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Corticosteroid response predicts success of laparoscopic splenectomy in treating immune thrombocytopenia
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Corticosteroid response predicts success of laparoscopic splenectomy in treating immune thrombocytopenia✩ Alexandra C. Istl a,∗, Greig McCreery a, Laura J. Allen a, Kelly Vogt a, Luc Dubois b, Daryl K. Gray a a b
Division of General Surgery, London Health Sciences Centre, London, ON, Canada Division of Vascular Surgery, London Health Sciences Centre, London, ON, Canada
a r t i c l e
i n f o
Article history: Accepted 14 February 2018 Available online xxx
a b s t r a c t Background: Laparoscopic splenectomy is a second-line therapy for immune thrombocytopenia with a sustained success rate of 66%. In a climate of new available medical therapies for immune thrombocytopenia, the comparative safety and efficacy of laparoscopic splenectomy are worthy of attention. The purpose of this study is to identify factors predictive of laparoscopic splenectomy success that will enable preoperative prognostication. Methods: A retrospective cohort study was conducted of patients undergoing laparoscopic splenectomy for immune thrombocytopenia. The data collected evaluated response to medical and surgical therapy, which was defined on a platelet level of 50 × 109 /L with no bleeding events. Univariate and multivariate analyses were conducted to evaluate factors predictive of laparoscopic splenectomy success, with an additional subanalysis planned to assess for laparoscopic splenectomy safety in individuals ≥65 years. Results: One hundred forty-one patients were reviewed. Operative outcomes showed a 3.6% conversion rate and 8.5% complication rate. Disease remission was achieved in 78.7% of patients. Response to initial corticosteroid therapy was associated with a laparoscopic splenectomy success rate of 90% and increased odds of surgical success by 5.58 over individuals with no response to corticosteroids. Age did not confer an increased risk of failure or complications. Conclusion: Laparoscopic splenectomy is a safe and effective intervention for immune thrombocytopenia regardless of age. Initial response to corticosteroids is associated with laparoscopic splenectomy success rate of 90% and improved odds of surgical success. Laparoscopic splenectomy should be the standard second-line therapy for immune thrombocytopenia, especially in patients responding to corticosteroids. © 2018 Elsevier Inc. All rights reserved.
The optimal therapeutic sequence in the management of immune thrombocytopenia (ITP) is controversial. Based on the American Society of Hematology 2011 guidelines, splenectomy is the recommended second-line therapy in patients who do not respond to or relapse after corticosteroid therapy (Grade 1B).1 Some practitioners defer surgical referral to avoid perioperative morbidity and mortality despite a lack of evidence directly comparing nonoperative interventions to splenectomy.2 Modern laparoscopic techniques have made splenectomy a safe operation, demonstrating equal efficacy and a lower complication rate compared to open surgery,3 as well as a lower adverse event rate than reported for common medical therapies.4–6 To identify ✩
Presented at the Canadian Surgical Forum as a poster presentation in Victoria, BC, Canada in September 2017. ∗ Corresponding author: Department of Surgery, Western University and London Health Sciences Centre, 800 Commissioners Rd. E, London, ON N6A 5W9 Canada. E-mail address: [email protected] (A.C. Istl).
the patients that would benefit most from surgical intervention, observational studies have attempted to elucidate factors predictive of splenectomy success in the treatment of ITP.7–15 The majority of these studies were small, assessed only open splenectomy (74%), and demonstrated heterogeneous results.7 The goals of this study were first, to assess the success and complication rate of laparoscopic splenectomy (LS) at our center given a large sample size compared to the existing literature, and second, to determine factors predictive of LS success that can guide therapeutic decision-making and prognostication. Identifying factors that enable prediction of surgical success preoperatively may change the second-line interventions patients are offered. Methods All patients who underwent LS for ITP at London Health Science Centre (LHSC) from 20 0 0 to 2015 were identified. LHSC is a quaternary care referral center with a catchment area of approximately
https://doi.org/10.1016/j.surg.2018.02.005 0039-6060/© 2018 Elsevier Inc. All rights reserved.
Please cite this article as: A.C. Istl et al., Corticosteroid response predicts success of laparoscopic splenectomy in treating immune thrombocytopenia, Surgery (2018), https://doi.org/10.1016/j.surg.2018.02.005
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1.6 million people. All diagnoses of ITP were made following consultation with hematologists at LHSC. Patients with a diagnosis of primary ITP (platelets <100 × 109 /L with no other causative process) were included in the analysis. Patients found postoperatively to have thrombocytopenia secondary to a separate disease process, such as lymphoma or a myeloproliferative disorder, were excluded. The morcellated spleen was sent to pathology following every operative case. An electronic chart review was undertaken to extract information pertaining to patient demographics, operative details, and preand postoperative medical management. Paper charts were evaluated for data points prior to 2006. Preoperative platelet response to primary corticosteroid treatment was recorded. Platelet response to second-, third-, and fourth-line treatment regimens could not be established given the potential confounding effects of multiple medical therapies, and was therefore not reported. Platelet counts were recorded preoperatively and immediately postoperatively. Peak and trough platelet levels for the initial 72 hours postoperatively were documented, as were platelet levels at the time of each patient’s most recent follow-up visit where available. Intraoperative and postoperative complications were identified. Medical therapies implemented postoperatively for refractory ITP were recorded. The electronic medical record allows capture of followup visits at LHSC and referring hospitals within the catchment area, as well as all laboratory results. Therefore, LS success or failure was determined at the time of data collection using the most recent patient information available.
Definitions Platelet response to therapy was determined on a threshold of 50 × 109 /L. This was the generally acceptable threshold for proceeding with surgical intervention at the time of data collection and was the most agreed-upon value for corticosteroid nonresponsiveness used in the literature.16 Success of LS was defined as the achievement of a platelet count of greater than 50 × 109 /L with no need for postoperative medical management during the follow-up period. Failure of LS was defined as a persistent postoperative platelet level of less than 50 × 109 /L or thrombocytopenia with bleeding symptoms requiring medical intervention. Any requirement for postoperative medical intervention was considered a failure. LS success or failure was determined by the authors at the time of data collection given the most recent information available in the patient’s chart rather than at the time of last follow-up. Thus, any LS successes are considered to have sustained remission to date based on the most recent electronic data. Use of medical interventions for ITP at our center has corresponded with the evolution of medical therapies and evidencebased recommendations for their use. At our institution, preoperative corticosteroids are administered as per ASH guidelines for individuals with platelet counts lower than 30 × 109 /L as standard first-line therapy. Prednisone is typically the therapy of choice at our institution with a starting dose of approximately 1mg/kg/day. Primary dexamethasone is used rarely. Rate of taper depends on patient factors including patient response and toxicity. In our study, corticosteroid response was stratified based on response to the first course of corticosteroids received after diagnosis: complete initial responders maintained a platelet count of >50 × 109 /L for any length of time after corticosteroid therapy was stopped. Transient responders achieved a platelet count of >50 × 109 /L but fell below 50 × 109 /L while still on corticosteroid therapy. Nonresponders failed to demonstrate an increase in platelet count above 50 × 109 /L at all. The first course of corticosteroids was assessed because 98% of patients received corticosteroids as first-line
therapy. Later courses of corticosteroid therapy were not assessed given the confounding effects of other interventions. Length of follow-up was defined as the time between surgery and the last recorded clinic visit. Incidence of overwhelming postsplenectomy infection (OPSI) was also determined at this time point. However, success or failure of LS was determined at the time of data collection based on the patient’s most recent laboratory values and electronic clinical data, rather than at the time of last follow-up. Statistical analysis Descriptive statistics were completed using means with standard deviations, medians with interquartile ranges, and frequencies where appropriate. Univariate analyses were conducted to assess differences between LS failure and LS success groups using Student’s t test or Mann-Whitney U tests for continuous data and Pearson χ 2 statistic or Fisher exact test for categorical variables. The number of preoperative medical therapies was analyzed as a discrete nominal variable. The platelet counts included in the analyses were those measured immediately preoperatively and immediately postoperatively. Preoperative data was subjected to multivariate logistic regression analysis to identify factors independently associated with failure of laparoscopic splenectomy for the treatment of ITP. Thirty LS failures were identified and therefore we included 3 variables, each with 10 events and 10 nonevents per covariable. Variables were identified a priori as age, response to initial course of corticosteroid therapy, and number of preoperative medical therapies. Age was analyzed as a continuous variable without cutoff values. Response to corticosteroids was analyzed as a categorical variable with stratifications as described above. Postoperative data were collected and reported; however, these were not subjected to regression analysis as they cannot contribute to preoperative prognostication. An additional subanalysis was completed comparing individuals <65 years to those ≥65 years with respect to complication rate, rate of conversion to open, and success of LS for treatment of ITP using a Pearson χ 2 statistic. Significance was determined using Fisher exact test. A cutoff age of 65 was chosen to ensure comparability with other studies assessing safety and efficacy of LS that used age 65 as a threshold. All statistical analysis was completed using IBM SPSS Statistics version 22 (IBM Corp, Armonk, NY). Results From 20 0 0 to 2015, 141 patients underwent an attempted laparoscopic splenectomy for ITP. Of those, 39.7% were male. Mean age at the time of surgery was 49 years. In 96.4% of cases, splenectomy was completed laparoscopically as planned. There was no significant difference in age, gender, American Society of Anesthesiologists class, or time from diagnosis to surgery between LS success and LS failure groups (Table 1). Those refractory to splenectomy had significantly longer length of stay (P < .05) and follow-up period (P < 0.05) compared to LS success group. It should be noted that the mean length of follow-up in the LS success group was still greater than 1 year. Preoperative platelet measures were significantly higher in the LS success group (P < .01) (Table 1). Overall, successful LS requiring no further medical management was observed in 111 patients (78.7%). Conversion from laparoscopic to open occurred in 5 patients (3.6%). Two cases were converted due to technical difficulties attributed to the patients’ body habitus. One was for control of active hemorrhage. One was for difficulty with a concomitant laparoscopic cholecystectomy. The last was to facilitate a thorough
Please cite this article as: A.C. Istl et al., Corticosteroid response predicts success of laparoscopic splenectomy in treating immune thrombocytopenia, Surgery (2018), https://doi.org/10.1016/j.surg.2018.02.005
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Table 1 Demographic characteristics for ITP patients undergoing LS.
Patients Age (mean ± SD) Male (%) ASA class (mean ± SD) Preoperative platelet count (mean∗ ± SD) Postoperative platelet count (mean∗ ± SD) Time from diagnosis to surgery (months, mean ± SD) Follow-up (months, mean ± SD) Length of stay (days, mean ±SD)
Overall
LS success
LS failure
P value
141 49 ± 19 39.7 3 ± 0.5 97 ± 75 119 ± 79 46 ± 62 16 ± 25 1.9 ± 2.2
111 48 ± 19 39.6 3 ± 0.5 107 ± 77 128 ± 83 45 ± 60 13 ± 23 1.7 ± 1.8
30 53 ± 18 40.0 3 ± 0.5 60 ± 52 81 ± 47 49 ± 70 25 ± 27 2.7 ± 3.4
.272 1.00 .925 .002 .004 .764 .021 .023
ASA, American Society of Anesthesiologists; SD, standard deviation. ∗ × 109 /L Table 2 Operative factors and complication rates for ITP patients undergoing LS.
OR time (minutes, mean ± SD) Intraoperative platelet transfusion, N (%) Conversion to open, N (%) Postoperative complication, N (%)
Overall
LS Success
LS Failure
P value
65 ± 26.6 16 (12.9) 5 (3.6) 12 (8.5)
66 ± 26.9 11 (10.0) 2 (1.8) 7 (6.3)
62 ± 25.8 5 (16.7) 3 (10.0) 5 (16.7)
.552 .335 .066 .131
OR, operating; SD, standard deviation.
intra-abdominal washout after spillage of splenic tissue. Complications were identified in 8.5% of patients (Table 2). Two patients had intraoperative gastric perforations, which were immediately repaired with no sequelae. Three had postoperative hemorrhages requiring return to the operating room, one of whom developed a pleural effusion, and one of whom required transfusion. One developed a fever of undetermined origin 6 weeks postoperatively. One had an intraoperative stapler misfire with no clinical sequelae. Two developed a postoperative ileus, 1 of whom required exploratory surgery. One patient developed a diaphragmatic hernia. Overall, there was no significant difference in complications between LS failure and LS success groups (P = .131). We had 2 deaths, with an overall 30-day mortality rate of 1.4%. One patient developed Staphylococcus bacteremia and an intracranial hemorrhage. This individual singularly accounted for our OPSI rate of 0.7%. The other patient was 84 years of age, had a pulseless electrical activity arrest on postoperative day 1 presumed to be secondary to bleeding, underwent a repeat operation where the bleeding was controlled, had a massive transfusion resulting in abdominal compartment syndrome, and developed multiorgan failure after which her family withdrew care.
Fig. 1. Percentage of patients responding to laparoscopic splenectomy and response to initial corticosteroid course.
tients received was significantly different between LS success and LS failure groups (P < .001) (Fig. 2). Preoperative therapy Logistic regression All subjects received medical therapy prior to being considered for surgery. Of the patients, 97.9% received corticosteroids as firstline treatment, and the median number of preoperative corticosteroid courses in both groups was 2 (interquartile range 1-2). On univariate analysis, initial response to corticosteroid therapy was predictive of response to LS (P < .001). Overall, 50.7% of patients met our definition of complete initial corticosteroid response and 90% of these had a successful LS (P < .001). Of the patients, 20.3% were transient responders (those who relapsed with platelet count <50 × 109 /L while still on corticosteroids), and 85.7% of these had a successful LS (P < .01). Twenty-nine percent demonstrated no response to corticosteroids; only 52.5% of these had a successful LS for ITP (Fig. 1). Significantly more patients failed laparoscopic splenectomy if they were treated preoperatively with any of intravenous immunoglobin, rituximab, azathioprine, cyclophosphamide, or danazol (Table 3). The number of preoperative medical therapies pa-
Multivariate logistic regression assessing age at the time of surgery, response to initial course of corticosteroids, and the number of preoperative medical interventions was performed to assess predictors of LS success (Table 4). There was no effect of age on LS success (P = .957). Response to corticosteroid therapy was associated with significantly improved odds of LS success for both complete responders (OR [odds ratio] = 5.58 [1.870-16.665]) and transient responders (OR = 4.15 [1.131-15.231]). Each additional preoperative medical therapy significantly reduced the odds of LS success (OR = 0.27 [0.136-0.544]) compared to those receiving fewer medical interventions. Postoperative interventions Thirty patients did not demonstrate disease response following splenectomy, and 60% of these received 2 or more
Please cite this article as: A.C. Istl et al., Corticosteroid response predicts success of laparoscopic splenectomy in treating immune thrombocytopenia, Surgery (2018), https://doi.org/10.1016/j.surg.2018.02.005
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A.C. Istl et al. / Surgery 000 (2018) 1–6 Table 3 Preoperative medical therapies administered to all ITP patients undergoing LS. Variable
Overall, N (%)
Patients with preoperative medical therapy, N (%) Corticosteroids, N (%) Number of corticosteroid courses, median (IQR) IVIG, N (%) IVRhIg, N (%) Rituximab, N (%) Romiplostim, N (%) Eltrombopag, N (%) Azathioprine, N (%) Cyclophosphamide, N (%) Danazol, N (%)
141 (100) 138 (97.9) 86 (61.0) 7 (5.0) 4 (2.8) 7 (5.0) 3 (2.1) 13 (9.2) 4 (2.8) 2 (1.4)
LS Success, N (%)
LS Failure, N (%)
P value
108 (97.3) 2 (1-2) 62 (55.9) 5 (4.5) 1 (0.9) 4 (3.6) 2 (1.8) 6 (5.4) 1 (0.9) 0 (0)
30 (100) 2 (1-2) 24 (80.0) 2 (6.7) 3 (10.0) 3 (10.0) 1 (3.3) 7 (23.3) 3 (10.0) 2 (6.7)
1.00 .974 .020 .461 .030 .166 .515 .007 .030 .044
IVIG, intravenous immunoglobulin.
Fig. 2. Success of LS based on number of medical interventions given preoperatively for the treatment of ITP. Table 4 Logistic regression of the effects of age, number of preoperative medical interventions, and corticosteroid response on the success of LS.
Age Number of preoperative medical therapies Response to corticosteroids Transient response Complete response
OR [95% CI]
P value
1.00 [0.975–1.027] 0.27 [0.136–0.544]
.957 <.001
4.15 [1.131–15.231] 5.58 [1.870–16.665]
<.05 <.01
CI, confidence interval.
postoperative medical interventions. The most common postoperative interventions administered were corticosteroids (56.7%), azathioprine (33.3%), and rituximab (23.3%), respectively. Relationship between age and outcomes An additional subanalysis, planned a priori, determined whether age ≥65 in patients undergoing LS was predictive of adverse events. Of 141 patients, 23.4% were age 65 or older. Age ≥65 was not predictive of LS failure. There were no significant differences between groups with respect to procedure-related complications (P = .152) or conversion to open surgery (P = .085). Given the above findings, a proposed algorithm for the management of ITP based on corticosteroid response is depicted in Fig. 3. Projected success rates for LS irrespective of age are included. Discussion In this study, we sought to identify preoperative factors predictive of LS success in the treatment of ITP. We included all factors
that have been evaluated in recent literature including age, preoperative platelet levels,5 , 8–11 corticosteroid response,8,10 , 12 time from diagnosis to surgery,8,10 , 12 and preoperative medications.9,13 As corroborated by other studies, the LS success group had higher preoperative platelet levels.8,10 , 14 Postoperative platelet count was a commonly evaluated measure, but was not included in our analysis because it does not enable preoperative risk stratification. Our study was unique in that it identified factors that can inform therapeutic decision-making early in a patient’s disease course. With respect to the safety of LS, our complication rate (8.5%) and procedure-related mortality rate (1.4%) are consistent with those reported in the literature7 and lower than those reported for common medical therapies. Although the risk of severe complications associated with LS—such as diaphragmatic hernia—demand serious consideration, equally concerning complications of medical interventions cannot be ignored. Thrombopoietin receptor agonist therapy with romiplostim was found to have a serious adverse event rate of 8% and mortality of 5%.5 On systematic review, rituximab therapy was associated a 3.7% life-threatening adverse event rate and an overall mortality rate of 2.9% in the ITP population.4 A pilot randomized control trial assessing rituximab found 66% of patients failed treatment, 61% had infusion reactions, and 25% had significant bleeding.17 Despite these risks, 65% of patients in our study had been prescribed 2 or more medical therapies prior to undergoing splenectomy. In keeping with this observation, Lozano et al published an article in 2016 demonstrating that medical therapies such as thrombopoietin receptor agonists are increasingly used as second-line therapy after steroids, despite guidelines stating that they should be used in cases refractory to splenectomy.18 In addition to these interventions affecting quality of life, we found the odds of successful LS were significantly decreased with each additional preoperative medical intervention. By deferring surgical referral in favor of attempting second-line medical therapies, patients may be suffering unnecessary morbidity. Our study shows that patients receiving splenectomy as the primary second-line therapy have a higher rate of response than those receiving LS as a third- or fourth-line intervention. One of the most significant concerns with LS is the risk of overwhelming post-splenectomy infection (OPSI). A review of studies from 1966 to 1996 showed an OPSI rate of 2.1% in the ITP population.19 However, this review largely assessed open splenectomy and the data predates post-splenectomy vaccination, which has significantly decreased the incidence of OPSI.20 Unfortunately, the benefit of vaccination in splenectomized patients has not been well quantified due to inconsistent prescribing patterns: In their study of critically ill patients, Theilacker et al found that only 47% of septic splenectomized patients had been vaccinated.21 In our study, 100% of LS patients were vaccinated preoperatively for Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis. Our OPSI rate was 0.7%.
Please cite this article as: A.C. Istl et al., Corticosteroid response predicts success of laparoscopic splenectomy in treating immune thrombocytopenia, Surgery (2018), https://doi.org/10.1016/j.surg.2018.02.005
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Fig. 3. Flowchart for the management of ITP in surgically fit patients undergoing first-line steroid therapy. Sustained response rates for each respective intervention are denoted in brackets. Sustained response rates for surgical interventions based on our study data are denoted in blue.
Our overall LS success rate of 78.7% is comparable to those reported in other studies assessing laparoscopic splenectomy.8–12 We identified an even higher success rate in patients demonstrating a response to their initial course of corticosteroids: 90% of complete responders and 85.7% of transient responders had a successful LS for ITP. Conversely, only 52.5% of nonresponders had a successful LS. In our logistic regression, response to corticosteroid therapy was an independent predictor for LS success, with transient and complete responders having 4.15 and 5.58 greater odds of successful splenectomy, respectively. Of note, all patients included in the study had failed first-line corticosteroid therapy, as has any patient referred for surgery for ITP. However, the context in which they fail provides valuable information: initial response to corticosteroids followed by relapse after cessation or while still on treatment predicts surgical success compared to individuals who have no response to corticosteroids at all. Corticosteroid response is a potent factor for study. It enables preoperative prognostication and can be evaluated in almost all patients referred for LS. Numerous LS studies report 100% of patients underwent primary corticosteroid therapy,5,8 , 10,22 and we have shown that a good response to corticosteroids is the most robust predictor of successful LS for ITP. Age has also been a factor of interest when assessing both the efficacy and safety of splenectomy. Gonzalez et al suggested that increased age is a predictor of failure and that more complications in elderly patients might exclude splenectomy as a safe option for those over age 65.13 However, they only assessed open splenectomy. Many studies have reported that age is not a discriminating factor in disease response or complication rate.8–10 , 15 In our study, age did not predict LS failure, nor did patients over age 65 have more complications or an increased rate of conversion to open. Advantages of this study included the large sample size from a single center with splenectomy performed by a single surgeon. This is one of the only studies assessing both number of preoperative medical therapies and specific medical agents in association with the success of LS. Limitations of the study included its retrospective design and potential bias due to referral patterns for LS. Given limited precision of retrospective data, we were unable to assess specific medical regimens as factors predictive for LS failure or delineate individual effects of possible concomitant medical interventions. We were also unable to explore differences in corticosteroid administration such as exact duration of therapy or length of taper. Additionally, some patients may have recurred after follow-up was dis-
continued, although the most recent medical records available for each patient were assessed at the time of data collection. We are recommending LS for any patient who is both (1) fit for and agreeable to surgery, and (2) has relapsed while on steroid therapy, but who has also demonstrated an elevation in platelet count over 50 × 109 /L at any point during their corticosteroid therapy, as this denotes some degree of response. Because splenectomy is considered definitive management for ITP, any alternative therapy should be directly compared for equivalence or superiority. There is interest in identifying medical therapies for ITP that will prevent progression to surgery, but new medical therapies are not without risk. The risks associated with medical intervention must be carefully considered in the context of improved minimally invasive surgical techniques that confer decreased morbidity and mortality.
Conclusions LS is a safe and effective procedure for treating ITP, and age should not preclude referral. Successful disease remission was achieved in 78.7% of all patients and 90% of patients that responded to corticosteroids. Response to corticosteroids independently predicts success of LS, and those demonstrating an initial response to corticosteroids should be referred for LS as secondline therapy. The observation that a greater number of preoperative medical therapies was significantly associated with LS failure (OR = 0.27) suggests that initiating multiple medical interventions prior to referral for splenectomy may cause morbidity and delay successful management. This requires further investigation through direct comparative studies. References 1. Neunert C, Lim W, Crowther M, Cohen A, Solberg L, Crowther MA. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;177:4190–4207. 2. Auger S, Duny Y, Francois J, Quittet P. Rituximab before splenectomy in adults with primary idiopathic thrombocytopenic purpura: a meta-analysis. Brit J Haematol. 2012;158:386–398. 3. Mikhael J, Northridge K, Lindquist K, Kessler C, Deuson R, Danese M. Short-term and long-term failure of laparoscopic splenectomy in adult immune thrombocytopenic purpura patients: a systematic review. Am J Hematol. 2009;84:743–748. 4. Arnold DM, Dentali F, Crowther MA, Meyer RM, Cook RJ, Sigouin C, et al. Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura. Ann Int Med. 2007;146:25–33.
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5. Antel KR, Panieri E, Novitzky N. Role of splenectomy for immune thrombocytopenic purpura (ITP) in the era of new second-line therapies and in the setting of a high prevalence of HIV-associated ITP. SAMJ. 2015;105:408–412. 6. Kuter DJ, Bussel JB, Newland A, Baker RI, Lyons RM, Wasser J, et al. Long-term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy. Br J Haematol. 2013;161:411–423. 7. Kojouri K, Vesely SK, Terrell DR, George JN. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood. 2004;104:2623–2634. 8. Kiudelis M, Mickevicius A, Dambrauskiene R, Gerbutavicius R, Griniute R, Adukauskiene D. Prognostic factors for positive immune thrombocytopenic purpura outcome after laparoscopic splenectomy. Cent Eur J Med. 2010;6:123–130. 9. Montalvo J, Velazquez D, Pantoja JP, Sierra M, Lopez-Karpovitch X, Herrera MF. Laparoscopic splenectomy for primary immune thrombocytopenia: clinical outcome and prognostic factors. J Laparoendosc Adv Surg Tech. 2014;24:466–470. 10. Rijcken E, Mees ST, Bisping G, Krueger K, Bruewer M, Senninger N, et al. Laparoscopic splenectomy for medically refractory immune thrombocytopenia (ITP): a retrospective cohort study on longtime response predicting factors based on consensus criteria. Int J Surg. 2014;12:1428–1433. 11. Pace DE, Chiasson PM, Schlachta CM, Mamazza J, Poulin EC. Laparoscopic splenectomy for idiopathic thrombocytopenic purpura (ITP). Surg Endosc. 2003;7:95–98. 12. Kwon HC, Moon CH, Cho YR, Kim MC, Kim KH, Han JY, et al. Prognostic factors of response to laparoscopic splenectomy in patients with idiopathic thrombocytopenic purpura. J Korean Med Sci. 2005;20:417–420.
13. Gonzalez-Porras JR, Escalante F, Pardal E, Sierra M, Garcia-Frade LJ, Redondo S, et al. Safety and efficacy of splenectomy in over 65-yrs-old patients with immune thrombocytopenia. Eur J Haematol. 2013;91:236–241. 14. Duperier T, Brody F, Felsher J, Walsh M, Rosen M, Ponsky J. Predictive factors for successful laparoscopic splenectomy in patients with immune thrombocytopenic purpura. Arch Surg. 2004;139:61–66. 15. Balague C, Vela S, Targarona EM, Gich J, Muniz E, D’Ambra A, et al. Predictive factors for successful laparoscopic splenectomy in immune thrombocytopenic purpura; study of clinical and laboratory data. Surg Endosc. 2006;20:1208–1213. 16. Ruggeri M, Fortuna S, Rodeghiero F. Heterogeneity of terminology and clinical definitions in adult idiopathic thrombocytopenic purpura: a critical appraisal from a systemic review of the literature. Haematologica. 2008;93:98–103. 17. Arnold DM, Heddle NM, Carruther J, Cook DJ, Crowther MA, Meyer RM, et al. A pilot randomized trial of adjuvant rituximab or placebo for nonsplenectomized patients with immune thrombocytopenia. Blood. 2012;119:1356–1362. 18. Lozano ML. Real-life management of primary immune thrombocytopenia (ITP) in adult patients and adherence to practice guidelines. Ann Hematol. 2016;95:1089–1098. 19. Di Sabatino A, Carsetti R, Corazza GR. Post-splenectomy and hyposplenic states. Lancet. 2011;378:86–97. 20. Rubin LG, Schaffner W. Care of the asplenic patient. N Engl J Med. 2014;371:349–356. 21. Theilacker C, Ludewig K, Serr A, Schimpf J, Held J, Bogelein M, et al. Overwhelming postsplenectomy infection: a prospective multicenter cohort study. Clin Infect Dis. 2016;62:871–878. 22. Cai Y, Liu X, Peng B. Should we routinely transfuse platelet for immune thrombocytopenia patients with platelet count less than 10 × 109 /L who underwent laparoscopic splenectomy? World J Surg. 2014;38:2267–2272.
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Corticosteroid response predicts success of laparoscopic splenectomy in treating immune thrombocytopenia✩ Alexandra C. Istl a,∗, Greig McCreery a, Laura J. Allen a, Kelly Vogt a, Luc Dubois b, Daryl K. Gray a a b
Division of General Surgery, London Health Sciences Centre, London, ON, Canada Division of Vascular Surgery, London Health Sciences Centre, London, ON, Canada
a r t i c l e
i n f o
Article history: Accepted 14 February 2018 Available online xxx
a b s t r a c t Background: Laparoscopic splenectomy is a second-line therapy for immune thrombocytopenia with a sustained success rate of 66%. In a climate of new available medical therapies for immune thrombocytopenia, the comparative safety and efficacy of laparoscopic splenectomy are worthy of attention. The purpose of this study is to identify factors predictive of laparoscopic splenectomy success that will enable preoperative prognostication. Methods: A retrospective cohort study was conducted of patients undergoing laparoscopic splenectomy for immune thrombocytopenia. The data collected evaluated response to medical and surgical therapy, which was defined on a platelet level of 50 × 109 /L with no bleeding events. Univariate and multivariate analyses were conducted to evaluate factors predictive of laparoscopic splenectomy success, with an additional subanalysis planned to assess for laparoscopic splenectomy safety in individuals ≥65 years. Results: One hundred forty-one patients were reviewed. Operative outcomes showed a 3.6% conversion rate and 8.5% complication rate. Disease remission was achieved in 78.7% of patients. Response to initial corticosteroid therapy was associated with a laparoscopic splenectomy success rate of 90% and increased odds of surgical success by 5.58 over individuals with no response to corticosteroids. Age did not confer an increased risk of failure or complications. Conclusion: Laparoscopic splenectomy is a safe and effective intervention for immune thrombocytopenia regardless of age. Initial response to corticosteroids is associated with laparoscopic splenectomy success rate of 90% and improved odds of surgical success. Laparoscopic splenectomy should be the standard second-line therapy for immune thrombocytopenia, especially in patients responding to corticosteroids. © 2018 Elsevier Inc. All rights reserved.
The optimal therapeutic sequence in the management of immune thrombocytopenia (ITP) is controversial. Based on the American Society of Hematology 2011 guidelines, splenectomy is the recommended second-line therapy in patients who do not respond to or relapse after corticosteroid therapy (Grade 1B).1 Some practitioners defer surgical referral to avoid perioperative morbidity and mortality despite a lack of evidence directly comparing nonoperative interventions to splenectomy.2 Modern laparoscopic techniques have made splenectomy a safe operation, demonstrating equal efficacy and a lower complication rate compared to open surgery,3 as well as a lower adverse event rate than reported for common medical therapies.4–6 To identify ✩
Presented at the Canadian Surgical Forum as a poster presentation in Victoria, BC, Canada in September 2017. ∗ Corresponding author: Department of Surgery, Western University and London Health Sciences Centre, 800 Commissioners Rd. E, London, ON N6A 5W9 Canada. E-mail address: [email protected] (A.C. Istl).
the patients that would benefit most from surgical intervention, observational studies have attempted to elucidate factors predictive of splenectomy success in the treatment of ITP.7–15 The majority of these studies were small, assessed only open splenectomy (74%), and demonstrated heterogeneous results.7 The goals of this study were first, to assess the success and complication rate of laparoscopic splenectomy (LS) at our center given a large sample size compared to the existing literature, and second, to determine factors predictive of LS success that can guide therapeutic decision-making and prognostication. Identifying factors that enable prediction of surgical success preoperatively may change the second-line interventions patients are offered. Methods All patients who underwent LS for ITP at London Health Science Centre (LHSC) from 20 0 0 to 2015 were identified. LHSC is a quaternary care referral center with a catchment area of approximately
https://doi.org/10.1016/j.surg.2018.02.005 0039-6060/© 2018 Elsevier Inc. All rights reserved.
Please cite this article as: A.C. Istl et al., Corticosteroid response predicts success of laparoscopic splenectomy in treating immune thrombocytopenia, Surgery (2018), https://doi.org/10.1016/j.surg.2018.02.005
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1.6 million people. All diagnoses of ITP were made following consultation with hematologists at LHSC. Patients with a diagnosis of primary ITP (platelets <100 × 109 /L with no other causative process) were included in the analysis. Patients found postoperatively to have thrombocytopenia secondary to a separate disease process, such as lymphoma or a myeloproliferative disorder, were excluded. The morcellated spleen was sent to pathology following every operative case. An electronic chart review was undertaken to extract information pertaining to patient demographics, operative details, and preand postoperative medical management. Paper charts were evaluated for data points prior to 2006. Preoperative platelet response to primary corticosteroid treatment was recorded. Platelet response to second-, third-, and fourth-line treatment regimens could not be established given the potential confounding effects of multiple medical therapies, and was therefore not reported. Platelet counts were recorded preoperatively and immediately postoperatively. Peak and trough platelet levels for the initial 72 hours postoperatively were documented, as were platelet levels at the time of each patient’s most recent follow-up visit where available. Intraoperative and postoperative complications were identified. Medical therapies implemented postoperatively for refractory ITP were recorded. The electronic medical record allows capture of followup visits at LHSC and referring hospitals within the catchment area, as well as all laboratory results. Therefore, LS success or failure was determined at the time of data collection using the most recent patient information available.
Definitions Platelet response to therapy was determined on a threshold of 50 × 109 /L. This was the generally acceptable threshold for proceeding with surgical intervention at the time of data collection and was the most agreed-upon value for corticosteroid nonresponsiveness used in the literature.16 Success of LS was defined as the achievement of a platelet count of greater than 50 × 109 /L with no need for postoperative medical management during the follow-up period. Failure of LS was defined as a persistent postoperative platelet level of less than 50 × 109 /L or thrombocytopenia with bleeding symptoms requiring medical intervention. Any requirement for postoperative medical intervention was considered a failure. LS success or failure was determined by the authors at the time of data collection given the most recent information available in the patient’s chart rather than at the time of last follow-up. Thus, any LS successes are considered to have sustained remission to date based on the most recent electronic data. Use of medical interventions for ITP at our center has corresponded with the evolution of medical therapies and evidencebased recommendations for their use. At our institution, preoperative corticosteroids are administered as per ASH guidelines for individuals with platelet counts lower than 30 × 109 /L as standard first-line therapy. Prednisone is typically the therapy of choice at our institution with a starting dose of approximately 1mg/kg/day. Primary dexamethasone is used rarely. Rate of taper depends on patient factors including patient response and toxicity. In our study, corticosteroid response was stratified based on response to the first course of corticosteroids received after diagnosis: complete initial responders maintained a platelet count of >50 × 109 /L for any length of time after corticosteroid therapy was stopped. Transient responders achieved a platelet count of >50 × 109 /L but fell below 50 × 109 /L while still on corticosteroid therapy. Nonresponders failed to demonstrate an increase in platelet count above 50 × 109 /L at all. The first course of corticosteroids was assessed because 98% of patients received corticosteroids as first-line
therapy. Later courses of corticosteroid therapy were not assessed given the confounding effects of other interventions. Length of follow-up was defined as the time between surgery and the last recorded clinic visit. Incidence of overwhelming postsplenectomy infection (OPSI) was also determined at this time point. However, success or failure of LS was determined at the time of data collection based on the patient’s most recent laboratory values and electronic clinical data, rather than at the time of last follow-up. Statistical analysis Descriptive statistics were completed using means with standard deviations, medians with interquartile ranges, and frequencies where appropriate. Univariate analyses were conducted to assess differences between LS failure and LS success groups using Student’s t test or Mann-Whitney U tests for continuous data and Pearson χ 2 statistic or Fisher exact test for categorical variables. The number of preoperative medical therapies was analyzed as a discrete nominal variable. The platelet counts included in the analyses were those measured immediately preoperatively and immediately postoperatively. Preoperative data was subjected to multivariate logistic regression analysis to identify factors independently associated with failure of laparoscopic splenectomy for the treatment of ITP. Thirty LS failures were identified and therefore we included 3 variables, each with 10 events and 10 nonevents per covariable. Variables were identified a priori as age, response to initial course of corticosteroid therapy, and number of preoperative medical therapies. Age was analyzed as a continuous variable without cutoff values. Response to corticosteroids was analyzed as a categorical variable with stratifications as described above. Postoperative data were collected and reported; however, these were not subjected to regression analysis as they cannot contribute to preoperative prognostication. An additional subanalysis was completed comparing individuals <65 years to those ≥65 years with respect to complication rate, rate of conversion to open, and success of LS for treatment of ITP using a Pearson χ 2 statistic. Significance was determined using Fisher exact test. A cutoff age of 65 was chosen to ensure comparability with other studies assessing safety and efficacy of LS that used age 65 as a threshold. All statistical analysis was completed using IBM SPSS Statistics version 22 (IBM Corp, Armonk, NY). Results From 20 0 0 to 2015, 141 patients underwent an attempted laparoscopic splenectomy for ITP. Of those, 39.7% were male. Mean age at the time of surgery was 49 years. In 96.4% of cases, splenectomy was completed laparoscopically as planned. There was no significant difference in age, gender, American Society of Anesthesiologists class, or time from diagnosis to surgery between LS success and LS failure groups (Table 1). Those refractory to splenectomy had significantly longer length of stay (P < .05) and follow-up period (P < 0.05) compared to LS success group. It should be noted that the mean length of follow-up in the LS success group was still greater than 1 year. Preoperative platelet measures were significantly higher in the LS success group (P < .01) (Table 1). Overall, successful LS requiring no further medical management was observed in 111 patients (78.7%). Conversion from laparoscopic to open occurred in 5 patients (3.6%). Two cases were converted due to technical difficulties attributed to the patients’ body habitus. One was for control of active hemorrhage. One was for difficulty with a concomitant laparoscopic cholecystectomy. The last was to facilitate a thorough
Please cite this article as: A.C. Istl et al., Corticosteroid response predicts success of laparoscopic splenectomy in treating immune thrombocytopenia, Surgery (2018), https://doi.org/10.1016/j.surg.2018.02.005
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Table 1 Demographic characteristics for ITP patients undergoing LS.
Patients Age (mean ± SD) Male (%) ASA class (mean ± SD) Preoperative platelet count (mean∗ ± SD) Postoperative platelet count (mean∗ ± SD) Time from diagnosis to surgery (months, mean ± SD) Follow-up (months, mean ± SD) Length of stay (days, mean ±SD)
Overall
LS success
LS failure
P value
141 49 ± 19 39.7 3 ± 0.5 97 ± 75 119 ± 79 46 ± 62 16 ± 25 1.9 ± 2.2
111 48 ± 19 39.6 3 ± 0.5 107 ± 77 128 ± 83 45 ± 60 13 ± 23 1.7 ± 1.8
30 53 ± 18 40.0 3 ± 0.5 60 ± 52 81 ± 47 49 ± 70 25 ± 27 2.7 ± 3.4
.272 1.00 .925 .002 .004 .764 .021 .023
ASA, American Society of Anesthesiologists; SD, standard deviation. ∗ × 109 /L Table 2 Operative factors and complication rates for ITP patients undergoing LS.
OR time (minutes, mean ± SD) Intraoperative platelet transfusion, N (%) Conversion to open, N (%) Postoperative complication, N (%)
Overall
LS Success
LS Failure
P value
65 ± 26.6 16 (12.9) 5 (3.6) 12 (8.5)
66 ± 26.9 11 (10.0) 2 (1.8) 7 (6.3)
62 ± 25.8 5 (16.7) 3 (10.0) 5 (16.7)
.552 .335 .066 .131
OR, operating; SD, standard deviation.
intra-abdominal washout after spillage of splenic tissue. Complications were identified in 8.5% of patients (Table 2). Two patients had intraoperative gastric perforations, which were immediately repaired with no sequelae. Three had postoperative hemorrhages requiring return to the operating room, one of whom developed a pleural effusion, and one of whom required transfusion. One developed a fever of undetermined origin 6 weeks postoperatively. One had an intraoperative stapler misfire with no clinical sequelae. Two developed a postoperative ileus, 1 of whom required exploratory surgery. One patient developed a diaphragmatic hernia. Overall, there was no significant difference in complications between LS failure and LS success groups (P = .131). We had 2 deaths, with an overall 30-day mortality rate of 1.4%. One patient developed Staphylococcus bacteremia and an intracranial hemorrhage. This individual singularly accounted for our OPSI rate of 0.7%. The other patient was 84 years of age, had a pulseless electrical activity arrest on postoperative day 1 presumed to be secondary to bleeding, underwent a repeat operation where the bleeding was controlled, had a massive transfusion resulting in abdominal compartment syndrome, and developed multiorgan failure after which her family withdrew care.
Fig. 1. Percentage of patients responding to laparoscopic splenectomy and response to initial corticosteroid course.
tients received was significantly different between LS success and LS failure groups (P < .001) (Fig. 2). Preoperative therapy Logistic regression All subjects received medical therapy prior to being considered for surgery. Of the patients, 97.9% received corticosteroids as firstline treatment, and the median number of preoperative corticosteroid courses in both groups was 2 (interquartile range 1-2). On univariate analysis, initial response to corticosteroid therapy was predictive of response to LS (P < .001). Overall, 50.7% of patients met our definition of complete initial corticosteroid response and 90% of these had a successful LS (P < .001). Of the patients, 20.3% were transient responders (those who relapsed with platelet count <50 × 109 /L while still on corticosteroids), and 85.7% of these had a successful LS (P < .01). Twenty-nine percent demonstrated no response to corticosteroids; only 52.5% of these had a successful LS for ITP (Fig. 1). Significantly more patients failed laparoscopic splenectomy if they were treated preoperatively with any of intravenous immunoglobin, rituximab, azathioprine, cyclophosphamide, or danazol (Table 3). The number of preoperative medical therapies pa-
Multivariate logistic regression assessing age at the time of surgery, response to initial course of corticosteroids, and the number of preoperative medical interventions was performed to assess predictors of LS success (Table 4). There was no effect of age on LS success (P = .957). Response to corticosteroid therapy was associated with significantly improved odds of LS success for both complete responders (OR [odds ratio] = 5.58 [1.870-16.665]) and transient responders (OR = 4.15 [1.131-15.231]). Each additional preoperative medical therapy significantly reduced the odds of LS success (OR = 0.27 [0.136-0.544]) compared to those receiving fewer medical interventions. Postoperative interventions Thirty patients did not demonstrate disease response following splenectomy, and 60% of these received 2 or more
Please cite this article as: A.C. Istl et al., Corticosteroid response predicts success of laparoscopic splenectomy in treating immune thrombocytopenia, Surgery (2018), https://doi.org/10.1016/j.surg.2018.02.005
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A.C. Istl et al. / Surgery 000 (2018) 1–6 Table 3 Preoperative medical therapies administered to all ITP patients undergoing LS. Variable
Overall, N (%)
Patients with preoperative medical therapy, N (%) Corticosteroids, N (%) Number of corticosteroid courses, median (IQR) IVIG, N (%) IVRhIg, N (%) Rituximab, N (%) Romiplostim, N (%) Eltrombopag, N (%) Azathioprine, N (%) Cyclophosphamide, N (%) Danazol, N (%)
141 (100) 138 (97.9) 86 (61.0) 7 (5.0) 4 (2.8) 7 (5.0) 3 (2.1) 13 (9.2) 4 (2.8) 2 (1.4)
LS Success, N (%)
LS Failure, N (%)
P value
108 (97.3) 2 (1-2) 62 (55.9) 5 (4.5) 1 (0.9) 4 (3.6) 2 (1.8) 6 (5.4) 1 (0.9) 0 (0)
30 (100) 2 (1-2) 24 (80.0) 2 (6.7) 3 (10.0) 3 (10.0) 1 (3.3) 7 (23.3) 3 (10.0) 2 (6.7)
1.00 .974 .020 .461 .030 .166 .515 .007 .030 .044
IVIG, intravenous immunoglobulin.
Fig. 2. Success of LS based on number of medical interventions given preoperatively for the treatment of ITP. Table 4 Logistic regression of the effects of age, number of preoperative medical interventions, and corticosteroid response on the success of LS.
Age Number of preoperative medical therapies Response to corticosteroids Transient response Complete response
OR [95% CI]
P value
1.00 [0.975–1.027] 0.27 [0.136–0.544]
.957 <.001
4.15 [1.131–15.231] 5.58 [1.870–16.665]
<.05 <.01
CI, confidence interval.
postoperative medical interventions. The most common postoperative interventions administered were corticosteroids (56.7%), azathioprine (33.3%), and rituximab (23.3%), respectively. Relationship between age and outcomes An additional subanalysis, planned a priori, determined whether age ≥65 in patients undergoing LS was predictive of adverse events. Of 141 patients, 23.4% were age 65 or older. Age ≥65 was not predictive of LS failure. There were no significant differences between groups with respect to procedure-related complications (P = .152) or conversion to open surgery (P = .085). Given the above findings, a proposed algorithm for the management of ITP based on corticosteroid response is depicted in Fig. 3. Projected success rates for LS irrespective of age are included. Discussion In this study, we sought to identify preoperative factors predictive of LS success in the treatment of ITP. We included all factors
that have been evaluated in recent literature including age, preoperative platelet levels,5 , 8–11 corticosteroid response,8,10 , 12 time from diagnosis to surgery,8,10 , 12 and preoperative medications.9,13 As corroborated by other studies, the LS success group had higher preoperative platelet levels.8,10 , 14 Postoperative platelet count was a commonly evaluated measure, but was not included in our analysis because it does not enable preoperative risk stratification. Our study was unique in that it identified factors that can inform therapeutic decision-making early in a patient’s disease course. With respect to the safety of LS, our complication rate (8.5%) and procedure-related mortality rate (1.4%) are consistent with those reported in the literature7 and lower than those reported for common medical therapies. Although the risk of severe complications associated with LS—such as diaphragmatic hernia—demand serious consideration, equally concerning complications of medical interventions cannot be ignored. Thrombopoietin receptor agonist therapy with romiplostim was found to have a serious adverse event rate of 8% and mortality of 5%.5 On systematic review, rituximab therapy was associated a 3.7% life-threatening adverse event rate and an overall mortality rate of 2.9% in the ITP population.4 A pilot randomized control trial assessing rituximab found 66% of patients failed treatment, 61% had infusion reactions, and 25% had significant bleeding.17 Despite these risks, 65% of patients in our study had been prescribed 2 or more medical therapies prior to undergoing splenectomy. In keeping with this observation, Lozano et al published an article in 2016 demonstrating that medical therapies such as thrombopoietin receptor agonists are increasingly used as second-line therapy after steroids, despite guidelines stating that they should be used in cases refractory to splenectomy.18 In addition to these interventions affecting quality of life, we found the odds of successful LS were significantly decreased with each additional preoperative medical intervention. By deferring surgical referral in favor of attempting second-line medical therapies, patients may be suffering unnecessary morbidity. Our study shows that patients receiving splenectomy as the primary second-line therapy have a higher rate of response than those receiving LS as a third- or fourth-line intervention. One of the most significant concerns with LS is the risk of overwhelming post-splenectomy infection (OPSI). A review of studies from 1966 to 1996 showed an OPSI rate of 2.1% in the ITP population.19 However, this review largely assessed open splenectomy and the data predates post-splenectomy vaccination, which has significantly decreased the incidence of OPSI.20 Unfortunately, the benefit of vaccination in splenectomized patients has not been well quantified due to inconsistent prescribing patterns: In their study of critically ill patients, Theilacker et al found that only 47% of septic splenectomized patients had been vaccinated.21 In our study, 100% of LS patients were vaccinated preoperatively for Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis. Our OPSI rate was 0.7%.
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Fig. 3. Flowchart for the management of ITP in surgically fit patients undergoing first-line steroid therapy. Sustained response rates for each respective intervention are denoted in brackets. Sustained response rates for surgical interventions based on our study data are denoted in blue.
Our overall LS success rate of 78.7% is comparable to those reported in other studies assessing laparoscopic splenectomy.8–12 We identified an even higher success rate in patients demonstrating a response to their initial course of corticosteroids: 90% of complete responders and 85.7% of transient responders had a successful LS for ITP. Conversely, only 52.5% of nonresponders had a successful LS. In our logistic regression, response to corticosteroid therapy was an independent predictor for LS success, with transient and complete responders having 4.15 and 5.58 greater odds of successful splenectomy, respectively. Of note, all patients included in the study had failed first-line corticosteroid therapy, as has any patient referred for surgery for ITP. However, the context in which they fail provides valuable information: initial response to corticosteroids followed by relapse after cessation or while still on treatment predicts surgical success compared to individuals who have no response to corticosteroids at all. Corticosteroid response is a potent factor for study. It enables preoperative prognostication and can be evaluated in almost all patients referred for LS. Numerous LS studies report 100% of patients underwent primary corticosteroid therapy,5,8 , 10,22 and we have shown that a good response to corticosteroids is the most robust predictor of successful LS for ITP. Age has also been a factor of interest when assessing both the efficacy and safety of splenectomy. Gonzalez et al suggested that increased age is a predictor of failure and that more complications in elderly patients might exclude splenectomy as a safe option for those over age 65.13 However, they only assessed open splenectomy. Many studies have reported that age is not a discriminating factor in disease response or complication rate.8–10 , 15 In our study, age did not predict LS failure, nor did patients over age 65 have more complications or an increased rate of conversion to open. Advantages of this study included the large sample size from a single center with splenectomy performed by a single surgeon. This is one of the only studies assessing both number of preoperative medical therapies and specific medical agents in association with the success of LS. Limitations of the study included its retrospective design and potential bias due to referral patterns for LS. Given limited precision of retrospective data, we were unable to assess specific medical regimens as factors predictive for LS failure or delineate individual effects of possible concomitant medical interventions. We were also unable to explore differences in corticosteroid administration such as exact duration of therapy or length of taper. Additionally, some patients may have recurred after follow-up was dis-
continued, although the most recent medical records available for each patient were assessed at the time of data collection. We are recommending LS for any patient who is both (1) fit for and agreeable to surgery, and (2) has relapsed while on steroid therapy, but who has also demonstrated an elevation in platelet count over 50 × 109 /L at any point during their corticosteroid therapy, as this denotes some degree of response. Because splenectomy is considered definitive management for ITP, any alternative therapy should be directly compared for equivalence or superiority. There is interest in identifying medical therapies for ITP that will prevent progression to surgery, but new medical therapies are not without risk. The risks associated with medical intervention must be carefully considered in the context of improved minimally invasive surgical techniques that confer decreased morbidity and mortality.
Conclusions LS is a safe and effective procedure for treating ITP, and age should not preclude referral. Successful disease remission was achieved in 78.7% of all patients and 90% of patients that responded to corticosteroids. Response to corticosteroids independently predicts success of LS, and those demonstrating an initial response to corticosteroids should be referred for LS as secondline therapy. The observation that a greater number of preoperative medical therapies was significantly associated with LS failure (OR = 0.27) suggests that initiating multiple medical interventions prior to referral for splenectomy may cause morbidity and delay successful management. This requires further investigation through direct comparative studies. References 1. Neunert C, Lim W, Crowther M, Cohen A, Solberg L, Crowther MA. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;177:4190–4207. 2. Auger S, Duny Y, Francois J, Quittet P. Rituximab before splenectomy in adults with primary idiopathic thrombocytopenic purpura: a meta-analysis. Brit J Haematol. 2012;158:386–398. 3. Mikhael J, Northridge K, Lindquist K, Kessler C, Deuson R, Danese M. Short-term and long-term failure of laparoscopic splenectomy in adult immune thrombocytopenic purpura patients: a systematic review. Am J Hematol. 2009;84:743–748. 4. Arnold DM, Dentali F, Crowther MA, Meyer RM, Cook RJ, Sigouin C, et al. Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura. Ann Int Med. 2007;146:25–33.
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5. Antel KR, Panieri E, Novitzky N. Role of splenectomy for immune thrombocytopenic purpura (ITP) in the era of new second-line therapies and in the setting of a high prevalence of HIV-associated ITP. SAMJ. 2015;105:408–412. 6. Kuter DJ, Bussel JB, Newland A, Baker RI, Lyons RM, Wasser J, et al. Long-term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy. Br J Haematol. 2013;161:411–423. 7. Kojouri K, Vesely SK, Terrell DR, George JN. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood. 2004;104:2623–2634. 8. Kiudelis M, Mickevicius A, Dambrauskiene R, Gerbutavicius R, Griniute R, Adukauskiene D. Prognostic factors for positive immune thrombocytopenic purpura outcome after laparoscopic splenectomy. Cent Eur J Med. 2010;6:123–130. 9. Montalvo J, Velazquez D, Pantoja JP, Sierra M, Lopez-Karpovitch X, Herrera MF. Laparoscopic splenectomy for primary immune thrombocytopenia: clinical outcome and prognostic factors. J Laparoendosc Adv Surg Tech. 2014;24:466–470. 10. Rijcken E, Mees ST, Bisping G, Krueger K, Bruewer M, Senninger N, et al. Laparoscopic splenectomy for medically refractory immune thrombocytopenia (ITP): a retrospective cohort study on longtime response predicting factors based on consensus criteria. Int J Surg. 2014;12:1428–1433. 11. Pace DE, Chiasson PM, Schlachta CM, Mamazza J, Poulin EC. Laparoscopic splenectomy for idiopathic thrombocytopenic purpura (ITP). Surg Endosc. 2003;7:95–98. 12. Kwon HC, Moon CH, Cho YR, Kim MC, Kim KH, Han JY, et al. Prognostic factors of response to laparoscopic splenectomy in patients with idiopathic thrombocytopenic purpura. J Korean Med Sci. 2005;20:417–420.
13. Gonzalez-Porras JR, Escalante F, Pardal E, Sierra M, Garcia-Frade LJ, Redondo S, et al. Safety and efficacy of splenectomy in over 65-yrs-old patients with immune thrombocytopenia. Eur J Haematol. 2013;91:236–241. 14. Duperier T, Brody F, Felsher J, Walsh M, Rosen M, Ponsky J. Predictive factors for successful laparoscopic splenectomy in patients with immune thrombocytopenic purpura. Arch Surg. 2004;139:61–66. 15. Balague C, Vela S, Targarona EM, Gich J, Muniz E, D’Ambra A, et al. Predictive factors for successful laparoscopic splenectomy in immune thrombocytopenic purpura; study of clinical and laboratory data. Surg Endosc. 2006;20:1208–1213. 16. Ruggeri M, Fortuna S, Rodeghiero F. Heterogeneity of terminology and clinical definitions in adult idiopathic thrombocytopenic purpura: a critical appraisal from a systemic review of the literature. Haematologica. 2008;93:98–103. 17. Arnold DM, Heddle NM, Carruther J, Cook DJ, Crowther MA, Meyer RM, et al. A pilot randomized trial of adjuvant rituximab or placebo for nonsplenectomized patients with immune thrombocytopenia. Blood. 2012;119:1356–1362. 18. Lozano ML. Real-life management of primary immune thrombocytopenia (ITP) in adult patients and adherence to practice guidelines. Ann Hematol. 2016;95:1089–1098. 19. Di Sabatino A, Carsetti R, Corazza GR. Post-splenectomy and hyposplenic states. Lancet. 2011;378:86–97. 20. Rubin LG, Schaffner W. Care of the asplenic patient. N Engl J Med. 2014;371:349–356. 21. Theilacker C, Ludewig K, Serr A, Schimpf J, Held J, Bogelein M, et al. Overwhelming postsplenectomy infection: a prospective multicenter cohort study. Clin Infect Dis. 2016;62:871–878. 22. Cai Y, Liu X, Peng B. Should we routinely transfuse platelet for immune thrombocytopenia patients with platelet count less than 10 × 109 /L who underwent laparoscopic splenectomy? World J Surg. 2014;38:2267–2272.
Please cite this article as: A.C. Istl et al., Corticosteroid response predicts success of laparoscopic splenectomy in treating immune thrombocytopenia, Surgery (2018), https://doi.org/10.1016/j.surg.2018.02.005