Corrections to the nifedipine meta-analysis.
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Biomedical subjects
Publications and source records attributed to B M Psaty.
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The calcium antagonist (CA) controversy has been fueled in part by disagreements among scientists and clinicians over the scientific documentation required for drugs used to treat lifelong conditions. From a public health perspective, there are three unanswered questions: (1) Does long-term use of CAs convey health benefits to patients with cardiovascular disease (CVD)? (2) Is the long-term use of CAs safe? (3) Is the use of CAs cost effective? The answers to these questions determine the pertinence of three secondary questions: (4) Do the effects of CAs reflect a class action or are there important differences in health outcomes among subclasses of CAs? (5) Are the short-acting, immediate-release (IR) formulations different from the long-acting or the slow-release (SR) formulations? (6) What is prudent use of CAs? The purpose of this report is to summarize the answers to these questions from a public health perspective. (1) To date, use of CAs has not been documented to reduce the risks of cardiovascular complications of hypertension-stroke, myocardial infarction, congestive heart failure, or renal dysfunction. (2) The clinical trial database is inadequate to determine the long-term safety of CAs. The available data suggest that some formulations of CAs may be associated with an increased risk of cardiovascular and noncardiovascular events. (3) Even if slow-release CAs conveyed a benefit, their cost-effectiveness ratios are unlikely to be acceptable. (4) The non-dihydropyridines may offer an advantage over the dihydropyridines. (5) Whether the slow-release formulations differ from the immediate-release formulations in terms of their health effects remains to be seen. (6) It may be prudent clinically to restrict the use of CAs until proper documentation of long-term safety and efficacy and cost effectiveness is available.
BACKGROUND: Previous studies have raised the concern that the reduction of diastolic blood pressure below 85 mm Hg among treated hypertensive patients may have cardiac hazards. However, these reports have not fully assessed potential confounding from coexisting cardiovascular disease. METHODS: We conducted a population-based case-control study to examine the relation between treated diastolic blood pressure and the risk of primary cardiac arrest among hypertensive patients free of clinically diagnosed cardiovascular disease. Cases were hypertensive enrollees of the Group Health Cooperative of Puget Sound, an HMO, who had primary cardiac arrest between 1977 and 1990 (n = 80). Control patients were a stratified random sample of hypertensive enrollees (n = 426). Ambulatory-care records were reviewed to assess blood pressures and other clinical characteristics. Medication use was assessed through the HMO computerised pharmacy database. RESULTS: Logistic regression models suggested a curvilinear relation between the level of treated diastolic blood pressure and the risk of primary cardiac arrest, after adjustment for pretreatment diastolic blood pressure, antihypertensive therapy, and other potential confounders. Compared with a treated diastolic blood pressure of 85 mm Hg, a treated diastolic blood pressure of 80 mm Hg was associated with a small increase in risk (relative risk [RR] 1.2; 95% confidence interval [CI] 1.0, 1.6), 75 mm Hg was associated with a modest increase in risk [RR 1.6; 95% CI 1.2, 2.1], and 70 mm Hg was associated with more than a twofold increase in the risk of primary cardiac arrest [RR 2.3; 95% CI 1.4; 3.8). There was little evidence of effect modification by pretreatment diastolic blood pressure. CONCLUSIONS: Our findings support available evidence that among hypertensive patients a treated diastolic blood pressure level below 85 mm Hg is associated with cardiac hazards.
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Outcomes research seeks to identify effective evidence-based methods of providing the best medical care. While randomized clinical trials (RCT) usually provide the clearest answers, they are often not done or not practicable. More than a decade after the introduction of calcium channel blockers and angiotensin converting enzyme (ACE) inhibitors, clinical trial data about their effect on major disease endpoints in patients with hypertension are still not available. The primary alternatives are the use of randomized trials that include surrogate endpoints, such as level of blood pressure or extent of carotid atherosclerosis, and the use of observational studies that include major disease endpoints. Both approaches, their strengths and limitations, are discussed in detail. The possibility of residual confounding limits the strength of inferences that can be drawn from observational studies. Similarly, the possibility of important drug effects, other than those involving the surrogate endpoint, limits the inferences that can be drawn from randomized trials that rely solely on surrogate outcomes as guides to therapy. In the absence of evidence from large clinical trials that include major disease endpoints, treatment decisions and guidelines need to synthesize the best available information from a variety of sources. Consistency of findings across various study designs, outcomes, and populations is critical to the practice of evidence-based medicine and the effort to maximize the health benefits of antihypertensive therapies.
The cardioprotective effects of combined estrogen/progestin replacement therapy have been questioned. Therefore, we have compared carotid arterial wall thickening and the prevalence of carotid stenosis in elderly women (> or = 65 years old) currently using replacement estrogen/progestins (E + P) with arterial pathology and its prevalence in women using unopposed estrogens (E). This cross-sectional study used baseline data from all 2962 women participating in the Cardiovascular Health Study, a population-based study of coronary heart disease and stroke in elderly adults. Users of hormone replacement therapy (HRT) were categorized as never (n = 1726), past (n = 787), current E (n = 280), or current E + P (n = 73). Maximal intimal-medial thicknesses of the internal and common carotid arteries and stenosis of the internal carotid arteries were measured by ultrasonography. Current E + P users resembled current E users in most respects, although some lifestyle factors were more favorable among E + P users. Current E + P use and current E use (as compared with no use) were associated with smaller internal carotid wall thicknesses (-0.22 mm; P = 0.003; and -0.09 mm; P = 0.05, respectively) and smaller common carotid wall thicknesses (-0.05 mm; P = 0.03; and -0.02 mm; P = 0.1, respectively) and lower odds ratios (OR) for carotid stenosis (> or = 1% vs. 0%); OR = 0.61; 95% confidence interval [CI]: 0.36 to 1.01; and OR = 0.91, 95% CI: 0.67 to 1.24, respectively), after adjustment for current lifestyle and risk factors. When both groups of current HRT users were compared, there were no significant differences in carotid wall thicknesses or prevalence of carotid stenosis. For this sample of elderly women, both current E + P therapy and current E therapy were associated with decreased measures of carotid atherosclerosis. These measures did not differ significantly between the two groups of HRT users.
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Studies suggest that thrombosis is important in the progression of atherosclerotic lesions. The biochemical markers prothrombin fragment 1-2 and fibrinopeptide A reflect in vivo thrombin generation and activity, respectively. As such, they are markers that might be associated with cardiovascular risk. From the Cardiovascular Health Study, a cohort study of 5201 persons over 65 years of age, 399 persons free of clinical cardiovascular disease (CVD) at the baseline examination were selected for study of specialized markers of hemostasis. We report the cross-sectional relationships of the thrombin markers to CVD risk factors and measures of subclinical CVD. The range of fragment 1-2 2 was 0.12 to 0.85 nmol/L. The range of fibrinopeptide A was 0.9 to 44.1 micrograms/L. High levels of fragment 1-2 and fibrinopeptide A were associated with age, with levels higher in women than men. Fragment 1-2 was associated with smoking; high levels of triglyceride, creatinine, and C-reactive protein; and low levels of glucose. Fibrinopeptide A was associated with high C-reactive protein and apolipoprotein(a) and lower ankle-brachial index. There were no significant associations of the thrombin markers with race, fibrinogen, alcohol consumption, diabetes, or most measures of subclinical CVD. Study findings support a hypothesis that there are physiological interrelationships between cardiac risk factors, hemostasis, inflammation, and progression of atherosclerosis.
In order to determine whether a hostile attitude is associated with hypertension in post-menopausal women, we conducted a cross-sectional study of a sample of post-menopausal women enrollees from the Group Health Cooperative (Seattle, Washington). Out-patient medical records were reviewed for all subjects. Hypertension was defined as a recorded diagnosis of hypertension and treatment with an anti-hypertensive drug. Borderline hypertensives were excluded. Women were interviewed by telephone and asked the 14 questions comprising the Hostile-Affect (HOS) and Aggressive-Responding (AGGR) factors of the Cook-Medley hostility scale. Scores were grouped into high vs low HOS and AGGR. The AGGR score was available for 430 hypertensives and 628 normotensives. The HOS score was available for 436 hypertensives and 616 normotensives. High AGGR scores had a borderline association with hypertension (Odds Ratio (OR) = 1.26; 95% Confidence interval (CI) = 0.97-1.62). HOS was not associated with hypertension. Adjusting for age, physical activity, diabetes mellitus, cholesterol level, tobacco and alcohol use, weight and race, changed the association of AGGR with hypertension only slightly (OR = 1.22; CI = 0.92-1.63). We found a weak association between the prevalence of treated hypertension and AGGR in post-menopausal women. There was no association between the HOS component and hypertension. The results of this study support the need for prospective studies of the role of psychological factors in the development of hypertension in post-menopausal women. If this association is confirmed, AGGR measures may help identify women at high-risk who are most likely to benefit from hypertension screening and primary prevention.
BACKGROUND: Few studies have examined the association of physical activity with coronary heart disease among women. OBJECTIVE: To examine whether participation in physical activity during leisure time decreases the risk of myocardial infarction in postmenopausal women. METHOD: A population-based, case-control study among enrollees of the Group Health Cooperative of Puget Sound, a health maintenance organization based in Seattle, Wash. Cases were postmenopausal women who sustained an incident nonfatal myocardial infarction during the period 1986 through 1991. Controls were a random sample of Group Health Cooperative enrollees who were frequency matched to the cases by age and calendar year. Participation in physical activity during leisure time was assessed from a telephone interview. A total of 268 cases and 925 controls were interviewed. RESULTS: After adjustment for potential confounding factors, the odds ratios for nonfatal myocardial infarction for women in the second, third, and fourth quartile of total energy expenditure, relative to women in the first quartile, were 0.52 (95% confidence interval, 0.34 to 0.80), 0.40 (95% confidence interval, 0.26 to 0.63), and 0.40 (95% confidence interval, 0.25 to 0.63), respectively. Similar odds ratios were associated with the energy expended in nonstrenuous leisure-time physical activity, and with walking for exercise. CONCLUSION: This case-control study suggests that the risk of myocardial infarction among postmenopausal women is decreased by 50% with modest leisure-time energy expenditures, equivalent to 30 to 45 minutes of walking for exercise three times a week.
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BACKGROUND: The purpose of this study was to assess the effect of the dose of nifedipine, a dihydropyridine calcium antagonist, on the increased risk of mortality seen in the randomized secondary-prevention trials and to review the mechanisms by which this adverse effect might occur. METHODS AND RESULTS: We restricted the dose-response meta-analysis to the 16 randomized secondary-prevention trials of nifedipine for which mortality data were available. Recent trials of any calcium antagonist and formulation were also reviewed for information about the possible mechanisms of action that might increase mortality. Overall, the use of nifedipine was associated with a significant adverse effect on total mortality (risk ratio, 1.16, with a 95% CI of 1.01 to 1.33). This summary estimate fails to draw attention to an important dose-response relationship. For daily doses of 30 to 50, 60, and 80 mg, the risk ratios for total mortality were 1.06 (95% CI, 0.89 to 1.27), 1.18 (95% CI, 0.93 to 1.50), and 2.83 (95% CI, 1.35 to 5.93), respectively. In a formal test of dose response, the high doses of nifedipine were significantly associated with increased mortality (P = .01). While the mechanism of this adverse effect is not known, there are several plausible explanations, including the established proischemic effect, negative inotropic effects, marked hypotension, recently reported prohemorrhagic effects attributed to antiplatelet and vasodilatory actions of calcium antagonists, and possibly proarrhythmic effects. CONCLUSIONS: In patients with coronary disease, the use of short-acting nifedipine in moderate to high doses causes an increase in total mortality. Other calcium antagonists may have similar adverse effects, in particular those of the dihydropyridine type. Long-term safety data are lacking for most calcium antagonists.
BACKGROUND: The primary aim of the present study was to determine the relation between measures of subclinical cardiovascular disease and the incidence of clinical cardiovascular disease among 5201 adults 65 years of age or older who were participating in the Cardiovascular Health Study. METHODS AND RESULTS: A new method of classifying subclinical disease at baseline examination in the Cardiovascular Health Study included measures of ankle-brachial blood pressure, carotid artery stenosis and wall thickness, ECG and echocardiographic abnormalities, and positive response to the Rose Angina and Claudication Questionnaire. Participants were followed for an average of 2.39 years (maximum, 3 years). For participants without evidence of clinical cardiovascular disease at baseline, the presence of subclinical disease compared with no subclinical disease was associated with a significant increased risk of incident total coronary heart disease including CHD deaths and nonfatal MI and angina pectoris for both men and women. For individuals with subclinical disease, the increased risk of total coronary heart disease was 2.0 for men and 2.5 for women, and the increased risk of total mortality was 2.9 for men and 1.7 for women. The increased risk changed little after adjustment for other risk factors, including lipoprotein levels, blood pressure, smoking, and diabetes. CONCLUSIONS: The measurement of subclinical disease provides an approach for identifying high-risk older individuals who may be candidates for more active intervention to prevent clinical disease.
OBJECTIVE: To describe the changing patterns of antihypertensive medication use in the years immediately before and after the publication of the results of three major clinical trials of the treatment of hypertension in older adults. DESIGN: In this cohort study, adults 65 years or older were examined annually on four occasions between June 1989 and May 1992, and the use of antihypertensive medications was assessed by inventory at each visit. The four visits defined the boundaries of three study periods. For each study period, participants receiving antihypertensive therapy were either continuous users (n = 1667, 1643, and 1605, respectively) or starters (n = 157, 142, 120) of hypertensive therapy. The large clinical trials that convincingly proved the efficacy and safety of low-dose diuretic therapy in older adults were published during the latter parts of period 2 and the early parts of period 3. RESULTS: Among starters, the proportion initiating therapy on diuretics increased from 35.9% in period 2 to 47.5% in period 3, significantly so among women (P = .04). The proportions initiating other drugs displayed no significant trends. Among continuous users, the use of diuretics, beta-blockers, and vasodilators generally decreased over the 3-year period, while the use of calcium channel blockers and angiotensin-converting enzyme inhibitors increased significantly in each of the three periods (P < .05). The decline of 2.7% in the prevalence of diuretic use in period 1 abated during period 2 (1.8% decline), and it slowed significantly (P = .03) to almost a complete halt during period 3 (0.2% decline). The rate of increase in the use of calcium channel blockers slowed significantly (P = .01) between period 1 (+6.7%) and period 3 (+2.8%). CONCLUSIONS: Although other factors such as cost may have been important, the temporal trends in antihypertensive drug therapy coincided in time with and may have reflected in part the influence of the major clinical trials on the patterns of clinical practice.
BACKGROUND: Two new classes of antihypertensive agents were introduced in the 1980s, but their effectiveness in preventing heart disease and stroke has not been demonstrated. Lack of evidence of their efficacy might reasonably be expected to discourage their widespread use in management of hypertension. METHODS: Use of various classes of antihypertensive agents was estimated from published drug use information in an effort to estimate trends in antihypertensive drug use and evaluate the impact of these trends on costs of antihypertensive therapy in the United States. RESULTS: Proportionate use of the five major antihypertensive drug classes shifted markedly between 1982 and 1993. Diuretics accounted for 56% of all hypertensive drug mentions in 1982 but only 27% in 1993, a relative decline of 52%. Use of beta-blockers and central agents also declined during this period. Proportionate use of calcium antagonists showed the greatest gains, increasing from 0.3% to 27%, while the use of angiotensin-converting enzyme inhibitors increased from 0.8% to 24%. Given the higher costs of the newer agents, and assuming an estimated total cost of antihypertensive medications in 1992 of $7 billion, approximately $3.1 billion would have been saved had 1982 prescribing practices remained in effect in 1992. CONCLUSIONS: Use of calcium antagonists and angiotensin-converting enzyme inhibitors in hypertension has increased dramatically in the past 10 years. Without convincing evidence of the advantages of these agents, it is difficult to explain the continued decline in the use of less expensive agents, such as diuretics and beta-blockers, which are the only antihypertensive agents proved to reduce stroke and coronary disease in hypertensive patients.
BACKGROUND: This paper examines whether an "environmental indicator"--a survey of grocery store product displays--can provide a realistic alternative to individual-level telephone surveys for the evaluation of community-based nutrition programs. METHODS: Telephone and grocery store measures were used separately to evaluate three community-level dietary interventions that were part of the Kaiser Family Foundation Community Health Promotion Grants Program (CHPGP). Both surveys were conducted in the three intervention and seven control communities at three points in time: 1988, 1990, and 1992. The grocery store survey recorded the relative availability of low-fat and high-fiber products and the amount of store-provided health-education information. Self-reported dietary intake of residents was obtained in the same communities using a telephone survey. RESULTS: In the one community in which the intervention seemed to have contributed to reduced fat consumption, the grocery store and telephone surveys showed very similar relative changes for the only variable they had in common, low-fat milk consumption. In another community, both survey approaches indicated that there was no change or perhaps a slight worsening in the treatment relative to the controls. The third community produced the only contradictory results: the telephone survey suggested no change or perhaps a worsening, while the grocery store results were generally positive, though not statistically significant. CONCLUSION: These results, combined with the much lower cost of the grocery store survey, justify further pursuit of environmental indicators as an evaluation tool.
Cardiovascular and all-cause mortality are higher in black than white Americans, but racial differences in clinical and subclinical cardiovascular disease (CVD) have not been examined in older adults. Clinical and subclinical CVD and its risk factors were compared in 4926 white and 244 black men and women aged 65 years and older. Black participants had lower socioeconomic status and generally higher prevalences of CVD and its risk factors, except for adverse lipid profiles. Common carotid wall thickness was greater in black than white women, and ankle-arm blood pressure ratios were lower in black women and men (p < 0.01). After adjustment for CVD risk factors, common carotid walls were significantly thicker and ankle-arm ratios were lower in blacks than whites of both sexes, while internal carotid walls were significantly thinner in black women. Racial differences in clinical and subclinical CVD in older adults are similar to those reported in younger populations and do not appear to be explained by CVD risk factors.