Change in Therapeutic Apheresis Practices: Role of Continuing Medical Education (CME)

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1 Journal of Clinical Apheresis 31:16 21 (2016) Change in Therapeutic Apheresis Practices: Role of Continuing Medical Education (CME) Aseem Kumar Tiwari, 1 * Ravi C. Dara, 1 Prashant Pandey, 2 Dinesh Arora, 1 Ganesh Rawat, 1 and Vimarsh Raina 3 1 Department of Transfusion Medicine, Medanta-the Medicity, Gurgaon, India 2 Department of Transfusion Medicine, Jaypee Hospital, Greater Noida, India 3 Laboratory Services and Transfusion Medicine, Medanta-the Medicity, Gurgaon, India Introduction: American society for apheresis (ASFA) publishes guidelines for therapeutic apheresis (TA) and physicians ordering TA procedures should be aware of the appropriate indications based on scientific evidence. Transfusion Medicine specialists (apheresis physicians) can steer physicians in right direction through CME on right indications, duration of therapy and replacement fluid. Therefore, authors reviewed, collated, and interpreted effect of formal CME interventions. Materials and Methods: Retrospective study was conducted in a large hospital in India. CME interventions to teach clinical and managerial aspects of TA were conducted in the first quarter of Sessions involved ASFA guidelines and recommendations for TA. Data was collected and changes in practice related to TA before (March 2010 to December 2011) and after (April 2012 to December 2013) the intervention was analyzed. Results: Seventy-three subjects participated in the interventions. Five hundred and eighty-nine TA procedures were performed during study period; 214 procedures in 49 patients before intervention and 375 procedures in 84 patients after intervention. After intervention there was significant improvement in indications of category I (38.7% vs. 64.3%; P ), category II (22.5% vs. 16.6%), category III (12.2% vs. 11.9%), and category IV (6.1% vs. 2.4%; P ). Significant reduction was seen in procedures not belonging to any category from 20.5% to 4.8% (P ). Change in practices was also observed in context of duration of therapy and replacement fluid. Conclusion: CME intervention, based on the 2010 edition of ASFA guidelines for therapeutic apheresis appears to have had a positive impact on physicians TA practices. J. Clin. Apheresis 31:16 21, VC 2015 Wiley Periodicals, Inc. Key words: therapeutic plasma exchange; apheresis; American society for apheresis (ASFA) INTRODUCTION Therapeutic apheresis is an effective modality of therapy guided largely by the published guidelines from American Society for Apheresis (ASFA), which is updated every few years [1]. In India, according to the published report [2] most common indications for which therapeutic apheresis has been performed are Acute Inflammatory Demyelinating Polyneuropathy/ Guillain Barre syndrome (AIDP/GBS), Myasthenia gravis (MG), leukocytosis/thrombocytosis and atypical hemolytic uremic syndrome (ahus). In the last couple of decades there has been a remarkable increase in number of centers practicing therapeutic apheresis in India as evidenced by several publications on this subject [3 10]. Physicians ordering therapeutic apheresis procedures on their patients for various indications should be aware of the appropriate indications based on scientific evidence. However, there seems to be a wide gap in knowledge with regards to not just indications but even frequency of procedures and use of replacement fluids VC 2015 Wiley Periodicals, Inc. in this therapeutic intervention. Transfusion Medicine specialists who perform this therapy on patients may steer the treating physicians in right direction through continuing medical education (CME). CMEs have been used often to improve patient care. Many CME intervention review studies show that simple interventions or multiphasic educational interventions remarkably influence the physician behavior, practice and reinforce change [11,12]. The purpose of the present study was to review, collate and interpret the effect of formal CME interventions on practices of physicians in context of therapeutic apheresis procedures. *Correspondence to: Aseem K. Tiwari, MD, Associate Director, Department of Transfusion Medicine, Medanta-The Medicity, Sector-38, Gurgaon aseemtwr@yahoo.co.in Received 9 October 2014; Accepted 12 March 2015 Published online 7 April 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: /jca.21397

2 Therapeutic Apheresis Practices 17 MATERIAL AND METHODS Setting This study was conducted in a large tertiary care hospital in National Capital Region of India. Data of Therapeutic Apheresis between March 2010 and December 2013 was analyzed. Ethics committee approval was not required as it was retrospective observational study. TA was ordered by the treating physician from Neurology, Nephrology, Hemato-oncology, Internal Medicine and Anesthesia from this single center. TA procedure was performed by Transfusion Medicine physicians (Apheresis physicians). Apheresis physicians (consultants and director) who imparted training were MD Transfusion Medicine/Pathology having experience of performing at least 100 TA procedures independently. Subjects Subjects were treating physicians who were ordering this therapeutic intervention. Interventions Different CME interventions that incorporated didactic sessions and practical experiences were conducted in the first quarter of 2012 with the aim to teach the subjects about the indications, clinical and managerial aspects of therapeutic apheresis as per ASFA 2010 guidelines [1]. The intervention program objectives were defined as follows: 1. Principles of TA definition, filtration versus centrifugal technology, intermittent versus continuous flow centrifugal machines, various available apheresis equipment. 2. Types of TA plasmapheresis, cytapheresis (leukocytapheresis, thrombocytapheresis, erythrocytapheresis), RBC exchange, cascade plasmapheresis, doublefiltration plasmapheresis (DFPP) and photopheresis. 3. Indications ASFA 2010 categories and all common disease conditions falling under each category. 4. Adequacy of TA treatment how to assess the response to TA and decide upon discontinuation of therapy and adjunctive therapies. 5. Managerial Aspects of TA patient selection, patient education and consenting, vascular access, anticoagulation, blood flow rate, replacement fluids, calcium supplementation, patient monitoring during the procedure, adverse events and their treatment. The learning objectives of subjects were: 1. Shall be able to differentiate TA modalities that can be performed by different type of apheresis equipment. 2. Shall be referring to ASFA 2010 guidelines to decide upon appropriateness of ordering TA and discontinuation of therapy based on patient s response to treatment. 3. Shall be able to discuss vascular access, replacement fluid, recognition and management of possible adverse reactions. One Day CME in the form power-point presentation sessions was conducted by the authors (apheresis physicians) covering the basics of apheresis comprising basic principles, procedures, prescribing, patient management and care of patients. Updates on disease indications for therapeutic plasmapheresis, photopheresis and other cytapheresis procedures as per ASFA 2010 guidelines [1] were covered supplemented with case studies. CME was accredited by CME credit hours. Physician meet, clinical rounds and one to one interaction with the subjects were performed by apheresis physicians on regular basis. Physician meet (one-to-many): Discipline specific meeting were conducted with physicians to discuss indications, efficacy and adequacy of TA pertaining to that particular discipline, for e.g., TTP-HUS with nephrologists, Myasthenia gravis with neurologists and hyperleukocytosis with hemato-oncologists. Clinical rounds (one-to-many/one-to-one): Apheresis physicians were involved in the clinical rounds to access patient suitability for TA. One-to-one interactions (one-to-one): These interactions were done at the patient bed side giving direct guidance to subjects about the principle of apheresis, options for vascular access, anticoagulation, and rationale for the various apheresis techniques, replacement fluids and the complications associated with TA. Data Collection and Analysis Data was collected and changes in practice related to therapeutic apheresis procedures before (March 2010 to December 2011) and after (April 2012 to December 2013) the intervention was analyzed. TA data during intervention period (January 2012 to March 2012) was not considered in the analysis. Data analysis included indication category, replacement fluid type and usage, adverse events and adequacy of therapy (duration or discontinuation of therapy) as per 2010 ASFA guidelines. For example if the guidelines prescribe 5 6 TPE procedures for AIDP and only three procedures were performed in a patient, it was considered inadequate [1]. Similarly, in atypical Hemolytic Uremic Syndrome (ahus), the number of procedures were considered inadequate if these were fewer than recommended by European Group in 2010 ASFA guidelines.

3 18 Tiwari et al. TABLE I. Clinical Indications of TA Category Indications Pre Post P value (Z test) Post renal transplant rejection (antibody-mediated 9 11 rejection) Anti-glomerular basement membrane disease 2 5 (Goodpasture s syndrome) with diffuse alveolar hemorrhage (DAH/dialysis independent) Acute inflammatory demyelinating polyneuropathy 3 9 (Guillain-Barre Syndrome) Chronic inflammatory demyelinating 0 2 polyradiculoneuropathy I Myasthenia gravis 2 6 Thrombotic thrombocytopenic purpura (TTP) 3 9 Hyperleukocytosis 0 1 Wilson s disease (Fulminant hepatic failure) 0 4 ANCA-associated rapidly progressive 0 5 glomerulonephritis (Wegener s granulomatosis) with diffuse alveolar hemorrhage (DAH/dialysis dependent) Familial hypercholesterolemia 0 1 Focal segmental glomerulosclerosis (recurrent) 0 1 Sub total 19 (38.7%) 54 (64.3%) 0.004* Atypical hemolytic uremic syndrome (ahus) 10 5 Multiple Sclerosis (Acute) 1 0 Systemic lupus erythematosus (SLE) 0 2 II Acute disseminated encephalomyelitis 0 1 ABO incompatible solid organ transplantation (renal) 0 5 Malaria (severe) 0 1 Sub total 11 (22.5%) 14 (16.6%) Multiple sclerosis (chronic) 3 2 Warm autoimmune haemolytic anemia (AIHA) 1 0 Immune complex rapidly progressive 1 2 glomerulonephritis III ANCA-associated rapidly progressive 1 1 glomerulonephritis (Wegener s granulomatosis) (dialysis independent) ABO incompatible solid organ transplantation (liver) 0 3 Multiple myeloma 0 2 Sub total 6 (12.2%) 10 (11.9%) Immune thrombocytopenic purpura (ITP) 3 0 IV Polymyositis 0 1 Anti-glomerular basement membrane disease 0 1 (Goodpasture s syndrome; without DAH/dialysis dependent) Sub total 3 (6.1%) 2 (2.4%) * Not defined TPE in graft vs. host disease (GvHD) 2 0 Dengue haemorrhagic fever 3 2 Sepsis (without multi organ failure) 5 1 Alcoholic chronic liver disease 0 1 Sub total 10 (20.5%) 4 (4.8%) 0.002* Total *P values Statistical Analysis Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS), version 20.0 (SPSS, Chicago, IL). Z test was used for data comparison. A P value less than <0.05 was considered statistically significant. RESULTS Seventy-three subjects participated in the study interventions. Of these 76% were males with the mean age of years. Total of 589 different therapeutic apheresis procedures in 133 patients with the mean of 4.4 procedures per patient were performed

4 during the study period. Two hundred and fourteen procedures were pre-intervention while 375 procedures were post-intervention in 49 and 84 patients, respectively. Out of 589 procedures, 95.5% (563) were therapeutic plasma exchange performed for multiple indications, 3.9% (23) were double filtration plasmapheresis performed in ABO incompatible desensitization regime for solid organ transplants, 0.3% (2) and 0.1% (1) were leukacytapheresis and red cell exchange, respectively (Table I). The effect of CME interventions were assessed by measuring the indications, replacement fluid usage, adverse events and duration or discontinuation of therapy. Fig. 1. Therapeutic Apheresis Practices 19 TA indications before and after interventions. Preintervention 213 (99.5%) therapeutic plasma exchanges and 1 (0.5%) therapeutic cytapheresis were performed in 48 and 1 patient, respectively. Nineteen (38.7%) patients belonged to ASFA category I, 11 (22.5%) belongs to category II while 6 (12.2%) cases belongs to category III and 3 (6.1%) cases belongs to category IV. Total of 10 (20.4%) cases did not belong to any category defined by ASFA (Table I; Fig. 1). Out of the 214 TA procedures performed during the pre-intervention period, in 181 (89%) procedures Fresh Frozen Plasma (FFP) was used as a replacement fluid. Albumin was used in 4 (2%) procedures while combination of plasma and albumin was used in 19 (9%) of procedures. Adverse events were reported in 18 (36.7%) of 49 patients. The most common complications in patients were hypotension (44.4%), hypocalcemic symptoms (27.7%) and urticaria (16.6%). More than one complication was observed in six patients. All the 18 patients with adverse reactions were received FFP as a replacement fluid. Prophylactic calcium supplementation was not given to any patients during the pre-intervention period. Adequacy of therapeutic apheresis in terms of duration of TA procedures or discontinuation of procedures was observed in 44.8% of patients while in 55.1% of patient s adequacy was not there. In the pre-intervention period, the subjects decided upon indications, replacement fluid and duration or discontinuation of therapy. Postintervention About 350 (93.3%) TPE, one (0.2%) therapeutic cytapheresis, one (0.2%) red blood cell exchange (RBC exchange) and 23 (6.1%) double filtration plasmapheresis (DFPP) were performed in 77, 1, 1 and 5 patients, respectively. Post-intervention there was increase in number in patients undergoing TA with 54 (64.3%) patients belonged to ASFA category I, 14 (16.6%) belongs to category II while 10 (11.9%) cases belongs to category III and 2 (2.4%) cases belongs to category IV. Total of 4 (4.8%) cases did not belong to any category defined by ASFA. There was significant (P < 0.004) increase in patients undergoing TA in category I and in category III there was significant decrease (P < ). Cases which did not belong to any category reduced from 20.5% to 4.8% which was also statistically significant (P < 0.002) (Table I; Fig. 1). In comparison to preintervention period where there was 89% FFP usage there was significant (P < ) decrease in usage of FFP as a replacement fluid to 47% in TA procedures post-intervention. Usage of albumin also increased (2% to 47%) to a great extent (P < ). Similar reduction was also seen in rate of adverse events in the patients undergoing TA procedures postintervention; 14 (16.6%) out of 84 patients reported adverse events post-intervention compared to 18 (36.7%) out of 49 patients in the pre-intervention (P < 0.009) period. More than one complication was observed in two patients, out of these 14 patients who had adverse reactions post-intervention 10 received FFP, three received albumin and one received FFP and albumin in combination. Improvement in adequacy of TA procedures was an increase from 44.8% (preintervention) to 61.9% (postintervention) (P < 0.057) while in 38.1% of patients, adequacy of TA procedures was not seen even in postintervention period. These 38.1% inadequacy in TA patients was seen mostly in AIDP, anti-gbm disease, antibody mediated rejection, and ABO-incompatible renal transplants. These were because of variety of reasons like possibly sub-optimal awareness in few of the subjects, early clinical response, no response, cost or institutional protocol at variance with ASFA 2010 guidelines. The institutional protocol at authors institute undertakes ABO-incompatible renal transplant at a titer of 8 which is different from 4 recommended in guidelines.

5 20 Tiwari et al. In the post-intervention period, the subjects decided upon indications, replacement fluid and duration or discontinuation of therapy in consultation with apheresis physician. DISCUSSION In India apheresis with the help of blood cell separators have been used by and large to collect platelets. Only few tertiary care hospitals in the country perform therapeutic apheresis comprising of mainly plasma exchange and other therapeutic procedures. In the present study, we share our experience of change in practices related to TA after CME interventions. During the study period total of 589 procedures were performed in 133 patients. About 214 procedures were performed preintervention while 375 procedures were performed post-intervention in 49 and 84 patients respectively. This study, possibly for the first time, brings out the change in therapeutic apheresis practices. The study results show significant change in practice for the category I indications as a result of the CME interventions. Change in practices include TA being used not just for appropriate indications based on scientific evidence; it also resulted in better replacement fluid usage, fewer adverse reactions and more appropriate duration of therapy. In the post-intervention period FFP use was largely limited to TTP, ahus, anti-gbm with DAH, RPGN with DAH and in patients with deranged coagulation profile. Post-intervention our patient selection and ASFA categorization was similar to European, Asian, and South American studies [13 16]. Postintervention there was increase in usage of TA mainly for neurological disorders and use of DFPP for ABOincompatible solid organ transplant cases as preconditioning regime. Fewer adverse reactions were in concert with change in the replacement fluid which was very similar to the findings of Basic-Jukic et al. [17] and Shemin et al. [18]. This study is important because there is limited data about apheresis education in the Indian literature [3 10]. Several studies using formal CME activities, academic detailing, and even continuous performance improvement in management of diabetes [19], pain management [20], osteoporosis screening [21], and many others have been shown to be effective in changing physician practices. To the best of our knowledge, no systematic study has been conducted to assess the effectiveness of CME on TA practices. Few factors also limit this study. All the participants were from single hospital willing to engage in practice improvement. The study sample size is comparatively small which may not represent overall population of primary care providers or practices. There was no control group in the study. We have no way to conclude whether the change in practices seen in the study is actually related to CME interventions alone or to what extent these changes were directly attributable to the intervention. The changes could also be attributed to the trend in the post-intervention period, where the treating physicians began deciding upon indications, replacement fluid and duration or discontinuation of therapy in consultation with apheresis physician. In conclusion, the CME intervention, based on the 2010 edition of ASFA guidelines for therapeutic apheresis appears to have had a positive impact on physicians TA practices. We also acknowledge the limitations, but our results do suggest improvement in both pattern and usage of this therapeutic intervention. Finally, we suggest that CME interventions do have a role in changing treatment practices. ACKNOWLEDGMENTS The authors thank Mr. Manish Kumar Singh and Dr. Padam Singh for statistical assistance. 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