The role of menopausal hormone therapy in preventing osteoporotic fractures: a critical review of the clinical evidence.

Osteoporosis is a common disease resulting in millions of potentially preventable fractures each year. Women are disproportionately affected by osteoporosis compared to men, with loss of gonadal functioning and aging being the 2 most important contributing factors to osteoporosis. For many decades, menopausal hormone therapy (HT) has been the mainstay for the prevention and treatment of osteoporosis among menopausal women. While recent randomized trial data have confirmed findings from observational studies concerning HT's protective effect on osteoporosis, they showed that HT increases the risks of breast cancer, venous thromboses, stroke, and coronary heart disease. With a strong body of evidence showing the benefit of HT in preventing osteoporotic fractures, the challenge facing clinicians is not whether HT helps to prevent osteoporotic fractures, but whether HT's fracture-prevention benefits outweigh its risks. With several medications now available having efficacy comparable to HT in preventing fractures, decisions about therapy for osteoporosis or osteopenia should take into consideration bone mineral density, other risk factors for osteoporotic fracture, and a careful examination of the benefits and risks of each treatment option. After a brief discussion of the epidemiology and pathophysiology of osteoporosis, we review the evidence from observational studies and randomized studies examining the impact of menopausal hormone therapy on osteoporosis. We focus on whether there are specific subgroups of women that accrue greater or smaller benefit from HT in terms of osteoporotic fracture reduction. We then expand our perspective to include clinical endpoints other than osteoporosis, presenting a framework for factoring in the many risks and benefits of HT. We conclude that all women should be informed of all alternative treatment options and allowed to make an informed treatment decision according to their personal risks, preferences, values, and willingness to tolerate the risks of treatment.

Identifying patient preferences for communicating risk estimates: a descriptive pilot study.

BACKGROUND: Patients increasingly seek more active involvement in health care decisions, but little is known about how to communicate complex risk information to patients. The objective of this study was to elicit patient preferences for the presentation and framing of complex risk information. METHOD: To accomplish this, eight focus group discussions and 15 one-on-one interviews were conducted, where women were presented with risk data in a variety of different graphical formats, metrics, and time horizons. Risk data were based on a hypothetical woman's risk for coronary heart disease, hip fracture, and breast cancer, with and without hormone replacement therapy. Participants' preferences were assessed using likert scales, ranking, and abstractions of focus group discussions. RESULTS: Forty peri- and postmenopausal women were recruited through hospital fliers (n = 25) and a community health fair (n = 15). Mean age was 51 years, 50% were non-Caucasian, and all had completed high school. Bar graphs were preferred by 83% of participants over line graphs, thermometer graphs, 100 representative faces, and survival curves. Lifetime risk estimates were preferred over 10 or 20-year horizons, and absolute risks were preferred over relative risks and number needed to treat. CONCLUSION: Although there are many different formats for presenting and framing risk information, simple bar charts depicting absolute lifetime risk were rated and ranked highest overall for patient preferences for format.

Hormone replacement therapy after breast cancer: a systematic review and quantitative assessment of risk.

PURPOSE: Hormone replacement therapy (HRT) is typically withheld from women with breast cancer because of concern that it might increase the risk of recurrence. The purpose of this study was to quantify the risk of recurrent breast cancer associated with HRT among breast cancer survivors. METHODS: We performed a systematic literature review through May 1999, calculating the relative risk (RR) of breast cancer recurrence in each study by comparing the number of recurrences in the HRT group to those in the control group. In studies that did not contain a control group, we constructed one by estimating the expected number of recurrences based on data from the Early Breast Cancer Trialists' Collaborative Group, adjusting for nodal status and disease-free interval. RRs across all studies were combined using random-effects models. RESULTS: Of the 11 eligible studies, four had control groups and included 214 breast cancer survivors who began HRT after a mean disease-free interval of 52 months. Over a mean follow-up of 30 months, 17 of 214 HRT users experienced recurrence (4.2% per year), compared with 66 of 623 controls (5.4% per year). HRT did not seem to affect breast cancer recurrence risk (RR = 0.64, 95% confidence interval [CI], 0.36 to 1.15). Including all 11 studies in the analyses (669 HRT users), using estimated control groups for the seven uncontrolled trials, the combined RR was 0.82 (95% CI, 0.58 to 1.15). CONCLUSION: Although our analyses suggest that HRT has no significant effect on breast cancer recurrence, these findings were based on observational data subject to a variety of biases.

A cost-effectiveness analysis of axillary node dissection in postmenopausal women with estrogen receptor-positive breast cancer and clinically negative axillary nodes.

PURPOSE: The purpose of this study was to examine the cost-effectiveness of immediate axillary lymph node dissection (ALND) in estrogen receptor-positive women with clinically negative nodes. METHODS: We constructed a Markov model comparing hypothetical cohorts of postmenopausal women who were estrogen receptor positive with clinically negative axillae. The women underwent immediate ALND or watchful waiting, with ALND performed only for those patients developing palpable axillary nodes. Recurrence risks, chemotherapeutic benefits, and treatment costs were estimated from the published literature. The main outcome measures were quality-adjusted survival and incremental cost per quality-adjusted life-year (QALY). RESULTS: For 55-year-old women with palpable (3 cm) tumors, immediate ALND results in improved survival (10.3 versus 10.05 QALYs) and a cost-effectiveness ratio of $36,700 per QALY, if chemotherapy is given to those with histologically positive lymph nodes. The benefits of ALND are greatest for younger women with larger palpable tumors. Because of the lower risk of nodal metastases, patients with 1-cm nonpalpable tumors experience minimal benefit at markedly higher incremental costs ($308,000 per QALY). If chemotherapy will not be given to patients with histologically positive lymph nodes because of a patient's or a physician's wishes, then there is no benefit to immediate ALND in any patient subgroup. CONCLUSION: When the results of ALND are used to guide postoperative decisions, immediate ALND results in considerable benefit at a reasonable cost for most women with palpable tumors. Because the benefits are lower in patients with nonpalpable tumors, ALND should not be considered mandatory for that subgroup. Decisions for ALND should be based on patient age, tumor size and palpability, individual patient preferences, the likelihood of receiving postoperative chemotherapy, and other prognostic factors.

Individualizing therapy to prevent long-term consequences of estrogen deficiency in postmenopausal women.

BACKGROUND: Alendronate sodium and raloxifene hydrochloride were recently approved for the prevention of postmenopausal osteoporosis, but data on their clinical efficacy are limited. We compared these drugs with hormone replacement therapy (HRT) to help women and physicians guide postmenopausal treatment decisions. OBJECTIVE: To help physicians understand how they can best help women choose the most beneficial therapy after menopause based on their individual risk profile. METHODS: We developed a decision analytic Markov model to compare the effects of alendronate therapy, raloxifene therapy, and HRT on risks of hip fracture, coronary heart disease (CHD), breast cancer, and life expectancy. Regression models linked individual risk factors to future disease risks and were modified by drug effects on bone density, lipid levels, and associated breast cancer effects. RESULTS: Hormone replacement therapy, alendronate therapy, and raloxifene therapy have similar predicted efficacies in preventing hip fractures (estimated relative risk, 0.57, 0.54, and 0.58, respectively). Hormone replacement therapy should be more than 10 times more effective than raloxifene therapy in preventing CHD, but raloxifene therapy may not induce breast cancer. Women at low risk for hip fracture, CHD, and breast cancer do not benefit significantly from any treatment. Among women at average risk, HRT was preferred unless raloxifene therapy could reduce the risk of breast cancer by at least 66%, compared with a 47% increase for HRT. Women at high risk for CHD benefit most from HRT; women at high risk for breast cancer but low risk for CHD benefit most from raloxifene therapy, but only if it lowers the risk of breast cancer. CONCLUSION: Because of significant differences in the impact of these drugs, treatment choice depends on an individual woman's risk for hip fracture, CHD, and breast cancer.

Fitting nutrition into the medical model: the role of decision analytic cost-effectiveness techniques.

Physicians are accustomed to making decisions based on information regarding the prevalence of disease, symptoms, physical signs, laboratory test results, and the risks and benefits of alternative treatments. If nutritional assessment and therapeutics are to become more common components of medical practice, significant barriers in each of these areas must be overcome. Even rudimentary dietary assessment is often missing from physician education. Dietary assessment tools that are readily available and that have demonstrated usefulness are largely unknown. In addition, many nutritional interventions have not been formally investigated in randomized, controlled trials, and thus their cost-effectiveness remains unknown. We present one approach to these issues by discussing the construction of a decision model examining strategies for vitamin D and calcium screening. The application of medical decision making techniques to problems in clinical nutrition illustrates how findings from research studies may be used to determine the risks, benefits and costs of alternative population based health related nutrition policies which can then be applied by physicians in their daily interactions with patients.

The learning curve for sentinel node biopsy in breast cancer: practical considerations.

HYPOTHESIS: Performance of sentinel node biopsy (SNB) instead of full axillary lymph node dissection (ALND) by inexperienced surgeons will lead to understaging of some women with breast cancer and increased costs. DESIGN: A decision analysis model was used to investigate the implications of SNB vs. full ALND during the learning phase (60-80 procedures). This model simulates a randomized trial of 10000 women in each arm. Data regarding the learning curve were obtained from published series. MAIN OUTCOME MEASURES: Percentage of women with inaccurate staging of their breast cancer, overall survival, quality-adjusted survival, and potential costs of SNB vs ALND. RESULTS: Performance of SNB instead of ALND results in inability to locate a sentinel node in 38% of attempts during the learning phase (compared with 10% in later cases) and understaging in 12% of patients during the learning phase (compared with 0% in later cases). This understaging is associated with a small decrement in survival (1%-2%) and an increased risk of axillary recurrence. Sentinel node biopsy is cost-effective only when the ability to detect sentinel nodes exceeds 80%; and the cost of SNB is less than 50% of the cost of ALND. CONCLUSIONS: To ensure accurate staging of patients with breast cancer, all surgeons should perform full ALND while learning SNB techniques. Only after documentation of accuracy of SNB (sensitivity >90%) should full ALND be omitted for women with negative sentinel nodes.

Patient-specific decisions about hormone replacement therapy in postmenopausal women.

OBJECTIVE: To examine the effect of hormone replacement therapy on life expectancy in postmenopausal women with different risk profiles for heart disease, breast cancer, and hip fracture. DESIGN: Decision analysis using a Markov model. Published regression models were used to link risk factors to disease incidence and to estimate the lifetime risks of developing coronary heart disease (CHD), breast cancer, hip fracture, and endometrial cancer. The impact of hormone therapy on disease incidence was estimated from published epidemiologic studies. SETTING: Mathematical model applicable to primary care. INTERVENTIONS: Treatment with hormone replacement therapy or no hormone replacement therapy. MAIN OUTCOME MEASURE: Life expectancy. RESULTS: Hormone replacement therapy should increase life expectancy for nearly all postmenopausal women, with some gains exceeding 3 years, depending mainly on an individual's risk factors for CHD and breast cancer. For women with at least 1 risk factor for CHD, hormone therapy should extend life expectancy, even for women having first-degree relatives with breast cancer. Women without any risk factors for CHD or hip fracture, but who have 2 first-degree relatives with breast cancer, however, should not receive hormone therapy. CONCLUSIONS: The benefit of hormone replacement therapy in reducing the likelihood of developing CHD appears to outweigh the risk of breast cancer for nearly all women in whom this treatment might be considered. Our analysis supports the broader use of hormone replacement therapy.

The impact of clinical trials on the use of medications for acute myocardial infarction. Results of a community-based study.

BACKGROUND: The impact of clinical trials on medical practice remains controversial, in part because of weak study designs and nonrepresentative study samples. OBJECTIVE: To assess changes in trends in medication use in the setting of acute myocardial infarction (AMI) before and after publication of two large clinical trials: the Second International Study of Infarct Survival (ISIS-2) trial that supported the use of aspirin after AMI and the Multi-center Diltiazem Postinfarction Trial that reported no overall benefit from the use of calcium antagonists after AMI. METHODS: Study patients consisted of 2114 patients hospitalized with AMI in 16 hospitals in metropolitan Worcester, Mass, during 1986, 1988, and 1990. Data were obtained from medical records. We used multivariable logistic regression models to examine the rate of change in the use of selected medications before and after trial publication, controlling for medical history, characteristics and complications of AMI, medications taken, and procedures performed during hospitalization. The dependent variable was receipt of the specific medication under investigation. RESULTS: Before publication of ISIS-2, 26% of patients with AMI received aspirin while hospitalized compared with 66% after its publication. However, in-hospital aspirin use began to rise before ISIS-2 with an immediate increase in the level of use occurring after trial publication but with no significant change in the rate of increase. Before publication of the Multicenter Diltiazem Postinfarction Trial, 57% of patients with AMI were new recipients of calcium antagonists compared with 51% after trial publication. The decrease in calcium antagonist use began after trial publication (odds ratio, 0.79 per 6-month period; 95% confidence interval, 0.71 to 0.88). CONCLUSIONS: The published results of large trials of cardiovascular therapies have had variable impact on medication use. Efforts to assess the effects of publication of new scientific information on medical care need to consider prior trends in treatment patterns and the varying contexts of medical care. They should consider both direct and indirect routes of influence.

Does aspirin consumption affect the presentation or severity of acute myocardial infarction?

BACKGROUND: While consumption of aspirin has been shown to decrease the occurrence of nonfatal cardiac events, the majority of studies have not demonstrated any impact of aspirin intake on cardiovascular mortality. The present population-based study explores the possibility that aspirin consumption affects the presentation and severity of acute myocardial infarction (AMI), and hence the likelihood of clinical detection. METHODS: We monitored the use of aspirin before admission for 2114 patients with a validated diagnosis of AMI in 16 hospitals in the Worcester, Mass, metropolitan area during 1986, 1988, and 1990. The AMIs were characterized as Q wave vs non-Q wave and large (peak creatine kinase levels more than five times normal) vs small (peak creatine kinase levels less than two times normal). RESULTS: A total of 332 patients (16%) with validated AMI took aspirin before hospital admission. Nearly 65% of aspirin users had non-Q wave AMIs, compared with 49% of nonaspirin users. Thirty percent of aspirin users sustained small AMIs, compared with 22% of nonaspirin users. These findings persisted after stratifying for previous AMI, history of coronary disease, receipt of thrombolytic therapy, and exclusion of early hospital deaths. Using multivariable regression models to control for age, gender, previous evidence of coronary disease, and use of other medications, prior aspirin consumption remained independently associated with AMI type (non-Q-wave AMI) and smaller infarct size. CONCLUSION: Aspirin consumption appears to modify the presentation of AMI, increasing the likelihood that the infarct will be of the small, non-Q-wave variety.

Frequency of inclusion of patients with cardiogenic shock in trials of thrombolytic therapy.

The purpose of this study was to determine the extent to which patients with cardiogenic shock have participated in trials of thrombolytic therapy, to examine factors associated with their exclusion from these trials, and to summarize data on the efficacy of thrombolysis in these patients. Previous publications were searched for all randomized, controlled studies involving the use of thrombolytic medications used in the treatment of acute myocardial infarction. Data were abstracted for year of trial publication, performance location, sample size, maximal allowable delay between symptom onset and treatment, and exclusion criteria. Of the 94 trials included in the analysis, 22% included patients with cardiogenic shock, 37% excluded them, and the remainder contained no information on their inclusion or exclusion. Only 2 trials provided data on the efficacy of thrombolytic therapy in patients with cardiogenic shock. Multivariate analysis revealed that studies conducted exclusively in the U.S. were significantly more likely to exclude patients in cardiogenic shock than those conducted outside of the U.S., as were studies that excluded patients with a previous myocardial infarction, studies published more recently, and smaller trials. Patients with cardiogenic shock have frequently been excluded from clinical trials of thrombolytic agents. As a result, data on the efficacy of thrombolytic agents in these patients is extremely limited.

The exclusion of the elderly and women from clinical trials in acute myocardial infarction.

OBJECTIVE: To determine the extent to which the elderly have been excluded from trials of drug therapies used in the treatment of acute myocardial infarction, to identify factors associated with such exclusions, and to explore the relationship between the exclusion of elderly and the representation of women. DATA SOURCES: We conducted a systematic search of the English-language literature from January 1960 through September 1991 to identify all relevant studies of specific pharmacotherapies employed in the treatment of acute myocardial infarction. To accomplish this, we searched MEDLINE, major cardiology textbooks, meta-analyses, reviews, editorials, and the bibliographies of all identified articles. STUDY SELECTION: Only trials in which patients were randomly allocated to receive a specific therapeutic regimen or a placebo or nonplacebo control regimen were included for review. DATA EXTRACTION: Studies were abstracted for year of publication, source of support, performance location, drug therapies to which patients were randomized, use of invasive diagnostic tests or therapeutic procedures, exclusion criteria, size and demographic characteristics of the randomized study population, and principal outcome measures. DATA SYNTHESIS: A total of 214 trials met inclusion criteria, involving 150,920 study subjects. Over 60% of trials excluded persons over the age of 75 years. Studies published after 1980 were more likely to have age-based exclusions compared with studies published before 1980 (adjusted odds ratio, 4.92; 95% confidence interval, 2.33 to 10.54). Trials of thrombolytic therapy involving an invasive procedure were more likely to exclude elderly patients compared with other studies (adjusted odds ratio, 2.45; 95% confidence interval, 1.10 to 5.47). Studies with age-based exclusions had a smaller percentage of women compared with those without such exclusions (18% vs 23%; P = .0002), with the mean age of the study population significantly associated with the proportion of women participants (P = .0001, R2 = .29). CONCLUSIONS: Age-based exclusions are frequently used in clinical trials of medications used in the treatment of acute myocardial infarction. Such exclusions limit the ability to generalize study findings to the patient population that experiences the most morbidity and mortality from acute myocardial infarction.

Estimating worldwide current antibiotic usage: report of Task Force 1.

Estimates of antibiotic availability from a number of countries throughout the world were developed as an indicator of potential patterns of human antibiotic use. Data were organized by major classes of antibiotics and by some individual products and converted to units of weight and defined daily dosages per 1,000 population per day. Estimates were based either on sales or on production and trade data, including global production of penicillins, cephalosporins, tetracyclines, and erythromycins. The data obtained showed that antibiotic availability can vary widely among countries as well as from year to year in the same country.