Early combination therapy with telmisartan plus amlodipine for rapid achievement of blood pressure goals.

BACKGROUND: Rapid and sustained blood pressure (BP) goal attainment is important to reduce cardiovascular risk. Initial use of combination therapy may improve BP goal attainment. METHODS: The Boehringer Ingelheim trial database was searched for randomised, double-blind studies comparing telmisartan/amlodipine combination therapy with monotherapy. Eight studies were identified. Eight separate analyses were used to compare combination therapy with respective monotherapies at the earliest available time points (weeks 1, 2 and/or 4). RESULTS: In patients initiated on combination therapy, greater systolic BP (SBP)/diastolic BP (DBP) reductions were seen with combination therapy (p < 0.0001); BP (< 140/90 mmHg), SBP (< 140 mmHg) and DBP (< 90 mmHg) goal attainment rates were significantly higher with combination therapy at all time points. In patients uncontrolled by monotherapy, greater SBP/DBP reductions were seen with combination therapy (p < 0.05 in all but one measure), and all goal attainment rates were significantly higher with combination therapy, except in one measure. CONCLUSION: Many people can achieve their BP targets when taking a combination of telmisartan and amlodipine after failing to do so with monotherapy. Furthermore, BP targets can be achieved more rapidly using a combination of telmisartan and amlodipine as initial therapy than with either monotherapy.

Valacyclovir in the treatment of facial herpes simplex virus infection.

The objective of this multicenter, randomized, double-blind, noninferiority trial was to investigate valacyclovir as treatment for facial herpes simplex virus (HSV) outbreaks. In total, 308 otherwise healthy outpatients self-initiated therapy with valacyclovir, either 1000 mg twice daily for 1 day or 500 mg twice daily for 3 days, for treatment of one facial HSV episode. Aborted lesions were the primary end point. Secondary end points included episode and pain resolution and lesion healing. By regimen (1 or 3 days), aborted lesions occurred in 42.2% versus 46.7% of patients, treatment difference, -4.5% (95% confidence interval, -16.3% to 7.4%; P=.49). Subgroup findings showed that about half the episodes aborted when therapy started during the prodrome/macule stages or within 6 h of first symptoms. Episode and pain resolved rapidly, with results similar for both treatments. Adverse events were infrequent and similar for the two regimens.

Antihypertensive treatment in elderly patients aged 75 years or over: a 24-week study of the tolerability of candesartan cilexetil in relation to hydrochlorothiazide.

OBJECTIVE: To assess the safety and tolerability of the AT1-receptor blocker candesartan cilexetil in relation to the diuretic hydrochlorothiazide (HCTZ) in elderly patients. DESIGN AND SETTING: A multicentre, double-blind, randomised, parallel group study. 32 general practice centres and 3 hospital centres in Denmark and Finland participated in this study. PATIENTS: 185 patients aged > or =75 years with mean sitting diastolic blood pressure (DBP) of 95 to 114mm Hg. INTERVENTIONS: After a placebo run-in period of 4 to 8 weeks, patients were randomised to once daily treatment with candesartan cilexetil 8mg or HCTZ 12.5mg for 24 weeks. In both treatment groups the dosage could be doubled after > or =2 weeks [according to blood pressure (BP) response] and, if necessary, subsequently decreased if the higher dosage was poorly tolerated. MAIN OUTCOME MEASURES: Proportion of patients with at least 1 adverse event; changes in laboratory values, electrocardiogram and BP during the double-blind treatment period. RESULTS: Once daily candesartan cilexetil 8 to 16mg was very well tolerated. The most common adverse events in both treatment groups were dizziness or vertigo and headache. Although the profile of adverse events was generally similar in the 2 treatment groups, it was notable that hypokalaemia and hyperuricaemia were not found in patients treated with candesartan cilexetil but occurred in 8.1 and 6.5%, respectively, of patients treated with HCTZ. At week 24, the adjusted mean changes in sitting DBP (24 hours postdose) from baseline were -12.0mm Hg [95% confidence interval (CI) -1 0.4 to -13.6] in patients treated with candesartan cilexetil and -11.4mm Hg (95% CI -9.3 to -13.6) in patients treated with HCTZ. The difference between treatments in favour of candesartan cilexetil was not statistically significant. CONCLUSIONS: This study shows that antihypertensive treatment with candesartan cilexetil in elderly patients (aged > or =75 years) is well tolerated with a good safety profile and avoids the metabolic adverse effects of diuretic therapy.

Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study.

OBJECTIVES: To assess and compare the effects of candesartan or lisinopril, or both, on blood pressure and urinary albumin excretion in patients with microalbuminuria, hypertension, and type 2 diabetes. DESIGN: Prospective, randomised, parallel group, double blind study with four week placebo run in period and 12 weeks' monotherapy with candesartan or lisinopril followed by 12 weeks' monotherapy or combination treatment. SETTING: Tertiary hospitals and primary care centres in four countries (37 centres). PARTICIPANTS: 199 patients aged 30-75 years. INTERVENTIONS: Candesartan 16 mg once daily, lisinopril 20 mg once daily. MAIN OUTCOME MEASURES: Blood pressure and urinary albumin:creatinine ratio. RESULTS: At 12 weeks mean (95% confidence interval) reductions in diastolic blood pressure were 9.5 mm Hg (7.7 mm Hg to 11.2 mm Hg, P<0.001) and 9.7 mm Hg (7.9 mm Hg to 11.5 mm Hg, P<0.001), respectively, and in urinary albumin:creatinine ratio were 30% (15% to 42%, P<0.001) and 46% (35% to 56%, P<0.001) for candesartan and lisinopril, respectively. At 24 weeks the mean reduction in diastolic blood pressure with combination treatment (16.3 mm Hg, 13.6 mm Hg to 18.9 mm Hg, P<0. 001) was significantly greater than that with candesartan (10.4 mm Hg, 7.7 mm Hg to 13.1 mm Hg, P<0.001) or lisinopril (mean 10.7 mm Hg, 8.0 mm Hg to 13.5 mm Hg, P<0.001). Furthermore, the reduction in urinary albumin:creatinine ratio with combination treatment (50%, 36% to 61%, P<0.001) was greater than with candesartan (24%, 0% to 43%, P=0.05) and lisinopril (39%, 20% to 54%, P<0.001). All treatments were generally well tolerated. CONCLUSION: Candesartan 16 mg once daily is as effective as lisinopril 20 mg once daily in reducing blood pressure and microalbuminuria in hypertensive patients with type 2 diabetes. Combination treatment is well tolerated and more effective in reducing blood pressure.

Candesartan Cilexetil, 16 mg, Provides a Greater Antihypertensive Effect than Losartan, 50 mg, in Patients with Mild to Moderate Hypertension.

Candesartan is a new angiotensin II type 1 (AT 1 ) receptor blocker, which binds tightly to and dissociates slowly from the AT 1 -receptor. These binding characteristics underpin the long duration of action and antihypertensive efficacy of candesartan, and help to differentiate it from losartan, which was the first AT 1 -receptor blocker to be approved for the treatment of hypertension. This study compared the antihypertensive effect and tolerability of candesartan cilexetil, 8 or 16 mg once daily, with that of placebo and of losartan, 50 mg once daily, in patients with mild to moderate primary hypertension. The dose of 50 mg for losartan was chosen, as this is the dose usually recommended; higher doses do not seem to result in further reductions in blood pressure. Men and women, aged 20-80 years, with primary hypertension and a sitting diastolic blood pressure (DBP) of 95-114 mmHg at the end of a 4-week placebo run-in period, were randomized to once-daily, double-blind treatment with candesartan cilexetil, 8 mg ( n = 82), candesartan cilexetil, 16 mg ( n = 86), losartan, 50 mg ( n = 84), or placebo ( n = 85) for 8 weeks. Blood pressure was measured 6 and 24 h after dosing, i.e. at the times of peak and trough effects, respectively. Differences among treatments in changes in blood pressure from randomization to the end of the study were assessed by analysis of variance. Patients were defined as having responded to treatment if sitting DBP was 90 mmHg or below at week 8 or if sitting DBP had been reduced by more than 10 mmHg from baseline to week 8. The proportion of responders in each treatment group was 15% for placebo, 46% for losartan, 50 mg, 50% for candesartan cilexetil, 8 mg, and 57% for candesartan cilexetil, 16 mg. The reduction in sitting DBP at trough (the primary effect variable) was significantly greater in patients treated with candesartan cilexetil, 16 mg, than in patients treated with losartan, 50 mg (see Table). In addition, both doses of candesartan cilexetil had a trough-to-peak ratio of approximately 1.0, compared with 0.7 for losartan. Both candesartan cilexetil and losartan were well tolerated, with the incidence of adverse events similar to placebo in both treatment groups. Overall, the most common new-onset adverse events reported were headache and respiratory infection, both of which are common in this type of patient population. In conclusion, candesartan cilexetil, 8 or 16 mg once daily, is an effective and well-tolerated antihypertensive treatment, with a trough-to-peak ratio close to 1.0. Candesartan cilexetil, 16 mg once daily, produces a significantly greater reduction in blood pressure than losartan, 50 mg once daily.

The antihypertensive effect and tolerability of candesartan cilexetil, a new generation angiotensin II antagonist, in comparison with losartan.

This multicentre study compared the antihypertensive effect and tolerability of the novel angiotensin II antagonist candesartan cilexetil with those of losartan and placebo. Men and women aged 20-80 years, with primary hypertension and sitting diastolic blood pressure (DBP) 95-114 mm Hg after a 4-week placebo run-in period, were randomized to once daily double-blind treatment with candesartan cilexetil 8 mg (n=82), candesartan cilexetil 16 mg (n=84), losartan 50 mg (n=83) or placebo (n=85) for 8 weeks. Blood pressure was measured 6 and 24 h after dose, i.e. at peak and trough. Differences between treatments were analysed by analysis of covariance, and the primary effect variable was reduction in trough sitting DBP. Compared with placebo treatment, trough DBP was significantly reduced by a mean (95% CI) of 8.9 (6.0; 11.8) mm Hg with 8 mg and 10.3 (7.4; 13.2) mm Hg with 16 mg candesartan cilexetil. The 8 mg dose was as effective as losartan 50 mg, while 16 mg candesartan cilexetil was significantly more effective, with a difference between treatments of 3.7 (0.8; 6.7) mm Hg (p=0.013). The placebo corrected trough/peak ratio was 0.9-1.1 with candesartan cilexetil and 0.7 with losartan. Candesartan cilexetil was similarly well tolerated as placebo. In conclusion, candesartan cilexetil 8 mg or 16 mg once daily is an effective and well tolerated antihypertensive treatment. Candesartan cilexetil 16 mg is significantly more effective than losartan 50 mg once daily.

Intrapartum fetal heart rate monitoring in a combined low- and high-risk population: a controlled clinical trial.

In a prospective clinical randomized investigation 487 women had the condition of the fetus during labour supervised by means of stethoscope (AUS), while 482 women went through labour under surveillance of electronic fetal monitoring, cardiotocography (EFM). 349 women refused to participate in the investigation (NAI) and had delivery conducted according to the normal procedures of the department (70% AUS, 30% EFM). Significantly more pathological fetal heart rate patterns (FHR) were found in the EFM group compared to the AUS group in both the first and the second stage of labour. As a result significantly more vacuum extractions were performed in the EFM group than in the AUS group, while no statistical difference was found between the groups in the incidence of acute cesarean sections carried out for asphyxia. One case of intrapartum death occurred in the AUS group. No differences were found in Apgar scores after 1 and 5 min or in neonatal morbidity at examination on the 2nd and 5th days after delivery. A tendency towards more biochemically compromised children was found in the AUS group. The specificity for both methods was found to be acceptably high (80%), while the predictive value for both methods was low (50%). More research is therefore urgently needed to evaluate supplementary investigations and parameters for the evaluation of the intrapartum fetal condition.

Maternal attitudes to fetal monitoring.

During a randomized clinical trial concerning alternative methods of intrapartum fetal surveillance (electronic fetal monitoring (EFM) and auscultation (AUS)) an investigatory interview was carried out. Out of 655 expecting mothers the antepartum preference of EFM was 39.5%, of AUS 32.3% and 28.1% were undecided (UD). EFM was especially preferred by obstetrical high-risk patients. Reasons for preference of AUS were a natural childbirth, a non-technological milieu, and the lack of supposed discomfort from sensors and belts. The pregnant women found as major advantages of EFM continuous observation and the possibility of quick intervention. Postpartum 385 patients were again interviewed. The majority upheld the original preference if that method was used. If the non-preferred method had been applied many would stick to the primary preference although a tendency to prefer the experienced method was seen. The patients who antepartum preferred AUS, but had EFM, became more positive toward the method, and a significantly increased number were positively influenced by the EFM signal/trace and found the method promoting their partner's involvement in labor. Enforced immobility, however, was a major disadvantage as well as the technical milieu. If EFM is to be accepted by a majority of women giving birth it is necessary to increase the pregnant women's knowledge of the method and to take milieu factors into consideration in order to reduce the intrinsic depersonalization of EFM.

Premature rupture of the membranes and Ritodrine treatment.

The treatment with Ritodrine of 38 women with preterm rupture of the membranes (PROM) and 109 with intact membranes (ITM) was compared. Before the 36th gestational week, parturition could be postponed significantly longer in the ITM group than in the PROM group (p less than 0.01), whereas there was no difference between the two groups after the 36th week. Parturition could be postponed significantly longer in the PROM group, when Bishop's score was below or equal to 6, than when it was above, while the same was true for ITM, when the score was even 9 or below (p less than 0.001). Therefore, it seems like that PROM adds 3 points to the Bishop score, when the score is used as a prognostic index for the ability to postpone parturition. There was no significant difference in the occurrence of RDS between the PROM group and the ITM group, although birth weight was significantly higher in the ITM group (mean 2799.5 g) than in the PROM group (mean 1985.5 g) (p less than 0.001). No serious side effects of the treatment given were seen, either in the mothers or in the infants. It is concluded that all women with preterm labor should be treated with ritodrine and bedrest, if betamethasone treatment of the mothers is indicated, as parturition could be postponed for at least 24 h in all pregnancies in both groups.

Fetal activity acceleration during early labor.

Altogether 59 women (53 normal and 6 high-risk pregnancies) underwent a fetal activity acceleration determination (FAD) during the first stage of labor. 52 FAD were considered reactive, while 5 were non-reactive and 2 technically inadequate. Four of the 5 fetuses with a non-reactive FAD showed signs of fetal compromise during labor and 1 died intra-uterinely. There were significantly more normal births and non-compromised fetuses in the FAD reactive group than in the non-reactive (p less than 0.002, chi 2-test), while there were significantly more acute cesarean sections in the non-reactive group (p less than 0.001, chi 2-test). Of the 12 vacuum extractions (all in the FAD reactive group) 4 were performed because of prolonged 2nd stage and 8 because of suspected because of prolonged 2nd stage and 8 because of suspected intra-uterine asphyxia, but all infants did well after delivery, and the umbilical arterial pH was in all cases above 7.15. It is concluded that when a FAD test is reactive in the first stage of labor, one can expect a positive outcome of the birth, whereas a non-reactive test arouses suspicion of fetal compromise and implies that one must carefully monitor the progress of the birth so that the fetus can be delivered promptly if any sign of late decelerations should appear. A reactive FAD is, on the other hand, rather reassuring for the fetal state.

Effect of maternal triglyceride ingestion on fetal respiratory movements.

The fetal breathing index is the time in which a fetus undertakes respiratory movements, expressed as a percentage of a 30-minute observation period. The fetal breathing index was studied following maternal ingestion of either a 100-ml triglyceride emulsion (Lipomul) plus 250 ml mineral water, or ingestion of 350 weeks' gestation were examined. The fetal breathing index increased similarly and significantly in both groups. As expected, maternal plasma triglyceride levels increased significantly in the triglyceride-stimulated group 180 minutes after ingestion of triglyceride emulsion plus water. The fetal breathing index for the triglyceride-stimulated group increased from 19.1 +/- 5.7% (SEM) to 38.8 +/- 10.5% at 90 minutes after ingestion, and to 44.4 +/- 14.1% after 180 minutes (P less than .05). In the control group (ingesting mineral water only), the fetal breathing index increased form 8.6 +/- 3.5% to 44.9 +/- 6.9% and 49.0 +/- 13.1% (P less than .05) after 90 and 180 minutes, respectively. Plasma triglyceride levels remained unchanged. No significant increase in maternal plasma free fatty acids, glucose, insulin, glucagon, total cortisol, or free cortisol levels was found. No increase in the fetal breathing index was found over a 180-minute period in 6 pregnant women who had not had oral intake of food or water (P = .17). The results suggest that oral intake of water, with or without added triglycerides, by fasting mothers might stimulate fetal respiratory movements.

Fetal respiratory movements: relationship to postnatal respiratory capacity.

Sixty-six normal and 346 pathologic pregnancies have been investigated by means of dynamic ultrasound for determination of fetal intrauterine respiratory amplitudes in over 930 scans of 30-minute duration. Ten fetuses developed respiratory distress syndrome (RDS), and all of these showed antenatally either falling (more than 2 SD) or abnormally low thoracic and abdominal amplitudes. No fetuses with amplitude measurements within the normal range (mean +/- 2 SD) developed RDS (p less than 0.001, X2 test). In 74 women, measurement of amniotic lecithin was performed within one half hour before a dynamic ultrasound registration, predictive value, or specificity between these two methods in identifying RDS. The conclusion is that the pathogenesis of RDS may be both biochemical and biophysical, and that this new noninvasive method may easily be used as a screening test for postnatal respiratory capacity in high-risk pregnancies, since only 10 equal and regular respiratory movements are needed for this measurement.

Fetal respiratory movements: a nomogram for fetal thoracic and abdominal respiratory movements.

A nomogram for fetal thoracic and abdominal amplitudes during respiration is presented. The correlation coefficient between the thoracic amplitude and gestational age was 0.973, and that for the abdominal amplitude was 0.920, thus suggesting a strong correlation between gestational age and respiratory amplitude (p less than 0.001), whereas no correlation was found between respiratory amplitude and fetal weight. The respiratory amplitudes were not influenced by intake of meals or time of the day when examination was carried out. The respiratory amplitudes were found to be very reproducible (SEM=0.1 mm, N=42). This new noninvasive method to predict the respiratory distress syndrome seems to be very promising.