A systematic survey of 13 randomized trials of non-steroidal anti-inflammatory drugs for the prevention of heterotopic bone formation after major hip surgery.

We performed a systematic survey of randomized trials to determine the effects of perioperative NSAIDs on the occurrence of heterotopic bone formation, gastrointestinal side-effects and long-term clinical outcomes after major hip surgery. 13 trials involving 4,129 individuals were identified. Overall, in 12 small trials of medium-to-high-dose regimens, there was a 57% reduction (95% confidence interval 51%-63%) in the risk of heterotopic bone formation. The results of one large trial of low-dose aspirin differed markedly (2% reduction (95% CI 12% reduction to 15% increase)). The NSAID regimens studied had no definite effect on gastrointestinal complications, and data about the effects of NSAIDs on pain and function were too few, and too incompletely reported, to draw conclusions about their effects on these outcomes. Routine prophylaxis against heterotopic bone formation with NSAIDs may be a useful adjuvant therapy for patients undergoing major hip surgery, but the overall balance of risks and benefits requires assessment in a large-scale randomized trial.

No effect of low-dose aspirin for the prevention of heterotopic bone formation after total hip replacement: a randomized trial of 2,649 patients.

2,649 patients scheduled for elective total hip replacement were recruited to the Heterotopic Bone Formation Sub-study of the Pulmonary Embolism Prevention Trial. Heterotopic bone formation was determined by radiographic examination and associated late postoperative outcomes were assessed by telephone interview. Heterotopic bone formation was observed in 627 (31%) of 2,048 radiographic examinations. There was no detectable effect of low-dose aspirin on the risks of heterotopic bone formation (RR 0.98; 95% CI 0.85-1.12), late postoperative pain (RR 1.10; 95%CI 0.91-1.35) or late postoperative impaired function (RR 1.03; 95% CI 0.94-1.12). The balance of benefits and risks of low-dose aspirin is determined by its effects on vascular events and bleeding, since it has no major effects on heterotopic bone formation or associated clinical outcomes.

A prospective cohort study of blood donors: methodological issues in the investigation of injuries and chronic diseases.

Blood donors have made important contributions to research, most notably in cross-sectional seroprevalence studies. The proposed New Zealand Blood Donors Health Study is a prospective cohort study of 30,000 New Zealand donors designed to investigate the determinants of common injuries, cardiovascular disease and cancer. While robust from an analytic perspective, the execution of prospective cohort studies in many settings is impeded by methodological, economic and organisational barriers. We examined the operational considerations of implementing a large-scale cohort study at a transfusion centre and evaluated measures taken to optimise data collection procedures. A pilot study of 1,000 participants revealed donor motivation to participate in this research was high (91% response rate). Comprehensive exposure data on lifestyle, behavioural and psychosocial factors were obtained from 95% of participants. Substantial heterogeneity in levels of potential risk factors was noted among respondents. Detailed dietary habit information and a study blood sample were obtained from 67% and 100% of participants, respectively. Study recruitment and baseline data collection was feasible during routine donor visits with minimal interruption to donor centre staff and procedures. We conclude the study design and characteristics of the regional donor program enhance the efficiency and significance of the proposed research.

Controlled clinical trials of drug treatment for hypertension. A review.

We reviewed the designs and major results of 17 large-scale, controlled, clinical trials that reported the effects of drug treatment for hypertension on morbidity or mortality. Seven trials conducted in study populations with more-severe hypertension (diastolic blood pressures 100-120 mm Hg or higher), including the more-severe stratum of the Veterans Administration Trial, showed large reductions in stroke, other "hypertensive" events, and, in one trial, total mortality. Of 11 trials in populations with less-severe hypertension (diastolic blood pressures predominantly below 105 mm Hg), including the less-severe stratum of the Veterans Administration Trial, nine met the criteria for pooling of results. Among the aggregate 43,000 patients in the nine trials who were followed up for an average of 5.6 years, mean diastolic blood pressure reduction was 5.8 mm Hg, and a significant 11% reduction in total mortality was observed. This benefit was largely attributable to a 38% reduction in fatal strokes; nonfatal strokes were similarly reduced. Coronary heart disease mortality was 8% lower in drug treatment than in control groups, but this difference was not significant. A similar result was observed for combined coronary mortality and nonfatal myocardial infarction. A possible explanation for the inconclusive result regarding coronary end points was an adverse trend, observed in several trials, in a subgroup with baseline resting electrocardiographic abnormalities. Because all the trials except the propranolol arm of the Medical Research Council trial used drug regimens based on thiazide-like diuretic agents, and because there are now several new drug classes proposed as initial therapy, additional large-scale clinical trials may need to be considered.

Diabetes and the risk of stroke. The Honolulu Heart Program.

From 1965 to 1968, the Honolulu Heart Program began following up a cohort of men in a prospective study of cardiovascular disease. For this report, we examined the 12-year risk of stroke in 690 diabetic and 6908 nondiabetic subjects free of coronary heart disease and a history of stroke at study entry. In 12 years of follow-up, 62.3 per 1000 diabetic men and 32.7 per 1000 nondiabetic men experienced a stroke. The relative risk of thromboembolic stroke for those with diabetes compared with those without diabetes was 2.0 (95% confidence limits, 1.4 to 3.0). Although diabetes was usually associated with an atherogenic risk profile, control of hypertension, complicating myocardial infarction, and other risk factors failed to diminish the effect of diabetes on stroke. Among those without diabetes, the relative risk of thromboembolic stroke for those at the 80th percentile of serum glucose level compared with those at the 20th percentile (199 vs 115 mg/dL [11.0 vs 6.4 mmol/L]) was 1.4 (95% confidence limits, 1.1 to 1.8). In the nondiabetic sample, the relative risk of thromboembolic stroke for those with glucosuria compared with those without glucosuria was 2.7 (95% confidence limits, 1.6 to 4.5). There was no association between diabetes, or measures of glucose intolerance, and hemorrhagic stroke. We conclude that diabetes, even in a possibly undiagnosed subset of hyperglycemic individuals, imparts an additional independent risk of stroke unexplained by clinically measured risk factors.

Risk of infective endocarditis in mitral valve prolapse with and without precordial systolic murmurs.

The risk of infective endocarditis (IE) associated with a systolic murmur in patients with mitral valve prolapse (MVP) was investigated in a case-control study. The case group comprised all patients with MVP (n = 19) from a series of 136 consecutive adult admissions for IE. Three matched control subjects were chosen for each case from a series of 144 MVP patients without IE. Seventeen of the 19 cases (89%) had documented evidence of systolic murmurs existing before the IE episode; systolic murmurs were documented in 25 of the 57 control subjects (47%). The data indicate a significant increase in the risk of IE in MVP patients with a systolic murmur (p less than 0.01). The absolute probability of IE developing in a patient with MVP and a murmur was estimated to be approximately 1 in 1,400 per year; this was 35 times greater than the probability in a patient with MVP without a murmur. The results suggest that by restricting prophylaxis to MVP patients with a systolic murmur, cover would be provided for almost 90% of those with MVP in whom IE would be likely to develop.

Relationship of blood pressure to coronary and stroke morbidity and mortality in clinical trials and epidemiological studies.

We compared pooled mortality and morbidity results from nine randomized trials of antihypertensive drug treatment (total n = 43,139), in which diastolic blood pressure (DBP) was reduced by a mean of 5.8 mmHg, with mortality and morbidity differences associated with the same DBP difference in two large prospective, observational studies [the follow-up study of the Multiple Risk Factor Intervention Trial (MRFIT) screenees and the Framingham Study]. These results indicate that the effect on stroke of BP reduction in the trials (-36%, 95% confidence interval +/- 10%) was about 80% of that estimated from the epidemiological studies, suggesting that the effects of long-term BP elevation on the cerebral vasculature are mostly reversible over 5-6 years of BP reduction. For coronary heart disease (CHD), the effect of BP reduction in the trials (-9 +/- 10%) was about 36% of that estimated from the epidemiological studies. This difference may reflect chronic processes involved in the pathophysiological association of BP with CHD; however, selective treatment of control patients at high risk of CHD and an adverse effect of diuretics on serum cholesterol may have influenced the effect of treatment in the trials.

The effect of weight reduction on left ventricular mass. A randomized controlled trial in young, overweight hypertensive patients.

We compared the effects of weight reduction, metoprolol, and placebo on M-mode echocardiographic measurements of the thickness and mass of the left ventricular wall in a 21-week, randomized controlled trial that enrolled 41 young, overweight patients with hypertension. At the end of the follow-up period, the patients in the weight-reduction group had lost an average of 8.3 kg, and their blood pressure had decreased by an average of 14/13 mm Hg, as compared with 12/8 mm Hg in the metoprolol group and 9/4 mm Hg in the placebo group. In the weight-reduction group, interventricular septal and posterior-wall thickness decreased by 14 percent and 11 percent, respectively, and left ventricular mass decreased by 20 percent (16 percent when adjusted for body-surface area). Decreases in interventricular septal and posterior-wall thickness and in left ventricular mass in the weight-reduction group were significantly greater than those in the placebo group. The changes in thickness of the interventricular septum and the left ventricular mass in the weight-reduction group were also greater than those in the metoprolol group. Changes in weight, independent of changes in blood pressure, were directly associated with changes in left ventricular mass. We conclude that weight reduction decreases left ventricular mass in overweight hypertensive patients and that control of obesity is important not only for the treatment of hypertension but also for the prevention of left ventricular hypertrophy.

Antihypertensive treatment and plasma lipoprotein levels. The associations in data from a population study.

In clinical trials, antihypertensive therapy with beta blockers and methyldopa has resulted in adverse changes in high-density lipoprotein cholesterol levels. To investigate whether such effects can be observed in a general population in which beta blockers and methyldopa are prescribed widely for the treatment of high blood pressure, plasma lipid and lipoprotein levels were compared in subjects receiving antihypertensive treatment, subjects with untreated high blood pressure, and subjects with normal blood pressure; these subjects were drawn from a random sample of 5,603 men and women screened in a national study of risk-factor prevalence in Australia. In both sexes, high-density lipoprotein cholesterol levels were lower in the group receiving treatment for hypertension than in the other groups (p less than 0.001). High-density lipoprotein cholesterol levels in normotensive subjects and subjects with untreated high blood pressure were identical. In men, triglyceride levels and the ratio of total cholesterol to high-density lipoprotein cholesterol were higher in the group receiving treatment than in the other groups (p less than 0.001 and p less than 0.05, respectively). In both sexes, the differences in plasma lipids and lipoproteins between treated and untreated hypertensive groups were independent of age, body mass index, alcohol consumption, and smoking. More than 40 percent of untreated hypertensive subjects and more than 50 percent of treated hypertensive subjects had elevated total cholesterol levels (greater than or equal to 252 mg/dl) or an elevated ratio of total cholesterol to high-density lipoprotein cholesterol (greater than or equal to 6.0) in comparison with less than 30 percent of normotensive subjects. These results indicate that even without treatment, a large proportion of persons with high blood pressure had a significant abnormality in plasma cholesterol. The observation of a lower high-density lipoprotein cholesterol level in subjects receiving treatment for high blood pressure suggests that antihypertensive therapy as prescribed in this study population had worsened the already poor plasma lipid and lipoprotein profile of the average hypertensive patient.

Plasma lipoprotein levels in treated and untreated hypertensive men and women. The National Heart Foundation of Australia Risk Factor Prevalence Study.

Experimental studies have reported that common antihypertensive drugs such as diuretics, beta-blockers, and methyldopa have adverse effects on plasma lipids and lipoproteins. To investigate whether such effects can be observed in the general population, plasma lipid and lipoprotein levels were compared in subjects receiving antihypertensive treatment, subjects with untreated high blood pressure, and subjects with normal blood pressure in a random sample of 5603 subjects screened in a national study of risk factor prevalence in Australia. In both sexes, high density lipoprotein (HDL) cholesterol was lower in the group receiving treatment than in the others (p less than 0.001). In men, triglycerides (TG) (p less than 0.001) and the ratio of total cholesterol to HDL cholesterol (TC/HDL cholesterol) (p less than 0.05) were higher in the group receiving treatment. In both sexes, the differences in plasma lipids and lipoproteins between treated and untreated hypertensive groups were independent of age, body mass index, alcohol consumption, and smoking. More than 40% of the treated or untreated hypertensive men and women had elevated total cholesterol (TC greater than 252 mg/dl) or an elevated TC/HDL cholesterol ratio (greater than 6.0). In men receiving antihypertensive treatment, the prevalence of an elevated TC/HDL cholesterol ratio was significantly greater than in men with untreated high blood pressure (p less than 0.01). The results of this study suggest that the effects of antihypertensive treatment on plasma lipids and lipoproteins can be observed in population lipid and lipoprotein levels. Even before treatment, a large proportion of high blood pressure patients have a significant plasma cholesterol abnormality, which may be aggravated by conventional antihypertensive therapy.

Comparison of weight reduction with metoprolol in treatment of hypertension in young overweight patients.

Weight reduction was compared with metoprolol (200 mg daily) in a randomised placebo-controlled trial of first-line treatment of mild hypertension (diastolic blood pressure 90-109 mm Hg) in 56 overweight patients aged under 55 years. After 21 weeks of follow up the weight-reduction group had lost an average of 7.4 kg. The fall in their systolic pressure of 13 mm Hg was significantly greater than that in the placebo group (7 mm Hg) but not different from that in the metoprolol group (10 mm Hg). Their fall in diastolic pressure (10 mm Hg) was greater than that in both the metoprolol (6 mm Hg) and placebo (3 mm Hg) groups. At the end of the follow-up period 50% of patients in the weight-reduction group had a diastolic pressure of less than 90 mm Hg. In the metoprolol group there was a decrease in high density lipoprotein (HDL)-cholesterol and an increase in the ratio of total to HDL-cholesterol; in the weight-reduction group there was a decrease both in total cholesterol and in the ratio of total to HDL-cholesterol. Thus in this study population weight reduction produced significant and clinically important reductions in blood pressure but not the adverse effects on plasma lipids commonly associated with antihypertensive drug therapy.

A randomized controlled trial of weight reduction and metoprolol in the treatment of hypertension in young overweight patients.

The effects of weight reduction and metoprolol (100 mg, b.d.) in the treatment of hypertension (diastolic blood pressure 90-109 mmHg) in 56 young, overweight patients were investigated in a randomized placebo controlled trial. After a 4-week baseline, subjects were followed up for 21 weeks. In the weight reduction group, the fall in systolic and diastolic blood pressure (13/10 mmHg), associated with a mean group weight loss of 7.4 kg, was greater (P less than 0.001) than that in the placebo group (7/3 mmHg); the fall in diastolic pressure but not systolic pressure was also greater than that in the metoprolol group (10/6 mmHg). At the end of follow-up, 50% of the weight reduction group, 39% of the metoprolol group and 17% of the placebo group had a diastolic blood pressure of less than 90 mmHg. In the weight reduction group there was a fall in total cholesterol and the ratio of total to HDL-cholesterol (P less than 0.001); in the metoprolol group there was a fall in HDL-cholesterol and an increase in the ratio of total to HDL-cholesterol (P less than 0.001). The results suggest that in the first step of treatment for hypertension in overweight patients, modest weight reduction produces significant and clinically important reductions in blood pressure, without incurring the adverse effects on plasma lipids and lipoproteins often associated with the first step of drug therapy.

Mitral valve prolapse and bacterial endocarditis: when is antibiotic prophylaxis necessary?

We investigated the association between mitral valve prolapse (MVP) and bacterial endocarditis (BE) in a case-control study of 56 patients with BE and 168 age- and sex-matched controls who had had echocardiography. Cases and controls were selected from patients without other known cardiovascular risk factors for BE. Twenty percent of the BE cases (11 of 56) and 4% of the controls (7 of 168) had MVP; the odds ratio of 5.3 (95% confidence interval 2.0 to 14.4) indicated a significantly greater risk of BE in patients with MVP. This increased those who had preexisting systolic murmurs (9 of 11). Exposure to repeated vascular instrumentation also increased the risk of BE (odds ratio 6.2, 95% confidence interval 2.3 to 16.4); this was independent of the risk associated with MVP. Based upon these data and the incidence of BE in New South Wales, Australia, in 1980, we estimate that 14 of every 100,000 adult patients with MVP would develop BE over a 1-year period, compared with three people in every 100,000 without other known risk factors for BE in the general population. Thus, although the risk of BE is five times greater in patients with MVP, the absolute risk remains small. This indicates that antibiotic prophylaxis is unnecessary for the majority of patients with MVP. We suggest that for patients with MVP not otherwise known to be at high risk of BE, routine antibiotic prophylaxis should be advised only for those who have systolic murmurs.

Blood pressure levels and mortality from cerebrovascular disease in Australia and the United States.

Blood pressure distributions were compared in two groups of subjects aged 25-64 years surveyed in the Risk Factor Prevalence Study in Australia and the Lipid Research Clinics Prevalence Study in North America. In men and women of all age groups, systolic and diastolic blood pressures were greater in the Australian study than in the North American study; the prevalence of hypertension was almost twice as great in the Australian study. The proportion of the total population receiving antihypertensive treatment was also greater in the Australian study. However, among those subjects classified as hypertensive, a greater proportion were receiving treatment in the North American study. The differences in blood pressure levels did not appear to be due to differences in body mass index. In men, possible differences in alcohol consumption could account for some of the difference in blood pressure levels but data from the Australian study suggest that such differences could only account for a small proportion of the difference in prevalence of hypertension. The higher blood pressures and greater prevalence of hypertension in the Australian study were consistent with a 40-55% greater mortality from cerebrovascular disease in Australia than the United States (1968-1977), observed in both men and women from age 45 years onwards. In Australia in 1978, this difference accounted for over 4,200 excess deaths (4% of annual mortality), 600 of which occurred in men and women below the age of 65 years. Mortality from other hypertensive diseases was also greater in Australia than in the United States, which gives further support to the suggestion that population blood pressures and hypertension-related mortality are greater in Australia than they are in the United States.

Obesity, alcohol consumption and blood pressure in Australian men and women. The National Heart Foundation of Australia Risk Factor Prevalence Study.

The associations of obesity and alcohol consumption with blood pressure and the prevalence of hypertension were studied in 5550 male and female subjects aged 25 to 64 years, surveyed in the National Heart Foundation of Australia 1980 Risk Factor Prevalence Study. Body mass index was significantly and independently associated with blood pressure levels in both sexes. A maximum of 30% of hypertension in the study population could be attributed to overweight. The association between body mass index and hypertension was greater in men under 45 years in whom a maximum of 60% of hypertension could be attributed to overweight. In both men and women receiving antihypertensive treatment, body mass index was positively associated with blood pressure. Overweight hypertensives were less likely to achieve normal blood pressure on treatment. Alcohol consumption was significantly and independently associated with blood pressure levels in males. A similar trend in females failed to reach statistical significance because of the lesser consumption of alcohol by females. A maximum of 11% of hypertension in males and 1% in females could be attributed to alcohol consumption. These estimates were reduced when age and body mass were taken into account.