Methotrexate in ectopic pregnancy prof.salah roshdyPresentation Transcript
Comparison Of Double & Single-dose Methotrexate Protocols ForTreatment Of Ectopic Pregnancy Salah Roshdy Ahmed a, MD; Hossam O a b Hamed , MD; Abullah A Alghasham, MDDepartments of Obstetrics and Gynecology a and b Pharmacology College of Medicine, Qassim University 2012/2013
Introduction• Ectopic pregnancy complicates 2-5% of all pregnancies and carries significant risks for maternal health.• More than 90% of cases are sited in the Fallopian tube resulting in tubal rupture with development of hemoperitoneum after few days or weeks from missed menstrual period.• In early-diagnosed cases and before tubal rupture, we have the opportunity to manage the patient medically by methotrexate instead of surgical intervention.
Introduction• The medical treatment by methotrexate has been developed in the last decade and accepted as first-line treatment or a cost-effective alternative to laparoscopy in well-selected patients .• Among multiple methotrexate protocols, multi- dose regimen includes IM administration of 4 methotrexate doses alternating with folinic acid in a course that extends for 8 days. While single- dose protocol comprises single dose administration which could be repeated weekly up to 4 weeks in poor-responders.
Introduction• The potential advantages of single protocol over multi-dose one are elimination of folinic acid use, lower incidence of side effects, and better compliance and convenience.• Although the efficacy of both methotrexate regimens had been studied extensively, there is no consensus for optimum Protocol. Why?
Introduction• The single-dose protocol in a large meta-analysis conducted by Barnhart et al in 2003 was associated with significantly lower success rate compared with multi-dose regimen (88% vs. 93%). But, these data were not proved in multiple subsequent studies which showed comparable success rates in both regimens. (Lipscomb et al 2005 and Alleyassin et al 2006)
Introduction• On the other hand, the outcome of single-dose regimen is inconsistent in multiple studies depending on initial β-hCG level, gestational mass size, and the number of repeated dosages.• A success rate as low as 35% with β-hCG > 4000 IU/L and as high as 98% with levels < 1000 IU/L was previously reported.
Introduction• The challenge to develop an optimum regimen that balance between efficacy and safety in one side and convenience in other side was attempted by Barnhart et al (2007)who first described what is called double-dose protocol.• In his study that included 101 patients, 2 doses of methotrexate were administered at day 0 and 4 without measuring β-hCG between doses and reported 76% success rate.
Introduction• Although their reported rate is comparable to that of single-dose regimen, there are no clinical trials in literature have compared both regimens.• We hypothesize that efficacy of double-dose protocol could be more effective than non- repeated single-dose regimen especially in patients with high baseline β-hCG and large gestational mass.
Aim of the study
Aim of the work• The aim of this study was to assess the efficacy and safety of double-dose regimen in which methotrexate is given alone and only at day 0 and 4 to non-repeated single dosage at day 0 in patients with tubal EP.• The end-points for comparison are: 1. Success rate, 2. Duration of follow up until complete resolution, and 3. Methotrexate adverse effects.
Patients and Methods
Inclusion criteriaDiagnosis of EP was diagnosed with non-laparoscopic algorithm(Stovall et al 1990).The inclusion criteria were: 1) Gestational mass in adnexa with maximum diameter ≤ 4 cm; 2) Baseline β-hCG <15000 mIU/ml; 3) Hemodynamically stable patients; 4) Absence of gestational cardiac activity 5) Patients agreed to methotrexate therapy and follow-up.
Exclusion criteriaWe excluded patients with: 1) Non-tubal EP 2) Clinically suspected tubal rupture; 3) Free fluid at TVS extending beyond Douglas pouch; 4) Low platelet count or abnormal liver or kidney functions.
Sample size• Sample size calculation was based on the biggest difference reported between success rates of non- repeated double and single-dose protocols. The lowest success rate of one-dose regimen and the highest success rate of double-dose protocol in unselected population with adnexal EP were 65% and 76%, respectively (Barnhart et al 2007).• A total of 152 patients were required to find this 11% difference with statistical significance setting α at 0.05 and β at 0.2.
Randomization• Enrolled patients were randomized to either – group (1) which received non-repeated double- dose methotrexate regimen in a dose of 50 mg/m2 IM on day 0 and day 4] (Barnhart et al 2007) or – group (2) whose patients had the same dosage once on day 0 (Stovall and Ling 2003).• Randomization was performed using a computer- generated random numbers table.
Patients assessed forParticipants eligibility (n = 189) flow chart Total excluded patients due to Enrollment presence of exclusion criteria or refusal to take methotrexate: n=32 Randomization (n= 157) Group (1) (n= 79) Group (2) (n= 78) Received double-dose Received single-dose regimen (50 mg/m2 IM regimen (50 mg/m2 IM on on day 0 and 4) day 0) Follow up for negative β-hCG or 6 weeks, which comes first -Patients had persistence or< 15 % drop of β-hCG between day 4 and day Patients had > 15 % drop of β- 7. or hCG between day 4 and day 7 -Persistent serum pregnancy test and negative serum pregnancy positive beyond 6 weeks. or test within 6 weeks. -Surgical intervention due to suspected tubal rupture Successful Failed Treatment Treatment
Management of failures• Further management of patients with treatment failure was arranged but not counted in current results. Failures of group (1) was managed by elective surgical intervention while in group (2) the choice of repeating methotrexate dosage or surgical intervention was based on discretion of the physician and patient wishes.
Statistical analysis plain– Student-t- test was used to compare means while the 2 or Fisher exact tests were used when appropriate to compare the dichotomous variables.– Receiver operator characteristics (ROC) curves for initial β-hCG concentration and longest ectopic mass diameter was created to establish cut-off points that associated with success in both groups.– P value <0.05 was considered statistically significant.
Demographic and baseline criteria in both groups. Baseline criteria Group 1 Group 2 Pa (n =79) (n =78) valuePatient age (years) mean ± SD (range) 23.1 ± 6.5 (19-35) 25.4 ± 4.7 (18-36) .3BMI mean ± SD (range) 25.6 ± 8.4 ( 20-39) 26.21 ± 7.7 (22-38) .6Parity : 29 (36.7) 25 (32.1) .61 (%) 31 (39.2) 36 (46.1)2 (%) 19 (24.0) 17 (21.8)>2 (%)History of spontaneous abortion (%) 21 (26.5) 24 (30.7) .8History of previous ectopic pregnancy (%) 7 (8.8) 6 (7.6) .2History of ovulation induction (%) 12 (15.0) 10 (12.8) .1History of IVF (%) 4 (5.0) 6 (7.6) .2Gestational age (days) mean ± SD (range) 43.4 ± 17.1( 35-58) 45.1 ± 14.9 (37-62) .4hCG (mIU/ml) mean ± SD 3565.8 ± 1977.6 3158.4 ± 1462.4 .1 (range) (550 – 9200) (450 – 8800)Longest ectopic mass diameter (cm) 2.7 ± 0.9 (0.5 – 4.0) 2.6 ± 0.8 (0.8 –4.0) .6mean ± SD (range)Patients presented by pelvic pain (%) 16 (20.2) 17 (21.7) .7Patients presented by vaginal bleeding (%) 14 (17.7) 13 (16.6) .9
ROC curve for serum β-hCG and longest gestational mass length in relation to successful outcome in group (1).ROC curve analysis shows: Figure 2-A: ROC Curve in group 1 1.00• at β-hCG cut-off level ≤ 5500 mIU/ML, the sensitivity .75 and specificity for success were 81% and 89% (area .50 under curve is 0.822), also• at mass diameter cut-off ≤ Reference Line Sensitivity .25 3.5 cm the sensitivity and Mass length specificity for success were 0.00 B-hCG 73% and 78%, (area under 0.00 .25 .50 .75 1.00 curve is 0.813) 1 - Specificity B-hCG: area under curve = 0.822. SE = 0.06. P = 0.002 Mass length: area under curve = 0.813. SE = 0.07. P = 0.002
ROC curve for serum β-hCG and longest gestational mass length in successful outcome in group (2).ROC curve analysis shows: Figure 2-B: ROC Curve in group 2• at β-hCG cut-off level ≤ 1.00 3600 mIU/ML, the sensitivity and specificity for success .75 outcome were 75% and 86% (area under curve is .50 0.768).• at mass diameter cut-off ≤ Reference Line Sensitivity .25 2.7 cm the sensitivity and Mass length specificity for success were 0.00 B-hCG 72% and 71% (area under 0.00 .25 .50 .75 1.00 curve is 0.79). 1 - Specificity B-hCG: area under curve = 0.768. SE = 0.06. P = 0.002 Mass length: area under curve = 0.790. SE = 0.06. P = 0.001
Success rate in relation to baseline β-hCG ectopic mass diameter in both groups Outcome Group 1 Group 2 Relative risk P (n =79) (n = 78) OR (95% CI) ValueSuccess rate in relation to:Baseline β-hCG (mIU/ml):- < 3600 33/35 (94.3) 48/50 (96.0) 0.68 (0.09-5.1) 1.0- 3600- 5500 24/27 (88.9) 11/19 (57.9) 5.80 (1.29-26.2) .03> 5500 13/17 (77.5) 5/9 (55.6) 2.60 (0.46-14.6) .3Ectopic mass diameter (cm):- < 2.7 37/40 (92.5) 45/46 (95.7) 0.56 (0.08-3.5) .6- 2.7-3.5 21/23 (91.3) 12/19 (63.2) 6.12 (1.09-34.3) .05- > 3.5 12/16 (75.0) 8/13 (61.5) 1.87 (0.38–9.1) .6
Tubal rupture rateOn failure side, we had 2 patients (2.5%) out of 9counted as failures in double-dose developedtubal rupture during first week of startingmethotrexate. This is compared to 3 patients(3.8%) out of 14 failures in one-dose regimen.
Overall success rates• This trial demonstrated higher but insignificant overall success rate with double-dose regimen (88% vs. 82%). This rate is higher than Barnhart et al who first described double-dose protocol and reported 76% in his study that included 101 patients.• The overall success rate of current one-dose treatment is comparable to others reported 65-96% depending on number of repeated doses and initial β-hCG concentration.
Success rates in subgroupsWhy double-dose regimen is more effective in the subgroups with high β-hCG and large ectopic mass?• The larger the size of ectopic mass the higher possibility of β-hCG production and the higher methotrexate dose required to control active trophoblastic cells.• The double-dose protocol has the potential advantage of close proximity of second to first dose; a factor that highly suggested to enhance its effect on patients with high trophoblastic-cell load
Success rates in subgroups• This could explain the reported higher cut-off points of β-hCG and ectopic mass diameter that associated with success in double-dose regimen compared to single- dose.• The significant difference in success rates between groups was lost when β-hCG exceeded 5500 mIU/Ml and the mass diameter exceeded 3.5 cm which suggests the possibility of an upper limit of trophoblastic mass that is sensitive to methotrexate treatment
Adverse effects of Methotrexate• The types and frequency of methotrexate adverse effects in current study are comparable in both groups (30% vs. 26%) and similar to others reported 25-32%.• The most frequent adverse effect was pelvic pain (8.8% vs. 7.7%) which is mostly caused by resolving EP rather than methotrexate itself.• The low rate of adverse effects with current double- dose regimen should be taken carefully as an indicator for safety of using 2 methotrexate doses, 4 days apart, without folinic acid rescue.
Conclusion and recommendation• In conclusion, double-dose protocol is an efficient and safe alternative for one-dose regimen. It is more effective, within limits, in patients with high initial β- hCG and large ectopic mass.• We recommend conducting randomized trials with adequate power to compare both regimens on selected population with potential risks for methotrexate failure to establish an effective management protocol in those patients.