Background The optimal combination drug therapy for hypertension is not established, although current U.S. guidelines recommend inclusion of a diuretic. We hypothesized that treatment with the combination of an angiotensin-converting–enzyme (ACE) inhibitor and a dihydropyridine calcium-channel blocker would be more effective in reducing the rate of cardiovascular events than treatment with an ACE inhibitor plus a thiazide diuretic. Methods In a randomized, double-blind trial, we assigned 11,506 patients with hypertension who were at high risk for cardiovascular events to receive treatment with either benazepril plus amlodipine or benazepril plus hydrochlorothiazide. The primary end point was the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization. Results The baseline characteristics of the two groups were similar. The trial was terminated early after a mean follow-up of 36 months, when the boundary of the prespecified stopping rule was exceeded. Mean blood pressures after dose adjustment were 131.6/73.3 mm Hg in the benazepril–amlodipine group and 132.5/74.4 mm Hg in the benazepril–hydrochlorothiazide group. There were 552 primary-outcome events in the benazepril–amlodipine group (9.6%) and 679 in the benazepril–hydrochlorothiazide group (11.8%), representing an absolute risk reduction with benazepril–amlodipine therapy of 2.2% and a relative risk reduction of 19.6% (hazard ratio, 0.80, 95% confidence interval [CI], 0.72 to 0.90; P<0.001). For the secondary end point of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke, the hazard ratio was 0.79 (95% CI, 0.67 to 0.92; P = 0.002). Rates of adverse events were consistent with those observed from clinical experience with the study drugs. Conclusions The benazepril–amlodipine combination was superior to the benazepril–hydrochlorothiazide combination in reducing cardiovascular events in patients with hypertension who were at high risk for such events. (ClinicalTrials.gov number, NCT00170950.)

/pdf/benazepril-plus-amlodipine-or-hydrochlorothiazide-for-1s0msigofy.pdf

Benazepril plus Amlodipine or Hydrochlorothiazide for Hypertension in High-Risk Patients

A b s t r ac t Background Microalbuminuria is an early predictor of diabetic nephropathy and premature cardiovascular disease. We investigated whether treatment with an angiotensin-receptor blocker (ARB) would delay or prevent the occurrence of microalbuminuria in patients with type 2 diabetes and normoalbuminuria. Methods In a randomized, double-blind, multicenter, controlled trial, we assigned 4447 patients with type 2 diabetes to receive olmesartan (at a dose of 40 mg once daily) or placebo for a median of 3.2 years. Additional antihypertensive drugs (except angiotensin-converting–enzyme inhibitors or ARBs) were used as needed to lower blood pressure to less than 130/80 mm Hg. The primary outcome was the time to the first onset of microalbuminuria. The times to the onset of renal and cardiovascular events were analyzed as secondary end points. Results The target blood pressure (<130/80 mm Hg) was achieved in nearly 80% of the patients taking olmesartan and 71% taking placebo; blood pressure measured in the clinic was lower by 3.1/1.9 mm Hg in the olmesartan group than in the placebo group. Microalbuminuria developed in 8.2% of the patients in the olmesartan group (178 of 2160 patients who could be evaluated) and 9.8% in the placebo group (210 of 2139); the time to the onset of microalbuminuria was increased by 23% with olmesartan (hazard ratio for onset of microalbuminuria, 0.77; 95% confidence interval, 0.63 to 0.94; P = 0.01). The serum creatinine level doubled in 1% of the patients in each group. Slightly fewer patients in the olmesartan group than in the placebo group had nonfatal cardiovascular events — 81 of 2232 patients (3.6%) as compared with 91 of 2215 patients (4.1%) (P = 0.37) — but a greater number had fatal cardiovascular events — 15 patients (0.7%) as compared with 3 patients (0.1%) (P = 0.01), a difference that was attributable in part to a higher rate of death from cardiovascular causes in the olmesartan group than in the placebo group among patients with preexisting coronary heart disease (11 of 564 patients [2.0%] vs. 1 of 540 [0.2%], P = 0.02). Conclusions Olmesartan was associated with a delayed onset of microalbuminuria, even though blood-pressure control in both groups was excellent according to current standards. The higher rate of fatal cardiovascular events with olmesartan among patients with preexisting coronary heart disease is of concern. (Funded by Daiichi Sankyo; ClinicalTrials.gov number, NCT00185159.)

/pdf/olmesartan-for-the-delay-or-prevention-of-microalbuminuria-1gay6bh9gy.pdf

Olmesartan for the Delay or Prevention of Microalbuminuria in Type 2 Diabetes

The purpose of this consensus statement is to offer primary care providers (including physicians, nurse practitioners, and physician assistants) a practical, evidence-based clinical tool for achieving blood pressure goals in African American patients. The need for specific recommendations for African Americans is highlighted by compelling evidence of a higher prevalence of hypertension and poorer cardiovascular and renal outcomes in this group than in white Americans. African Americans have disturbingly higher rates of cardiovascular mortality, stroke, hypertension-related heart disease, congestive heart failure, type 2 diabetes mellitus, hypertensive nephropathy, and end-stage renal disease (ESRD). 1,2 .

/pdf/management-of-high-blood-pressure-in-african-americans-45cyqp93yo.pdf

Management of High Blood Pressure in African Americans: Consensus Statement of the Hypertension in African Americans Working Group of the International Society on Hypertension in Blacks

Up to 75% of adults with diabetes also have hypertension, and patients with hypertension alone often show evidence of insulin resistance. Thus, hypertension and diabetes are common, intertwined conditions that share a significant overlap in underlying risk factors (including ethnicity, familial, dyslipidemia, and lifestyle determinants) and complications. These complications include microvascular and macrovascular disorders. The macrovascular complications, which are well recognized in patients with longstanding diabetes or hypertension, include coronary artery disease, myocardial infarction, stroke, congestive heart failure, and peripheral vascular disease. Although microvascular complications (retinopathy, nephropathy, and neuropathy) are conventionally linked to hyperglycemia, studies have shown that hypertension constitutes an important risk factor, especially for nephropathy. The familial predisposition to diabetes and hypertension appears to be polygenic in origin, which militates against the feasibility of a "gene therapy" approach to the control or prevention of these conditions. On the other hand, the shared lifestyle factors in the etiology of hypertension and diabetes provide ample opportunity for nonpharmacologic intervention. Thus, the initial approach to the management of both diabetes and hypertension must emphasize weight control, physical activity, and dietary modification. Interestingly, lifestyle intervention is remarkably effective in the primary prevention of diabetes and hypertension. These principles also are pertinent to the prevention of downstream macrovascular complications of the two disorders. In addition to lifestyle modification, most patients will require specific medications to achieve national treatment goals for hypertension and diabetes. Management of hyperglycemia, hypertension, dyslipidemia, and the underlying hypercoagulable and proinflammatory states requires the use of multiple medications in combination.

/pdf/comorbidities-of-diabetes-and-hypertension-mechanisms-and-1j1bxy5p7c.pdf

Comorbidities of Diabetes and Hypertension: Mechanisms and Approach to Target Organ Protection

Diabetic nephropathy is the most important long-term complication of diabetes mellitus and is a major cause of end-stage renal disease. The condition is associated with excess cardiovascular morbidity and mortality, as well as other diabetic microvascular complications. The etiopathogenesis of diabetic nephropathy appears to involve both genetic and environmental factors leading to disease in a subgroup of patients. Improved knowledge of the natural history and pathophysiology of the condition have enabled therapeutic strategies to be employed that have improved the outlook for patients with nephropathy. Strategies aimed at the identification of patients at high risk of nephropathy could have a major impact on the overall cardiovascular and renal morbidity in diabetic patients.

Pathogenesis of diabetic nephropathy.

c Over 11 million Americans have both diabetes and hypertension— comorbid diseases that strongly predispose people to both renal as well as cardiovascular (CV) injury. Hypertension substantially contributes to CV morbidity and mortality in people with diabetes. Diabetes is the most common cause of end-stage renal disease in the United States. Furthermore, hypertension and diabetes are particularly prevalent in certain populations, such as AfricanAmericans and Native Americans. Since the 1994 Working Group Report on Hypertension and Diabetes, a large body of clinical trial data has affirmed the original blood pressure goal of less than 130/85 mmHg recommended to preserve renal function and reduce CV events in people with hypertension and diabetes. Data that are more recent have emerged, however, to support an even lower diastolic blood pressure goal, ie, 80 mmHg, in order to optimally preserve renal function and reduce CV events in people with diabetic nephropathy. A review of clinical trials indicates that more than 65% of people with diabetes and hypertension will require two or more different antihypertensive medications to achieve the new suggested target blood pressure of 130/80 mmHg. The purpose of this report is to update the previous recommendations with a focus on level of blood pressure control, proteinuria reduction, and therapeutic approaches to achieve these goals. We provide an evidence-based approach, integrating data from the major clinical trials that were designed as randomized prospective, long-term studies that had as a primary endpoint either progression of diabetic nephropathy or reduction in CV events. This report also addresses socioeconomic and cultural barriers that hinder achievement of blood pressure goals. Lastly, the report discusses approaches to resolve cultural barriers, both physician- and patient-derived, that interfere with achievement of lower blood pressure goals. © 2000 by the National Kidney Foundation, Inc.

William J. Elliott

Papers

SPECIAL REPORT Preserving Renal Function in Adults With Hypertension and Diabetes: A Consensus Approach

Who is an expert? Reply