Suzanne Oparil

Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol

BACKGROUND Blood pressure reduction achieved with beta-blockers and diuretics is the best recorded intervention to date for prevention of cardiovascular morbidity and death in patients with hypertension. Left ventricular hypertrophy (LVH) is a strong independent indicator of risk of cardiovascular morbidity and death. We aimed to establish whether selective blocking of angiotensin II improves LVH beyond reducing blood pressure and, consequently, reduces cardiovascular morbidity and death. METHODS We did a double-masked, randomised, parallel-group trial in 9193 participants aged 55-80 years with essential hypertension (sitting blood pressure 160-200/95-115 mm Hg) and LVH ascertained by electrocardiography (ECG). We assigned participants once daily losartan-based or atenolol-based antihypertensive treatment for at least 4 years and until 1040 patients had a primary cardiovascular event (death, myocardial infarction, or stroke). We used Cox regression analysis to compare regimens. FINDINGS Blood pressure fell by 30.2/16.6 (SD 18.5/10.1) and 29.1/16.8 mm Hg (19.2/10.1) in the losartan and atenolol groups, respectively. The primary composite endpoint occurred in 508 losartan (23.8 per 1000 patient-years) and 588 atenolol patients (27.9 per 1000 patient-years; relative risk 0.87, 95% CI 0.77-0.98, p=0.021). 204 losartan and 234 atenolol patients died from cardiovascular disease (0.89, 0.73-1.07, p=0.206); 232 and 309, respectively, had fatal or non-fatal stroke (0.75, 0.63-0.89, p=0.001); and myocardial infarction (non-fatal and fatal) occurred in 198 and 188, respectively (1.07, 0.88-1.31, p=0.491). New-onset diabetes was less frequent with losartan. Interpretation Losartan prevents more cardiovascular morbidity and death than atenolol for a similar reduction in blood pressure and is better tolerated. Losartan seems to confer benefits beyond reduction in blood pressure.

2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8)

Hypertension is the most common condition seen in primary care and leads to myocardial infarction, stroke, renal failure, and death if not detected early and treated appropriately. Patients want to be assured that blood pressure (BP) treatment will reduce their disease burden, while clinicians want guidance on hypertension management using the best scientific evidence. This report takes a rigorous, evidence-based approach to recommend treatment thresholds, goals, and medications in the management of hypertension in adults. Evidence was drawn from randomized controlled trials, which represent the gold standard for determining efficacy and effectiveness. Evidence quality and recommendations were graded based on their effect on important outcomes. There is strong evidence to support treating hypertensive persons aged 60 years or older to a BP goal of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg; however, there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal, or in those younger than 30 years for a diastolic goal, so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion. The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease (CKD) as for the general hypertensive population younger than 60 years. There is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or thiazide-type diuretic in the nonblack hypertensive population, including those with diabetes. In the black hypertensive population, including those with diabetes, a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy. There is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes. Although this guideline provides evidence-based recommendations for the management of high BP and should meet the clinical needs of most patients, these recommendations are not a substitute for clinical judgment, and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient.

A Randomized Trial of Intensive versus Standard Blood-Pressure Control.

BACKGROUND The most appropriate targets for systolic blood pressure to reduce cardiovascular morbidity and mortality among persons without diabetes remain uncertain. METHODS We randomly assigned 9361 persons with a systolic blood pressure of 130 mm Hg or higher and an increased cardiovascular risk, but without diabetes, to a systolic blood-pressure target of less than 120 mm Hg (intensive treatment) or a target of less than 140 mm Hg (standard treatment). The primary composite outcome was myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. RESULTS At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the standard-treatment group. The intervention was stopped early after a median follow-up of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group than in the standard-treatment group (1.65% per year vs. 2.19% per year; hazard ratio with intensive treatment, 0.75; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). All-cause mortality was also significantly lower in the intensive-treatment group (hazard ratio, 0.73; 95% CI, 0.60 to 0.90; P=0.003). Rates of serious adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure, but not of injurious falls, were higher in the intensive-treatment group than in the standard-treatment group. CONCLUSIONS Among patients at high risk for cardiovascular events but without diabetes, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01206062.).

Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol

BACKGROUND The most suitable antihypertensive drug to reduce the risk of cardiovascular disease in patients with hypertension and diabetes is unclear. In prespecified analyses, we compared the effects of losartan and atenolol on cardiovascular morbidity and mortality in diabetic patients. METHODS As part of the LIFE study, in a double-masked, randomised, parallel-group trial, we assigned a group of 1195 patients with diabetes, hypertension, and signs of left-ventricular hypertrophy (LVH) on electrocardiograms losartan-based or atenolol-based treatment. Mean age of patients was 67 years (SD 7) and mean blood pressure 177/96 mm Hg (14/10) after placebo run-in. We followed up patients for at least 4 years (mean 4.7 years [1.1]). We used Cox regression analysis with baseline Framingham risk score and electrocardiogram-LVH as covariates to compare the effects of the drugs on the primary composite endpoint of cardiovascular morbidity and mortality (cardiovascular death, stroke, or myocardial infarction). FINDINGS Mean blood pressure fell to 146/79 mm Hg (17/11) in losartan patients and 148/79 mm Hg (19/11) in atenolol patients. The primary endpoint occurred in 103 patients assigned losartan (n=586) and 139 assigned atenolol (n=609); relative risk 0.76 (95% CI 0.58-.98), p=0.031. 38 and 61 patients in the losartan and atenolol groups, respectively, died from cardiovascular disease; 0.63 (0.42-0.95), p=0.028. Mortality from all causes was 63 and 104 in losartan and atenolol groups, respectively; 0.61 (0.45-0.84), p=0.002. INTERPRETATION Losartan was more effective than atenolol in reducing cardiovascular morbidity and mortality as well as mortality from all causes in patients with hypertension, diabetes, and LVH. Losartan seems to have benefits beyond blood pressure reduction.

Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women—2011 Update: A Guideline From the American Heart Association

Substantial progress has been made in the awareness, treatment, and prevention of cardiovascular disease (CVD) in women since the first women-specific clinical recommendations for the prevention of CVD were published by the American Heart Association (AHA) in 1999.1 The myth that heart disease is a “mans disease” has been debunked; the rate of public awareness of CVD as the leading cause of death among US women has increased from 30% in 1997 to 54% in 2009.2 The age-adjusted death rate resulting from coronary heart disease (CHD) in females, which accounts for about half of all CVD deaths in women, was 95.7 per 100 000 females in 2007, a third of what it was in 1980.3,4 Approximately 50% of this decline in CHD deaths has been attributed to reducing major risk factors and the other half to treatment of CHD including secondary preventive therapies.4 Major randomized controlled clinical trials such as the Womens Health Initiative have changed the practice of CVD prevention in women over the past decade.5 The investment in combating this major public health issue for women has been significant, as have the scientific and medical achievements. Despite the gains that have been made, considerable challenges remain. In 2007, CVD still caused ≈1 death per minute among women in the United States.6 These represent 421 918 deaths, more womens lives than were claimed by cancer, chronic lower respiratory disease, Alzheimer disease, and accidents combined.6 Reversing a trend of the past 4 decades, CHD death rates in US women 35 to 54 years of age now actually appear to be increasing, likely because of the effects of the obesity epidemic.4 CVD rates in the United States are significantly higher for black females compared with their white counterparts (286.1/100 000 versus …

A controlled trial of renal denervation for resistant hypertension.

BACKGROUND Prior unblinded studies have suggested that catheter-based renal-artery denervation reduces blood pressure in patients with resistant hypertension. METHODS We designed a prospective, single-blind, randomized, sham-controlled trial. Patients with severe resistant hypertension were randomly assigned in a 2:1 ratio to undergo renal denervation or a sham procedure. Before randomization, patients were receiving a stable antihypertensive regimen involving maximally tolerated doses of at least three drugs, including a diuretic. The primary efficacy end point was the change in office systolic blood pressure at 6 months; a secondary efficacy end point was the change in mean 24-hour ambulatory systolic blood pressure. The primary safety end point was a composite of death, end-stage renal disease, embolic events resulting in end-organ damage, renovascular complications, or hypertensive crisis at 1 month or new renal-artery stenosis of more than 70% at 6 months. RESULTS A total of 535 patients underwent randomization. The mean (±SD) change in systolic blood pressure at 6 months was -14.13±23.93 mm Hg in the denervation group as compared with -11.74±25.94 mm Hg in the sham-procedure group (P<0.001 for both comparisons of the change from baseline), for a difference of -2.39 mm Hg (95% confidence interval [CI], -6.89 to 2.12; P=0.26 for superiority with a margin of 5 mm Hg). The change in 24-hour ambulatory systolic blood pressure was -6.75±15.11 mm Hg in the denervation group and -4.79±17.25 mm Hg in the sham-procedure group, for a difference of -1.96 mm Hg (95% CI, -4.97 to 1.06; P=0.98 for superiority with a margin of 2 mm Hg). There were no significant differences in safety between the two groups. CONCLUSIONS This blinded trial did not show a significant reduction of systolic blood pressure in patients with resistant hypertension 6 months after renal-artery denervation as compared with a sham control. (Funded by Medtronic; SYMPLICITY HTN-3 ClinicalTrials.gov number, NCT01418261.).

Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease: A Scientific Statement From the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention

Epidemiological studies have established a strong association between hypertension and coronary artery disease (CAD). Hypertension is a major independent risk factor for the development of CAD, stroke, and renal failure. The optimal choice of antihypertensive agents remains controversial, and there are only partial answers to important questions in the treatment of hypertension in the prevention and management of ischemic heart disease (IHD), such as: ● What are the appropriate systolic blood pressure (SBP) and diastolic blood pressure (DBP) targets in patients at high risk of developing CAD or in those with established CAD? ● Are the beneficial effects of treatment simply a function of blood pressure (BP) lowering, or do particular classes of drugs have uniquely protective actions in addition to lowering BP? ● Are there antihypertensive drugs that have shown particular efficacy in the primary and secondary prevention of IHD? ● Which antihypertensive drugs should be used in patients who have established CAD with stable or unstable angina pectoris, in those with non–ST-elevation myocardial infarction (NSTEMI), and in those with ST-elevation myocardial infarction (STEMI)?

Essential hypertension. Part I: definition and etiology.

Essential hypertension remains a major modifiable risk factor for cardiovascular disease (CVD) despite important advances in our understanding of its pathophysiology and the availability of effective treatment strategies. High blood pressure (BP) increases the risk of CVD for millions of people worldwide, and there is evidence that the problem is only getting worse. In the past decade, age-adjusted rates of stroke incidence have risen, and the slope of the age-adjusted rate of decline in coronary disease has leveled off. The incidence of end-stage renal disease and the prevalence of heart failure have also increased. A major contributor to these trends is inadequate control of BP in the hypertensive population. This review of current concepts regarding the definition, etiology, and treatment of essential hypertension is intended to aid the clinician in identifying those individuals at high risk who need to undergo evaluation and treatment, as well as in selecting optimal treatment strategies for hypertensive patients with comorbid conditions and/or target organ damage. The part of the review that deals with the genetic basis of hypertension and the gene/environment interaction that may lead to elevated BP is still a work in progress. Information gained from the Human Genome Project and from ongoing studies of the genetic basis of hypertension both in animal models and human populations may revolutionize the treatment of hypertension by replacing current empirical therapy with more effective, targeted treatments based on the genotype of the patient. Concepts introduced in this review form the basis for such “pharmacogenomic” approaches to antihypertensive therapy. BP is a quantitative trait that is highly variable1 ; in population studies, BP has a normal distribution that is slightly skewed to the right. There is a strong positive and continuous correlation between BP and the risk of CVD (stroke, myocardial infarction, heart failure), renal disease, …

Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: losartan intervention for endpoint reduction in hypertension study.

Few data are available to clarify whether changes in albuminuria over time translate to changes in cardiovascular risk. The aim of the present study was to examine whether changes in albuminuria during 4.8 years of antihypertensive treatment were related to changes in risk in 8206 patients with hypertension and left ventricular hypertrophy in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Urinary albumin/creatinine ratio (UACR) was measured at baseline and annually. Time-varying albuminuria was closely related to risk for the primary composite end point (ie, when UACR decreased during treatment, risk was reduced accordingly). When the population was divided according to median baseline value (1.21 mg/mmol) and median year 1 UACR (0.67 mg/mmol), risk increased stepwise and significantly for the primary composite end point from those with low baseline/low year 1 (5.5%), to low baseline/high year 1 (8.6%), to high baseline/low year 1 (9.4%), and to high baseline/high year 1 (13.5%) values. Similar significant, stepwise increases in risk were seen for the components of the primary composite end point (cardiovascular mortality, stroke, and myocardial infarction). The observation that changes in UACR during antihypertensive treatment over time translated to changes in risk for cardiovascular morbidity and mortality was not explained by in-treatment level of blood pressure. We propose that monitoring of albuminuria should be an integrated part of the management of hypertension. If albuminuria is not decreased by the patient’s current antihypertensive and other treatment, further intervention directed toward blood pressure control and other modifiable risks should be considered.

Albuminuria and Cardiovascular Risk in Hypertensive Patients with Left Ventricular Hypertrophy: The LIFE Study

Context Microalbuminuria is a known risk factor for cardiovascular disease. Contribution In this large prospective study of hypertensive patients with left ventricular hypertrophy, increasing microalbuminuria was associated with increasing risks for cardiovascular disease. Risks continuously increased without evidence of a threshold or plateau level. Implications Microalbuminuria assessment in hypertensive patients may improve cardiovascular risk stratification. Cautions The study was based on data collected during a randomized, controlled trial of antihypertensive therapy. Albuminuria was measured as the albumincreatinine ratio in a single spot urine collection. Other than for the study drug received, the authors did not adjust for treatments received during the trial. The Editors Microalbuminuria was first associated with essential hypertension in nondiabetic individuals by Parving and colleagues (1), and subsequent studies (2, 3) confirmed the association. Albuminuria is an independent risk factor for cardiovascular disease and increased all-cause mortality in relatively unselected (4, 5) or general (6-8) populations, postmenopausal women (9), older people (10, 11), diabetic patients (12, 13), hypertensive patients with or without concomitant diabetes (8, 14, 15), and people with known high risk for cardiovascular disease (16). Left ventricular hypertrophy is an independent predictor of adverse prognosis (17-19) and is related to albumin excretion independent of age, blood pressure, diabetes, race, serum creatinine level, or smoking; these associations suggest parallel cardiac damage and increased renal albumin excretion rate (20). Other studies suggest that albuminuria at levels well below traditional partition values is a risk factor for coronary vascular disease in patients with and without diabetes (16, 21), indicating that the relation between albuminuria and cardiovascular risk from other populations cannot be directly applied to nondiabetic hypertensive patients. More precise information about the relation between albuminuria and cardiovascular risk would not only help clinicians better estimate the patients absolute risk but also strengthen the decision to initiate antihypertensive treatment, since current guidelines consider not only blood pressure but also target organ damage (for example, albuminuria) (22). We conducted a prospective study to determine the albuminuria level at which cardiovascular morbidity and mortality are increased in a large group of hypertensive patients with left ventricular hypertrophy. In a predefined protocol, we hypothesized that no unique albuminuria threshold predicts increased cardiovascular risk but rather that increasing albuminuria is associated with a graded increase in risk. We anticipated that in hypertensive patients with left ventricular hypertrophy, any threshold identified would be much lower than the threshold traditionally defined in diabetic populations. Methods Patients Participants in our study were outpatients between 55 and 80 years of age. They were recruited from a mix of general and hospital practices and had previously untreated or treated stage II or III hypertension with electrocardiographically confirmed left ventricular hypertrophy (measured according to the product of QRS duration multiplied by Cornell voltage or according to SokolowLyon voltage). The patients were randomly assigned to receive double-blind therapy with losartan or atenolol in the Losartan Intervention For Endpoint reduction (LIFE) study (23, 24). Study Design The hypotheses of the current study were prespecified as part of the LIFE protocol. Inclusion criteria were a mean trough sitting systolic blood pressure of 160 to 200 mm Hg or a diastolic blood pressure of 95 to 115 mm Hg after 1 and 2 weeks of single-blind placebo treatment and no other antihypertensive medication at the time of randomization. Exclusion criteria were myocardial infarction or stroke within 6 months, current congestive heart failure or previously known left ventricular ejection fraction less than 0.40, and renal insufficiency (serum creatinine level >160 mmol/L [>1.8 mg/dL]). We excluded patients who had a condition that the treating physician believed required treatment with losartan or another angiotensin II-receptor blocker, atenolol or another -blocker, hydrochlorothiazide, or angiotensin-converting enzyme inhibitors. Patients gave informed consent under protocols approved by the ethics committees of the participating institutions. End Points and Adjudication This study of the 8206 LIFE participants who had baseline albuminuria determinations (>90% of the entire sample) is based on analysis of a primary composite end point (n = 971): the first occurrence of cardiovascular death, fatal or nonfatal stroke, and fatal or nonfatal myocardial infarction. Additional end points were all-cause mortality (n = 703) and the first occurrence of each component of the composite end point, regardless of whether it was preceded by another component of the primary end point: 383 cardiovascular deaths, 479 strokes, and 344 myocardial infarctions. In the nondiabetic subgroup there were 755 composite end points, including 292 cardiovascular deaths, 379 fatal and nonfatal strokes, 261 fatal and nonfatal myocardial infarctions, and 554 all-cause deaths. Investigators reported all end points; source data were verified by independent monitors and were adjudicated by an independent committee on the basis of definitions provided in a predefined end point manual (24). Patients and the investigators reported the prevalences of coronary, cerebral, or peripheral vascular disease and smoking habits. Diabetes was defined according to investigator report and plasma glucose level. The Framingham risk score (25) was estimated from baseline blood pressure, total cholesterol level, high-density lipoprotein cholesterol level, smoking status, glucose level, and level of left ventricular hypertrophy on electrocardiography (ECG). Renal Evaluation On the same day, a spot urine sample was collected as the first morning voiding and the serum creatinine level was measured. Urine albumin concentration was determined by standard methods (26) using a turbidometric method (Hitachi 717 analyzer, Hoffmann-La Roche Ltd., Basel, Switzerland) (27) on a single urine specimen. Both serum and urine levels of creatinine were analyzed by using the Jaff reaction without deproteinizing and then quantified by a photometric method using the same analyzer. The ratio of urine albumin (in mg/L) to creatinine concentration (UACR) (in mmol/L) provided a composite measure (in mg/mmol) of renal glomerular capillary permeability that adjusted for urine dilution (28). To derive U.S. measures of UACR (mg/g), UACR in mg/mmoL is multiplied by 8.84. Statistical Analysis We used SPSS software, version 11.0.1 (SPSS, Inc., Chicago, Illinois), for statistical analyses. The study sample as a whole and the nondiabetic patients were divided into UACR deciles; diabetic patients were divided into UACR quintiles. We used Cox proportional-hazards models to compare hazard ratios among groups and to evaluate the contributions of differences in the degree of left ventricular hypertrophy (both Cornell voltage duration product and SokolowLyon voltage as continuous variables), the Framingham risk score (25), and treatment allocation (losartan or atenolol) as covariates. To express the increase in risk per increase in UACR as a continuous variable, we log-transformed UACR. We used a Cox model in the test for trend and used the decile group as a continuous variable. Hazard ratios from the decile groups were then used to estimate the best-fitting curve (SPSS curve estimation function). Two-tailed P values less than 0.05 were considered statistically significant. Role of the Funding Source The funding source had no role in the design, analysis, and reporting of the study or in the decision to submit the manuscript for publication. Results Patient Characteristics Descriptive data for the LIFE study sample (23) and relations of microalbuminuria and macroalbuminuria to cardiovascular risk factors have been reported elsewhere (20). Of the 9193 patients participating in the LIFE study, 8206 had the baseline UACR measurements necessary for inclusion in the present study. The mean age (SD) was 66 7 years; 54% of patients were women, and 92% were white. Thirteen percent had diabetes, 13.5% had coronary heart disease, and 7.7% had had a stroke. The mean arterial blood pressure (SD) was 174 14/98 9 mm Hg, the mean serum creatinine level (SD) was 87 20 mmol/L, and the median UACR was 1.28 mg/mmol. Additional baseline characteristics of patients with albuminuria are described elsewhere (20). To stratify risk in hypertensive patients with albuminuria and left ventricular hypertrophy, patients were divided into UACR deciles, with 814 to 821 patients in each group. Patients were followed for a median of 4.8 years and a total of 39 122 patient-years. End point rates were 24.8 per 1000 patient-years of follow-up for the composite endpoint, 9.4 for cardiovascular mortality, 17.6 for all-cause mortality, 11.9 for stroke, and 8.5 for myocardial infarction. Age; sex; race; body mass index; blood pressure; level of left ventricular hypertrophy on ECG; Framingham risk score; prevalence of known diabetes, coronary heart disease, or peripheral vascular disease; and smoking habits did not differ between the patients who provided a urine sample and the 987 patients who did not. The prevalence of history of cerebral vascular disease (13.2% vs. 10.5%; P = 0.029) and mean serum creatinine level (90.0 vs. 86.7 mmol/L; P = 0.001) were higher in patients who did not provide a urine sample than in those who did. When we considered differences in left ventricular mass on ECG, Framingham risk score, and study treatment, patients without a urine sample had a 52% higher all-cause mortality rate (95% CI, 23% to 87%); the rates of t