Physical health, behavioral and emotional functioning in children of gulf war veterans.

OBJECTIVE: We examined whether the prevalence of medical and behavioral conditions is higher in children of deployed veterans (DVs) versus non-deployed veterans (NDVs) after the 1991 Gulf War. METHODS: We examined 1387 children of 737 veterans. Children ages 2-18 had physical exams and parental reports of physical history and behavior. RESULTS: Physical health was analyzed using GEE models. Behavioral health [total, internalizing, and externalizing behavior problems (TBP, IBP, EBP)] was analyzed with mixed-effects regression models. Analyses were conducted by age group (2-3, 4-11, 12-18), and gender (ages 4-11, 12-18). Children of DVs ages 2-3 had significantly worse dentition (13.9% vs. 4.8%, P = 0.03) and more EBP {least square means (lsmeans) 54.31 vs. 47.59, P = 0.02}. Children of DVs ages 4-11 had significantly more obesity (18.8% vs. 12.7%, P = 0.02). Among children 4-11, male children of DVs had significantly more TBP (lsmeans 70.68 vs. 57.34, P = 0.003), IBP (lsmeans 63.59 vs. 56.16, P = 0.002) and EBP (lsmeans 61.60 vs. 52.93, P = 0.03), but female children did not. For children ages 12-18, male children of DVs had more EBP (lsmeans 63.73 vs. 43.51, P = 0.008), while female children of DVs had fewer EBP (lsmeans 45.50 vs. 50.48, P = 0.02). Veteran military characteristics and mental health, and children's social status and health, including obesity, predicted children's TBP for one or more age groups. CONCLUSIONS: Children of DVs experienced worse dentition, greater obesity, and more behavioral problems compared to NDV children, suggesting adverse health effects associated with parental deployment in need of further exploration.

Classification and valuation of postoperative complications in a randomized trial of open versus laparoscopic ventral herniorrhaphy.

PURPOSE: Generic instruments used for the valuation of health states (e.g., EuroQol) often lack sensitivity to notable differences that are relevant to particular diseases or interventions. We developed a valuation methodology specifically for complications following ventral incisional herniorrhaphy (VIH). METHODS: Between 2004 and 2006, 146 patients were prospectively randomized to undergo laparoscopic (n = 73) or open (n = 73) VIH. The primary outcome of the trial was complications at 8 weeks. A three-step methodology was used to assign severity weights to complications. First, each complication was graded using the Clavien classification. Second, five reviewers were asked to independently and directly rate their perception of the severity of each class using a non-categorized visual analog scale. Zero represented an uncomplicated postoperative course, while 100 represented postoperative death. Third, the median, lowest, and highest values assigned to each class of complications were used to derive weighted complication scores for open and laparoscopic VIH. RESULTS: Open VIH had more complications than laparoscopic VIH (47.9 vs. 31.5%, respectively; P = 0.026). However, complications of laparoscopic VIH were more severe than those of open VIH. Non-parametric analysis revealed a statistically higher weighted complication score for open VIH (interquartile range: 0-20 for open vs. 0-10 for laparoscopic; P = 0.049). In the sensitivity analysis, similar results were obtained using the median, highest, and lowest weights. CONCLUSION: We describe a new methodology for the valuation of complications following VIH that allows a direct outcome comparison of procedures with different complication profiles. Further testing of the validity, reliability, and generalizability of this method is warranted.

Clinical and laboratory assessment of distal peripheral nerves in Gulf War veterans and spouses.

BACKGROUND: The prevalence of symptoms suggesting distal symmetric polyneuropathy (DSP) was reported to be higher among deployed veterans (DV) to the Persian Gulf in 1990-1991 than to control non-deployed veterans (NDV). The authors therefore compared the prevalence of DSP by direct examination of DV and their spouses to control NDV and spouses. METHODS: The authors performed standardized neurologic examinations on 1,061 DV and 1,128 NDV selected from a cohort of veterans who previously participated in a national mail and telephone survey. Presence of DSP was evaluated by history, physical examination, and standardized electrophysiologic assessment of motor and sensory nerves. Similar examinations were performed without electrophysiologic tests in 484 DV spouses and 533 NDV spouses. Statistical analyses were performed with appropriate adjustments for the stratified sampling scheme. RESULTS: No differences between adjusted population prevalence of DSP in DV and NDV were found by electrophysiology (3.7% vs 6.3%, p = 0.07), by neurologic examination (3.1% vs 2.6%, p = 0.60), or by the methods combined (6.3% vs 7.3%, p = 0.47). Excluding veterans with non-military service related diseases that may cause DSP did not alter outcomes. DV potentially exposed to neurotoxins from the Khamisiyah ammunition depot explosion did not significantly differ in DSP prevalence compared to non-exposed DV. The prevalence of DSP in DV spouses did not differ from NDV spouses (2.7% vs 3.2%, p = 0.64). CONCLUSIONS: Neither veterans deployed during the Gulf War era nor their spouses had a higher prevalence of DSP compared to NDV and spouses.

Pulse pressure changes with six classes of antihypertensive agents in a randomized, controlled trial.

Pulse pressure has been more strongly associated with cardiovascular outcomes, especially myocardial infarction and heart failure, than has systolic, diastolic, or mean arterial pressure in a variety of populations. Little is known, however, of the comparative effects of various classes of antihypertensive agents on pulse pressure. In retrospective analyses of the Veterans Affairs Single-Drug Therapy for Hypertension Study, we compared changes in pulse pressure with 6 classes of antihypertensive agents: 1292 men with diastolic blood pressure of 95 to 109 mm Hg on placebo were randomized to receive hydrochlorothiazide, atenolol, captopril, clonidine, diltiazem, prazosin, or placebo. Drug doses were titrated to achieve a goal diastolic blood pressure of <90 mm Hg during a 4- to 8-week medication titration phase. Pulse pressure change (placebo subtracted) was assessed from baseline to the end of the 3-month titration and 1-year maintenance. Mean baseline systolic, diastolic, and pulse pressures were 152, 99, and 53 mm Hg, respectively. Reductions in pulse pressure during titration were greater (P<0.001) with clonidine (6.7 mm Hg) and hydrochlorothiazide (6.2 mm Hg) than with captopril (2.5 mm Hg), diltiazem (1.6 mm Hg), and atenolol (1.4 mm Hg); reduction with prazosin (3.9 mm Hg) was similar to all but clonidine. After 1 year, pulse pressure was reduced significantly more (P<0.001) with hydrochlorothiazide (8.6 mm Hg) than with captopril and atenolol (4.1 mm Hg with both); clonidine (6.3 mm Hg), diltiazem (5.5 mm Hg), and prazosin (5.0 mm Hg) were intermediate. These data show that classes of antihypertensive agents differ in their ability to reduce pulse pressure. Whether these differences affect rates of cardiovascular events remains to be determined.

Diagnostic value of iron indices in hemodialysis patients receiving epoetin.

BACKGROUND: Iron deficiency remains a common cause of hyporesponsiveness to epoetin in hemodialysis patients. However, considerable controversy exists regarding the best strategies for diagnosis and treatment. METHODS: As part of a multicenter randomized clinical trial of intravenous versus subcutaneous administration of epoetin, we made monthly determinations of serum iron, total iron binding capacity, percentage transferrin saturation, and serum ferritin. If a patient had serum ferritin <100 ng/mL or the combination of serum ferritin <400 ng/mL and a transferrin saturation <20%, he/she received parenteral iron, given as iron dextran 100 mg at ten consecutive dialysis sessions. We analyzed parenteral iron use during the trial, the effect of its administration on iron indices and epoetin dose, and the ability of the iron indices to predict a reduction in epoetin dose in response to parenteral iron administration. RESULTS: Eighty-seven percent of the 208 patients required parenteral iron to maintain adequate iron stores at an average dose of 1516 mg over 41.7 weeks, or 36 mg/week. Only two of 180 patients experienced serious reactions to intravenous iron administration. Two thirds of the patients receiving parenteral iron had a decrease in their epoetin requirement of at least 30 U/kg/week compared with 29% of patients who did not receive iron (P = 0.004). The average dose decrease 12 weeks after initiating iron therapy was 1763 U/week. A serum ferritin <200 ng/mL had the best positive predictive value (76%) for predicting a response to parenteral iron administration, but it still had limited clinical utility. CONCLUSIONS: Iron deficiency commonly develops during epoetin therapy, and parenteral iron administration may result in a clinically significant reduction in epoetin dose. The use of transferrin saturation or serum ferritin as an indicator for parenteral iron administration has limited utility.

Ventricular and myocardial function following treatment of hypertension.

This study assesses and evaluates left ventricular (LV) contractile function after treatment of hypertension, with an emphasis on LV midwall mechanics. Although prior studies have assessed cardiac function after hypertension treatment, none has performed an analysis of LV midwall mechanics. The Veterans Affairs Study of monotherapy in hypertension was a study large enough to permit analysis of midwall mechanics across a wide spectrum of mass changes accompanying hypertension treatment. LV chamber function was assessed by computing fractional shortening at the endocardial surface; LV midwall shortening was used to define myocardial function. Both shortening indexes were related to end-systolic circumferential stress in the entire population by partitioning values of mass and relative wall thickness changes. Two hundred sixty-eight patients were studied at baseline and again after a 1- or 2-year period. In the entire group, there was no significant change in circumferential shortening either at the endocardium (38 +/- 8% at baseline vs 37 +/- 7% at follow up, p = 0.29) or in shortening at the midwall (20 +/- 3% vs 20 +/- 3%, p = 0.53). However, 83 patients had a reduction in relative wall thickness and an increase in midwall shortening. The change in midwall shortening was significantly related to changes in relative wall thickness (r = -0.53, p = 0.0001). Thus, reductions in LV mass associated with antihypertensive therapy are generally not accompanied by a decrement in LV chamber or myocardial function. Improvement in midwall shortening is more closely related to normalization of LV geometry than to reduction in LV mass.

Placebo-associated blood pressure response and adverse effects in the treatment of hypertension: observations from a Department of Veterans Affairs Cooperative Study.

BACKGROUND: The use of placebo in clinical trials has been vigorously debated. Placebo control may be useful in disease states, such as stage 1 and stage 2 hypertension as defined by the Sixth Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC VI), in which response rates for placebo are high or close to response rates for effective therapies, or when established interventions have significant adverse effects. OBJECTIVE: To compare rates for the control of blood pressure and adverse effects of placebo vs active treatment in patients with stage 1 and stage 2 hypertension. METHODS: This study is a randomized controlled trial evaluating the blood pressure response and adverse effects of placebo vs 6 active treatments administered in 15 Veterans Affairs hypertension centers. The 1292 subjects of the Veterans Affairs Cooperative Study receiving single-drug therapy for hypertension were randomly allocated to receive treatment with 1 of 6 active drugs (n= 1105) or placebo (n=187). Treatment success was defined as maintaining a diastolic blood pressure of less than 95 mm Hg for at least 1 year. We compared treatment success rates for the control of blood pressure and adverse effects of placebo vs active treatment. Using the Kaplan-Meier method, we also compared rates of discontinuation from placebo vs active drug treatment over time as a result of adverse drug effects and blood pressure exceeding safety limits. RESULTS: At the end of the titration phase, 58 patients who were treated with placebo (31%) achieved a goal diastolic blood pressure lower than 90 mm Hg and 57 (30%) achieved success at 1 year. Older white patients who received placebo had a success rate of 38% vs 23% to 27% for the other age-race subgroups. The rates of discontinuation as a result of adverse drug effects were 13% for patients receiving placebo vs 12% for patients receiving active treatment (P=.40). The rates of discontinuation for blood pressure being too high were 14% for patients receiving placebo vs 7% for patients receiving active treatment (P=.01). CONCLUSIONS: Placebo control provides an important benchmark for both efficacy and adverse effects. It continues to have an appropriate place in certain therapeutic trials, particularly those involving the treatment of stage 1 and stage 2 hypertension.

Regional and racial differences in response to antihypertensive medication use in a randomized controlled trial of men with hypertension in the United States. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

BACKGROUND: Stroke incidence and mortality rates are higher in the southeastern region of the United States, which is called the "Stroke Belt." We compared the response to antihypertensive medication use in patients from different US regions. METHODS: The short-term and 1-year efficacy of the antihypertensive medications hydrochlorothiazide, atenolol, diltiazem hydrochloride (sustained release), captopril, prazosin hydrochloride, and clonidine was compared by US region in a randomized controlled trial of 1,105 men with hypertension from 15 US Veterans Affairs medical centers. RESULTS: Compared with patients outside the Stroke Belt, patients inside the Stroke Belt achieved significantly lower treatment success rates of diastolic blood pressure control at 1 year with hydrochlorothiazide (63% vs 41%), atenolol (62% vs 46%), captopril (60% vs 30%), and clonidine (69% vs 43%); there were no differences in treatment success rates with diltiazem (70% vs 71%) or prazosin (54% vs 53%). When controlling for race, patients inside the Stroke Belt had significantly lower treatment success rates with hydrochlorothiazide (P = .003) and clonidine (P = .003), and the lower success rate with atenolol approached significance (P = .15). Regardless of region, blacks were less likely than whites to achieve treatment success with atenolol (P = .02) or prazosin (P = .03) and more likely with diltiazem (P = .05). There was a trend for blacks residing inside the Stroke Belt to have a lower treatment success rate than other race-region groups when treated with captopril (P = .07). Many regional and racial differences in diet, lifestyle, and other characteristics were observed. After adjustment for these characteristics by regression analysis, the effect of residing inside the Stroke Belt remained for captopril (P = .01) and clonidine (P = .01) and approached significance for hydrochlorothiazide (P = .10). CONCLUSIONS: Hypertension in patients residing inside the Stroke Belt responded less to the use of several antihypertensive medications and important differences were shown in a number of characteristics that may affect the control of blood pressure, compared with patients residing outside the Stroke Belt.

Accessing data from external centralized sources to enhance analysis of a completed clinical trial.

After the data collection phase of a clinical trial has been completed, new hypotheses may surface which require additional data before they can be tested. In the Veterans Affairs Cooperative Study on Single Drug Therapy of Hypertension, we investigated the relationship between location of the participating center, race and ability to control blood pressure. The analysis indicated poorer blood pressure control among sites located in the "stroke belt" (southeastern United States), especially among African-Americans. We sought to determine whether the effect was attributable to socioeconomic patterns; however, income data were not collected as part of the original study. Therefore, we accessed centralized data bases to obtain zipcode-level income information for the randomized study patients. This approach yielded estimates of income data for 94.3% of the patients and compared favorably to data acquisition rates for variables which were collected prospectively in the study.

Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular manifestations of the seronegative spondylarthropathies: a Department of Veterans Affairs cooperative study.

OBJECTIVE: To determine if the peripheral articular manifestations of the seronegative spondylarthropathies (SNSA) respond differently than the axial manifestations to treatment with sulfasalazine (SSZ). METHODS: This is a reanalysis of a previously reported series of randomized, double-blind, placebo-controlled, multicenter trials comparing the effects of SSZ, 2,000 mg/day, and placebo on the axial and peripheral articular manifestations of ankylosing spondylitis (AS), psoriatic arthritis (PsA), and reactive arthritis (ReA; Reiter's syndrome). Patients were classified as treatment responders on the basis of meeting predefined improvement criteria in 4 outcome measures: namely, patient and physician global assessments in all patients, morning stiffness and back pain in patients with axial manifestations, and joint pain/tenderness scores and joint swelling scores in patients with peripheral articular manifestations. RESULTS: Six hundred nineteen SNSA patients (264 AS, 221 PsA, and 134 ReA) were studied. One hundred eighty-seven of these patients had only axial manifestations of their disease, while 432 patients had peripheral articular manifestations. Of the patients with axial disease, 40.2% of the SSZ group and 43.3% of the placebo group met the predefined response criteria (P = 0.67). Of the peripheral articular group, 59.0% of the SSZ-treated patients and 42.7% of the placebo-treated patients showed a response (P = 0.0007). CONCLUSION: In a large group of affected individuals, the response of SNSA patients to SSZ appears to be related to the articular manifestations of their disease. These data demonstrate that the axial and peripheral articular manifestations of SNSA respond differently to treatment with SSZ. In SNSA patients with persistently active peripheral arthritis, SSZ is safe, well tolerated, and effective.

Baseline relationships between psoriasis and psoriatic arthritis: analysis of 221 patients with active psoriatic arthritis. Department of Veterans Affairs Cooperative Study Group on Seronegative Spondyloarthropathies.

OBJECTIVE: To determine differences in disease onset, extent, and manifestations of psoriasis among patients with active, inflammatory psoriatic arthritis (PsA), and to examine relationships that may exist between psoriasis and PsA. METHODS: Baseline demographic, clinical, and laboratory data were analyzed from 221 patients enrolled in a multicenter cooperative study, and relationships between measures of psoriasis and PsA were determined. RESULTS: Mean percentage of body surface area (BSA) affected by psoriasis was modest (12+/-17), and mean severity of erythema, induration, and scaling was moderate (4.9+/-2.1 on a 0-9 scale). Spanish Americans tended to have a higher mean percentage of BSA (18.5%) than Caucasians (11%; p = 0.067), as well as higher target lesion severity (5.55 vs. 4.84; p = 0.077). Patients with psoriatic nail disease (180/221, 81%) had significantly greater number of involved distal interphalangeal (DIP) joints (p = 0.004). There were no other significant associations of skin pattern or regional involvement with PsA. CONCLUSION: Patients with active PsA have generally mild skin disease, and baseline relationships between psoriasis and PsA tend to be weak except for nail involvement and DIP joint activity.

The prevalence of sacroilitis in psoriatic arthritis: new perspectives from a large, multicenter cohort. A Department of Veterans Affairs Cooperative Study.

OBJECTIVE: To determine the prevalence of radiographic evidence of sacroiliitis in a large population of patients with psoriatic arthritis. PATIENTS AND DESIGN: Patients were recruited from 15 clinical centers. This was part of a large, multicenter study of patients with an established diagnosis of ankylosing spondylitis, psoriatic arthritis, or reactive arthritis. For this cohort, an established diagnosis of psoriatic arthritis was required, with cutaneous manifestations and involvement of at least three appendicular joints. At entry, patients were not selected for the presence of axial involvement. Radiographs - one anteroposterior view of the pelvis and one oblique view of each sacroiliac joint - were graded using the New York classification scale by a musculoskeletal radiologist masked to the specific diagnosis and clinical symptoms. Re-evaluation of 10% of the films 3 years later quantified intraobserver variability. RESULTS: Two hundred and two patients with psoriatic arthritis were studied. Duration of the disease averaged 12 years; all patients had psoriasis and peripheral arthritis. The prevalence of radiographic evidence of sacroiliitis (grade 2 or higher) was 78%; 71% of these had grade 3 disease. CONCLUSIONS: Previously reported prevalence of sacroiliitis in patients with psoriatic arthritis ranges from 30% to 50%. The prevalence of radiographic evidence of sacroiliitis in this large multicenter cohort of patients with appendicular psoriatic arthritis was substantially higher.

Diuretics and beta-blockers do not have adverse effects at 1 year on plasma lipid and lipoprotein profiles in men with hypertension. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

BACKGROUND: Concern based on the reported short-term adverse effects of antihypertensive agents on plasma lipid and lipoprotein profiles (PLPPs) has complicated the therapy for hypertension. OBJECTIVE: To compare the long-term (1-year) effects of 6 different antihypertensive drugs and placebo on PLPPs in a multicenter, randomized, double-blind, parallel-group clinical trial in 15 US Veterans Affairs medical centers. PATIENTS AND METHODS: A total of 1292 ambulatory men, 21 years or older, with diastolic blood pressures (DBPs) ranging from 95 to 109 mm Hg taking placebo were randomized to receive placebo or 1 of 6 antihypertensive drugs: hydrochlorothiazide, atenolol, captopril, clonidine, diltiazem, or prazosin. After drug titration, patients with a DBP of less than 90 mm Hg were followed up for 1 year. Plasma lipids and lipoprotein profiles were determined at baseline, after initial titration, and at 1 year. RESULTS: After 8 weeks on a regimen of hydrochlorothiazide, increases of 3.3 mg/dL (0.09 mmol/L) in total cholesterol and 2.7 mg/dL in apolipoprotein B were significantly different (P< or =.05) from decreases of 9.3 mg/dL in total cholesterol and 5.4 mg/dL in ApoB levels while receiving prazosin but not from placebo. Patients achieving positive DBP control using hydrochlorothiazide (responders) showed no adverse changes in PLPPs, whereas nonresponders exhibited increases in triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels. Plasma lipids and lipoprotein profiles did not change significantly among treatment groups after 1 year except for minor decreases in high-density lipoprotein 2 levels using hydrochlorothiazide, clonidine, and atenolol. CONCLUSIONS: None of these 6 antihypertensive drugs has any long-term adverse effects on PLPPs and, therefore, may be safely prescribed. Previously reported short-term adverse effects from using hydrochlorothiazide are limited to nonresponders.

Effects of antihypertensive single-drug therapy on heart rate. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

Heart rate increasingly is being recognized either as an independent risk factor for a wide variety of cardiovascular disorders or as a surrogate marker for them. We analyzed the changes in heart rate associated with antihypertensive therapy with six drugs and placebo from the VA Cooperative Study on Single-Drug Therapy. These results were published previously (American Journal of Hypertension 1998;11:597-601). This paper provides a summary of the earlier publication with the addition of three figures not previously published. Atenolol had the greatest effect on heart rate reduction, followed by clonidine and diltiazem-SR. Hydrochlorothiazide and captopril were associated with small reductions in heart rate over time, whereas prazosin increased heart rate. Patients whose blood pressure was controlled by placebo had a 3.1 beats/min reduction of heart rate at 2 years. When the baseline heart rate was 65 beats/min or less, all drugs increased the heart rate except for atenolol, which further reduced it. Although it is clear that each of the six drugs used in our study had a different effect on heart rate, we cannot state that drug-induced reduction in heart rate per se confers a decrease in cardiovascular risk.

Radiographic diagnosis of sacroiliitis--are sacroiliac views really better?

OBJECTIVE: To determine whether detailed oblique radiographs of the sacroiliac (SI) joints provide significant diagnostic advantage to a single AP projection of the pelvis in establishing the presence and severity of sacroiliitis. METHODS: Radiographs (both AP pelvis and detailed oblique projections) of 445 right SI joints and 442 left SI joints were obtained from patients with an established diagnosis of a seronegative spondyloarthropathy, and interpreted for severity. Data for the right and left SI joints were analyzed, comparing interpretations of severity based on AP pelvis projections with oblique views. RESULTS: Analysis of these data showed an agreement rate between AP views and SI views of 89.7% for the right SI joint radiographs and 86.4% for the left SI joint. There was no instance in which a patient with "unequivocal abnormalities"of the SI joints on the AP pelvis was read as having "normal" SI views. Similarly, there were no cases in which "normal" SI joints on AP pelvis films were read as having unequivocal abnormalities on SI views. CONCLUSION: In this group of patients with seronegative spondyloarthropathies, there was very close agreement between severity score of sacroiliitis from AP pelvis radiographs and SI joint views. We conclude that in most circumstances, the AP pelvis film will yield the diagnosis of sacroiliitis without the additional radiation exposure and expense related to specific SI joint radiographs.

Age-race subgroup compared with renin profile as predictors of blood pressure response to antihypertensive therapy. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

CONTEXT: Renin profiling and age-race subgroup may help select single-drug therapy for stage 1 and stage 2 hypertension. OBJECTIVE: To compare the plasma renin profiling and age-race subgroup methods as predictors of response to single-drug therapy in men with stage 1 and 2 hypertension as defined by the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. DESIGN: The Veterans Affairs Cooperative Study on Single-Drug Therapy of Hypertension, a randomized controlled trial. SETTING: Fifteen Veterans Affairs hypertension centers. PATIENTS: A total of 1105 ambulatory men with entry diastolic blood pressure (DBP) of 95 to 109 mm Hg, of whom 1031 had valid plasma and urine samples for renin profiling. INTERVENTIONS: Randomization to 1 of 6 antihypertensive drugs: hydrochlorothiazide, atenolol, captopril, clonidine, diltiazem (sustained release), or prazosin. MAIN OUTCOME MEASURE: Treatment response as assessed by percentage achieving goal DBP (<90 mm Hg) in response to a single drug that corresponded to patients' renin profile vs a single drug that corresponded to patients' age-race subgroup. RESULTS: Clonidine and diltiazem had consistent response rates regardless of renin profile (76%, 67%, and 80% for low, medium, and high renin, respectively, for clonidine and 83%, 82%, and 83%, respectively, for diltiazem for patients with baseline DBP of 95-99 mm Hg). Hydrochlorothiazide and prazosin were best in low- and medium-renin profiles; captopril was best in medium- and high-renin profiles (low-, medium-, and high-renin response rates were 82%, 78%, and 14%, respectively, for hydrochlorothiazide; 88%, 67%, and 40%, respectively, for prazosin; and 51%, 83%, and 100%, respectively, for captopril for patients with baseline DBP of 95-99 mm Hg). Response rates for patients with baseline DBP of 95 to 99 mm Hg by age-race subgroup ranged from 70% for clonidine to 90% for prazosin for younger black men, from 50% for captopril to 97% for diltiazem for older black men, from 70% for hydrochlorothiazide to 92% for atenolol for younger white men, and from 84% for hydrochlorothiazide to 95% for diltiazem for older white men. Patients with a correct treatment for their renin profile but incorrect for age-race subgroup had a response rate of 58.7%; patients with an incorrect treatment for their renin profile but correct for age-race subgroup had a response rate of 63.1% (P = .30). After controlling for DBP and interactions with treatment group, age-race subgroup (P<.001) significantly predicted response to single-drug therapy, whereas renin profile was of borderline significance (P= .05). CONCLUSIONS: In these men with stage 1 and stage 2 hypertension, therapeutic responses were consistent with baseline renin profile, but age-race subgroup was a better predictor of response.

Subcutaneous compared with intravenous epoetin in patients receiving hemodialysis. Department of Veterans Affairs Cooperative Study Group on Erythropoietin in Hemodialysis Patients.

BACKGROUND: Several studies have suggested that if recombinant human erythropoietin (epoetin) is administered subcutaneously rather than intravenously, a lower dose may be sufficient to maintain the hematocrit at a given level. METHODS: In a randomized, unblinded trial conducted at 24 hemodialysis units at Veterans Affairs medical centers, we assigned 208 patients who were receiving long-term hemodialysis and epoetin therapy to treatment with either subcutaneous or intravenous epoetin. The dose was initially reduced until the hematocrit was below 30 percent and then was gradually increased to a level that would maintain the hematocrit in the range of 30 to 33 percent for 26 weeks. We compared the average doses in the 26-week maintenance phase and the discomfort associated with the two routes of administration. RESULTS: For the 107 patients treated by the subcutaneous route, the average weekly dose of epoetin during the maintenance phase was 32 percent less than that for the 101 patients treated by the intravenous route (mean [+/-SD], 95.1+/-75.0 vs. 140.3+/-88.5 U per kilogram of body weight per week; P<0.001). Only one patient in the subcutaneous-therapy group withdrew from the study because of pain at the injection site, and 86 percent rated the pain associated with subcutaneous administration as ranging from absent to mild. CONCLUSIONS: In patients receiving hemodialysis, subcutaneous administration of epoetin can maintain the hematocrit in a desired target range, with an average weekly dose of epoetin that is lower than with intravenous administration.

Effect of single-drug therapy on reduction of left atrial size in mild to moderate hypertension: comparison of six antihypertensive agents.

BACKGROUND: Cardiac effects of hypertension include increased left ventricular (LV) mass and LV hypertrophy, as well as increased left atrial size, a predictor of stroke and atrial fibrillation. Although literature on reduction of LV mass with antihypertensive therapy is extensive, little information is available on effects of treatment on left atrial size. METHODS AND RESULTS: Patients with mild to moderate hypertension (diastolic blood pressure 95 to 109 mm Hg) were randomly allocated to treatment with atenolol, captopril, clonidine, diltiazem, hydrochlorothiazide, or prazosin in a double-masked trial. Two-dimensional targeted M-mode echocardiography was used to assess left atrial size and LV mass at baseline, 8 weeks, and 1 and 2 years. Longitudinal analysis examined changes in left atrial size from the baseline study, statistically adjusting for age, race, pretreatment left atrial size and LV mass, and serial measurements of systolic blood pressure, body weight, urinary sodium excretion, and physical activity score. Without adjustment for covariates, only hydrochlorothiazide was associated with decreases in left atrial size from baseline at 8 weeks (-1.0 +/- 5.2 mm; P=0.052), 1 year (-2.0 +/- 5.1 mm; P=0.02), and 2 years (4.6+/-7.2 mm; P=0.002). After adjustment for effects of covariates, patients with normal left atrial size had greater reduction (-3.3 mm) in left atrial size at 2 years with hydrochlorothiazide than with any other drug. For patients with left atrial enlargement, left atrial size decreased significantly with hydrochlorothiazide, atenolol, clonidine, and diltiazem at 1 year and with all treatments at 2 years. However, reduction at 2 years was greater with hydrochlorothiazide than with captopril or prazosin. CONCLUSIONS: Antihypertensive drugs differ in their effects on left atrial size. Hydrochlorothiazide was associated with greater overall reduction of left atrial size than other drugs effective for the treatment of hypertension. Reduction of left atrial size with therapy is in part independent of factors known to influence left atrial size, including LV mass and reduction of LV mass with treatment. The clinical benefit of reducing left atrial size with antihypertensive treatment remains to be determined.

Comparison of effects of antihypertensive drugs on heart rate: changes from baseline by baseline group and over time. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

Baseline heart rate is becoming recognized as a predictor of cardiovascular risk. Various antihypertensive drugs have differing effects on heart rate. A randomized controlled clinical trial of 1292 ambulatory men with stage 1 or 2 hypertension was conducted in 15 Veterans Affairs medical centers. Patients were treated with hydrochlorothiazide, atenolol, captopril, clonidine, diltiazem, prazosin, or placebo for up to 2 years. Heart rates were measured at baseline, the end of titration, 1 year, and 2 years. Data were also stratified by baseline heart rate. A subset of patients had heart rate also determined by electrocardiogram. All drugs except prazosin reduced heart rate from baseline; additional small decreases were obtained over time with hydrochlorothiazide and placebo. The decrease initially achieved with clonidine was attenuated over time. The overall reduction in heart rate was greatest for atenolol (-12.2 beats/min) and least for prazosin (+3.8 beats/min). Only atenolol effected a further reduction of heart rate for patients whose baseline rate was < or =65 beats/min. All drugs reduced heart rate when the baseline was > or =85 beats/min. Data derived by electrocardiogram yielded similar results. The drugs used in this study differ in their ability to reduce heart rate, sustain that reduction over time, and to change heart rate in groups with high or low rates at baseline. The importance of these comparative changes as independent cardiac risk factor variables remains to be determined.

5-year outcome of surgical resection and watchful waiting for men with moderately symptomatic benign prostatic hyperplasia: a Department of Veterans Affairs cooperative study.

PURPOSE: We determine outcomes after 5 years of followup for men who were randomized to receive transurethral resection or watchful waiting for moderate symptoms of benign prostatic hyperplasia. MATERIALS AND METHODS: A total of 556 patients were evaluated up to 60 months after randomization providing 966 patient-years of followup for transurethral prostatic resection and 990 for watchful waiting. Patients randomized to watchful waiting were evaluated according to whether they remained on treatment or crossed over to surgery. Outcomes included treatment failure, a genitourinary symptom score, peak flow rate, post-void residual urine volume and the degree of bother from genitourinary symptoms. RESULTS: All outcomes were significantly better for transurethral prostatic resection than for watchful waiting. Treatment failure rates were 10% for transurethral prostatic resection versus 21% for watchful waiting (p = 0.0004). The crossover rate at 5 years was 36% and was positively associated with the degree of bother. Men with low pretreatment peak flow rates who were randomized to transurethral prostatic resection had 85% greater improvement in peak flow rate than comparable men who were randomized to watchful waiting and eventually crossed over to resection. However, after crossover, bother from genitourinary symptoms was similar to that of the resection group. CONCLUSIONS: For men with moderate symptoms of benign prostatic hyperplasia transurethral prostatic resection has more favorable outcomes up to 5 years of followup compared to watchful waiting. While many men do well on watchful waiting, those who undergo transurethral prostatic resection after a trial of watchful waiting have less improvement in measures of bladder function than men randomized to resection, although there is no difference in serious adverse outcomes or bother from genitourinary symptoms.