Proactive safety surveillance.

Growth in health information systems presents opportunities to enhance postmarketing safety surveillance of medical products. Spontaneous suspected side effect reports provide the foundation, but we need to 'proactively' improve their quality and our strategies to seek signals. In our more familiar 'reactive' mode, we examine hypotheses from inquiries or publicity. Such responsive evaluations remain essential but may miss latent information on unsuspected risks. Efficient techniques to disclose hidden clusters and associations may emerge through adaptation of approaches from industrial quality control and other disciplines. Data-driven techniques like exploratory analysis, control charts, and time series modeling may help in sifting through accumulated data and in screening consecutive submissions to discern hints of new product hazards or of more specific understanding about previously identified potential side effects. We also need to cultivate non-spontaneous data for hypothesis generation as well as testing, the systematic epidemiologic evaluation of questions and concerns. This hypothesis testing function will assume greater importance if proactive safety surveillance methods yield larger numbers of putatively positive findings. Whether from spontaneous reports or other sources, signals that could have arisen by chance alone usually represent only clues to potential hazards until or unless they can be verified through independent studies.

Stevens-Johnson syndrome and toxic epidermal necrolysis after vaccination: reports to the vaccine adverse event reporting system.

We conducted a telephone survey of reports of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) to the Vaccine Adverse Event Reporting System. We identified six cases of SJS or TEN after vaccination without other obvious triggers, suggesting that SJS and TEN might very rarely be caused by vaccination. Confirmation of this hypothesis will likely require controlled studies.

The epidemiology of fatalities reported to the vaccine adverse event reporting system 1990-1997.

PURPOSE: To examine the fatalities reported to the federally administered Vaccine Adverse Event Reporting System (VAERS), a passive surveillance system, in its first 7 years. METHODS: The working data set included variables such as demographic information, dates of vaccination, adverse event onset and death, vaccines administered, and vaccination facility data. Frequencies for these data and state reporting rates were calculated. RESULTS: A total of 1266 fatalities were reported to VAERS during July 1990 through June 1997. The number of death reports peaked in 1992-1993 and then declined. The overall median age of cases was 0.4 years, with a range of 1 day to 104 years. Nearly half of the deaths were attributed to sudden infant death syndrome (SIDS). CONCLUSIONS: The trend of decreasing numbers of deaths reported to VAERS since 1992-1993 follows that observed for SIDS overall for the US general population following implementation of the 'Back to Sleep' program. These data may support findings of past controlled studies showing that the association between infant vaccination and SIDS is coincidental and not causal. VAERS reports of death after vaccination may be stimulated by the temporal association, rather than by any causal relationship.

Infant immunization with acellular pertussis vaccines in the United States: assessment of the first two years' data from the Vaccine Adverse Event Reporting System (VAERS).

OBJECTIVE: To evaluate the safety of infant immunization with acellular pertussis vaccines in the United States. BACKGROUND: The US Food and Drug Administration approved the first acellular pertussis vaccine for use in infants in the United States on July 31, 1996. OUTCOME MEASURES: Adverse events in the United States after infant immunization with pertussis-containing vaccines, representing temporal (but not necessarily causal) associations between vaccinations and adverse events. DATA SOURCE: Reports to the Vaccine Adverse Event Reporting System (VAERS), a passive national surveillance system. DESIGN: Reports concerning infant immunization against pertussis between January 1, 1995 (when whole-cell vaccine was in exclusive use) and June 30, 1998 (when acellular vaccine was in predominant use) were analyzed, if the reports were entered into the VAERS database by November 30, 1998. RESULTS: During the study, there were 285 reports involving death, 971 nonfatal serious reports, and 4514 less serious reports after immunization with any pertussis-containing vaccine. For 1995 there were 2071 reports; in 1996 there were 1894 reports; in 1997 there were 1314 reports, and in the first half of 1998 there were 491 reports. Diphtheria-tetanus-pertussis vaccine (DTP) was cited in 1939 reports, diphtheria-tetanus-whole-cell pertussis-Haemophilus influenzae type b vaccine (DTPH) in 2918 reports, and diphtheria-tetanus-acellular pertussis vaccine (DTaP) in 913 reports. The annual number of deaths during the study was 85 in 1995, 82 in 1996, 77 in 1997, and 41 in the first half of 1998. The annual number of reported events categorized as nonfatal serious (defined as events involving initial hospitalization, prolongation of hospitalization, life-threatening illness, or permanent disability) to VAERS for all pertussis-containing vaccines declined: 334 in 1995, 311 in 1996, 233 in 1997, and 93 in the first half of 1998. Similarly, the annual number of less serious reports to VAERS for pertussis-containing vaccines declined: 1652 in 1995, 1501 in 1996, 1004 in 1997, and 357 in the first half of 1998. A comparison of the adverse event profiles (proportional distributions) for DTaP, DTP, and DTPH, as well as an analysis of specific adverse events considered in a 1991 Institute of Medicine report on the safety of diphtheria-tetanus-pertussis vaccine, did not identify any new, clear safety concerns. CONCLUSIONS: These findings reflect the administration of millions of doses of acellular pertussis vaccine and are reassuring with regard to the safety of marketed acellular pertussis vaccines. VAERS data, although subject to the limitations of passive surveillance, support the prelicensure data with regard to the safety of the US-licensed acellular pertussis vaccines that we evaluated.

Postlicensure safety surveillance for varicella vaccine.

CONTEXT: Since its licensure in 1995, the extensive use of varicella vaccine and close surveillance of the associated anecdotal reports of suspected adverse effects provide the opportunity to detect potential risks not observed before licensure because of the relatively small sample size and other limitations of clinical trials. OBJECTIVES: To detect potential hazards, including rare events, associated with varicella vaccine, and to assess case reports for clinical and epidemiological implications. DESIGN AND SETTING: Postlicensure case-series study of suspected vaccine adverse events reported to the US Vaccine Adverse Event Reporting System (VAERS) from March 17, 1995, through July 25, 1998. MAIN OUTCOME MEASURES: Numbers of reported adverse events, proportions, and reporting rates (reports per 100,000 doses distributed). RESULTS: VAERS received 6574 case reports of adverse events in recipients of varicella vaccine, a rate of 67.5 reports per 100,000 doses sold. Approximately 4% of reports described serious adverse events, including 14 deaths. The most frequently reported adverse events were rashes, possible vaccine failures, and injection site reactions. Misinterpretation of varicella serology after vaccination appeared to account for 17% of reports of possible vaccine failures. Among 251 patients with herpes zoster, 14 had the vaccine strain of varicella zoster virus (VZV), while 12 had the wild-type virus. None of 30 anaphylaxis cases was fatal. An immunodeficient patient with pneumonia had the vaccine strain of VZV in a lung biopsy. Pregnant women occasionally received varicella vaccine through confusion with varicella zoster immunoglobulin. Although the role of varicella vaccine remained unproven in most serious adverse event reports, there were a few positive rechallenge reports and consistency of many cases with syndromes recognized as complications of natural varicella. CONCLUSION: Most of the reported adverse events associated with varicella vaccine are minor, and serious risks appear to be rare. We could not confirm a vaccine etiology for most of the reported serious events; several will require further study to clarify whether varicella vaccine plays a role. Education is needed to ensure appropriate use of varicella serologic assays and to eliminate confusion between varicella vaccine and varicella zoster immunoglobulin. JAMA. 2000;284:1271-1279

Neonatal deaths after hepatitis B vaccine: the vaccine adverse event reporting system, 1991-1998.

OBJECTIVE: To evaluate reports of neonatal deaths (aged 0-28 days) after hepatitis B (HepB) immunization reported to the national Vaccine Adverse Event Reporting System (VAERS). DESIGN: Case series; review of autopsy reports. SETTING: Voluntary reports submitted to VAERS, a passive surveillance system, from the US population. PATIENTS: All US neonates (0-28 days of age) whose deaths after HepB vaccination given alone were reported to VAERS, occurring from January 1, 1991, through October 5, 1998. INTERVENTION: None (observational database). RESULTS: Of 1771 neonatal reports, there were 18 deaths in 8 boys and 9 girls (1 patient unclassified). The mean age at vaccination for these 18 cases was 12 days (range, 1-27 days); median time from vaccination to onset of symptoms was 2 days (range, 0-20 days); and median time from symptoms to death was 0 days (range, 0-15 days). The mean birth weight of the neonates (n = 15) was 3034 g (range, 1828-4678 g). The causes of death for the 17 autopsied cases were sudden infant death syndrome for 12, infection for 3, and 1 case each of intracerebral hemorrhage, accidental suffocation, and congenital heart disease. CONCLUSION: Few neonatal deaths following HepB vaccination have been reported, despite the use of at least 86 million doses of pediatric vaccine given in the United States since 1991. While the limitations of passive surveillance systems do not permit definitive inference, these data suggest that HepB immunization is not causing a clear increase in neonatal deaths.

An overview of the vaccine adverse event reporting system (VAERS) as a surveillance system. VAERS Working Group.

We evaluated the Vaccine Adverse Event Reporting System (VAERS), the spontaneous reporting system for vaccine-associated adverse events in the United States, as a public health surveillance system, using evaluation guidelines from the Centers for Disease Control and Prevention. We found that VAERS is simple for reporters to use, flexible by design and its data are available in a timely fashion. The predictive value positive for one severe event is known to be high, but for most events is unknown. The acceptability, sensitivity and representativeness of VAERS are unknown. The study of vaccine safety is complicated by underreporting, erroneous reporting, frequent multiple exposures and multiple outcomes.

The renal effects of nonsteroidal anti-inflammatory drugs in older people: findings from the Established Populations for Epidemiologic Studies of the Elderly.

OBJECTIVE: To determine whether older people who use nonsteroidal anti-inflammatory agents (NSAIDs) have increased levels of blood urea nitrogen (BUN), serum creatinine, and BUN:serum creatinine ratio. DESIGN: Cross-sectional, secondary data analysis. SETTING: Older people living in the communities of East Boston, MA, New Haven, CT, and Washington and Iowa Counties, Iowa. PARTICIPANTS: A total of 4099 people aged 70 years or older who were participants in the National Institute on Aging's Established Populations for Epidemiologic Studies of the Elderly project, had survived to the 6-year follow-up interview and had consented to the blood drawing. MEASUREMENTS: We assessed use of the NSAIDs at the 3- and 6-year interviews through a drug inventory and visual review of medication containers. Markers of renal function assessed through analysis of blood samples drawn at the time of the interview included BUN and creatinine. RESULTS: Fifteen percent of the cohort reported use of NSAIDs during the 2 weeks preceding the 6-year interview. Controlling for age, sex, and a range of potential confounding variables, NSAID users had significant prevalence odds ratios of 1.9 (95% confidence interval (CI), 1.5-2.3) for being in the highest quartile of BUN (>23), 1.3 (CI 1.1-1.7) for the highest quartile of serum creatinine (> or =1.4), and 1.7 (CI 1.4-2.1) for the highest quartile of the BUN:creatinine ratio (> or = 19.4). Chronic NSAID users (those who reported NSAID use at both the 3-year and 6-year interviews) accounted for the increased risk of high serum creatinine levels. CONCLUSION: Community-dwelling older people who use NSAIDs tend to have higher levels of common laboratory markers of renal dysfunction. This hypothesis requires further testing in prospective cohort studies designed a priori to evaluate these issues.

Predictors and correlates of prevention research careers: a national study of residency graduates.

BACKGROUND: Factors associated with research productivity among residency graduates are not well understood. The objectives of this study are to describe research productivity among preventive medicine residency (PMR) graduates and to identify factors that are correlated with high levels of productivity. METHODS: A detailed survey was mailed to all (n = 1,070) graduates from U.S. PMRs between 1979 and 1989. Main outcome measures for this analysis were (1) 25% of the workweek or more research time and (2) 20 or more publications since training completion. RESULTS: A total of 797 completed surveys were received for a response rate of 75%. Among respondents, 33% devoted at least 25% of their time to research and 13% had 20 or more publications. Independent positive predictors (P < 0.05) based on education and training of high research productivity as measured by both outcomes included research self-motivation, training at the Centers for Disease Control and Prevention, and clinical board certification. Concurrent correlates of current high research productivity by both outcomes included employment by the federal government or academia and academic appointment. CONCLUSIONS: Factors associated with high research productivity could be utilized to improve the resident selection process and promote research careers. This could enhance research programs and education and promote the overall prevention research agenda.

Report of a US public health service workshop on hypotonic-hyporesponsive episode (HHE) after pertussis immunization.

Hypotonic-hyporesponsive episode (HHE) is a term used to describe a somewhat heterogenous group of clinical disorders that have been reported primarily in association with whole-cell pertussis vaccination. A 1991 review by the Institute of Medicine determined that the evidence available was indeed consistent with a causal relation between whole-cell pertussis-diphtheria-tetanus immunization and HHE, but that the evidence was insufficient to indicate a causal relationship between HHE and the subsequent development of permanent neurologic damage. More recent data from clinical trials conducted in Europe suggest that HHE also occurs after vaccination with acellular pertussis vaccines. The US Food and Drug Administration, in collaboration with the US Public Health Service, sponsored a workshop on HHE in Rockville, Maryland, on June 19, 1997. The primary goals of the workshop were to develop a case definition of HHE and to evaluate the general design and feasibility of possible studies of HHE using the federal Vaccine Adverse Event Reporting System (VAERS), a national passive surveillance system. The goals of such studies would be to understand better the acute HHE event and to evaluate the possibility of long-term sequelae. Case Definition. There has been no generally accepted definition of HHE, and a standard definition would be useful for vaccine safety work and would potentially facilitate interstudy comparisons of the growing number of licensed vaccines containing acellular pertussis components. The workshop defined HHE as an event of sudden onset occurring within 48 hours of immunization, with duration of the episode ranging from 1 minute to 48 hours, in children younger than 10 years of age. All of the following must be present: 1) limpness or hypotonia, 2) reduced responsiveness or hyporesponsiveness, and 3) pallor or cyanosis or failure to observe or to recall skin coloration. HHE is not considered to have occurred if there is a known cause for these signs (eg, postictal), if urticaria is present during the event, if normal skin coloration is observed throughout the episode, or if the child is simply sleeping. This inclusive (sensitive) case definition will allow investigators, through the technique of stratification according to certain characteristics (eg, time from vaccination to onset of HHE), to attempt to hone the definition and make it more specific. Refinement of the definition of HHE has been hindered by the lack of information on its pathophysiology and by the lack of pathognomonic signs, symptoms, and diagnostic tests. Another hindrance is that by the time the child presents for medical evaluation, the signs of HHE often have normalized. Moreover, different mechanisms may be involved in different individuals whose events meet this workshop's HHE definition. Further Study of HHE. Probably the most important question about HHE is whether it has any permanent sequelae. The workshop assessed the possible contribution VAERS-based studies could make to answering this question and found substantial methodologic problems; however, ongoing studies in Sweden and The Netherlands have the potential to provide useful information on this question. The most useful contribution of VAERS data would be in a descriptive study of HHE, with a possible case-control study of factors that may affect the risk of HHE after vaccination, rather than a study of possible permanent sequelae. The workshop participants felt that a detailed descriptive study of approximately 100 HHE events reported during a 1- to 2-year period could provide a more in-depth description of HHE cases in greater numbers than has been published previously, but the study would not address the issue of long-term sequelae of HHE. Better descriptive data may lead to new hypotheses concerning risk factors, etiology, and pathophysiology of HHE that might be evaluated further by studying subsequent cases and controls from VAERS or from other sources, depending on the hypoth

Hair loss after routine immunizations.

CONTEXT: Alopecia is a recognized adverse effect of numerous medications, but vaccines are not normally considered a cause for unexpected loss of hair. OBJECTIVE: To describe case reports of hair loss after routine vaccines and to assess the hypothesis that vaccinations might induce hair loss. DESIGN: Case series with telephone follow-up. METHODS: Review of spontaneous reports to the Food and Drug Administration, the Centers for Disease Control and Prevention, and the Vaccine Adverse Event Reporting System. MAIN OUTCOME MEASURE: Loss of hair following immunization. RESULTS: A total of 60 evaluable reports submitted since 1984 and coded for "alopecia" after immunizations included 16 with positive rechallenge (hair loss after vaccination on more than 1 occasion), 4 of which were definite and 12 possible or probable. Of the 60 cases, 46 had received hepatitis B vaccines. Both of the currently available recombinant products, as well as the former plasma-derived product, were represented. Females predominated in all age groups. The majority of patients recovered, but clinical features, such as intervals from vaccination until onset and the extent and reversibility of hair loss, varied widely. Nine patients reported previous medication allergy. CONCLUSION: There may be an association, probably very rare, between vaccinations and hair loss. More than 1 pathophysiologic mechanism may be responsible. Since apparently nonrandom distributions by vaccine, age, and sex could reflect biased case ascertainment, further research will be needed in defined populations with consistent case detection.

Preventive medicine physician satisfaction and its relation to practice characteristics.

BACKGROUND: Physicians specializing in general preventive medicine and public health manage programs, conduct research, and care for patients. This study examines their satisfaction overall and in five dimensions: contribution to people's lives, respect from physicians in clinical practice, research opportunities, income, and time to pursue outside interests. METHODS: A survey of 1979-1989 graduates of preventive medicine residencies rated satisfaction on a five-point scale. Linear models were used to regress physician satisfaction against employer, hours worked, practice content, and other covariates. RESULTS: Respondents' (n = 778) overall job satisfaction was high, with 44% very satisfied, 44% satisfied, 7% neutral, and 6% dissatisfied. Federal government physicians had the highest satisfaction overall and for research opportunities and time for outside interests. Independent, statistically significant (p < .001) associations were found between higher satisfaction with research opportunities among academic and federal government employers, among Caucasians, and those with substantial epidemiologic practice; and lower satisfaction with time to pursue outside interests, more hours worked, and among women. CONCLUSIONS: Physician satisfaction could be understood in relation to a number of practice characteristics including its content, hours worked, income, and employer. The results suggest ways to improve physician satisfaction, including balancing competing demands of practice and focusing the physicians' responsibilities.

Clarifying the direct relation between total cholesterol levels and death from coronary heart disease in older persons.

BACKGROUND: The importance of total cholesterol level as a risk factor for coronary heart disease in older adults is controversial. OBJECTIVE: To determine whether findings showing that total cholesterol level is not an important risk factor for coronary heart disease in older adults are the result of inadequate adjustment for co-occurring diseases and frailty. DESIGN: Multicenter, longitudinal study with 5-year follow-up for death. PARTICIPANTS: 4066 men and women from East Boston, Massachusetts; Iowa and Washington counties, Iowa; and New Haven, Connecticut. MEASUREMENTS: In 1988, participants were interviewed about their health status and had blood samples taken. Mortality follow-up was through 1992. RESULTS: In analyses that included all fatal coronary heart disease events (252 deaths) and did not adjust for risk factors for coronary heart disease and measures of frailty, persons with the lowest total cholesterol levels (< or = 4.15 mmol/L [< or = 160 mg/dL]) had the highest rate of death from coronary heart disease, whereas those with elevated total cholesterol levels (> or = 6.20 mmol/L [> or = 240 mg/dL]) seemed to have a lower risk for death from coronary heart disease (P for trend = 0.04). After adjustment for established risk factors for coronary heart disease and markers of poor health (including chronic conditions, low serum iron and albumin levels) and exclusion of 44 deaths from coronary heart disease that occurred within the first year, elevated total cholesterol levels predicted increased risk for death from coronary heart disease, and the risk for death from coronary heart disease decreased as cholesterol levels decreased (P for trend = 0.005). CONCLUSIONS: Elevated total cholesterol level is a risk factor for death from coronary heart disease in older adults, and the apparent adverse effects associated with low cholesterol levels are secondary to comorbidity and frailty. This suggests that excluding older persons from cholesterol screening is inappropriate, but interpretation of screening results in older persons requires clinical judgment. Results from controlled clinical trials are needed to clarify this issue.

Serum iron level, coronary artery disease, and all-cause mortality in older men and women.

The association between iron levels and coronary artery disease (CAD) mortality is controversial. Whereas most data show no association, some have raised the possibility of a causal role, while others have suggested a protective effect of iron on CAD. To address these possibilities, we examined the association between serum iron and CAD, cardiovascular disease, and all-cause mortality in a large cohort of 3,936 persons aged > or =71 years who completed an interview, had a serum iron determination, and survived at least 1 year after baseline. The median follow-up time was 4.4 years. Serum iron levels were categorized according to sex-specific quartiles. Relative risks (RR) and 95% confidence intervals (CI) were calculated from proportional-hazards regression models adjusted for age, race, education, creatinine, serum albumin, serum lipids, use of iron supplementation, smoking, use of alcohol, blood pressure, body mass index, and presence of chronic conditions. There was a gradual decrease in the RRs of CAD, cardiovascular disease, and all-cause mortality with increasing serum iron levels (all tests for trend, p <0.05). Men in the highest iron quartile were one fifth as likely to die of CAD as men in the lowest iron quartile (RR 0.22; 95% CI 0.11 to 0.48), and women in the highest quartile had half the risk of women in the lowest quartile (RR 0.48; 95% CI 0.27 to 0.87). When compared with the lowest quartile, risk of all-cause mortality was 38% lower in men in the highest iron quartile (RR 0.62; 95% CI 0.46 to 0.85) and 28% lower in women in the highest quartile (RR 0.72; 95% CI 0.53 to 0.96). Results of similar strength and magnitude were observed for cardiovascular disease mortality and in analyses that excluded the first 3 years of follow-up. In this large cohort of persons aged > or =71 years, there was consistent evidence of increasing risk of mortality at lower serum iron levels. In fact, lower serum iron levels were associated with an increased risk of CAD, cardiovascular disease, and all-cause mortality. The results are compatible with the possibility that in an older population, there is an inverse association between serum iron levels and risk of mortality.

Effect of age and severity of disability on short-term variation in walking speed: the Women's Health and Aging Study.

Standardized objective measures of human performance have been introduced in clinical and epidemiologic studies of older populations. Reliability of these measures has usually been estimated by comparing two measures obtained in the same person. However, no information is available on variability of multiple measures collected serially over short time intervals. This study uses data from the Weekly Disability Study, a component of the Women's Health and Aging Study, to describe fluctuations in physical performance over multiple, consecutive time intervals. Walking speed was measured weekly over a 6-month period in 99 older women affected by mild to severe disability. Overall, 2120 observations were explored using techniques developed for the analysis of repeated measures. Results showed that the correlations between observations in the same person were inversely related to their separation in time. The decay in the autocorrelation function was steeper in the least disabled. However, even with 20-week separations in assessments, correlations remained above 0.6 in all age and severity of disability subgroups. Changes over time in performance differed somewhat between disability subgroups, but the relative performance across subgroups remained stable over the entire course of the study. A clear learning effect was found only in those in the middle disability subgroup. Results support the utilization of repeated measures of physical performance in research that evaluates older persons over time.

Preventive services for breast and cervical cancer in U.S. office-based practices.

BACKGROUND: This study was undertaken to examine patterns of delivery of preventive services for breast and cervical cancer and the bundling of several preventive services. METHODS: Data from the National Ambulatory Medical Care Survey on visits by women ages > or = 45 years to office-based physicians during 1989 and 1990 were analyzed for delivery of clinical breast examination, mammography, breast self-examination counseling, pelvic examination, and Pap smear. RESULTS: An estimated 38.7 million office visits included one or more preventive services for breast and cervical cancer (46.7 visits per 100 women per year). Visits that included clinical breast examination, Pap smear, and mammography together were largely provided by obstetricians and gynecologists, less by general/ family practice and general internal medicine physicians, and rarely by subspecialists. Twenty-two percent of these visits were periodic preventive visits, lowest for subspecialists and highest for general internists. Major sources of payment included insurance and personal resources at younger ages and Medicare at ages > or = 65. CONCLUSIONS: The periodic preventive visit has received only limited acceptance by physicians who provide preventive care for adult women. Payment for preventive visits changes with age and may affect the appropriate provision of services.

Alcohol consumption and risk of deep venous thrombosis and pulmonary embolism in older persons.

OBJECTIVES: To assess whether low to moderate alcohol consumption decreases the risk of deep venous thrombosis and pulmonary embolism. DESIGN: Prospective cohort study. SETTING: Three communities of the Established Populations for Epidemiologic Studies of the Elderly. PARTICIPANTS: A total of 7959 persons aged 68 years or older. MEASUREMENTS: The incidence of deep venous thrombosis and pulmonary embolism was assessed by surveying hospital discharge diagnoses and deaths from 1985 through 1992. Those participants who estimated they used alcohol less than 1 time, on average, in the past month, less than 1 ounce per day, and 1 ounce or more per day were compared with those who reported no alcohol intake in the past year. Age, gender, race, body mass index, smoking, education, income, disability, cognitive function, arterial pressure, medication use, baseline chronic conditions, number of hospital admissions in past year, and occurrence of disease during follow-up were examined as possible confounders. RESULTS: During 48,038 person-years of follow-up, 155 events were observed (35 deep venous thromboses and 123 pulmonary emboli). Compared with non-drinkers, after adjusting for potential confounding variables, the relative risks (95% confidence interval) for deep venous thrombosis and pulmonary embolism associated with increasing alcohol consumption levels were 0.7 (0.4-1.1), 0.6 (0.4-0.9), and 0.5 (0.2-1.1), respectively (P for trend = .004). The results were unchanged after stratifying on health status and disability. CONCLUSIONS: Low to moderate alcohol consumption is associated with a decreased risk of deep venous thrombosis and pulmonary embolism in older persons.

Calcium-channel blockade and incidence of cancer in aged populations.

BACKGROUND: Calcium-channel blockers can alter apoptosis, a mechanism for destruction of cancer cells. We examined whether the long-term use of calcium-channel blockers is associated with an increased risk of cancer. METHODS: Between 1988 and 1992 we carried out a prospective cohort study of 5052 people aged 71 years or more and who lived in three regions of Massachusetts, Iowa, and Connecticut USA. Those taking calcium-channel blockers (n = 451) were compared with all other participants (n = 4601). The incidence of cancer was assessed by survey of hospital discharge diagnoses and causes of death. These outcomes were validated by the cancer registry in the one region where it was available. Demographic variables, disability, cigarette smoking, alcohol consumption, blood pressure, body-mass index, use of other drugs, hospital admissions for other causes, and comorbidity were all assessed as possible confounding factors. FINDINGS: The hazard ratio for cancer associated with calcium-channel blockers (1549 person-years, 47 events) compared with those not taking calcium-channel blockers (17225 person-years, 373 events) was 1.72 (95% CI 1.27-2.34, p = 0.0005), after adjustment for confounding factors. A significant dose-response gradient was found. Hazard ratios associated with verapamil, diltiazem, and nifedipine did not differ significantly from each other. The results remained unchanged in community-specific analyses. The association between calcium-channel blockers and cancer was found with most of the common cancers. INTERPRETATION: Calcium-channel blockers were associated with a general increased risk of cancer in the study populations, which suggested a common mechanism. These observational findings should be confirmed by other studies.

Do calcium channel blockers increase the risk of cancer?

Calcium channel blockers can block calcium signals that trigger cell differentiation and apoptosis, which are important mechanisms of cancer growth regulation. To ascertain whether calcium channel blocker use was associated with an increased risk of cancer, 750 hypertensive persons age > or = 71 years, with no history of cancer at baseline, were followed from 1988 through 1992. The patients were using either beta-blockers, angiotensin converting enzyme inhibitors or calcium channel blockers (verapamil, nifedipine, and diltiazem; mainly of the short-acting variety). Compared to beta-blockers (n = 424, 28 events), after adjusting for age, gender, race, smoking, body mass index, and number of hospital admissions not related with cancer, the relative risks of cancer (95% confidence interval) for angiotensin converting enzyme inhibitors (n = 124, 6 events) and calcium channel blockers (n = 202, 27 events) were 0.73 (0.30 to 1.78) and 2.02 (1.16 to 3.54), respectively. These findings indicate that calcium channel blocker therapy might increase the risk of cancer. New data are needed in patients using modern calcium channel blocker agents with more gradual absorption. This report should encourage further study of cancer outcomes in elderly patients who are vulnerable to cancer and who are receiving calcium channel blockers.