- Email: [email protected]
Meta-analysis of Nifedipine versus Beta-sympathomimetic Agents for Tocolysis during Preterm Labour
' ' ' ' ' ' '
OBSTETRI CS
' ' ' ' ' ' '
META--ANALYSIS OF NIFEDIPINE VERSUS BETA--SYMPATHOMIMETIC AGENTS FOR TOCOLYSIS DURING PRETERM LABOUR Joel G. Ray, MD, Departments of Medicine, and Clinical Epidemiology and Biostatistics, McMaster University ABSTRACT Objective: successful rocolysis during tyreterm labour enables the clinician to gain time in order to administer corticosteroids to the labouring woman in an effort to tyromote fetal lung maturation and reduce neonatal morbidity and mortality. Our current meta-analysis compared the effectiveness of nifedipine and beta-sympathomimetic agents in achieving rocolysis at 48 hours. In addition a comparison of maternal side effects was made. Data Sources: studies were identified through Ovid MEDLINE ( 1966 to December 1996). The following MEDLINE search terms were included, using both major MeSH headings and textwords: "rocolytic agents," "nifedipine," "calcium channel blocker( s)" and "dihydropyridines." AU abstracts, review articles and letters were read, and their bibliographies searched for relevant additional articles. Methods of Study Selection: tyrospective studies were selected if they included more than 20 subjects, tyrovided a formal definition of tyreterm labour, compared nifedipine with another sympathomimetic agent, randomly allocated subjects to treatment and examined rates for successful rocolysis at 48 hours. Nine randomized clinical t:ritili were identified, of which seven were eligible for our meta-analysis. Tabulation, Integration and Results: data were extracted by a single, non-blinded reviewer for study design, interventions, rates of successful rocolysis at 48 hours, number of extra days achieved with each agent and any significant drug side effects. Both a fixed-effects and random-effects model were used for the meta-analysis. The mean gestational age among the 217 women randomized to receive nifedipine was 31.2 weeks (range 22 to 35 weeks), compared to the 207 women receiving beta-agonists (30.9 weeks; range 22 to 35 weeks). Six t:ritili used intravenous ritodrine in the beta-mimetic arm, while another initiated therapy with magnesium sulphate, thereafter switching to oral terbutaline. Based on an intention-to-treat analysis, short-term rocolysis was favoured slightly with the use of nifedipine (pooled odds ratio [OR]1.34, 95% CI 0.83 to 2.15). An on-treatment analysis also favoured nifedipine (pooled OR 1.27, 95% CI 0.83 to 1.95). Due to the tyresence of a significant degree of heterogeneity across these studies, the data were also analysed using a random-effects model, with similar findings to those above. Nifedipine appeared to tyrolongtyregnancy by a mean of8.6 days (95% CI 5.8 to 11.5 days) over betaagonists (p=O .03). There were significantly fewer serious side effects observed with nifedipine than with beta-agonists (pooled OR 0.22, 95% CI 0.06 to 0.80). There were eight instances in which beta-agonists were stopped due to serious adverse side effects, compared to only one instance with nifedipine (pooled OR 0.29, 95% CI 0.08 to 1.06). Conclusions: the available data suggest that there is no apparent difference, and possibly a greater tocolytic effect at both 48 hours and up to the time of delivery, with nifedipine, compared to beta-sympathomimetic agents. The number of serious maternal side effects with nifedipine are also fewer. In certain situations where sympathomimetics are poorly tolerated, oral or sublingual nifedipine can be tried for the medical management of tyreterm labour. A large randomized clinical trial is needed to compare the neonatal outcomes of the therapies, in addition to their relative cost, ease of administration and major maternal side effects.
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' ' ' RESUME
Objectif: Pendant le travail avant terme, Ia reussite d'une wcolyse permettra au clinicien de gagner du temps pour administrer des corticosteroU:les a Ia femme en travail afin de favoriser Ia maturation pulmonaire du foetus et de reduire Ia marbidite et Ia martalite neonatales. Dans Ia presente meta-analyse, nous avons compare l' efficacire de Ia nifedipine a celle d' agents beta-sympa.thomimetiques pour obtenir Ia wcolyse apres 48 heures. De plus, on a effectue une comparaison des effets secondaires chez Ia mere. Sources des donnees: OvidMEDLINE ( 1966 adecembre 1996) aservi areperer les etudes. Les mots des suivants ant servi arealiser Ia recherche dans MEDLINE, a Ia fois dans les vedettes-matieres principales du MeSH et le texte : « agents tocolyti4_ues », « ni[edipine », « inhibiteur(s) calcique(s) " et « dihydropyridines "· Taus les resumes, articles de synthese et lettres ant ere lus, et on a recherche d'autres articles pertinents dans leurs bibliographies. Methodes de selection des etudes : Les etudes prospectives etaient retenues si elles comportaient plus de 20 sujets, une definition formelle du travail avant terme, une comparaison de Ia nifedipine avec un autre agent sympathomimetique, Ia repartition aleatoire des sujets au traitement et des taux observes de reussite de Ia tocolyse apres 48 heures. On a repere neuf essais cliniques randomises, dont sept etaient admissibles a notre meta-analyse. Mise en tableaux, integration et resultats : Un seul evaluateur a extrait, sans insu, les donnees relatives au plan d' etude, aux interventions, aux taux de reussite de Ia tocolyse apres 48 heures, au nombre de jours supplementaires obtenus au moyen de choque agent eta rout effet secondaire significatif des medicaments. Un modele a effets constants et un modele a effets aleawires ant servia effectuer Ia metaanalyse. L'{lge gestationnel moyen des 217 femmes selectionnees au hasardafin de recevoir Ia ni[edipine etait de 31,2 semaines (ecart de 22 a 35 semaines), par comparaison avec celui des 207 femmes ayant re0l des beta-agonistes (30,9 semaines; ecart de 22 a 35 semaines). Dans six etudes, on a utilise Ia riwdrine par voie intraveineuse dans Ia branche beta-mimeti4_ue, alors que dans une autre etude on a entrepris le traitement au sulfate de magnesium pour passer ensuite a Ia terbutaline par voie orale. D' apres une analyse de !'intention thirapeuti4_ue, Ia tocolyse de courte duree etait ligerementfavorisee par le recours a Ia ni[edipine (risque relatif[RR] combine de 1,34, IC de 95 %, 0,83 a 2,15). Une analyse en cours de traitement aaussifavorise Ia nifedipine (RR combine de 1,27, IC de 95 %, 0,83 a 1,95). Etant donne Ia presence d' un degre d'hirerogeneire significatif dans routes ces etudes, on a aussi analyse les donnees grace a un modele a effets aliawires, et les constatations etaient semblables a celles qui figurent ci-dessus. La ni[edipine semblait prolonger Ia grossesse de 8,6 jours en moyenne (IC de 95 %, 5,8 a 11,5 jours) de plus que les beta-agonistes (p = 0,03). On a observe beaucoup mains d'effets secondaires graves avec Ia ni[edipine qu'avec les beta-agonistes (RR combine de 0,22, IC de 95 %, 0,06 a 0,80). Dans huit cas, onadu mettrefina l' administration des beta-agonistes en raison d' effets indesirables graves par comparaison avec un seul cas d' arret du traitement a Ia nifedipine (RR combine de 0,29, IC de 95 %, 0,08 a 1,06). Conclusions : D' apres les donnees obtenues, Ia ni[edipine ne semble presenter aucune difference et elle provoque peut-etre meme un effet tocolytique accru apres 48 heures et au moment de l' accouchement, par comparaison avec les agents beta-sympathomimetiques. La nifediPine provoque egalement mains d' effets secondaires graves chez Ia mere. Dans certaines situations aU. les sympathamimeti4_ues sont mal wlires, on peut faire l' essai de Ia nifedipine par voie orale au sublinguale comme traitement medical du travail avant terme. Un essai clinique randomise a grande echelle s'impose afin de comparer les resultats neonatals des traitements, en plus de leur CoUt re/atif, de leur facilite d' administration et des principaux effets secondaires chez Ia mere. JSOC OBSTET GYNAECOL CAN 1998;20:259-69
KEY WORDS
Preterm labor, tocolytic agents, beta-sympa.thomimetics, nifedipine, meta-analysis. Received on May 7th, 1997. Revised and accepted on July 2nd, 1997.
INTRODUCTION
administered and transport to a high-risk obstetrics centre organized. 1' 2 Beta-agonists continue to remain the recommended first choice for tocolysis during preterm labour, 3· 5 with proven efficacy over a placebo in 14 clinical trials (pooled odds ratio [OR] for delivery within 24 hours: 0.30; 95% confidence interval [CI] 0.21 to 0.42). 6 Nifedipine, a dihydropyridine calcium channel blocker, was first tested for its tocolytic properties by Ulmsten and colleagues in 10 patients with premature labour. 7 In all 10 patients, uterine activity was abolished during the
The principal use of tocolytic agents in the modem era is for the temporary delay of preterm labour in an effort to permit steps to be taken to promote fetal maturation and prepare the fetus for extra-uterine life. The routine use of corticosteroids among women with preterm labour, for example, has markedly lessened neonatal morbidity and mortalityY By achieving tacolysis during the first 48 hours following the onset of premature labour, maternal corticosteroids can be
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' ' ' three days of treatment, as were their deliveries postponed, allowing glucocorticoids to be given. Nifedipine may induce fewer side effects than beta-mimetics, yet provide equal tocolytic effectY These issues were systematically addressed within the current meta-analysis. · We questioned whether nifedipine was as efficacious as beta-mimetics for short-term tocolysis at 48 hours. Secondly, we examined how their side effects compare.
elucidated. Quality rating systems have yet to be validated, and there is an advantage to describing the strengths and weaknesses of each study for the design of future trials. 10 The principal meta-analysis technique was based on a fixed-effects model described by Yusuf and Peto.U The odds ratios were calculated for each individual study and then pooled accordingly. The 95 percent confidence intervals for the summary effects were calculated using this same method. The numbers needed to treat (NNT) were derived from a recent publication by Sackett and colleagues, 12 and were based on the weighted control event rates derived from the pooled data. All hypotheses were explored using a two-sided (2-p) test. Homogeneity across the studies was assessed by qualitative visual inspection, as well as by fonnal statistical testing using the Breslow-Day method.U Rejection of the hypothesis that the studies were homogeneous occurred at a p value of less than 0.10. In the presence of heterogeneity across studies, the DerSimonian and Laird random-effects model was also used to determine the pooled odds ratios. 14 Although the fixed-effects model considers the variance within studies, a random-effects design also includes betweenstudy variance. Hence, the latter is ofren more conservative in its estimate of the pooled effect size, especially in the presence of significant heterogeneity. 15 A further meta-analysis of the number of days to delivery following administration of the tocolytic agents was performed using the inverse variance-weighted method. 16 The statistical software programmes used for these analyses included Meta-Analyst
METHODS
Studies were identified through Ovid MEDLINE ( 1966 to December 1996), searching under both the MeSH and textword headings "tocolytic agents," "nifedipine," "calcium channel blocker(s)," "dihydropyridines." These were matched against the terms "labour," and "premature labour." Studies were limited to those involving human subjects, at any phase of a clinical trial. Studies were selected if they: 1) were prospective in design; 2) included more than 20 subjects; 3) provided a formal definition of preterm labour; 4) compared nifedipine with a sympathomimetic agent used for the purpose of tocolysis; 5) randomly allocated subjects to receive one of two treatments; 6) compared outcomes of the achievement of short-term tocolysis at 48 hours. Data were extracted on study type, inclusion and exclusion criteria, dose, route and duration of the comparative interventions, form of fetal and maternal monitoring and other therapeutic co-interventions. Rates of successful tocolysis at 48 hours were calculated from outcomes from the assigned treatment groups at randomization (intention-to-treat analysis), and whether the assigned agent appeared to achieve 48-hour tocolysis (on-treatment analysis.) The number of extra days achieved between initial presentation with preterm labour and subsequent delivery were also recorded. Drug side effects, both associated with major maternal symptoms, or leading to cessation of therapy, were recorded. Although of clinical importance, perinatal outcomes were not included in this analysis. This choice was made based on the paucity of and inconsistency in reporting perinatal outcomes across the various studies. Moreover, it was apparent at the outset that adequate statistical power to compare perinatal events across the trials was lacking, as the sample size for such a comparison would have to be extremely large. 9 Formal scoring of the quality of each trial was not performed, but particular weaknesses from each were
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RESULTS
During the literature search, a total of 1,555 articles was retrieved, of which seven met all inclusion criteria. 19-25 Two trials 26•27 were excluded because they failed to provide data on tocolysis rates at 48 hours. The overall mean gestational age (MGA) at randomization was clinically and statistically similar in those randomized to nifedipine (MGA 31.2 weeks; range 22 to 35 weeks) and those receiving beta-mimetics (MGA 30.9 weeks; range 22 to 35 weeks) (mean difference 0.313 weeks; unpaired t-test, 2-p=0.11). In total, 217 women were assigned to receive nifedipine and 207, beta-mimetics. A description of the general characteristics of the seven studies is provided in Table 1. All were randomized trials without blinding. There was minimal description of
261
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INTRODUCING
®5mg FOS THE POWER TO PREVENT OSTEOPOROSIS ANEW OPTION TO PROTECT YOUR MENOPAUSAL PATIENTS AGAINST THE RISK OF FUTURE FRACTURES Accelerated bone loss occurs at the Lime of menopause 1 Early intervention at menopause to low or stop accelerated bone loss can reduce a woman's risk of fracture FOSAMAL'(®is now indicated for Lhe prevention of osteoporosis in po tmenopausal women*·t • FOSAMAX may be considered in postmenopausal women who are at risk of developing osteoporosis and for whom the desired clinical outcome is to mainta1n bone mass and to reduce the risk of future fracture. t Please refer to the enclosed prescrib1ng mformat1on for contraindicat1ons and precaut1ons with respect to upper gastrointestinal adverse events. Reference: 1. Hawker G. Bone biology and the investigation of osteoporosis. Osteoporosis. Journal SOGC Supplement 1996; 18(7):1 -6 .
.j MERCK FROSST M ERCK SHARP & DOH M E CANADA DIV. OF MERCK FROSST CANADA INC. KIRKLAND. QUEBEC
BEFORE PRESCRIBING, PLEASE CONSULT THE ENCLOSED PRESCRIBING INFORMATION ®Trademark Merck & Co., Inc., Merck Frosst Canada Inc., licensed user
FSMP-97-CDN-2131 -JA
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~ ~ ~ {lJ PREVENTION
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IS THE BEST ~® PROTECTION
alendronate sodium
' ' ' TABLE 1 CHARACTERISTICS OF 7 STUDIES COMPARING NIFEDIPINE WITH BETA-SYMPATHOMIMETIC AGENTS FOR TOCOLYSIS IN PRETERM LABOUR THAT ARE INCLUDED IN THE META-ANALYSIS Study
Read 19
Design
Subject
Nifedipine group
Inclusion MGA+
Dose/ route/
Cnteria" (weeks)
duration
Randomized Pre term 32.3 +/-1 .4 non-blinded labour at 20-35 trial weeks
30 mg pox 1 dose then 20 mg po q8h X 72h
Beta-agomst group MGA " Type"" (weeks)
Dose/route/
I Ritod . 31 .9 +1-1.61 I
!
SOug/min IV up to 300ug/min pm max or until maternal heart rate > 140/min or FHR > 180/min or intolerable side effects
30.1 Ritod . Ritod. SOug/min N up (estima- Terbut. to 350ug/min pm max ted) or intolerable side effects. After 12h, stop ritod. and start terbut. Smg po q6h
Randomized Preterm 31 .2 30mgpox (estoma· 1 dose then non-blinded labour trial 20mg po at 22-35 ted) weeks q6h
Ferguson 21
10 mg siS x 30.8 Ritod . Randomozed Preterm 30.7 non-blinded labour +1- 3.1 1 dose, then +I- 2.4 10mg sl q trial at 20-36 we ks 20mon pm max of40mg x 1h, then 20mg po q4 -6h or more often if need d
50 um/min IV up to 350 ug/min pm max or intolerable side effects After 12h, wean down IV and start ritod. 10-20mg po q4-6h
Janky22
Randomized Preterm 32.2 20 mg sl x +/- 2.3 1 dose, non -blinded labour then 20 mg trial at 28-36 we ks po q8h
200-300ug/min IV. Then, after cessatoon of contractoons, 100ug/min x 24h, then 20mg po
Randomozed Preterm 33 non-blinded labour +1- 3 trial at20-36 weeks
30 mg pox 1 dose, then 20mg po q6h X 24h, then 20mg po q8-12h
31 .6 Ritod . 1+1- 2.3
32
Ritod .
+1-3
Initial
ring
Interventions
1. BP and HR FHR q 15min x 2h, initially then q 1h x 24h 2. Uterine contractions initially
None listed
1 BP and HR q 10mon x 3h, and ECGspm
FHR 12h
1. Bed rest x 72h 2. Morphine 10mgiV 3. RL1LIV
1. Vital signs frequently, and ECG at 12h 2. Uterine contractions inotially
FHR initialy
11BPq1h. 2. Uterine contractions q 4h initially
I
FHR None listed q4h initially
I
Crystalloids SOOmLIV
SOug/min IV up to 300ug/min prn max. or intolerable side effects. After 12h, wean down IV and start ritod . 1Omg po q3h
1 BP q 15min x 3h, then preand post-dose 2. Uterine contractions initially
FHR
1. Dextrose· saline SOOmL N 2. Betamethasone
1 BP q 15min x 2h, then q2-4h 2. Uterine contractions initially
FHR
1. Betamethasone 2. Ampicillin 2g N x 1 dose, then more if urogenital cultures posotove. 3. Rest x 24-48h 4. Dextrose-saline 1 SOOmL N bolus, then 100 mllh
30.4 MgSO• MgS0•6g Nx +/-1 .8 Terbut. 1 dose, then 2-4g/h x 24h, then wean MgSO• and start terbut. Smg poq4-6h
Most studoes xdud patoents woth th presenc of polyhydramnoos, cervocal dolatatoon greater th n 4 em, ontra-uterone onfectoon. antepartum ha morrhag , rupture of m mbranes, ontra-uterone growth restroctoon, or maternal hypertensoon or cardoac dosease • MGA. m ang tatoonal ag s sl, sublongu 1 .. Rotod . rotodrone, Terbut, terbutalone, MgS04 magn soum sulphate •• BP, blood pressure, HR, heart rate, ECG, elottrocardoogram
264
RL0.2LIV bolus, then 100mUh
FHR
Glock 2S
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X
HR, BP
30.2 Ritod . +/-1 .9 (5 sets of twons)
10mg sl x 1 dose, then 10mg sl q 20mon pm max of 40mg x 1h, then 20mgpoq4h x 48h, then 10mg po q8h
Other
1OOug/min IV up to 350ug/min prn max. After 12h, wean down N and start ritod 10mg po q2h x 2h, then q4h x 24h, then 10-20mg po q4-6h
Kupfermonc24 Randomized Preterm 30.1 30 mg pox +/-1.6 1dose, then non-blinded labour tnal at 26-34 (6 sets 20 mg pox of 1, then 20 weeks twons) mg poq8h
Randomized Preterm 30.2 non-blinded labour +/- 1.7 trial at 20-34 weeks
Fetal Monito-
duration
Meyer20
Bracero2l
Maternal Monitoring++
MARCH 1998
·~
' ' ' either subject recruitment or randomization methods. None of the studies formally defined their primary or secondary outcomes nor did they reveal a calculation for the sample size. Six trials used intravenous ritodrine in their betamimetic arm, while another initiated therapy with magnesium sulphate, thereafter switching to oral terbutaline.25 The initial dose of nifedipine varied from 10 to 40 mg during the first hour, usually with the administration of higher doses in an attempt to suppress ongoing contractions. The mean administered dose of nifedipine or ritodrine was not disclosed. During the initial phase of intravenous beta-mimetic or oral nifedipine administration, both maternal and fetal vital signs were monitored. Five studies initiated therapy with an average of 500 mL of intravenous crystalloids, mostly to improve maternal rehydration in an effort to arrest labour. Two studies added betamethasone to induce fetal lung maturity.24. 25
contamination within most studies (Table 2). This usually occurred following early failure to achieve tocolysis, according to pre-defined study protocol criteria. 19-21·24. 25 Short-term tocolysis appeared to be more successful with nifedipine than with beta-mimetics both according to the intention-to-treat (ITT) (Yusuf-Peto pooled OR 1.34, 95% CI 0.83 to 2.15), and the on-treatment (OT) (Yusuf-Peto pooled OR 1.27, 95% CI 0.83 to 1.95) handling of the data (Table 2, Figure 1). In neither case, however, was the difference statistically significant. Due to the presence of a qualitative trend or statistically significant test for heterogeneity, the summary odds ratios were re-calculated using a random effects approach (Table 2, Figure 2). The trend again was in favour of nifedipine, but was not statistically significant. Using a sensitivity analysis, the exclusion of the study by Glock and Morales,Z5 in which magnesium sulphate was the initial tocolytic agent administered, did not alter the results based on an ITT analysis (DerSimonian-Laird pooled OR 1.62, 95% CI 0.81 to 3.25; 2-p=0.17), or an OT
There was a large amount of co-intervention and TABLE 2
SHORT-TERM TOCOLYSIS FROM 7 STUDIES COMPARING NIFEDIPINE WITH BETA·SYMPATHOMIMETIC AGENTS FORTOCOLYSIS IN PRETERM LABOUR, BY INTENTION-TO-TREAT (ITT) AN D ON-TREATMENT (On ANALYSES Study
No. reported/ No. randomozed
No. patients who receoved a second tocolytic; % of those who then achieved tocolytic success
No. patients (%) who achieved tocolysos by 48 hours according to ITI analysis
Odds ratio (9S% Cl) for ITI analysos
Nifedipone b-agonist Nifedipine b·agonist Nifedipine b·agonist
No. patients(%) who achieved tocolysis by 48 hours according to OT analysis
Odds ratio (95% CL) for OT analysos
Nifedipine b-agonist
Read 19
20120
20/20
5/ 20; 20%
0120
16/20 (80)
9/20 (45)
Meyer20
34134
24124
15/34; 67%
14124; 67%
29/34 (85)
19/24 (79)
1.53 (0.39 to 6.01)
Ferguson 21
32/ 33
32/33
5/32, 60%
30/32 (94)
Janky22
30130
32/32
5/32; 60% NA+
NA
Bracero2l
26/26
23/23
2/26; 50%
Kupferminc24
36/ 36
35/35
Glock 25
39/ 39
41 / 41
15/20 (75) 4.29 (1 .21 to 15.18)
9/20 (45)
3.67 (0.96 to 14 03)
19/ 34 (56)
10/24 (42)
1.77 (0.62 to 5.10)
26/32 (81)
27/32 (84) 3.08 (0.71 to 13 40)
23/ 32
2.11 (0.62 to 7 20)
19/30 (63)
23/32 (72)
068 (0.24 to 1.96)
19/30 (63)
23/32
(72)
0.68 (0.23 to 1.97)
2/23; NA
17/26 (65)
17/23 (74)
0.67 (0 20 to 2.25)
16/26 (62)"
17/23 (74)
0.56 (0.17 to 1.91)
7/36; 28%
0/35
32/36 (89)
26/35 (74)
2.62 (0.79 to 8.65)
30/36 (83)
26/35 (74)
1.73 (0.54 to 5.51 I
8/39; 25
7/41 ; 57%
33/39 (85)
38/41 (93)
0.45 (0 11 to 1 79
31/39 (79)
34/41 (83
0.80 (0 26 to 2.46)
Yusuf-Peto (fixed-effects) pooled odds ratio (95% Cl):
1.34 (0.83 to 2.1 5; 2-p• 0.23)
(72)
1.27 (0.83 to 1.95, 2-p - 0.27)
NNT (based upon a tocolysis success rate of 76% in the beta-agonist group):
17
22
Breslow-Day test for homogeneity:
11.28 (p• 0.081 ; not homogeneous)
7.53 (p • 0.27, homogeneous)
DerSimonian-Laird (random-effects) pooled odds ratio (95% Cl):
1.38 (0.70 to 2.72; 2-p• 0.36)
1.28 (0.78 to 2.08, 2-p - 0.33)
• NA. data not ava•l ble • DJ~a r present successful tocolys s at 72 hours
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' ' ' TABL
1 COMPARISON OF NIFEDIPINE VERSUS BETA-SYMPATHOMIMETICS FOR SHORT-TERM TOCOLYSIS INTENTION-TO-TREAT ANALYSIS
F•voul'$ Beta-agonist Study Ye•r
Read 19 Meyer 20
Ferguson 11
Janli:y12 Brace roll Kupf rm1nc ,. Glock
001 OQ2
oos 01
111
Favoul'$ Nifedipine
Odds Rot<> 95% Cl
OS
MEAN NUMBER OF DAYS GAINED UNTIL DELIVERY FOL· LOWING TOCOLYSIS FOR PRETERM LABOUR NIFEDIPINE VERSUS BETA-MIMETICS,INTENTION-TO-TREAT ANALYSIS
'
20
1-
"' ""
Pooled odds ratio
I •
121
-
2P•02·
c_., •
• .• sIll cu
OS
I
Pooled odds rat10
1
-on
2P • 036
-
--
Data presented as odds rat,os with 95% Cis on log scale, based on a random-effects model.
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Ferguson 21
NA+
NA
Janky22
42 +/- 21 9
Bracero2l
28 +/- 21
35 +/- 15.6 21 +/- 21
Kupferminc2 4
NA
NA
26.4 (p < 0.01; not homogeneous)
-
This meta-analysis of seven clinical trials found no difference, and possibly a greater tocolytic effect at both 48 hours and up to the time of delivery, with nifedipine compared to beta-mimetic agents. Moreover, the maternal side effects from oral or sublingual nifedipine were fewer than with beta-agonists. The biological rationale for nifedipine's action as a tocolytic agent is through its blocking of myometrial intracellular calcium transport, and hence, calcium binding to calmodulin. About 90 percent of the drug is absorbed from the gastro-intestinal tract, and with its peak effect at 15 to 30 minutes, high drug concentrations may reach the very vascular uterine muscle. 28 The in vitro study of non-pregnant human myometrial strips demonstrated greater smooth muscle relaxation with nifedipine than with ritodrine, terbutaline or magnesium sulphate agents, although no difference was seen among tissue samples from pregnant women. 29 Although perinatal outcomes were not addressed in this analysis, the evidence suggests that there are no adverse fetal effects with the use of nifedipine. 8 Even if nifedipine does cross the placenta28 within five hours of its administration, there is no apparent alteration of maximum Doppler ultrasonographic velocity waveforms within either the fetal circulation or the uterine arteries.30 Similarly, no important effect was observed on peak systolic to end-diastolic (S/D) flow velocity ratios within the uterine artery following administration of
1986
1990 1990 1990 1991 1993 1993
25.1 +/- 5.7 24.4 +/· 32.9
-
DISCUSSION
C 11>
36.3 +/- 5.1 21 3 +I· 24 1'
• Figures estimated from data • NA, data not ava,lable
Favours Nifedipine 9'
b-agomst
Test for homogeneity:
COMPARISON OF NIFEDIPINE VERSUS BETA-SYMPATHOMIMETIC5 FOR SHORT-TERM TOCOLYSIS. INTENTION-TO-TREAT ANALYSIS
OddsRa
.
Nifedipine
-
-
Fl URE 2
Favoul'$ Beta-agonist
Mean no. days gamed(+/- SD)
Glock 25 30.1 +/- 19.6 33.6 +/- 21.7 !Overall difference in mean no. days (95% Cl): 8.6 (5.8 to 11.5; p • 0.03)
analysis (DerSimonian-Laird pooled OR 1.39, 95% Cl 0.80 to 2.42; 2-p=0.24). Table 3 represents the mean number of extra days achieved following administration of nifedipine. Approximately 8.6 (95% CI 5.8 to 11.5) days were gained in the nifedipine group, which was statistically significant (p=0.03 ). There was a significantly greater frequency of bothersome side-effects reported among those women who received beta-mimetics (Table 4). The most common complaints were palpitations, chest pain and nausea and vomiting, which were much more frequent than the typical side-effects of flushing and headache reported in the nifedipine group (DerSimonian-Laird pooled OR 0.22, 95% CI 0.06 to 0.80; 2-p=0.021). There were eight reported instances in which beta-mimetics were stopped due to adverse side effects, versus only one among the nifedipine group (DerSimonian-Laird pooled OR 0.29, 95% CI 0.08 to 1.06; 2-p=0.06).
Gloc
~ead 19 Meyer20
Data presented as odds rat,os w1th 95% Cis on log scale, based on a fixed-effects model.
Read 19 Meyer 20 Ferguson :II Jankyn Braceroll Kupferminc 2•
--·
I
1986
1990 1990 1990 1991 1993 1993
Study
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' ' ' TABL 4
The apparent lack of difference between nifedipine and betamimetics for short-term tocolysis rNo. patients with side be qualified. First, in a sigshould effects necessitating Major side effects• discontinuation of nificant number of instan ces therapy among the trials included herein No. Nifedipine Nifedipine No. b-agonist b-agonist 1---Study there was both contamination and Flushing 1120 Palp1tations Read 19 13/20 0120 0/20 with other tocolyco-intervention or anxiety an intentionAlthough drugs. tic Diaphoresis and 1/34 Chest pain M eye.-20 6/24 1/34 4/24 shortness of breath to-treat analysis may seem Ferguson2 1 Flushing or 4/33 Chest pain or 17/ 33 0/33 2/33 appropriate in this circumstance, headache tightness, I does it offer a meaningful comparnausea or vomiting I ison between the two agents ?31 Janky22 Flushing or 10/30 Palpitations I 0/30 4/32 0132 I headache Moreover, the results of"negative" Bracero23 11/ 19 2/19 Flushing, 0123 8/23 Chest pain, or "no difference" trials are often headache palpitations, attributable to a Type II error, arisheadache ing from small sample sizes with Kupf rminc2• Flushing, 0130 0/30 8/ 30 Chest pain, 23/ 30 headach palpitations, insufficient statistical power, rather nausea or vom1ting than an absence of some real difNausea or vomiting, NA" Chest pain, Glock25 NA NA NA ference between groups.35 transient hypotension pulmonary oedema Designing a clinical trial to ·Yusuf-Peto pooled odds demonstrate equivalence (or nearratio (95% Cl): 0.25 (0.08 to 0.78; 2-p=0.018) 0.26 (0.16 to 0.43; 2-p < 0.001) equivalence) may require a more DerSimonian-Laird pooled 0.29 (0.08 to 1.06; 2-p• 0.06) odds ratio (95% Cl): 0.22 (0.06 to 0.80; 2-p • 0.021) rigorous approach than one aimed , s•gnifiQmt p olp•tat ons, pulmon ry oedema, nau a or vom•t•ng, • Def,ned .os chest pain or 11ght proving the superiority of one at headache or flush•ng. therapy over anoth er. 36 A future •• NA, data not available trial comparing nifedipine to another agent, for example, ritodrine, needs to consider nifedipine, with S/0 ratios returning to control values this in its estimation of sample size: the approximate numby 60 minutes. 31 ber of subjects for an equivalence trial, in which the 48In the current overview, the mean gestational age at hour tocolysis success rate is 75 percent with the "old" trial entry was around 3 1 weeks, starting as early as 22 treatment, and no more than 10 percent higher or lower weeks. The criteria for subject inclusion/exclusion were with nifedipine, varies from between 788 (alpha=O.OS, generally reflective of those applied within most centres. power 80%), up to 1,152 subjects in total (power 95%).36 H ence, these dat a are probably gen eralizable to the Future studies might measure the comparative ease of "average" case of preterm labour. The earliest gestational administration of either therapy during ambulance transage at which tocolysis should be attempted, however, The relative cost, number of days required in hospiport. depends on the availability of both adequate follow-up tal and the major maternal side effects with each agent and neonatal care. One cost-benefit analysis suggested a should be assessed, as th ey are often appreciable. The disadvantage with the use of beta-agonists after 34 ongoing debate over the risks of sh ort-acting calcium weeks. 32 channel blockers among patients with underlying coroThe current finding that nifedipine is better tolerated 33 8 nary artery disease h as yet to be resolved.3H 0 These obserthan beta-agonists has been observed elsewh ere. · At vations were also based upon older patients, however, who pharmacological doses, ritodrine often causes chest pain, were on long-term therapy, at higher doses. A pregnant palpitations and nausea and vomiting, which seem prowoman receiving several weeks of n ifedipine, whether as h ibitive when nifedipine is compared. Unlike betaa tocolytic agent or in the treatment ofhypertension,11 mimetics, nifedipine is rarely discontinued due to should not be considered part of this controversy. maternal side effects. MATERNAL SIDE EFFECTS COMPARING NIFEDIPINE TO BETA-SYMPATHOMIMETIC AGENTS IN PRETERM LABOUR
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' ' ' on-treatment analysis leaves some uncertainty about the external validity of their data.
Until further data are made available, clinicians are left with a choice: the current evidence, though limited and somewhat biased, suggests that nifedipine is probably as efficacious as beta-mimetics for the achievement of short-term tocolysis. Nifedipine has fewer serious maternal side effects, with no proven adverse consequences for the fetus.4.4 1 In certain situations where the administration of sympathomimetics is not feasible or is poorly tolerated, oral or sublingual nifedipine, 20 to 30 mg q6h, can be tried for the medical management of preterm labour. Routine follow-up and monitoring of both maternal and fetal well-being are necessary thereafter until delivery. Corticosteroids should be administered in the interim as soon as tocolysis is achieved.
REFERENCES 1.
2. 3. 4.
5.
ADDENDUM
6.
After completion of this meta-analysis, a subsequent multicentre, randomized, non-blinded trial was published (Papatsonis DNM, van Geijn HP, Ader HJ, Lange FM, Bieker OP, Dekker GA. Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial. Obstet Gynecol1997;90:230-4). In this trial, women in preterm labour between 20 to 33 4/7 weeks gestation were randomized either to oral nifedipine (n=95) or intravenous ritodrine (n=90). The treatment protocol was similar to that of previous studies, with the exception that women with ruptured membranes were also included. Due to severe maternal side effects, ritodrine was stopped in 12/90 women, usually after 48 hours of treatment, while none of the nifedipine users required drug cessation (RR 0.79, 95% CI 0.33 to 1.87 in favour of nifedipine). Using an on-treatment analysis only, 95/95 nifedipine recipients and 78/90 ritodrine recipients had reported outcomes. In the nifedipine group, 48-hour tocolysis was achieved among 74/95 (77.9%) women, versus 49/78 (62.8%) in the ritodrine group (RR 1.24, 95% CI 1.00 to 1.52 in favour of nifedipine). Delivery occurred later with nifedipine (33.4 +/- 4.5 weeks) than with ritodrine (32.1 +/- 4.1 weeks) (mean diference 0.44 weeks, 95% CI 0.00 to 2.6). Indomethacin was administered for tocolysis to 26/95 (27.4%) nifedipine users and 20/78 (25.6%) of those taking ritodrine (RR 1.07, 95% CI 0.62 to 1.85). Although these results further support both the safety, and probable superiority, of nifedipine over ritodrine for short-term tocolysis, the authors' exclusive use of an
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7.
8.
9.
10.
11.
12. 13.
14. 15.
16.
17. 18.
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Anonymous. Effect of corticosteroids for fetal maturation on perinatal outcomes. NIH Consensus Statement 1994;12:1-24. Gardner MO, Goldenberg RL. The clinical use of antenatal corticosteroids. Clin Obstet Gynecol1995;38:746-54. Souney PF, Kaul AF, Osathanondh R. Pharmacotherapy of preterm labor. Clin Pharm 1983;2:29-44. Higby K, Xenakis EMJ, Pauerstein CJ. Do tocolytic agents stop preterm labor? A critical and comprehensive review of efficacy and safety. Am J Obstet Gynecol 1993; 168:1247-59. McCombs J. Update on tocolytic therapy. Ann Pharmacother 1995;29:515-22. Keirse MJNC, Grant A, King JF. Preterm labour. In: Chalmers I, En kin M, Keirse MJNC (Eds.) Effective Care in Childbirth. Oxford: Oxford University Press 1989:694-745. Ulmsten U, Andersson KE, Wingerup L. Treatment of premature labor with the calcium antagonist nifedipine. Arch Gynecol 1980;229:1-5. Murray C, Haverkamp AD, Orleans M, Berga S, Pecht D. Nifedipine for treatment of preterm labor: a historic prospective study. Am J Obstet Gynecol1992;167:52-6. Mittendorf R, Arun V, Sapugay AMV. The problem of the type II statistical error. Obstet Gynecol1995;86: 857-9. Moher D, Jadad AR, Tugwell. Assessing the quality of randomized controlled trials: current issues and future directions. lnt J Technol Assess Health Care 1996; 12:195-208. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985;27:335-71. Sackett DL, Deeks JJ, Altman DG. Down with odds ratios! Evidence-Based Medicine 1996;1 :164-6. Breslow NE, Day NE. Statistical methods in cancer research. Vol. 1: The analysis of case-control studies. Oxford, UK: Oxford University Press, 1980. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88. Petitti DB. Meta-analysis, decision analysis, and costeffective analysis: methods for quantitative synthesis in medicine. New York, NY: Oxford University Press, 1994, pp. 90-130,228. Hasselblad V, McCrory DC. Meta-analytic tools for medical decision making: a practical guide. Med Decis Making 1995;15:81-96. Lau J. Meta-Analyst0· 998 Statistical Software. Boston, Mass, 1995. Julian J. Metanal Statistical Software. Hamilton, ON. 1988.
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' ' ' 19. Read MD, Wellby DE. The use of a calcium antagonist (nifedipine) to suppress preterm labour. Br J Obstet Gynaecol1986;93:933-7. 20. Meyer WR, Randall HW, Graves WL. Nifedipine versus ritodrine for suppressing preterm labor. J Reprod Med 1990;35:649-53. 21. Ferguson JE, Dyson DC, Schutz T, Stevenson DK. A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome. Am J Obstet Gynecol1990;163:105-11. 22. Janky E, Leng JJ, Cormier P, Salamon R, Meynard J. A randomized study of treatment of threatened premature labour: nifedipine against ritodrine. J Gynecol Obstet Bioi Reprod 1990;19:478-82. 23. Bracero LA, Leikin E, Kirshenbaum N, Tejani N. Comparison of nifedipine and ritodrine for the treatment of preterm labor. Am J Perinatol1991 ;8:365-9. 24. Kupferminc M, Lessing JB, Yaron Y, Peyser MR. Nifedipine versus ritodrine for suppression of preterm labour. Br J Obstet Gynaecol1993;100:1090-4. 25. Glock JL, Morales WJ. Efficacy and safety of nifedipine versus magnesium sulfate in the management of preterm labor: a randomized study. Am J Obstet Gynecol 1993;169:960-4. 26. Smith CS, Woodland MB. Clinical comparison of oral nifedipine and subcutaneous terbutaline for initial tocolysis. Am J Perinatol1993;10:280-4. 27. Roy UK, PanS. Use of calcium antagonist (nifedipine) in premature labour. J Indian Med Assoc 1993;91:8-10. 28. Ferguson JE, Schutz T, Pershe R, Stevenson DK, Blaschke T. Nifedipine pharmacokinetics during preterm labor tocolysis. Am J Obstet Gynecol 1989; 161 :1485-90. 29. Saade GR, Taskin 0, Belfort MA eta/. In vitro comparison of four tocolytic agents, alone and in combination. Obstet Gynecol1994;84:374-8. 30. Mari G, Kirshon B, Moise KJ Jr, Lee W, Cotton DB. Doppler assessment of the fetal and uteroplacental circulation during nifedipine therapy for preterm labor. Am J Obstet Gynecol 1989; 161:1514-8. 31. Thaler I, Wiener Z, Manor D, ltskovitz J. Effect of calcium channel blocker nifedipine on uterine artery flow velocity waveforms. J Ultrasound Med 1991;10:301-4. 32. Korenbrot CC, Aalto LH, Laros RK. The cost effectiveness of stopping preterm labor with beta-adrenergic treatment. N Engl J Med 1984;310:691-6. 33. van Dijk KGJ, Dekker GA, van Geijn HP. Ritodrine and nifedipine as tocolytic agents: a preliminary comparison. J Perinat Med 1995;23:409-15. 34. Gent M, Sackett DL. The quantification and disqualification of patients and events in long-term cardiovascular clinical trials. Thromb Haemost 1979;41 :123-34. 35. Freiman JA, Chalmers TC, Smith H Jr, Kuebler RR. The importance of beta, the type II error and sample size in the design and interpretation of the randomized controlled trial: survey of 71 "negative" trials. N Eng I J Med 1978;299:690-4.
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36. Jones B, Jarvis P, Lewis JA, Ebbutt AF. Trials to assess equivalence: the importance of rigorous methods. BMJ 1996;313:36-9. 37. Furberg CD eta/. Nifedipine: dose-related increase in mortality in patients with coronary artery disease. Circulation 1995;92:1326-31. 38. Braun S et a/. Calcium antagonists and mortality in patients with coronary artery disease: a cohort study of 11,575 patients. J Am Coli Cardiol1996;28:7 -11. 39. Yamashita S. Current controversies in calcium channel blocker therapy. Can J Clin Pharmacol1996;3:99-1 08. 40. Lip GYH, Beevers DG. Are calcium antagonists safe in hypertension? Postgrad Med J 1996;72:193-5. 41. Childress CH, Katz VL. Nifedipine and its indications in obstetrics and gynecology. Obstet Gynecol 1994;83:616-24.
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OBSTETRI CS
' ' ' ' ' ' '
META--ANALYSIS OF NIFEDIPINE VERSUS BETA--SYMPATHOMIMETIC AGENTS FOR TOCOLYSIS DURING PRETERM LABOUR Joel G. Ray, MD, Departments of Medicine, and Clinical Epidemiology and Biostatistics, McMaster University ABSTRACT Objective: successful rocolysis during tyreterm labour enables the clinician to gain time in order to administer corticosteroids to the labouring woman in an effort to tyromote fetal lung maturation and reduce neonatal morbidity and mortality. Our current meta-analysis compared the effectiveness of nifedipine and beta-sympathomimetic agents in achieving rocolysis at 48 hours. In addition a comparison of maternal side effects was made. Data Sources: studies were identified through Ovid MEDLINE ( 1966 to December 1996). The following MEDLINE search terms were included, using both major MeSH headings and textwords: "rocolytic agents," "nifedipine," "calcium channel blocker( s)" and "dihydropyridines." AU abstracts, review articles and letters were read, and their bibliographies searched for relevant additional articles. Methods of Study Selection: tyrospective studies were selected if they included more than 20 subjects, tyrovided a formal definition of tyreterm labour, compared nifedipine with another sympathomimetic agent, randomly allocated subjects to treatment and examined rates for successful rocolysis at 48 hours. Nine randomized clinical t:ritili were identified, of which seven were eligible for our meta-analysis. Tabulation, Integration and Results: data were extracted by a single, non-blinded reviewer for study design, interventions, rates of successful rocolysis at 48 hours, number of extra days achieved with each agent and any significant drug side effects. Both a fixed-effects and random-effects model were used for the meta-analysis. The mean gestational age among the 217 women randomized to receive nifedipine was 31.2 weeks (range 22 to 35 weeks), compared to the 207 women receiving beta-agonists (30.9 weeks; range 22 to 35 weeks). Six t:ritili used intravenous ritodrine in the beta-mimetic arm, while another initiated therapy with magnesium sulphate, thereafter switching to oral terbutaline. Based on an intention-to-treat analysis, short-term rocolysis was favoured slightly with the use of nifedipine (pooled odds ratio [OR]1.34, 95% CI 0.83 to 2.15). An on-treatment analysis also favoured nifedipine (pooled OR 1.27, 95% CI 0.83 to 1.95). Due to the tyresence of a significant degree of heterogeneity across these studies, the data were also analysed using a random-effects model, with similar findings to those above. Nifedipine appeared to tyrolongtyregnancy by a mean of8.6 days (95% CI 5.8 to 11.5 days) over betaagonists (p=O .03). There were significantly fewer serious side effects observed with nifedipine than with beta-agonists (pooled OR 0.22, 95% CI 0.06 to 0.80). There were eight instances in which beta-agonists were stopped due to serious adverse side effects, compared to only one instance with nifedipine (pooled OR 0.29, 95% CI 0.08 to 1.06). Conclusions: the available data suggest that there is no apparent difference, and possibly a greater tocolytic effect at both 48 hours and up to the time of delivery, with nifedipine, compared to beta-sympathomimetic agents. The number of serious maternal side effects with nifedipine are also fewer. In certain situations where sympathomimetics are poorly tolerated, oral or sublingual nifedipine can be tried for the medical management of tyreterm labour. A large randomized clinical trial is needed to compare the neonatal outcomes of the therapies, in addition to their relative cost, ease of administration and major maternal side effects.
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' ' ' RESUME
Objectif: Pendant le travail avant terme, Ia reussite d'une wcolyse permettra au clinicien de gagner du temps pour administrer des corticosteroU:les a Ia femme en travail afin de favoriser Ia maturation pulmonaire du foetus et de reduire Ia marbidite et Ia martalite neonatales. Dans Ia presente meta-analyse, nous avons compare l' efficacire de Ia nifedipine a celle d' agents beta-sympa.thomimetiques pour obtenir Ia wcolyse apres 48 heures. De plus, on a effectue une comparaison des effets secondaires chez Ia mere. Sources des donnees: OvidMEDLINE ( 1966 adecembre 1996) aservi areperer les etudes. Les mots des suivants ant servi arealiser Ia recherche dans MEDLINE, a Ia fois dans les vedettes-matieres principales du MeSH et le texte : « agents tocolyti4_ues », « ni[edipine », « inhibiteur(s) calcique(s) " et « dihydropyridines "· Taus les resumes, articles de synthese et lettres ant ere lus, et on a recherche d'autres articles pertinents dans leurs bibliographies. Methodes de selection des etudes : Les etudes prospectives etaient retenues si elles comportaient plus de 20 sujets, une definition formelle du travail avant terme, une comparaison de Ia nifedipine avec un autre agent sympathomimetique, Ia repartition aleatoire des sujets au traitement et des taux observes de reussite de Ia tocolyse apres 48 heures. On a repere neuf essais cliniques randomises, dont sept etaient admissibles a notre meta-analyse. Mise en tableaux, integration et resultats : Un seul evaluateur a extrait, sans insu, les donnees relatives au plan d' etude, aux interventions, aux taux de reussite de Ia tocolyse apres 48 heures, au nombre de jours supplementaires obtenus au moyen de choque agent eta rout effet secondaire significatif des medicaments. Un modele a effets constants et un modele a effets aleawires ant servia effectuer Ia metaanalyse. L'{lge gestationnel moyen des 217 femmes selectionnees au hasardafin de recevoir Ia ni[edipine etait de 31,2 semaines (ecart de 22 a 35 semaines), par comparaison avec celui des 207 femmes ayant re0l des beta-agonistes (30,9 semaines; ecart de 22 a 35 semaines). Dans six etudes, on a utilise Ia riwdrine par voie intraveineuse dans Ia branche beta-mimeti4_ue, alors que dans une autre etude on a entrepris le traitement au sulfate de magnesium pour passer ensuite a Ia terbutaline par voie orale. D' apres une analyse de !'intention thirapeuti4_ue, Ia tocolyse de courte duree etait ligerementfavorisee par le recours a Ia ni[edipine (risque relatif[RR] combine de 1,34, IC de 95 %, 0,83 a 2,15). Une analyse en cours de traitement aaussifavorise Ia nifedipine (RR combine de 1,27, IC de 95 %, 0,83 a 1,95). Etant donne Ia presence d' un degre d'hirerogeneire significatif dans routes ces etudes, on a aussi analyse les donnees grace a un modele a effets aliawires, et les constatations etaient semblables a celles qui figurent ci-dessus. La ni[edipine semblait prolonger Ia grossesse de 8,6 jours en moyenne (IC de 95 %, 5,8 a 11,5 jours) de plus que les beta-agonistes (p = 0,03). On a observe beaucoup mains d'effets secondaires graves avec Ia ni[edipine qu'avec les beta-agonistes (RR combine de 0,22, IC de 95 %, 0,06 a 0,80). Dans huit cas, onadu mettrefina l' administration des beta-agonistes en raison d' effets indesirables graves par comparaison avec un seul cas d' arret du traitement a Ia nifedipine (RR combine de 0,29, IC de 95 %, 0,08 a 1,06). Conclusions : D' apres les donnees obtenues, Ia ni[edipine ne semble presenter aucune difference et elle provoque peut-etre meme un effet tocolytique accru apres 48 heures et au moment de l' accouchement, par comparaison avec les agents beta-sympathomimetiques. La nifediPine provoque egalement mains d' effets secondaires graves chez Ia mere. Dans certaines situations aU. les sympathamimeti4_ues sont mal wlires, on peut faire l' essai de Ia nifedipine par voie orale au sublinguale comme traitement medical du travail avant terme. Un essai clinique randomise a grande echelle s'impose afin de comparer les resultats neonatals des traitements, en plus de leur CoUt re/atif, de leur facilite d' administration et des principaux effets secondaires chez Ia mere. JSOC OBSTET GYNAECOL CAN 1998;20:259-69
KEY WORDS
Preterm labor, tocolytic agents, beta-sympa.thomimetics, nifedipine, meta-analysis. Received on May 7th, 1997. Revised and accepted on July 2nd, 1997.
INTRODUCTION
administered and transport to a high-risk obstetrics centre organized. 1' 2 Beta-agonists continue to remain the recommended first choice for tocolysis during preterm labour, 3· 5 with proven efficacy over a placebo in 14 clinical trials (pooled odds ratio [OR] for delivery within 24 hours: 0.30; 95% confidence interval [CI] 0.21 to 0.42). 6 Nifedipine, a dihydropyridine calcium channel blocker, was first tested for its tocolytic properties by Ulmsten and colleagues in 10 patients with premature labour. 7 In all 10 patients, uterine activity was abolished during the
The principal use of tocolytic agents in the modem era is for the temporary delay of preterm labour in an effort to permit steps to be taken to promote fetal maturation and prepare the fetus for extra-uterine life. The routine use of corticosteroids among women with preterm labour, for example, has markedly lessened neonatal morbidity and mortalityY By achieving tacolysis during the first 48 hours following the onset of premature labour, maternal corticosteroids can be
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' ' ' three days of treatment, as were their deliveries postponed, allowing glucocorticoids to be given. Nifedipine may induce fewer side effects than beta-mimetics, yet provide equal tocolytic effectY These issues were systematically addressed within the current meta-analysis. · We questioned whether nifedipine was as efficacious as beta-mimetics for short-term tocolysis at 48 hours. Secondly, we examined how their side effects compare.
elucidated. Quality rating systems have yet to be validated, and there is an advantage to describing the strengths and weaknesses of each study for the design of future trials. 10 The principal meta-analysis technique was based on a fixed-effects model described by Yusuf and Peto.U The odds ratios were calculated for each individual study and then pooled accordingly. The 95 percent confidence intervals for the summary effects were calculated using this same method. The numbers needed to treat (NNT) were derived from a recent publication by Sackett and colleagues, 12 and were based on the weighted control event rates derived from the pooled data. All hypotheses were explored using a two-sided (2-p) test. Homogeneity across the studies was assessed by qualitative visual inspection, as well as by fonnal statistical testing using the Breslow-Day method.U Rejection of the hypothesis that the studies were homogeneous occurred at a p value of less than 0.10. In the presence of heterogeneity across studies, the DerSimonian and Laird random-effects model was also used to determine the pooled odds ratios. 14 Although the fixed-effects model considers the variance within studies, a random-effects design also includes betweenstudy variance. Hence, the latter is ofren more conservative in its estimate of the pooled effect size, especially in the presence of significant heterogeneity. 15 A further meta-analysis of the number of days to delivery following administration of the tocolytic agents was performed using the inverse variance-weighted method. 16 The statistical software programmes used for these analyses included Meta-Analyst
METHODS
Studies were identified through Ovid MEDLINE ( 1966 to December 1996), searching under both the MeSH and textword headings "tocolytic agents," "nifedipine," "calcium channel blocker(s)," "dihydropyridines." These were matched against the terms "labour," and "premature labour." Studies were limited to those involving human subjects, at any phase of a clinical trial. Studies were selected if they: 1) were prospective in design; 2) included more than 20 subjects; 3) provided a formal definition of preterm labour; 4) compared nifedipine with a sympathomimetic agent used for the purpose of tocolysis; 5) randomly allocated subjects to receive one of two treatments; 6) compared outcomes of the achievement of short-term tocolysis at 48 hours. Data were extracted on study type, inclusion and exclusion criteria, dose, route and duration of the comparative interventions, form of fetal and maternal monitoring and other therapeutic co-interventions. Rates of successful tocolysis at 48 hours were calculated from outcomes from the assigned treatment groups at randomization (intention-to-treat analysis), and whether the assigned agent appeared to achieve 48-hour tocolysis (on-treatment analysis.) The number of extra days achieved between initial presentation with preterm labour and subsequent delivery were also recorded. Drug side effects, both associated with major maternal symptoms, or leading to cessation of therapy, were recorded. Although of clinical importance, perinatal outcomes were not included in this analysis. This choice was made based on the paucity of and inconsistency in reporting perinatal outcomes across the various studies. Moreover, it was apparent at the outset that adequate statistical power to compare perinatal events across the trials was lacking, as the sample size for such a comparison would have to be extremely large. 9 Formal scoring of the quality of each trial was not performed, but particular weaknesses from each were
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RESULTS
During the literature search, a total of 1,555 articles was retrieved, of which seven met all inclusion criteria. 19-25 Two trials 26•27 were excluded because they failed to provide data on tocolysis rates at 48 hours. The overall mean gestational age (MGA) at randomization was clinically and statistically similar in those randomized to nifedipine (MGA 31.2 weeks; range 22 to 35 weeks) and those receiving beta-mimetics (MGA 30.9 weeks; range 22 to 35 weeks) (mean difference 0.313 weeks; unpaired t-test, 2-p=0.11). In total, 217 women were assigned to receive nifedipine and 207, beta-mimetics. A description of the general characteristics of the seven studies is provided in Table 1. All were randomized trials without blinding. There was minimal description of
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IS THE BEST ~® PROTECTION
alendronate sodium
' ' ' TABLE 1 CHARACTERISTICS OF 7 STUDIES COMPARING NIFEDIPINE WITH BETA-SYMPATHOMIMETIC AGENTS FOR TOCOLYSIS IN PRETERM LABOUR THAT ARE INCLUDED IN THE META-ANALYSIS Study
Read 19
Design
Subject
Nifedipine group
Inclusion MGA+
Dose/ route/
Cnteria" (weeks)
duration
Randomized Pre term 32.3 +/-1 .4 non-blinded labour at 20-35 trial weeks
30 mg pox 1 dose then 20 mg po q8h X 72h
Beta-agomst group MGA " Type"" (weeks)
Dose/route/
I Ritod . 31 .9 +1-1.61 I
!
SOug/min IV up to 300ug/min pm max or until maternal heart rate > 140/min or FHR > 180/min or intolerable side effects
30.1 Ritod . Ritod. SOug/min N up (estima- Terbut. to 350ug/min pm max ted) or intolerable side effects. After 12h, stop ritod. and start terbut. Smg po q6h
Randomized Preterm 31 .2 30mgpox (estoma· 1 dose then non-blinded labour trial 20mg po at 22-35 ted) weeks q6h
Ferguson 21
10 mg siS x 30.8 Ritod . Randomozed Preterm 30.7 non-blinded labour +1- 3.1 1 dose, then +I- 2.4 10mg sl q trial at 20-36 we ks 20mon pm max of40mg x 1h, then 20mg po q4 -6h or more often if need d
50 um/min IV up to 350 ug/min pm max or intolerable side effects After 12h, wean down IV and start ritod. 10-20mg po q4-6h
Janky22
Randomized Preterm 32.2 20 mg sl x +/- 2.3 1 dose, non -blinded labour then 20 mg trial at 28-36 we ks po q8h
200-300ug/min IV. Then, after cessatoon of contractoons, 100ug/min x 24h, then 20mg po
Randomozed Preterm 33 non-blinded labour +1- 3 trial at20-36 weeks
30 mg pox 1 dose, then 20mg po q6h X 24h, then 20mg po q8-12h
31 .6 Ritod . 1+1- 2.3
32
Ritod .
+1-3
Initial
ring
Interventions
1. BP and HR FHR q 15min x 2h, initially then q 1h x 24h 2. Uterine contractions initially
None listed
1 BP and HR q 10mon x 3h, and ECGspm
FHR 12h
1. Bed rest x 72h 2. Morphine 10mgiV 3. RL1LIV
1. Vital signs frequently, and ECG at 12h 2. Uterine contractions inotially
FHR initialy
11BPq1h. 2. Uterine contractions q 4h initially
I
FHR None listed q4h initially
I
Crystalloids SOOmLIV
SOug/min IV up to 300ug/min prn max. or intolerable side effects. After 12h, wean down IV and start ritod . 1Omg po q3h
1 BP q 15min x 3h, then preand post-dose 2. Uterine contractions initially
FHR
1. Dextrose· saline SOOmL N 2. Betamethasone
1 BP q 15min x 2h, then q2-4h 2. Uterine contractions initially
FHR
1. Betamethasone 2. Ampicillin 2g N x 1 dose, then more if urogenital cultures posotove. 3. Rest x 24-48h 4. Dextrose-saline 1 SOOmL N bolus, then 100 mllh
30.4 MgSO• MgS0•6g Nx +/-1 .8 Terbut. 1 dose, then 2-4g/h x 24h, then wean MgSO• and start terbut. Smg poq4-6h
Most studoes xdud patoents woth th presenc of polyhydramnoos, cervocal dolatatoon greater th n 4 em, ontra-uterone onfectoon. antepartum ha morrhag , rupture of m mbranes, ontra-uterone growth restroctoon, or maternal hypertensoon or cardoac dosease • MGA. m ang tatoonal ag s sl, sublongu 1 .. Rotod . rotodrone, Terbut, terbutalone, MgS04 magn soum sulphate •• BP, blood pressure, HR, heart rate, ECG, elottrocardoogram
264
RL0.2LIV bolus, then 100mUh
FHR
Glock 2S
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X
HR, BP
30.2 Ritod . +/-1 .9 (5 sets of twons)
10mg sl x 1 dose, then 10mg sl q 20mon pm max of 40mg x 1h, then 20mgpoq4h x 48h, then 10mg po q8h
Other
1OOug/min IV up to 350ug/min prn max. After 12h, wean down N and start ritod 10mg po q2h x 2h, then q4h x 24h, then 10-20mg po q4-6h
Kupfermonc24 Randomized Preterm 30.1 30 mg pox +/-1.6 1dose, then non-blinded labour tnal at 26-34 (6 sets 20 mg pox of 1, then 20 weeks twons) mg poq8h
Randomized Preterm 30.2 non-blinded labour +/- 1.7 trial at 20-34 weeks
Fetal Monito-
duration
Meyer20
Bracero2l
Maternal Monitoring++
MARCH 1998
·~
' ' ' either subject recruitment or randomization methods. None of the studies formally defined their primary or secondary outcomes nor did they reveal a calculation for the sample size. Six trials used intravenous ritodrine in their betamimetic arm, while another initiated therapy with magnesium sulphate, thereafter switching to oral terbutaline.25 The initial dose of nifedipine varied from 10 to 40 mg during the first hour, usually with the administration of higher doses in an attempt to suppress ongoing contractions. The mean administered dose of nifedipine or ritodrine was not disclosed. During the initial phase of intravenous beta-mimetic or oral nifedipine administration, both maternal and fetal vital signs were monitored. Five studies initiated therapy with an average of 500 mL of intravenous crystalloids, mostly to improve maternal rehydration in an effort to arrest labour. Two studies added betamethasone to induce fetal lung maturity.24. 25
contamination within most studies (Table 2). This usually occurred following early failure to achieve tocolysis, according to pre-defined study protocol criteria. 19-21·24. 25 Short-term tocolysis appeared to be more successful with nifedipine than with beta-mimetics both according to the intention-to-treat (ITT) (Yusuf-Peto pooled OR 1.34, 95% CI 0.83 to 2.15), and the on-treatment (OT) (Yusuf-Peto pooled OR 1.27, 95% CI 0.83 to 1.95) handling of the data (Table 2, Figure 1). In neither case, however, was the difference statistically significant. Due to the presence of a qualitative trend or statistically significant test for heterogeneity, the summary odds ratios were re-calculated using a random effects approach (Table 2, Figure 2). The trend again was in favour of nifedipine, but was not statistically significant. Using a sensitivity analysis, the exclusion of the study by Glock and Morales,Z5 in which magnesium sulphate was the initial tocolytic agent administered, did not alter the results based on an ITT analysis (DerSimonian-Laird pooled OR 1.62, 95% CI 0.81 to 3.25; 2-p=0.17), or an OT
There was a large amount of co-intervention and TABLE 2
SHORT-TERM TOCOLYSIS FROM 7 STUDIES COMPARING NIFEDIPINE WITH BETA·SYMPATHOMIMETIC AGENTS FORTOCOLYSIS IN PRETERM LABOUR, BY INTENTION-TO-TREAT (ITT) AN D ON-TREATMENT (On ANALYSES Study
No. reported/ No. randomozed
No. patients who receoved a second tocolytic; % of those who then achieved tocolytic success
No. patients (%) who achieved tocolysos by 48 hours according to ITI analysis
Odds ratio (9S% Cl) for ITI analysos
Nifedipone b-agonist Nifedipine b·agonist Nifedipine b·agonist
No. patients(%) who achieved tocolysis by 48 hours according to OT analysis
Odds ratio (95% CL) for OT analysos
Nifedipine b-agonist
Read 19
20120
20/20
5/ 20; 20%
0120
16/20 (80)
9/20 (45)
Meyer20
34134
24124
15/34; 67%
14124; 67%
29/34 (85)
19/24 (79)
1.53 (0.39 to 6.01)
Ferguson 21
32/ 33
32/33
5/32, 60%
30/32 (94)
Janky22
30130
32/32
5/32; 60% NA+
NA
Bracero2l
26/26
23/23
2/26; 50%
Kupferminc24
36/ 36
35/35
Glock 25
39/ 39
41 / 41
15/20 (75) 4.29 (1 .21 to 15.18)
9/20 (45)
3.67 (0.96 to 14 03)
19/ 34 (56)
10/24 (42)
1.77 (0.62 to 5.10)
26/32 (81)
27/32 (84) 3.08 (0.71 to 13 40)
23/ 32
2.11 (0.62 to 7 20)
19/30 (63)
23/32 (72)
068 (0.24 to 1.96)
19/30 (63)
23/32
(72)
0.68 (0.23 to 1.97)
2/23; NA
17/26 (65)
17/23 (74)
0.67 (0 20 to 2.25)
16/26 (62)"
17/23 (74)
0.56 (0.17 to 1.91)
7/36; 28%
0/35
32/36 (89)
26/35 (74)
2.62 (0.79 to 8.65)
30/36 (83)
26/35 (74)
1.73 (0.54 to 5.51 I
8/39; 25
7/41 ; 57%
33/39 (85)
38/41 (93)
0.45 (0 11 to 1 79
31/39 (79)
34/41 (83
0.80 (0 26 to 2.46)
Yusuf-Peto (fixed-effects) pooled odds ratio (95% Cl):
1.34 (0.83 to 2.1 5; 2-p• 0.23)
(72)
1.27 (0.83 to 1.95, 2-p - 0.27)
NNT (based upon a tocolysis success rate of 76% in the beta-agonist group):
17
22
Breslow-Day test for homogeneity:
11.28 (p• 0.081 ; not homogeneous)
7.53 (p • 0.27, homogeneous)
DerSimonian-Laird (random-effects) pooled odds ratio (95% Cl):
1.38 (0.70 to 2.72; 2-p• 0.36)
1.28 (0.78 to 2.08, 2-p - 0.33)
• NA. data not ava•l ble • DJ~a r present successful tocolys s at 72 hours
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' ' ' TABL
1 COMPARISON OF NIFEDIPINE VERSUS BETA-SYMPATHOMIMETICS FOR SHORT-TERM TOCOLYSIS INTENTION-TO-TREAT ANALYSIS
F•voul'$ Beta-agonist Study
Read 19 Meyer 20
Ferguson 11
Janli:y12 Brace roll Kupf rm1nc ,. Glock
001 OQ2
oos 01
111
Favoul'$ Nifedipine
Odds Rot<> 95% Cl
OS
MEAN NUMBER OF DAYS GAINED UNTIL DELIVERY FOL· LOWING TOCOLYSIS FOR PRETERM LABOUR NIFEDIPINE VERSUS BETA-MIMETICS,INTENTION-TO-TREAT ANALYSIS
'
20
1-
"' ""
Pooled odds ratio
I •
121
-
2P•02·
c_., •
• .• sIll cu
OS
I
Pooled odds rat10
1
-on
2P • 036
-
--
Data presented as odds rat,os with 95% Cis on log scale, based on a random-effects model.
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Ferguson 21
NA+
NA
Janky22
42 +/- 21 9
Bracero2l
28 +/- 21
35 +/- 15.6 21 +/- 21
Kupferminc2 4
NA
NA
26.4 (p < 0.01; not homogeneous)
-
This meta-analysis of seven clinical trials found no difference, and possibly a greater tocolytic effect at both 48 hours and up to the time of delivery, with nifedipine compared to beta-mimetic agents. Moreover, the maternal side effects from oral or sublingual nifedipine were fewer than with beta-agonists. The biological rationale for nifedipine's action as a tocolytic agent is through its blocking of myometrial intracellular calcium transport, and hence, calcium binding to calmodulin. About 90 percent of the drug is absorbed from the gastro-intestinal tract, and with its peak effect at 15 to 30 minutes, high drug concentrations may reach the very vascular uterine muscle. 28 The in vitro study of non-pregnant human myometrial strips demonstrated greater smooth muscle relaxation with nifedipine than with ritodrine, terbutaline or magnesium sulphate agents, although no difference was seen among tissue samples from pregnant women. 29 Although perinatal outcomes were not addressed in this analysis, the evidence suggests that there are no adverse fetal effects with the use of nifedipine. 8 Even if nifedipine does cross the placenta28 within five hours of its administration, there is no apparent alteration of maximum Doppler ultrasonographic velocity waveforms within either the fetal circulation or the uterine arteries.30 Similarly, no important effect was observed on peak systolic to end-diastolic (S/D) flow velocity ratios within the uterine artery following administration of
1986
1990 1990 1990 1991 1993 1993
25.1 +/- 5.7 24.4 +/· 32.9
-
DISCUSSION
C 11>
36.3 +/- 5.1 21 3 +I· 24 1'
• Figures estimated from data • NA, data not ava,lable
Favours Nifedipine 9'
b-agomst
Test for homogeneity:
COMPARISON OF NIFEDIPINE VERSUS BETA-SYMPATHOMIMETIC5 FOR SHORT-TERM TOCOLYSIS. INTENTION-TO-TREAT ANALYSIS
OddsRa
.
Nifedipine
-
-
Fl URE 2
Favoul'$ Beta-agonist
Mean no. days gamed(+/- SD)
Glock 25 30.1 +/- 19.6 33.6 +/- 21.7 !Overall difference in mean no. days (95% Cl): 8.6 (5.8 to 11.5; p • 0.03)
analysis (DerSimonian-Laird pooled OR 1.39, 95% Cl 0.80 to 2.42; 2-p=0.24). Table 3 represents the mean number of extra days achieved following administration of nifedipine. Approximately 8.6 (95% CI 5.8 to 11.5) days were gained in the nifedipine group, which was statistically significant (p=0.03 ). There was a significantly greater frequency of bothersome side-effects reported among those women who received beta-mimetics (Table 4). The most common complaints were palpitations, chest pain and nausea and vomiting, which were much more frequent than the typical side-effects of flushing and headache reported in the nifedipine group (DerSimonian-Laird pooled OR 0.22, 95% CI 0.06 to 0.80; 2-p=0.021). There were eight reported instances in which beta-mimetics were stopped due to adverse side effects, versus only one among the nifedipine group (DerSimonian-Laird pooled OR 0.29, 95% CI 0.08 to 1.06; 2-p=0.06).
Gloc
~ead 19 Meyer20
Data presented as odds rat,os w1th 95% Cis on log scale, based on a fixed-effects model.
Read 19 Meyer 20 Ferguson :II Jankyn Braceroll Kupferminc 2•
--·
I
1986
1990 1990 1990 1991 1993 1993
Study
266
MARCH 1998
' ' ' TABL 4
The apparent lack of difference between nifedipine and betamimetics for short-term tocolysis rNo. patients with side be qualified. First, in a sigshould effects necessitating Major side effects• discontinuation of nificant number of instan ces therapy among the trials included herein No. Nifedipine Nifedipine No. b-agonist b-agonist 1---Study there was both contamination and Flushing 1120 Palp1tations Read 19 13/20 0120 0/20 with other tocolyco-intervention or anxiety an intentionAlthough drugs. tic Diaphoresis and 1/34 Chest pain M eye.-20 6/24 1/34 4/24 shortness of breath to-treat analysis may seem Ferguson2 1 Flushing or 4/33 Chest pain or 17/ 33 0/33 2/33 appropriate in this circumstance, headache tightness, I does it offer a meaningful comparnausea or vomiting I ison between the two agents ?31 Janky22 Flushing or 10/30 Palpitations I 0/30 4/32 0132 I headache Moreover, the results of"negative" Bracero23 11/ 19 2/19 Flushing, 0123 8/23 Chest pain, or "no difference" trials are often headache palpitations, attributable to a Type II error, arisheadache ing from small sample sizes with Kupf rminc2• Flushing, 0130 0/30 8/ 30 Chest pain, 23/ 30 headach palpitations, insufficient statistical power, rather nausea or vom1ting than an absence of some real difNausea or vomiting, NA" Chest pain, Glock25 NA NA NA ference between groups.35 transient hypotension pulmonary oedema Designing a clinical trial to ·Yusuf-Peto pooled odds demonstrate equivalence (or nearratio (95% Cl): 0.25 (0.08 to 0.78; 2-p=0.018) 0.26 (0.16 to 0.43; 2-p < 0.001) equivalence) may require a more DerSimonian-Laird pooled 0.29 (0.08 to 1.06; 2-p• 0.06) odds ratio (95% Cl): 0.22 (0.06 to 0.80; 2-p • 0.021) rigorous approach than one aimed , s•gnifiQmt p olp•tat ons, pulmon ry oedema, nau a or vom•t•ng, • Def,ned .os chest pain or 11ght proving the superiority of one at headache or flush•ng. therapy over anoth er. 36 A future •• NA, data not available trial comparing nifedipine to another agent, for example, ritodrine, needs to consider nifedipine, with S/0 ratios returning to control values this in its estimation of sample size: the approximate numby 60 minutes. 31 ber of subjects for an equivalence trial, in which the 48In the current overview, the mean gestational age at hour tocolysis success rate is 75 percent with the "old" trial entry was around 3 1 weeks, starting as early as 22 treatment, and no more than 10 percent higher or lower weeks. The criteria for subject inclusion/exclusion were with nifedipine, varies from between 788 (alpha=O.OS, generally reflective of those applied within most centres. power 80%), up to 1,152 subjects in total (power 95%).36 H ence, these dat a are probably gen eralizable to the Future studies might measure the comparative ease of "average" case of preterm labour. The earliest gestational administration of either therapy during ambulance transage at which tocolysis should be attempted, however, The relative cost, number of days required in hospiport. depends on the availability of both adequate follow-up tal and the major maternal side effects with each agent and neonatal care. One cost-benefit analysis suggested a should be assessed, as th ey are often appreciable. The disadvantage with the use of beta-agonists after 34 ongoing debate over the risks of sh ort-acting calcium weeks. 32 channel blockers among patients with underlying coroThe current finding that nifedipine is better tolerated 33 8 nary artery disease h as yet to be resolved.3H 0 These obserthan beta-agonists has been observed elsewh ere. · At vations were also based upon older patients, however, who pharmacological doses, ritodrine often causes chest pain, were on long-term therapy, at higher doses. A pregnant palpitations and nausea and vomiting, which seem prowoman receiving several weeks of n ifedipine, whether as h ibitive when nifedipine is compared. Unlike betaa tocolytic agent or in the treatment ofhypertension,11 mimetics, nifedipine is rarely discontinued due to should not be considered part of this controversy. maternal side effects. MATERNAL SIDE EFFECTS COMPARING NIFEDIPINE TO BETA-SYMPATHOMIMETIC AGENTS IN PRETERM LABOUR
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' ' ' on-treatment analysis leaves some uncertainty about the external validity of their data.
Until further data are made available, clinicians are left with a choice: the current evidence, though limited and somewhat biased, suggests that nifedipine is probably as efficacious as beta-mimetics for the achievement of short-term tocolysis. Nifedipine has fewer serious maternal side effects, with no proven adverse consequences for the fetus.4.4 1 In certain situations where the administration of sympathomimetics is not feasible or is poorly tolerated, oral or sublingual nifedipine, 20 to 30 mg q6h, can be tried for the medical management of preterm labour. Routine follow-up and monitoring of both maternal and fetal well-being are necessary thereafter until delivery. Corticosteroids should be administered in the interim as soon as tocolysis is achieved.
REFERENCES 1.
2. 3. 4.
5.
ADDENDUM
6.
After completion of this meta-analysis, a subsequent multicentre, randomized, non-blinded trial was published (Papatsonis DNM, van Geijn HP, Ader HJ, Lange FM, Bieker OP, Dekker GA. Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial. Obstet Gynecol1997;90:230-4). In this trial, women in preterm labour between 20 to 33 4/7 weeks gestation were randomized either to oral nifedipine (n=95) or intravenous ritodrine (n=90). The treatment protocol was similar to that of previous studies, with the exception that women with ruptured membranes were also included. Due to severe maternal side effects, ritodrine was stopped in 12/90 women, usually after 48 hours of treatment, while none of the nifedipine users required drug cessation (RR 0.79, 95% CI 0.33 to 1.87 in favour of nifedipine). Using an on-treatment analysis only, 95/95 nifedipine recipients and 78/90 ritodrine recipients had reported outcomes. In the nifedipine group, 48-hour tocolysis was achieved among 74/95 (77.9%) women, versus 49/78 (62.8%) in the ritodrine group (RR 1.24, 95% CI 1.00 to 1.52 in favour of nifedipine). Delivery occurred later with nifedipine (33.4 +/- 4.5 weeks) than with ritodrine (32.1 +/- 4.1 weeks) (mean diference 0.44 weeks, 95% CI 0.00 to 2.6). Indomethacin was administered for tocolysis to 26/95 (27.4%) nifedipine users and 20/78 (25.6%) of those taking ritodrine (RR 1.07, 95% CI 0.62 to 1.85). Although these results further support both the safety, and probable superiority, of nifedipine over ritodrine for short-term tocolysis, the authors' exclusive use of an
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7.
8.
9.
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11.
12. 13.
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' ' ' 19. Read MD, Wellby DE. The use of a calcium antagonist (nifedipine) to suppress preterm labour. Br J Obstet Gynaecol1986;93:933-7. 20. Meyer WR, Randall HW, Graves WL. Nifedipine versus ritodrine for suppressing preterm labor. J Reprod Med 1990;35:649-53. 21. Ferguson JE, Dyson DC, Schutz T, Stevenson DK. A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome. Am J Obstet Gynecol1990;163:105-11. 22. Janky E, Leng JJ, Cormier P, Salamon R, Meynard J. A randomized study of treatment of threatened premature labour: nifedipine against ritodrine. J Gynecol Obstet Bioi Reprod 1990;19:478-82. 23. Bracero LA, Leikin E, Kirshenbaum N, Tejani N. Comparison of nifedipine and ritodrine for the treatment of preterm labor. Am J Perinatol1991 ;8:365-9. 24. Kupferminc M, Lessing JB, Yaron Y, Peyser MR. Nifedipine versus ritodrine for suppression of preterm labour. Br J Obstet Gynaecol1993;100:1090-4. 25. Glock JL, Morales WJ. Efficacy and safety of nifedipine versus magnesium sulfate in the management of preterm labor: a randomized study. Am J Obstet Gynecol 1993;169:960-4. 26. Smith CS, Woodland MB. Clinical comparison of oral nifedipine and subcutaneous terbutaline for initial tocolysis. Am J Perinatol1993;10:280-4. 27. Roy UK, PanS. Use of calcium antagonist (nifedipine) in premature labour. J Indian Med Assoc 1993;91:8-10. 28. Ferguson JE, Schutz T, Pershe R, Stevenson DK, Blaschke T. Nifedipine pharmacokinetics during preterm labor tocolysis. Am J Obstet Gynecol 1989; 161 :1485-90. 29. Saade GR, Taskin 0, Belfort MA eta/. In vitro comparison of four tocolytic agents, alone and in combination. Obstet Gynecol1994;84:374-8. 30. Mari G, Kirshon B, Moise KJ Jr, Lee W, Cotton DB. Doppler assessment of the fetal and uteroplacental circulation during nifedipine therapy for preterm labor. Am J Obstet Gynecol 1989; 161:1514-8. 31. Thaler I, Wiener Z, Manor D, ltskovitz J. Effect of calcium channel blocker nifedipine on uterine artery flow velocity waveforms. J Ultrasound Med 1991;10:301-4. 32. Korenbrot CC, Aalto LH, Laros RK. The cost effectiveness of stopping preterm labor with beta-adrenergic treatment. N Engl J Med 1984;310:691-6. 33. van Dijk KGJ, Dekker GA, van Geijn HP. Ritodrine and nifedipine as tocolytic agents: a preliminary comparison. J Perinat Med 1995;23:409-15. 34. Gent M, Sackett DL. The quantification and disqualification of patients and events in long-term cardiovascular clinical trials. Thromb Haemost 1979;41 :123-34. 35. Freiman JA, Chalmers TC, Smith H Jr, Kuebler RR. The importance of beta, the type II error and sample size in the design and interpretation of the randomized controlled trial: survey of 71 "negative" trials. N Eng I J Med 1978;299:690-4.
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36. Jones B, Jarvis P, Lewis JA, Ebbutt AF. Trials to assess equivalence: the importance of rigorous methods. BMJ 1996;313:36-9. 37. Furberg CD eta/. Nifedipine: dose-related increase in mortality in patients with coronary artery disease. Circulation 1995;92:1326-31. 38. Braun S et a/. Calcium antagonists and mortality in patients with coronary artery disease: a cohort study of 11,575 patients. J Am Coli Cardiol1996;28:7 -11. 39. Yamashita S. Current controversies in calcium channel blocker therapy. Can J Clin Pharmacol1996;3:99-1 08. 40. Lip GYH, Beevers DG. Are calcium antagonists safe in hypertension? Postgrad Med J 1996;72:193-5. 41. Childress CH, Katz VL. Nifedipine and its indications in obstetrics and gynecology. Obstet Gynecol 1994;83:616-24.
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