Pharmacology Watch: HRT - Position Paper Places Benefits in Question
June 15, 2002
HRT: Position Paper Places Benefits in Question
This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. Telephone: (404) 262-5517. E-mail: [email protected]. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study.
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A soon-to-be published position paper will call into question the benefits of hormone replacement therapy (HRT) for women. The "International Position Paper on Women’s Health and Menopause" will go to press in June, but newspapers coast to coast are already publishing the recommendations of the document, which concludes that an evidence-based review of HRT does not support the use of HRT in preventing coronary artery disease, Alzheimer’s disease, depression, or urinary incontinence. The position paper was the product of an international group of 28 doctors and scientists and was funded by the National Institutes of Health and the Giovanni Loren Zini Medical Science Foundation of Italy. The recommendations reflect a shift in opinion for most physicians and epidemiologists who feel that HRT’s risks, which include increased risk of blood clots, cholelithiasis, and breast cancer do not outweigh the potential benefits. The thought process doctors must go through with patients when considering starting or discontinuing HRT is well laid out in a recent "Clinical Crossroads" paper in the Journal of the American Medical Association. Dr. Deborah Grady reviews the current literature, and dilemmas faced by both physicians and patients alike when trying to wade through conflicting studies. A self-avowed former proponent of HRT, Dr. Grady now feels that it should be reserved for treatment of vasomotor symptoms, and that it is second-line therapy to bisphosphonates for the treatment of osteoporosis (JAMA. 2002;287:2130-2137).
Alosetron Set for Comeback
Eighteen months after it was withdrawn from the US market, alosetron (Lotronex) GlaxoSmithKline’s irritable bowel syndrome (IBS) drug, may be making a limited comeback. The FDA’s Gastrointestinal Drugs and Drug Safety Advisory Committees approved the drug for patients with severe IBS symptoms. The drug was initially approved in February 2002 for the treatment of women with IBS characterized by diarrhea. However, soon after the drug was marketed, cases of severe constipation were reported along with several cases of ischemic colitis. Of the 7 deaths, alosetron was possibly a factor in all of them. The drug was effective in selected patients, however, and the FDA was inundated with requests to re-release the drug in a limited fashion. The current plan is to restrict the drug to patients with the most severe symptoms, and to require patients to sign a patient-physician agreement and to receive counseling about the potential risks of the drug. The FDA is also considering limiting the use of alosetron to gastroenterologists. GlaxoSmithKline is working out the plan for re-release of alosetron with the FDA and hopes the drug will be available before the end of the year.
Losartan Could Receive Expanded Indication
The angiotensin receptor blocker (ARB) losartan may soon be approved for prevention of renal disease in type 2 diabetes. The FDA is considering granting losartan the expanded indication based on a favorable vote by the FDA’s Cardiovascular and Renal Drugs Advisory Committee early in April. Angiotensin converting enzyme inhibitors (ACEIs) have long been considered first-line treatment of hypertension in type 2 diabetics because of studies that suggested that blockade of the renin-angiotensin system delays progression to end-stage renal disease. Whether this benefit extends to ARBs was debatable until 3 articles were published in the Sept. 20, 2001, New England Journal of Medicine confirming the benefit of ARBs in protecting patients with Type 2 diabetes from developing renal disease.
Merck supplied additional data to the FDA in April, which eventually led to the recommendation. The FDA is expected to endorse the committee’s recommendation, granting losartan the indication for reno-protection in type 2 diabetes, the first drug to receive such approval.
Viagra Shown Beneficial in Intensive Care Unit
Viagra (sildenafil) in the ICU? It may not be so far-fetched, and the benefit may be lifesaving for those with severe pulmonary hypertension. Sildenafil has been shown to cause pulmonary vasodilation along with its other well-known effects. German researchers looked at 30 patients with severe pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, or pulmonary hypertension due to aplasia of the left pulmonary artery. Patients were randomized to receive sildenafil alone or in combination with iloprost, a long-acting inhaled prostacyclin analogue. Maximum pulmonary vasodilatory potency (maximum reduction of pulmonary vascular resistance and increase in cardiac index) occurred with the combination of sildenafil 50 mg plus inhaled iloprost (-44.2%, 95% CI, -49.5% to -38.8%). This compared with a drop of 14.1% with inhaled nitric oxide. The combined effect of sildenafil with iloprost lasted longer than 3 hours and had minimal effect on systemic arterial pressure and arterial oxygenation. It was concluded that sildenafil is a potent pulmonary vasodilator that acts synergistically with inhaled iloprost (Ann Intern Med. 2002;136:515-522).
Smallpox Vaccination Needs Consideration
Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, has kicked off "an open and public dialogue" on the need for a national preemptive smallpox vaccination program (N Engl J Med. 2002;346:1319-1320). Nearly unthinkable a year ago, the events of Sept. 11 have focused the national health-care community on the real possibility of bioterrorism. And of all the potential bioterrorism pathogens, which include anthrax, plague, and even tularemia, it is smallpox that stands out as a true threat. Declared eradicated from the world in mid-1970s, routine vaccination for smallpox in this country was discontinued 30 years ago. As a result, more than half the American population is susceptible to smallpox infection. Samples of variola virus, the cause of smallpox, were stored at the CDC and were actually produced and stored in the former Soviet Union as part of a biologic warfare program. Those stores were reported destroyed by the current Russian government, but it is unknown whether samples of the deadly virus may have fallen into the hands of potential bioterrorists. Smallpox is a uniquely deadly bioterrorist weapon. Once infected, victims are most contagious prior to the development of symptoms, thus becoming unwitting agents of the bioterrorist, especially in our highly mobile society. Plus smallpox infection carries a relatively high mortality rate, from 5 to 20% based on 30-year-old data.
Current CDC policy for an attack focuses on a "ring-vaccination" strategy in which suspected or confirmed cases and their contacts are isolated and immediately vaccinated. This is the method that successfully eliminated smallpox 30 years ago. The CDC currently is advocating the strategy in the event of a bioterrorists attack. But critics, such as William J. Bicknell, MD, from Boston University School of Public Health, argue that ring-vaccination was effective against natural outbreaks of the virus but may not be effective against a deliberate bioterrorist attack. He makes the case for widespread voluntary smallpox vaccination, which would achieve protection for the majority of Americans and also act as a deterrent to attack (N Engl J Med. 2002;346:1323-1325). There is a risk to the vaccine including encephalitis and vaccinia, and vaccination of the majority of Americans would be expected to result in approximately 180 deaths. This debate would have been moot 2 months ago because it was felt that CDC did not have enough vaccine for a nationwide vaccination program. However, researchers from the National Institute of Allergy and Infectious Diseases Smallpox Vaccine Study Group have tested dilutions of a recently discovered cache of smallpox vaccine produced in 1982. The randomized single-blind trial of 680 adult volunteers showed that both 1:5 and 1:10 dilutions of the vaccine were as effective in conferring immunity as the full strength vaccine, with at least 97% of those vaccinated developing protective antibodies (N Engl J Med. 2002;346:1265-1274). The common side effects from the vaccine included formation of satellite skin lesions, regional lymphadenopathy, fever, headache, nausea, and other signs of a viral infection. But the true upshot of the study was the realization that as a nation, we suddenly have the ability to vaccinate the entire population. But with this realization comes the debate as to whether we should. The turning point in this deliberation may depend on our government’s ability to truly characterize the risk of a bioterrorist attack.
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