Identifying the independent effect of HbA1c variability on adverse health outcomes in patients with Type 2 diabetes.

AIMS: To characterize the relationship between HbA1c variability and adverse health outcomes among US military veterans with Type 2 diabetes. METHODS: This retrospective cohort study used Veterans Affairs and Medicare claims for veterans with Type 2 diabetes taking metformin who initiated a second diabetes medication (n = 50 861). The main exposure of interest was HbA1c variability during a 3-year baseline period. HbA1c variability, categorized into quartiles, was defined as standard deviation, coefficient of variation and adjusted standard deviation, which accounted for the number and mean number of days between HbA1c tests. Cox proportional hazard models predicted mortality, hospitalization for ambulatory care-sensitive conditions, and myocardial infarction or stroke and were controlled for mean HbA1c levels and the direction of change in HbA1c levels during the baseline period. RESULTS: Over a mean 3.3 years of follow-up, all HbA1c variability measures significantly predicted each outcome. Using the adjusted standard deviation measure for HbA1c variability, the hazard ratios for the third and fourth quartile predicting mortality were 1.14 (95% CI 1.04, 1.25) and 1.42 (95% CI 1.28, 1.58), for myocardial infarction and stroke they were 1.25 (95% CI 1.10, 1.41) and 1.23 (95% CI 1.07, 1.42) and for ambulatory-care sensitive condition hospitalization they were 1.10 (95% CI 1.03, 1.18) and 1.11 (95% CI 1.03, 1.20). Higher baseline HbA1c levels independently predicted the likelihood of each outcome. CONCLUSIONS: In veterans with Type 2 diabetes, greater HbA1c variability was associated with an increased risk of adverse long-term outcomes, independently of HbA1c levels and direction of change. Limiting HbA1c fluctuations over time may reduce complications.

A randomised trial of salsalate for insulin resistance and cardiovascular risk factors in persons with abnormal glucose tolerance.

AIMS/HYPOTHESIS: Chronic sub-acute inflammation contributes to the pathogenesis of type 2 diabetes mellitus and cardiovascular disease. High doses of salicylate reduce inflammation, glucose and triacylglycerols, and may improve insulin sensitivity, suggesting therapeutic potential in impaired fasting glucose and/or impaired glucose tolerance. This trial aimed to evaluate the effect of salsalate vs placebo on insulin resistance and glycaemia in impaired fasting glucose and/or impaired glucose tolerance. METHODS: We conducted a 12 week, two-centre, randomised, placebo-controlled study to evaluate the effect of salsalate (up to 4 g/day) vs placebo on systemic glucose disposal. Secondary objectives included treatment effects on glycaemia, inflammation and cardiovascular risk factors. Seventy-eight participants with impaired fasting glucose and/or impaired glucose tolerance from two VA healthcare systems were enrolled. Randomisation assignment was provided by the coordinating center directly to site pharmacists, and participants and research staff were blinded to treatment assignment. RESULTS: Seventy-one individuals were randomised to placebo (n = 36) or salsalate (n = 35). Glucose disposal did not change in either group (salsalate 1% [95% CI -39%, 56%]; placebo 6% [95% CI -20%, 61%], p = 0.3 for placebo vs salsalate). Fasting glucose was reduced by 6% during the study by salsalate (p = 0.006) but did not change with placebo. Declines in glucose were accompanied by declines in fasting C-peptide with salsalate. Insulin clearance was reduced with salsalate. In the salsalate group, triacylglycerol levels were lower by 25% (p = 0.01) and adiponectin increased by 53% (p = 0.02) at the end of the study. Blood pressure, endothelial function and other inflammation markers did not differ between groups. Adipose tissue nuclear factor κB (NF-κB) activity declined in the salsalate group compared with placebo (-16% vs 42%, p = 0.005), but was not correlated with metabolic improvements. The frequency of tinnitus was low but tended to be higher with salsalate therapy (n = 4 vs n = 2). CONCLUSIONS/INTERPRETATION: In summary, salsalate therapy was well tolerated, lowered fasting glucose, increased adiponectin and reduced adipose tissue NF-κB activity. These changes were not related to changes in peripheral insulin sensitivity, suggesting additional mechanisms for metabolic improvement. TRIAL REGISTRATION: ClinicalTrials.gov NCT00330733. FUNDING: Office of Research and Development, Medical Research Service, Department of Veterans Affairs and NIH K24 DK63214.

Prevalence of primary hyperaldosteronism in mild to moderate hypertension without hypokalaemia.

Screening for primary hyperaldosteronism (PHA) is often indicated in individuals with resistant hypertension or hypokalaemia. However, in the far larger subset of the hypertensive population who do not fit into these criteria, the evidence for screening is conflicting and dependent on the disease prevalence. The purpose of this study was to examine the prevalence of PHA in a large population with mild to moderate hypertension and without hypokalaemia using a carefully controlled study protocol including a normotensive control population. Hypertensive subjects underwent medication washout and both hypertensive and normotensive subjects placed on a high-sodium diet prior to biochemical and haemodynamic testing. Study specific cutoff values were based on results from the normotensive population studied under identical conditions. A screening test (serum aldosterone/PRA ratio [ARR]>25 with a serum aldosterone level >8 ng/dl) was followed by a confirmatory test (urine aldosterone excretion rate [AER] >17 microg/24 h) to demonstrate evidence of PHA. An elevated ARR with a concomitant elevated serum aldosterone was present in 26 (7.5%) individuals. Of these, 11 (3.2%) had an elevated AER, consistent with evidence of PHA. Individuals with PHA had higher blood pressure and lower serum potassium levels while on a high-sodium diet. Sodium restriction neutralized these differences between PHA and essential hypertensives. The prevalence of PHA in this mild to moderate hypertensive population without hypokalaemia is at most 3.2%, a rate that might lead to excessive false positives with random screening in comparable populations. Hyperaldosteronism, when present, is responsive to sodium restriction.

Redefining efficacy of antihypertensive therapies beyond blood pressure reduction--the role of angiotensin II antagonists.

Antihypertensive efficacy must be redefined beyond blood pressure (BP) lowering per se to include reducing the cardiovascular complications of hypertension. Treatment decisions should be based on results from large clinical trials with relevant clinical outcomes. Several recent morbidity and mortality trials with angiotensin II receptor antagonists (AIIAs) provide an evidence-based rationale for the use of AIIAs in patients with hypertension. Studies with AIIAs in comparison to conventional antihypertensive agents showed improved morbidity and mortality outcomes in patients with hypertension and left ventricular hypertrophy (losartan) and diabetes mellitus (losartan and irbesartan). Trials with some members of the AIIA class (candesartan and valsartan) have not demonstrated such benefits in comparison to conventional agents, possibly due to differences in BP control during the trials. The results of these AIIA outcome trials have impacted on recently issued clinical guidelines for management of hypertension.

Comparing office-based and ambulatory blood pressure monitoring in clinical trials.

Ambulatory blood pressure monitoring (ABPM) is commonly used in clinical trials. Yet, its ability to detect blood pressure (BP) change in comparison to multiple office-based measurements has received limited attention. We recorded ambulatory and five daily pairs of random zero (RZ) BPs pre- and post-intervention on 321 adult participants in the multicentre Dietary Approaches to Stop Hypertension trial. Treatment effect estimates measured by ambulatory monitoring were similar to those measured by RZ and did not differ significantly for waking vs 24-h ambulatory measurements. For systolic BP, the standard deviations of change in mean 24-h ambulatory BP (8.0 mmHg among hypertensives and 6.0 mmHg among nonhypertensives) were comparable to or lower than the corresponding standard deviations of change in RZ-BP based on five daily readings (8.9 and 5.9 mmHg). The standard deviations of change for mean waking ambulatory BP (8.7 and 6.7 mmHg) were comparable to those obtained using three to four daily RZ readings. Results for diastolic BP were qualitatively similar. Ambulatory monitoring was more efficient (ie, a smaller sample size could detect a given BP change) than three to four sets of daily RZ readings and required fewer clinic visits. The average of 33 ambulatory BP readings during the waking hours had an efficiency comparable to that from the mean of four daily pairs of RZ-BPs. Participants readily accepted the ABPM devices, and their use requires less staff training. ABPM provides a useful alternative to RZ-BP measurements in clinical trials.

Influence of dietary sodium on the renin-angiotensin-aldosterone system and prevalence of left ventricular hypertrophy by EKG criteria.

We investigated the interplay of dietary sodium and renin-angiotensin-aldosterone system (RAAS) activity with the prevalence of left ventricular hypertrophy (LVH) in essential hypertension. Electrocardiograms (EKG) were reviewed for the presence of LVH in 160 hypertensive patients. We then compared the rate of LVH to levels of plasma renin activity (PRA) and serum aldosterone under high and low sodium diet conditions. On high sodium diet, serum aldosterone was significantly higher (7.7+/-0.93 vs 5.7+/-0.35 ng/dl, P=0.02) in participants with LVH. With low sodium diet and upright posture, PRA was significantly lower in subjects with LVH vs those without (5.6+/-1.1 vs 7.6+/-0.56 ng/ml/h, P=0.026). Aldosterone levels on low sodium diet were not different between those with and those without LVH. PRA was then dichotomized at the lowest quartile under low sodium/upright posture conditions to define a 'low renin' group. In a multivariate logistic regression containing renin status (low renin vs normal/high renin), aldosterone on a high sodium diet, age, body mass index, gender, race, duration of hypertension, systolic and diastolic blood pressure and salt-sensitivity only low-renin status on a low sodium diet (P=0.019) and serum aldosterone on a high sodium diet (P=0.04) were significant predictors of LVH. Thus, reduced modulation of renin activity in response to sodium restriction and an increased aldosterone on a high sodium diet appear to identify characteristics of hypertensive patients predisposed to abnormal cardiac remodelling.

Increased red cell sodium-lithium countertransport and lymphocyte cytosolic calcium are separate phenotypes in patients with essential hypertension.

Increased red blood cell sodium-lithium countertransport (SLC) activity and elevated intracellular calcium have been observed in hypertensive patients. The association of these ion transport abnormalities with each other and with another phenotype, insulin resistance, has been suggested. We investigated whether elevated SLC activity and increased lymphocyte cytosolic calcium (Ca(cyt)) occur in the same individuals and whether either is associated with hyperinsulinaemia. We measured SLC activity, lymphocyte Ca(cyt)and fasting insulin levels in hypertensive patients and normal subjects. Consistent with prior studies, SLC activity was significantly and positively correlated with fasting insulin levels (r = 0.45, P < 0.01). However, SLC activity and lymphocyte Ca(cyt) were significantly but inversely correlated (r = -0.42, P < 0.01) and lymphocyte Ca(cyt) was also inversely correlated with fasting insulin (r = -0.55, P < 0.001). When the study participants were instead separated into two groups based on fasting insulin levels, those above the median (15 microU/ml) had significantly higher SLC activity and significantly lower Ca(cyt). When separated by lymphocyte Ca(cyt) levels (above or below 120 nM) those patients with low lymphocyte Ca(cyt) had significantly higher SLC activity and significantly higher insulin levels. Multiple linear regression showed that fasting insulin was significantly predictive of SLC activity (P = 0.05) and Ca(cyt) (P < 0.01). Thus, elevated SLC activity and increased lymphocyte Ca(cyt) are separate and distinct ion transport phenotypes in hypertensive patients, linked through a relationship to hyperinsulinaemia that is direct with SLC activity and inverse with lymphocyte Ca(cyt).

The impact of angiotensin II receptor blockade and the DASH diet on markers of endogenous fibrinolysis.

Hypertension is associated with impaired fibrinolysis. Both angiotensin receptor blockers (ARB) and the DASH (Dietary Approaches to Stop Hypertension) diet effectively lower blood pressure in hypertensive patients. Some evidence suggests that treatment with ARBs could increase fibrinolysis, however, data is conflicting. The impact of the DASH diet on fibrinolytic parameters is not known. Fifty-five hypertensive participants (35 African-American, 20 white) were randomly assigned to receive 8 weeks of either a control diet or the DASH diet. The diets did not differ in sodium content (approximately 3 g/day). Within each diet, individuals were randomly assigned to receive losartan or placebo for 4 weeks in double-blind, cross-over fashion. Tissue plasminogen activator (t-PA) antigen, t-PA activity, plasminogen activator inhibitor-1 (PAI-1) activity and plasma renin activity (PRA) were measured at the end of a 2-week run-in period on the control diet and after each treatment period. The DASH diet did not affect markers of fibrinolysis. Losartan significantly lowered t-PA antigen levels (-1.8 ng/mL, P = 0.045), but had no effect on t-PA or PAI-1 activities. This effect was more pronounced in whites (-4.1 ng/mL (P = 0.003)) compared with African-Americans (-0.3 ng/mL (P = 0.7), P-interaction = 0.03). Results were not materially affected by adjustment for basline values or changes in blood pressure. This study demonstrates that losartan reduces t-PA antigen levels in white, but not African-American hypertensive individuals. In contrast, the DASH diet had no significant effect on markers of fibrinolysis in whites or African-Americans.

Effects of diet and sodium intake on blood pressure: subgroup analysis of the DASH-sodium trial.

BACKGROUND: Initial findings from the Dietary Approaches to Stop Hypertension (DASH)-Sodium Trial demonstrated that reduction of sodium intake in two different diets decreased blood pressure in participants with and without hypertension. OBJECTIVE: To determine effects on blood pressure of reduced sodium intake and the DASH diet in additional subgroups. DESIGN: Randomized feeding study. SETTING: Four clinical centers and a coordinating center. PARTICIPANTS: 412 adults with untreated systolic blood pressure of 120 to 160 mm Hg and diastolic blood pressure of 80 to 95 mm Hg. INTERVENTION: Participants followed the DASH diet or a control (typical U.S.) diet for three consecutive 30-day feeding periods, during which sodium intake (50, 100, and 150 mmol/d at 2100 kcal) varied according to a randomly assigned sequence. Body weight was maintained. MEASUREMENTS: Systolic and diastolic blood pressure. RESULTS: In all subgroups, the DASH diet and reduced sodium intake were each associated with significant decreases in blood pressure; these two factors combined produced the greatest reductions. Among nonhypertensive participants who received the control diet, lower (vs. higher) sodium intake decreased blood pressure by 7.0/3.8 mm Hg in those older than 45 years of age (P < 0.001) and by 3.7/1.5 mm Hg in those 45 years of age or younger (P < 0.05). CONCLUSION: The DASH diet plus reduced sodium intake is recommended to control blood pressure in diverse subgroups.

Angiotensinogen genotype and blood pressure response in the Dietary Approaches to Stop Hypertension (DASH) study.

OBJECTIVE: To determine the relationship between angiotensinogen (ANG) genotype and blood pressure response to the dietary patterns of the Dietary Approaches to Stop Hypertension (DASH) trial. The angiotensin converting enzyme (ACE) gene was also tested. DESIGN: The DASH trial was a randomized outpatient feeding study comparing the effects on blood pressure (BP) of three dietary patterns: a control diet, similar to typical American intake; a 'fruits and vegetables' diet (F/V) that is rich in fruits and vegetables but otherwise resembles the control diet; and the DASH diet that is reduced in fats and that emphasizes fruits, vegetables and low-fat dairy products. Participants' genotype was also determined. SETTING: Four clinical sites. PARTICIPANTS: Adults with above-optimal BP or stage 1 hypertension. INTERVENTION: Participants ate one of the three dietary patterns for 8 weeks. Sodium intake and weight were held constant. In 355 of 459 DASH participants, DNA was extracted from leukocytes and genotyped for the G-6A ANG polymorphism and the D/I ACE polymorphism, by the polymerase chain reaction. MAIN OUTCOMES: Genotype at ANG and ACE loci; BP after 8 weeks of intervention diet. RESULTS: There was no association between ACE genotype and BP response. Associations with ANG polymorphism were significant: net systolic and diastolic BP response to the DASH diet was greatest in individuals with the AA genotype (-6.93/-3.68 mmHg) and least in those with the GG genotype (-2.80/0.20 mmHg). A similar relationship existed for the F/V diet. CONCLUSIONS: ANG genotype is associated with BP response to the DASH diet. The AA genotype confers excess risk of hypertension and is associated with increased responsiveness to diet.

DASH (Dietary Approaches to Stop Hypertension) diet is effective treatment for stage 1 isolated systolic hypertension.

Use of the DASH (Dietary Approaches to Stop Hypertension) diet, which is rich in fruits, vegetables, and low-fat dairy foods, significantly lowers blood pressure. Among the 459 participants in the DASH Trial, 72 had stage 1 isolated systolic hypertension (ISH) (systolic blood pressure, 140 to 159 mm Hg; diastolic blood pressure, <90 mm Hg). We examined the blood pressure response in these 72 participants to determine whether the DASH diet is an effective treatment for stage 1 ISH. After a 3-week run-in period on a typical American (control) diet, participants were randomly assigned for 8 weeks to 1 of 3 diets: a continuation of the control diet (n=25), a diet rich in fruits and vegetables (n=24), or the DASH diet (n=23). Sodium content was the same in the 3 diets, and caloric intake was adjusted during the trial to prevent weight change. Blood pressure was measured at baseline and at the end of the 8-week intervention period with standard sphygmomanometry. Use of the DASH diet significantly lowered systolic blood pressure compared with the control diet (-11.2 mm Hg; 95% confidence interval, -6.1 to -16.2 mm Hg; P<0.001) and the fruits/vegetables diet (-8.0 mm Hg; 95% confidence interval, -2.5 to -13.4 mm Hg; P<0.01). Overall, blood pressure in the DASH group fell from 146/85 to 134/82 mm Hg. Similar results were observed with 24-hour ambulatory blood pressure measurements. In the DASH diet group, 18 of 23 participants (78%) reduced their systolic blood pressure to <140 mm Hg, compared with 24% and 50% in the control and fruits/vegetables groups, respectively. Our results indicate that the DASH diet, which is rich in fruits, vegetables, and low-fat dairy foods, is effective as first-line therapy in stage 1 ISH.

Dietary modification and changes in blood pressure.

Several recently published clinical trials and epidemiological studies have added significant new data to our understanding of the impact of dietary modifications on blood pressure. Such studies confirm the blood pressure-lowering effects of sodium restriction, the consumption of diets that are low in fat and enriched in fruits and vegetables, and the sustained effects of weight reduction. This reaffirms the role of lifestyle modifications as both preventative and adjunctive means to lower blood pressure.

Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group.

BACKGROUND: The effect of dietary composition on blood pressure is a subject of public health importance. We studied the effect of different levels of dietary sodium, in conjunction with the Dietary Approaches to Stop Hypertension (DASH) diet, which is rich in vegetables, fruits, and low-fat dairy products, in persons with and in those without hypertension. METHODS: A total of 412 participants were randomly assigned to eat either a control diet typical of intake in the United States or the DASH diet. Within the assigned diet, participants ate foods with high, intermediate, and low levels of sodium for 30 consecutive days each, in random order. RESULTS: Reducing the sodium intake from the high to the intermediate level reduced the systolic blood pressure by 2.1 mm Hg (P<0.001) during the control diet and by 1.3 mm Hg (P=0.03) during the DASH diet. Reducing the sodium intake from the intermediate to the low level caused additional reductions of 4.6 mm Hg during the control diet (P<0.001) and 1.7 mm Hg during the DASH diet (P<0.01). The effects of sodium were observed in participants with and in those without hypertension, blacks and those of other races, and women and men. The DASH diet was associated with a significantly lower systolic blood pressure at each sodium level; and the difference was greater with high sodium levels than with low ones. As compared with the control diet with a high sodium level, the DASH diet with a low sodium level led to a mean systolic blood pressure that was 7.1 mm Hg lower in participants without hypertension, and 11.5 mm Hg lower in participants with hypertension. CONCLUSIONS: The reduction of sodium intake to levels below the current recommendation of 100 mmol per day and the DASH diet both lower blood pressure substantially, with greater effects in combination than singly. Long-term health benefits will depend on the ability of people to make long-lasting dietary changes and the increased availability of lower-sodium foods.

Four-Year persistence patterns among patients initiating therapy with the angiotensin II receptor antagonist losartan versus other artihypertensive drug classes.

BACKGROUND: It has been reported that a statistically greater percentage of patients initially treated with losartan, an angiotensin II receptor antagonist (AIIA), stayed on therapy at 1 year compared with patients treated with antihypertensive drugs from other classes. OBJECTIVE: The purpose of this study was to determine whether the stay-on-therapy (persistence) patterns observed in the previous analysis were maintained over a 4-year period. METHODS: We investigated a subgroup of 15,175 hypertensive patients from an earlier studied cohort who were continuously eligible for benefits over a 4-year follow-up period. A linear regression model was developed to test the statistical significance of differences in the percentage of patients staying on therapy from 12 months to 48 months for the different antihypertensive classes. RESULTS: From 12 to 48 months, there was a slow continuous decline in persistence that was similar across all classes of antihypertensive medications. A greater percentage of patients treated with an AIIA (losartan) stayed on therapy from 12 to 48 months compared with patients treated with angiotensin-converting enzyme inhibitors (67.4% vs 60.7% at 12 months, P < 0.01; 50.9% vs 46.5% at 48 months, P = 0.095), calcium antagonists (67.4% vs 54.1% at 12 months, P < 0.01; 50.9% vs 40.7% at 48 months, P < 0.03), beta-blockers (67.4% vs 45.6% at 12 months, P < 0.01; 50.9% vs 34.7% at 48 months, P < 0.03), or thiazide diuretics (67.4% vs 20.8% at 12 months, P < 0.01; 50.9% vs 16.4% at 48 months, P < 0.03). The percentage of patients staying on AIIA therapy from 12 months to 48 months was statistically greater (P < 0.001) than the percentage of patients staying on therapy with other antihypertensive drug classes. CONCLUSIONS: This analysis supports the observation that initiation of antihylertensive therapy with an AIIA such as losartan results in a greater persistence rate over a 4-year period than does therapy with any other antihypertensive class. These findings may have important implications for blood pressure control, reduction of cardiovascular risks, and health care resource utilization.

The effect of dietary patterns on blood pressure control in hypertensive patients: results from the Dietary Approaches to Stop Hypertension (DASH) trial.

To determine the impact of dietary patterns on the control of hypertension we studied the subgroup of 133 participants with systolic blood pressure (BP) of 140 to 159 mm Hg and/or diastolic BP of 90 to 95 mm Hg enrolled in the Dietary Approaches to Stop Hypertension (DASH) study. Participants were fed a control diet for a 3-week period and were then randomized to receive for 8 weeks either the control diet; a diet rich in fruits and vegetables, but otherwise similar to control; or a combination diet rich in fruits, vegetables, and low-fat dairy products, including whole grains, fish, poultry, and nuts, and reduced in fats, red meats, sweets, and sugar-containing beverages. Sodium intake and body weight were held constant throughout the study. The combination diet significantly reduced systolic BP (-11.4 mm Hg, P < .001) and diastolic BP (-5.5 mm Hg, P < .001). The fruits-and-vegetables diet also significantly reduced systolic BP (-7.2 mm Hg, P < .001) and diastolic BP (-2.8 mm Hg, P = .013). The combination diet produced significantly greater BP effects (P < .05) than the fruits-and-vegetables diet. Blood pressure changes were evident within 2 weeks of starting the intervention feeding. After the 8-week intervention period, 70% of participants eating the combination diet had a normal BP (systolic BP < 140 and diastolic BP < 90 mm Hg) compared with 45% on the fruits-and-vegetables diet and 23% on the control diet. In patients with hypertension, the DASH combination diet effectively lowers BP and may be useful in achieving control of Stage 1 hypertension.

Effect of indomethacin on blood pressure lowering by captopril and losartan in hypertensive patients.

NSAIDs are known to attenuate the effects of some antihypertensive medications. It is not known whether the new class of angiotensin II receptor antagonists is similarly affected. We conducted a multicenter study assessing the effect of indomethacin on the antihypertensive effects of losartan and captopril. After 4 weeks of placebo washout, hypertensive patients received 6 weeks of active antihypertensive therapy with either 50 mg losartan once daily (n=111) or 25 mg captopril twice daily for 1 week, which was increased to 50 mg twice daily for 5 weeks (n=105). This was followed by 1 week of concomitant therapy with indomethacin (75 mg daily). The primary outcome measure was the change in mean 24-hour ambulatory diastolic blood pressure after the addition of indomethacin. Both captopril and losartan significantly lowered ambulatory diastolic blood pressure (losartan -5.3 mm Hg, P:<0.001; captopril -5.6 mm Hg, P:<0.001) after 6 weeks of therapy. Indomethacin significantly attenuated the 24-hour ambulatory diastolic blood pressure for both losartan (2.2 mm Hg, P:<0.05) and captopril (2.7 mm Hg, P:<0.001) and also attenuated the effect of captopril on trough sitting diastolic blood pressure. Changes in daytime diastolic blood pressure (7:00 AM to 11:00 PM) were similar to the 24-hour response in both groups. Nighttime diastolic blood pressure (11:01 PM to 6:59 AM) was significantly attenuated in captopril-treated patients (2.0 mm Hg, P:<0.05), but losartan was unaffected (0.4 mm Hg). Thus, concurrent treatment with indomethacin similarly attenuates the 24-hour antihypertensive response to losartan and captopril.

Angiotensin II antagonists for hypertension: are there differences in efficacy?

We compared the antihypertensive efficacy of available drugs in the new angiotensin-II-antagonist (AIIA) class. The antihypertensive efficacy of losartan, valsartan, irbesartan, and candesartan was evaluated from randomized controlled trials (RCT) by performing a metaanalysis of 43 published RCT. These trials involved AIIA compared with placebo, other antihypertensive classes, and direct comparisons between AIIA. A weighted-average for diastolic and systolic blood pressure reduction with AIIA monotherapy, dose titration, and with addition of low-dose hydrochlorothiazide (HCTZ) were calculated. Weighted-average responder rates were also determined. The metaanalysis assessed a total of 11,281 patients. The absolute weighted-average reductions in diastolic (8.2 to 8.9 mm Hg) and systolic (10.4 to 11.8 mm Hg) blood pressure reductions (not placebo-corrected) for AIIA monotherapy were comparable for all AIIA. Responder rates for AIIA monotherapy were 48% to 55%. Dose titration resulted in slightly greater blood pressure reduction and an increase in responder rates to 53% to 63%. AIIA/hydrochlorothiazide combinations produced substantially greater reduction in systolic (16.1 to 20.6 mm Hg) and diastolic (9.9 to 13.6 mm Hg) blood pressure reductions than AIIA monotherapy and responder rates for AIIA/HCTZ combinations were 56% to 70%. This comprehensive analysis shows comparable antihypertensive efficacy within the AIIA class, a near-flat AIIA-dose response when titrating from starting to maximum recommended dose, and substantial potentiation of the antihypertensive effect with addition of HCTZ.

Benefits of angiotensin converting enzyme inhibition and angiotensin II receptor antagonists in hypertension.

It is through blood pressure lowering that reductions in cardiovascular morbidity and mortality are achieved. The treatment of hypertension patients should also focus on prevention and management of cardiovascular complications, not merely on achieving a target level of blood pressure. In making treatment decisions it is appropriate to assess patients for the presence or absence of risk factors and/or clinical cardiovascular disease. Clinicians should strive to use the least intrusive means possible to achieve goal blood pressure and the treatment regiment should be individualized for each patient. The review has illustrated specific clinical conditions where the use of an hypertensive agent that inhibits the renin-angiotensin system may offer added benefit to the patient while producing the needed anti-hypertensive effects.

An e-mail system for obtaining approval to use a restricted agent.

Because of concerns over cost, proper patient selection, and prescribing patterns, pharmacy and therapeutics committees must be very selective about which new medications can be added to formularies and used in health systems. However, in the final analysis, many problems with important new agents are easily solved when clinicians select the right patients and prescribe these agents properly. Physician specialists in appropriate fields often already know about important new medications from clinical trials, professional meetings, and published articles. In such cases, these specialists can help with the needed diffusion of information to other physicians so that a broad range of prescribers in a health system become familiar with the new agent, its advantages, what types of patients need the drug, and what problems may be encountered.

Effect of dietary patterns on ambulatory blood pressure : results from the Dietary Approaches to Stop Hypertension (DASH) Trial. DASH Collaborative Research Group.

We measured ambulatory blood pressure (ABP) in 354 participants in the Dietary Approaches to Stop Hypertension (DASH) Trial to determine the effect of dietary treatment on ABP (24-hour, day and night) and to assess participants' acceptance of and compliance with the ABP monitoring (ABPM) technique. After a 3-week run-in period on a control "typical" American diet, subjects (diastolic blood pressure [BP], 80 to 95 mm Hg; systolic BP, <160 mm Hg; mean age, 45 years) were randomly assigned to 1 of 3 diets for an 8-week intervention period: a continuation of the control diet; a diet rich in fruits and vegetables; and a "combination" diet that emphasized fruits, vegetables, and low-fat dairy products. We measured ABP at the end of the run-in and intervention periods. Both the fruit/vegetable and combination diets lowered 24-hour ABP significantly compared with the control diet (P<0. 0001 for systolic and diastolic pressures on both diets: control diet, -0.2/+0.1 mm Hg; fruit/vegetable diet, -3.2/-1.9 mm Hg; combination diet, -4.6/-2. 6 mm Hg). The combination diet lowered pressure during both day and night. Hypertensive subjects had a significantly greater response than normotensives to the combination diet (24-hour ABP, -10.1/-5.5 versus -2.3/-1.6 mm Hg, respectively). After correction for the control diet responses, the magnitude of BP lowering was not significantly different whether measured by ABPM or random-zero sphygmomanometry. Participant acceptance of ABPM was excellent: only 1 participant refused to wear the ABP monitor, and 7 subjects (2%) provided incomplete recordings. These results demonstrate that the DASH combination diet provides significant round-the-clock reduction in BP, especially in hypertensive participants.