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Issues raised recently concerning the safety of calcium channel blockers (CCBs) prompted an analysis of the occurrence of cardiovascular events and death in the Pfizer Inc. hypertension clinical trial databases for amlodipine (Norvasc) and nifedipine in the gastrointestinal therapeutic system (GITS) formulation (Procardia XL). Prospectively defined analyses of data from comparative and noncomparative trials of amlodipine and nifedipine GITS were conducted. Outcome measures included cardiovascular and noncardiovascular deaths, and adverse cardiovascular events including new/worsened angina, myocardial infarction (MI), serious arrhythmia, stroke, congestive heart failure, and bleeding. Among all amlodipine-treated patients (n = 32,920), the incidence rates for all-cause death, MI, and new/worsened angina were 3.0, 3.3, and 1.6/1,000 patient-years of exposure, respectively. Among those in comparative trials alone (n = 4,126), the all-cause death rate was 4.1/1,000 patient-years, which was comparable to that of other non-CCB agents and significantly less than that of other CCBs (23.8/1,000 patient-years, p = 0.015), although the difference in rates represents only 2 deaths. Among all nifedipine-GITS-treated patients (n = 2,645), the rate of all-cause death was 4.1/1,000 patient-years, of MI 6.5/1,000 patient-years, and of new/ worsened angina 5.7/1,000 patient-years. The incidence rates for MI and other cardiac events were low in these hypertension trials, and did not differ among treatment groups in either the amlodipine or nifedipine GITS comparative analyses. In the clinical trial databases analyzed, there is no signal suggesting excessive risk of death or cardiovascular events for hypertensive patients treated with amlodipine or nifedipine GITS. [ABSTRACT FROM AUTHOR]

Background: Potassium-induced natriuresis may contribute to the beneficial effects of potassium on blood pressure but has not been well-characterized in human postmenopausal hypertension. We determined the time course and magnitude of potassium-induced natriuresis and kaliuresis compared with hydrochlorothiazide in 19 hypertensive Hispanic postmenopausal women. We also determined the modulating effects of sodium intake, sodium-sensitivity, and activity of the thiazide-sensitive NCC (sodium-chloride cotransporter)., Methods: Sixteen-day inpatient confinement: 8 days low sodium followed by 8 days high sodium intake. During both periods, we determined sodium and potassium excretion following 35 mmol oral KCl versus 50 mg hydrochlorothiazide. We determined sodium-sensitivity as change in 24-hour systolic pressure from low to high sodium. We determined NCC activity by standard thiazide-sensitivity test., Results: Steady-state sodium intake was the key determinant of potassium-induced natriuresis. During low sodium intake, sodium excretion was low and did not increase following 35 mmol KCl indicating continued sodium conservation. Conversely, during high sodium intake, sodium excretion increased sharply following 35 mmol KCl to ≈37% of that produced by hydrochlorothiazide. Under both low and high sodium intake, 35 mmol potassium was mostly excreted within 5 hours, accompanied by a sodium load reflecting the steady-state sodium intake, consistent with independent regulation of sodium/potassium excretion in the human distal nephron., Conclusions: Potassium-induced natriuresis was not greater in sodium-sensitive versus sodium-resistant hypertensives or hypertensives with higher versus lower basal NCC activity. We studied an acute KCl challenge. It remains to further characterize potassium-induced natriuresis during chronic potassium increase and when potassium is administered a complex potassium-containing meal.

The thiazide-sensitive sodium-chloride cotransporter (NCC;SLC12A3) is central to sodium and blood pressure regulation. Metabolic syndrome induces NCC upregulation generating sodium-sensitive hypertension in experimental animal models. We tested the role of NCC in sodium sensitivity in hypertensive humans with metabolic syndrome. Conversely, oral potassium induces NCC downregulation producing potassium-induced natriuresis. We determined the time course and magnitude of potassium-induced natriuresis compared with the natriuresis following hydrochlorothiazide (HCTZ) as a reference standard. We studied 19 obese hypertensive humans with metabolic syndrome during 13-day inpatient confinement. We determined sodium sensitivity by change in 24-hour mean systolic pressure by automated monitor from days 5 (low sodium) to 10 (high sodium). We determined NCC activity by standard 50 mg HCTZ sensitivity test (day 11). We determined potassium-induced natriuresis following 35 mmol KCl (day 13). We determined (1) whether NCC activity was greater in sodium-sensitive versus sodium-resistant participants and correlated with sodium sensitivity and (2) time course and magnitude of potassium-induced natriuresis following 35 mmol KCl directly compared with 50 mg HCTZ. NCC activity was not greater in sodium-sensitive versus sodium-resistant humans and did not correlate with sodium sensitivity. Thirty-five-millimoles KCl produced a rapid natriuresis approximately half that of 50 mg HCTZ with a greater kaliuresis. Our investigation tested a key hypothesis regarding NCC activity in human hypertension and characterized potassium-induced natriuresis following 35 mmol KCl compared with 50 mg HCTZ. In obese hypertensive adults with metabolic syndrome ingesting a high-sodium diet, 35 mmol KCl had a net natriuretic effect approximately half that of 50 mg HCTZ.

Objectives: Acute severe hypertension is a common problem among inner-city ethnic minority populations. Nevertheless, the effects of currently employed treatment regimens on blood pressure have not been determined in a clinical practice setting. We determined the SBP responses to acute antihypertensive drug protocols and the 2-year natural history of patients presenting with severe hypertension., Methods: Retrospective cohort investigation in consecutive patients with SBP at least 220 mmHg and/or DBP at least 120 mmHg during 3-month enrollment in 2014 with 2-year follow-up. Primary outcomes were SBP versus time for the first 5 h of emergency treatment and 2-year follow-up including repeat visits, target organ events, and hospitalizations., Results: One hundred and fifty-six unique patients met criteria with 69% Black; 34% Hispanic; 56% had previous visits for severe hypertension; 31% had preexisting target injury. Acute management: Acute antihypertensive regimens resulted in grossly unpredictable and often exaggerated effects on SBP. Treatment acutely reduced SBP to less than 140 mmHg in 30 of 159 patients. Clonidine reduced SBP to less than 140 mmHg in 19/61. Two-year follow-up: We observed 389 repeat visits for severe hypertension, 99 new target events, and 76 hospitalizations accounting for 620 hospital days., Conclusion: Acute treatment of severe hypertension produced unpredictable and potentially dangerous responses in SBP. Two-year follow-up demonstrated extraordinary rates of recurrent visits, target organ events, and hospitalizations. Our findings indicate a need to develop effective management strategies to lower blood pressure safely and to prevent long-term consequences. Our findings may apply to other hospitals caring for ethnic minority populations.

Prehypertension (systolic blood pressure 120-139 or diastolic blood pressure 80-89 mm Hg) confers a risk of progression to hypertension, impairment of cognitive function, increased left ventricular mass, risk of end-stage renal disease, and an association with arteriosclerosis. Recent studies provide data that could support the rationale for treating prehypertensives subjects with antihypertensive medications in addition to lifestyle modification, especially if they have concomitant cardiovascular risk factors., (Copyright © 2017 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Extant data indicate that treating to lower systolic pressure confers significant advantage to younger people in general good health and to relatively healthy octogenarians. Few data exist to guide practitioners on the treatment of frail elderly hypertensives. Chronological age alone does not suffice to make useful judgments regarding therapy. The definition of frailty remains controversial. One method, use of a simple questionnaire or a test of walking speed is practical but not universally accepted. Frail subjects, while at higher risk for cardiovascular complications, seem to benefit less or not at all from antihypertensive drug treatment. Clinicians should treat robust older patients as they would younger patients because the benefits far outweigh the low risk of adverse effects. Successful antihypertensive therapy in those younger than 80 years should not be discontinued simply because that age milestone has been crossed. Treatment of frail older patients must be individualized. Some frail survivors age 80 years or older may actually fare better with elevated systolic pressures. Pending the cognitive function substudy of Systolic Blood Pressure Intervention Trial, there is little evidence that antihypertensive treatment benefits established cognitive dysfunction. Because hypertension in middle age is a good predictor of later cognitive dysfunction, the clinical approach should be one of early prevention., (Copyright © 2016 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Elevated blood pressure (BP) is a common problem in patients hospitalized for reasons other than hypertension. Unexpected elevations commonly result in calls to physicians who too often prescribe medication to reduce the numbers without evaluating the patient or determining the cause of the elevation. This may result in unnecessary and sometimes harmful treatment. Such BP elevation has many potential causes. These include anxiety, post-operative salt and volume overload, failure to administer the patient's known antihypertensive medication, inability to give oral antihypertensive medication to patients who cannot take pills by mouth, incipient heart failure, previously unrecognized renal failure, obstructive uropathy and other causes. These must be identified and treated prior to addressing only the elevated BP numbers. We present an algorithm for evaluating hospitalized patients with elevated BP in order to assist physicians in identifying the true cause of the elevation, treating the identified cause, and giving appropriate drug treatment. We also note that this is a golden opportunity for communication with the outpatient providers who will follow the patient.

Several consistent lines of evidence indicate an association between sodium sensitivity and impaired nitric oxide bioactivity. Nevertheless, whether restoring nitric oxide in humans by pharmacological means can ameliorate sodium sensitivity has not been investigated. Because nebivolol has been demonstrated to increase nitric oxide bioactivity in both laboratory and clinical investigations, we hypothesized that nebivolol might ameliorate sodium sensitivity and improve renal sodium handling in comparison to metoprolol. We therefore conducted a randomized, 2-treatment-period crossover trial in 19 Hispanic postmenopausal women with hypertension to determine the comparative effects of nebivolol versus metoprolol on (1) 24-hour ambulatory blood pressure response to an increase in dietary sodium from 5 days of low sodium to 5 days of high sodium, (2) renal natriuretic response to a 1-L saline challenge, and (3) asymmetrical dimethylarginine. Clinic blood pressure and heart rate were significantly reduced after 4 weeks of treatment with both nebivolol and metoprolol. Twenty-four–hour mean systolic blood pressure increased sharply from low sodium to high sodium for both nebivolol and metoprolol. Nevertheless, the increases in blood pressure did not differ between the 2 drugs: 7.7 (3.1, 12.3) mm Hg with metoprolol and 9.3 (4.6, 13.9) mm Hg with nebivolol (P=0.63). Furthermore, we observed no differences between the drugs in natriuretic response to saline challenge or asymmetrical dimethylarginine. In a sodium-sensitive population, at doses sufficient to produce reductions in blood pressure and heart rate, nebivolol did not demonstrate a significant effect on sodium sensitivity or sodium handling compared with metoprolol.

We provide a review of recent additions to the antihypertensive armamentarium in the form of combination therapy. These include two-drug and three-drug combinations in a single pill. There is evidence that such combinations are more efficacious than the individual components and that patient adherence to therapy is improved., (Copyright © 2013 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Hypertension is prevalent in an estimated 29% to 80% of patients treated with peritoneal dialysis (PD). Cardiovascular disease represents the most common cause of mortality in this population, and hypertension (HTN) plays an important role. Volume overload is prevalent in PD patients because of liberal intake of fluids and loss of residual renal function (RRF). Noncompliance with salt restriction causes weight gain and makes HTN more difficult to manage. Physiology of the peritoneal membrane and its transport characteristics governs the ultrafiltration rate and consequently both volume and HTN. Therapeutic options for blood pressure control are ultrafiltration through the osmotic or colloid osmotic effects of dialysis solutions, salt restriction, and the use of antihypertensive medications such as diuretics, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Loop diuretics are used to maintain urine output in nonoliguric patients. Doses may exceed 250 mg of furosemide; ototoxicity is not problematic if blood levels are monitored carefully. Preservation of RRF is important for maintaining volume control and, thereby, control of HTN., (Copyright © 2011 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Nonadherence and poor or no persistence with taking antihypertensive medications results in uncontrolled high blood pressure, poor clinical outcomes and preventable health care costs. Factors associated with nonadherence are multilevel and relate not only to the patient, but also to the provider, health care system, health care organization, and community. National guideline committees have called for more aggressive approaches to implement strategies known to improve adherence and technologies known to enable changes at the systems level including improved communication among providers and patients. Improvements in adherence and persistence are likely to be achieved by supporting patient self-management, a team approach to patient care, technology-supported office practice systems, better methods to measure adherence, and less clinical inertia. Integrating high blood pressure control into health care policies that emphasize and improve prevention and management of chronic illness remains a challenge. Four strategies are proposed: focusing on clinical outcomes; empowering informed, activated patients; developing prepared proactive practice teams; and advocating for health care policy reform. With hypertension remaining the most common reason for office visits, the time is now., (Copyright © 2011 Wiley Periodicals, Inc. Published by Elsevier Inc. All rights reserved.)

A substantial body of evidence has implicated several aspects of diet in the pathogenesis of elevated blood pressure (BP). Well-established risk factors for elevated BP include excess salt intake, low potassium intake, excess weight, high alcohol consumption, and suboptimal dietary pattern. African Americans are especially sensitive to the BP-raising effects of excess salt intake, insufficient potassium intake, and suboptimal diet. In this setting, dietary changes have the potential to substantially reduce racial disparities in BP and its consequences. In view of the age-related rise in BP in both children and adults, the direct, progressive relationship of BP with cardiovascular-renal diseases throughout the usual range of BP, and the worldwide epidemic of BP-related disease, efforts to reduce BP in nonhypertensive as well as hypertensive individuals are warranted. In nonhypertensives, dietary changes can lower BP and delay, if not prevent, hypertension. In uncomplicated stage I hypertension, dietary changes serve as initial treatment before drug therapy. In hypertensive individuals already on drug therapy, lifestyle modifications can further lower BP. The current challenge is designing and implementing effective clinical and public health interventions that lead to sustained dietary changes among individuals and more broadly in the general population., (Copyright 2010 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

This American Society of Hypertension position paper focuses on the importance of out-of-office blood pressure (BP) measurement for the clinical management of patients with hypertension and its complications. Studies have supported direct and independent associations of cardiovascular risk with ambulatory BP and inverse associations with the degree of BP reduction from day to night. Self-monitoring of the BP (or home BP monitoring) also has advantages in evaluating patients with hypertension, especially those already on drug treatment, but less is known about its relation to future cardiovascular events. Data derived from ambulatory BP monitoring (ABPM) allow the identification of high-risk patients, independent from the BP obtained in the clinic or office setting. While neither ABPM nor self-BP monitoring are mandatory for the routine diagnosis of hypertension, these modalities can enhance the ability for identification of white-coat and masked hypertension and evaluate the extent of BP control in patients on drug therapy., (Copyright 2010 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

The goal of antihypertensive therapy is to abolish the risks associated with blood pressure (BP) elevation without adversely affecting quality of life. Drug selection is based on efficacy in lowering BP and in reducing cardiovascular (CV) end points including stroke, myocardial infarction, and heart failure. Although the choice of initial drug therapy exerts some effect on long-term outcomes, it is evident that BP reduction per se is the primary determinant of CV risk reduction. Available data suggest that at least 75% of patients will require combination therapy to achieve contemporary BP targets, and increasing emphasis is being placed on the practical tasks involved in consistently achieving and maintaining goal BP in clinical practice. It is within this context that the American Society of Hypertension presents this Position Paper on Combination Therapy for Hypertension. It will address the scientific basis of combination therapy, present the pharmacologic rationale for choosing specific drug combinations, and review patient selection criteria for initial and secondary use. The advantages and disadvantages of single pill (fixed) drug combinations, and the implications of recent clinical trials involving specific combination strategies will also be discussed., (Copyright 2010 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Since the publication of a paper by the American Society of Hypertension, Inc. Writing Group in 2003, some refinements have occurred in the definition of hypertension. Blood pressure is now recognized as a biomarker for hypertension, and a distinction is made between the various stages of hypertension and global cardiovascular risk. This paper discusses the logic underlying the refinements in the definition of hypertension., (2009 Wiley Periodical, Inc.)

A substantial body of evidence has implicated several aspects of diet in the pathogenesis of elevated blood pressure (BP). Well-established risk factors for elevated BP include excess salt intake, low potassium intake, excess weight, high alcohol consumption, and suboptimal dietary pattern. African Americans are especially sensitive to the BP-raising effects of excess salt intake, insufficient potassium intake, and suboptimal diet. In this setting, dietary changes have the potential to substantially reduce racial disparities in BP and its consequences. In view of the age-related rise in BP in both children and adults, the direct, progressive relationship of BP with cardiovascular-renal diseases throughout the usual range of BP, and the worldwide epidemic of BP-related disease, efforts to reduce BP in nonhypertensive as well as hypertensive individuals are warranted. In nonhypertensives, dietary changes can lower BP and delay, if not prevent, hypertension. In uncomplicated stage I hypertension, dietary changes serve as initial treatment before drug therapy. In hypertensive individuals already on drug therapy, lifestyle modifications can further lower BP. The current challenge is designing and implementing effective clinical and public health interventions that lead to sustained dietary changes among individuals and more broadly in the general population.

In the 50 years since the introduction of cholorothiazide by Fries and Wilson for the treatment of hypertension, numerous thiazide and thiazide-like diuretics have been marketed. Orally-administered diuretics enhanced the therapeutic efficacy of extant antihypertensive medications and reduced the doses required; adverse effects were thereby reduced as well. Initially, high doses of diuretics were employed at least in part because of the misconception that substantial natriuresis was required for their antihypertensive effect. As the long-term vasodilating effects of the thiazides became appreciated, it was possible to separate antihypertensive dose-response from natriuretic dose-response. As ever lower doses of thiazides were proven to be effective, most of their associated biochemical side and adverse effects were also reduced. Fifty years later, thiazide diuretics maintain a key role in the treatment of hypertension-especially in combination with one or more non-diuretic drugs.

Amlodipine is a highly effective and safe antihypertensive dihydropyridine calcium channel blocker. It is even more effective when used in combination with other antihypertensive medications, including hydrochlorothiazide. When antihypertensive calcium channel blockers were first introduced, evidence in the laboratory that they had some natriuretic properties was adduced to suggest that they would be "the diuretics of the 1990s." This turned out not to be the case. Because of its clinical efficacy, amlodipine is frequently used in fixed-dose combination products, but it is not likely to replace hydrochlorothiazide.