After Baycol, Now What: part 2

Posted by James

Modifications of the lipid and lipoprotein classification now identify LDL cholesterol below 100 mg/dl as optimal. What is now considered to be low HDL cholesterol has changed to values below 40 mg/dl, up from the previous 35 mg/dl. The optimal triglyceride level has been determined to be less than 150 mg/dl. The new guidelines suggest a comprehensive lipoprotein panel (total, LDL-C, HDL-C, and triglycerides) as the preferred initial test, rather than the previous recommendation of total cholesterol and HDL-C alone. The new guidelines also encourage a more rapid initiation of drug therapy, sometimes simultaneously with lifestyle modifications.

In the near future, newer modalities will be available to treat hypercholesterolemia. For example, ezetimide is a new cholesterol-absorption inhibitor being developed by Schering-Plough that is believed to have a reduced potential for systemic side effects because it is non-absorbed. It has been used as monotherapy and in conjunction with statins. Rosuvas-tatin is a new, more potent statin that should be available later this year. In clinical trials, rosuvastatin generic has proved to be more effective that atorvastantin.

On January 18, 2002, Bayer announced that it was aware of over 100 deaths linked to the use of cerivastatin. Studies from the FDA have determined that the rate of fatal rhab-domyolysis associated with cerivastatin is 16 to 80 times as high as the rate for any other statin. Among patients in whom cerivastatin was used without the concomitant use of gemfibrazole, deaths were twice as likely to occur at the 0.8-mg dose than at the 0.4-mg dose. The majority of complications and deaths occurred in elderly patients and occurred more frequently in women.

Former cerivastatin patients can be classified as symptomatic, asymptomatic, and fearful. Those that were symptomatic were the easiest to identify. However, even asymptomatic patients might be at a permanently increased risk of liver, kidney, cardiac, and skeletal muscle damage, especially during re-challenge to a statin or upward titration. Those patients who are now fearful of the entire statin class require the assistance of the health care team to educate them on the risk/benefit ratio of statins. It is hoped that those in need will realize that the benefits of cholesterol reduction with statins far outweigh the risks associated with treatment.

The actual cause of statin-induced mylagia is not known. One theory suggests that the mylagia, usually expressed and pronounced in the calves and low back, increases with dose and might be caused by interference with oxidative phosphory-lation and the depletion of coenzyme Q (ubiquinone).
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In essence, former cerivastatin patients who are now on a different statin might represent a new class of patients. The estimated 700,000 to 800,000 former cerivastatin patients should be treated with the same caution and monitoring as subjects enrolled in clinical trials, and might benefit from closer monitoring of their liver and muscle enzymes than is currently recommended by the manufacturers for patients beginning therapy on a statin de novo.

We encourage the pharmaceutical industry to form a collaborative effort with its physician and pharmacist partners to establish registries to track patients who have been subjected to adverse effects of medications. One such example is the registry that was created by GlaxoSmithKline to track patients with irritable bowel disease who were exposed to alosetron (Lotronex). We know of no such registry funded by Bayer’s pharmaceutical division for cerivastatin. If the pharmaceutical industry doesn’t participate in helping to create these registries, physicians should seek a government endowment or other private funding.

A registry of former cerivastatin patients might reveal patterns of early indications of myalgia and rhabdomyolysis. More importantly, we must address the question of why deaths occurred. Were they predictable, and therefore avoidable? Were other confounding factors, such as alcohol usage, involved? Key questions such as these cannot be answered without the formation of registries to effectively track and monitor patients. cheap cialis canadian pharmacy

One irony of properly designed clinical trials is that subject protection frequently precludes all but the healthiest patients from participating. Therefore, we might not be getting a true picture of how those patients who would not have met entry criteria might respond to a given medication. Post-marketing self-reporting by physicians remains an imperfect solution because of physician under-reporting to the FDA.

In summary, the adverse reactions and deaths suffered by patients exposed to cerivastatin have brought to light a whole new series of challenges for P&T committees and all health care providers involved in patient safety. Although the exact cause of these adverse reactions is not known, the growing pool of patients exposed to statins intensifies the need to better track these patients. This situation also exposes the need for P&T committees to have in place methods to review new dosages and indications for medications, along with adequate monitoring systems to track adverse reactions.