Michael A. Weber

ACCF/AHA 2011 Expert Consensus Document on Hypertension in the Elderly A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents

This document has been developed as an expert consensus document by the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA), in collaboration with the American Academy of Neurology (AAN), the American College of Physicians (ACP), the American Geriatrics Society (AGS), the American Society of Hypertension (ASH), the American Society of Nephrology (ASN), the American Society for Preventive Cardiology (ASPC), the Association of Black Cardiologists (ABC), and the European Society of Hypertension (ESH). Expert consensus documents are intended to inform practitioners, payers, and other interested parties of the opinion of ACCF and document cosponsors concerning evolving areas of clinical practice and/or technologies that are widely available or new to the practice community. Topics chosen for coverage by expert consensus documents are so designed because the evidence base, the experience with technology, and/or clinical practice are not considered sufficiently well developed to be evaluated by the formal ACCF/AHA practice guidelines process. Often the topic is the subject of considerable ongoing investigation. Thus, the reader should view the expert consensus document as the best attempt of the ACCF and document cosponsors to inform and guide clinical practice in areas where rigorous evidence may not yet be available or evidence to date is not widely applied to clinical practice. When feasible, expert consensus documents include indications or contraindications. Typically, formal recommendations are not provided in expert consensus documents as these documents do not formally grade the quality of evidence, and the provision of “Recommendations” is felt to be more appropriately within the purview of the ACCF/AHA practice guidelines. However, recommendations from ACCF/AHA practice guidelines and ACCF appropriate use criteria are presented where pertinent to the discussion. The writing committee is in agreement with these recommendations. Finally, some topics covered by expert consensus documents will be addressed subsequently by the ACCF/AHA …

Comparison of effects of controlled onset extended release verapamil at bedtime and nifedipine gastrointestinal therapeutic system on arising on early morning blood pressure, heart rate, and the heart rate-blood pressure product.

We assessed the differential effects of a chronotherapeutic agent (controlled-onset extended release [COER] verapamil), administered at bedtime versus a conventional, homeostatic therapy (nifedipine gastrointestinal therapeutic system [GITS]) taken in the morning, on early morning and 24-hour blood pressure (BP), heart rate (HR), and the HR x systolic BP product. The study was a multicenter (n = 51), randomized, double-blind prospective clinical trial with a 10-week treatment period. Dose titration was performed by study investigators based on systolic and diastolic BP values at the doctors office. Ambulatory BP monitoring was performed at placebo baseline, after 4 weeks of stable double-blind therapy, and at end of the study. Twenty-four-hour BP profiles were studied in 557 hypertensive patients. Changes in BP, HR, slope of the rate of rise of BP and HR, and the HR-systolic BP product during the 4 hours from 1 hour before to 3 hours after awakening were evaluated. The study was powered to show equivalence between the 2 regimens, predefined as a difference between treatment groups in mean change from baseline in early morning BP of +/- 5 mm Hg systolic and +/- 3 mm Hg diastolic. Changes in the early morning BP fell within the definition of equivalence for the 2 treatment strategies (-12.0/-8.2 mm Hg for COER-verapamil and -13.9/-7.3 mm Hg for nifedipine GITS). Changes in both the early morning HR and rate-pressure product were significantly greater following COER-verapamil therapy versus nifedipine GITS (HR, -3.8 beats/minute vs +2.6 beats/minute, p < 0.001 and HR-systolic BP product, -1,437 beats/min x mm Hg vs -703 beats/min x mm Hg, respectively, p < 0.001). Changes in ambulatory BP demonstrated clinically similar reductions for the awake period, but nifedipine GITS lowered systolic BP to a greater extent than COER-verapamil during sleep (-11.0 vs -5.8 mm Hg, p < 0.001). COER-verapamil and nifedipine GITS had equivalent effects (+/- 5/3 mm Hg) on early morning BP. In addition, both extended-release calcium antagonists effectively lowered 24-hour BP. However, COER-verapamil had greater effects than nifedipine GITS on early morning hemodynamics (HR, HR-systolic BP product, rate of rise of BP and HR) and lesser effects during sleep due to its intrinsic pharmacologic properties and chronotherapeutic delivery system.

Interrupting the renin-angiotensin system: the role of angiotensin-converting enzyme inhibitors and angiotensin ii receptor antagonists in the treatment of hypertension

Abstract The renin-angiotensin system has two roles in clinical hypertension: its vasoconstrictor properties directly govern blood pressure, and its actions on arterial smooth muscle, connective tissue, and endothelial integrity affect cardiovascular prognosis. Additionally, the direct actions of angiotensin II on the function and structure of the heart and renal vasculature influence clinical events. Angiotensin-converting enzyme (ACE) inhibitors have produced functional and clinical outcome benefits in clinical trials of patients with congestive heart failure, systolic dysfunction after myocardial infarction, and diabetic nephropathy. Similar favorable trends have been noted in observational studies in hypertension. Because such enzymes as chymase can substitute for ACE, the ACE inhibitors may not completely block angiotensin II formation, although they enhance bradykinin accumulation and secondarily stimulate nitric oxide and vasodilatory prostaglandins. Angiotensin II receptor blockers (ARB) selectively block the angiotensin II type 1 (AT1) receptor that not only mediates the known effects of angiotensin II but, according to recent reports, might be responsible for sequestering angiotensin II molecules in renal and cardiac cells. Moreover, by increasing plasma concentrations of angiotensin II, the ARB stimulate the unblocked angiotensin II type 2 (AT2) receptors, which—if they exist in meaningful numbers in human hypertension—mediate additional vasodilatory and antiproliferative effects. The contrasting actions of these two classes of drugs might be clinically relevant. For example, they may have additive antihypertensive efficacy; they have differing effects on renal plasma flow; and in a small pilot study of patients with congestive heart failure, the ARB demonstrated an apparent advantage in survival. Ongoing clinical trials will try to determine whether the effects of ARB can equal or even exceed the beneficial effects of ACE inhibitors on cardiovascular prognosis.

A new chronotherapeutic oral drug absorption system for verapamil optimizes blood pressure control in the morning

A novel verapamil chronotherapeutic oral drug absorption system (CODAS-Verapamil) designed for bedtime dosing and with controlled onset and extended-release properties was evaluated in 257 patients with mild-to-moderate essential hypertension in an 8-week, double-blind, placebo-controlled trial. After bedtime dosing (9 PM to 11 PM, this delivery system delays drug release for 4 to 5 h, and provides the highest concentrations of verapamil between 6 AM and noon. The study results showed that CODAS-verapamil produced its greatest antihypertensive effect during this morning period (6 AM to 12 noon) and also provided effective trough diastolic blood pressure reductions at 200, 300, and 400 mg. Significant trough systolic blood pressure reductions were achieved only with the 300- and 400-mg doses. The nighttime dosing regimen was not associated with excessive blood pressure (BP) reductions during the sleeping hours, when the antihypertensive effect was generally slightly less than that of the 24-h mean reduction. The CODAS-verapamil provides enhanced BP reduction during the morning period when compared with other time intervals of the 24-h dosing period.

Is high blood pressure a late manifestation of the hypertension syndrome

Because hypertension has generally been defined as a disease of elevated systolic and diastolic blood pressure, the goals of treating hypertension have been simply to normalize the blood pressure. It was believed that if normal blood pressure were achieved, patients with hypertension would experience significant reductions in the incidence of associated cardiovascular events. However, studies to assess cardiovascular events in patients with hypertension have repeatedly demonstrated that reducing blood pressure results in very impressive reductions in cerebrovascular disease but in reductions of only about 16% in coronary artery disease, which is far lower than what was statistically predicted from the reductions in blood pressure. Although there are probably several reasons for the poor rate of reductions in the incidence of coronary artery disease, one of the most compelling appears to be the realization that hypertension is not simply a disease of numbers but rather a complex inherited syndrome of cardiovascular risk factors, all of which contribute to the development of heart disease in these patients. Included in the hypertension syndrome are abnormalities of lipid profile and insulin resistance, changes in renal function, endocrine changes, obesity, abnormalities of coagulation factors, and changes in the structure and function of the left ventricle and of vascular smooth muscle in the vasculature. In many patients, high blood pressure is a late manifestation of this disease process and is preceded by some or all of the associated cardiovascular risk factors. This paradigm suggests that therapeutic strategies for hypertension should be interventions that target both the hemodynamic and nonhemodynamic mechanisms of this syndrome to more completely reduce cardiovascular morbidity and mortality in patients with hypertension.

Comparisons of the effects of different long-acting delivery systems on the pharmacokinetics and pharmacodynamics of diltiazem

The benzothiazepine calcium channel antagonist diltiazem is a short-acting drug. To achieve effective 24-h blood pressure control with once-daily dosing, it relies on various extended drug-delivery systems that have grown in importance as a result of the recent reports relating the use of short-acting calcium channel antagonists to increased cardiovascular morbidity. This study examines the pharmacokinetics and resulting pharmacodynamics of two different delivery systems, each loaded with 240 mg of diltiazem and administered to 40 moderately hypertensive patients in a randomized, double-blind crossover trial. After a 4-week, single-blind placebo lead-in, patients with a clinical diastolic blood pressure of > or =100 mm Hg were randomized to either the single or dual microbead diltiazem delivery system for a 4-week period. At the end of this period, each subject was evaluated with 24-h ambulatory blood pressure monitoring and subjected to 24-h inpatient pharmacokinetic analysis on separate days. This was followed by a similar 4-week period in which each subject was treated with the alternative delivery system. For diltiazem, the area under the curve for plasma concentration versus time and the maximum plasma concentration attained by the single microbead system exceeded the values achieved by the dual bead system by 15% and 25%, respectively. These differences were greatest from the 3rd through the 13th h after dosing. During this period, both systolic and diastolic ambulatory blood pressure was significantly lower when the single microbead system was used. When compared with baseline blood pressure, blood pressure reductions achieved with the single microbead system exceeded reductions achieved with the dual microbead system by at least 2 mm Hg for 10 of the 24 postdose hours. Heart rates were slightly reduced but not significantly different. This improved blood pressure control at higher plasma levels of diltiazem suggests that a more efficient delivery system could provide better blood pressure control for identical doses of diltiazem.

Guidelines for assessing outcomes of antihypertensive treatment

Because of the changing nature of medical practice and the need to more accurately monitor and quantify the clinical benefits and cost-effectiveness of treatment, the Sixth Report of the Joint National Committee (JNC VI) recommends that the outcomes of antihypertensive therapy be classified as short, intermediate, and long term. Short-term outcomes are most relevant to the practitioner and include such measures as blood pressure control, laboratory changes, and quality of life. In contrast, long-term outcomes, typically measured in randomized clinical trials, are of particular interest to policy makers and guidelines writers, and focus on whether treatments affect survival and the incidence of major cardiovascular events. Intermediate-term outcomes, usually measurable within months of starting treatment, deal with such clinical surrogates as treatment-induced changes in left ventricular structure, arterial compliance, and renal function. No longer are the traditional short-term outcomes adequate to describe a new drug; hypertension specialists, formulary committees, healthcare economists, and even regulatory agencies now expect sponsors to plan studies that define a drugs full range of outcomes. This article briefly discusses some of the criteria for these outcome measures.

Unsolved problems in treating hypertension: rationale for new approaches.

Two major problems continue to challenge hypertension experts and clinical practitioners. The first is the apparently simple issue of controlling blood pressure; only one-quarter of hypertensive patients in the United States have blood pressures reduced to less than 140/90 mm Hg. Even those known to be receiving treatment have barely a 50% success rate. Explanations include inadequate commitments by physicians to achieve target blood pressures, but it is also likely that effectively decreasing blood pressure--despite the currently available panoply of antihypertensive agents--is a truly difficult task. The second problem is that despite our success in decreasing stroke incidence, hypertension treatment with traditional agents, largely diuretic-based, has not adequately protected patients against coronary events and renal insufficiency. Such new drug classes as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and calcium channel blockers exhibit vascular effects that might inhibit atherosclerotic changes and reduce clinical events, but we are still awaiting definitive confirmation of these properties from ongoing clinical outcomes studies in hypertension. Therapy with fixed combinations of antihypertensive drugs is now recognized as a potentially useful approach. Innovative combinations, including ACE inhibitors and calcium channel blockers, can provide enhanced antihypertensive efficacy while avoiding or minimizing adverse metabolic and clinical side effects. These approaches are also convenient and cost-effective. It remains to be learned whether newer drug combinations might exhibit additive cardiovascular protective actions.

MEASUREMENT OF SHORT-TERM, INTERMEDIATE, AND LONG-TERM OUTCOMES OF TREATING HYPERTENSION

Hypertension is widely treated by primary care physicians as well as by cardiologists and other specialists. Clinical progress is often monitored by blood pressure measurements and other routine evaluations, but more sophisticated approaches may be required to learn whether treatment is effectively protecting the heart, kidneys, and other susceptible areas. Outcome measures therefore involve quantification of short-term, intermediate and long-term clinical observations; and, in addition, assessment of overall effectiveness must take into account economic factors and the levels of satisfaction perceived by patients, physicians, and health plans.

Tolerability profile of tasosartan, a long-acting angiotensin II AT1 receptor blocker, in the treatment of patients with essential hypertension

Abstract This paper summarizes tolerability data for 1420 patients with essential hypertension who were enrolled in eight double-masked, controlled clinical trials and who received tasosartan, a long-acting, nonpeptidic angiotensin II AT 1 receptor blocker. A total of 2084 patients were included in all treatment groups in these studies. Patients were treated with tasosartan at doses ranging from 10 to 600 mg, over periods of 3 to 16 weeks, except for one study with a 6-day treatment period. Tasosartan was administered once daily (seven studies) or twice daily (one study). No adverse events occurred at a significantly greater frequency in tasosartan-treated patients than in patients who received placebo. Headache, the most frequently reported adverse event, occurred significantly less frequently among tasosartan-treated patients than among those taking placebo (19% and 28%, respectively). The following adverse events (tasosartan and placebo groups) were reported by at least 3% of tasosartan-treated patients: asthenia (7% in each group), pharyngitis (7% in each group), dizziness (7% and 5%, respectively), infection (6% and 7%, respectively), rhinitis (4% and 6%, respectively), pain (4% in each group), diarrhea (4% in each group), nausea (3% in each group), and dyspepsia (3% and 2%, respectively). Cough occurred with a similar frequency in the tasosartan group and in the placebo group (2% and 3%, respectively). Peripheral edema occurred in 2.7% of tasosartan-treated patients and 3.4% of the patients who received placebo. Hyperglycemia occurred in