ABSTRACT
Clinical trials have become an essential research tool for the evaluation of the benefit and risk of new interventions for the treatment or prevention of disease. Clinical trials represent the experimental approach to clinical research. Take, for example, the modification of risk factors for cardiovascular disease. Large observational studies such as the Framingham Heart Study (Dawber et al. 1951) indicated a correlation between high cholesterol, high blood pressure, smoking, and diabetes with the incidence of cardiovascular disease. Focusing on high cholesterol, basic researchers sought interventions that would lower serum cholesterol. While interventions were discovered that lowered cholesterol, they did not demonstrate a significant reduction in cardiovascular mortality.1 Finally, in 1994, a trial evaluating a member of the statin class of drugs demonstrated a reduction in mortality (Scandanavian Simvistatin Survival Study 1994). With data from well-controlled clinical trials, an effective and safe intervention was identified. Sometimes interventions can be adopted without good evidence and even become widely used. One case was the use of hormone replacement therapy (HRT) that is used to treat symptoms in postmenopausal women and is also known to reduce bone loss in these women, leading to reduced bone fracture rates. HRT also reduces serum cholesterol leading to the belief that it should also reduce cardiovascular mortality and morbidity. In addition, large observational studies have shown lower cardiovascular mortality for women using HRT than for those not using HRT (BarrettConnor and Grady 1998). These observations led to a widespread use of HRT for the prevention of cardiovascular mortality and morbidity as well as the other indications. Subsequently, two trials evaluated the benefits of HRT in postmenopausal women: one trial in women with existing cardiovascular disease and a second without any evident disease. The first trial, known as HERS, demonstrated no benefit and suggested a possible risk of thrombosis (i.e., blood clots) (Grady et al. 1998). The second trial, known as the Women’s Health Initiative, or WHI, demonstrated a harmful effect due to blood clotting and no cardiovascular benefit.2 These trials contradicted evidence derived from non-randomized trials and led to a rapid decline in the use of HRT for purposes of reducing cardiovascular disease. HRT is still used when indicated for short-term symptom relief in postmenopausal women.
