Severe hypoglycemia monitoring and risk management procedures in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

Hypoglycemia is a potentially serious side effect of blood glucose lowering in diabetes mellitus. The intensive glycemia treatment arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is designed to treat patients with type 2 diabetes with target glycemia within the normal range (ie, glycosylated hemoglobin <6%). Because it is known that treating glycemia to such a low level in patients with diabetes will result in episodes of hypoglycemia, it is necessary to address prevention and treatment of such episodes to ensure patient safety. Thus, several approaches are being taken in the ACCORD trial to prevent initial episodes of severe hypoglycemia, to monitor the frequency of episodes that do occur, and to prevent recurrence. This report describes the processes used in the ACCORD trial, including the definition of severe hypoglycemia, the type of education provided to participants and staff members to prevent initial and subsequent episodes of severe hypoglycemia, and the monitoring systems implemented to identify severe hypoglycemia and prevent its recurrence. The ACCORD trial conducts review and oversight of individual cases of severe hypoglycemia and monitors rates of severe hypoglycemia by clinical site and treatment arm. If the ACCORD intensive glycemia treatment is found to be efficacious in preventing cardiovascular disease events, assessment of the risk and benefit will be essential. In addition, translation of the principles behind the monitoring of severe hypoglycemia in ACCORD into feasible strategies for use in clinical practice will be needed.

Relationship of antihypertensive treatment regimens and change in blood pressure to risk for heart failure in hypertensive patients randomly assigned to doxazosin or chlorthalidone: further analyses from the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial.

BACKGROUND: The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial reported that treatment initiated with doxazosin compared with chlorthalidone doubled the risk for heart failure in high-risk hypertensive patients (relative risk, 2.04 [95% CI, 1.79 to 2.32]). Patients assigned to doxazosin therapy had a mean in-trial systolic/diastolic blood pressure 3/0 mm Hg higher than that in patients assigned to chlorthalidone. Sixty-eight percent (6167 of 9061) of the former patients and 59% (9081 of 15 256) of the latter patients were given additional medications to achieve a target blood pressure of less than 140/90 mm Hg. OBJECTIVE: To ascertain the influence of open-label antihypertensive drugs and subsequent blood pressure on relative risk for heart failure. DESIGN: Randomized, double-blind, active-controlled clinical trial. SETTING: 623 sites in the United States and Canada. PATIENTS: Hypertensive patients 55 years of age or older with at least one additional risk factor for cardiovascular disease. INTERVENTION: Chlorthalidone (12.5 to 25 mg/d) or doxazosin (2 to 8 mg/d) for a planned follow-up of 4 to 8 years. MEASUREMENTS: Data on blood pressure, medication, and incident heart failure (treated outside hospital, hospitalized, or fatal) from February 1994 through December 1999. RESULTS: After the treatment groups were categorized as having no exposure to open-label medications (monotherapy) or exposure to open-label therapy, the relative risk for heart failure with doxazosin versus chlorthalidone was 3.10 (CI, 2.51 to 3.82) and 1.42 (CI, 1.20 to 1.69), respectively. After adjustment for follow-up systolic/diastolic blood pressure, the overall relative risk was 2.00 (CI, 1.72 to 2.32). CONCLUSION: In high-risk patients with hypertension, the higher risk for heart failure while taking doxazosin compared with chlorthalidone is attenuated but not eliminated by adding other antihypertensive drugs. The small observed difference in systolic blood pressure does not explain this increased risk.

Sex hormone replacement therapy reverses altered venous contractility in rats after pharmacological ovariectomy.

OBJECTIVE: Female sex hormones have several important effects on the venous system. We earlier found that hormone replacement has a significant effect on venous distensibility, but effects of menopause and hormone replacement on venous contractility have never been studied. Therefore, and because the changes we found earlier in distensibility were most likely caused by alterations of contractility, we examined the changes in contractility of saphenous vein caused by depletion and replacement of sex hormones in female rats. DESIGN: Twenty Sprague-Dawley rats were pharmacologically ovariectomized by triptorelin. Ten of these rats received combined sex hormone replacement (HRT) with estradiol propionate and medroxyprogesterone acetate. The rest were given vehicle. Ten animals without ovariectomy served as controls. After 3 months of treatment, segments of the saphenous vein were dissected. Pressure-diameter curves were recorded in relaxed, contracted, and control states. RESULTS: Venous diameter, adjusted for body weight, was significantly decreased after pharmacological ovariectomy. HRT increased the diameter. The presence of sex hormones augmented norepinephrine contraction measured at physiological pressures (control: 19.2 +/- 2.3%; pharmacological ovariectomy: 15.2 +/- 1.4%, p < 0.05 and 17.8 +/- 2.2% following HRT). Myogenic (spontaneous) tone of the saphenous vein did not change after ovariectomy, but it was lowered by hormone replacement (control: 8 +/- 1.1%; ovariectomy: 6.9 +/- 2.5%; ovariectomy + HRT: 2.7 +/- 1.1%, p < 0.05). CONCLUSIONS: Sex hormone depletion induces significant alterations in contractility of the saphenous vein, which could perturb venous capacitance function and distensibility. This effect has a potential role in the development of hypertension and venous varicosity, and these changes could possibly be prevented by HRT.

Lack of association between thiazolidinediones and macular edema in type 2 diabetes: the ACCORD eye substudy.

OBJECTIVE: To assess the cross-sectional association of thiazolidinediones with diabetic macular edema (DME). METHODS: The cross-sectional association of DME and visual acuity with thiazolidinediones was examined by means of baseline fundus photographs and visual acuity measurements from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Visual acuity was assessed in 9690 participants in the ACCORD trial, and 3473 of these participants had fundus photographs that were centrally read in a standardized fashion by masked graders to assess DME and retinopathy from October 23, 2003, to March 10, 2006. RESULTS: Among the subsample, 695 (20.0%) people had used thiazolidinediones, whereas 217 (6.2%) people had DME. Thiazolidinedione use was not associated with DME in unadjusted (odds ratio [OR], 1.01; 95% confidence interval [CI], 0.71-1.44; P = .95) and adjusted (OR, 0.97; 95% CI, 0.67-1.40; P = .86) analyses. Significant associations with DME were found for retinopathy severity (P < .001) and age (OR, 0.97; 95% CI, 0.952-0.997; P = .03) but not for hemoglobin A(1c) (P = .06), duration of diabetes (P = .65), sex (P = .72), and ethnicity (P = .20). Thiazolidinedione use was associated with slightly greater visual acuity (0.79 letter; 95% CI, 0.20-1.38; P = .009) of uncertain clinical significance. CONCLUSIONS: In a cross-sectional analysis of data from the largest study to date, no association was observed between thiazolidinedione exposure and DME in patients with type 2 diabetes; however, we cannot exclude a modest protective or harmful association. Trial Registration clinicaltrials.gov Identifier: NCT00542178.

Clinical events in high-risk hypertensive patients randomly assigned to calcium channel blocker versus angiotensin-converting enzyme inhibitor in the antihypertensive and lipid-lowering treatment to prevent heart attack trial.

The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) provides a unique opportunity to compare the long-term relative safety and efficacy of angiotensin-converting enzyme inhibitor and calcium channel blocker-initiated therapy in older hypertensive individuals. Patients were randomized to amlodipine (n=9048) or lisinopril (n=9054). The primary outcome was combined fatal coronary heart disease or nonfatal myocardial infarction, analyzed by intention-to-treat. Secondary outcomes included all-cause mortality, stroke, combined cardiovascular disease (CVD), end-stage renal disease (ESRD), cancer, and gastrointestinal bleeding. Mean follow-up was 4.9 years. Blood pressure control was similar in nonblacks, but not in blacks. No significant differences were found between treatment groups for the primary outcome, all-cause mortality, ESRD, or cancer. Stroke rates were higher on lisinopril in blacks (RR=1.51, 95% CI 1.22 to 1.86) but not in nonblacks (RR=1.07, 95% CI 0.89 to 1.28), and in women (RR=1.45, 95% CI 1.17 to 1.79), but not in men (RR=1.10, 95% CI 0.92 to 1.31). Rates of combined CVD were higher (RR=1.06, 95% CI 1.00 to 1.12) because of higher rates for strokes, peripheral arterial disease, and angina, which were partly offset by lower rates for heart failure (RR=0.87, 95% CI 0.78 to 0.96) on lisinopril compared with amlodipine. Gastrointestinal bleeds and angioedema were higher on lisinopril. Patients with and without baseline coronary heart disease showed similar outcome patterns. We conclude that in hypertensive patients, the risks for coronary events are similar, but for stroke, combined CVD, gastrointestinal bleeding, and angioedema are higher and for heart failure are lower for lisinopril-based compared with amlodipine-based therapy. Some, but not all, of these differences may be explained by less effective blood pressure control in the lisinopril arm.