In a lead article published in the June issue of the American Journal of Cardiovascular Drugs, Florida Atlantic University researcher Charles H. Hennekens, M.D., the first Sir Richard Doll Research Professor in the Charles E. Schmidt College of Biomedical Science and a renowned expert who has elucidated numerous causal, therapeutic and preventive factors in the treatment and prevention of cardiovascular disease (CVD), most notably low-dose aspirin, discusses the strengths, limitations, and clinical and regulatory considerations of fixed-dose combination therapy with statins.

Statins are used for the treatment of lipid disorders, in particular, elevated LDL (bad) cholesterol in patients with and without prior CVD. These drugs reduce risks of myocardial infarction, stroke and deaths from CVD. In the U.S. today, for secondary prevention, approximately 12.4 million people are eligible for treatment with statins and, for primary prevention, approximately 24 million are eligible. Even before the more stringent guidelines were promulgated in 2004, only about one third of eligible patients were being treated and about 37% were achieving the federally mandated goals. While newer and more potent statins such as rosuvastatin and atorvastatin can achieve the goals for the majority of patients, often statins are prescribed along with other cholesterol-lowering drugs such as nicotinic acid (niacin) or ezetimibe (Zetia).

Fixed-dose combination drugs which include statins first appeared on the market in 2004. For example, Pravigard contains pravastatin to inhibit atherosclerosis and aspirin to inhibit thrombosis. More recently, Vytorin combined simvastatin to reduce the production of LDL cholesterol and ezetimibe to reduce absorption.

“The controversies surrounding fixed-dose combination statins have drawn attention to Vytorin as well as issues in drug development and approval,” said Hennekens.

In his article, “Fixed-dose Combination Therapy with Statins,” Hennekens cites both strengths and limitations of these therapies. The potential strengths include: (1) increased compliance; (2) convenience; and (3) cost savings. In contrast, potential limitations include: (1) reduced flexibility in dosing; (2) exposure of some patients to therapies they do not require; and (3) increased risks of adverse effects without additional benefits.

“The current FDA policy for fixed-dose combination drugs was established in 1971, and its primary goal was to implement the efficacy requirement added in 1962 to the Federal Food, Drug, and Cosmetic Act (FDCA),” said Hennekens. “The objective was to remove numerous fixed-dose combination products from the market that lacked a reasonable medical basis for combined use.”

According to Hennekens, the fixed-dose combination drug approval policy remains a valid framework and includes four key components, namely efficacy, safety, independent contribution and medical need.

The article briefly describes the FDA regulatory process for the approved fixed-dose combination therapies with statins including niacin/lovastatin (trade name Advicor), ezetimibe/simvastatin (trade name Vytorin), amlodipine/atorvastatin (trade name Caduet) and aspirin/pravastatin (trade name Pravigard PAC).

Hennekens’ concluding remarks note that regulatory approval of fixed-dose drug combination products includes consideration of numerous issues. For example, the efficacy of both products combined should be demonstrated to be greater than either agent alone. Finally, there must be an unmet need and the demonstration of a population at risk which would benefit from the fixed-dose drug combination.

According to the American Heart Association, approximately 73 million people in the U.S. age 20 and older have high blood pressure and one in three adults has high blood pressure. In addition, approximately 105 million Americans age 20 and older have total blood cholesterol levels of 200 mg/dL and higher, 50 million are men and 55 million are women. Of these, about 42 million have total blood cholesterol levels of 240 mg/dL or higher, 18 million are men and 24 million are women. Higher LDL cholesterol levels combined with other risk factors including hypertension increase the risks of heart attacks, strokes and deaths from cardiovascular disease.

“The availability to healthcare providers of several statins of varying efficacy on lipid levels as well as fixed-dose drug combinations, reinforces the need for astute and individual clinical judgment in the context of the results of randomized trials in order to do more good than harm,” said Hennekens.

Florida Atlantic University opened its doors in 1964 as the fifth public university in Florida. Today, the University serves more than 26,000 undergraduate and graduate students on seven campuses strategically located along 150 miles of Florida's southeastern coastline. Building on its rich tradition as a teaching university, with a world-class faculty, FAU hosts ten colleges: College of Architecture, Urban & Public Affairs, Dorothy F. Schmidt College of Arts & Letters, the Charles E. Schmidt College of Biomedical Science, the Barry Kaye College of Business, the College of Education, the College of Engineering & Computer Science, the Harriet L. Wilkes Honors College, the Graduate College, the Christine E. Lynn College of Nursing and the Charles E. Schmidt College of Science.

Nearly one in 10 obstetricians in a new study has considered giving up obstetric practice because of the emotional toll of stillbirths and infant deaths.

Three-quarters of the 804 obstetricians who responded to a survey by researchers at the University of Michigan Health System reported that the experience took a large emotional toll on them personally.

“Our survey reveals that perinatal death has a profound effect on obstetricians, and 8 percent had considered giving up obstetrics because of the emotional difficulty of caring for patients with perinatal death,” says lead author Katherine Gold, M.D., MSW, of U-M’s Department of Family Medicine and Department of Obstetrics and Gynecology.

“We know that stillbirth and infant death are traumatic events for families; this study suggests that they are also traumatic for the physician.”

The study appears in the July issue of the journal Obstetrics & Gynecology.

Approximately 15 percent of pregnancies end in early losses (before 20 weeks gestation). In the United States, 1.3 percent of pregnancies end in either stillbirth (losses after 20 weeks but before delivery) or infant death (deaths in the first year of life, most of which occur in the first week). On average, the typical obstetrician performing 140 deliveries a year could encounter nearly two dozen women with a miscarriage and one to two with stillbirth or infant death, the study says.

“Obstetricians want to see a healthy baby. When a fetus or baby dies, the loss can be devastating for the physician,” Gold notes. “Half of the time, the medical cause of a stillbirth is unknown, but physicians still may struggle with feelings of guilt or self-blame.

“When a fetus or baby dies, we focus on the family's needs, but obstetricians are often struggling with their own emotions too.”

The threat of lawsuits also weighs heavily on physicians. Stillbirths are the number two reason for lawsuits against obstetricians in the United States, preceded only by allegations involving births with adverse neurologic outcomes. In the study, 43 percent of obstetricians who responded said they had worried about disciplinary or legal action due to a perinatal death with no identified cause.

Improved physician training would help obstetricians, according to a majority of the study’s respondents. Physicians who said they’d had adequate bereavement training were less likely to report that they had considered giving up obstetric practice because of the emotional difficulty of perinatal death, the study notes. Physicians who perceived their own training as adequate were less likely to worry about disciplinary or legal action when cause of death was unknown.

“As physicians, we get a lot of training in medicine but little in death and bereavement. Sudden and unexpected losses can be terribly difficult both for families and for the physicians involved in caring for the family,” Gold says. “This study shows that stillbirths and infant deaths can have profound and persistent effects on obstetricians. We need to find ways to help both families and physicians cope with these devastating events.”

Two-thirds of physicians supported training by formal presentations or seminars, and nearly half recommended informal gatherings for physicians to discuss difficult experiences. Many respondents suggested that a meeting with bereaved parents could serve as a useful training strategy as well as a way of helping physicians cope with their own feelings about the loss.

Methodology: A total of 1,500 randomly selected U.S. obstetricians were mailed a self-administered survey with 51 questions about their experiences and attitudes in dealing with perinatal death. Eight hundred four physicians (54 percent) completed the entire survey.

Authors: In addition to Gold, authors were Rodney Hayward, M.D., of the Department of Internal Medicine and the School of Public Health, and Angela L. Kuznia, MPH, of the Department of Obstetrics and Gynecology and School of Public Health.

Funding: The research was supported by the Robert Wood Johnson Clinical Scholars Program and the U-M Department of Obstetrics and Gynecology.

Reference: Obstetrics & Gynecology, “How physicians cope when a baby dies: a national survey of obstetricians,” Vol. 112, issue 1, pages 29-34.

For more information:

Pregnancy complications http://www.womenshealth.gov/pregnancy/complications/complicationssp.cfm

Information about stillbirth from the March of Dimes http://www.marchofdimes.com/professionals/14332_1198.asp

Dr. Katherine Gold http://www2.med.umich.edu/pcdv2/provider/dsp_provprofile.cfm?individual_id=93928&um_department=Family%20Medicine

People who have a birthweight over 10 pounds are twice as likely to develop rheumatoid arthritis when they are adults compared to individuals born with an average birthweight, according to a study published by researchers from Hospital for Special Surgery online in advance of print in the Annals of the Rheumatic Diseases. While the mechanism for this association is unclear, the study identifies a potentially modifiable risk factor and highlights a potential way to decrease the incidence of the disease.

“There may be a relationship between being born over 10 pounds and getting rheumatoid arthritis later in life,” said Lisa Mandl, M.D., MPH, who led the study and is an attending rheumatologist at Hospital for Special Surgery (HSS) in New York City. “If there was some way that you could prevent someone from getting rheumatoid arthritis by making sure their birth weight wasn’t over 10 pounds, this is a risk factor that could be modifiable. You can’t change someone’s age. You can’t change someone’s gender, but potentially you could change someone’s birth weight. This is however only speculative at this point.”

Previously, investigators have demonstrated that an increased risk of adult onset chronic disease can be a function of the fetal environment. Strong associations between low birth weight and an increased risk of type 2 diabetes mellitus, coronary heart disease and hypertension have been documented in a number of different populations. Published in 2003, a case-control study of roughly 400 individuals in Sweden identified an association between high birthweight and rheumatoid arthritis.

To see if this association played out in a larger population, Dr. Mandl and colleagues turned to a study of 87,077 women in the Nurses’ Health Study. In 1976, nurses were invited to participate in this study that involved a baseline survey and then a biennial questionnaire regarding health status, lifestyle, family medical history and health practices. The investigators excluded women who had cancer or any type of connective tissue disease at baseline or follow-up because these can cause joint swelling, symptoms that can be confused with rheumatoid arthritis. Also excluded were women who reported having rheumatoid arthritis or connective tissue disease during follow-up, but in whom the diagnosis could not be confirmed by review of their medical record. The study population included only women who answered a 1992 survey that collected information about birthweight. After these exclusions, 87,077 individuals were included in the study and 619 of them developed rheumatoid arthritis.

Through statistical analysis, the investigators discovered that a birthweight of greater than 4.54 kg doubled the risk that a person would develop rheumatoid arthritis as an adult compared with individuals who had an average birthweight.

“In utero, the fetus will react appropriately to different stressors. However, this may preprogram the fetus so that when it gets out into the world, this preprogramming is not helpful out in the ‘real world’,” said Dr. Mandl. In other words, the fetal environment may be preprogramming people’s brains or endocrine systems to be maladapted in later life.

“There have now been two different groups, in different countries with different patients born at different times, that both suggest a similar relationship between birthweight and rheumatoid arthritis,” said Dr. Mandl. “I hope that other people will think about looking for this association in other populations.”

Dr. Mandl says that patients with rheumatoid arthritis are known to have a dysregulated hypothalamic-pituitary-adrenal (HPA) axis, and this axis may be affected in utero. The HPA axis is the body’s neuroendocrine system that involves the hypothalamus, pituitary and adrenal glands; this system is responsible for handling stress by regulating the production of cortisol, neurotransmitters and key hormones.

“If you look at this as a theoretic biologic underpinning for why this might be true, it might give basic scientists interesting ideas to think about regarding what causes rheumatoid arthritis, and provide support for a new hypothesis,” Dr. Mandl said.

According to the National Institute of Arthritis and Musculoskeletal and Skin Diseases, about 2.1 million people, or between 0.5 and 1 percent of the U.S. adult population, have rheumatoid arthritis, an autoimmune disease that causes chronic inflammation of the joints. The disease is more common in women and has no cure, but can be managed in a way that allows individuals to live productive lives.

In addition to researchers from Hospital for Special Surgery and Weill Cornell Medical College, investigators from the Brigham and Women’s Hospital, Harvard Medical School contributed to the study. This research was supported by grants from the National Institutes of Health.

About Hospital for Special Surgery

Founded in 1863, Hospital for Special Surgery (HSS) is a world leader in orthopedics, rheumatology and rehabilitation. HSS is nationally ranked No. 1 in orthopedics and No. 3 in rheumatology by U.S. News & World Report (2007), and has received Magnet Recognition for Excellence in Nursing Service from the American Nurses Credentialing Center. In 2008 and 2007, HSS was a recipient of the HealthGrades Joint Replacement Excellence Award. A member of the NewYork-Presbyterian Healthcare System and an affiliate of Weill Cornell Medical College, HSS provides orthopedic and rheumatologic patient care at NewYork-Presbyterian Hospital at New York Weill Cornell Medical Center. All Hospital for Special Surgery medical staff are on the faculty of Weill Cornell Medical College. The hospital's research division is internationally recognized as a leader in the investigation of musculoskeletal and autoimmune diseases. Hospital for Special Surgery is located in New York City and online at http://www.hss.edu.