Overview of the Evolution of Hypertension: From Ancient Chinese Emperors to Today.

Hypertension is one of the most commonly treated conditions in modern medical practice, but despite its long history, it was largely ignored until the midpoint of the 20th century. This article will review the origins of elevated blood pressure from when it was first appreciated in 2600 BC to its most recent emerging treatments. Awareness of sustained elevations in blood pressure goes back to the Chinese Yellow Emperor's Classic of Internal Medicine (2600 BC); even then, salt was appreciated as a contributor to elevated pressure. Early treatments included acupuncture, venesection, and bleeding by leeches. About 1000 years later, the association between the palpated pulse and the development of heart and brain diseases was described by Ebers Papyrus (1550 BC). But really, it has only been since well after World War II that hypertension has finally been appreciated as the cause of so much heart, stroke, and kidney disease. We review the development of effective treatments for hypertension while acknowledging that so many people with hypertension in need of treatment have unacceptably poor blood pressure control. We explore why, despite our considerable and growing knowledge of hypertension, it remains a significant public health problem globally.

Peripheral edema and headache associated with amlodipine treatment: a meta-analysis of randomized, placebo-controlled trials.

OBJECTIVE: Use of amlodipine for treatment of arterial hypertension and stable coronary artery disease (CAD) is sometimes limited by occurrence of peripheral edema and headache. We aimed to explore the true magnitude of this phenomenon by determining the rate and placebo-adjusted rate of these side effects. METHODS: We performed a meta-analysis by including all randomized, placebo-controlled trials reporting edema and headache with amlodipine in patients with arterial hypertension and CAD. Placebo-adjusted rate (%) was determined as follows: (SE amlodipine % - SE placebo %)/SE amlodipine %. RESULTS: Data from 7226 patients of 22 trials were analyzed. Rate of edema was higher on amlodipine vs. placebo (16.6 vs. 6.2%, risk ratio: 2.9, 95% CI: 2.50-3.36, P < 0.0001). The placebo-adjusted rate was 63%, indicating that 37% of edema cases were unrelated to amlodipine. Treatment with low/medium doses (2.5-5 mg) resulted in lower rates of edema (risk ratio: 2.01, 95% CI: 1.41-2.88, P = 0.0001) vs. high dose (10 mg) (risk ratio: 3.08, 95% CI 2.62-3.60, P < 0.0001, Pforinteraction = 0.03). Incidence of headache was reduced using amlodipine vs. placebo (7.9 vs. 10.9%, risk ratio: 0.77, 95% CI: 0.65-0.90, P = 0.002) and was driven by use of low/medium doses (risk ratio: 0.52, 95% CI: 0.40-0.69, P < 0.00001 vs. risk ratio: 0.92, 95%-CI: 0.74-1.15, P = 0.45, for high doses, Pforinteraction = 0.002). CONCLUSION: Although risks of peripheral edema are three-fold higher on amlodipine, up to one-third of edema cases on amlodipine might not be induced by amlodipine. Headache is reduced on amlodipine treatment, mainly driven by use of this drug at low/medium doses.

Perspectiva clínica sobre el tratamiento antihipertensivo en adultos con hipertensión grado 1 y riesgo cardiovascular bajo a moderado: consulta internacional de expertos

[RESUMEN]. La hipertensión arterial es el principal factor de riesgo de la carga global de las enfermedades. Una pregunta en debate es si la hipertensión arterial grado 1 (140–159/90–99 mm Hg) con riesgo cardiovascular (RCV) total bajo (mortalidad cardiovascular < 1% a los 10 años) a moderado (mortalidad cardiovascular > 1% y < 5% a los 10 años) debe ser tratada con agentes antihipertensivos. Un proceso de consulta virtual internacional fue realizado para resumir las opiniones de los expertos seleccionados. Después del análisis holístico de todos los elementos epidemiológicos, clínicos, psicosociales y de salud pública, este proceso de consulta llegó al siguiente consenso para adultos hipertensos < 80 años de edad: 1) La interrogante, de si el tratamiento medicamentoso en la hipertensión grado 1 debe ser precedido por un periodo de algunas semanas o meses, durante el cual solo se recomienden medidas sobre el estilo de vida no está basada en evidencia, pero el consenso de opinión es reservar un periodo para solo cambios en el estilo de vida únicamente en los pacientes con hipertensión grado 1 “aislada” (hipertensión grado 1 no complicada con RCV total absoluto bajo, y sin otros factores de RCV mayores ni modificadores del riesgo). 2) El inicio del tratamiento antihipertensivo medicamentoso en pacientes con hipertensión grado 1 y RCV absoluto moderado no debe demorarse. 3) Los hombres ≥ 55 años y las mujeres ≥ 60 años con hipertensión grado 1 no complicada deben ser automáticamente clasificados dentro de la categoría de RCV total absoluto moderado, incluso en ausencia de otros factores de riesgo mayores y modificadores del riesgo. 4) Las estatinas deben tenerse en cuenta junto con la terapia antihipertensiva, independientemente de los valores de colesterol, en pacientes con hipertensión grado 1 y RCV moderado.

[ABSTRACT]. Hypertension is a leading risk factor for disease burden globally. An unresolved question is whether grade 1 hypertension (140-159/90-99 mmHg) with low (cardiovascular mortality < 1% at 10 years) to moderate (cardiovascular mortality > 1% and < 5% at 10 years) absolute total cardiovascular risk (CVR) should be treated with antihypertensive agents. A virtual international consultation process was undertaken to summarize the opinions of select experts. After holistic analysis of all epidemiological, clinical, psychosocial, and public health elements, this consultation process reached the following consensus in hypertensive adults aged < 80 years: (1) The question of whether drug treatment in grade 1 should be preceded by a period of some weeks or months during which only life style measures are recommended cannot be evidence based, but the consensus opinion is to have a period of lifestyle alone reserved only to patients with grade 1 “isolated” hypertension (grade 1 uncomplicated hypertension with low absolute total CVR, and without other major CVR factors and risk modifiers). (2)The initiation of antihypertensive drug therapy in grade 1 hypertension with moderate absolute total CVR should not be delayed. (3) Men ≥ 55 years and women ≥ 60 years with uncomplicated grade1 hypertension should automatically be classified within the moderate absolute total CVR category, even in the absence of other major CVR factors and risk modifiers. (4) Statins should be considered along with blood-pressure lowering therapy, irrespective of cholesterol levels, in patients with grade 1 hypertensive with moderate CVR.

Clinical Perspective on Antihypertensive Drug Treatment in Adults With Grade 1 Hypertension and Low-to-Moderate Cardiovascular Risk: An International Expert Consultation.

Hypertension is a leading risk factor for disease burden globally. An unresolved question is whether grade 1 hypertension (140-159/90-99mmHg) with low (cardiovascular mortality <1% at 10 years) to moderate (cardiovascular mortality ≥1% and <5% at 10 years) absolute total cardiovascular risk (CVR) should be treated with antihypertensive agents. A virtual international consultation process was undertaken to summarize the opinions of select experts. After holistic analysis of all epidemiological, clinical, psychosocial, and public health elements, this consultation process reached the following consensus in hypertensive adults aged <80 years: (1) The question of whether drug treatment in grade 1 should be preceded by a period of some weeks or months during which only lifestyle measures are recommended cannot be evidence based, but the consensus opinion is to have a period of lifestyle alone reserved only to patients with grade 1 "isolated" hypertension (grade 1 uncomplicated hypertension with low absolute total CVR, and without other major CVR factors and risk modifiers). (2) The initiation of antihypertensive drug therapy in grade 1 hypertension with moderate absolute total CVR should not be delayed. (3) Men ≥55 years and women ≥60 years with uncomplicated grade 1 hypertension should automatically be classified within the moderate absolute total CVR category, even in the absence of other major CVR factors and risk modifiers. (4) Statins should be considered along with blood-pressure lowering therapy, irrespective of cholesterol levels, in patients with grade 1 hypertensive with moderate CVR.

Assessment of drug-induced increases in blood pressure during drug development: report from the Cardiac Safety Research Consortium.

This White Paper, prepared by members of the Cardiac Safety Research Consortium, discusses several important issues regarding the evaluation of blood pressure (BP) responses to drugs being developed for indications not of a direct cardiovascular (CV) nature. A wide range of drugs are associated with off-target BP increases, and both scientific attention and regulatory attention to this topic are increasing. The article provides a detailed summary of scientific discussions at a Cardiac Safety Research Consortium-sponsored Think Tank held on July 18, 2012, with the intention of moving toward consensus on how to most informatively collect and analyze BP data throughout clinical drug development to prospectively identify unacceptable CV risk and evaluate the benefit-risk relationship. The overall focus in on non-CV drugs, although many of the points also pertain to CV drugs. Brief consideration of how clinical assessment can be informed by nonclinical investigation is also outlined. These discussions present current thinking and suggestions for furthering our knowledge and understanding of off-target drug-induced BP increases and do not represent regulatory guidance.

Treatment of patients with hypertension and arthritis pain: new concepts.

Arthritis pain often occurs concurrently with hypertension and other cardiovascular risk factors. Treating patients with hypertension who have arthritis and other painful conditions can be a challenge because of potential risks associated with the agents commonly used to treat pain and inflammation. Hypertension is associated with endothelial dysfunction and decreased bioavailability of nitric oxide (NO). Naproxcinod, an investigational drug, is the first in a new class of agents called cyclooxygenase-inhibiting NO donators. They differ from traditional nonsteroidal anti-inflammatory drugs in their ability to donate NO, a signaling molecule known to have potentially beneficial effects on the vasculature and the gastrointestinal tract. Naproxcinod, by donating NO, offers a therapeutic option that might mitigate the negative blood pressure effects and adverse gastrointestinal effects associated with traditional arthritis therapies. This article reviews some preliminary preclinical and clinical studies of key safety data of an investigational new NO-donating anti-inflammatory agent.

The role of the new beta-blockers in treating cardiovascular disease.

The beta-adrenergic receptor blockers play an important role in the management of cardiovascular disease, including hypertension and chronic heart failure. However, concerns regarding safety and tolerability with currently available agents can limit their use. The beta-blockers vary with regard to several pharmacologic properties, including beta1/beta2 selectivity, intrinsic sympathomimetic activity, and, with the newest beta-blockers, vasodilation. These pharmacologic differences may result in clinically important differences in tolerability and hemodynamic properties. Nebivolol is a novel beta-blocker with both a greater degree of selectivity for beta1-adrenergic receptors than other agents in this class and an ability to stimulate endothelial nitric oxide production, leading to vasodilation and other potential clinical effects. Published randomized, controlled, multicenter studies with nebivolol have shown that once-daily treatment significantly reduces systolic and diastolic blood pressure in patients with mild-to-moderate hypertension, compared with placebo, in a dose-dependent manner, and is well tolerated, with an adverse event profile similar to that of placebo. When compared with other beta-blockers as well as with other antihypertensive classes of agents in head-to-head trials, nebivolol demonstrated similar antihypertensive efficacy and a lower incidence of adverse events. Nebivolol has also been shown to significantly reduce morbidity and mortality in a large population of elderly patients with chronic heart failure, independent of left ventricular ejection fraction. Nebivolol is currently available in Europe for the management of hypertension and is expected to be available soon in the United States.

Circadian variations in cardiovascular disease: chronotherapeutic approaches to the management of hypertension.

Blood pressure (BP) exhibits strong circadian variation, and this variation may contribute to the increase of acute cardiovascular events that peak in the morning hours. Reducing morning BP may prevent these occurrences, so identifying data on the true duration of action of antihypertensive agents is essential. Ambulatory BP monitoring has uncovered important differences in commonly used once-daily therapies and has provided insights into the cardiovascular risks associated with BP variability. This article will explore chronotherapeutic antihypertensive agents that have been formulated to address the circadian challenges in controlling BP, and will consider the implications of chronotherapeutics in managing cardiovascular disease.

The antihypertensive efficacy and safety of a chronotherapeutic formulation of propranolol in patients with hypertension.

This study evaluated the antihypertensive efficacy and tolerability of a chronotherapeutic formulation of propranolol designed for nighttime dosing (propranolol controlled release [CR]). A total of 434 patients with mild-to-moderate hypertension were randomized to placebo or to one of four doses of propranolol CR (80, 120, 160, or 640 mg/d). At baseline, the mean morning blood pressures were similar in each treatment group and averaged 152/101 mm Hg. After 8 weeks of treatment, morning diastolic blood pressure, the primary efficacy measurement, was significantly reduced from baseline in placebo (-6.98 mm Hg) and all propranolol groups (p<0.001). The decreases ranged from 10.1 mm Hg in the 80-mg/d group to 11.0 mm Hg in the 120-mg/d group and were significantly larger than placebo in the 120-, 160-, and 640-mg/d groups (p<0.05). Blood pressure measured in the evening (trough) demonstrated similar antihypertensive efficacy. Heart rate and rate-pressure product were reduced in a dose-related manner by propranolol CR. The formulation was well tolerated with only fatigue and dizziness being reported more frequently than in the placebo group. Propranolol CR is an effective antihypertensive formulation that may reduce blood pressure during the morning period of maximum cardiovascular risk.

Treatment of elderly hypertensive patients with a delayed-release verapamil formulation in a community-based trial.

This report of a practice-based clinical trial describes an open-label, multicenter dose-titration study of an elderly (age >or=65 years) subset of patients (N=628) with systolic blood pressures between 140 and 179 mm Hg or diastolic blood pressures between 90 and 109 mm Hg, to assess the effects of the Chronotherapeutic Oral Drug Absorption System (CODAS) formulation of verapamil hydrochloride. After starting 200 mg/d at bedtime, dosing was titrated to a maximum of 400 mg/d at 4-week intervals to achieve a target blood pressure of <140/<90 mm Hg using morning blood pressure measurements. Target blood pressure was reached in 57.1% of the elderly patients with CODAS verapamil monotherapy. A diastolic response (<90 mm Hg or a 10 mm Hg reduction from baseline) was achieved in 89.5% of these subjects, and a systolic blood pressure response (<140 mm Hg or 10% reduction from baseline) was attained in 75.5%. The percentages of patients achieving target blood pressure or the diastolic and systolic blood pressure responses were comparable to those previously reported for younger patients. It is notable that although 359 of the 628 patients reached control on treatment, 182 of the remaining 269 noncontrolled patients were not titrated to higher doses, indicating that even with a well tolerated drug there may be reluctance among clinicians to increase doses. CODAS verapamil was found to be efficacious and well tolerated among elderly hypertensive patients in this community trial.

Creating a combination antihypertensive regimen: what does the research show?

Major randomized clinical trials have demonstrated unquestionable clinical benefits of lowering blood pressure without establishing superiority of any specific antihypertensive medication. Most notably, these trials have indicated that a majority of patients with hypertension will require more than one drug to control blood pressure. The recognition that many patients with hypertension should receive a combination of two agents as initial therapy is reflected in current hypertension guidelines, including the recently published consensus statement by the Hypertension in African Americans Working Group (HAAWG) and the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). In addition, there are some data that suggest that combination therapy may afford greater cardioprotection compared to monotherapy. For example, findings from A Lotrel Evaluation of Hypertensive Patients with Arterial Stiffness and Left Ventricular Hypertrophy (ALERT) indicated that low-dose combined angiotensin-converting enzyme inhibitor and calcium channel blocker antihypertensive treatment improved measures of cardiovascular structure and function compared with high-dose monotherapy with either component. Intuitive clinical wisdom suggests that some combinations of antihypertensive agents may provide enhanced clinical benefits; however, clinical trial data have not established optimal combination regimens. Thus, a challenging task for investigators is to determine which combination therapy regimens will provide the greatest cardiovascular benefits for patients with hypertension. A trial that is now in progress, Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH), directly compares cardiovascular mortality and morbidity rates for two preselected, fixed-dose combination therapies.

The 24-hour blood pressure pattern: does it have implications for morbidity and mortality?

The onset of adverse cardiovascular events demonstrates a circadian pattern that reaches a peak in the morning shortly after awakening and arising. A parallel, 24-hour cyclical pattern has also been observed in the activities of various physiologic measurements, including blood pressure, heart rate, sympathetic nervous system activity, and platelet adhesiveness. Although a direct link has not yet been established, it can be postulated that the early morning surge in blood pressure may be a factor in precipitating acute cardiovascular episodes. Similar to the early morning blood pressure surge, blood pressure variability throughout the day appears to be a further independent risk factor for hypertensive target organ damage. Thus, it is reasonable to select an antihypertensive agent that offers smooth and well-sustained blood pressure control for the full 24-hour dosing interval, including the vulnerable early morning period. The results of clinical trials using ambulatory blood pressure monitoring have shown that telmisartan, an angiotensin II receptor antagonist, possesses such properties. Whether or not these attributes of telmisartan might translate into improvements in cardiovascular morbidity and mortality will be explored in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). This study will compare the effects of telmisartan 80-mg monotherapy, ramipril 10-mg monotherapy, or a combination of telmisartan 80 mg plus ramipril 10 mg, on cardiovascular endpoints in patients at high risk of cardiovascular events, several of whom are likely to be hypertensive at baseline. Inclusion of the telmisartan plus ramipril treatment arm will allow investigation of the potential advantages presented by combining an angiotensin-converting enzyme inhibitor with an angiotensin II receptor antagonist.

Low Dose Combination Therapy vs. High Dose Monotherapy in the Management of Hypertension.

A common approach to the management of hypertension suggests the use of an initial drug and the addition of a second agent if goal blood pressures (BPs) are not achieved. The Sixth Report of the Joint National Committee (JNC VI) suggests that the use of low dose combination therapy may be an appropriate alternative to initial treatment. In this prospective, randomized, open label, blinded end point (PROBE) study, following a 2 week single blind placebo washout period, qualified patients were started on a calcium channel blocker, felodipine 5 mg for 2 weeks. Patients who were nonresponders (DBP equals 90 mm Hg) were randomized to either felodipine 10 mg (n equals 17, mean age 52.4, 12 males), an ACE inhibitor, enalapril 5 mg/felodipine 5 mg (n equals 20 mean, mean age 52.1, 13 males), or another ACE inhibitor, benazepril 10 mg/amlodipine 5 mg (n equals 18, mean age 53.9, 15 males) for an additional 6 weeks. Ambulatory BP monitoring was performed at the end of the single blind placebo washout period and again at the end of the study. All three treatment groups had significant reductions in mean 24 hour systolic and diastolic BP compared to baseline. The reduction in mean 24 hour systolic and diastolic BPs in the benazepril/amlodipine treated patients (-17.2/-9.7 mm Hg) was significantly greater (p equals 0.05) than in the felodipine 10 mg treated patients (-11.9/-6.4 mm Hg) and was also numerically but not statistically significantly greater than in the enalapril/felodipine treated patients (-14.2/-8.2 mm Hg). Similar differences were seen when assessing daytime BP (06:00-21:59) and nighttime BP (10:00-05:59). The reductions in morning systolic and diastolic BP (6 am-noon) in the benazepril/amlodipine treated patients (-18.6/-10.7 mm Hg) were numerically but not statistically significantly greater than the enalapril/felodipine treated patients (-13.6/-7.5 mm Hg) and the felodipine 10 mg treated patients (-14.9/-8.3 mm Hg). The data from this study suggests that using low dose combination therapy in patients who are nonresponders to first line monotherapy with a calcium channel blocker provides greater blood pressure control than up titration to higher dose monotherapy. Low dose combination therapy may therefore be an important early alternative to up titration of monotherapy in patients who are nonresponders. These data confirm other observations with combination therapy with à -blockers/ diuretics, ACE inhibitors/diuretics, and angiotensin II (AII) receptor blockers/diuretics. (c)1999 by Le Jacq Communications, Inc.

Uma análise do fosinopril: um novo inhibidor da ECA / Overview of fusinopril: a novel ACE inhibitor

O fosinopril - uma pró-droga do composto diácido ativo fosinoprilato é o precursor de uma nova classe química de inibidores da enzima conversora da angiotensina (ECA), os ácidos fosfínicos. É indicado, em administraçäo diária única, no tratamento da hipertensäo leve a moderada. Após a administraçäo oral, o fosinopril reduz eficazmente a pressäo arterial sistólica e diastólica durante 24 horas. Ensaios clínicos de curto prazo (oito a 12 semanas) constataram que a administraçäo diária de 10 a 40mg de fosinopril é significativamente mais eficaz que placebo e comparável a 40 a 80mg de propranolol duas vezes ao dia no tratamento de pacientes com hipertensäo essencial leve a moderada ou moderada severa que näo reagiam ao tratamento com diuréticos. Em um ensaio de 12 semanas, a administraçäo diária única de fosinopril ou de enalapril produziu efeitos anti-hipertensivo equivalentes em pacientes com hipertensäo essencial leve a moderada. Em pacientes idosos com hipertensäo leve a moderada, o fosinopril reduziu a pressäo arterial com eficácia equivalente à da nifedipina de liberaçäo prolongada (SR) e, aparentemente, com melhor tolerância. O fosinopril foi bem tolerado pelos pacientes estudados nos ensaios clínicos; a incidência de efeitos adversos foi semelhante à observada com placebo, propranolol ou enlapril. As ocorrências mais freqüentes foram cefaléia, tosse e tontura, mas estes sintomas säo