The risks associated with short-term placebo-controlled antihypertensive clinical trials: a descriptive meta-analysis.

Short-term (4-8 weeks) placebo-controlled trials are used to evaluate new antihypertensive drug treatment. To evaluate the consequences of such practice, a descriptive meta-analysis was conducted, consisting of blinded review of original case report forms for all patients who died or left a study before its completion for all short-term, placebo-controlled hypertension trials submitted to the Food and Drug Administration from 1973 through 2001. There were 93 marketing applications or supplements involving 590 individual trials that involved 86137 randomized patients (64438 randomized to experimental drug and 21 699 randomized to placebo) with 12658 patient years of observation. There were 9636 dropouts (mean time to dropout was 28 days) and relative risk (RR (placebo/drug))= 1.33 (95% confidence limits, 1.28, 1.39; P < 10(-16)). As expected, lack of blood pressure (BP) control was far more common in patients randomized to placebo; therapeutic failure, RR = 2.53 (2.35, 2.73; P < 10(s15)) and hypertensive emergency, RR = 2.75 (2.19, 3.57; P < 10(-15)). When administrative dropouts and dropouts resulting from inadequate BP control were excluded, the remaining 38% of dropouts were disproportionately more from drug (2810 drug, 816 placebo), RR = 0.80 (0.74, 0.86; P < 10(-8)). There were 43 deaths, RR=0.72 (0.33, 1.45; P=0.37); 40 strokes, RR = 1.43 (0.68, 2.81; P=0.33) and 77 myocardial infarctions, RR=1.06 (0.62, 1.75; P= 0.82). Irreversible harm (a combination of death, stroke and myocardial infarction, 160 total events) was equally distributed between the drug and placebo groups, RR=1.03 (0.71, 1.47; P=0.86).

Assessment of antihypertensive activity in the regulatory setting.

Before a new antihypertensive drug receives regulatory approval, it must demonstrate a significant blood pressure-lowering effect over its entire dosing interval. The Food and Drug Administration recognizes several different methods for demonstrating antihypertensive activity, the gold standard continuing to be the office/casual blood pressure at the end of the dosing interval (trough). There should be at least two studies demonstrating a significant antihypertensive effect, at least one of which should include a placebo. Data obtained using ambulatory blood pressure monitoring are used for showing the time-course of the antihypertensive effect, particular attention being given to possible marked differences between the drug's maximum (peak) effect and its activity during the trough. In Europe, the Committee for Proprietary Medicinal Products also considers the office/casual blood pressure at trough to be a primary measure of outcome, responder rates using office/casual readings also being noted. The Committee recommends that data be obtained using ambulatory blood pressure monitoring in order to demonstrate a drug's antihypertensive activity. In addition, it specifically requests that a trough : peak ratio be calculated, whereas the Food and Drug Administration does not require this information.

Myonecrosis after revascularization procedures.

The detection of elevated cardiac enzyme levels and the occurrence of electrocardiographic (ECG) abnormalities after revascularization procedures have been the subject of recent controversy. This report represents an effort to achieve a consensus among a group of researchers with data on this subject. Creatine kinase (CK) or CK-MB isoenzyme (CK-MB) elevations occur in 5% to 30% of patients after a percutaneous intervention and commonly during coronary artery bypass graft surgery (CABG). Although Q wave formation is rare, other ECG changes are common. The rate of detection is highly dependent on the intensity of enzyme and ECG measurement. Because most events occur without the development of a Q wave, the ECG will not definitively diagnose them; even the ECG criteria for Q wave formation signifying an important clinical event have been variable. At least 10 studies evaluating > 10,000 patients undergoing percutaneous intervention have demonstrated that elevation of CK or CK-MB is associated not only with a higher mortality, but also with a higher risk of subsequent cardiac events and higher cost. Efforts to identify a specific cutoff value below which the prognosis is not impaired have not been successful. Rather, the risk of adverse outcomes increases with any elevation of CK or CK-MB and increases further in proportion to the level of intervention. This information complements similar previous data on CABG. Obtaining preprocedural and postprocedural ECGs and measurement of serial cardiac enzymes after revascularization are recommended. Patients with enzyme levels elevated more than threefold above the upper limit of normal or with ECG changes diagnostic for Q wave myocardial infarction (MI) should be treated as patients with an MI. Patients with more modest elevations should be observed carefully. Clinical trials should ensure systematic evaluation for myocardial necrosis, with attention paid to multivariable analysis of risk factors for poor long-term outcome, to determine the extent to which enzyme elevation is an independent risk factor after considering clinical history, coronary anatomy, left ventricular function and clinical evidence of ischemia. In addition, tracking of enzyme levels in clinical trials is needed to determine whether interventions that reduce periprocedural enzyme elevation also improve mortality.

On the trough-to-peak ratio of drug effect in antihypertensive trials.

Blood pressure in hypertensives (treated or untreated) varies over the course of the day, and, although animal models and human intervention studies have demonstrated that the ill effects of hypertension are mediated by the pressure itself, and not by some confounder, it remains unknown what time-related function of pressure (simple mean, root-mean-square, duration of pressure above some threshold, and so on) might be the best predictor of hypertension-related morbidity There is no accepted means of describing the time course of blood pressure, let alone a difference between two such descriptions, which might then be a description of the time course of a drug effect. In a document dated 1988, the US Food and Drug Administration (FDA) defined the trough-to-peak drug-effect ratio and indicated that drug approval would be granted only when values of this statistic were satisfactory. The FDA's belief in the importance of the time-course of drug effect has grown stronger over time, but the idea that only drugs with certain trough-to-peak ratios could be approved was discarded by the FDA within months of its appearance. In recent years, more promising means of assessing the time-course of drug effect have begun to take shape.

Defining the regulatory role of ambulatory blood pressure monitoring. ABPM Steering Committee.

Our division is in a privileged position to study the usefulness of ABPM in the clinical development of antihypertensive agents. Most trials involving ABPM are commercially sponsored, and in due course, much of that data is presented to the Division. As such studies become more prominent in drug development, the Agency must make decisions on how such data are analyzed and interpreted. These should be seen as this project's short-term goals. In the longer term, the accumulation of ABPM data from clinical trials will be a valuable resource that researchers can use to address questions about what aspects of hypertension are most associated with prognosis and which treatments affect those aspects.

Metabolism of benzocaine during percutaneous absorption in the hairless guinea pig: acetylbenzocaine formation and activity.

The effect of dose and enzymatic inhibition on the percutaneous absorption and metabolism of benzocaine was studied in vitro in the hairless guinea pig. At the dose level of 2 micrograms/cm2, benzocaine was rapidly absorbed and extensively metabolized (80%) by acetyltransferase. As the applied dose of benzocaine was increased to 40 and 200 micrograms/cm2, N-acetylation of benzocaine decreased to 44 and 34%, respectively, suggesting saturation of the acetyltransferase system. Total 14C absorption after benzocaine application was not significantly different between control and enzyme-inhibited skin and therefore does not appear to be affected by the extent of benzocaine metabolism during percutaneous penetration. Skin provides a significant first-pass metabolic effect for therapeutic doses of percutaneously absorbed benzocaine, and the primary metabolite formed, acetylbenzocaine, is biologically active.

Trough: peak ratio: the rationale behind the United States Food and Drug Administration recommendations.

TROUGH EFFECT: For most formulations of most antihypertensive drugs which are administered in a chronic multiple-dose regimen, one of the requirements for approval is an estimate of the magnitude of effect (decrease in blood pressure minus that elicited with a placebo) obtained just before the next dose is taken. This estimate of effect is generally referred to as the 'trough' effect and is, by conventional practice (although not required to be), usually the effect before the first morning dose. PEAK EFFECT: Another estimate of effect, which represents the maximum effect of any single dose administered during a multiple-dose regimen, is strongly recommended for most drugs for most indications. This estimate of effect is generally referred to as the 'peak' effect and is, by conventional practice, usually the effect of the first morning dose measured a few hours after the dose is taken. TROUGH: PEAK RATIO: The two measurements, trough and peak, are intended to estimate the duration of effect of a single dose. Generally, if 50-75% of the peak effect of a dose is preserved at trough, issues concerning the proper dosing interval do not arise. The closer to no loss of effect throughout the dosing interval the better.

Short and long-acting oral nitrates for stable angina pectoris.

Nitroglycerin (NTG) spray and sublingual tablets rapidly relieve an established attack of angina, and their infrequent use is not associated with the development of tolerance. Although, following a suitable nitrate-free interval, the first dose of oral, long-acting nitrates produces significant hemodynamic effects, increases angina free walking, and decreases exercise-induced ischemia, during continued long-term therapy tolerance limits their usefulness. Appropriate dosing regimens of controlled-release formulations of isosorbide dinitrate (ISDN) and controlled-release NTG during long-term therapy have not been established. Use of immediate-release formulation of 15-120 mg of ISDN in a qid regimen lead to a marked reduction in the size and duration of antianginal effects compared to the initial dose. Asymmetric tid therapy with 30 mg of ISDN (7 a.m., 1 p.m., and 6 p.m.) is also associated with the development of partial tolerance and appears to provide antianginal prophylaxis for only a period of 6 hours each day. Asymmetric bid therapy with ISDN at 7 a.m. and noon may give sustained effect but is supported by only a single, small study that did not examine effectiveness after the noon dose in long-term use. Isosorbide-5-mononitrate (IS-5-MN) has been the subject of more recent studies than other nitrates because of attempts to bring a number of products into the U.S. market. IS-5-MN in qid, tid, and standard bid (8 a.m. and 8 p.m.) dosing regimens produce tolerance. Asymmetric regimens of immediate-release IS-5-MN (10 and 20 mg) given bid (once in the morning and again 7 hours later) decrease the development of tolerance compared to symmetric regimens and produce an increased exercise duration after each dose of the day; the 20 mg bid dosing is more effective. Similarly, once-daily 120 and 240 mg controlled-release IS-5-MN does not produce tolerance and gives a sustained increase in daytime exercise duration. Both asymmetric bid immediate-release and once-daily controlled-release IS-5-MN preparations do not produce deterioration in exercise performance prior to the administration of the medication in the morning (i.e., no zero-hour effect). Further studies are needed to establish useful dosing regimens for ISDN, for controlled-release ISDN, and for controlled-release nitroglycerin. None of the dosing regimens of any oral, long-acting nitrate (including IS-5-MN) provide 24 hour antianginal and antiischemic effects.(ABSTRACT TRUNCATED AT 400 WORDS)

Ointments and transdermal nitroglycerin patches for stable angina pectoris.

Nitroglycerin (NTG) ointment is used for the prophylaxis against angina pectoris, but there are no data to support its effectiveness during long-term therapy. Continuous, once-daily application of isosorbide dinitrate cream produces tolerance with complete loss of efficacy within 1 week. Nitroglycerin patches are very popular and continuous once-daily application is still claimed by some investigators to provide 24 hour antiischemic and antianginal efficacy. This claim is based on data from postmarketing studies in a very large number of patients and placebo-controlled studies in smaller groups of patients from Italy, Yugoslavia, Greece, and Germany. In contrast, studies from the United States, Canada, England, and some centers in Germany have failed to show superiority of patches over placebo during continuous therapy. This controversy was addressed by the NTG cooperative study group, in which a total of 562 patients who were responders to sublingual nitroglycerin were studied. Patients received either placebo or NTG patches delivering low (15-30 mg/24 hr), moderate (45-60 mg/24 hr), or large (75 and 105 mg/24 hr) amounts of NTG. Four hours after the initial application, NTG patches increased exercise duration compared to placebo, but this beneficial effect had disappeared by 24 hours. Furthermore, after 8 weeks of continuous therapy, none of the NTG patches were superior to placebo, whether patients were or were not taking concomitant beta-blockers. Therefore, current opinion is that continuous therapy with NTG patches produces pharmacologic tolerance and is ineffective.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of surrogate end points in the evaluation of drugs for heart failure.

To be of clinical value in the treatment of heart failure, a drug must permit patients either to feel better or to live longer, or both. Yet, because the assessment of both quality and quantity of life is difficult, many investigators have proposed using alternate measures (namely, surrogate end points) that may indicate the probable effect of a drug on symptoms or survival but are not direct measures of clinical benefit. Surrogate end points are usually physiologic variables that are known to be statistically associated and are believed to be pathophysiologically related to the clinical outcome. Although the adoption of such surrogate end points would dramatically facilitate the evaluation of new drugs, experience to date has shown that the effect of a drug on a surrogate end point is not a reliable predictor of the clinical utility of the drug, usually because the assumption that the end point is pathophysiologically related to the outcome proves to be invalid. Consequently, the evaluation of the effect of a drug on a surrogate end point provides us with a hypothesis rather than data about the possible effect of a drug on clinical events; such a hypothesis can be tested in controlled clinical trials that directly measure the clinical benefit of the therapeutic intervention. In the area of heart failure, no surrogate end point currently exists that can be used in lieu of the direct assessment of a drug on symptoms or survival, ideally in the context of a placebo-controlled trial.

A viewpoint on drugs that prolong the QTc interval.

Insufficient evidence exists to suggest that prolongation of the QT interval corrected for heart rate (QTc) is necessarily beneficial. In all but life-threatening situations, QTc prolongation resulting from pharmacologic agents must be considered a risk. Because dose-response relations for torsades de pointes cannot be established and because prolongation of the QTc interval is thought to precede the development of torsades, it is reasonable to assume that the QTc prolongation itself constitutes the marker of risk. An assessment of the relation between the dose of a given drug and its effect on the QTc interval will aid in making the judgment that the potential benefit outweighs the risk. Ideally, a drug should demonstrate as wide a safety margin as possible, as reflected in a large separation between the ED50 value associated with therapeutic benefit and that associated with QTc prolongation.

Testing for the existence of a desirable dose combination.

We consider the problem of studying several dose combinations of two drugs for a therapeutic endpoint in a multilevel factorial clinical trial. Two test statistics are constructed to test whether there exists at least one dose combination that is more effective than its component doses. Their distributions involve nuisance parameters quantifying the mean differences among the doses of the two component drugs. It is shown that their power functions achieve maxima as all the nuisance parameters approach infinity in absolute value. The significance levels of the two tests are derived and two alpha-level tests are proposed. Tables are given to provide the alpha-level critical values for these tests and to gain insights into their power performances.

Exposing patients with chronic, stable, exertional angina to placebo periods in drug trials.

Because the safety of withholding standard therapy and enrolling patients with stable angina in placebo-controlled trials is not known, we identified all events leading to dropout from trials of 12 antianginal drugs submitted in support of new drug applications to the US Food and Drug Administration. Persons who dropped out of the trials were classified as cause due to adverse cardiovascular events or other causes without knowledge of drug assignment. There were 3161 subjects who entered any randomized, double-blind phase of placebo-controlled protocols; 197 (6.2%) withdrew because of cardiovascular events. There was no difference in risk of adverse events between drug and placebo groups. A prospectively defined subgroup analysis showed that groups who received calcium antagonists were at an increased risk of dropout compared with placebo groups (P = .04), primarily because of a disproportionate number of adverse events in studies of one drug. In conclusion, there were few adverse experiences associated with short-term placebo use. Withholding active treatment does not increase the risk of serious cardiac events.

Determination of K(+)-channel relaxation times in squid axon membrane by Hodgkin-Huxley and by direct linear analysis.

An assumption in the use of the Hodgkin-Huxley (HH) formulation (A.L. Hodgkin and A.F. Huxley, J. Physiol. 117 (1952) 500) to extract kinetic parameters from ion conductance responses to step voltage changes across biological membranes is that estimates obtained from such an analysis are equivalent to those obtained by direct, small-perturbation analysis. Comparison of the estimates of the K(+)-conductance relaxation time, tau n, derived from HH vs rapid, complex admittance determinations in the same squid giant axons shows significant differences for the same step changes over a 60 mV range from holding (-65 mV). The admittance determinations (2.5-5000 Hz) are shown to satisfy criteria of linear analysis (i.e., estimates are equivalent to a small-step analysis and are time invariant). The discrepancies between the two methods arise from the fact that the HH power-law description for a constant power does not yield a best fit of data over the voltage range examined and thus best estimates of tau n are power dependent. Furthermore, the large step changes in membrane voltage may excite nonlinear modes unrelated to conductance gating that contaminate the data to which the nonlinear formulation is applied to estimate linear kinetic parameters. Thus, the long-standing assumption that application of the HH methodology and empiricism is equivalent to a direct linear analysis is not substantiated. This result suggests that in comparisons between microscopic and macroscopic conduction data, microkinetic parameters derived from analysis of single ion-channel data should not be compared to macrokinetic parameters from a large population of the channel derived by HH analysis.

Sodium currents in human skeletal muscle fibers.

Sodium currents from human external intercostal muscle fibers were recorded using the Hille-Campbell voltage clamp method. Sodium currents are analyzed in terms of the m and h parameters of the Hodgkin-Huxley model. The results indicate that the kinetics and voltage dependence of sodium currents in human skeletal muscle fibers are very similar to those reported in rat fibers.

Antihypertensive effects of lofexidine in patients with essential hypertension.

1 Single oral doses of lofexidine, 0.1, 0.3, and 0.6 mg produced dose related decreases in supine and standing arterial pressure and heart rate in nineteen patients with essential hypertension. 2 A mean oral antihypertensive threshold dose of less than 0.1 mg was estimated. 3 Lofexidine decreased mean urinary noradrenaline excretion 28% and caused significant retention of sodium and water. 4 The most prominent side effects were sedation and orthostatic dizziness. 5 Lofexidine is pharmacologically similar to, but apparently less potent than clonidine as an antihypertensive agent.

Effects of yohimbine on squid axons.

Yohimbine, an indolealkylamine alkaloid, reduces the amplitude of the sodium current in the squid giant axon. For doses that reduce sodium current amplitude by up to 50%, there is no significant change in the kinetics or in any of the voltage-dependent parameters associated with sodium channels. The effective equilibrium constant for yohimbine binding to the sodium channel is 3 x 10(-4) M. Repetitive depolarizing pulses increase the inhibition of squid axon sodium current by yohimbine. This use-dependent inhibition is enhanced by increasing the concentration of yohimbine, by increasing the frequency of pulsing, and by increasing the magnitude or the duration of depolarization. It is reduced by hyperpolarizing prepulses. This behavior can be explained by a model wherein yohimbine binds more readily to open sodium channels than to closed sodium channels and wherein the Hodgkin-Huxley kinetic parameters are modified by the binding of the drug. This type of model may also explain the tonic and use-dependent inhibition previously described by others for local anesthetics.