heavy menstrual bleeding , or menorrhagia , is defined as excessive menstrual blood loss that occurs alone or in combination with other symptoms and has a negative impact on a woman s physical , social , emotional , and material quality of life . approximately 30% of women are negatively affected by menorrhagia during their reproductive years , resulting in increased health care costs . previous cochrane reviews [ 57 ] found that tranexamic acid and danazol were more effective than non - steroidal anti - inflammatory drugs ( nsaids ) , combined oral contraceptives , or oral progestogens ; treatment with danazol caused more adverse events than other treatments , which may affect its acceptability and its long - term use . however , these conclusions were based on a small number of trials , all of which were underpowered , limiting the recommendations for clinical use . the levonorgestrel - releasing intrauterine system ( lng - ius ) is a reversible method of contraception that has a known efficacy in the treatment of menorrhagia . several studies have assessed the clinical effectiveness and cost - effectiveness of lng - ius and surgical interventions ( hysterectomy , first- and second - generation endometrial ablation ) , [ 1012 ] but a clearly superior approach to management of menorrhagia remains elusive . while surgical approaches may be effective , they are associated with perioperative and long - term complication risks . moreover , 80% of women treated for menorrhagia have no uterine abnormality   and over a third of women undergoing hysterectomies for menorrhagia have normal uteri . in addition , many women with menorrhagia desire to preserve their potential for childbearing . therefore , surgical options should be reserved for women who have pelvic pathology and for those who fail medical treatment . the lng - ius is an inexpensive and minimally invasive procedure that could be an alternative to oral drug treatment as a first - line agent . in 2007 , guidelines from the uk national institute for health and clinical excellence recommended the lng - ius as a first - line treatment for menorrhagia on the basis of limited evidence . recently , several randomized trials have shown the superiority of lng - ius over conventional medical treatments in reducing menstrual blood loss in women with menorrhagia [ 1720 ] . the eclipse study , a more recent multicenter randomized trial , added evidence that the lng - ius was more effective than conventional medical treatment in reducing the effect of menorrhagia on quality of life . however , a comprehensive summary of the pertinent evidence has not been published to date . therefore , we performed a systematic review and meta - analysis to compare the effectiveness of lng - ius with that of conventional medical treatment in women with menorrhagia . the preferred reporting items for systematic reviews and meta - analyses ( prisma ) statement was followed for the performance and reporting of this systematic review . a literature search of medline ( 1948april 2014 ) , embase ( 1980april 2014 ) , and the cochrane central register of controlled trials ( central ) ( up to april 2014 ) was performed in week 2 of april 2014 . the following medical subject headings ( mesh ) terms and text words were combined and used : ( levonorgestrel - releasing intrauterine system or levonorgestrel intrauterine system or levonorgestrel - ius or lng - ius or progestogen releasing intrauterine systems or mirena ) ; ( norethisterone or tranexamic acid or mefenamic acid or danazol or oral contraceptives or progestin or medroxyprogesterone or medical treatment or medical therapy ) ; ( menorrhagia or menometrorrhagia or dysfunctional uterine bleeding or heavy menstrual bleeding or excessive uterine bleeding ) . a search of ongoing or recently completed trials was performed with the united kingdom ( www.controlled-trials.com ) and united states clinical trials registries ( www.clinicaltrials.gov ) . all searches were performed by 2 independent researchers ( q.y.w . and j.h . ) without geographic or language restrictions . two reviewers ( q.y.w . and j.h . ) identified and screened the search findings for potentially eligible randomized controlled trials ( rcts ) that compared the lng - ius with conventional medical treatment in patients with menorrhagia . for inclusion in the meta - analysis , a study had to fulfill the following criteria : an rct article published in a peer - reviewed journal , with the report describing at least 1 of the primary outcomes mentioned below . when studies were reported by the same institution and/or authors , either the better quality study or the more recent publication was included . the following reports were excluded : abstracts , letters , editorials , expert opinions , case reports , reviews without original data , and studies lacking a control group . any disagreements about inclusion were resolved by consensus or arbitration by a third reviewer ( j.q . ) . independently and in duplicate , the same 2 reviewers ( q.y.w . and j.h . ) extracted the data ( first author , year of publication , country where the study was performed , sample size , study population characteristics , medical treatment option and dosage , follow - up , and outcomes of interest ) into a standardized collection form and entered the data into the revman program ( version 5.1.0 , 2011 ; the nordic cochrane centre , the cochrane collaboration , copenhagen , denmark ) . some data in this meta - analysis may differ slightly from those included in the original studies because we standardized outcome definitions for data analysis . although menstrual blood loss can be directly measured using the alkaline hematin method , indirect determination of menstrual bleeding using a validated pictorial bleeding assessment chart ( pbac ) is a more practical approach and is commonly used in clinical trials . a previous study demonstrated a correlation ( correlation coefficient=0.847 ) between the objective measurement of blood loss ( alkaline hematin method ) and self - assessed pbac scores , with a score of 100 to have a sensitivity of 86% and a specificity of 89% to diagnose a blood loss of 80 ml , which is the definition of menorrhagia . in our study , data of direct measurement of menstrual blood loss and indirect evaluation using pbac were extracted from the included trials to provide the most complete information on menstrual blood loss . because reduction in blood loss does not always correlate with satisfaction with treatment , rate of satisfaction with treatment was used as another primary outcome measure . satisfied  were considered to be a positive response , and  very dissatisfied  or uncertain  were conservatively judged to be a negative rating of treatment . for studies not reporting level of satisfaction , we used surrogate outcomes ( major problem resolved / menstrual symptoms successfully treated / willing to continue with the treatment ) . secondary outcome measures included rate of discontinuation , treatment failure , serious adverse events , and quality of life . although not consistently defined across studies , treatment failure included menstrual blood loss 80 ml or a pbac score 100 , unacceptable bleeding profile , persistent or recurrent heavy bleeding , major change in allocated treatment ( one medical treatment to another , lngius to medical treatment , or medical treatment to lngius ) , removal of lng - ius , and discontinuation of medical treatment . serious adverse events were defined as those resulting in death , disability , or hospitalization . to assess quality of life , the medical outcomes study 36-item short - form health survey ( sf36 ) and the euroqol group 5-dimension self - report ( eq-5d ) questionnaires were utilized . studies were critically evaluated for design and risk of bias , according to criteria in the cochrane handbook for systematic reviews of interventions . each rct was assessed according to 7 criteria : ( 1 ) sequence generation ; ( 2 ) allocation concealment ; ( 3 ) blinding of participants , personnel , and outcome assessors ; ( 4 ) incomplete outcome data ; ( 5 ) selective outcome reporting ; ( 6 ) other sources of bias ; and ( 7 ) intention - to - treat analysis . in addition , trials were rated for levels of evidence according to the oxford centre for evidence - based medicine in the uk . all studies presented their data on menstrual blood loss using the alkaline hematin method as median ( range ) except for a study by shabaan et al . , which presented it as mean  standard deviation . thus , these data were not used because of the relatively small number of studies available . to obtain a summary estimate of menstrual blood loss , we pooled pbac scores and report the weighted mean difference ( wmd ) . for dichotomous variables , odds ratios ( ors ) we estimated the degree of heterogeneity among studies using the cochrane q statistic ( p < .10 was considered to be statistically significant heterogeneity ) and the i statistic ( i > 50% was considered to be statistically significant heterogeneity ) . initially , a fixed - effects model was used to synthesize all data . however , if there was evidence of heterogeneity among the included studies , random - effects analysis according to dersimonian and laird was used . an estimation of potential publication bias was executed by funnel plot , in which the se of log ( or ) of each study was plotted against its log ( or ) . asymmetry in such funnel plots , usually caused by small trials reporting greater effects on average than large trials , suggests a possible publication bias . we used the grade methodology to assess the quality of evidence for each outcome across studies . the electronic database search resulted in 1198 citations : 481 from medline , 658 from embase , and 59 from cochrane library . in addition , searching reference lists for all relevant papers , recent editorials , and related review articles yielded 7 more records . after further screening of the 12 full - text articles , 2 studies   were excluded because they were prospective , non - randomized studies . the remaining 9 studies were included in qualitative analysis , with 1 duplicate report of an rct excluded , leaving 8 studies [ 1721,3638 ] in the final meta - analysis . table 1 outlines the characteristics of the 8 trials included in our meta - analysis . of these studies , 3 were conducted in the uk , and the remainder were performed in finland , usa , canada , turkey , and egypt . in total , there were 562 patients in the lng - ius group and 608 patients in the conventional medical treatment group . medical treatments differed between studies : 2 studies used mefenamic acid , 2 studies used medroxyprogesterone , 2 studies used combined oral contraceptive pills , and 1 study used norethisterone . in the largest multicenter randomized trial , conventional treatment included mefenamic acid , tranexamic acid , norethindrone , medroxyprogesterone acetate injection , combined oral contraceptive pills , and combinations of these methods . one study compared the lng - ius to both depot and oral medroxyprogesterone acetate , with 44 patients in each arm . women with idiopathic menorrhagia ( menstrual blood loss 80 ml ) were included in these trials ; however , there were differing enrollment criteria . all but 1 study   reported the exclusion of women who had fibroids or other disorders . six [ 1921 , 3638 ] of the included trials had an adequate generation for randomization . none of the trials blinded the participants to treatment group , and none mentioned whether outcome assessors were blinded . one study did not provide the reasons for patients who were lost to follow - up ; therefore , the risk of incomplete outcome data was unclear . the risk of selective outcome reporting was unknown in 4 studies because of insufficient information . five studies [ 1921,36,37 ] appeared to be free of other sources of bias , leaving the remaining studies unclear . finally , all of the included studies reported intention - to - treat analysis , allowing us to use the results from intention - to - treat analysis in the meta - analysis . six [ 1720,36,38 ] of 8 studies provided measured menstrual blood loss or estimated pbac scores ( table 2 ) . five studies [ 1820,36,38 ] reported the mean percentage change from baseline in menstrual blood loss , which ranged from 70.8% to 94% in the lng - ius group and from 21.5% to 87% in the usual - treatment group . five studies demonstrated the lng - ius to be superior to conventional medical treatment [ 1720 
 38 ] , while 1 study found no statistically significant difference between the lng - ius and norethisterone . we were unable to pool data on menstrual blood loss measured by the alkaline hematin method because only 1 study reported the mean and standard deviation ; on the other hand , pooling data on pbac scores showed significantly higher reductions of menstrual blood loss in the lng - ius group compared to the conventional treatment group ( wmd 136.00 , 95% ci 74.43197.57 , p<.001 ) , although substantial heterogeneity across studies was observed ( q statistic=33.80 , p<.001 , i=94% ) ( figure 3 ) . more women were satisfied with the lng - ius compared to conventional medical treatment ( or 5.19 , 95% ci 2.739.86 , p<.001 ) , although there was significant heterogeneity between study estimates ( q statistic=28.33 , p<.001 , i=72% ) ( figure 4 ) . further sensitivity analyses demonstrated that the heterogeneity was the effect of all 8 varied outcomes , not the effect of any single study . . a lower proportion of women in the lng - ius group discontinued the primary treatment as compared with the medical treatment group ( 14.6% vs. 28.9% , or 0.39 , 95% ci 0.200.74 , p=.004 ) ( figure 5 ) . slight heterogeneity between studies was observed in this result ( q statistic=9.58 , p=0.09 , i=48% ) . sensitivity analyses showed that 1 independent study by lhteenmki et al . , which reported that 26 of 28 ( 93% ) patients discontinued the treatment of mefenamic acid at 12 months , was the main origin of this heterogeneity . the heterogeneity was effectively decreased by excluding this study ( q statistic=3.67 , p=0.45 , i=0% ) . however , results from pooled estimates of rate of discontinuation remained similar after excluding this study ( or 0.45 , 95% ci 0.310.66 , p<.001 ) . with respect to treatment failures , women receiving the lng - ius had a lower incidence of treatment failures than those receiving conventional medical treatment ( or 0.18 , 95% ci 0.100.34 , p<.001 ) ( figure 6 ) . there was some evidence of heterogeneity between studies in this result ( q statistic=18.54 , p=0.02 , i=57% ) . sensitivity analyses were then performed by examining the influence on the overall effect of removing individual data from the analysis . the study by kaunitz et al . , which reported significantly more successful treatment with the lng - ius ( 67/79 , 84.8% ) than medroxyprogesterone acetate ( 18/81 , 22.2% ) , was the origin of the heterogeneity in this outcome . after exclusion of this study , the heterogeneity was effectively reduced ( q statistic=6.85 , p=0.44 , i=0% ) . however , the incidence of treatment failure was still significantly lower for the lng - ius ( or 0.25 , 95% ci 0.160.39 , p<.001 ) , compared with conventional medical treatment , after the exclusion of the study . three studies were not estimable , as no serious adverse events for either treatment were reported . pooled data from the remaining 3 studies   showed no statistically significant difference in serious adverse events between the lng - ius and medical treatment groups ( or 0.88 , 95% ci 0.591.33 , p=.54 ) , with no obvious heterogeneity observed ( q statistic=2.06 , p=0.36 , i=3% ) ( figure 7 ) . only 3 studies reported quality of life as an outcome measure . this outcome was assessed in different ways ; therefore , pooling the data for meta - analysis was not possible . assessed quality of life as general wellbeing , work performance , physical activity , sex life , and leisure time activity by the visual analogue scale . there was no improvement in quality of life scores in the medical treatment group ( mefenamic acid ) but there was significant improvement in patients with the lng - ius in all aspects . in a trial comparing the lng - ius with combined oral contraceptive pills , health - related quality of life and lost work days were analyzed via the hrqol-4 questionnaire . the authors found a significant reduction in the number of lost work days in the lng - ius group ( p<.001 ) , although overall health , physically ill days , and mentally ill days were comparable between groups . in the most recent randomized trial , 3 instruments were used to assess quality of life : the sf-36 and eq-5d questionnaires , and the eq-5d visual analogue scale . the investigators demonstrated a significant improvement from baseline on the sf36 in both groups , with better scores in the lngius group in 7 of the 8 domains ( physical functioning , physical role , emotional role , social functioning , energy and vitality , pain , and perception of general health ) . no significant differences were observed between groups for the eq5d questionnaire and eq-5d visual analogue scale ( p=.38 and p=.12 , respectively ) . assessment of a funnel plot of rate of satisfaction suggests there was no publication bias . we found the quality of evidence for pbac scores , rate of satisfaction , and serious adverse events to be moderate . we found the quality of evidence for treatment failure and rate of discontinuation to be moderate ( table 3 ) . based on the available evidence , the lng - ius significantly reduced menstrual blood loss from baseline and was more effective than conventional medical treatment . women who received the lng - ius were more satisfied than those receiving conventional medical therapy . in an analysis of secondary outcomes , the lng - ius was associated with a lower rate of discontinuation and a lower incidence of treatment failures . in addition , quality of life indicators were superior for women with the lng - ius compared with those receiving conventional medical treatment , although the data were not pooled for meta - analysis because these indicators were inconsistent between studies . our review provides evidence that lng - ius is the more effective first choice for the treatment of menorrhagia , compared with medical treatment . although the medical treatment approaches differed in each study reviewed , these agents are representative of current clinical practice and the majority of women with menorrhagia were treated solely with these agents in primary care . in addition , meta - analyses of rcts suggest that these agents are similar in their efficacy to reduce menstrual blood loss [ 57 ] . therefore , our meta - analysis is a valid comparison of the lng - ius with conventional medical treatment . the lng - ius has been approved in 120 countries worldwide for contraception and in 115 countries for the management of menorrhagia . we found the lng - ius to be superior to conventional medical therapy in reducing menstrual blood loss , although this result was from pooled data on pbac scores . as there is a good correlation between pbac scores and menstrual blood volume , pbac scores may substitute for the alkaline hematin method , which is not applicable to routine clinical use . in addition , more women were satisfied after using the lng - ius than medical treatment , suggesting that more women had their major problems resolved with the lng - ius . moreover , the incidence of treatment failures was lower in the lng - ius group , which contributes to the strong evidence that the lng - ius is more effective than conventional medical therapies . although losses of 80 ml or more are traditionally considered the criterion for menorrhagia , which was used in trials included in this review and many other treatment trials , only about half of women seeking treatment meet this criterion   and there is heterogeneity among studies with regards to blood loss . clinical guidelines now recommend the use of patient - based outcome measures ( e.g. , measures of quality of life ) rather than menstrual blood loss because they capture the effect of heavy bleeding on women s psychological and physical well - being . sf36 and eq-5d questionnaires have been shown to be practical , reliable , and valid instruments for measuring health status and medical outcomes . although women receiving the lng - ius had superior quality of life in 3 of 8 trials , we were unable to pool this data due to differing quality measurements among these studies , limiting the power of the evidence . upcoming trials should access the impact of menorrhagia on women s quality of life and use robust and clinically - accepted instruments . it has been previously reported that a high proportion of women who were originally prescribed lng - ius had terminated its use at 2 years ( 28% ) , and this rate increased after 45 years ( 50% ) . . however , another randomized trial showed that depression may have also have been partly responsible . it appears that success or failure of treatment with the lng - ius is multifactorial and difficult to predict on a case - by - case basis . nonetheless , the discontinuation rate of the lng - ius was much lower than that of conventional medical treatment , according to our review . this is in agreement with a recent multicenter study also demonstrating a lower discontinuation rate at 12 months in the lng - ius group ( 13.3% ) . this may reflect greater symptom relief with the lng - ius , although another possible explanation is that the cessation of medications does not require consultation with a physician . when comparing the efficacy of the lng - ius with that of conventional medical therapy , safety should also be carefully evaluated . in the 2 studies   that analyzed occurrence of adverse events using statistical methods , there was no significant difference between the 2 groups . also , most of the adverse events were reported to be mild - to - moderate in intensity in both groups . in the 6 trials reporting serious adverse events , of note , no uterine perforations were reported with the lng - ius in these trials . thus , both the lng - ius and medical treatment have favorable safety profiles and are well tolerated . with regards to long - term use of the lng - ius , hormone - related adverse events may occur if a second lng - ius is implemented after 5 years , due to increased serum lng levels . one prospective , multicenter , non - comparative study examined the bleeding pattern and safety of consecutive use of multiple lng - ius devices , and found hormone - related adverse events to be uncommon ; no discontinuations could be attributed to hormone - related adverse events . therefore , women contemplating lng - ius replacement after 5 years should be informed of the remote possibility of hormone - related adverse events , which wound not be likely to result in discontinuation of the lng - ius . the incidence of amenorrhea was reported in 2 trials . more women were amenorrheic after 3 months of treatment with the lng - ius compared to norethisterone ( 32% vs. 0% ) . in another study , 7 women ( 12.5% ) in the lng - ius group had amenorrhea within 12 months of follow - up ; there was no amenorrhea in the combined oral conceptive pills group . previous studies demonstrated that approximately 30% of women were amenorrheic after using the lng - ius for 5 years ; a higher proportion ( up to 60% ) was seen after using a second lng - ius . thus , women who do not wish to experience amenorrhea may not be the best candidates for use of the lng - ius as a first choice . the lng - ius has consistently been shown to be cost - effective for the treatment of menorrhagia in multiple clinical settings . a recent cost - effectiveness analysis by the national health service in the uk compared hysterectomy , endometrial ablation ( both first and second generation ) , and the lng - ius for the treatment of menorrhagia and concluded that hysterectomy would be the preferred first intervention for treating menorrhagia . although hysterectomy is more expensive than endometrial ablation or long - term lng - ius use ( 10 years ) , it produced more quality - adjusted life - years ( qalys ) in comparison . however , due to its invasiveness , hysterectomy should not be considered a first - line treatment . another study demonstrated that initial use of the lng - ius was less costly and more effective compared with combined oral conception or progestogens for the treatment of dysfunctional uterine bleeding . however , there are only limited data available on long - term follow - up . other medical therapies with drugs such as tranexamic acid , a safe and cost - effective treatment for menorrhagia , have not been compared with the lng - ius . this is the first systematic review and meta - analysis comparing the lng - ius with conventional medical treatment for menorrhagia . we used optimal methods , complying with guidelines on reporting of systematic reviews and meta - analyses . an extensive literature search was conducted , with no language restrictions , minimizing the risk of missing information and publication bias . furthermore , this meta - analysis was conducted at an appropriate time , because enough data have accumulated to make an adequate analysis of the lng - ius , which is being used more frequently to replace conventional medical therapy worldwide . our results did not change considerably after sensitivity analysis , indicating our analysis to be stable . first , the range of medications administered to patients in this review complicates any efforts to compare the lng - ius with individual agents . second , the duration of follow - up varied from 3 months to 2 years , limiting our ability to assess long - term outcomes . finally , there was notable statistical heterogeneity across studies , as reflected in our outcome measures , although the results were stable as indicated by sensitivity analysis . our findings concur with nice guidelines for the use of lng - ius as a first - line treatment for menorrhagia . patient satisfaction rates were higher with the use of the lng - ius compared with conventional medical treatment . use of the lng - ius is associated with a lower rate of discontinuation and fewer treatment failures compared with medical treatment . quality of life analysis favored the lng - ius over medical therapy , although our study may be too underpowered to draw strong conclusions because of the varied outcome measures and the relatively small number of studies available . the lng - ius should be considered as first - line treatment in patients with menorrhagia if pharmaceutical treatment is indicated , whether or not contraception is needed . long - term , randomized trials are required to further investigate patient - based outcomes and evaluate the cost - effectiveness of the lng - ius and other medical treatments .
backgroundthe aim of this study was to compare the effects of the levonorgestrel - releasing intrauterine system ( lng - ius ) with conventional medical treatment in reducing heavy menstrual bleeding.material/methodsrelevant studies were identified by a search of medline , embase , the cochrane central register of controlled trials , and clinical trials registries ( from inception to april 2014 ) . 
 randomized controlled trials comparing the lng - ius with conventional medical treatment ( mefenamic acid , tranexamic acid , norethindrone , medroxyprogesterone acetate injection , or combined oral contraceptive pills ) in patients with menorrhagia were included.resultseight randomized controlled trials that included 1170 women ( lng - ius , n=562 ; conventional medical treatment , n=608 ) met inclusion criteria . 
 the lng - ius was superior to conventional medical treatment in reducing menstrual blood loss ( as measured by the alkaline hematin method or estimated by pictorial bleeding assessment chart scores ) . 
 more women were satisfied with the lng - ius than with the use of conventional medical treatment ( odds ratio [ or ] 5.19 , 95% confidence interval [ ci ] 2.739.86 ) . compared with conventional medical treatment , 
 the lng - ius was associated with a lower rate of discontinuation ( 14.6% vs. 28.9% , or 0.39 , 95% ci 0.200.74 ) and fewer treatment failures ( 9.2% vs. 31.0% , or 0.18 , 95% ci 0.100.34 ) . furthermore , quality of life assessment favored lng - ius over conventional medical treatment , although use of various measurements limited our ability to pool the data for more powerful evidence . 
 serious adverse events were statistically comparable between treatments.conclusionsthe lng - ius was the more effective first choice for management of menorrhagia compared with conventional medical treatment . 
 long - term , randomized trials are required to further investigate patient - based outcomes and evaluate the cost - effectiveness of the lng - ius and other medical treatments .