An oxytocin receptor antagonist (atosiban) in the treatment of preterm labor: a randomized, double-blind, placebo-controlled trial with tocolytic rescue. A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). [A randomized study of the treatment of threatened premature labor. Nifedipine versus ritodrine]. A randomized comparison of nifedipine and ritodrine for suppression of preterm labor. The use of a calcium antagonist (nifedipine) to suppress preterm labour. Clinical investigation in Duchenne dystrophy. VI. Double-blind controlled trial of nifedipine. Controlled double-blind trial of dazoxiben and nifedipine in the treatment of Raynaud's phenomenon. A prospective, randomized trial of nifedipine vs. ritodrine in threatened preterm labor.
This study was designed to evaluate the efficacy and safety of the oxytocin receptor antagonist atosiban in the treatment of preterm labor.
                A multicenter, double-blind, placebo-controlled trial with tocolytic rescue was designed. Five hundred thirty-one patients were randomized to receive, and 501 received, either intravenous atosiban (n = 246) or placebo (n = 255), followed by subcutaneous maintenance with the assigned agent. Standard tocolytics as rescue tocolysis were permitted after 1 hour of either placebo or atosiban if preterm labor continued. The primary end point was the time from the start of study drug to delivery or therapeutic failure. Secondary end points were the proportion of patients who remained undelivered and did not receive an alternate tocolytic at 24 hours, 48 hours, and 7 days.
                No significant difference was found in the time from start of treatment to delivery or therapeutic failure between atosiban and placebo (median, 25.6 days vs 21.0 days, respectively; P =.6). The percentages of patients remaining undelivered and not requiring an alternate tocolytic at 24 hours, 48 hours, and 7 days were significantly higher in the atosiban group than in the control group (all P < or =.008). A significant treatment-by-gestational age interaction existed for the 48-hour and 7-day end points. Atosiban was consistently superior to placebo at a gestational age of > or =28 weeks. Fourteen atosiban-treated patients and 5 placebo-treated patients were randomized at <24 weeks; the incidence of fetal-infant deaths was higher for the atosiban group at <24 weeks. Maternal-fetal adverse events were similar except for injection-site reactions, which occurred more often with atosiban.
                In this trial the treatment of patients in preterm labor with atosiban resulted in prolongation of pregnancy for up to 7 days for those at a gestational age > or =28 weeks, and this occurred with a low rate of maternal-fetal adverse effects. In addition, at a gestational age > or =28 weeks, the infant morbidity and mortality of atosiban-initiated standard care were similar to those with placebo-initiated standard care. Given that all patients in this study were eligible for tocolysis and that, in practice, nearly all patients who are eligible for a tocolytic receive one, the benefit of using atosiban is the placebo-like maternal-fetal side effect profile. These observations support the use of this oxytocin receptor antagonist in the treatment of patients in preterm labor with intact membranes. Efficacy and infant outcome data at <28 weeks are inconclusive. Nifedipine, a dihydropyridone calcium entry blocker, has been used with increasing frequency in the treatment of preterm labor. We studied 66 patients in this prospective, randomized trial to evaluate the efficacy and maternal, fetal, and neonatal outcome associated with tocolysis with nifedipine or ritodrine. Delivery was delayed for 48 hours, 7 days, and until the thirty-sixth week of gestation in 84%, 70%, and 41%, respectively, of patients in the nifedipine group, compared with 72%, 63%, and 52% of patients in the ritodrine group (difference not significant). Maternal side effects were more common and more serious in the group of patients who received ritodrine compared with those who received nifedipine (18 of 38 versus 5 of 38, p less than 0.01); however, fetal and neonatal outcome appeared to be similar when the groups were compared. On the basis of this study, it appears that tocolysis with either nifedipine or ritodrine is equally efficacious; however, maternal side effects are less common with nifedipine treatment. We conclude that nifedipine may have a role in the treatment of preterm labor but suggest further careful evaluation of this agent before it is considered for routine clinical use. The efficacy of antihypertensive drugs newer than diuretics and beta-blockers has not been established. We compared the effects of the calcium-channel blocker nifedipine once daily with the diuretic combination co-amilozide on cardiovascular mortality and morbidity in high-risk patients with hypertension.
                We did a prospective, randomised, double-blind trial in Europe and Israel in 6321 patients aged 55-80 years with hypertension (blood pressure > or = 150/95 mm Hg, or > or = 160 mm Hg systolic). Patients had at least one additional cardiovascular risk factor. We randomly assigned patients nifedipine 30 mg in a long-acting gastrointestinal-transport-system (GITS) formulation (n=3157), or co-amilozide (hydrochlorothiazide 25 mg [corrected] plus amiloride 2.5 mg; n=3164). Dose titration was by dose doubling, and addition of atenolol 25-50 mg or enalapril 5-10 mg. The primary outcome was cardiovascular death, myocardial infarction, heart failure, or stroke. Analysis was done by intention to treat.
                Primary outcomes occurred in 200 (6.3%) patients in the nifedipine group and in 182 (5.8%) in the co-amilozide group (18.2 vs 16.5 events per 1000 patient-years; relative risk 1.10 [95% CI 0.91-1.34], p=0.35). Overall mean blood pressure fell from 173/99 mm Hg (SD 14/8) to 138/82 mm Hg (12/7). There was an 8% excess of withdrawals from the nifedipine group because of peripheral oedema (725 vs 518, p<0.0001), but serious adverse events were more frequent in the co-amilozide group (880 vs 796, p=0.02). Deaths were mainly non-vascular (nifedipine 176 vs co-amilozide 172; p=0.81). 80% of the primary events occurred in patients receiving randomised treatment (157 nifedipine, 147 co-amilozide, difference 0.33% [-0.7 to 1.4]).
                Nifedipine once daily and co-amilozide were equally effective in preventing overall cardiovascular or cerebrovascular complications. The choice of drug can be decided by tolerability and blood-pressure response rather than long-term safety or efficacy. The authors compare the efficiency of two drugs in the treatment of threatened premature labour, the one being the calcium inhibitor (nifedipine) and the other a beta-mimetic drug (ritodrine). 62 patients after random selection were divided into two groups: 32 treated with ritodrine and 30 treated with nifedipine. The treatment was carried out over 7 days. The success rate was similar in both groups -72% for the ritodrine group and 63.33% for the nifedipine group. Women receiving nifedipine had slightly greater gain in weeks, six as against five for ritodrine. The side effects which were often found with nifedipine were; hot flushes (in 10 cases) and headaches (4 cases). These symptoms appeared 15-30 minutes after the first dose and were transitory. No neonatal complications were found. The ease with which a calcium inhibitor can be given suggests that it should be used more frequently in the treatment of threatened premature labour and particularly when there are contra-indications to the use of beta-mimetic drugs. To compare the efficacy and safety of nifedipine and ritodrine in preventing preterm labor, and to evaluate maternal side effects and neonatal outcome.
                Non-blind, randomized controlled trial
                A randomized trial of 102 pregnant women with gestational ages under 34 weeks, including 24 with twin pregnancies and 45 on betasympathicomimetic drugs, who had regular uterine contractions with either observed cervical changes or preterm rupture of membranes. After stratification women were randomly assigned to receive either ritodrine intravenously or nifedipine orally. Fifty-five women were randomized to the nifedipine group and 47 to the ritodrine group. As expected, both groups were comparable in terms of several entry variables, including mean gestational age, ruptured membranes, treatment with tocolytic drugs, cervical examination, contraction frequency, age, and twin gestation. Delivery of women in the nifedipine group was delayed for 48 h, 7 days, and until 34 weeks gestation in 33 (60%), 26 (47%) and 21(38%) cases, respectively, compared with 31 (66%), 21(45%) and 11(23%) women in the ritodrine group (no significant difference). Maternal side effects were significantly less common in the nifedipine group than in the ritodrine group, however after 7 days of therapy there was no difference between the two groups. Neonatal outcome was similar in the two groups, with four neonatal deaths in the nifedipine and five in the ritodrine group.
                Nifedipine seems to be as effective as ritodrine in the treatment of preterm labor and is associated with less frequent side effects. The efficacy of an orally administered calcium antagonist, nifedipine, in suppressing premature uterine activity, was compared with intravenous ritodrine and no treatment. Nifedipine was found to be significantly more effective than ritodrine or withholding therapy, and was almost devoid of side-effects. Excessive accumulation of intracellular calcium in Duchenne muscular dystrophy (DMD) may be a necessary step in the process that causes muscle damage in this disease. Because of this possibility, a controlled trial of the calcium channel blocking agent nifedipine was undertaken. One hundred and five patients were randomized and treated in a double-blind manner for 18 months. Muscle strength, contractures, functional ability, cardiopulmonary changes, and laboratory data were monitored. The dose of nifedipine was 0.75-1 mg/kg/day in the first 6 months and 1.5-2 mg/kg/day for the next 12 months. Satisfactory blood levels of nifedipine were attained. The study had a power greater than 0.99 to detect a slowing of the illness to 25% of its original rate of progression. No significant improvement was demonstrated in the treated group. One or more of the frequent mild side effects of flushing, dizziness, and leg edema, often associated with the use of nifedipine in adults, occurred transiently in approximately one-half of the patients in the nifedipine group and in 21% of the placebo group. Four patients died, two on nifedipine and two on placebo. This study demonstrates that nifedipine is safe to administer in children, but that it is without beneficial effect on the course of DMD. The prostaglandin thromboxane A2 causes platelet aggregation and vasoconstriction and may be important in the pathogenesis of Raynaud's phenomenon. Therefore, a randomized, double-blind, placebo-controlled trial was conducted to assess the effectiveness of dazoxiben, a selective thromboxane synthetase inhibitor, in the treatment of Raynaud's phenomenon and to compare it with nifedipine, a calcium channel blocker. Twenty-two subjects who had at least one episode of Raynaud's phenomenon per day entered the study. Three patients withdrew from the study because of side effects while taking nifedipine. There was no difference among the subjects' subjective evaluation of the three treatments. Seven of 19 (44 percent) reported a moderate to marked improvement while taking placebo compared with 12 of 19 (63 percent) taking nifedipine and five of 19 (26 percent) taking dazoxiben (p = NS). Similarly, there was no difference in the mean two-week episode rate among the three treatments: placebo 30.4 +/- 4.5, nifedipine 24.7 +/- 5.6, dazoxiben 32.0 +/- 4.9 (p = NS). Twelve of 22 subjects experienced side effects while taking nifedipine as compared with two of 21 taking placebo and eight of 21 taking dazoxiben (p less than 0.005). These data show that dazoxiben is not effective in the treatment of Raynaud's phenomenon and suggest that thromboxane does not cause the vasoconstriction that characterizes this disorder. To compare the tocolytic efficacy and maternal tolerance of nifedipine with ritodrine in the management of threatened preterm labor.
                Prospective randomized study of 52 singleton pregnancies with preterm labor between 26 and 34 week's gestation. The capacity to delay delivery 48 h, 7 days, until week 36 or until fetal weight reached 2500 g were the outcome variables assessed. Doppler ultrasound studies were performed on the fetal umbilical artery as control.
                No significant differences were found in the delay of delivery, but significantly fewer maternal side-effects were found in the nifedipine group. Doppler ultrasound results were similar in both groups.
                Nifedipine is a valid and well-tolerated alternative among the tocolytic drugs, and apparently does not significantly alter fetal vascular blood flow.
This review failed to demonstrate the superiority of atosiban over betamimetics or placebo in terms of tocolytic efficacy or infant outcomes. The finding of an increase in infant deaths in one placebo controlled trial warrants caution. A recent Cochrane review suggests that calcium channel blockers (mainly nifedipine) are associated with better neonatal outcome and fewer maternal side-effects than betamimetics. However, a randomised comparison of nifedipine with placebo is not available. Further well-designed randomised controlled trials of tocolytic therapy are needed. Such trials should incorporate a placebo arm.
[Note: The 24 citations in the awaiting classification section of the review may alter the conclusions of the review once assessed.]