Jay S. Cohen M.D.       http://medicationsense.com      1337 Camino Del Mar   Suite C       Del Mar, CA 92014       Phone: 858.345.1760       Fax: 858.509.8944


The Truth About Crestor: Is Crestor Dangerous and If So, Why?

The Intensive Marketing of This New, Super-Strong, Cholesterol-Lowering Statin Drug Raises Questions and Concerns. Are Crestor Users in Jeopardy? Is Crestor Especially Dangerous for Asians? Who Should Take Crestor and When? A Lower, Safer Approach That Most Doctors and Patients Don't Know About
.

What is Crestor and What Is the Problem?
Crestor is the newest statin and the strongest statin yet. Statins are the highly touted drugs for reducing cholesterol. Studies clearly show that statins improve cholesterol numbers (by lowering LDL and raising HDL) and may reduce C-reactive protein. Statins impede atherosclerosis, reduce heart attacks and strokes, and cardiac death. Thus, the statins Lipitor and Zocor are not only the #1 and #2 top-selling drugs in America, but also household names.

Other statins include Pravachol, Mevacor, and Lescol -- and now ultra-potent Crestor. Until 2001, there was another statin: Baycol. It was then the newest statin and a potent statin -- until it was withdrawn because of dozens of deaths. Is Crestor another Lipitor or another Baycol? Although Crestor has been on the market only a year, it has already been linked to numerous cases of severe muscle breakdown, kidney toxicity, and deaths. Public Citizen recently petitioned the FDA to ban Crestor.

The Marketing of Super-Strong Crestor
Crestor's introduction in August 2003 provides a textbook example of how marketing strategies can supersede medical science and common sense. Taking a page from Lipitor's highly successful marketing campaign in 1997, Crestor is now being aggressively marketed as the strongest statin of all.

The manufacturer's recommended initial dose of Crestor is 10 mg/day (except for people with kidney problems). This dosage is so strong that Crestor's advertising can boast it is stronger than equivalent doses of any other statin. This is quite a claim, because Lipitor and Zocor are pretty strong themselves. Indeed, their top-selling status has been built on their own advertising about their power to reduce cholesterol and LDL-cholesterol (LDL-C) levels.

But more isn't necessarily better with most medications, including statins. As I've written in medical journal articles and in my upcoming book (What You Need To Know About Statin Drugs And Their Natural Alternatives),1 the standard starting doses of Lipitor and Zocor are often double or quadruple the amounts that millions of people actually need, triggering many avoidable side effects. So what can we say about super-strong Crestor, which is even stronger? We can say that the drug company-recommended, super-strong initial 10-mg dose of Crestor has already been linked to severe toxicities.1A This should not surprise anyone.

Excessive Doses = More Side Effects
One of my basic principles is: The best dose of any medication is the least amount that works. Medical science agrees. Most people with elevated cholesterol or LDL-C have mild-to-moderate elevations. For many, dietary interventions are enough. For others, modest statin doses are often plenty. But the recommended initial doses of Lipitor, Zocor, and Pravachol are strong, yet that's what doctors prescribe to most people, even to people who don't need such strong statin therapy. This is the crux of the problem of statin side effects such as muscle aches, joint pains, abdominal discomfort, memory and cognitive impairment.2-6 Side effects are a major reason that 60%-75% of people started on statins quit treatment.7,8 The average time until they discontinue treatment: 8 months. Many people quit within a few months.

Liver injury, liver toxicity, and death are also concerns with statins. Like other statin side effects, these reactions are dose-related: the greater the dose, the greater the risk. Dr. W.C. Roberts, the editor-in-chief of the American Journal of Cardiology, warns: "With each doubling of the [statin] dose, the frequency of liver enzyme elevations [indicating liver irritation or injury] also doubles.9"

Nerve injuries have now been documented in people taking statins long-term.10, 11 The incidence is low, perhaps 1 in 2000 to 5,000, but with millions taking statins, this adverse effect will afflict thousands of people each year. These injuries can be severe and permanent, and even mild nerve injuries can take months to fade away.

Doctors cannot anticipate who will develop a long-term side effect with statins, but doctors should (but usually don't) anticipate that they will occur in some people. The only defense: using the least amount of medication you need.

Do We Need a Stronger Statin?
The standard starting dose of Crestor is 10 mg, which reduces LDL-C a whopping 46%-52%.12 Some people, especially those with serious coronary disease, require this degree of LDL-C reduction, but most people with elevated cholesterol require only 20%-30% reductions -- and therefore much less medication.

Crestor's manufacturer does recommend a lower 5-mg dose for people requiring "less aggressive LDL-C reductions.12" Yet, 5-mg Crestor reduces LDL-C 42%, still far more than most people with elevated cholesterol need.

And remember, this 42% LDL-C reduction represents the average among study subjects. Many people get even greater reductions with this dosage. In one study, 5 mg of Crestor reduced LDL-C as much as 71% in subjects.13 This is an impressive number, but reducing cholesterol too aggressively is believed to be a trigger for cognitive, memory, and mood problems with statins. And too low cholesterol levels aren't good either, because cholesterol is a necessary building block in human cells and a substrate of many of our hormones.

So contrary to Crestor's marketing, we shouldn't be overly impressed with which statin is strongest. You don't want the strongest statin. You want the mildest statin that works for you.

Lower, Safer Doses of Crestor Work -- But Your Doctor Doesn't Know About Them The lowest marketed dose of Crestor is 5 mg. Yet, studies show that 2.5 mg of Crestor reduces LDL-C 40%, and just 1 mg reduces LDL-C 34%, on average.13, 14 These doses are still stronger than the standard initial doses of Pravachol, Mevacor, Zocor, and Lescol, and they would certainly be strong enough for most people with elevated cholesterol. Indeed, the lead author of one Crestor study stated: "Even at 1 mg/day, rosuvastatin [Crestor] reduced LDL-C by 35%, the same percentage reduction seen with simvastatin [Zocor] 20 and 40 mg.14"

Yet, you won't find any information about this in the Crestor package insert,12 pharmacy slips, or the Physicians' Desk Reference.2 Crestor's manufacturer isn't going to inform you or your doctor about lower Crestor doses that aren't available, even if they are effective -- and safer. This goes right to the heart of the issue of informed consent. Your right of informed consent is denied if you aren't given enough information to make an intelligent choice.15 You aren't alone: one study showed that only 9% of office patients receive enough information to fulfill their right of informed consent .16 No wonder medication side effects continue to be one of the leading causes of death in America.

The Marketing of Crestor
Why isn't Crestor marketed at lower, safer doses? Drug companies like to keep dosing simple, because simple dosing makes doctors' job easier. The fact is, doctors are inadequately trained about medications. Their one pharmacology course covers hundreds upon hundreds of drugs, but not deeply. Doctors assume that drug companies and the FDA are providing complete information with the best doses, when in fact they aren't. That's why doctors rarely question irrational drug company guidelines even when the guidelines tell doctors to prescribe the same strong doses to young and old, big and small, healthy and frail.

I could list hundreds of quotes about problems with drug research and marketing, but the following two will suffice. The first is from Dr. Andrew Herxheimer, the highly respected expert at Britain's renowned Cochrane Centre:


"Drugs are often introduced at a dose that will be effective in around 90% of the target population, because this helps market penetration. The 25% of patients who are most sensitive to the drug get much more than they need.17"


Actually, with statins, the number is probably much higher. Dr. David Kessler, when he was FDA commissioner, wrote this about marketing strategies vs. medical science:


"Pharmaceutical companies are waging aggressive campaigns to change prescribers' habits and to distinguish their products from competing ones, even when products are virtually indistinguishable. Victory in these therapeutic-class wars can mean millions [billions today] of dollars for a drug company. But for patients and providers it can mean misleading promotions, conflicts of interest, increased costs for health care, and ultimately, inappropriate prescribing.18"


My articles and books contain dozens of examples of excessively dosed drugs. Crestor is another. In October 2003, Dr. Richard Horton, editor of the Lancet, published a scathing critique of Crestor's marketing, stating that the manufacturer's tactics "raise disturbing questions about how drugs enter clinical practice and what measures exist to protect patients from inadequately investigated medicines...." Yet, Horton added, the manufacturer will "do whatever it takes to persuade doctors to prescribe rosuvastatin, including launching an estimated $1 billion first-year promotional campaign.19"

So, even though the FDA has repeatedly cautioned doctors about using new drugs when older, better known drugs are available, the onslaught of drug reps and intensive advertising pushing Crestor has worked. By early 2004, 27% of all new prescriptions for statin drugs was for Crestor. The Wall Street Journal reported:


"AstraZeneca sales force (Crestor) was making more calls to doctors than any of its competitors. Beginning in late February, reflecting the sales calls, new prescriptions of Crestor began to rise and overtook Lipitor by the beginning of March.20"


Once again, intensive marketing trumps medical science -- and patient safety. Is this how we want our health care system to run?

Is Crestor Risky for Asians?
In studies, blood levels of Crestor rose twice as high in Chinese and Japanese subjects as in other groups. Higher blood levels mean stronger effects and greater risks of side effects. The only place in the lengthy Crestor package insert that specifically describes this problem is the "Clinical Pharmacology, Special Populations" section, which many doctors won't notice. Yet, the all-important "Dosage and Administration" section, which most doctors do read, makes no mention of Asian patients. It does make a vague statement about patients "who have predisposing factors" to side effects, but many doctors will miss the implication and prescribe the same strong standard doses of Crestor to Asian patients. If you are of Asian heritage, it is better to use other statins that don't pose particular risks to Asians.

Crestor? Crestor vs. Lipitor, Zocor, Pravachol, Mevacor, and Lescol
How does Crestor compare with other statins? Who should get Crestor? As it is, many doctors are already prescribing overly strong doses of statins to people who don't need such intensive treatment. Stories abound about doctors prescribing excessively strong doses and ignoring obvious, serious side effects.

It is important to remember that in most instances, elevated cholesterol is not an emergency. There's time to use caution, to use the "Start Low, Go Slow" method that allows you and your doctor to gauge the exact amount of medication you need. Different people get widely differing responses to statins. Some people get large LDL-C reductions with tiny doses. Others require stronger doses. The only way to know your response is to start low and, if needed, increase gradually. Of all the statins, this is least possible with Crestor.

Who actually needs Crestor? Hardly anyone. Other statins have much longer track records and should be used first. The respected Medical Letter on Drugs and Therapeutics agrees, recommending Crestor only for "non-Asian patients who have not responded adequately to statins with a longer record.21"

The fact is, milder statins such as Mevacor, Lescol, and Pravachol are strong enough for most people. Lipitor and Zocor are strong enough for almost all of the rest. There are very few people who actually require super-strong Crestor. Moreover, Mevacor is now available as generic lovastatin and much cheaper at pharmacies such as Costco.

What You Should Do
A favorite tactic of drug companies is to provide free samples. Drug companies know that once you are started on a medication, you won't want to switch. So sales reps shower doctors with samples, and doctors think they are doing you a favor by giving you a free sample when starting a medication. But they aren't doing you a favor at all.

So if your doctor offers you free samples of Crestor, respectfully decline. Drug companies don't provide samples because of their altruism, but as hooks to boost sales of new drugs against established competitors. Unless a new drug really offers something important, resist the pitch.

When Baycol was withdrawn because of dozens of deaths, Newsweek asked me what I thought. My response: "I think it's frightening that 800,000 people were taking Baycol. Baycol was the newest and least known statin, and it offered nothing superior to other statins. No one should have been exposed to Baycol unless the other five statins had been tried first unsuccessfully, and that is very few people.22" My opinion remains exactly the same about Crestor.

The marketing of Crestor is an outrage. The frequent prescribing of super-strong Crestor by doctors is symptomatic of how dominant the drug industry is in influencing the knowledge and decisions of doctors. We must change this. If your doctor suggests Crestor, ask why. Unless there's a very good reason, tell your doctor you would prefer a statin with a longer track record. If your doctor dismisses your opinion, you can quote the top drug experts at the FDA, as they recently wrote in the Journal of the American Medical Association:


"Clearly, physicians and patients should be aware that recently marketed drugs are at risk of being found to cause unsuspected serious adverse effects.... A physician considering prescribing a new drug should consider carefully the reason for the choice, particularly when an equally effective alternative is available, as there is always some risk of an undiscovered adverse drug reaction.23"


If you are feeling bold, ask your doctor why he/she is suggesting the least-known, most-powerful statin that already has been linked to multiple toxicities, rather than better known, apparently safer other statins. Until we hold our own doctors accountable for their thoughtless decisions, nothing will change and our children will be subjected to the same drug-company controlled health care system.

You may also want to tell your doctor that you would rather start with a low-dose statin. Many people get good results with low doses. If you don't, the dosage can be easily, gradually increased so that you get the right amount of statin for you and not a milligram more. Remember, the best dose of any medication is the lowest dose that works. If the medical community applied this principle consistently, we would not have a side-effect epidemic today.

References
1. Cohen, JS. What You Need to Know about Statin Drugs and Their Natural Alternatives. Square One Publishing, New York: September 2004.
1A. More Crestor Safety Concern; Call for Ban Renewed. Dickinson's FDA Webview, 5/17/2004.
2. Physicians' Desk Reference, 57th Edition, Montvale, N.J.: Medical Economics Company, 2003.
3. Wierzbicki, AS, Lumb, PJ, Semra, et al. Atorvastatin compared with simvastatin-based therapies in the management of severe familial hyperlipidaemias. Qjm 1999;92(7):387-94.
4. Nawrocki, JW, Weiss, SR, Davidson, MH, et al. Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor. Arteriosclerosis, Thrombosis, and Vascular Biology 1995;15(5):678-82.
5. Bertolini, S, Bon, GB, Campbell, LM, et al. Efficacy and safety of atorvastatin compared to pravastatin in patients with hypercholesterolemia. Atherosclerosis 1997;130(1-2):191-7.
6. Marz W, Wollschlager H, Klein G, et al. Safety of low-density lipoprotein cholestrol reduction with atorvastatin versus simvastatin in a coronary heart disease population (the TARGET TANGIBLE trial). American Journal of Cardiology 1999;84(1):7-13.
7. Jackevicius, CA, Mamdani, M, Tu, JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA 2002;288:462-467.
8. Benner, JS, Glynn, RJ, Mogun, H, et al. Long-term persistence in use of statin therapy in elderly patients. JAMA 2002;288:455-461.
9. 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.
10. Gaist, D, Jeppesen, U, Andersen, M, et al. Statins and the risk of polyneuropathy: a case-control study. Neurology 2002;58:1333-1337.
11. Peripheral neuropathy due to statins: a rare but potentially incapacitating adverse effect. Prescribe International 2000;9:115.
12. Crestor Package Insert. AstrZeneca Pharmaceuticals LP, Wilmington DE:2003.
13. Olsson, AG, Pears, J, McKellar, J, et al. Effect of rosuvastatin on low-density lipoprotein cholesterol in patients with hypercholesterolemia. American Journal of Cardiology 2001;88:504-508.
14. Olsson, AG. A new statin: a new standard. The American Journal of Managed Care 2001;7:S152.
15. American Medical Association Council on Ethical and Judicial Affairs. Code of Medical Ethics, 1998-1999 Edition. American Medical Association, Chicago, IL.
16. Braddock, CH, Edwards, KA, Hasenberg, NM, et al. Informed Decision Making in Outpatient Practice: Time to Get Back to Basics. JAMA 1999;282:2313-20.
17. Herxheimer, A. How much drug in the tablet? Lancet 1991;337:346-8.
18. Kessler, DA, Rose, JL, Temple, RJ, Schapiro, R, Griffin, JP. Therapeutic-class wars--drug promotion in a competitive marketplace. New England Journal of Medicine 1994;331(20):1350-3.
19. Horton, R. The statin wars: why AstraZeneca must retreat [editorial]. Lancet 2003 (Oct. 25);362:1341.
20. Winslow, R. Lipitor prescriptions surge in wake of big study. Wall Street Journal, Mar. 18, 2004:D4.
21. Rosuvastatin -- a new lipid-lowering drug. The Medical Letter on Drugs and Therapeutics, Oct. 2003;45:81-83.
22. Cohen, JS. Too Much of a Good Thing? Baycol: A Cholesterol Drug Is Pulled after 31 People Died -- What Happened? Newsweek.MSNBC.com, Aug. 10, 2001:www.msnbc.com/news/612443.asp.
23. Temple, RJ, Himmel, MH. Safety of Newly Approved Drugs. JAMA, May 1, 2002;287:2273-2275.





NOTE TO READERS: The purpose of this E-Letter is solely informational and educational. Theinformation herein should not be considered to be a substitute forthe direct medical advice of your doctor, nor is it meant to encourage the diagnosis or treatment of any illness, disease, or other medical problem by laypersons. If you are under a physician's care for any condition, he or she can advise you whether the information in this E-Letter is suitable for you. Readers should not make any changes in drugs, doses, or any other aspects of their medical treatment unless specifically directed to do so by their own doctors.

If you have questions about your medications or medical care, Dr. Cohen is available for consultation at his office or by telephone.

If you find this article informative, please tell your friends, family members, colleagues, and doctors about www.MedicationSense.com and the free MedicationSense E-Newsletter.