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The Department of Veterans Affairs (VA) assumed an early leadership role in focusing on care of elderly adults. In 1998, the Federal Advisory Committee on the Future of VA Long-Term Care, appointed by the VA Undersecretary for Health, recommended redirection of VA's extended care programs toward noninstitutional forms. A decade later, VA's Office of Geriatrics and Extended Care (GEC) initiated a strategic planning process by convening experts in geriatrics and health care, policy, and finance in Virginia on March 25 to 27, 2008, to present to VA clinicians and clinical managers the 'State of the Art' of VA GEC. Recurring clinical themes included rising numbers and complexity of aging veterans, recent addition of younger veterans to VA's extended care mix, challenges that dementia and mental illness exert throughout GEC, and need for seamlessness in delivery of care across multiple venues. Ongoing research efforts quantifying demand and resources and validating models of care will remain indispensible for meeting clinical challenges. Serious undersupply of clinicians of all disciplines with general or specialty geriatrics knowledge persists. Much of VA's healthcare workforce and leadership are approaching retirement age, driving the need for new educational approaches, recruitment and retention strategies, and innovative delivery systems. Growing dependence on informal caregivers highlights the need for supporting these partners. VA's healthcare budget allocation illustrates how national policy dictates systemic, regional, and local clinical decisions. Rehabilitation of the newest veterans is resulting in systemwide efficiencies. Educating and empowering patients and families results in optimized utilization of health resources. [ABSTRACT FROM AUTHOR]

Although the medical profession strives for safe prescribing, most medications are unique challenges even when prescribed by an experienced provider. In this article we discuss the pitfalls associated with drug interactions between commonly used antibiotics and anticoagulants, the complexities associated with the administration of novel reversible anticoagulants, the often-overlooked severe adverse drug reactions from commonly used classes of medications such as corticosteroids, the nuances of managing an acetaminophen overdose, and uncommon yet serious adverse events associated with the use of contraceptive hormone drugs., (© 2019, The American College of Clinical Pharmacology.)

The Federal Policy for the Protection of Human Subjects, generally referred to as the "Common Rule," is the basis for the human research protection policies of 16 signatory federal agencies and governs virtually all federally funded research involving humans. The Common Rule was originally published in 1991. It has been recognized that changes to the Common Rule are needed to accommodate changes in the research environment and advances in information technology. The Department of Health & Human Services (HHS) issued an Advance Notice of Proposed Rulemaking in the Federal Register in 2011 and a Notice of Proposed Rulemaking in 2015. The final rule was published on January 19, 2017, just prior to the change in presidential administrations. The long gestation of the new Common Rule reflects the difficulty of obtaining consensus on a number of controversial issues. HHS received more than 2100 public comments on the proposed rule. The revised rule introduces important changes that may be particularly relevant to clinical pharmacology research and drug development. These include: (1) revised informed consent requirements, (2) procedures for "broad consent" to facilitate secondary research use of identifiable private information and/or biological specimens, (3) a mandate to promote review by a single institutional review board (IRB) for oversight of federally funded domestic cooperative research involving multiple institutions, (4) expansion of the categories of exempt research, and (5) removal of the requirement for annual continuing IRB review of research in which the remaining activities are limited to data analysis or accessing clinical follow-up data. Also noteworthy are proposed revisions not included in the final rule, including one to extend the Common Rule to multicenter studies that are not federally funded and one to require informed consent for research use of de-identified biological specimens. Major changes could also be coming for approval of new drugs by the Food and Drug Administration (FDA), although it is not a signatory to the Common Rule. The 21st Century Cures Act, which became law in December 2016, enables faster drug approvals by expanding the kinds of evidence, beyond traditional clinical trials, that the FDA can consider when reviewing new drug applications. For example, the law allows greater use of surrogate markers and data from "real-world experience" to evaluate a drug's efficacy. The Cures Act requires HHS and the FDA to harmonize differences between the Common Rule and FDA regulations for protection of human subjects in research., (© 2017, The American College of Clinical Pharmacology.)

Differences in physiology related to young or old age and/or organ system impairment alter the absorption, distribution, metabolism, and excretion of many medications and consequently their effectiveness and toxicity. This module discusses common alterations in medication use and dosage that are required in the pediatric age group, in the elderly, and in patients with renal or hepatic disease., (© 2016, The American College of Clinical Pharmacology.)

The leaders of Geriatrics and Extended Care (GEC) in the Veterans Health Administration (VHA) undertook a strategic planning process that led to approval in 2009 of a multidisciplinary, evidence-guided strategic plan. This article reviews the four goals contained in that plan and describes VHA's progress in addressing them. The goals included transforming the healthcare system to a veteran-centric approach, achieving universal access to a panel of services, ensuring that the Veterans Affair's (VA) healthcare workforce was adequately prepared to manage the needs of the growing elderly veteran population, and integrating continuous improvement into all care enhancements. There has been substantial progress in addressing all four goals. All VHA health care has undergone an extensive transformation to patient-centered care, has enriched the services it can offer caregivers of dependent veterans, and has instituted models to better integrate VA and non-VA cares and services. A range of successful models of geriatric care described in the professional literature has been adapted to VA environments to gauge suitability for broader implementation. An executive-level task force developed a three-pronged approach for enhancing the VA's geriatric workforce. The VHA's performance measurement approaches increasingly include incentives to enhance the quality of management of vulnerable elderly adults in primary care. The GEC strategic plan was intended to serve as a road map for keeping VHA aligned with an ambitious but important long-term vision for GEC services. Although no discrete set of resources was appropriated for fulfillment of the plan's recommendations, this initial report reflects substantial progress in addressing most of its goals., (© 2013, Copyright the Authors Journal compilation © 2013, The American Geriatrics Society.)

The authors provide brief information about the Department of Veterans Affairs (VA) and the Veterans Health Administration, to establish an understanding of this large, multifaceted organization. They then offer an overview of the VA's Office of Research and Development, with particular emphasis on recent and ongoing efforts to enhance protection of the rights of human participants in clinical research. The authors discuss various policies and regulations intended to protect human participants in any type of VA research. The protection of human research participants must be a major concern for all researchers. Patients should be well informed about the scope of the research and what their participation entails, and there should be no question as to the voluntariness of their consent. Making sure that these standards are met for each and every veteran who participates in VA research is of the utmost importance.

The high incidence of hypertension among the elderly makes a once-daily multimechanism antihypertensive an advantageous agent for the control of hypertension. Because of its safety and efficacy in earlier studies, a low-dose multimechanism à -blocker/diuretic, bisoprolol fumarate 2.5, 5, or 10 mg combined with HCTZ 6.25 mg, was evaluated in multicenter studies, including a subgroup analysis of elderly patients at or above 60 years of age. Results indicate that all 3 dosage strengths of this once-daily agent are effective in reducing blood pressure in this population throughout a 24-hour period. Since low doses of both components are used to achieve efficacy, the incidence of side effects with all 3 dosage strengths is similar to that of placebo. In particular, this agent does not cause hypokalemia. Bisoprolol fumarate/HCTZ is an appropriate therapeutic option for elderly patients with hypertension because of its ability to effectively and safely control blood pressure in this difficult to treat population.

Adverse metabolic effects have been associated with drugs used in the therapy of hypertension, especially diuretics and beta-blockers. These effects include electrolyte, glucose/insulin, lipid and uric acid disturbances. This may explain, at least in part, why early trials examining the impact of antihypertensive pharmacotherapy with diuretics and beta-blockers showed beneficial effects on coronary artery disease that fell disappointingly short of the predicted effect. Among therapeutic drugs, diuretics cause disturbances in electrolyte homeostasis, e.g. hypokalaemia, hypomagnesaemia, and hyponatraemia. In contrast, ACE inhibitors cause hyperkalaemia under certain circumstances. Both diuretics and beta-blockers, especially nonselective beta-blockers that lack intrinsic sympathomimetic capabilities, have been associated with disturbances in glucose/insulin metabolism and can cause deleterious alterations in the profile of circulating plasma lipids. Hyperuricaemia, associated with diuretic use, appears to be a problem only in those patients who are predisposed to high circulating levels of uric acid.

Hypertension is highly prevalent among African Americans, who are also more likely than whites to develop end-organ complications of hypertension. Traditional diuretic-based stepcare therapy has successfully reduced such complications of hypertension as stroke, congestive heart failure, and premature death in all populations tested. Prevention of coronary deaths has been less successful. Potentially adverse metabolic effects of thiazide diuretics and some beta-blockers may partially explain the less successful cardiac outcomes. Use of antihypertensive agents lacking adverse metabolic effects but still achieving effective blood pressure control could improve cardiac outcomes while maintaining the benefits achieved with older forms of therapy. Achievement of improved cardiac outcomes is now one of the principal goals of hypertension research and treatment.

Angiotensin converting enzyme (ACE) inhibitors are increasingly important in antihypertensive therapy because of their efficacy, tolerability, and specific benefits in subsets of patients. They are pharmacologically diverse. Whereas most benefits have been proven with older agents (captopril, enalopril), newer agents, such as benazepril, quinapril, and ramipril, offer potential advantages that remain to be proven.

This 30-center, randomized, double-blind, placebo-controlled, parallel-group study was designed to (1) establish that 6.25 mg of hydrochlorothiazide (HCTZ) given once daily with 5 mg of bisoprolol fumarate can contribute to antihypertensive effectiveness in patients with stage I and stage II (mild to moderate) systemic hypertension; and (2) assess whether this formulation was more effective or possessed a safety advantage over standard monotherapy with bisoprolol or 25 mg of HCTZ. Results showed that HCTZ 6.25 mg contributed significantly to the antihypertensive effectiveness of bisoprolol 5 mg. Bisoprolol 5 mg/HCTZ 6.25 mg (B5/H6.25) produced significantly greater mean reductions from baseline in sitting systolic and diastolic blood pressure (-15.8 mm Hg/-12.6 mm Hg) than bisoprolol 5 mg alone (-10.0 mm Hg/-10.5 mm Hg) and HCTZ 25 mg alone (-10.2 mm Hg/-8.5 mm Hg). A 73% response rate was achieved with the low-dose formulation compared with 61% for the bisoprolol 5 mg (B5) group and 47% for the HCTZ 25 mg (H25) group. B5/H6.25 was found to be significantly more effective than B5 or H25 in all subgroups of patients, regardless of gender, race, age, or smoking history. Antihypertensive effects were maintained during the 24-hour dosing interval. The incremental effectiveness of B5/H6.25 was not accompanied by an increase in the frequency or severity of adverse experiences; the incidence of adverse experiences in the B5/H6.25 group was comparable to that in the placebo group. B5/H6.25 was shown to provide safety advantages over H25, as shown by less hypokalemia (< 1% with B5/H6.25 versus 6.5% with H25).(ABSTRACT TRUNCATED AT 250 WORDS)

In the final analysis of this study at Week 26, 26% of the patients randomized to receive amlodipine attained blood pressure control with amlodipine alone compared with 33% of the patients allocated to hydrochlorothiazide (HCTZ). Neither amlodipine nor HCTZ produced clinically significant changes in pulse rate or in the electrocardiogram. Amlodipine treatment did not appear to produce clinically significant changes in blood lipids; HCTZ, however, produced an increase in total plasma cholesterol (delta 22.9 +/- 8.6 mg/dl). The incidence of side effects and the rate of patient withdrawal in the amlodipine and HCTZ groups were comparable. As expected, HCTZ therapy caused well-recognized biochemical alterations in cholesterol and potassium levels, whereas amlodipine was metabolically neutral.

Certain high-risk populations, such as diabetics and blacks, have sustained elevation in blood pressure and heart rate throughout the day and night, with blunting of the usual diurnal variability pattern. This may contribute to their higher incidence of left ventricular hypertrophy (blacks) and cardiovascular complications (diabetics). Hypertensives who maintain a diurnal pattern of blood pressure variation still exhibit higher daytime and nocturnal blood pressure levels than normotensives. Thus, to achieve maximum effectiveness in treating hypertension, 24-hour control of blood pressure is necessary. Antihypertensive agents should effectively reduce blood pressure consistently throughout a 24-hour period. The objective of this study was to assess the effects of amlodipine, 5 mg once daily, on blood pressure measured by 24-hour ambulatory monitoring in a randomized, double-blind, placebo-controlled single-site study. Patients with mild-to-moderate essential hypertension were randomized to receive amlodipine (n = 11) or placebo (n = 5) in a 2:1 ratio. A 4-week single-blind placebo run-in period was followed by a 4-week double-blind phase. Ambulatory monitoring of blood pressure was carried out for 24 hours at the end of each 4-week phase. Patients receiving amlodipine had significantly lower blood pressure compared with placebo 24 hours after the last dose (supine blood pressure -25.1/-10.1 mm Hg; standing blood pressure -21.2/-9.7 mm Hg) after 4 weeks of treatment. This effect was clearly demonstrated by the 24-hour postdose measurement and the mean blood pressure over the 24-hour interval as measured by ambulatory recordings.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular diseases are the leading causes of death in the United States, with hypertension being amongst the most prevalent of the cardiovascular risk factors. Improvement of hypertension management has, in consequence, received much attention. Extensive pre- and post-marketing experience with the transdermal formulation of clonidine marketed in the USA in the mid-1980s has now been accumulated. Transdermal clonidine is effective as monotherapy in mild-moderate hypertension, and in combination with diuretics, calcium antagonists and ACE inhibitors in more resistant cases. It controls blood pressure throughout the 24-h circadian cycle. It is effective and generally well-tolerated in adolescents, the elderly, blacks, diabetics, and subjects with chronic renal insufficiency. It has been used perioperatively and for suppression of adrenergic symptoms in subjects withdrawing from addicting substances. In comparison with oral clonidine, transdermal clonidine reduces the incidence and severity of such symptomatic side-effects as dry mouth, drowsiness, and sexual dysfunction. Minor skin reactions occur at the site of application of the transdermal patch with moderate frequency. Adherence to transdermal clonidine therapy is high, and patients commonly prefer it to oral therapy. Transdermal administration of clonidine is a useful therapeutic advance in the long-term management of hypertension.

Despite the strong association between hypertension and accelerated atherosclerosis, and the known beneficial clinical effects of beta-blockers in patients with coronary artery disease, antihypertensive trials of beta-blockers have shown only modest protection against fatal and nonfatal myocardial infarction. This review explores the explanations put forth for this apparent failure of beta-blockers. It also examines the clinical relevance of the metabolic effects of beta-blockers within the framework of the heterogeneity of this class of drugs. Recent evidence indicates that long-term treatment of hypertension with beta-blockers that do not possess intrinsic sympathomimetic activity reduces the occurrence of cardiac complications of hypertension. There are no data to show a quantified effect on clinical outcome of the lipid and glucose changes associated with beta-blocker therapy. The metabolic influence of these drugs varies considerably within the class and may be of little clinical relevance. Unless it is contraindicated, an appropriate beta-blocker should be considered for the treatment of hypertension in patients who have coronary artery disease or who are at high risk for coronary artery disease.

Hypertension, more prevalent with aging, is a major risk factor for cardiovascular disorders. Accordingly, it is important to decrease blood pressure and maintain it in an acceptable range to lessen morbidity and mortality. When nonpharmacological therapy fails, drug therapy should be instituted. The ideal drugs lower blood pressure, have few adverse side effects, and may have additional benefits on coexisting maladies. ACE (angiotensin-converting enzyme) inhibitors are excellent first-line drugs because they have few adverse effects and may have additional benefits on cardiac and renal status. This overview discusses many aspects of hypertension and its therapy, but emphasizes use of ACE inhibitors in the elderly.

Ambulatory blood pressure monitoring (ABPM) has been available since the mid-1970s. Widespread use of ABPM in research settings has led to an appreciation of its advantages and disadvantages. ABPM is a valuable research tool because of its ability to evaluate the duration and consistency of action with new antihypertensive agents. It has also been used to exclude patients who have white-coat hypertension from pharmacotherapy. Past and current clinical studies are reviewed to illustrate the role of this technique in the development of a new angiotensin converting enzyme inhibitor, ramipril. The studies involve administering a single daily dose of ramipril to lower blood pressure and ABPM. Three double-blinded, randomized studies and one placebo-controlled, crossover study are reviewed. In these studies of patients with essential hypertension, once-daily ramipril controlled blood pressure, reduced systolic/diastolic blood pressure throughout a 24-hour period, and did not interfere with normal circadian blood pressure patterns. Lessons learned from research suggest that ABPM will find a niche in clinical practice.

This double-blind, double-dummy, randomized clinical trial, conducted in elderly patients with mild hypertension, compared adherence to treatment, efficacy, side effects, and quality of life during treatment with transdermal clonidine versus oral sustained-release verapamil (verapamil-SR). Blood pressure declined significantly--from 148/95 mm Hg at baseline to 139/84 after titration and 135/86 after maintenance--with transdermal clonidine (n = 29), and from 156/96 to 144/85 and 148/88, respectively, with verapamil-SR (n = 29). Adverse event rates and quality-of-life questionnaire responses were similar in the two treatment groups. Transdermal clonidine was worn as directed during more than 96% of patient-weeks of treatment. Compliance with the oral verapamil regimen was less consistent: Verapamil-SR was taken as directed during approximately 50% of patient-weeks of therapy, and individual compliance, assessed by tablet counts, varied from 50-120%. In all, 86% of subjects were satisfied or highly satisfied with the convenience of transdermal therapy; 87% reported that side effects were slightly or not bothersome; 65% indicated that transdermal patches were more convenient than oral therapy; and almost 60% preferred transdermal to oral therapy. In this study transdermal clonidine and oral verapamil were equally safe and effective. A substantial majority of patients preferred transdermal to oral therapy, and adherence to treatment was greater with transdermal therapy.

Hypertension, a major risk factor for cardiovascular disease, is common in older patients. Optimal selection of antihypertensive therapy in the elderly requires consideration of the unique risks, physiology and concomitant illnesses in this age group. Since the U.S. population is aging rapidly, appropriate management of hypertension in older patients is likely to remain an important concern.

Labetalol was evaluated in a multicenter, placebo-controlled study of elderly patients (greater than or equal to 60 years) with mild to moderate essential hypertension. After a placebo-washout period, doses were titrated from 100 mg BID to a maximum of 400 mg BID over a 6-week period. Once blood pressure control (standing diastolic blood pressure [SDBP] less than 90 mm Hg and greater than or equal to 10 mm Hg reduction from baseline) was achieved or the maximum allowable dosage had been given, the dosage remained the same until the end of the study. The titration phase was followed by a 4-week maintenance period. Blood pressure control was achieved in 37/54 (69%) of the patients who were treated with labetalol compared with 21/58 (36%) of the patients who received placebo (P less than .001). Twenty-nine (78%) of those controlled on labetalol responded to doses of 200 mg or less BID, and there was no significant difference between groups with respect to orthostatic blood pressure changes. Adverse experiences were generally mild and occurred with similar frequency in the labetalol and placebo groups; six patients who received labetalol and five who received placebo withdrew from the study due to adverse experiences, but in only one case (labetalol) was the adverse experience considered drug-related. In summary, labetalol effectively and safely lowered diastolic blood pressure in the elderly without producing significant orthostatic changes.

Vascular impotence is a common medical problem for which available therapies are limited. Three impotent patients observed in the authors' practice who were receiving pentoxifylline for treatment of claudication of the lower extremities spontaneously reported improved sexual function. A controlled trial of pentoxifylline for vascular impotence may be warranted.

More than half of all older Americans die of cardiovascular diseases. Hypertension is a major risk factor for cardiovascular diseases, and its prevalence increases with age. Older patients are both at higher risk for end-organ complications and less likely than younger ones to survive such complications as myocardial infarction and stroke. Clinical studies have shown that reduction of elevated blood pressure is beneficial in many older persons. Optimal selection of antihypertensive therapy requires consideration of the special characteristics of the elderly, who differ from their younger counterparts in physiology, response to therapy and frequency of concomitant illnesses and medications. Calcium antagonists are particularly effective in these patients; other agents are useful in selected situations. Drugs that are likely to cause central nervous system side effects or orthostatic hypotension generally should be avoided in this patient population. Therapy should begin with a low dose and be titrated upward slowly, thus avoiding excessive reduction of blood pressure and the development of orthostatic hypotension. Treatment should be altered as necessary to minimize side effects that may impair quality of life or lead to poor compliance.

The antihypertensive efficacy of ramipril was evaluated using 24-h noninvasive ambulatory sphygmomanometry in this double-blind, placebo-controlled study. One hundred subjects with mild-to-moderate essential hypertension were randomized to ramipril, 10 mg or placebo once daily for a 4-week treatment period. Ramipril decreased systolic and diastolic blood pressures throughout the 24-h period after dosing. Blood pressures measured manually 24 h postdose also showed that ramipril significantly reduced supine and standing blood pressures when compared with placebo. Incidences of adverse events were similar in the two study groups. Ramipril proved to be a well-tolerated agent with a sustained 24-h antihypertensive effect in this study.

The effects of amlodipine on ambulatory blood pressure were investigated in patients with mild-to-moderate hypertension. Ambulatory recordings showed that amlodipine maintained diastolic and systolic blood pressure below baseline levels for a full 24-h period without altering the normal circadian rhythm. No reflex tachycardia occurred and side effects were rare.

Sixteen hypertensive patients (diastolic blood pressure of 95-114 mm Hg) were randomized to receive 5 mg of amlodipine daily or placebo, double blind, for 4 weeks. Antihypertensive efficacy was assessed using ambulatory blood pressure monitoring at baseline and following double-blind therapy in conjunction with sphygmomanometric measurement at 2-week intervals. Laboratory tests, ECG, and adverse effects were recorded to assess tolerability. Amlodipine treatment significantly reduced ambulatory blood pressure without altering the normal circadian variation throughout the monitoring period. Supine and standing blood pressure were significantly reduced by amlodipine 24 h postdose. Amlodipine was well tolerated and was not associated with reflex tachycardia.

Cilazapril, an angiotensin converting enzyme (ACE) inhibitor with a long half-life, effectively reduced sitting diastolic blood pressure in patients with uncomplicated essential hypertension at dosages of 2.5, 5.0, and 10.0 mg/day, evaluated in a double-blind, placebo-controlled study. After a four-week placebo run-in period, 235 patients received either cilazapril or placebo for four weeks. At the end of the treatment period, significant decreases from baseline in sitting diastolic blood pressure were seen in all four groups (mean decreases of 3.3 mm Hg with placebo and 6.4, 9.2 and 8.3 mm Hg with 2.5, 5.0 and 10.0 mg cilazapril, respectively). The cilazapril groups had significantly greater blood pressure reductions than did the placebo group (p less than or equal to 0.02). The 5.0 mg cilazapril dose was significantly more effective than the 2.5 mg dose (p less than 0.03). The response rate was notably greater in the cilazapril treatment groups than in the placebo group (placebo, 27.5%; 2.5 mg cilazapril, 42.9%; 5.0 mg cilazapril 62.5%; 10.0 mg cilazapril, 50.0%). Cilazapril was well tolerated at all three dosages.

Antihypertensive therapy with labetalol was evaluated in a prospective, randomized, multicenter, double-blind study of 133 elderly patients with isolated systolic hypertension (standing systolic blood pressure [BP] greater than or equal to 160 mm Hg; diastolic BP less than 95 mm Hg). Following a placebo-washout period, patients received either labetalol (n = 70) or placebo (n = 63), which was titrated as necessary from 100 to 400 mg twice a day over a 6-week period. Once the BP was controlled (standing systolic BP less than 160 mm Hg, and greater than or equal to 10-mm Hg decrease from baseline) or the maximum dosage had been given, patients continued receiving the same regimen until the end of the titration period and throughout a 4-week maintenance period. Blood pressure was controlled in 57 (81%) of 70 of the labetalol-treated patients (86% receiving less than or equal to 200 mg twice a day) compared with 34 (54%) of 63 of the placebo-treated patients. Throughout the active treatment periods, BP was significantly lower in patients treated with labetalol compared with those taking placebo; mean standing systolic BP decreased 26 mm Hg in the labetalol group vs 9 mm Hg in the placebo group. Side effects were generally mild, and the dropout rates due to adverse experiences were similar between treatment groups (14% in the labetalol group vs 10% in the placebo group). In summary, labetalol can effectively lower systolic BP in the elderly without causing adverse orthostatic changes.

This multicenter, factorial-design trial assessed the safety and additive antihypertensive efficacy of a slow-release (SR) formulation of diltiazem hydrochloride given alone or in combination with hydrochlorothiazide for treatment of mild to moderate hypertension. After a 4- to 6-week placebo run-in period, 297 qualifying patients were randomized to receive placebo, 1 of 4 doses of diltiazem SR monotherapy, 1 of 3 doses of hydrochlorothiazide monotherapy, or 1 of 12 possible combinations of diltiazem SR and hydrochlorothiazide for 6 weeks. A dose-related reduction in blood pressure was demonstrated for each drug as monotherapy and for the two drugs in combination. Absolute blood pressures of patients who received combination therapy were lower by an overall mean of 3.0 mm Hg diastolic and 8.0 mm Hg systolic vs diltiazem SR used alone and 3.5 mm Hg diastolic and 4.0 mm Hg systolic vs hydrochlorothiazide used alone. At the largest doses used, 50% of patients achieved goal blood pressure while taking hydrochlorothiazide, 57% while taking diltiazem SR, and 75% while taking combination therapy. Combination therapy was well tolerated. This trial clearly demonstrates that diltiazem SR and hydrochlorothiazide have additive antihypertensive effects.