Jewish World Review Dec. 7, 2004 / 24 Kislev, 5765

Vioxx: Merck's debacle; a new cure for congestive heart failure?; ovary transplantation preserves ovarian function in young cancer patients

By Robert A. Wascher, M.D., F.A.C.S. | Lancet: By now, most readers know that Merck, the manufacturer of the anti-arthritis drug Vioxx, pulled the blockbuster medication off of the market in September of 2004 after several compelling research studies associated the use of Vioxx with an increased risk of heart attack and stroke. Pharmaceutical industry analysts are now conservatively estimating Merck's potential liability for Vioxx-related litigation at $18 billion or more, and Merck's stock, not surprisingly, has taken a dive in recent weeks. However, a newly published retrospective analysis of the cumulative scientific data on Vioxx suggests that ample evidence for concern about the drug's safety profile existed as early as 2000.

Vioxx (also know by its generic name, rofecoxib) was a market leader in a relatively new class of nonsteroidal antiinflammatory drugs (NSAIDs) known as COX-2 inhibitors. Unlike older generations of NSAIDs that equally block the effects of both known forms of the COX enzyme (COX-1 and COX-2), the newer COX-2 inhibitors block only the COX-2 form that is associated with inflammation and pain. Other drugs in this class, which are still on the market, include Celebrex and Bextra.

Using a sophisticated statistical method (meta-analysis) that allows scientists to compare multiple small studies, including research studies conducted using different methodologies, the authors evaluated 18 randomized controlled trials and 11 non-randomized clinical trials involving Vioxx. Based upon an analysis of the existing research data published in the worldwide medical literature by the end of 2000, the incidence of heart attack associated with the use of Vioxx was already more than twice that seen in study participants not taking the anti-arthritis drug. By the end of 2001, after an additional year of follow-up, the risk of heart attack among study participants taking Vioxx was still more than twice that of patients who were not taking Vioxx. Furthermore, the more than doubled risk of heart attack associated with Vioxx use was consistently observed in research studies that compared Vioxx with placebos (sugar pills) as well as studies that compared Vioxx with other types of NSAID drugs.

These findings raise obvious concerns about the pharmaceutical industry's accountability for the drugs that it produces and markets. Even more worrisome, in the minds of some people, was the Food & Drug Administration's (FDA's) apparent failure to compel Merck to withdraw Vioxx from the market prior to Merck's decision to do so itself in September 2004. Vioxx joins a growing list of "bad boy" drugs that have been withdrawn from the market after receiving full FDA certification. In some cases, these drugs are pulled out of the marketplace because uncommon side effects did not become evident until large numbers of patients were taking the medications. In other cases, investigations have determined that pharmaceutical company scientists and program managers disregarded (or worse…) worrisome data collected during early testing of new drugs prior to their release to the general public. Still other drugs, as appears to be the case with Vioxx, were rapidly observed to be associated with serious side effects, but neither the manufacturer nor the FDA intervened in a timely fashion to halt the sales of such drugs.

In light of the Vioxx controversy, the FDA is currently considering the imposition of a so-called "black box" warning for Bextra. This action is being contemplated due to recent findings that the use of Bextra in patients undergoing open heart surgery was associated with an increased incidence of heart attack and stroke….

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While some critics accuse the FDA of being too cozy with the pharmaceutical industry, the agency often faces the polar opposite criticism of erecting unnecessary obstacles to the timely approval of promising new drugs. At the same time, the FDA is woefully under-resourced when compared to the multi-billion dollar arsenal of Big Pharma. In my new book (to be published in late 2005), The Great Hormone Replacement Therapy (HRT) Debate: What Every Woman (and Man) Should Know About HRT!, another cautionary tale about the pharmaceutical industry is explored. The carefully constructed mythology built-up around Premarin and Prempro, Wyeth-Ayerst's phenomenally successful HRT drugs, withstood growing scientific concerns and scrutiny for more than five decades before incontrovertible scientific evidence refuted many of Wyeth's claims about the drugs, both in terms of their alleged benefits and their long-suspected side effects.

As has occurred in the past, we are probably seeing the beginning of an oscillation back towards a period of greater FDA scrutiny of new drugs following the recent withdrawal of Vioxx and several other prescription medications. Predictably, this anticipated reaction by the FDA will result in equally passionate and sincere calls for the FDA to back-off when it comes to perceptions that the chronically beleaguered agency is holding-up approval of innovative new drugs until potential safety concerns can be thoroughly vetted….

Journal of Clinical Investigation: Congestive heart failure (CHF) is a serious health problem that afflicts nearly 5 million Americans, with more than 500,000 new cases diagnosed each year. Nearly 1 out of every 100 people aged 50 and above will have CHF, and the incidence rises to more than 5 percent after age 75. About 10 percent of patients with CHF will die within one year of their diagnosis, and 50 percent will die within 5 years.

CHF results from a reduced ability of the heart to pump blood throughout the body, and through the blood vessels of the lungs. Due to this "pump failure," the hearts of patients with CHF cannot supply enough oxygen-rich blood to the body's organs and tissues. Patient become short of breath, and sometimes even while at rest in cases of advanced CHF. Ankles and feet swell due to increased pressure in the arterial and venous vessels of the lower body. While medications can help an ailing heart to pump more effectively, heart transplantation remains the only cure for end-stage CHF (temporary heart-assisting devices, called ventricular assist devices, are also sometimes used as a bridge to transplantation).

A new study has evaluated the use of gene therapy to restore the pump function of heart cells in rats with experimentally induced CHF, and the results appear to be striking. S100A1, a calcium-binding protein, is known to improve the pumping action of normal heart muscle cells, and is also known to be reduced in the hearts of patients with CHF. In a very elegant study, the researchers inserted the gene for S100A1 into Adenovirus, a virus that commonly causes flu-like symptoms in humans, and then injected the modified virus into rats with CHF. Following injection of the S100A1 gene into the hearts of these rats, normal levels of the protein encoded by the gene were restored within the damaged heart muscle cells. More importantly, normal heart contractile function was restored to the ailing hearts of these animals.

While the use of gene transfer therapy in humans remains controversial, this study is stunning in its implications. By demonstrating the feasibility of restoring normal heart muscle function in rats with CHF though the use of gene therapy, this study raises the possibility that CHF, a disease that is both highly lethal and rarely curable (due to the shortage of donor hearts), might someday be cured by transferring a specific gene into the hearts of humans with CHF. As with all gene therapies, the biggest hurdle yet to be overcome involves finding an efficient and safe method to deliver the therapeutic gene(s) into the target organs or tissues in the body. Many strains of viruses, including Adenovirus, have previously been used for this purpose. However, there have been occasionally disastrous outcomes associated with using viruses as vectors for gene transfer. A great deal of research is, therefore, currently underway in an effort to find an efficient by relatively nontoxic vector, or vehicle, for therapeutic gene delivery.

Cancer: Women who are treated for cancer of the cervix (and other cancers) with chemotherapy or radiation therapy are often rendered infertile as a result of such treatments. As a result, young women who undergo these cancer therapies are often thrown into premature menopause, with all of the attendant symptoms and risks of menopause, including infertility, hot flashes, osteoporosis, and atrophy of their urogenital system. In view of the potentially serious side effects associated with premature ovarian failure in young women, a pioneering new surgical procedure has been successfully attempted. Surgeons are now reporting the successful "autotransplantation" of an ovary into a woman's left upper arm at the time of surgery for her cervical cancer. Following surgery, the implanted ovary was monitored with ultrasound and other studies. After more than a year of follow-up, the implanted ovary was confirmed to be functioning normally in its new home! This remarkable procedure may offer hope of future fertility, and a continuation of normal ovarian function, for young women who must undergo potentially ovary-damaging chemotherapy, radiation therapy or surgery for cancer.

JWR contributor Dr. Robert Wascher is an oncologic surgeon, professor of surgery, oncology research scientist, and author. He lives in Honolulu with his wife and two daughters. Comment by clicking here.



© 2004, Dr. Robert A. Wascher