Kenneth Jamerson

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

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.)

Intensive blood-pressure control in hypertensive chronic kidney disease.

BACKGROUND In observational studies, the relationship between blood pressure and end-stage renal disease (ESRD) is direct and progressive. The burden of hypertension-related chronic kidney disease and ESRD is especially high among black patients. Yet few trials have tested whether intensive blood-pressure control retards the progression of chronic kidney disease among black patients. METHODS We randomly assigned 1094 black patients with hypertensive chronic kidney disease to receive either intensive or standard blood-pressure control. After completing the trial phase, patients were invited to enroll in a cohort phase in which the blood-pressure target was less than 130/80 mm Hg. The primary clinical outcome in the cohort phase was the progression of chronic kidney disease, which was defined as a doubling of the serum creatinine level, a diagnosis of ESRD, or death. Follow-up ranged from 8.8 to 12.2 years. RESULTS During the trial phase, the mean blood pressure was 130/78 mm Hg in the intensive-control group and 141/86 mm Hg in the standard-control group. During the cohort phase, corresponding mean blood pressures were 131/78 mm Hg and 134/78 mm Hg. In both phases, there was no significant between-group difference in the risk of the primary outcome (hazard ratio in the intensive-control group, 0.91; P=0.27). However, the effects differed according to the baseline level of proteinuria (P=0.02 for interaction), with a potential benefit in patients with a protein-to-creatinine ratio of more than 0.22 (hazard ratio, 0.73; P=0.01). CONCLUSIONS In overall analyses, intensive blood-pressure control had no effect on kidney disease progression. However, there may be differential effects of intensive blood-pressure control in patients with and those without baseline proteinuria. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center on Minority Health and Health Disparities, and others.)

2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines

Glenn N. Levine, MD, FACC, FAHA, Chair Patrick T. O’Gara, MD, MACC, FAHA, Chair-Elect Jonathan L. Halperin, MD, FACC, FAHA, Immediate Past Chair Sana M. Al-Khatib, MD, MHS, FACC, FAHA Joshua A. Beckman, MD, MS, FAHA Kim K. Birtcher, MS, PharmD, AACC Biykem Bozkurt, MD, PhD, FACC, FAHA

Stenting and Medical Therapy for Atherosclerotic Renal-Artery Stenosis

BACKGROUND Atherosclerotic renal-artery stenosis is a common problem in the elderly. Despite two randomized trials that did not show a benefit of renal-artery stenting with respect to kidney function, the usefulness of stenting for the prevention of major adverse renal and cardiovascular events is uncertain. METHODS We randomly assigned 947 participants who had atherosclerotic renal-artery stenosis and either systolic hypertension while taking two or more antihypertensive drugs or chronic kidney disease to medical therapy plus renal-artery stenting or medical therapy alone. Participants were followed for the occurrence of adverse cardiovascular and renal events (a composite end point of death from cardiovascular or renal causes, myocardial infarction, stroke, hospitalization for congestive heart failure, progressive renal insufficiency, or the need for renal-replacement therapy). RESULTS Over a median follow-up period of 43 months (interquartile range, 31 to 55), the rate of the primary composite end point did not differ significantly between participants who underwent stenting in addition to receiving medical therapy and those who received medical therapy alone (35.1% and 35.8%, respectively; hazard ratio with stenting, 0.94; 95% confidence interval [CI], 0.76 to 1.17; P=0.58). There were also no significant differences between the treatment groups in the rates of the individual components of the primary end point or in all-cause mortality. During follow-up, there was a consistent modest difference in systolic blood pressure favoring the stent group (-2.3 mm Hg; 95% CI, -4.4 to -0.2; P=0.03). CONCLUSIONS Renal-artery stenting did not confer a significant benefit with respect to the prevention of clinical events when added to comprehensive, multifactorial medical therapy in people with atherosclerotic renal-artery stenosis and hypertension or chronic kidney disease. (Funded by the National Heart, Lung and Blood Institute and others; ClinicalTrials.gov number, NCT00081731.).

The Chronic Renal Insufficiency Cohort (CRIC) Study: Design and Methods

Insights into end-stage renal disease have emerged from many investigations but less is known about the epidemiology of chronic renal insufficiency (CRI) and its relationship to cardiovascular disease (CVD). The Chronic Renal Insufficiency Cohort (CRIC) Study was established to examine risk factors for progression of CRI and CVD among CRI patients and develop models to identify high-risk subgroups, informing future treatment trials, and increasing application of preventive therapies. CRIC will enroll approximately 3000 individuals at seven sites and follow participants for up to 5 yr. CRIC will include a racially and ethnically diverse group of adults aged 21 to 74 yr with a broad spectrum of renal disease severity, half of whom have diagnosed diabetes mellitus. CRIC will exclude subjects with polycystic kidney disease and those on active immunosuppression for glomerulonephritis. Subjects will undergo extensive clinical evaluation at baseline and at annual clinic visits and via telephone at 6 mo intervals. Data on quality of life, dietary assessment, physical activity, health behaviors, depression, cognitive function, health care resource utilization, as well as blood and urine specimens will be collected annually. (125)I-iothalamate clearances and CVD evaluations including a 12-lead surface electrocardiogram, an echocardiogram, and coronary electron beam or spiral CT will be performed serially. Analyses planned in CRIC will provide important information on potential risk factors for progressive CRI and CVD. Insights from CRIC should lead to the formulation of hypotheses regarding therapy that will serve as the basis for targeted interventional trials focused on reducing the burden of CRI and CVD.

Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial.

BACKGROUND The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial showed that initial antihypertensive therapy with benazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide in reducing cardiovascular morbidity and mortality. We assessed the effects of these drug combinations on progression of chronic kidney disease. METHODS ACCOMPLISH was a double-blind, randomised trial undertaken in five countries (USA, Sweden, Norway, Denmark, and Finland). 11 506 patients with hypertension who were at high risk for cardiovascular events were randomly assigned via a central, telephone-based interactive voice response system in a 1:1 ratio to receive benazepril (20 mg) plus amlodipine (5 mg; n=5744) or benazepril (20 mg) plus hydrochlorothiazide (12.5 mg; n=5762), orally once daily. Drug doses were force-titrated for patients to attain recommended blood pressure goals. Progression of chronic kidney disease, a prespecified endpoint, was defined as doubling of serum creatinine concentration or end-stage renal disease (estimated glomerular filtration rate <15 mL/min/1.73 m(2) or need for dialysis). Analysis was by intention to treat (ITT). This trial is registered with ClinicalTrials.gov, number NCT00170950. FINDINGS The trial was terminated early (mean follow-up 2.9 years [SD 0.4]) because of superior efficacy of benazepril plus amlodipine compared with benazepril plus hydrochlorothiazide. At trial completion, vital status was not known for 143 (1%) patients who were lost to follow-up (benazepril plus amlodipine, n=70; benazepril plus hydrochlorothiazide, n=73). All randomised patients were included in the ITT analysis. There were 113 (2.0%) events of chronic kidney disease progression in the benazepril plus amlodipine group compared with 215 (3.7%) in the benazepril plus hydrochlorothiazide group (HR 0.52, 0.41-0.65, p<0.0001). The most frequent adverse event in patients with chronic kidney disease was peripheral oedema (benazepril plus amlodipine, 189 of 561, 33.7%; benazepril plus hydrochlorothiazide, 85 of 532, 16.0%). In patients with chronic kidney disease, angio-oedema was more frequent in the benazepril plus amlodipine group than in the benazepril plus hydrochlorothiazide group. In patients without chronic kidney disease, dizziness, hypokalaemia, and hypotension were more frequent in the benazepril plus hydrochlorothiazide group than in the benazepril plus amlodipine group. INTERPRETATION Initial antihypertensive treatment with benazepril plus amlodipine should be considered in preference to benazepril plus hydrochlorothiazide since it slows progression of nephropathy to a greater extent. FUNDING Novartis.

Avosentan for Overt Diabetic Nephropathy

In the short term, the endothelin antagonist avosentan reduces proteinuria, but whether this translates to protection from progressive loss of renal function is unknown. We examined the effects of avosentan on progression of overt diabetic nephropathy in a multicenter, multinational, double-blind, placebo-controlled trial. We randomly assigned 1392 participants with type 2 diabetes to oral avosentan (25 or 50 mg) or placebo in addition to continued angiotensin-converting enzyme inhibition and/or angiotensin receptor blockade. The composite primary outcome was the time to doubling of serum creatinine, ESRD, or death. Secondary outcomes included changes in albumin-to-creatinine ratio (ACR) and cardiovascular outcomes. We terminated the trial prematurely after a median follow-up of 4 months (maximum 16 months) because of an excess of cardiovascular events with avosentan. We did not detect a difference in the frequency of the primary outcome between groups. Avosentan significantly reduced ACR: In patients who were treated with avosentan 25 mg/d, 50 mg/d, and placebo, the median reduction in ACR was 44.3, 49.3, and 9.7%, respectively. Adverse events led to discontinuation of trial medication significantly more often for avosentan than for placebo (19.6 and 18.2 versus 11.5% for placebo), dominated by fluid overload and congestive heart failure; death occurred in 21 (4.6%; P = 0.225), 17 (3.6%; P = 0.194), and 12 (2.6%), respectively. In conclusion, avosentan reduces albuminuria when added to standard treatment in people with type 2 diabetes and overt nephropathy but induces significant fluid overload and congestive heart failure.

Reflex sympathetic activation induces acute insulin resistance in the human forearm.

Inferences about the association between sympathetic overactivity and insulin resistance have been drawn from the infusion of sympathomimetic amines in supraphysiological doses. We used the isolated perfused human forearm to investigate the effect of reflex-induced sympathetic nervous system activation on the peripheral utilization of glucose in the skeletal muscles of 14 healthy men. Local hyperinsulinemia in the forearm (132 +/- 25 microunits/mL for 90 minutes) induced a significant increase in the utilization of glucose from baseline (16.4 +/- 3.1 mg.dL-1.min-1 per 100 mL forearm volume) to a plateau (85.7 +/- 15.1 mg.dL-1.min-1 per 100 mL forearm volume) between 40 and 60 minutes of insulin infusion but did not alter the utilization of oxygen. Reflex sympathetic nervous system activation was elicited by unloading of cardiopulmonary receptors with bilateral thigh cuff inflation to 40 mm Hg between 60 and 90 minutes of insulin infusion. Blood flow in the forearm was significantly decreased with inflation of thigh cuffs (average decrease of 19%, p < 0.0001). As a result of thigh cuff inflation, there was a reduction in the utilization of glucose (a decrease of 23%, p < 0.02), whereas oxygen utilization was unchanged. We find that an increase in sympathetic nervous system activation (within the normal range of physiological responses) can cause acute insulin resistance in the forearm of healthy volunteers. The reflex caused no change in oxygen utilization, but the same stimulus elicited a decrease in the utilization of glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Surrogate Markers for Cardiovascular Disease Functional Markers

The endothelium constitutes the largest organ system in the body. “Endothelial function” refers to a multitude of physiological functions of the vascular endothelium that are achieved via secretion of diverse bioactive substances. This renders the endothelium an active participant in healthy homeostasis of the vascular wall that includes normal vasomotion, inhibition of platelet aggregation and thrombus generation, and maintenance of relative impermeability. Cardiovascular risk factors activate a number of pro-oxidative genes in the vascular wall resulting in generation of reactive oxygen species that ultimately promote endothelial release of transcriptional and growth factors, proinflammatory cytokines, chemoattractant substances, and adhesion molecules.1–3 This complex cascade of events underlies the transition from normal endothelial function to endothelial dysfunction. One of the earliest manifestations of increased vascular oxidant stress is the reduced bioavailability of nitric oxide (NO) as a result of inhibition and uncoupling of endothelial NO synthase, the enzyme responsible for generation of NO, and from rapid catabolism of available NO by reactive oxygen species to peroxynitrite and hydrogen peroxide that can further amplify vascular oxidative stress. The resulting functional consequences include abnormal vasomotor activity, development of a procoagulant endothelial surface, inflammation, and, ultimately, plaque formation. Clinical measurements of endothelium-dependent vasodilation (NO-mediated process) by a variety of different techniques provide a marker of endothelial integrity. Almost all conventional risk factors for atherosclerosis are associated with endothelial dysfunction. These include sedentary lifestyle and obesity, hypercholesterolemia, hypertension, diabetes, insulin resistance, smoking, and aging. The extent of endothelial dysfunction appears to correlate with the traditional risk factor “burden,” thus implying that combined or repeated injury to the vascular endothelium results in greater dysfunction. Nevertheless, there is considerable heterogeneity in the magnitude of dysfunction observed in individuals with similar risk factor profiles.4,5 Novel risk factors such as infections, hyperhomocystinemia, genetic heterogeneity, and the variable duration of …

Cardiovascular Events During Differing Hypertension Therapies in Patients With Diabetes

OBJECTIVES The aim of this study was to determine which combination therapy in patients with hypertension and diabetes most effectively decreases cardiovascular events. BACKGROUND The ACCOMPLISH (Avoiding Cardiovascular Events Through COMbination Therapy in Patients Living With Systolic Hypertension) trial compared the outcomes effects of a renin-angiotensin system blocker, benazepril, combined with amlodipine (B+A) or hydrochlorothiazide (B+H). A separate analysis in diabetic patients was pre-specified. METHODS A total of 6,946 patients with diabetes were randomized to treatment with B+A or B+H. A subgroup of 2,842 diabetic patients at very high risk (previous cardiovascular or stroke events) was also analyzed, as were 4,559 patients without diabetes. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for angina, resuscitated arrest, and coronary revascularization. RESULTS In the full diabetes group, the mean achieved blood pressures in the B+A and B+H groups were 131.5/72.6 and 132.7/73.7 mm Hg; during 30 months, there were 307 (8.8%) and 383 (11.0%) primary events (hazard ratio [HR]: 0.79, 95% confidence interval [CI]: 0.68 to 0.92, p = 0.003). For the diabetic patients at very high risk, there were 195 (13.6%) and 244 (17.3%) primary events (HR: 0.77, 95% CI: 0.64 to 0.93, p = 0.007). In the nondiabetic patients, there were 245 (10.8%) and 296 (12.9%) primary events (HR: 0.82, 95% CI: 0.69 to 0.97, p = 0.020). In the diabetic patients, there were clear coronary benefits with B+A, including both acute clinical events (p = 0.013) and revascularizations (p = 0.024). There were no unexpected adverse events. CONCLUSIONS In patients with diabetes and hypertension, combining a renin-angiotensin system blocker with amlodipine, compared with hydrochlorothiazide, was superior in reducing cardiovascular events and could influence future management of hypertension in patients with diabetes. (Avoiding Cardiovascular Events Through COMbination Therapy in Patients Living With Systolic Hypertension [ACCOMPLISH]; NCT00170950).