(Hypertension. 1995;26:942-949.)
© 1995 American Heart Association, Inc.
Articles |
The Trough-to-Peak Ratio as an Instrument to Evaluate Antihypertensive Drugs
Correspondence to Jan A. Staessen, MD, PhD, Klinisch Laboratorium Hypertensie, Inwendige Geneeskunde-Cardiologie, UZ Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
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Abstract |
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Abstract The U.S. Food and Drug Administration designed the trough-to-peak ratio as an instrument for the evaluation of long-acting antihypertensive drugs, but the ratios are usually reported without accounting for interindividual variability. This study investigated how the trough-to-peak ratio would be affected by interindividual and intraindividual variability and by smoothing of the diurnal blood pressure profiles. The ambulatory blood pressure was recorded on placebo in 143 hypertensive patients (diastolic pressure on conventional measurement >95 mm Hg). After 2 months, the recordings were repeated on 10 mg (n=66) or 20 mg (n=77) lisinopril given once daily between 7 and 11 PM. The baseline-adjusted trough-to-peak ratios were determined from diurnal blood pressure profiles with 1-hour precision. Lisinopril reduced (±SD) the 24-hour pressure by 16±17 mm Hg for systolic and 10±10 mm Hg for diastolic (P<.001). According to the usual approach, disregarding interindividual variability, the trough-to-peak ratio was 0.72 for systolic pressure and 0.67 for diastolic pressure. In the 143 patients the ratios were not normally distributed. They were the same on both lisinopril doses. When interindividual variability was accounted for, the median trough-to-peak ratio was 0.34 (P5 to P95 interval, -0.46 to 0.87) for systolic pressure and 0.26 (-0.44 to 0.84) for diastolic pressure. In 66 patients examined twice on 10 mg lisinopril at a median interval of 32 days, the trough-to-peak ratios were characterized by large intraindividual variability. The median trough-to-peak ratios increased (P<.001) when the individual blood pressure profiles were progressively smoothed by substituting 1-hour averages by 2-hour moving averages (systolic/diastolic pressure, 0.41/0.27), 2-hour averages (0.43/0.29), 3-hour moving averages (0.42/0.34), or 3-hour averages (0.47/0.36). In conclusion, the trough-to-peak ratio is idealized by not accounting for interindividual and intraindividual variabilities and by smoothing of the diurnal blood pressure profiles. If after review of its usefulness the trough-to-peak ratio is further instituted as an instrument in the evaluation of long-acting antihypertensive drugs, its determination and presentation must be regulated beyond the presently available recommendations.
Key Words: antihypertensive therapy • blood pressure monitoring, ambulatory • lisinopril
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Introduction |
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Monitoring the ambulatory blood pressure instead of taking blood pressure readings at the hospital avoids the so-called white-coat effect1 2 and allows more readings to be obtained over longer time periods. In crossover trials focusing on the average 24-hour blood pressure, ambulatory monitoring also improves the accuracy of the blood pressure estimates and increases the statistical power.3 4 5 6 7 For these reasons, ambulatory monitoring is increasingly being used in clinical trials,8 9 10 11 in particular with the purpose to license long-acting antihypertensive agents.
In an attempt to create an operational index of the duration of antihypertensive activity, the U.S. Food and Drug Administration in 1988 introduced and promulgated the trough-to-peak ratio of blood pressure responses.12 13 14 15 The American guidelines indicate that in addition to maintaining a useful antihypertensive effect at the end of the dosage interval, the trough effect should be at least half of the peak effect once appropriate adjustments have been made for placebo effects. However, the guidelines do not define "useful" and do not stipulate how interindividual variability and smoothing of the diurnal blood pressure profiles should be handled.12 13 14 15 The influence of the latter two factors on the trough-to-peak ratio was therefore examined by analysis of the ambulatory blood pressure recordings from the patients who had been enrolled in the APTH (Ambulatory Blood Pressure and Treatment of Hypertension) Trial.16
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Methods |
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Study Design
The protocol of the APTH Trial, which has been reviewed and approved by the Ethics Committee of the Faculty of Medicine at the University of Leuven, has been published in detail elsewhere.16 After a 2-month, single-blind, run-in period on placebo, hypertensive patients were randomized into two groups, ie, one group in which the target was a sitting diastolic pressure from 80 through 89 mm Hg measured during the day by conventional sphygmomanometry and one group in which on ambulatory monitoring during daytime (from 10 AM to 8 PM) an average diastolic pressure from 80 through 89 mm Hg had to be achieved and maintained.
Patients and Treatments
At the first screening visit, all patients gave informed consent
and were started single-blind on one placebo tablet per day, to be
taken in the evening. In previously treated patients, antihypertensive
medications were gradually discontinued.
After the patients had been without antihypertensive treatment for at least 1 month, their sitting blood pressure was measured by an auscultating observer at two further run-in visits on placebo 1 month apart. If at these two visits the last of three consecutive diastolic blood pressure readings averaged 95 through 114 mm Hg, the patients were randomized. Patients whose sitting diastolic pressure exceeded 114 mm Hg were also eligible, but they were examined at intervals of only a few days so that after collection of all baseline data, active treatment could be started without further delay. Eligible patients were at least 18 years old. Women with childbearing potential practiced adequate contraceptive measures. Patients were excluded if one of the following conditions was present: the need for sustained treatment with blood pressure–lowering medications, complications of hypertension, major noncardiovascular diseases, and a serum creatinine concentration in excess of 135 µmol/L (1.5 mg/dL).
The same standardized treatment regimen was used in the two arms of the trial.16 After randomization, antihypertensive treatment was started in all patients with lisinopril 10 mg per day. One month later, lisinopril could either be continued at a daily dose of 10 mg or 20 mg or discontinued, depending on whether the diastolic pressure was at, above, or below the target level. Further evaluations were scheduled 4 and 6 months after randomization but were not included in the present analysis.16
On December 1, 1994, 272 patients had been randomized into the trial. Of these, 129 were excluded from the analysis because they had not yet proceeded to the second visit after randomization (n=47), because they had been started on atenolol or hydrochlorothiazide instead of lisinopril to avoid previously experienced adverse effects to angiotensin-converting enzyme inhibitors (n=18), because at the first visit after randomization active antihypertensive treatment had been discontinued (n=27), or because according to the patient's diary lisinopril had not been taken between 7 and 11 PM (n=37).
The remaining 143 patients, who were selected for the analysis, all had been followed for 2 months or longer. At 2 months they were taking either 10 mg or 20 mg lisinopril in a single daily dose between 7 and 11 PM. On monitoring days, they had noted the precise hour of drug intake in a diary.
Blood Pressure Measurements
SpaceLabs 90207 monitors17 were programmed to
obtain blood pressure readings at intervals of 15 minutes from 8
AM to 10 PM and at 30-minute intervals for the
remainder of the day. The clinic pressures corresponding with the
recordings were the averages of three measurements obtained by
auscultation of the Korotkoff sounds after the patients had rested in
the sitting position for 5 minutes.16 The clinic blood
pressure readings were obtained on weekdays during regular working
hours.
Analysis of Ambulatory Recordings
If the ambulatory recordings were longer than 24 hours,
only the first 24 hours was used for analysis. Editing the
recordings according to previously published
criteria18 excluded fewer than 0.5% of the readings and
did not influence the results. Only the findings from unedited
recordings are therefore presented.
The ambulatory measurements were averaged with weights according to the time interval between consecutive readings.19 20 Daytime was defined as the period from 10 AM to 8 PM, and nighttime ranged from midnight to 6 AM.18 The trough-to-peak ratios were determined from diurnal blood pressure profiles with 1-hour resolution. The effects of smoothing were investigated by substituting the 1-hour blood pressure averages by 2-hour and 3-hour averages. Moving averages were calculated using steps of 1 hour.
To calculate the effect of treatment, the diurnal blood pressure profiles were synchronized by the hour of lisinopril intake. Following published recommendations,12 the blood pressure level at baseline was subtracted from the corresponding value at 2 months for all time intervals considered in the analysis. In keeping with current guidelines,13 14 the trough treatment effect was determined at the last interval before lisinopril intake. The peak effect was considered to have occurred at the interval during which the blood pressure at 2 months was maximally lowered compared with the baseline blood pressure.
In keeping with the current literature,21 the trough and peak effects and their ratios were first determined in all patients combined (global estimates). In addition, in order to evaluate intraindividual and interindividual variabilities, these parameters were also obtained from profiles in every patient separately. Trough-to-peak ratios on 10 and 20 mg lisinopril were contrasted to exclude that the dose of lisinopril had influenced the results.
Other Statistical Methods
Because the distribution of the trough-to-peak ratio in
all patients combined deviated from normality on Shapiro-Wilk's
test,22 the central tendency and spread of the individual
data were represented by the median and the 5th to 95th
percentile interval. The 95% confidence interval of the median was
calculated according to Campbell and Gardner's method.23
Wilcoxon's test was used to compare the trough-to-peak
ratios and Student's t test for all other comparisons.
Reproducibility of the measurements was studied by Bland and Altman's technique24 in the 66 patients in whom the ambulatory blood pressure had been recorded on 10 mg lisinopril at 1 and 2 months. The repeatability coefficients24 were expressed as a percentage of the range representing nearly maximal variation, ie, the 5th to 95th percentile interval for the trough-to-peak ratios, and four times the standard deviation of the underlying measurement for all other parameters.19
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Results |
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Patients at Baseline and at 2 Months
The 143 participants, 70 men and 73 women, were 53±11 years old (mean±SD) (range, 23 to 78 years). At baseline, their conventional blood pressure averaged 166±20 mm Hg systolic (range, 124 to 238 mm Hg) and 104±10 mm Hg diastolic (95 to 141 mm Hg); the 24-hour pressures were 147±17 mm Hg (110 to 194 mm Hg) and 92±10 mm Hg (69 to 125 mm Hg), respectively. Body mass index averaged 28.4±3.5 kg/m2 in men and 28.8±4.8 kg/m2 in women. Of the 143 patients, 78 had been randomized to treatment guided by conventional sphygmomanometry.
At 2 months, the daily dose of lisinopril was 10 mg in 66 patients and 20 mg in 77 patients. On lisinopril (Table 1), the clinic as well as the 24-hour, daytime and nighttime pressures decreased significantly (P<.001). Comparison of the diurnal blood pressure profiles at baseline and at 2 months (Fig 1) confirmed that the treatment effect (Fig 2) persisted throughout the day.
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Estimating the Trough-to-Peak Ratio in Groups
Global Versus Individual Estimates
The parameters globally derived from the diurnal
treatment effect curves in all 143 patients combined (Fig 2) were compared with the averages of the individual
estimates obtained in each patient separately (Table 2). Both approaches yielded similar
estimates of the trough effect because the latter was always determined
at the last interval before dosage. As far as the peak effect was
concerned, there was in individual patients large variability not only
in the magnitude of the maximal blood pressure reduction but also in
the time-to-peak. By contrast, in the global approach both the
timing and the magnitude of the peak blood pressure reduction were read
from the overall treatment effect curve in all patients combined (Fig 2). Not accounting for the interindividual variation in
the time-to-peak explained why the average peak effect in the
global approach differed largely from the mean of the individual peak
effects and therefore why also the estimates of the
trough-to-peak ratios were widely discordant (Table 2).
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Responders Versus Nonresponders
The distribution of the trough-to-peak ratio in all
patients combined (n=143) deviated (P<.001) from normality
(Fig 3). In some patients the blood
pressure at the end of the dosage interval was higher at 2 months than
at baseline, explaining why the baseline-adjusted
trough-to-peak ratio was negative (positive denominator divided
by negative nominator).
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In a further step of the analysis the patients were subdivided
into responders (<90 mm Hg) and nonresponders (
90 mm Hg) on the
basis of their diastolic blood pressure at 2 months, ie,
the conventionally measured diastolic pressure in the
patients (n=78) randomized to treatment guided by the clinic pressure
or the daytime diastolic pressure in the patients (n=65) in
whom the ambulatory recordings had been used to adjust
treatment.
In responders and nonresponders, considered separately, the trough-to-peak ratios were normally distributed with the exception of the systolic ratio (P<.001) in the nonresponders. In the responders (51% of the patients) the median trough-to-peak ratio was 0.36 for systolic pressure (5th to 95th percentile interval [PI], -0.05 to 1.00) and 0.35 (PI, -0.41 to 0.89) for diastolic pressure. In the nonresponders (49%) these values were 0.34 (PI, -0.47 to 0.77) and 0.22 (PI, -0.44 to 0.84), respectively.
Effects of Smoothing
The diurnal treatment effect curves were increasingly smoothed by
substituting 1-hour averages, respectively, by 2-hour moving averages,
2-hour averages, 3-hour moving averages, and by 3-hour averages.
Smoothing did not affect the estimates of the trough effect (Table 3). By contrast, as the diurnal profiles
were progressively smoothed, the apparent peak effects became smaller,
such that the corresponding median trough-to-peak ratios
increased.
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Influence of Daily Dose
The estimated trough and peak treatment effects, and hence the
trough-to-peak ratios, were the same in patients taking a daily
dose of 10 or 20 mg lisinopril. The median
trough-to-peak ratios on 10 mg lisinopril were 0.30
for systolic pressure and 0.28 for diastolic
pressure; the corresponding trough-to-peak ratios on 20 mg were
0.34 and 0.23, respectively (Table 4).
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Reproducibility of Trough-to-Peak Ratio in Individual
Patients
The reproducibility of the trough-to-peak ratios was
estimated in 66 patients in whom at 1 and 2 months of follow-up the
blood pressure had been monitored on a daily dose of 10 mg
lisinopril. The median interval between these duplicate
recordings was 32 days (range, 21 to 55 days).
The group means of the treatment effect parameters could be reliably reproduced, as the average changes between the duplicate measurements approximated to zero and were not significant (Table 5). However, the within-subject reproducibility of the treatment effect parameters was poor (Table 5). The repeatability coefficients ranged from 36% to 89%. In particular, for the trough-to-peak ratios, the repeatability coefficients expressed as a percentage of the 5th to 95th percentile range were 89% for systolic pressure and 86% for diastolic pressure.
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Discussion |
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The quest for long-acting antihypertensive agents is vigorously pursued by the pharmaceutical industry21 because once-daily administration is thought to increase patient compliance25 26 and because the still unproven27 hypothesis prevails that in order to reduce the cardiovascular complications of hypertension, blood pressure must be evenly lowered throughout the whole day. Against this background, the trough-to-peak ratio was originally conceptualized because of the growing concern that relatively short-acting antihypertensive drugs might be administered in inappropriately large doses in order to prolong the dosage interval.12 13 14 15 28 If such drugs were prescribed, the peak depressor action would be substantially larger than the trough effect, increasing the likelihood of hypotension and of wide swings in the blood pressure level at some time during the day. For instance, a regimen of isradipine 5 mg twice daily has been shown to produce a pronounced fall in blood pressure within 2 hours of drug intake.29 If the two daily doses were halved in an attempt to prevent the early peak hypotensive response, blood pressure control was lost during most of the dosage interval.29 Thus, the trough-to-peak ratio should never be considered in isolation but viewed in relation to the absolute treatment-induced decrease in blood pressure at the end of the dosage interval.
Conventional sphygmomanometry allows the determination of the
trough-to-peak ratio.14 30 However, the number of
blood pressure readings that an auscultating observer can practically
obtain in a group of patients constitutes a major limiting factor. As a
consequence, with the use of conventional blood pressure measurements,
the peak depressor action is usually determined at an arbitrarily
defined time point, which is often chosen to coincide with the peak
concentrations of the antihypertensive agent.31 This
approach does not fully account for the interindividual variation in
the timing of the peak depressor effect. Its occurrence is not only
dependent on between-subject and circadian32 variation
in the pharmacokinetics of the antihypertensive agent but also on
between-subject differences in the mechanisms, which sustain the
elevated blood pressure through the day, such as for instance
-adrenergic tone33 34 and the activity of the renin
axis.35 The present study demonstrated large
variability in the timing and in the size of the peak depressor effect
(Tables 2 and 3) for which, in addition to random variation, several
factors could account. The blood pressure profiles were synchronized by
the hour of lisinopril intake, but the interval during
which the patients took their medicine was 4 hours long. Physical
activity and sleeping hours were not standardized on monitoring days.
Along these lines, the average of the three blood pressure readings in
the hospital could even be viewed as a measurement that was more
standardized than the highly variable36 1-hour
averages of the ambulatory recordings, during which neither
physical nor mental activities had been controlled. On the other hand,
the two doses of lisinopril yielded similar estimates of
the trough-to-peak ratios. Moreover, the bioavailability of
lisinopril after oral intake, averaging 25%, is not
influenced by the presence of food in the gastrointestinal
tract.37
In calculating the trough-to-peak ratio, it is critical to subtract the placebo effect.12 13 14 28 38 Some investigators have failed to do this and have miscalculated the ratios.12 To correct for placebo effects, the trough blood pressure on placebo should be subtracted from the corresponding level on active treatment, and this difference should be divided by the equivalent pressure difference at peak antihypertensive activity.12 At peak, when by definition the antihypertensive action is maximal, these differences are likely to be negative in most if not all patients. However, at trough, it may happen that the blood pressure on placebo is actually lower than on active treatment, especially if the dosage interval is stretched beyond reasonable limits, or if in a clinical trial outside the clinic environment some noncompliant patients skipped their last dose. In this case, the denominator of the trough-to-peak ratio is positive, the nominator negative and hence the ratio itself becomes negative. Several excellent reviews on the trough-to-peak ratio12 13 14 28 30 38 carefully outlined the necessity to adjust the ratio for placebo effects as well as for the circadian variation in blood pressure. However, few stressed the importance of the intraindividual and interindividual variabilities.30 38 The possibility of observing negative trough-to-peak ratios in therapeutic trials was rarely mentioned.30
The ratio between trough and peak responses is most often expressed as a percentage or as a decimal fraction of one, which is then related to the values recommended in the guidelines proposed by the Food and Drug Administration. These guidelines suggested that the placebo-adjusted depressor action at trough should be no less than one half to two thirds of the placebo-corrected peak effect. Thus, by definition, 0.50 (50%) is the minimal acceptable value for the ratio. In most publications39 40 41 42 43 44 45 the trough-to-peak ratio was calculated by dividing the average trough effect in all patients combined by the average peak depressor action, which is equivalent to the global approach outlined in the present analysis (Table 2). The latter fails to appreciate the large interindividual variability (Fig 3). This analysis demonstrated that both the global and the individual approaches yielded similar estimates of the trough effects, whereas the peak effects, and hence the trough-to-peak ratios, differed largely (Table 2). Not only the point estimate of the ratio is relevant, but its distribution as well. With the notable exception of a few reports,30 38 46 its standard deviation and confidence interval or range were not reported yet reflect the precision by which advisory boards may need to be guided. Thus, the global approach is delivering an idealized estimate of the trough-to-peak ratio and should be abandoned in favor of estimates, which do fully account for interindividual variability.
A previous analysis based on the Syst-Eur Trial47 suggested that the apparent trough-to-peak ratio could be manipulated by changing the resolution of the diurnal profile. With the use of 1-hour intervals, the difference between the largest and smallest blood pressure reduction through the day averaged 10.7 mm Hg for systolic pressure and 7.6 mm Hg for diastolic pressure.47 These differences averaged 8.5 and 6.0 mm Hg for profiles with 2-hour intervals and 7.3 and 5.9 mm Hg for profiles with 4-hour intervals. The present study, in which all patients were on monotherapy with lisinopril, corroborated these findings. As the diurnal profiles were increasingly smoothed, the apparent trough-to-peak ratios increased (Table 3).
After oral intake, lisinopril is absorbed intact, attaining peak serum concentrations within 6 to 8 hours.37 Lisinopril is not metabolized or bound to plasma proteins and is eliminated primarily if not exclusively by the kidneys.37 Steady state serum concentrations are achieved within 2 to 3 days.48 In view of these pharmacokinetic characteristics37 48 49 and the pharmacodynamic50 and clinical51 properties of lisinopril, this inhibitor of the angiotensin-converting enzyme is generally considered to behave as a once-daily antihypertensive agent. The present study was not designed to evaluate the duration of action of lisinopril and therefore should not be interpreted as negating these previous findings.37 48 50 51 Although in short-term studies the placebo effect on the ambulatory blood pressure is deemed to be smaller than in long-term (1 year) trials,52 a randomized placebo-controlled design should actually be used to investigate the duration of action of antihypertensive agents. Moreover, the timing of drug intake should be standardized to a higher degree than was the case in the present study. To the extent that this is feasible, the same also applies to sleep and physical activity on monitoring days. Nevertheless, the APTH database provided the opportunity to highlight certain difficulties in determining the trough-to-peak ratio, which in like manner would be encountered in trials with a more specific design.
Based on the present observations and recent literature data,30 38 several possible recommendations come to mind. (1) The trough-to-peak ratio, adjusted for placebo effects,12 13 14 28 should be calculated from 24-hour blood pressure profiles in individual subjects, and its distribution must be presented. Interindividual variability also should be reported for the peak and trough depressor actions and for the time-to-peak. Such an approach would explore the full range of values of the trough-to-peak ratio and would make it possible to evaluate in how many patients the dosage interval was stretched beyond full coverage. (2) One possible argument in favor of a once-daily administration could be the observation that in all compliant patients the trough-to-peak ratio remains positive in 24-hour ambulatory recordings. Conversely, the longest acceptable dosage interval could be defined as the period over which the ratio stays positive in cooperative patients. The implementation of these criteria would require that patient compliance, an important confounder in all therapeutic trials, be checked in an objective manner. (3) Drug intake should be timed, not only depending on the pharmacokinetic properties of a novel agent, but also taking into account the circadian rhythmicity of the blood pressure regulating mechanisms33 34 35 with which the new agent is assumed or proven to interfere. In this context one should keep in mind that the trough-to-peak ratio may be biased toward lower values by administering a long-acting antihypertensive agent upon awakening in the morning. By doing this, the peak effect would tend to coincide with the high daytime pressure and the trough effect with the lower nighttime pressure, while in general the ambulatory blood pressure falls more with higher prevailing blood pressure levels.53 54
Intraindividual and interindividual variability in the trough-to-peak ratio is a major problem facing decision makers, which in fact is not resolved by but is highlighted by the technique of ambulatory blood pressure monitoring. In the light of the present findings and other published data,30 38 the drug licensing agencies in the United States and in Europe may need to revise the use of the trough-to-peak ratio in clinical trials. If as a result of this review process the ratio is further instituted as an instrument for the evaluation of long-acting antihypertensive agents, the procedures for its determination must be thoroughly regulated so that diverse studies and agents can be easily compared and so that experiments and analyses cannot be adapted to suit the needs of a particular antihypertensive agent. Moreover, the appropriateness of a cutoff point for the trough-to-peak ratio indicating coverage of the whole dosage interval, if deemed necessary for licensing purposes, should be based on criteria, which are scientifically rather than arbitrarily defined, and which also account for the absolute blood pressure reduction at trough.
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Acknowledgments |
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The APTH Trial was conducted under the auspices of the Belgian Hypertension Committee and is supported by ZENECA (Destelbergen, Belgium). The study medication was donated by ZENECA and Roerig-Pfizer (Brussels, Belgium). The secretarial assistance of R. Crabbé is gratefully acknowledged.
APTH Investigators: In Belgium: G. Adriaens (Neerwinden), M. Beenaerts, S. Henderickx, J.H. Keijser, P. Van Den Eluen, R.A. Van Der Have (Lommel), N. Bernard (Beyne-Heusay), C.H. Berthe (Saint Nicolas), L. Bieniaszewski, H. Celis, R. Fagard, J.A. Staessen, L. Thijs (Hypertensie en Cardiovasculaire Revalidatie Eenheid, Departement Moleculair en Cardiovasculair Onderzoek, K.U. Leuven, Leuven), H. Bruggeman (Sint Jozefziekenhuis, Maasmechelen), F. Buntinx, P. De Cort, P. De Hertogh, J. Heirman (Centrum voor Huisartsgeneeskunde, K.U. Leuven, Leuven), E. Cerstelotte (Beringen), G. Charbel (Clinique Saint Etienne, Bruxelles), J. Claessens, D. Staessen (Eeuwfeestkliniek, Antwerpen), V. De Bock (Kliniek Louise-Marie, Antwerpen), G. De Ceuster, E. Verlinden (Boechout), E. De Graef (Humbeek), L. De Groote (Kessel-Lo), P. De Jaegher, I. Elegeert (Sint Niklaaskliniek, Kortrijk), J. Dekelver (Maasmechelen), F. Delvaux (Winksele), J.F. Deplaen (Clinique Universitaire Saint Luc, U.C. Louvain, Bruxelles), M. Deruyver (Leest), M. Derveaux, B. Vergauwen (Sint Jozefkliniek, Mortsel), A. De Vlieger (Koekelare), L. De Wolf (Heilig Hart Kliniek, Tienen), V. Fronville (Namur), M. Geboers (Sint Jozefziekenhuis), M. Geeraert (Ichtegem), J. Geurts (Rotem-Dilsen), Y. Haralambidis (Bruxelles), M.C. Herregodts, A. Vandeplas (Medisch Centrum der Huisartsen, Leuven), V. Immegeers (Heilig Hartziekenhuis, Asse), S. Lens, R. Lins (Stuivenbergziekenhuis, Antwerpen), H. Lesseliers, J. Thoeng (Turnhout), I. Leunckens (Antwerpen), F. Libaut (Opwijk), M. Maes (Beverlo), K. Mechelmans (Zwartberg), J. Panneels (Wezembeek-Oppem), A. Pattyn, J. Van De Bruaene (Deerlijk), E. Philips (Oostende), S. Rigo (Maasmechelen), J. Schurmans (Medisch Centrum, Tessenderlo), A.M. Spaey (Heverlee), R. Stroobandt (Sint Jozefkliniek, Oostende), R. Van Boxstael (Betekom), K. Van Cleemput (Eppegem), D. Vandenbrande (Brussel), S. Vanden Bempt (Veltem), S. Van Den Noortgate (Wilrijk), E. Vanderputte (Leut), S. Van Der Vliet (Eppegem), J. Van De Walle (Boechout), A. Van Dorpe (Mariaziekenhuis, Lommel), F. Van Essche (Tervuren), L. Van Geel (Boechout), M. Van Halewijn (Brussel), R. Van Hoof (Militair Hospitaal, Brussel), P. Vankrunkelsven, C. Vanwelden (Laakdal), J. Van Leeuwe (Tervuren), F. Van Lint, J. Van Lint (Arendonk), W. Van Mieghem (Kliniek André Dumont, Genk), W. Van Peer (Boechout), G. Vereeken (Halen), I. Verscheuren (Wilsele), K. Von Kemp (Wemmel) and H. Willems (Overijse). In other countries: N. Atkins, F. Mee, E.T. O'Brien (Beaumont Hospital, Dublin, Ireland), P. De Leeuw (Universitair Ziekenhuis Maastricht, Netherlands) and P. Frambach (Luxembourg, Luxembourg).
Advisory Board: Belgian members: A. Amery (died on 2 November 1994), F. Buntinx, R. Fagard, J.A. Staessen (Leuven), D. Clement (Gent), J.P. Degaute, J.F. Deplaen (Bruxelles), G. Rorive (Liège), and R. Lins (Antwerpen). Other members: P. De Leeuw (Maastricht, Netherlands), and E.T. O'Brien (Dublin, Ireland).
Trial Management: The APTH Trial is managed by J. Polfliet, J. Staessen (Campus Gasthuisberg, Leuven, Belgium), and G. Byttebier, M. De Bosschere, H. De Roeck, T. Van Hedent, C. Vincent (ZENECA, Destelbergen, Belgium).
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Footnotes |
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A complete list of the participants of this study appears in "Acknowledgments."
Received March 1, 1995; first decision March 28, 1995; accepted June 22, 1995.
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References |
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