Risk assessment and treatment benefit in intensively treated hypertensive patients of the hypertension Optimal Treatment (HOT) study.

BACKGROUND: The Hypertension Optimal Treatment (HOT) Study provided information about cardiovascular events in 18,790 hypertensives, subjected to pronounced blood pressure lowering for a mean of 3.8 years. METHODS AND RESULTS: The HOT Study data have been further analysed after risk stratification of the patients (1999 World Health Organization and International Society of Hypertension guidelines criteria): (i) no patients of the HOT Study were classified as low risk, 50% were classified as medium risk, 20.2% as high risk and 29.8% as very high risk; (ii) incidence of cardiovascular events in these patients with excellent blood pressure control [92% had diastolic blood pressure (DBP) < or = 90 mmHg] remained proportional to pretreatment risk. The relative risk of very high- versus medium-risk strata was between two and three both when HOT Study patients were considered independently of, or within the DBP target group they had been randomized to; and (iii) event rates in all risk strata were calculated to be much lower (possibly 60% lower) than rates expected from baseline risk calculated approximately by the Framingham equation. CONCLUSIONS: The low event rate in HOT Study patients is likely to result from pronounced blood pressure lowering, and is not explained by a lower risk profile than in previous controlled trials of antihypertensive treatment. The persistence of a risk gradient despite intensive blood pressure lowering suggests a combination of blood pressure control with other strategies of risk correction and the need to initiate antihypertensive therapy before complications develop.

Influence of gender and age on preventing cardiovascular disease by antihypertensive treatment and acetylsalicylic acid. The HOT study. Hypertension Optimal Treatment.

OBJECTIVE: We have assessed the influence of gender and age on the main outcome results of the Hypertension Optimal Treatment (HOT) study. DESIGN AND INTERVENTIONS: The aims of the HOT study were to study the relationship between three levels of target office diastolic blood pressure (BP) (< or = 90, < or = 85 or < or = 80 mmHg) and cardiovascular (CV) events in hypertensive patients, and to examine the effects of 75 mg acetylsalicylic acid (ASA) daily versus placebo. SETTING: Outpatient clinical trial in 26 countries. PATIENTS: A total of 18790 patients (mean age 61.5 years, range 50-80) were randomized and followed for an average of 3.8 years until 71051 patient-years and 683 events had occurred. MAIN OUTCOME MEASURES: CV death, myocardial infarction (MI) and stroke. RESULTS: There were significantly fewer MIs in those in the lower diastolic BP target groups (3.0 versus 1.2 and 1.7 MIs/1000 patient-years, P for trend = 0.034) in women (n = 8883), whereas the similar but smaller trend (4.1 versus 4.1 and 3.4 MIs/1000 patient-years) was not statistically significant in men nor in the subgroup analysis of younger and older subjects. The effect of ASA on preventing MI was not influenced by age < 65 years (P= 0.02) or age > or = 65 years (P = 0.04) but was influenced by gender (P = 0.38 in women and P = 0.001 in men, lowered by 42% corresponding to a reduction from 5.0 to 2.9 MIs/1000 patient-years). CONCLUSIONS: The data of this HOT study sub-analysis suggest somewhat differentiated optimal gender- and age-dependent effects of anti-hypertensive and anti-platelet therapies; lowering of diastolic BP to about 80 mmHg in hypertensive women and, in addition, the administration of 75 mg of ASA to well-treated hypertensive men appear to effectively reduce the most common cardiovascular complication, i.e. myocardial infarction, in patients with essential hypertension.

Influence of gender on prevention of myocardial infarction by antihypertensives and acetylsalicylic acid: the HOT study.

OBJECTIVE: The aims of the Hypertension Optimal Treatment (HOT) Study were to investigate the relationship between three levels of target office diastolic blood pressure (BP; < or = 90, < or = 85, and < or = 80 mm Hg) and cardiovascular death, myocardial infarction (MI), and stroke in hypertensive patients, and to examine the effects of 75 mg of acetylsalicylic acid (ASA) daily versus placebo. DESIGN: Randomized, double-blind study. This substudy assessed the influence of gender on the incidence of MI. SUBJECTS: A total of 18,790 patients (mean age, 61.5 years; range, 50-80 years). METHODS: Patients were randomized and followed for an average of 3.8 years until 71,051 patient-years had elapsed and 683 events, including 215 MIs, had occurred. RESULTS: There were significantly fewer MIs in the lowest diastolic BP target group (P = .034) in women (n = 8883); a similar but smaller trend was not statistically significant in men. The effect of ASA on preventing MI was also influenced by gender (P = .38 in women; P = .001 in men [lowered by 42%]). CONCLUSION: Lowering diastolic BP to about 80 mm Hg in hypertensive women and administering 75 mg of ASA daily to well-treated hypertensive men reduces MI in patients with essential hypertension.

Metoprolol-induced reduction in postinfarction mortality: pooled results from five double-blind randomized trials.

Several postinfarction trials have evaluated the effect of secondary prophylaxis with different beta-blockers. Although so called meta-analysis of the results from all the trials have shown a beneficial effect of postinfarction beta-blockade, many of the individual studies have shown inconclusive results, mainly due to low statistical power. In order to obtain an evaluation of the merits of postinfarction therapy with metoprolol, data from the five available studies with metoprolol have been pooled into one database. In the total material 5474 patients (4353 men, 1121 women) have been studied during double-blind therapy with metoprolol 100 mg twice daily or matching placebo. The follow-up ranges from 3 months to 3 years. In total 4732 patient years of observation have been obtained. In total there were 223 deaths in the placebo-treated patients as compared to 188 deaths in the metoprolol-treated patients (P = 0.036), which corresponds to mortality rates of 97.0 and 78.3 per 1000 patient years, respectively. The mortality reduction was found both in men and women. As has been reported from individual postinfarction beta-blocker trials, the pooled results showed a marked reduction in sudden deaths (104 in the placebo group, 62 in the metoprolol group, P = 0.002). In a Cox regression model the influence of sex, age and smoking habits on the effect of metoprolol was evaluated. None of these factors influenced the metoprolol effect significantly. It is concluded that metoprolol therapy after acute myocardial infarction reduces the total number of deaths, and especially sudden cardiac deaths. The mortality reduction was independent of gender, age and smoking habits. Available data support a continuous beneficial effect.

Metoprolol versus thiazide diuretics in hypertension. Morbidity results from the MAPHY Study.

The present study in hypertensive men (40-64 years old) with untreated diastolic blood pressure above 100 mm Hg was aimed at investigating whether metoprolol (n = 1,609) given as initial treatment would lower the risk for coronary events (sudden death and myocardial infarction) more effectively than thiazide diuretics (n = 1,625). A substantial part of this study was the metoprolol arm of the Heart Attack Primary Prevention in Hypertension (HAPPHY) study. The HAPPHY study was a pooling of the effect of different beta-blockers, mainly metoprolol and atenolol, in which no favorable effect in relative risk was observed for atenolol as compared with diuretics. In the present study, 255 patients suffered definite coronary events during follow-up; 25% of these events were fatal, 39% were acute myocardial infarctions, and 36% were silent myocardial infarctions. The risk for coronary events was significantly lower in patients on metoprolol than in patients on diuretics (111 versus 144 cases, p = 0.001, corresponding to 14.3 versus 18.8 cases/1,000 patient years and a relative risk of 0.76 at the end of the trial; 95% confidence interval 0.58-0.98). This difference in risk has potentially important implications for clinical practice because of the large number of hypertensive patients who are at increased risk for coronary events. Because a placebo group, for ethical reasons, could not be included, relative risk can only be expressed in relation to diuretics. There was no difference between the two treatment groups in baseline characteristics, blood pressure during follow-up, or stroke rates. Thus, the difference in risk for coronary events is probably mediated via mechanisms other than blood pressure control. However, present data might suggest that different beta-blockers may have different efficacy in preventing coronary events. The reasons for this possibility are as yet unknown.

Primary prevention of sudden cardiovascular death in hypertensive patients. Mortality results from the MAPHY Study.

In a randomized primary prevention trial including 3,234 men with mild to moderate uncomplicated hypertension, the effect of the beta-blocker metoprolol or a thiazide diuretic as an initial antihypertensive therapy was compared regarding the risk of sudden cardiovascular death during a follow-up ranging from 2.3 to 10.8 years (median of 4.2 years). Only men aged 40 to 64 years were included in the study. The randomization of patients into the metoprolol (n = 1,609) or diuretic group (n = 1,625) was performed after stratification for age, smoking habits, serum cholesterol, and systolic blood pressure. At baseline the two treatment groups were well matched. Metoprolol was given in a mean dose of 174 mg daily and the mean dose of thiazide diuretic was either 46 mg hydrochlorothiazide daily or 4.4 mg bendroflumethiazide daily. Identical blood pressure control was achieved using the fixed therapeutic schedule. Total and cardiovascular mortality were significantly lower for metoprolol than for diuretics, owing to fewer deaths from coronary heart disease and stroke. Of the cardiovascular deaths, 78% were classified as sudden cardiovascular deaths (occurred within 24 h after the onset of symptoms). There were significantly fewer sudden cardiovascular deaths in the metoprolol group compared to the diuretic group (32 v 45, P = .017). The present results suggest that initial antihypertensive therapy with metoprolol is associated with a lesser incidence of sudden cardiovascular deaths than initial diuretic treatment in uncomplicated hypertension.

Effect on whole-body protein synthesis after institution of intravenous nutrition in cancer and non-cancer patients who lose weight.

Cancer and non-cancer patients received total parenteral nutrition (TPN) corresponding to either 120% or 200% non-protein energy resting energy expenditure. Whole-body tyrosine flux and leg exchange of various metabolites were measured in the fasted and fed state. Feeding with the moderate TPN rate did not stimulate whole-body protein synthesis in either group, but the high rate did. Both TPN rates switched an efflux of branched-chain aminoacids from the leg to an uptake in both groups, but this did not apply to tyrosine or phenylalanine. Only the high TPN rate stimulated glucose uptake across the leg in both groups. The leg exchanges of lactate, glycerol and free fatty acids were not significantly influenced by moderate or high TPN rates in either group, although changes in arterial concentrations indicated significant exchanges in compartments other than leg tissues. Thus standard TPN is insufficient to stimulate overall protein synthesis in both malnourished cancer and non-cancer patients, which may explain why previous studies have demonstrated insignificant functional effects with nutritional support to cancer patients.

Effect of short-term beta blockade on serum lipid levels and on the interaction of LDL with human arterial proteoglycans.

In view of conflicting evidence suggesting that beta-blockers have an anti-atherogenic effect as well as induce a potentially atherogenic lipoprotein profile, the effects of a short term beta-blockade on serum lipoproteins were studied in 39 healthy volunteers. Because the interaction of LDL with arterial proteoglycans appears to play a role in lipoprotein accumulation during atherogenesis, the effects of metoprolol and atenolol on low density lipoprotein interaction with human aortic proteoglycans were included in the study. We could confirm that the beta-blockers caused a decrease in HDL cholesterol and an increase in triglycerides, both potentially undesirable effects. In addition, however they induced a significant decrease in the in vitro LDL affinity for arterial proteoglycans. Since there appears to be a strong association between LDL reactivity with proteoglycans and risk for myocardial infarction, this effect of the beta-blockers may be an anti-atherogenic effect which overrides other effects on the lipoprotein pattern.

Coronary artery disease can be prevented by antihypertensive therapy: experiences from the MAPHY Study.

The present randomized primary prevention study in hypertensive men aged 40-64 years (n = 3,234) was aimed at investigating whether metoprolol given as initial treatment would prevent coronary artery disease (CAD) better than thiazide diuretics. Two hundred fifty-five patients had a definite CAD event during the 15,730 patient-years of follow-up; 25% of these events were fatal, and 38% were definite acute myocardial infarctions. The incidence of CAD was significantly lower during follow-up in patients randomized to metoprolol than in patients randomized to diuretics: 111 vs. 144 cases (p = 0.001). Stroke mortality was significantly lower in the metoprolol group than in the diuretic group, but the overall stroke incidence was similar in the two treatment groups. A majority of events occurred among smokers in both treatment groups although only one-third of patients were smokers at baseline. Blood pressure (BP) control was similar in the two treatment groups; therefore, the difference between the groups in CAD events is mediated via mechanisms other than the BP-reducing effect of metoprolol.

Decreased coronary heart disease in hypertensive smokers. Mortality results from the MAPHY study.

The present primary prevention study aimed at investigating whether metoprolol given as initial antihypertensive treatment would lower cardiovascular complications of high blood pressure to a greater extent than thiazide diuretics. Patients were randomized to metoprolol (n = 1,609, 8,110 patient-years) or a thiazide diuretic (n = 1,625, 8,070 patient-years). At randomization, 535 patients in the metoprolol group and 524 patients in the diuretic group were classified as smokers. Blood pressure control during follow-up was equally effective regardless of smoking habits at randomization. Cardiovascular and coronary heart disease mortality was three to four times higher in smokers than in nonsmokers, underlining the importance of smoking as a risk factor. Total and cardiovascular mortality were significantly lower for the metoprolol group than for the thiazide diuretic group in the whole study population (p = 0.028 and p = 0.012), as well as in smokers (p = 0.013 and p = 0.016). Coronary heart disease mortality was significantly lower for patients on metoprolol than for patients on diuretics in the whole study population (p = 0.048) as well as in smokers (p = 0.021). The results suggest that initial antihypertensive therapy with metoprolol is associated with a lesser incidence of total, cardiovascular, and coronary heart disease mortality as compared with initial diuretic treatment, both in the whole study population and in smokers. The favorable effect of metoprolol must be mediated via mechanisms other than the blood pressure-lowering effect of metoprolol because equal blood pressure control was achieved with both types of medication, irrespective of smoking habits at randomization.

The inefficiency of total parenteral nutrition to stimulate protein synthesis in moderately malnourished patients.

The acute whole-body and peripheral tissue protein response to total parenteral nutrition (TPN) was evaluated before surgery in moderately malnourished patients with stable disease. A primed constant infusion of (U-14C) tyrosine was used in combination with simultaneous measurements of the leg exchange of amino acids, glucose, glycerol, and free fatty acids (FFA). Energy expenditure was measured by indirect calorimetry. Sixteen patients with stable disease and in need of nutritional support were randomized to receive TPN at rates either corresponding to resting requirements (nonprotein calories at 120% of REE with 0.2 g of N/kg/d) or at increased rates (200% of REE with 0.33 g of N/kg/d). Energy expenditure was not affected by the low rate of TPN, but increased with the high rate, with a thermic effect corresponding to 16% of basal levels. Tyrosine flux and incorporation rate into whole-body proteins (protein synthesis) were not altered by the low TPN rate, but increased with the high rate. Estimates of protein breakdown decreased, and tyrosine oxidation increased significantly with both rates of TPN. Protein synthesis was stimulated at the high dose rate only. However, a positive whole-body tyrosine balance (net protein synthesis) measured by the 14C tyrosine technique was associated with a continued negative tyrosine balance across the skeletal muscle compartment in the leg. The results demonstrate that TPN given at rates corresponding to resting needs of 0.2 g of N/kg/day is insufficient to promote protein synthesis in the majority of body proteins. Skeletal muscles may remain in negative protein balance even at high TPN loads. Our results reflect the difficulties of expanding lean body mass through intravenous nutrition in moderately malnourished patients--even those with stable disease.

Primary prevention with metoprolol in patients with hypertension. Mortality results from the MAPHY study.

The present study of primary prevention in white men aged 40 to 64 years attempts to investigate whether a beta-blocker given as initial antihypertensive treatment would lower total mortality to a greater extent than thiazide diuretics. Patients were randomized to metoprolol (n = 1609, 8110 patient-years) or a thiazide diuretic (n = 1625, 8070 patient-years). The median follow-up time was 4.2 years. The mean dose of metoprolol was 174 mg/d, and of thiazide diuretics, 46 mg/d of hydrochlorothiazide or 4.4 mg/d of bendroflumethiazide. Identical control of blood pressure was achieved using a fixed therapeutic schedule. Total mortality was significantly lower for metoprolol than for thiazide diuretics because of fewer deaths from coronary heart disease and stroke. Total mortality was also significantly lower in smokers randomized to metoprolol. The benefit demonstrated in patients treated with metoprolol seems to have important implications for clinical practice.

Nutritional assessment of hospitalized patients with head and neck cancer.

Nutritional assessment is an important part of the oncologic management of the cancer patient. Although it may be easy to identify weight loss, the criteria for negative energy balance are difficult to display in an ordinary clinical setting. In the present study we assessed the nutritional status and calculated the energy balance in 10 randomly selected cancer patients who were hospitalized at our ENT department. Loss greater than 10% of habitual weight was apparent in 5 patients, while only 2 of these had subnormal serum albumin levels. Another 1 of these patients with weight loss demonstrated reduced arm muscle circumference. Weight index, total body potassium and other anthropometric data did not significantly correlate with weight loss. Although supplementary nutrition was administered to most patients during hospitalization, only 4 patients were in positive energy balance as calculated from food tables. Only 2 out of 5 patients with a history of weight loss were in a positive energy balance. A questionnaire disclosed that insufficient considerations for the patients' food availability were shown. We conclude that malnutrition is a common and often an occult phenomenon in hospitalized patients. This may have an unfavorable influence on oncologic treatment and clinical outcome.

The immediate and long-term effects of postoperative total parenteral nutrition on body composition.

The short and long-term effects of postoperative total parenteral nutrition (TPN) on body composition were studied in a randomised series of patients undergoing major colorectal surgery. Ninety-two patients (colorectal cancer: 50, ulcerative colitis or Crohn's disease: 42) were grouped according to diagnosis and clinical inflammatory activity. TPN was given for 9.7 +/- 1.1 days. The complication rate was not changed by the TPN. Nitrogen balance was studied during the first week. Body weight, total body potassium, triceps skinfold, serum albumin and body water were measured before and at intervals up to 24 weeks after the operation. Cumulative nitrogen balance in control patients at 7 days after surgery was -47.3 g. Patients given TPN balanced nitrogen intake and output (cancer patients and patients with quiescent inflammatory bowel disease, IBD) or were in positive balance (patients with active IBD). Weight loss at 1 week after surgery was less in TPN patients compared to controls and this difference remained statistically significant up to 6 months after termination of the nutritional treatment. A similar, although not statistically significant, difference was noted in total body potassium and triceps skinfold. Patients with active IBD regained pre-operative body composition earlier than cancer patients and patients with quiescent IBD. It is concluded that TPN after major colorectal surgery reduces postoperative weight loss and that this effect lasts after termination of the nutritional treatment. In the absence of increased body potassium and increased body water, we conclude that the long-term effect of TPN on body weight is most likely due to preservation of fat.(ABSTRACT TRUNCATED AT 250 WORDS)

Postoperative complications in colorectal surgery in relation to preoperative clinical and nutritional state and postoperative nutritional treatment.

The impact of the pre-operative nutritional and clinical state on post-operative morbidity and mortality is not fully known and the effect of total parenteral nutrition (TPN) on the postoperative complication rate has not been established. We have investigated the effects of postoperative TPN on the complication rate in 92 patients after major colorectal surgery for carcinoma of the large bowel or inflammatory bowel disease in a controlled, randomised study. The complication rate was analysed against seven commonly used nutritional (biochemical and anthropometric) variables and against the diagnosis, clinical inflammatory activity and presence of pre-operative septic complication. Patients were randomly allocated to postoperative TPN or conventional fluid and electrolyte support. The results show no correlation between the complication rate and the nutritional and clinical state of the patients as assessed pre-operatively. The complication rate was not significantly reduced by postoperative TPN. This study indicates that biochemical and anthropometric nutritional variables do not identify patients at risk to develop postoperative complications. The presence of pre-operative complications showed a marginal correlation with postoperative morbidity, in agreement with previous experience. The result of this study obviates the use of TPN in routine postoperative care.

Clinical significance of preoperative nutritional status in 215 noncancer patients.

Preoperative nutritional status was assessed by: the percentage weight loss (% WL), body weight in relation to reference weight (WI), arm muscle circumference (AMC), and S-albumin (S-Alb) in a prospective study of 215 noncancer patients classified into three groups according to type of surgery: major vascular, minor vascular, and abdominal. The clinical significance of the nutritional markers was assessed by correlations to postoperative outcome and the time spent in the hospital after surgery. The influence of age on nutritional markers and clinical variables was evident but was ruled out in all correlations. If malnutrition was classified as two or more abnormal values in the nutritional markers (% WL, WI, AMC, S-Alb), the overall frequency was 12%, highest in the major vascular surgery group (18%) and lowest in the minor vascular group (4%). Patients with low nutritional status stayed an average of 29 days in the hospital compared to 14 days if the nutritional status was normal (p less than 0.01). The overall complication frequency was higher in patients with low nutritional status compared to normal status (48% and 23%, respectively, p less than 0.01). The frequency of serious complications was 31% in undernourished and 9% in well-nourished patients (p less than 0.05). Various nonnutritional variables such as age, diagnosis, and duration of surgery were shown to increase the predictive ability of nutritional status. The results of this study confirm that nutritional state per se is predictive for postoperative outcome even when variables were stabilized for different backgrounds with covariation to nutritional status.