Use of electronic pill boxes to assess risk of poor treatment compliance: results of a large-scale trial.

The objective of the present study was to determine the predictive factors of treatment compliance in hypertensive patients. This was an open large-scale multicenter study where mild to moderate essential hypertensive patients received trandolapril (2 mg) once daily for 30 to 60 days in addition to their usual treatment. Trandolapril was packed in electronic pill boxes that registered date and time of each opening. The main compliance parameters were the percentage of missed doses, the percentage of delayed doses, and the percentage of correct dosing periods. Predictive factors of poor compliance (correct dosing periods < 80%) were determined using a multivariate stepwise logistic regression analysis. Two thousand one hundred seventy-three patients aged 60 +/- 12 years were analyzed. Of the total patients 37% were poor compliers; 29% of patients forgot more than 10% of doses and 36% of patients delayed more than 10% of doses. Ranked predictive factors of poor compliance were: age < 60 years (odds ratio [OR], 1.80 [1.49 to 2.17], P = .0001), the Paris area (OR, 1.70 [1.32 to 2.19], P = .0001), smokers (OR, 1.65 [1.29 to 2.11], P = .0001), monotherapy (OR, 1.40 [1.14 to 1.72], P = .0012), and baseline diastolic blood pressure > or = 100 mm Hg (OR, 1.21 [1.01 to 1.46], P = .044). Therefore, we conclude that young hypertensives, large city dwellers, and smokers are more likely to be poor compliers. The presence of some of these characteristics might incite the physician either to encourage patient compliance or to prescribe antihypertensive drugs that have an effect that persists even beyond 24 h.

Short-term effects of withdrawing angiotensin converting enzyme inhibitor therapy on home self-measured blood pressure in hypertensive patients.

The aim of this study was to compare blood pressure rise after interruption of two angiotensin converting enzyme (ACE) inhibitors in hypertensive patients. After a 2-week placebo run-in period, hypertensive patients were treated with either trandolapril 2 mg once daily or perindopril 4 mg once daily for 4 weeks in a double-blind design. A placebo was then administered for 1 week. Three periods of 1-week home self-measured blood pressure (SMBP) were programmed: end of placebo run-in period, end of treatment period, and final withdrawal placebo period. Every day, three consecutive measurements were requested both in the evening and in the morning. Individual reversion to baseline BP level was studied in the subgroup of patients responding to therapy (evening diastolic SMBP decrease > or =6 mm Hg). The ratio (R) of mean post-drug DBP lowering (residual effect) over evening on-drug DBP lowering (full effect) was used to study reversion to baseline. Patients exhibiting a lower value than the median of this ratio were called Reverters, whereas others were called Nonreverters. One hundred-nineteen patients entered the analysis. During the treatment period, mean SMBP decreased significantly, from 150 +/- 14/97 +/- 7 mm Hg to 139 +/- 15/91 +/- 9 mm Hg (all P < .001). The on-drug BP level was similar in the evening in the two treatment groups. However, both systolic and diastolic morning SMBP levels were significantly lower in the trandolapril group. After drug discontinuation, the mean BP level significantly rose to 144 +/- 14/94 +/- 9 mm Hg (all P = .01) but remained lower than the baseline BP values (P = .003 for SBP and P = .002 for DBP). The post-drug BP level was significantly lower in the trandolapril group than in the perindopril group. Seventy-four patients were responders to therapy. In this subgroup, the median of the R ratio used to analyze reversion to baseline after drug discontinuation was 44%. Nonreverters were characterized by a sustained on-drug BP decrease, compared to Reverters. We therefore conclude that ACE inhibitor treatment withdrawal is accompanied by a rapid rise in BP (within 48 h), followed by a 5-day BP plateau that is lower than the initial level. Reverters to baseline after drug discontinuation were more likely to be insufficiently controlled during therapy, particularly in the morning. The longer duration of action of trandolapril was associated with a lower BP level during both the morning during the active treatment phase and the 1-week posttreatment phase.

Superiority of home blood pressure measurements over office measurements for testing antihypertensive drugs.

OBJECTIVE: To compare the effects on office blood pressure and home blood pressure of placebo and active drug administration. DESIGN: After a 2-week wash-out period, patients with mild-to-moderate hypertension entered a 2-week single-blind placebo period and then a 4-week double-blind period. Patients were randomly assigned to be administered either 2 mg trandolapril once daily or its placebo in a 2:1 proportion. Office blood pressure was measured by a physician at the end of each period, using a mercury sphygmomanometer (mean of three consecutive measurements). Home blood pressure was measured during the last week of each period according to standard procedure carefully taught to each patient by the physician. Compliance was checked by using electronic pill boxes. RESULTS: Data for 34 of the 44 patients who entered the study were eligible for analysis. Baseline systolic blood pressure/diastolic blood pressure were significantly (P = 0.0001/P = 0.0001) higher for office blood pressure (161/101 mmHg) than they were for home blood pressure (145/93 mmHg). There was no statistically significant difference between the placebo and active-treatment groups at baseline. During the single-blind period, blood pressures measured at the office and at home did not change significantly. Office blood pressure decreased by 2.7 +/- 10 mmHg for systolic blood pressure and by 0.5 +/- 4 mmHg for diastolic blood pressure whereas home blood pressure increased by 0.8 +/- 6 mmHg for systolic blood pressure and by 0.7 +/- 4 mmHg for diastolic blood pressure. During the double-blind period, office blood pressure fell significantly with trandolapril treatment (systolic by 10.2 +/- 12 mmHg, diastolic by 8.3 +/- 6 mmHg; P = 0.0005/0.0001, versus single-blind placebo period) but this decrease was not significantly different (P = 0.45/0.92) from the fall in members of the placebo group (systolic by 6.9 +/- 9 mmHg, diastolic by 8.0 +/-6 mmHg; P = 0.04/0.002, versus single-blind placebo period). Thus, no antihypertensive effect of trandolapril was demonstrated. The fall lin home blood pressure with trandolapril treatment was significant (systolic by 10.7 +/- 8 mmHg, diastolic by 5.8 +/- 5 mmHg; both P = 0.0001, versus single-blind placebo period) and was significantly greater (P = 0.0004/0.004) than the minimal change observed with placebo (systolic fell by 0.2 +/- 5mmHg, diastolic fell by 0.6 +/- 4 mmHg; P = 0.90/0.62, respectively, versus single-blind placebo period). The evening decrease in home blood pressure was similar to the morning decrease in home blood pressure in members of the trandolapril-treated group. The resulting morning:evening decrease in blood pressure ratio was 0.83 for diastolic blood pressure and 0.95 for systolic blood pressure. For the subgroup of responders, mean of individual ratios was 0.77 +/- 0.43 for diastolic blood pressure and 0.70 +/- 0.39 for systolic blood pressure. CONCLUSION: The placebo effect observed with office blood pressure measurements does not occur with home blood pressure measurements. Expected treatment effect can alter a physician's blood pressure readings. The precision of measurements is greater with home blood pressure (there is a lower SD). Use of home blood pressure measurements increases the power of comparative trials, allowing one either to study fewer subjects or to detect a smaller difference in blood pressure.

[Demonstration of differences in the effect of 2 antihypertensive agents by self blood pressure measurement: comparison of trandolapril and perindopril]. / Mise en évidence de différences dans l'effet de deux antihypertenseurs par automesure tensionnelle: comparaison du trandolapril et du périndopril.

In this double blind randomized study, blood pressure lowering effects and duration of action of two angiotensin converting enzyme (ACE) inhibitors were compared using home self blood pressure measurement (SBPM). After a two-week placebo run-in period, 128 hypertensive patients received during four weeks a daily morning dose of either perindopril (P) 4 mg or trandoplapril (T) 2 mg. One week of SBPM was planned at the end of both the run-in and the treatment period. Three consecutive measurements, with printed results, were requested in the morning before drug intake and in the evening. Run-in period home systolic (SBP) and diastolic (DBP) blood pressures were comparable in both groups: 149.9 +/- 14.5/97.3 +/- 8.1 mmHg in the P group (n = 63), 148.9 +/- 14.3/96.7 +/- 6.9 mmHg in the T group (n = 65). During the treatment period, evening BP was similar in the 2 groups: 139.1 +/- 14.3/89.9 +/- 9.1 mmHg in P group, 137.5 +/- 15.3/89.4 +/- 9.1 mmHg in T group (NS). On the other hand, morning BP was higher in the P group: 143.1 +/- 16.3/93.8 +/- 9.6 mmHg vs 137.4 +/- 16.7/90.3 +/- 9.7 mmHg (p < 0.05 for SBP and DBP-Student's t test). These results were confirmed by co-variance analysis after adjustment on initial BP. Due to standardized conditions of measurement, home SBPM was able to show a difference in BP lowering effects at the end of the inter-dose interval between two ACE inhibitors.

[Risk factors of adverse effects of angiotensin-converting enzyme inhibitors. Apropos of 30,072 patients treated by trandolapril]. / Facteurs de risque de survenue d'effets indésirables sous inhibiteur de l'enzyme de conversion: à propos de 30,072 patients traités per trandolapril.

SUMMARY: The aim of the present study was to investigate the incidence of adverse effects and the prognostic value of various risk factors in a large population of unselected hypertensive patients treated with the ACE inhibitor trandolapril. Among the 30 072 patients investigated in this post marketing retrospective study, 1813 patients (6.0 per cent) reported an adverse effect. The five most frequent side effects were coughing (3.1 per cent), dizziness (0.7 per cent), headache (0.6 per cent) asthenia (0.5 per cent) and nausea (0.3 per cent). Intolerance risk factors for trandolapril were researched using both univariate and multivariate analysis. In the univariate analysis, a prior intolerance of an ACE inhibitor and female gender were strongly correlated with either overall intolerance or coughing. The most relevant variables for the occurrence of adverse effects, listed according to their entry order in the multivariate analysis, were: prior intolerance of ACE inhibitors (OR: 4.19, 95 per cent CI: 3.66-4.78), female gender (OR: 1.46, 95 per cent CI: 1.31-1.63), prior intolerance of other antihpertensive agents (OR: 1.27, 95 per cent CI: 1.14-1.41), smoking (OR: 0.76, 95 per cent CI: 0.66-0.87) and combination with a beta blocker (OR: 1.31, 95 per cent CI: 1.08-1.58). A prior intolerance of an ACE inhibitor appears to be a very strong predictor of coughing (OR: 6.14, 95 per cent CI: 5.24-7.19). The following variables, namely female gender (OR: 1.61, 95 per cent CI: 1.40-1.85), age 60-80 (OR: 1.25, 95 per cent CI: 1.09-1.44) and prior intolerance of other antihypertensive agents (OR: 1.20, 95 per cent CI: 1.03-2.39) appear less significant.

Home self blood pressure measurement in general practice. The SMART study. Self-measurement for the Assessment of the Response to Trandolapril.

The SMART study (Self-Measurement for the Assessment of the Response to Trandolapril) was performed in general practice and enrolled 1710 patients in order to assess on a large scale the feasibility and informative value of self-measurement of blood pressure at home (SMBP), define home blood pressure (BP) levels in comparison to office readings, and determine the number of home measurements necessary to provide an accurate and precise BP value. After a 2-week washout period, patients with office diastolic blood pressure within the range 95 to 119 mm Hg received 2 mg trandolapril once daily in the morning for 4 weeks. Four days of SMBP were performed both at the end of the washout period and the end of the treatment period, with an automatic printer-equipped oscillometric device (A&D UA751). The first day values were not analyzed. Thus, the maximum number of BP measurements obtained per patient and per period was 18. Four hundred and twenty-four patients (25%) did not perform any measurements. One thousand one hundred and nine patients (65%) performed at least 4 measurements. Among them, 619 (36%) correctly performed all 18 measurements. A preference for digits 0 and 5 was detected in physicians' measurements (three consecutive values, during a single office visit). This digit preference was not found with the semiautomatic device. When the number of measurements selected for analysis was increased from 1 to 18, in the 604 patients who provided all recordings and fullfilled all protocol criteria, the standard deviation of the mean BP of the cohort was reduced by 17% for SBP and by 23% for DBP. Eighty-five percent of this reduction was already achieved by six home measurements taken at random. BP was significantly lower at home than at the office by 13 +/- 15 mm Hg for systolic BP (SBP), and 8 +/- 10 mm Hg for diastolic BP (DBP). This difference was independent of age, more marked in women (P < .001 for SBP and P < .05 for DBP), and had a Gaussian distribution. Under treatment, office SBP/DBP decreased from 166.4 +/- 14.8/101.4 +/- 5.7 mm Hg to 144.7 +/- 14.2/86.1 +/- 8.3 mm Hg, while SMBP decreased from 153.2 +/- 17.8/93.8 +/- 10.1 mm Hg to 139.4 +/- 16.4/85.1 +/- 9.5 mm Hg (all P < .0001). A major aim in research studies and individual care is to reduce BP measurements variability. This study demonstrates the ability to evaluate baseline SMBP level in two-thirds of patients previously unfamiliar with the method, the ability to evaluate treatment effect in about one-half of the patients, the improvement in the measurement precision obtained with the repetition of measures (at least six home measurements), and the absence of bias of SMBP as compared to office measurements.

Assessment of drug efficacy using home self-blood pressure measurement: the SMART study. Self Measurement for the Assessment of the Response to Trandolapril.

UNLABELLED: The SMART study (Self Measurement for the Assessment of the Response to Trandolapril) was a large scale trial conducted by general practitioners in order to assess the informative value of home self-measured blood pressure (BP) for the evaluation of therapeutic intervention. After a 2-week wash-out period, patients with office diastolic blood pressure (DBP) between 95 and 120 mm Hg received trandolapril, 2 mg once daily for 4 weeks. Four days of self-recorded BP were performed both at the end of the wash-out period and at the end of the treatment period with an automatic printerequipped device using the oscillometric method (A&D UA 751). Every day, a series of three consecutive measurements was planned in the morning before drug intake and repeated in the evening. A total of 1710 patients (946 men, 764 women) aged 56 +/- 11 entered the study. In the 816 patients who correctly performed self-measured blood pressure (SMBP) during both periods and followed the protocol schedule, office BP (SBP/DBP) decreased from 166.4 +/- 15/101.4 +/- 6 mm Hg to 144.7 +/- 14/86.1 +/- 8 mm Hg while SMBP decreased from 153 +/- 18/94 +/- 10 mm Hg to 139 +/- 16/85 +/- 10 mm Hg. A weak correlation was found between the two methods with regard to systolic (r = 0.47, P < 0.0001) and diastolic (r = 0.36, P < 0.0001) BP lowering. Individual response to therapy varied between the two methods: 633 patients (77.6%) exhibited at least a 10 mm Hg office DBP decrease while 493 (60.4%) presented at least a 6 mm Hg self measured DBP decrease in the evening; 65% of patients were considered as responders with both methods. The 24-h therapeutic coverage was assessed by the morning to evening BP decrease ratio (M/E ratio) which represents the ratio of the trough effect to the 12-h post dosing efficacy. Both population and individual M/E ratios ranged between 73% and 86% thus confirming the long duration of action of trandolapril. IN CONCLUSION: (1) discrepancies between office and self-measured BP evaluation of therapeutic response have been pointed out: agreement between the two methods is obtained in only 65% of patients, mainly due to intra-individual BP variability and recording conditions; and (2) self-measured BP could be a potential tool to explore the 24-h therapeutic coverage.

Errors in trough: peak ratio determinations induced by patient behaviour.

BACKGROUND: Trough: peak ratio is often used to evaluate the duration of antihypertensive action. Whatever the method of measurement chosen, trough effect has to be measured 24 h after the last drug intake for a once daily regimen. Peak effect is usually measured 4-6 h after drug intake. If patients' compliance to therapeutic instructions is perfect, then the 'intrinsic' trough: peak ratio of the drug is equal to the measured trough: peak ratio. Some patients do not follow these instructions, leading to biases in the evaluation of the ratio. For trough evaluation, all patients (N) are supposed to take the last dose of the drug the day before blood pressure measurement. However, if some patients (n1) wrongly take the drug in the morning of the visit, they will be evaluated at peak (type A error). For peak evaluation, all patients (N) are supposed to take the drug a few hours before blood pressure measurement. If some patients (n2) miss their morning dose, they will be evaluated at trough (type B error). METHODS: In the MACH 1 study, the use of an electronic pill count monitor allowed us to quantify n1/N and n2/N. A total of 452 hypertensive patients were randomly assigned to two groups. Patients in group 1 received written instructions to take their last dose during the morning of the day before the visit, whereas patients of group 2 had to take their last dose on the morning of the visit. RESULTS: Electronic pill-box recording revealed that 32.9%: of patients in group 1 committed type A error, whereas 27.7% of patients in group 2 committed type B error. The resulting 'pill-box corrected' trough: peak ratio was lower (87.5% for diastolic blood pressure and 93.1% for systolic blood pressure) than the uncorrected trough: peak ratio (95.2% for diastolic blood pressure and 96.0% for systolic blood pressure) of the population. CONCLUSION: The random behaviour of patients, with respect to treatment compliance, results in a systematic overestimation of the measured trough: peak ratio. The computation of this ratio may be optimized by improving patient compliance. Alternatively, only data from a patient subpopulation that complies with the therapeutic protocol, as reported by readings from electronic pill boxes, should be taken into account for its calculation.

Benefits of electronic pillboxes in evaluating treatment compliance of patients with mild to moderate hypertension.

OBJECTIVE: This study was designed to assess the compliance of hypertensive patients with a once-daily regimen of the angiotensin converting enzyme (ACE) inhibitor trandolapril and to evaluate the antihypertensive efficacy of the drug in relation to the time interval between taking the final dose and measuring the blood pressure (BP). DESIGN: After a 2-week wash-out period, hypertensive patients, recruited by cardiologists, received trandolapril 2 mg once daily in the morning for 4 weeks. METHODS: In order to assess compliance, each patient's supply of trandolapril capsules was presented in a pillbox that incorporated in its lid a microprocessor that recorded the date and time of each occasion that it was opened. BP was measured using validated semi-automatic devices, at the end of both the wash-out and the treatment period. RESULTS: A total of 590 patients entered the study. Compliance data were evaluable for 501 patients. Overall compliance, defined as the ratio of the number of openings recorded to the number of doses prescribed was less than 80, 80-100, and more than 100% in 17, 63 and 20% of patients, respectively. The average number (+/- SD) of missed doses was 4.5 +/- 8 (median 2). The average interval between successive openings was 25 h 07 min mean +/- 13 h (median 24 h). The average number of delayed doses (a delayed dose being defined as the box being opened 25-36 h after the previous occasion) was 5.6 +/- 3 (median 6). Patients living in the Paris area had more forgotten and delayed doses than those living in the provinces (7.9 versus 3.8 forgotten; P<0.0001 and 6.3 versus 5.5 delayed; P<0.005). Doses were forgotten and delayed more often during weekends than on weekdays. The greatest number of delayed doses occurred in those patients under 60 years of age (6.0 versus 5.2; P<0.01). Decreases in systolic blood pressure (SBP and diastolic blood pressure (DBP) were 20.3/12.8 mmHg, for patients whose final drug was taken on the same day as the BP measurement, and 18.9/11.2 mmHg for patients whose final dose was taken on the previous day. CONCLUSIONS: Electronic compliance monitoring allows refined analysis of the behaviour of hypertensive patients. In this study doses were missed and delayed frequently during the first month of treatment, depending on the patient's lifestyle.

[Behavior of patients with mild-to-moderate arterial hypertension in relation to their treatment. Contribution of an electronic pillbox]. / Comportement des patients ayant une hypertension artérielle légère à modérée vis-à-vis de leur traitement. Apport du pilulier électronique.

The objective of the MACH1 study (MEMS for the Assessment of Compliance of Hypertensives) was to evaluate the real behaviour of patients in relation to antihypertensive treatment administered as a single daily dose. After a 2-week period during which no other antihypertensive was allowed to be administered, 590 patients with mild-to-moderate hypertension received 2 mg of trandolapril as a single daily dose in the morning between 7:00 a.m. and 9:00 a.m. for 4 weeks. Treatment was packaged in electronic pillboxes recording the date and time of each opening. Various profiles were distinguished on the basis of the individual chronograms for the 501 patients able to be analysed in terms of compliance, and as a function of the deviations observed in relation to the treatment regimen prescribed. One hundred and two patients (20%) omitted more than 20% of the prescribed doses, either consecutive doses or scattered throughout the month of treatment; these patients were referred to as "omitters". The other patients were classified according to the scatter of openings in relation to the mean time of the dose: 10 "metronome" patients (2%), 126 "regular" patients (25%), 221 "irregular" patients (44%) and 42 "anarchic" patients (8%). Irregularities of dose times were more frequent on public holidays than on week days and in patients living in Paris or the Paris region. "Metronome" patients were older than the overall patient population. The use of an electronic pillbox could allow the attending physician to more adequately adapt his therapeutic approach and management of specific problems of compliance observed in hypertensive patients.

[Evaluation of trandolapril alone or in combination with a calcium channel blocker in hypertensive patients over 60 years of age]. / Evaluation du trandolapril seul ou en association à un inhibiteur calcique chez l'hypertendu âgé de plus de 60 ans.

The efficacy and safety of trandolapril alone and in combination with a calcium channel blocker were evaluated in 13,147 hypertensive patients over 60 years old. Two patient groups were constituted. After a 2-week wash-out period, the patients in group I received monotherapy with trandolapril 2 mg/day for 4 weeks. Trandolapril was continued for another 4 weeks in responding patient, otherwise the dosage of trandolapril was doubled or another antihypertensive was added. Group 2, composed of patients previously treated with a calcium channel blocker with insufficient efficacy, was treated according to the same treatment regimen, but the calcium channel blocker was maintained throughout the study. 13,147 patients (group 1: 11,329 patients, group 2: 1,818 patients) with a mean age of 68 +/- 7 years were followed. After 4 weeks of treatment, the blood pressure measured by mercury sphygmomanometer decreased from 176 + 11/99 +/- 8 mmHg to 164 +/- 12/87 +/- 7 mmHg (p < 0.0001). This blood pressure fall was similar in group 1 (-22 +/- 12/-12 +/- 8 mmHg) and in group 2 (-21 +/- 11/-12 +/- 8 mmHg). In the pure systolic HT subgroup treated by trandolapril monotherapy, the antihypertensive effect predominantly affected the SBP (-23 +/- 12/- 4 +/- 6 mmHg). The antihypertensive effect was correlated with the initial blood pressure. In group 1, in the case of insufficient response to trandolapril monotherapy, the addition of a calcium channel blocker was the strategy which achieved the most marked antihypertensive effect (ANOVA, p < 0.0001). This bitherapy was more effective than the trandolapril+diuretic combination (-18 +/- 11/- 11 +/- 8 mmHg and -15 +/- 10/- 9 +/- 7 mmHg, respectively (p < 0.001). A total of 1,270 adverse events were reported by 996 patients (7.6%), leading to discontinuation of treatment in 372 patients (2.8%). The most frequent adverse effects were cough (2.8%), headache (0.8%), vertigo (0.8%) and nausea (0.5%). Only one minor equivalent of angioneurotic oedema was reported. In conclusion, trandolapril is effective and well tolerated in elderly hypertensive patients. In the case of pure systolic HTA, its action is essentially exerted on SBP. The combination of trandolapril+calcium channel blocker appears to be the most effective strategy in the case of incomplete blood pressure control by trandolapril alone.

Differential effects of a missed dose of trandolapril and enalapril on blood pressure control in hypertensive patients.

A double blind randomised comparison of two angiotensin-converting enzyme (ACE) inhibitors was made in a study in which ambulatory blood pressure was monitored over a steady-state dosage interval and the subsequent 24-h period, the latter being designed to mimic a missed dose of drug. The blood pressure responses on active therapy were compared to an identical recording made at the end of a 3-week placebo run in period. Eighty-eight essential hypertensives were treated with a morning dose of either trandolapril 2 mg or enalapril 20 mg. Mean systolic (SBP) and diastolic blood pressure (DBP) were calculated on each of the following periods: daytime (8:31 a.m.-10:30 p.m.), nighttime (10:31 p.m.-6:30 a.m.), and early morning (6:31 a.m.-8:30 a.m.). Trough/peak was calculated for each group both on active treatment and after a missed dose. Twelve patients were excluded from analysis before opening the randomisation code because of inadequate ambulatory blood pressure monitoring (ABPM) recordings. Demographic data, placebo-period office blood pressure, and ABPM recordings were not significantly different between the two groups. Both trandolapril and enalapril effectively reduced blood pressure over the 24-h period. Twenty four-hour ambulatory SBP and DBP decreased from 148 +/- 14/92 +/- 10 mm Hg to 135 +/- 14/83 +/- 10 mm Hg in the trandolapril group (p < 0.001). The same parameters decreased to a quite similar extent after enalapril, from 143 +/- 13/91 +/- 5 mm Hg to 133 +/- 15/83 +/- 8 mm Hg (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Early termination of pregnancy with mifepristone (RU 486) and the orally active prostaglandin misoprostol.

BACKGROUND AND METHODS: The combination of mifepristone (RU 486) and a prostaglandin analogue given either intramuscularly or intravaginally is effective in terminating early pregnancy, but the prostaglandin component of the regimen is cumbersome to administer and has side effects. We conducted two studies to determine the efficacy of 600 mg of mifepristone followed by a small dose of misoprostol, an orally active prostaglandin E1 analogue, for the same purpose. In the first study, 505 women who had had amenorrhea for less than 50 days received 400 micrograms of misoprostol 48 hours after receiving mifepristone, if the pregnancy was not terminated within that period. In the second study, 390 women initially received the same treatment, but if the pregnancy was not terminated within four hours after the administration of misoprostol, they were offered an additional 200-micrograms dose of misoprostol. RESULTS: In study 1, the rate of success (termination of pregnancy and complete expulsion of the conceptus) was 96.9 percent (95 percent confidence interval, 94.1 to 97.7 percent)--similar to the success rate of approximately 95 percent for mifepristone followed by the intramuscular or intravaginal administration of prostaglandin. Abortion occurred in 2.9 percent of the women within 48 hours after the administration of mifepristone, in 60.9 percent within 4 hours after the administration of misoprostol, and in 33.2 percent thereafter. The failures included ongoing pregnancies in four women (0.8 percent) and incomplete abortions in nine (1.8 percent); two other women (0.4 percent) required vacuum aspiration for prolonged uterine bleeding. In study 2, pregnancy was terminated in 5.5 percent of the women before the administration of misoprostol and within four hours after the first dose of misoprostol in 69.1 percent. Among the 71 women who received a second dose of misoprostol, 67 had complete abortions, 2 had partial retention of the conceptus, 1 had synechia with ongoing pregnancy, and 1 had an ectopic pregnancy. One ongoing pregnancy, which was terminated by vacuum aspiration, was recorded among the 27 women who declined to take the second dose of misoprostol. The overall rate of success of the regimen with the optional second dose of misoprostol was 98.7 percent (95 percent confidence interval, 96.8 to 99.5 percent). No woman had any serious adverse event. CONCLUSIONS: The combination of mifepristone and misoprostol is effective for the termination of early pregnancy in terms of success, tolerance, safety, and practicality.

PIP: Between June and October 1991 health workers administered 1 dose of 600 mg mifepristone (RU-486) and a single oral dose of 400 mcg misoprostol on day 3 to at least 488 women at 25 centers in France to terminate pregnancy of less than 50 days duration. Pregnancy termination occurred within 48 hours in 2.9% of all women. They had only received RU-486. 1% vomited after taking the first dose of misoprostol, necessitating a second dose. The overall success rate for this regimen was 96.9%. 12 hours was the mean time between taking misoprostol and expulsion of the conceptus. The median time was 3 hours. The types of failure were incomplete expulsion of the conceptus (1.8%), ongoing pregnancy (0.8%), and prolonged bleeding (0.4%). Mean duration of bleeding following the regimen was 9 days. A second study occurred between March 1991 and March 1992 among at least 385 women at 1 center in France. They received RU-486 and misoprostol in the same manner as the women in study 1, but those who did not experience pregnancy termination within 4 hours after the initial dose received another 200 mcg dose of misoprostol. 5/5% experienced pregnancy termination before administration of misoprostol. 69.1% experienced termination within 4 hours. Pregnancy termination occurred within the first 3 hours in almost 90% of them. 27 women who did not abort within 4 hours did not take the additional dose and 26 of them aborted completely. The sole woman with a continued pregnancy underwent vacuum aspiration. 67 of the 71 women who took the second dose completely expelled the conceptus within 48 hours. Thus, 79.2% of all women aborted while being monitored at the center. The overall success rate was 98.7% . The leading side effects in both studies in order of frequency were uterine cramps and nausea, vomiting, and diarrhea. These results showed that oral administration of misoprostol is as effective and well tolerated as other prostaglandins administered parenterally or vaginally.

Demographic factors and the antihypertensive effect of diltiazem.

The maximum blood pressure (BP) decrease obtained after dose titration with calcium antagonists is said to be greater in older patients. Because the dose necessary to achieve this maximum effect may also vary, it is not clear whether the sensitivity to treatment is actually increased in older patients. We evaluated the possible influence of pretreatment BP, age, and weight on the BP and heart rate (HR) response to 14-day treatment with a fixed dose of 120 mg diltiazem twice daily (b.i.d.) in 231 hypertensive patients aged 24-82 years (44 +/- 27). Diltiazem decreased BP from 171 +/- 1/103 +/- 7 to 156 +/- 1/91 +/- 1 mm Hg. Decreases in both systolic and diastolic BP (SBP, DBP) were related to their pretreatment values (p less than 0.0001 for both). Although pretreatment SBP was related to age (p less than 0.0001), its decrease with diltiazem was not. Neither pretreatment DBP nor its decrease with diltiazem was related to age; BP decrease was not superior in elderly patients (aged greater than 60 years) as compared with that in younger patients (SBP -16 +/- 2 vs. -15 +/- 1 mm Hg, NS; DBP -13 +/- 1 vs. -12 +/- 1 mm Hg, NS). In conclusion, the response to this average dose of diltiazem is related to pretreatment BP and is not affected by patient's age. Because this result is at variance with the concept that calcium antagonists are more effective in the elderly, this concept should not be used as a general therapeutic guideline.

[Demographic characteristics and response to antihypertensive treatment. Study using fixed doses of diltiazem]. / Caractères démographiques et réponse au traitement antihypertenseur. Etude à dose fixe avec le diltiazem.

Since the stepped care approach has been widened to four classes of antihypertensive drugs, demographic considerations enter into the choice of the first line drug. Calcium antagonists have been claimed to be more active in older patients because the average BP decrease after dose titration could be greater in this age group than in younger people. In this study, the response to a fixed dose of diltiazem has been related to different demographic factors. The selected patients have been treated with diltiazem 120 mg b.i.d. in monotherapy for at least 14 days irrespective of their response to a lower dose. There were 231 patients (115 M, 116 F). Their average age was 59 +/- 11 years (24 to 82) and their treatment duration was 44 +/- 27 days. Diltiazem lowered BP from 171 +/- 1/103 +/- 7 mmHg to 156 +/- 1/91 +/- 1 mmHg. The decline in both SBP and DBP with diltiazem was significantly related to their control values (r = 0.31 and 0.28 respectively, p less than 0.0001 for both). Although control SBP was related to age (r = 0.40, p less than 0.0001), its decrease with diltiazem was not. Neither control DBP nor its decrease with diltiazem were related to age. Although the average SBP was higher in patients over 60 years than in younger patients (176 +/- 2 mmHg, n = 124 vs 166 +/- 2 mmHg, n = 107, p less than 0.01), its decrease with diltiazem was not significantly greater (- 16 +/- 2 vs - 15 +/- 1 mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)

[Prevention of per- and postoperative myocardial ischemia in non-cardiac surgery by intravenous diltiazem]. / Prévention de l'ischémie myocardique per- et postopératoire en chirurgie non cardiaque par le diltiazem intraveineux.

A controlled double-blind trial was carried out to assess the efficacy and safety of a continuous intravenous infusion of diltiazem in preventing perioperative myocardial ischaemia in patients with coronary artery disease. Sixty-six patients undergoing non cardiac surgical procedures (vascular surgery, n = 37; other, n = 29) were randomly chosen to receive either diltiazem (group D, n = 32); or placebo (group P, n = 34); there was no difference between these groups in the number of patients in each NYHA class (I: 13/16; II: 14/14; III: 5/4) or having had a previous myocardial infarct (20/22). ECG leads CM5 and CL5 were recorded continuously with an ICR 7200 Holter monitor. After starting recording, either placebo or a loading dose (0.5 mg.kg-1) of diltiazem was given, followed by an infusion of 5 micrograms.kg-1.min-1. Anaesthesia was induced by thiopentone and suxamethonium, and maintained with nitrous oxide (50%), fentanyl and either halothane or droperidol. The number of myocardial ischaemic episodes was significantly (p less than 0.05) lower in group D (2 ST depressions in two patients) than in group P (8 ST depressions in six patients, 2 myocardial infarcts and 1 pulmonary oedema). No conduction disturbance was observed; the lowest cardiac frequency was found in group P (32 b.min-1). Systolic and diastolic arterial blood pressures were lower in group D than in group P, but no difference was found in heart rate and rate-pressure product.(ABSTRACT TRUNCATED AT 250 WORDS)

RO 13-6438 in congestive heart failure: dose-response relationship after 3 single doses.

The dose-response for the new cardiotonic agent RO13-6438 was studied in 6 patients with grade III or IV congestive heart failure. Oral doses of 10, 20, or 30 mg of RO 13-6438 were administered on 3 consecutive days in accordance with a double-blind, randomized cross-over pattern. Hemodynamic changes, which were dose-dependent, included an increase in cardiac index combined with decreases in pulmonary capillary wedge pressure and systemic and pulmonary arterial pressures. Heart rate remained unchanged. The area under the plasma RO 13-6438 concentration time curve and the peak plasma concentration were dose-related. At each measurement, the log concentration of RO 13-6438 correlated with the percent changes in both cardiac index and capillary wedge pressure recorded at that time.

Contraception in hypertensive women using a vaginal ring delivering estradiol and levonorgestrel.

Contraception with a vaginal ring (CVR) that delivers estradiol and levonorgestrel was used during a mean of 15.6 menstrual cycles in 12 hypertensive women. Blood pressure (BP) was measured 5 times on each visit during 2 pretreatment control cycles; during the 1st, 2nd, 4th, 6th, and from the 9th to 12th cycles of CVR use; and again after a 1-month recovery period. No significant change in BP occurred during CVR use in any of the subjects. Plasma renin substrate and antithrombin III activity did not vary significantly, which suggests the utility of administering natural estradiol via the vagina, thus avoiding the first pass effect that occurs with oral contraceptives. Significant decreases in plasma sex hormone-binding globulin, cholesterol, high density lipoprotein cholesterol, phospholipids, and triglycerides occurred, indicating an androgenic effect of levonorgestrel. We conclude that the CVR is a method of contraception that does not elevate BP in hypertensive women.

PIP: Contraception with a vaginal ring (CVR) that delivers estradiol and levonorgestrel was used during a mean of 15.6 menstrual cycles in 12 hypertensive women. Blood pressure (BP) was measured 5 times on each visit during 2 pretreatment control cycles; during the 1st, 2nd, 4th, 6th, and from cycles 9-12 of CVR use; and again after a 1-month recovery period. No significant change in BP occurred during CVR use in any of the subjects. Plasma renin substrate and antithrombin III activity did not vary significantly, which suggests the utility of administering natural estradiol via the vagina, thus avoiding the 1st pass effect that occurs with oral contraceptives. Significant decreases in plasma sex hormone-binding globulin, cholesterol, high density lipoprotein cholesterol, phospholipids, and triglycerides occurred, indicating an androgenic effect of levonorgestrel. The authors conclude that the CVR is a method of contraception which does not elevate BP in hypertensive women.

Renal effects of calcium blockade by tiapamil in normal and hypertensive subjects.

The acute hypotensive and renal effects of the calcium antagonist tiapamil, a verapamil derivative, were studied in nine normal and 13 essential hypertensive subjects undergoing water diuresis. Tiapamil decreased mean arterial pressure slightly in normotensive subjects and more markedly in hypertensive patients (-6 +/- 1 versus -10 +/- 2%). The effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) were unaffected in both groups. A striking natriuresis was observed selectively in the hypertensive group (+344 +/- 84 versus +42 +/- 22 mmol/min) and was associated with an increase in the calculated fractional distal delivery of sodium and uric acid excretion rate. Plasma aldosterone concentration decreased moderately and to the same extent in both groups. In conclusion, tiapamil induced a marked natriuresis in essential hypertensive patients, despite a decrease in blood pressure, and in the absence of renal vasodilatation; this may suggest the existence in essential hypertension of a calcium-linked abnormality in the renal proximal tubular handling of sodium.