Hypertension Clinical Trials Research Articles

Diabetes and hypertension.

This article covers presentations and symposia dealing with the relation between diabetes and hypertension that were given at the 16th Scientific Meeting of the American Society of Hypertension, San Francisco, CA, 15–19 May 2001. At a symposium at the 16th Scientific Meeting of the American Society of Hypertension (ASH), San Francisco, CA, 15–19 May 2001, Willa Hsueh, Los Angeles, CA, discussed clinical trials in hypertension. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC-VI, 1997, available at http://www.nhlbi.nih.gov/guidelines/hypertension/jnc6.pdf) defined essential hypertension as a blood pressure (BP) >140/90 mmHg, but Hsueh noted that only 25% of patients with hypertension have no complications such as renal disease, cardiac disease, obesity, diabetes, and hyperlipidemia. BP goals are lower for patients with such complications. In the JNC-VI, patients with diabetes were noted to be at high risk and were given a BP goal of 1 g proteinuria, the goal to lessen target organ damage was set at 125/75 mmHg. In the U.K. Prospective Diabetes Study (UKPDS) patients were treated with either an ACE inhibitor (ACEI) or β-blocker (BB) and achieved levels of 144/82 vs. 154/87 mmHg over 8 years. However, at a question-and-answer session after the lecture, it was noted that captopril was given only once or twice daily and therefore may not have had optimal benefit. Both treatments reduced microvascular end points of renal and eye disease, macrovascular end points, and congestive heart failure (CHF), which may in part reflect diabetic cardiomyopathy. The Hypertension Optimal Therapy (HOT) trial of 18,790 patients, of whom 8% had diabetes and were treated with felodipine followed by ACEI and then followed by additional agents, showed a clear relation of BP to cardiovascular disease (CVD) events in the diabetes subgroup when comparing …

Medicine. Placebo-controls in short-term clinical trials of hypertension.

The decision to use placebo or active controls in clinical trials is critical to protecting research subjects and conducting worthwhile clinical investigations. On the one hand, it has been argued that using placebo is inappropriate when there exists a proven treatment for a particular disease under study. On the other hand, in some settings using placebos can increase the likelihood that the scientific endeavor will achieve interpretable results, an important ethical obligation whenever exposing patient-subjects to the risks and inconveniences of research. The decision about the use of controls hinges in large part on the likelihood of harming subjects, which is primarily an empirical question. In a meta-analysis of clinical trials of hypertension, a condition for which there are proven treatments, [ Al-Khatib et al .][1] found that exposure to placebo-controls in short-term clinical trials of antihypertensives was not associated with an increased risk of serious adverse events. This demonstrates the importance of using data to inform decisions about the appropriate selection of controls in clinical trials. [1]: http://www.sciencemag.org/cgi/content/full/292/5524/2013

The Therapeutic Potential of Candoxatril, a Neutral Endopeptidase Inhibitor, in Humans

ABSTRACTCandoxatril (UK‐79,300) is the orally active prodrug of candoxatrilat (UK‐73,967), the active enantiomer of (±) candoxatrilat (UK‐69,578), a potent neutral endopeptidase inhibitor. This article describes the rationale behind the use of this drug in the treatment of hypertension and chronic heart failure in humans. It further describes the pharmacokinetic and pharmacodynamics of candoxatril in preclinical animal studies, normal healthy individuals, and in patients with hypertension and chronic cardiac failure. In addition, we have described the initial results of clinical trials in hypertension and chronic cardiac failure, together with the potential future clinical developments of combined neutral endopeptidase/angiotensin converting enzyme inhibitors.

Updating Consensus in Portal Hypertension: Report of the Baveno III Consensus Workshop on definitions, methodology and therapeutic strategies in portal hypertension

Portal hypertension is the hemodynamic abnormality associated with the most severe complications of cirrhosis, including ascites, hepatic encephalopathy and bleeding from gastroesophageal varices. Since variceal bleeding is a medical emergency associated with significant morbidity and mortality, the evaluation of diagnostic tools and the design and conduct of good clinical trials for the treatment of this condition have always been difficult. Awareness of these difficulties has led to the organization of a series of meetings aimed at reaching consensus on the definitions of some key events related to portal hypertension and variceal bleeding, and at producing guidelines for the conduct of trials in this field. Such meetings took place in Groningen, the Netherlands in 1986 ( 1. Burroughs AK Methodology and Review of Clinical Trials in Portal Hypertension. Excerpta Medical Congress Service No 763, Amsterdam, New York, Oxford1987 Google Scholar ), in Baveno, Italy in 1990 (Baveno I) ( 2. de Franchis R Pascal JP Ancona E Burroughs AK Henderson JM Fleig W et al. Definitions, methodology and therapeutic strategies in portal hypertension A consensus development workshop. J Hepatol. 1992; 15: 256-261 Abstract Full Text PDF PubMed Scopus (164) Google Scholar ) and in 1995 (Baveno II) ( 3. de Franchis R Developing consensus in portal hypertension. J Hepatol. 1996; 25: 390-394 Abstract Full Text PDF PubMed Scopus (121) Google Scholar , 4. Portal Hypertension II Proceedings of the Second Baveno International Consensus Workshop on Definitions, Methodology and Therapeutic Strategies Oxford, Blackwell Science. 1996 Google Scholar ), in Milan, Italy in 1992 ( 5. Spina GP Arcidiacono R Bosch J Pagliaro L Burroughs AK Santambrogio R et al. Gastric endoscopic features in portal hypertension final report of a consensus conference. J Hepatol. 1994; 21: 461-467 Abstract Full Text PDF PubMed Scopus (103) Google Scholar ), and in Reston, USA ( 6. Grace ND Groszmann RJ Garcia-Tsao G Burroughs AK Pagliaro L Makuch RW et al. Portal hypertension and variceal bleeding an AASLD single topic symposium. Hepatology. 1998; 28: 868-880 Crossref PubMed Scopus (330) Google Scholar ), in 1996. All these meetings were successful and produced consensus statements on some important points, although several issues remained unsettled.

Tight blood pressure control in the UKPDS: Wednesday, may 17, broadway ballroom north, 7:00 am to 9:00 am. recent clinical trials in hypertension

Tight blood pressure control in the UKPDS: Wednesday, may 17, broadway ballroom north, 7:00 am to 9:00 am. recent clinical trials in hypertension

Autonomic imbalance, hypertension, and cardiovascular risk

Essential hypertension conveys an increased risk of cardiovascular morbidity and mortality. The common finding of an autonomic imbalance in these patients contributes not only to the etiology of hypertension itself, but also to the cardiac risk and resulting adverse sequelae. A high sympathetic tone in particular is responsible for many of the metabolic, hemodynamic, trophic, and rheologic abnormalities that cluster in patients with high blood pressure. Methods to clarify the respective importance of prereceptor versus receptor abnormalities for the etiology of insulin resistance are warranted. Results of large hypertension clinical trials examining the degree of cardioprotection offered by newer medications that are neutral or beneficial to the vast array of underlying abnormalities are a few years away. In the meantime, utilization of antihypertensive drugs that reduce sympathetic overactivity and are metabolically beneficial is a reasonable clinical alternative in hypertensive patients with the metabolic syndrome or with signs of autonomic imbalance.

A Design for Testing Interventions to Improve Adherence Within a Hypertension Clinical Trial

The Potassium Adherence Clinical Trial (PACT) incorporates one randomized clinical trial within another. A randomized trial of interventions to increase adherence to medication is nested within a second randomized clinical trial testing hypotensive effect of supplemental oral potassium. The trial aims principally to compare the effects of three intervention strategies: two sessions of individual patient counseling, two telephone contacts, or standard care. The trial aims secondarily to evaluate the effect of 60 mEq supplemental oral potassium daily on sitting systolic and diastolic blood pressure in hypertensive patients on established drug therapy. Therefore, it organizes the patients given potassium into three study groups for adherence interventions, and the patients assigned to placebo into a further three. We evaluate adherence primarily by means of the Medication Event Monitoring System (MEMS), an electronic system that records the date and time that the container of study medication is opened. Additional measurements, such as assessments of change in levels of urinary potassium, pill counts, appointment records, self-reporting by patients, and estimates by physician of adherence, are used and correlated with MEMS data. At a single center, the trial enrolled 107 participants between the ages of 26 and 80. This paper describes the background to this trial within a trial, details its design, documents the baseline characteristics of participants enrolled, and describes issues experienced during implementation of the trial. Control Clin Trials 2000;21:62–72

Translating the Dietary Approaches to Stop Hypertension Diet from Research to Practice: Dietary and Behavior Change Techniques

The Dietary Approaches to Stop Hypertension (DASH) clinical trial demonstrated that a diet that emphasizes fruits, vegetables, and low-fat dairy products, includes whole grains, nuts, fish, and poultry, and is reduced in fats, red meats, sweets, and sugar-containing beverages can be highly effective in lowering blood pressure. The National High Blood Pressure Education Program now suggests the DASH diet for preventing and managing hypertension. For persons modifying their diets, the DASH diet offers varied choices. However, simultaneously modifying several dimensions of a diet can be challenging, even for knowledgeable and motivated persons. Persons who are uncertain about modifying their diet may become overwhelmed by the needed dietary changes. Dietitians and other health care practitioners can help patients adopt the DASH diet by exploring possible ambivalence, increasing motivation, and strengthening commitment to change; encouraging patients to select dietary modifications that will fit their lifestyle; and, finally, offering information about how to change their eating behavior. In this article, we offer dietary advice and counseling suggestions for tailoring interventions to match patients’ readiness for adopting the DASH diet. J Am Diet Assoc. 1999;99(suppl):S90–S95.

Nonpharmacologic therapies that reduce blood pressure: a fresh perspective.

Traditional approaches to control the epidemic of blood pressure-related atherosclerotic cardiovascular disease (ASCVD) have largely focused on drug therapy in persons with hypertension. Still, nonpharmacologic therapy, also termed lifestyle modification, has an important and expanding role that complements drug therapy. Specifically, nonpharmacologic therapies can serve as initial therapy in Stage 1 hypertensive patients, facilitate medication step down or withdrawal in patients with well-controlled hypertension, prevent hypertension in high-risk populations, and reduce blood pressure in normotensive individuals and thereby lower their risk of ASCVD. Traditional lifestyle modifications that reduce blood pressure include sodium reduction, weight loss, moderation of alcohol intake, and increased physical activity. Such strategies have been prominently advocated in the Fifth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Recommendations to increase potassium, magnesium, and calcium intake were based primarily on general health considerations, not for control of high blood pressure. In its sixth and most recent report (JNC VI) published in 1997, the Joint National Committee has extended its recommendations. In addition to the traditional lifestyle recommendations, the JNC VI advocates increased potassium intake for control of high blood pressure. Furthermore, this policy-making body now recommends a healthy dietary pattern, that is, one that is rich in fruits, vegetables, and low-fat dairy products, and reduced in saturated fat, total fat, and cholesterol. This diet, which was rigorously evaluated in the Dietary Approaches to Stop Hypertension (DASH) clinical trial, substantially lowered blood pressure in normotensive and hypertensive individuals. These recent developments reinforce the hypothesis that multiple dietary factors influence blood pressure. Nonpharmacologic approaches have enormous potential as a means to reduce blood pressure and control hypertension, thereby preventing the occurrence of ASCVD. The current challenge to health care providers, government officials, and the general public is to develop and implement effective clinical and public health strategies that lead to desirable lifestyle modifications.

The nutritional aspects of hypertension.

This article reports dramatic results achieved by the Dietary Approaches to Stop Hypertension (DASH) and other clinical trials and studies in lowering blood pressure in both hypertensives and normotensives, suggesting that it could be useful in both preventing and managing blood pressure.

Endothelin in cardiovascular control: the role of endothelin antagonists.

Endothelin (ET) is a potent vasoconstrictor associated with various cardiovascular diseases. ET mediates its effects through ET receptors on vascular smooth muscle cells as well as on the vascular endothelium. Furthermore, a neurotransmitter role for ET has been suggested on the basis of experimental and human in vivo studies. ET antagonists are potent tools for studying the effects of ET and its receptors. They have been widely used in vitro and in experimental models of cardiovascular disease, where ET levels are elevated and reactivity to ET is altered. Promising clinical trials in hypertension, coronary artery disease, and congestive heart failure are discussed in this review. Different forms of renal failure are associated with markedly increased ET levels, and ET antagonists experimentally improve renal function in these models. Extrapolating from experimental and first clinical experience, ET antagonists could be useful in the treatment of hypertension, coronary artery disease, congestive heart failure, and renal failure, especially in combination with other drugs, ie, angiotensin converting enzyme inhibitors. The inhibition of ET-induced stimulation of nociception allows for speculation that ET antagonists might even have analgesic properties.

Safety of Long-Acting Dihydropyridine Calcium Channel Blockers in Hypertensive Patients

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.

Risk factors and drugs in the treatment of hypertension.

A wide range of drug classes, frequently including centrally acting agents, has been used in clinical trials in hypertension which have shown benefit. Although therapy has clearly limited the complications of hypertension, further improvement is needed, especially concerning coronary artery disease. Future interest therefore centres on drugs that do not worsen diabetes mellitus, do not cause dyslipidaemia, or induce potassium loss, while not provoking drowsiness, depression, other troublesome side-effects, or being associated with rebound hypertension when stopped. The centrally acting imidazoline agonists merit detailed study in this regard.

Ambulatory blood pressure monitoring: quality control and implications for clinical trials in hypertension.

Ambulatory blood pressure monitoring: quality control and implications for clinical trials in hypertension.

Results of recent clinical trials in hypertension with newer beta-adrenergic blocking agents

Results of recent clinical trials in hypertension with newer beta-adrenergic blocking agents

Ambulatory blood pressure monitoring in current clinical practice and research

As more scientific evidence accumulates concerning the relationship between ambulatory blood pressure and hypertensive organ disease, the technique of ambulatory blood pressure monitoring appears to be gaining a foothold in clinical practice and research. Over the past 2 years, an important follow-up study has revealed that 'white coat' hypertension has a low morbidity compared with sustained hypertension. However, other cross-sectional studies continue to fuel the debate regarding the definition and risks associated with white coat hypertension. The application of ambulatory blood pressure monitoring to clinical hypertension trials remains superior to that of office blood pressure measurements. As further data from other prospective interventional studies are published in the next few years, further definition of the utility of the technique will be possible.

Update on multicenter clinical trials in hypertension

Update on multicenter clinical trials in hypertension

New antihypertensive drugs and new approaches to hypertension

This review of new antihypertensive drugs concentrates on an exciting new class of antihypertensive agents, the orally active angiotensin II receptor antagonists, and their potential role in the management of hypertension. These drugs have been evaluated within the last year or so to determine their efficacy and safety as blood-pressure-lowering agents and to unravel the role of the renin-angiotensin system in the pathophysiology of hypertension. In addition, renin inhibitors have undergone further clinical trials in hypertension. The use of angiotensin-converting enzyme inhibitors for the treatment of symptomatic heart failure of all grades has become established since the publication of the report of the Studies of Left Ventricular Dysfunction (SOLVD) group and the Vasodilator Heart Failure Trial-ll (V-HeFT-ll) study. The role of newer β-blocking agents and novel formulations of drug delivery that have been applied to calcium antagonists in particular are discussed. The section on new approaches to hypertension treatment focuses on isolated systolic hypertension and hypertension in the elderly.

Long-term clinical trials in hypertension

Long-term clinical trials of antihypertensive therapy have demonstrated that diuretic-based therapy consistently reduced fatal and non-fatal cerebrovascular events regardless of age, race or gender; the frequency of ECG left ventricular hypertrophy, retinopathy and progression of hypertension were also reduced, and cardiomegaly and ECG left ventricular hypertrophy were reversed. A case can be made for initiating antihypertensive therapy whenever diastolic blood pressure remains greater than or equal to 90 mmHg despite a fair trial of non-pharmacologic treatment. Elderly patients with diastolic hypertension benefit from diuretic-based therapy at least until the age of 80 years. Whether ACE inhibitors or calcium channel blockers are more effective than diuretics in preventing cardiovascular complications remains to be seen. So far, there have been no long-term trials using these agents as initial therapy.

Pharmacological Profile of Carvedilol as a β-Blocking Agent with Vasodilating and Hypotensive Properties

Carvedilol is a new beta-receptor blocking and vasodilating drug that is presently undergoing clinical trials in hypertension and coronary heart disease. In this article, the pharmacodynamic properties of carvedilol are compared with those of standard drugs. The beta-blocking activity was characterized in isolated organs and in conscious rats, rabbits, and dogs. For the beta 1-blockade in guinea pig atria, the pA10 values were 7.44 +/- 0.16 for carvedilol and 6.77 +/- 0.08 for propranolol. Carvedilol is a noncardioselective beta-blocker. The i.v. doses that inhibited the tachycardia by 50% induced by 1 microgram/kg isoprenaline were 62 micrograms/kg in dogs, 138 micrograms/kg in rabbits and 841 micrograms/kg in rats. In rabbits carvedilol was slightly more active and in rats less active than propranolol. In all models, carvedilol was much more active than labetalol or prizidilol. In contrast to propranolol, carvedilol relaxed rat aortic strips. A dose-dependent decrease in arterial blood pressure was seen in different in vivo models. The total peripheral and coronary resistance were decreased in conscious dogs. The doses required for both beta-blockade and decrease in blood pressure were in the same range. The drug was also active after oral administration. There is no hint for development of tolerance.