Patricia R. Hebert

Blood pressure, stroke, and coronary heart disease: Part 2, short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context

There are 14 unconfounded randomised trials of antihypertensive drugs (chiefly diuretics or beta-blockers): total 37,000 individuals, mean treatment duration 5 years, mean diastolic blood pressure (DBP) difference 5-6 mm Hg. In prospective observational studies, a long-term difference of 5-6 mm Hg in usual DBP is associated with about 35-40% less stroke and 20-25% less coronary heart disease (CHD). For those dying in the trials, the DBP difference had persisted only 2-3 years, yet an overview showed that vascular mortality was significantly reduced (2p less than 0.0002); non-vascular mortality appeared unchanged. Stroke was reduced by 42% SD 6 (95% confidence interval 35-50%; 289 vs 484 events, 2p less than 0.0001), suggesting that virtually all the epidemiologically expected stroke reduction appears rapidly. CHD was reduced by 14% SD 5 (95% CI 4-22%; 671 vs 771 events, 2p less than 0.01), suggesting that just over half the epidemiologically expected CHD reduction appears rapidly. Although this significant CHD reduction could well be worthwhile, its size remains indefinite for most circumstances (though beta-blockers after myocardial infarction are of substantial benefit). At present, therefore, a sufficiently high risk of stroke (perhaps because of age, blood pressure, or, in particular, history of cerebrovascular disease) may be the clearest indication for antihypertensive treatment.

Prevention of disease progression, left ventricular hypertrophy and congestive heart failure in hypertension treatment trials.

OBJECTIVES This work was done to determine the role of hypertension treatment in the prevention of disease progression, left ventricular hypertrophy and congestive heart failure. BACKGROUND Lowering of blood pressure in hypertensive patients has been reported to reduce morbidity and mortality from strokes and myocardial infarction. Data on primary prevention of disease progression, left ventricular hypertrophy and congestive heart failure have not previously been carefully quantified. METHODS All the major long-term hypertension treatment trials over the past 20 years were reviewed. RESULTS One thousand four hundred ninety-three of 13,342 subjects in the control groups compared with only 95 of 13,389 in the treated groups progressed from less severe to severe hypertension. The incidence of left ventricular hypertrophy in treated compared with control or placebo subjects was 140 of 6,150 and 216 of 6,098 subjects, respectively; congestive heart failure occurred in 240 of 6,923 subjects in the control group compared with only 112 of 6,914 treated subjects. CONCLUSIONS The lowering of blood pressure over a 3- to 5-year period of time is effective in preventing severe disease, left ventricular hypertrophy and congestive heart failure in addition to strokes and myocardial infarction. In an era when expensive and often complicated methods are being used to prevent recurrence of congestive heart failure or myocardial infarction, it is important to highlight the role of antihypertensive therapy in primary prevention.

Evidence for a positive linear relation between blood pressure and mortality in elderly people

Many studies of blood pressure in the elderly have found higher death rates in groups with the lowest blood pressure than in those with intermediate values. In a large community study, we examined whether these findings are real or artifacts of short follow-up, co-morbidity, or low blood pressure in people near death. In 1982-83, we assessed drug use, medical history, disability, physical function, and blood pressure in 3657 residents of East Boston, Massachusetts, aged 65 and older. We identified all deaths (1709) up to 1992 and followed up survivors for an average of 10.5 (range 9.5-11.0) years. After adjustment for confounding variables (including frailty and disorders such as congestive heart failure and myocardial infarction) and exclusion of deaths within the first 3 years of follow-up, higher systolic pressure predicted linear increases in cardiovascular (p < 0.0001) and total (p < 0.0007) mortality. Higher diastolic pressure predicted increases in cardiovascular (p = 0.006) but not total (p = 0.48) mortality. These results differed from those for the first 3 years, during which groups with the lowest systolic and diastolic pressures had the highest death rates. In the long term, lower blood pressure in old age, as in middle age, is associated with better survival. Short-term findings may differ because of associations of co-morbidity and frailty with blood pressure near death. Overall, the findings support recommendations to treat high blood pressure in elderly people.

An application of conditional logistic regression and multifactor dimensionality reduction for detecting gene-gene Interactions on risk of myocardial infarction: The importance of model validation

BackgroundTo examine interactions among the angiotensin converting enzyme (ACE) insertion/deletion, plasminogen activator inhibitor-1 (PAI-1) 4G/5G, and tissue plasminogen activator (t-PA) insertion/deletion gene polymorphisms on risk of myocardial infarction using data from 343 matched case-control pairs from the Physicians Health Study. We examined the data using both conditional logistic regression and the multifactor dimensionality reduction (MDR) method. One advantage of the MDR method is that it provides an internal prediction error for validation. We summarize our use of this internal prediction error for model validation.ResultsThe overall results for the two methods were consistent, with both suggesting an interaction between the ACE I/D and PAI-1 4G/5G polymorphisms. However, using ten-fold cross validation, the 46% prediction error for the final MDR model was not significantly lower than that expected by chance.ConclusionsThe significant interaction initially observed does not validate and may represent a type I error. As data-driven analytic methods continue to be developed and used to examine complex genetic interactions, it will become increasingly important to stress model validation in order to ensure that significant effects represent true relationships rather than chance findings.

Sodium reduction for hypertension prevention in overweight adults: further results from the Trials of Hypertension Prevention Phase II

Sodium reduction is efficacious for primary prevention of hypertension, but the feasibility of achieving this effect is unclear. The objective of the paper is detailed analyses of adherence to and effects of the sodium reduction intervention among overweight adults in the Trials of Hypertension Prevention, Phase II. Sodium reduction (comprehensive education and counselling about how to reduce sodium intake) was tested vs no dietary intervention (usual care) for 36–48 months. A total of 956 white and 203 black adults, ages 30–54 years, with diastolic blood pressure 83–89 mmHg, systolic blood pressure (SBP) <140 mmHg, and body weight 110–165% of gender-specific standard weight were included in the study. At 36 months, urinary sodium excretion was 40.4 mmol/24 h (24.4%) lower in sodium reduction compared to usual care participants (P<0.0001), but only 21% of sodium reduction participants achieved the targeted level of sodium excretion below 80 mmol/24 h. Adherence was positively related to attendance at face-to-face contacts. Net decreases in SBP at 6, 18, and 36 months of 2.9 (P<0.001), 2.0 (P<0.001), and 1.3 (P=0.02) mmHg in sodium reduction vs usual care were associated with an overall 18% lower incidence of hypertension (P=0.048); were relatively unchanged by adjustment for ethnicity, gender, age, and baseline blood pressure, BMI, and sodium excretion; and were observed in both black and white men and women. From these beneficial but modest results with highly motivated and extensively counselled individuals, sodium reduction sufficient to favourably influence the population blood pressure distribution will be difficult to achieve without food supply changes.

Design of a multicenter trial to evaluate long-term life-style intervention in adults with high-normal blood pressure levels: Trials of hypertension prevention (phase II)

Phase II of the Trials of Hypertension Prevention (TOHP) is a multicenter, randomized trial sponsored by the National Heart, Lung, and Blood Institute designed to test whether weight loss alone, sodium reduction alone, or the combination of weight loss and sodium reduction will decrease diastolic (DBP) and systolic blood pressure (SBP) as well as the incidence of hypertension (DBP > or = 90 mm Hg, SBP > or = 140 mm Hg, and/or use of antihypertensive medications) in subjects with high-normal DBP (83 to 89 mm Hg) and SBP less than 140 mm Hg at entry. These interventions were chosen for longer-term testing with end points including hypertension prevention as well as blood pressure (BP) change based on their demonstrated short-term efficacy in reducing BP in phase I of TOHP. The phase II study population is comprised of 2382 participants (1566 men and 816 women) who are 110 to 165% of desirable body weight, allocated at random to the four treatment arms using a 2 x 2 factorial design. The trial has 80% power to detect an overall treatment effect on DBP of 1.2 mm Hg for weight loss or sodium reduction and a difference of 1.6 mm Hg between the combined intervention and placebo groups. BP observers are blinded to participant treatment assignments. Participants will be followed for 3 to 4 years. This trial may have important public policy implications concerning the ability of life-style modifications to reduce BP and prevent the development of hypertension over the long term, thereby avoiding the need for drug therapy which while effective is costly and may have side effects.

Baseline characteristics of participants in phase I of the trials of hypertension prevention

Phase I of the Trials of Hypertension Prevention was designed to test the effectiveness and safety of three life-style (weight loss, sodium restriction, and stress management) and four nutrition supplement (calcium, magnesium, potassium, and fish oil) interventions in reducing diastolic blood pressure (DBP) in persons with a high-normal blood pressure. A total of 2182 persons with a DBP between 80 and 89 mm Hg met the eligibility criteria for participation in phase I and were randomized to one of the active intervention or control treatment groups. Most were white (82%), male (70%), married (76%), nonsmoking (88%), college graduate (53%), full-time employees (91%). The average blood pressure prior to entry into the trial was 124.9 mm Hg systolic and 83.8 mm Hg diastolic. A variety of baseline observations, including sociodemographic characteristics, personal and family medical history, health habits, diet, and biologic measurements, were documented before randomization and compared among the seven active intervention and control groups. As might be expected in a randomized trial of this sample size, the distribution of measured baseline characteristics was virtually identical in the treated and control groups. Based on this finding and the knowledge that randomization procedures were implemented without deviation from the phase I protocol, it is probable that unknown potential confounders were also equally distributed at entry into the study. Given the achievement of high rates of follow-up, subsequent differences in blood pressure are unlikely to have been due to baseline differences between the active treatment and control groups, and can probably be attributed to effects of the active interventions.

The gender-specific role of polymorphisms from the fibrinolytic, renin-angiotensin, and bradykinin systems in determining plasma t-PA and PAI-1 levels

Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) directly influence thrombus formation and degradation and thus risk for arterial thrombosis. We report here results from a genetic analysis of plasma t-PA and PAI-1 levels in a large population-based sample from the PREVEND study in Groningen, the Netherlands (n = 2,527). We measured polymorphisms from genes of the fibrinolytic system, the renin-angiotensin system (RAS), and the bradykinin system. We found that males had higher levels of natural-log transformed t-PA, and PAI-1 (P < 0.01) compared to females. When stratifying females by menopausal status, PAI-1 levels were only significantly different between pre-menopausal females and males (p < 0.001). Furthermore, we found that age, body mass index, and waist-to-hip ratio were significant predictors of t-PA and PAI-1 in both females and males, and that the regression relationships between these factors and plasma t-PA and PAI-1 were dependent on gender. In addition, we found that the PAI-1 4G/5G polymorphism was a significant predictor of PAI-1 levels in both females and males, that the angiotensin II type I receptor A1166C was a significant predictor of t-PA and PAI-1 levels in females, and that the bradykinin receptor B2 58CT polymorphism was a significant predictor of t-PA levels in females. In conclusion, this large population-based study showed that t-PA and PAI-1 levels are determined by several demographic and genetic factors involved in the fibrinolytic, RAS and bradykinin system. In addition, the results support the idea that the biology of t-PA and PAI-1 is different between females and males.

Short report : the effect of fish oil on blood pressure and high-density lipoprotein-cholesterol levels in phase I of the trials of hypertension prevention

Objective To study the effects of moderate doses of fish oil on blood pressure and high-density lipoprotein (HDL)-cholesterol. Methods The participants were 350 normotensive men and women aged 30–54 years who were enrolled from seven academic medical centers in phase I of the Trials of Hypertension Prevention. They were randomly assigned to receive placebo or 6g purified fish oil once a day, which supplied 3g n-3 polyunsaturated fatty acids for 6 months. Results Baseline blood pressure was (mean ± SD) 123±9/81 ±5mmHg. The mean differences in the blood pressure changes between the fish oil and placebo groups were not statistically significant. There was no tendency for fish oil to reduce blood pressure more in subjects with baseline blood pressures in the upper versus the lower quartile (132/87 versus 114/75 mmHg), low habitual fish consumption (0.4 versus 2.9 times a week) or low baseline plasma levels of n-3 fatty acids. Fish oil increased HDL2-cholesterol significantly compared with the placebo group. Subgroup analysis showed this effect to be significant in the women but not in the men. Increases in serum phospholipid n-3 fatty acids were significantly correlated with increases in HDL2-cholesterol and decreases in systolic blood pressure. Conclusion Moderate amounts of fish oil (6g/day) are unlikely to lower blood pressure in normotensive persons, but may increase HDL2-cholesterol, particularly in women.

Gender-specific correlations of plasminogen activator inhibitor-1 and tissue plasminogen activator levels with cardiovascular disease-related traits

Summary.  Background: The purpose of this study was to examine the correlations between plasma levels of plasminogen activator inhibitor‐1 (PAI‐1) and tissue plasminogen activator (t‐PA) and cardiovascular disease‐related traits in a general population and whether these correlations differed between females and males. Methods: Plasma PAI‐1 and t‐PA antigen levels and C‐reactive protein (CRP), HDL‐cholesterol, triglycerides, total cholesterol, systolic blood pressure, diastolic blood pressure, urinary albumin excretion, and glucose were measured in the population‐based PREVEND study in Groningen, the Netherlands (n = 2527). Results: Except for CRP and total cholesterol levels, all traits were significantly different between gender (P < 0.001). PAI‐1 levels were correlated with all measured cardiovascular disease‐related traits (P < 0.01) in both females and males. Except for urinary albumin excretion, similar results, albeit less significant, were found for t‐PA levels. Age‐adjusted correlations between PAI‐1 and CRP, triglycerides, total cholesterol, systolic blood pressure, and diastolic blood pressure differed significantly between females and males (P < 0.01). Many of the gender differences were predominantly present between premenopausal females and males. Conclusion: PAI‐1 and t‐PA levels were correlated with cardiovascular disease‐related traits in subjects obtained from the general population and several of these correlations differed across gender. The correlations found in the present study suggest the presence of coordinated patterns of cardiovascular risk factors and indicate which traits might influence PAI‐1 and t‐PA levels and thereby provide a framework and potential tool for therapeutic intervention to reduce thromboembolic events in the general population.