers. Newsweek, Dec. 6, 1999: page 92.
Cohen, J.S. Ways To Minimize Adverse Drug Reactions: Individualized Doses and Common Sense Are Key. Postgraduate Medicine, Sept. 1999; 106: 163-72.
Cohen JS, Insel PA. The Physicians' Desk Reference. Problems and possible improvements. Archives of Internal Medicine, 1996;156(13):137580.