Search

The new drug application database submitted to the US Food and Drug Administration for drug approval (phases I-III or phases 1-3) is limited both in scope and size. Although randomized controlled trials, the hallmark of phase III trials, are the gold standard for the drug-approval process, they invariably have a number of limitations, including relatively small sample sizes, selective populations, short follow-up, the use of intermediate (surrogate) endpoints (almost always), and limited generalizability. The challenges of monitoring drugs once approved are also numerous. After approval by the Food and Drug Administration, marketed drugs undergo continued scrutiny, and this scrutiny is increasing because of problems that have surfaced with some drugs after their approval. Postmarketing research includes a variety of study designs and the use of registries and self-reporting of drug side effects. Along with this has come great confusion about what postmarketing research is and what a phase IV study is. Among the important strengths of phase IV research are the exposure of a broader range of patients to the drug under study, resulting in more "real-world" information about the drug's safety and efficacy, and consideration of a broader range of clinical endpoints. As a result, phase IV or postmarketing research, has become an integral part of the drug evaluation process for a wide range of agents. The authors discuss the different types of study designs that are common under the phase IV terminology and provide some examples. They also discuss the use of registries and self-reporting of adverse events using the Med Watch System. [ABSTRACT FROM AUTHOR]

Randomized controlled trials remain the gold standard study design and yield the highest level of scientific credence. However, recognition of the limitations of the randomized controlled trial is important. This review highlights 10 potentially problematic areas one should carefully assess when performing or reading an article reporting the results of a randomized controlled trial, problematic areasthat can affect the outcome of the trial and therefore mislead the reader. These areas include ethical issues, eligibility criteria, masking (blinding), randomization, analyticmethods, the selection of subjects for the interventional and comparison groups, selection of end points, and the interpretation of the results. Each of these is discussed,and examples of published articles are used to highlight the main points. [ABSTRACT FROM PUBLISHER]

: BackgroundAtherosclerosis begins in the arterial wall, with endothelial dysfunction accompanied by functional and structural changes that influence arterial stiffness. Pulse contour analysis provides an assessment of compliance or elasticity of the large conduit arteries (C1) and small microcirculatory arteries (C2). In this study, the predictive value of reduced elasticity of these arteries was evaluated by follow-up of subjects who underwent pulse contour analysis at the University of Minnesota.: MethodsQuestionnaires were sent to 870 subjects who had radial artery pulse wave analysis performed between 1993 and 1999 using a noninvasive sensor, parameter estimating algorithm and modified Windkessel model of the circulation. Responses from 419 subjects >19 years of age reported on any cardiovascular events including death, myocardial infarction, stroke, transient ischemic attacks, angina, or coronary or peripheral vascular interventional procedures.: ResultsOf the subjects, 168 (41%) reported one or more cardiovascular events. Events were more common in those with elevated blood pressure, elevated cholesterol, diabetes, and family history of events. Age, reduced C1, and reduced C2 were univariate predictors of events. After adjusting for age, a 2-unit decrease in C2 remained a significant predictor (odds ratio 1.50, P < .001), whereas C1 was no longer predictive.: ConclusionReduced small artery elasticity, which is a measure of endothelial dysfunction, is significantly associated with cardiovascular events independent of age. [Copyright &y& Elsevier]

Drugs and diseases have differential effects on functional and structural components of large-conduit arteries and smaller vessels. The objective of this study was to demonstrate functional and structural effects of doxazosin (DOX) on largevessel and small-vessel arterial elasticity in hypertension (HTN). This was an open-label, single-blind, active-therapy study. Patients with stage 1 to 2 HTN were administered DOX 2 mg/day for 3 months and 4 mg/day for 1 month, if indicated, followed by 2-week washout period. Arterial elasticity was measured noninvasively at baseline, at 3 months and 4 months of treatment, and 2 weeks following DOX withdrawal. Although the observed effects were not statistically significant, large-vessel elasticity (C1) increased in a dose-related manner and returned to baseline 2 weeks after drug withdrawal. There was a trend toward an increase in small-vessel elasticity in a dose-related manner. However, 2 weeks after drug withdrawal, C2 (distal elasticity) had not returned to baseline and was statistically significantly different from baseline (p = 0.032). It was concluded that large-artery compliance increased in a dose-related manner. Almost all benefit was lost within 2 weeks of discontinuation, suggesting the DOX effect was functional. Small-artery compliance improved in a dose-related manner but only partially returned to baseline after DOX withdrawal, suggesting changes in artery structure by DOX. [ABSTRACT FROM PUBLISHER]

Presents a study to examine whether low-density lipoprotein (LDL) size is an independent predictor of recurrent coronary events in patients with known coronary heart disease (CHD), as opposed to a marker for other lipid abnormalities. Context; Objective; Design and setting; Participants; Main outcome measure; Results; Conclusions.

Examines the effects of zatebradine, a sinus node inhibitor, on heart rate (HR) and exercise duration in stable angina pectoris. Exercise parameters at baseline and after four weeks of treatment with zatebradine; Assessment on the efficacy and safety of zatebradine; Relation of HR reduction in the improvement of anti-ischemic effects.

This is the first reported large clinical trial of the antianginal and acute ischemic effectiveness and safety of dilevalol (the R, R-isomer of labetalol) in patients with chronic stable angina pectoris. This was a multicenter double blind fixed-dose parallel group placebo controlled trial. Patients with chronic stable angina and positive and reproducible exercise tests (±20%) were included. If randomized, patients entered one of four fixed dose groups (twice a day placebo, 100 mgm, 200 mgm and 400 mgm bid for 2 weeks). Exercise testing was performed at 2 hours (peak) and 12 hours (trough) postdosing. This was followed by a 2-week once-a-day dosing regimen in which patients received the same total daily dose as the prior 2 weeks, with the full dose in the morning and a matched placebo in the evening. Exercise testing was performed at 2 hours (peak) and 24 hours (trough) postdosing. Anginal frequency and NTG consumption were significantly reduced, and equally so, by qd and bid regimens. The time of exercise to the onset of angina increased and the proportion of patients terminating exercise because of moderate angina decreased in a dose response fashion for both peak and trough tests and for both qd and bid regimens. There was also a dose related decrease in exercise induced ST segment depression and an increase in time to 1 mm ST depression. In 15 patients, 24-hour ambulatory monitoring also revealed a decrease in episodes of silent ischemia. No significant side effects related to the study drug occurred. Thus, dilevalol was effective in the treatment of angina pectoris since it was well tolerated, favorably improved exercise induced ischemia (both painful and silent ischemia), and reduced anginal frequency and NTG consumption. [ABSTRACT FROM AUTHOR]

This study was designed to evaluate the effects of a new beta-adrenergic blocking agent with beta2 agonist activity (dilevalol, an R-R' isomer of labetalol) on left ventricular hypertrophy regression as seen by M-mode echocardiography. The study design was a 2:1 double blind randomization of dilevalol versus metoprolol. There was an equal blood pressure reduction in the two groups (supine diastolic blood pressure fell from 101 ± 4.5 mm Hg to 87 ± 13.7 mm Hg, P < .001 in the dilevalol group, and 101 ± 4.3 mm Hg to 87 ± 8.6 mm Hg, P < .01, in the metoprolol group). At the end of 2 months, there was an overall 7.5% decrease in left ventricular mass index in the 16 dilevalol treated patients (this was due to a 4.4% decrease in posterior wall thickness, end diastolic dimension increased by only 1%). Of the seven patients with an increased left ventricular mass index, all demonstrated hypertrophy regression (mean 17.14%). In contrast, no significant change in left ventricular mass was seen in the metoprolol treated group. Echocardiography left ventricular mass index and electrocardiographic evidence of left ventricular hypertrophy (using the Sokolow-Lyons criteria and Romhilt-Estes point score) had poor correlation (r = .30 and r = .38, respectively). Resting ejection fraction increased by 5% and velocity of circumferential fiber shortening by 14% in the dilevalol treatment group (not significant), in conclusion, 1) echocardiographic left ventricular hypertrophy regression occurred with dilevalol treatment 2) this left ventricular regression was a result of a decrease in intraventricular septal thickness and posterior wall thickness 3) the poor correlation between echocardiographic increased left ventricular mass and electrocardiographic left ventricular hypertrophy was supported 4) dilevalol and metoprolol had equal antihypertensive effects. [ABSTRACT FROM AUTHOR]

This study addresses the effect of the three major classes of antianginal agents on asymptomatic myocardial ischemia in patients with chronic stable angina pectoris. The authors found that each class (given as monotherapy) resulted in a 50% reduction in asymptomatic ischemia (both in the number of episodes and the ST product). Dual therapy resulted in an overall four fold reduction compared to placebo. Therapy also resulted in a beneficial alteration in the frequency distribution of asymptomatic ischemia. Stratification into three age groups demonstrated an equal prevalence of asymptomatic ischemia in each. All ages had nearly equivalent reductions in asymptomatic ischemia by monotherapy and dual therapy, but the youngest age group seemingly responded better to monotherapy than did the oldest age group. [ABSTRACT FROM AUTHOR]