Alexander M. Walker

Obesity and Knee Osteoarthritis: The Framingham Study

STUDY OBJECTIVE To determine whether obesity preceded knee osteoarthritis and was thus a possible cause. DESIGN Cohort study with weight and other important variables measured in 1948 to 1951 (mean age of subjects, 37 years) and knee arthritis evaluated in 1983 to 1985 (mean age of subjects, 73 years). SETTING Population-based participants; a subset (n = 1420) of the Framingham Heart Study cohort. METHODS For those subjects in the Framingham Study having knee radiographs taken as part of the 18th biennial examination (1983 to 1985), we examined Metropolitan Relative Weight, a measure of weight adjusted for height at the onset of the study (1948 to 1951). Relative risks were computed as the cumulative incidence rate of radiographic knee osteoarthritis in the heaviest weight groups at examination 1 divided by the cumulative rate in the lightest 60% weight groups at examination 1. Relative risks were adjusted for age, physical activity level, and uric acid level. RESULTS In 1983 to 1985, 468 subjects (33%) had radiographic knee osteoarthritis. For men, the risk of knee osteoarthritis was increased in those in the heaviest quintile of weight at examination 1 compared with those in the lightest three quintiles (age-adjusted relative risk, 1.51; 95% confidence interval [CI], 1.14 to 1.98); risk was not increased for those in the second heaviest quintile (relative risk, 1.0). The association between weight and knee osteoarthritis was stronger in women than in men; for women in the most overweight quintile at examination 1, relative risk was 2.07 (95% CI, 1.67 to 2.55), and for those in the second heaviest group, relative risk was 1.44 (95% CI, 1.11 to 1.86). This link between obesity and subsequent osteoarthritis persisted after controlling for serum uric acid level and physical activity level, and was strongest for persons with severest radiographic disease. Obesity at examination 1 was associated with the risk of developing both symptomatic and asymptomatic osteoarthritis. CONCLUSIONS These results and other corroborative cross-sectional data show that obesity or as yet unknown factors associated with obesity cause knee osteoarthritis.

Folic Acid Antagonists during Pregnancy and the Risk of Birth Defects

Background Multivitamin supplementation in pregnant women may reduce the risks of cardiovascular defects, oral clefts, and urinary tract defects in their infants. We evaluated whether the folic acid component of multivitamins is responsible for the reduction in risk by examining the associations between maternal use of folic acid antagonists and these congenital malformations. Methods We assessed exposure to folic acid antagonists that act as dihydrofolate reductase inhibitors and to certain antiepileptic drugs in 3870 infants with cardiovascular defects, 1962 infants with oral clefts, and 1100 infants with urinary tract defects and also in 8387 control infants with malformations the risk of which is not reduced after vitamin supplementation. Mothers were interviewed within six months after delivery about their medication use during pregnancy. Results The relative risks of cardiovascular defects and oral clefts in infants whose mothers were exposed to dihydrofolate reductase inhibitors during the second o...

Body weight, body mass index, and incident symptomatic osteoarthritis of the hand, hip, and knee

Studies have shown a positive association between obesity and knee osteoarthritis. Studies evaluating hand or hip osteoarthritis and weight, however, have assessed x-ray osteoarthritis or been cross-sectional, or both, and results of these have been inconsistent. We assessed the association between body weight, body mass index, and incident symptomatic osteoarthritis in 134 matched case-control pairs of women who were part of a case-control study on estrogen replacement therapy and osteoarthritis. We identified incident symptomatic osteoarthritis cases of the hand, hip, and knee in women ages 20-89 years who were members of a health plan between January 1, 1990 and December 31, 1993. For each case we selected a control woman who was matched by closest date of birth to the case. Medical records were reviewed to obtain weight and height information for the period before disease onset. After controlling for estrogen use, smoking status, height, and health care use, we found that body weight was a predictor of incident osteoarthritis of the hand, hip, and knee. Odds ratios ranged from 3.0 to 10.5 for women in the upper tertiles of weight compared with women in the lowest tertile. Similar associations were observed for body mass index. Our results suggest that obesity is associated with the development of incident osteoarthritis at all joints studied.

Discontinuation of Antihyperlipidemic Drugs — Do Rates Reported in Clinical Trials Reflect Rates in Primary Care Settings?

BACKGROUND Discontinuation rates for drugs used to treat chronic conditions may affect the success of therapy. However, the discontinuation rates reported in clinical trials may not reflect those in primary care settings. METHODS We conducted a cohort study using computerized research files and medical records on 2369 new users of antihyperlipidemic therapy at two health maintenance organizations (HMOs) from 1988 through 1990. The rates of drug discontinuation in these primary care settings were compared with the rates reported in clinical trials published from 1975 through 1993, located with the Medline data base. RESULTS In the HMOs, the one-year probability of drug discontinuation was 41 percent for bile acid sequestrants (95 percent confidence interval, 38 to 44 percent), 46 percent for niacin (95 percent confidence interval, 42 to 51 percent), 15 percent for lovastatin (95 percent confidence interval, 11 to 19 percent), and 37 percent for gemfibrozil (95 percent confidence interval, 31 to 43 percent). For the bile acid sequestrants, niacin, and gemfibrozil, the risks of discontinuation were substantially higher in the HMOs than in randomized clinical trials, in which the summary estimates of this risk were 31 percent, 4 percent, and 15 percent, respectively, for trials of one year or longer. The rates of discontinuation in open-label studies were similar to those in the HMOs. CONCLUSIONS The discontinuation rates reported in randomized clinical trials may not reflect the rates actually observed in primary care settings. The effectiveness and tolerability of antihyperlipidemic medications should be studied further in populations that typically use the agents.

Mortality in current and former users of clozapine

Clozapine (Clozaril®), a tricyclic dibenzodiazepine, causes fewer extrapyramidal side effects than do other antipsychotic drugs. Because it can induce agranulocytosis, however, clozapine is indicated only for schizophrenia that is not responsive to other therapies. To describe the drugs effects on

Aprotinin during Coronary-Artery Bypass Grafting and Risk of Death

BACKGROUND Aprotinin (Trasylol) is used to mitigate bleeding during coronary-artery bypass grafting (CABG). Accumulating evidence suggests that this practice increases mortality. METHODS Using electronic administrative records of the Premier Perspective Comparative Database, we studied hospitalized patients with operating-room charges for the use of aprotinin (33,517 patients) or aminocaproic acid (44,682 patients) on the day CABG was performed. We tabulated the numbers of patients with a hospital-discharge status of death and performed three types of analyses: a multivariable logistic-regression analysis (primary analysis); propensity-score matching in the highly selected subcohort of patients who received full amounts of the study drug, who underwent CABG by surgeons who performed 50 or more CABG surgeries during the study period, and for whom information on 10 additional covariates was available because the surgery occurred on hospital day 3 or later; and an instrumental-variable analysis of data from patients whose surgeons showed a strong preference for one of the two study drugs. RESULTS In all, 1512 of the 33,517 aprotinin recipients (4.5%) and 1101 of the 44,682 aminocaproic acid recipients (2.5%) died. After adjustment for 41 characteristics of patients and hospitals, the estimated risk of death was 64% higher in the aprotinin group than in the aminocaproic acid group (relative risk, 1.64; 95% confidence interval [CI], 1.50 to 1.78). In the first 7 days after surgery, the adjusted relative risk of in-hospital death in the aprotinin group was 1.78 (95% CI, 1.56 to 2.02). The relative risk in a propensity-score-matched analysis was 1.32 (95% CI, 1.08 to 1.63). In the instrumental-variable analysis, the use of aprotinin was found to be associated with an excess risk of death of 1.59 per 100 patients (95% CI, 0.14 to 3.04). Postoperative revascularization and dialysis were more frequent among recipients of aprotinin than among recipients of aminocaproic acid. CONCLUSIONS Patients who received aprotinin alone on the day of CABG surgery had a higher mortality than patients who received aminocaproic acid alone. Characteristics of neither the patients nor the surgeons explain the difference, which persisted through several approaches to control confounding.

Replacement Estrogens and Endometrial Cancer

We examined the incidence of endometrial cancer in a large prepaid group practice in the Seattle area. From July, 1975, to July, 1977, there was a sharp downward trend in the incidence of endometrial cancer that paralleled a substantial reduction in prescriptions for replacement estrogens. Incidence rates were estimated for estrogen users and nonusers among women 50 to 64 years of age with intact uteri; current long-term users had an annual risk for endometrial cancer between 1 and 3 per cent, whereas nonusers had a risk less than 1/10th as great. These incidence rates remained fairly constant over time among users and nonusers; the drop in overall incidence soon after estrogen use declined suggests that the increased risk associated with estrogens falls quickly after discontinuation. The reduction in incidence of endometrial cancer in this group practice was part of a general decline in the United States after 1975.

Inhibition of Clinical Benefits of Aspirin on First Myocardial Infarction by Nonsteroidal Antiinflammatory Drugs

Background—There is clear evidence from numerous randomized trials and their meta-analyses that aspirin reduces risks of first myocardial infarction (MI). Recent data also suggest that other nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with this benefit of aspirin. Methods and Results—We performed subgroup analysis from a 5-year randomized, double-blind, placebo-controlled trial of 325 mg aspirin on alternate days among 22 071 apparently healthy US male physicians with prospective observational data on use of NSAIDs. A total of 378 MIs were confirmed, 139 in the aspirin group and 239 in the placebo group. Aspirin conferred a statistical extreme (P <0.00001) 44% reduction in risk of first MI. Among participants randomized to aspirin, use of NSAIDs on 1 to 59 d/y was not associated with MI (multivariable adjusted relative risk [RR], 1.21; 95% confidence interval [CI], 0.78 to 1.87), whereas the use of NSAIDs on ≥60 d/y was associated with MI (RR, 2.86; 95% CI, 1.25 to 6.56) compared with no use of NSAIDs. In the placebo group, the RRs for MI across the same categories of NSAID use were 1.14 (95% CI, 0.81 to 1.60) and 0.21 (95% CI, 0.03 to 1.48). Conclusions—These data suggest that regular but not intermittent use of NSAIDs inhibits the clinical benefits of aspirin. Chance, bias, and confounding remain plausible alternative explanations, despite the prospective design and adjustment for covariates. Nonetheless, we believe the most plausible interpretation of the data to be that regular but not intermittent use of NSAIDs inhibits the clinical benefit of aspirin on first MI.

Drug-associated antineutrophil cytoplasmic antibody-positive vasculitis: prevalence among patients with high titers of antimyeloperoxidase antibodies.

OBJECTIVE The triggers that induce antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis (APV) are largely unknown. However, there have been reports suggesting that hydralazine, propylthiouracil, and several other drugs may cause some cases of APV, and the majority of these cases have been associated with antimyeloperoxidase (anti-MPO) ANCA. Our experience led us to hypothesize that cases of high titers of anti-MPO antibodies are often drug-associated. METHODS In this study, we determined the prevalence of exposure to hydralazine, propylthiouracil, and other drugs previously implicated in APV among 30 patients with vasculitis and the highest titers of anti-MPO antibodies newly detected in our laboratory between 1994 and 1998. The clinical, histologic, and other serologic features of these 30 patients were also examined. RESULTS The 30 study patients accounted for 12% of the 250 new patients with APV and anti-MPO who were tested during the study period. All 30 study subjects had anti-MPO titers that were more than 12 times the median titer of the 250 patients. Ten (33%) of the 30 patients had been exposed to hydralazine and 3 (10%) had been exposed to propylthiouracil. An additional 5 patients (17%) had been exposed to 1 of the other previously reported candidate drugs: 2 to penicillamine, 2 to allopurinol, and 1 to sulfasalazine. One of the patients exposed to hydralazine had also been exposed to allopurinol. In all cases, the clinical and histologic findings were typical of APV. There was a strong association between the presence of antielastase and/ or antilactoferrin antibodies and exposure to candidate drugs. CONCLUSION These data suggest that a sizable proportion of cases of APV with high titers of anti-MPO antibodies are drug-associated, especially following exposure to hydralazine or propylthiouracil. We recommend that the use of these drugs should be sought in cases of anti-MPO-positive vasculitis, particularly among patients with high titers of these antibodies.

Statistical methods in evaluating the outcome of infertility therapy

Lack of standardization in analytic methods for assigning infertility data is attributed to inadequate classification of fertility problems, and a lack of consistent methodology in evaluating outcome of infertility therapy. A classification scheme ideally should consider types of fertility problems as well as clinical assessment of its severity. Until an adequate classification system is developed, researchers are encouraged to describe fully the nature of infertility problem examined, and present results for homogenous groups of patients. The life-table method of analysis is a useful technique for assessing infertility statistics. The starting point of this method should depend on the group examined and may be either the date of 1st visit to the clinic or the date that therapy is instituted. Approximate date of conception should be the endpoint. A mathematical model of infertility predicated on the assumption that there is a constant monthly probability of conception of fecundability can be used to derive equations with potential for clinical application.