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Reducing injection-related safety events in retina clinics | OPTH

Angiotensinogen and Risk of Stroke Events in Patients with Type 2 Diab | DMSO


Intravitreal injections are one of the most common medical procedures performed in the United States,1 and are performed in outpatient ophthalmology clinics to treat macular edema and choroidal neovascular membranes from various retinal diseases, including diabetic retinopathy, retinal vascular occlusions, posterior segment inflammation, endophthalmitis, age-related macular degeneration and myopic degeneration.2 Commonly administered medications into the posterior segment include anti-vascular endothelial growth factor agents (bevacizumab, ranibizumab, aflibercept and brolucizumab), corticosteroids (triamcinolone and dexamethasone), and various anti-infective medications (vancomycin, ceftazidime, voriconazole, foscarnet).3 These medications can be administered in one or both eyes, sometimes during the same visit. For many chronic retinal diseases, patients receive a series of intravitreal injections on a recurring schedule which necessitates having a safe injection protocol in place to prevent adverse events.

Despite the large number of intravitreal injections performed (estimated at 5.9 million injections in the United States in 2016),2 ophthalmologists vary widely in terms of preferred safety techniques and protocols.4 Intravitreal injection-related patient safety events can range in severity from causing no significant harm to the patient to having a severe adverse effect.5 Much of the emphasis on safety in intravitreal injections centers around the risk of post-injection endophthalmitis.1 At the Kellogg Eye Center (KEC), University of Michigan, we identified several injection-related safety events that led to a detailed systematic review of our entire injection process. The goal of this project was to reduce injection-related patient safety events to zero following implementation of a revised intravitreal injection protocol.

Materials and Methods

The objective of this Quality Improvement (QI) project was to (a) implement a practice to improve the quality of care, and (b) collect patient or provider data regarding the implementation of the practice for clinical, practical, or administrative purposes. Such activities do not satisfy the definition of “research” under 45 CFR 46.102(d), which is “ … a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge … ” Therefore, the Health and Human Services (HHS) regulations for the protection of human subjects do not apply to such quality improvement activities, and there is no requirement under these regulations for such activities to undergo review by an Institutional Review Board (IRB), or for these activities to be conducted with provider or patient informed consent. Exempt research is now codified at 45 CFR 46.104.

In March 2018, in response to safety events, Michigan Medicine’s KEC organized a multidisciplinary task force consisting of faculty retinal specialists, ophthalmic technicians, medical assistants, photographers, clerical staff, clinic administrators and continuous improvement specialists to analyze the current state of intravitreal injection workflow at our institution. Initial meetings focused on educating the team on the continuous improvement tools that would be used for the analysis, which included Lean strategies and Healthcare Failure Mode and Effect Analysis (HFMEA).6 The team met weekly or biweekly through the end of May 2018. During this time the team conducted observations and drafted process maps for all the key players/steps in the intravitreal injection process; status reports were submitted regularly to the department and hospital patient safety leadership. Injection-related risk reports were not rigorously reported prior to 2017, therefore the task force instituted a proactive risk assessment of the intravitreal injection process from 2017–18 using the HFMEA model developed by the Veterans Affairs National Center for patient safety in 2001 as a guide.6 The aim was to determine the vulnerabilities that contributed to previous safety events and to also identify additional potential points of failure that could be curtailed before they resulted in a near-miss or unintended adverse outcome. The task force identified the following possible injection-related major safety events: wrong patient, wrong site, wrong medication, and expired medication.

The HFMEA necessitates analyzing and diagramming the primary process steps or tasks and the subprocess steps for the intended procedure. Each subprocess step is further dissected to identify what could prevent the step from being completed correctly (failure modes [FMs]) and why these FMs occur (failure mode causes).7 Countermeasures are then proposed and implemented to address those vulnerabilities.


Greater than 15,000 injections are performed annually at the four retina clinics that span the main KEC location. We have 20 faculty physicians and 42 ophthalmic technicians and medical assistants who administer and assist the physician with intravitreal injections, respectively. The total number of injection-related safety events was one in 2017 (wrong eye) and 16 in early 2018 (two wrong medication, 14 expired medication) prior to this project. These injection-related safety events were not isolated to a particular faculty member, staff member or clinical site.

Figure 1 outlines the process map for intravitreal injections performed at KEC retina clinics at baseline. In conducting this review, a total of 12 potential vulnerabilities leading to a safety event were identified for 5 of the 7 steps (the check-out process and the examination by the physician were felt to be low risk for contributing to an error and were excluded as a vulnerable steps). Of the 12 vulnerabilities identified, 5 were prioritized as high-value/high-impact and are included in Figure 1.

Figure 1 Intravitreal injection process map.

The analysis of the process map led to several countermeasures and changes in how retina clinics perform intravitreal injections at KEC. The task force created an intravitreal injection Standard Operating Procedure (SOP) that was then applied to all KEC retina clinics and physicians. Notably, the SOP includes daily safety huddles focusing on team communication and identifying potential issues for the day, as well as mandating a 6-point standardized timeout process for every injection, specifically including laterality, medication name and expiration date (Figure 2).

Figure 2 Kellogg Eye Center pre-procedure time-out.

The task force then introduced the new SOP to all four KEC retina clinics (including faculty, trainees, and staff). This educational effort spanned two months (September-November 2018). Subsequently, periodic audits of adherence to the SOP by a team of independent outside observers were instituted and their aggregate results shared regularly with the retina clinic workforce. In the 18-month follow-up period (December 2018-May 2020) after implementation of the SOP, there were zero patient safety events associated with intravitreal injections at KEC. This ultimately resulted in an institutional safety award being granted to the main KEC retina clinic, marking the first time an ambulatory clinic at the University of Michigan received this recognition.


In 2018, 14 injection-related safety events were due to the use of expired medications. The cluster of expired medications came to one clinic together as one lot, and that lot was administered consecutively to different patients on the same day by the same team who did not realize the medications were expired.

Our task force’s in-depth review of the baseline intravitreal injection process identified many potential vulnerabilities. Using a simple impact/effort analysis, 5 high-priority vulnerabilities which could lead to patient safety events were further examined to assess if barriers to error were already in place or needed modification. The following changes were then implemented:

Clinic Staff Unaware of Patient Volume or Staffing Shortages

Planning for daily retina clinic huddles, which included sharing metrics to monitor patient volume and encouraging open communication between all team members, began in June 2018. The huddles were formally initiated the following month.

Prior Notes are Incomplete or Incorrect

The retina service chief addressed the critical importance of complete and accurate notes at a meeting with retina faculty and staff. In addition, staff were actively encouraged and empowered to speak up if they encountered a note with missing information.

The Wrong Patient Walks from the Waiting Room to Clinic

The use of 2-point patient identifiers (full name and date of birth) at the start of each clinic encounter and at all handoffs between caregivers was reinforced.

Incorrect Orders Entered Into the Electronic Health Record

Identifying countermeasures and streamlining the injection process led to creation and implementation of an intravitreal injection SOP designed to prevent patient harm. The SOP mandates verification of the order placed in the electronic medical record against the written plan. Since poor communication is a root cause of many safety errors,8 educating the retina clinic teams about implementing this SOP was a key step in improving the safety culture in our department as our teams pursue the goal of clear and open dialogue among all members.

The Standard Hospital Time-Out Does Not Include the Medication to Be Injected

A pre-existing standard KEC 6-point clinic procedure time-out used in all KEC clinics was modified to be relevant to clinic-performed intravitreal injections, as part of the SOP. These modifications included the additions of verifying medication name and expiration date aloud during the pre-injection time-out.

After daily huddles were initiated in all four retina clinics as part of this project, similar huddles also spread to other sections in our department; now all KEC clinical areas perform daily huddles. In addition, having independent auditors from outside the department observe the injection process periodically affords us the opportunity to refine and adjust the SOP. Moreover, the auditor team can evaluate SOP adherence and then discretely give feedback regarding an individual’s performance, which is a key factor in maintaining adherence.9

While auditing is helpful, positive feedback as well as the support of departmental and institutional leadership are key factors in the success of having zero harm events in the 18 months after implementation of the SOP. The main KEC retina clinic was awarded an institutional 365 Days of Safety Award in recognition of a full year without injection-related safety errors. Such recognition is a powerful tool to reward and incentivize the clinic team members in pursuit of the goal of patient safety. In addition, promoting an institutional approach of team-based systemic improvement rather than blaming specific individuals involved in safety errors contributes to the culture of safety that should be the goal of every healthcare delivery system.10

This project is potentially limited in that the workflow of KEC retina clinics may not be identical to other retina clinics. Thus, we would encourage tailoring of our intravitreal injection SOP to other sites and institutions as necessary. Also, follow-up longer than 18 months is needed to know if adherence to the SOP can be sustained with the goal of avoiding future adverse safety events.


This study demonstrated that it is possible to redesign and implement an intravitreal injection protocol to reduce the rate of safety events in a large academic eye center. It is important to engage clinical staff at all levels when creating and implementing a quality improvement plan. Promoting a culture of open communication, humility, and lack of individual blame can lead to continuous improvement in the safety of many tasks we perform daily as health care providers. Support and buy-in from leadership as well from every member of the clinical team is imperative towards the goal of achieving zero patient harm.


Current affiliation for Philip Lieu: Retina Specialists, 10740 N. Central Expy, Ste 100, Dallas, Texas, 75231, USA


This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.


The authors report no conflicts of interest in this work.


1. Haddock LJ, Ramsey DJ, Young LH. Complications of subspecialty ophthalmic care: endophthalmitis after intravitreal injections of anti-vascular endothelial growth factor medications. Semin Ophthalmol. 2014;29(5–6):263–275. doi:10.3109/08820538.2014.959616

2. Grzybowski A, Told R, Sacu S, et al. Update on Intravitreal Injections: euretina Expert Consensus Recommendations. Ophthalmologica. 2018;(239):181–193. doi:10.1159/000486145

3. Barash A, Lim JI, Tripathy K, et al. Intravitreal Injections. EyeWiki. 2020;1:34.

4. Uhr JH, Xu D, Rahimy E, et al. Current Practice Preferences and Safety Protocols for Intravitreal Injection of Anti-Vascular Endothelial Growth Factor Agents. Ophthalmol Retina. 2019;3(8):649–655. doi:10.1016/j.oret.2019.03.013

5. Kelly SP, Barua A. A Review of Safety Incidents in England and Wales For Vascular Endothelial Growth Factor Inhibitor Medications. Eye. 2011;25(6):710–716. doi:10.1038/eye.2011.89

6. DeRosier J, Stalhandske E, Bagian JP, et al. Using Health Care Failure Mode and Effect Analysis ™: the VA National Center for Patient Safety’s prospective risk analysis system. Jt. Comm J Qual Improv. 2002;28(248):209.

7. DeRosier JM, Hansemann BK, Smith-Wheelock MW, et al. Using Proactive Risk Assessment (HFMEA) to Improve Patient Safety and Quality Associated with Intraocular Lens Selection and Implantation in Cataract Surgery. Jt Comm J Qual Patient Saf. 2019;45(10):680–685. doi:10.1016/j.jcjq.2019.06.003

8. Burgener AM. Enhancing Communication to Improve Patient Safety and to Increase Patient Satisfaction. Health Care Manag (Frederick). 2017;36(3):238–243. doi:10.1097/HCM.0000000000000165

9. Hanskamp-Sebregts M, Ziegers M, Boeijen W, et al. Process evaluation of the effects of patient safety auditing in hospital care (part 2). Int J Qual Health Care. 2019;31(6):433–441. doi:10.1093/intqhc/mzy173

10. Reis CT, Paiva SG, Sousa P. The patient safety culture: a systematic review by characteristics of Hospital Survey on Patient Safety Culture dimensions. Int J Qual Health Care. 2018;30(9):660–677. doi:10.1093/intqhc/mzy080

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Ropeginterferon, Rusfertide Are Key to Reducing Thromboembolic Events in Polycythemia Vera

Ropeginterferon, Rusfertide Are Key to Reducing Thromboembolic Events in Polycythemia Vera

Thromboembolic events and risk of progression continue to affect patients with polycythemia vera (PV), but 2 recent advances may affect the natural course of the disease. The first, ropeginterferon alpha-2b (Besremi), targets the malignant clone associated with PV, and the second, rusfertide (PTG-300), an investigational hepcidin mimetic agent, demonstrated hematocrit control in patients with PV.

“It is estimated that 40% of patients with PV experience thromboembolic events, which are the primary cause of death among patients with PV,” said Srdan Verstovsek, MD, PhD, the United Energy Resources, Inc., Professor of Medicine, chief of the Section for Myeloproliferative Neoplasms and director of the Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms at The University of Texas MD Anderson Cancer Center in Houston, during the 26th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas, and Myeloma.1

Ropeginterferon alpha-2b

Besremi was approved by the FDA on November 21, 2021, to treat adults with PV. It is the first FDA-approved medication for PV that patients can take regardless of their treatment history, and the first interferon therapy specifically approved for PV.2

Verstovsek presented data from the long-term PROUD-PV/CONTINUATION-PV (EudraCT 2012-005259-18/2014-001357-17) trial, in which ropeginterferon was compared with standard cytoreductive therapy to determine the drug’s effect on thromboembolic and other adverse events.3 A total of 354 patients were randomized 1:1 to receive ropeginterferon (n = 127) or hydroxyurea (n = 127) at individualized doses for 12 months in the initial study (PROUD-PV). In the extension study (CONTINUATION-PV), patients in the cytoreductive arm were permitted to switch to best available treatment.

“Interestingly, about one-third of patients were previously exposed to hydroxyurea, but they were not necessarily resistant or refractory, just exposed to hydroxyurea,” Verstovsek said.

After 12 months of treatment in the PROUD-PV study, 89.6% of patients in the ropeginterferon arm and 68.5% of patients in the hydroxyurea arm continued to the long-term study (CONTINUATION-PV). At the 5-year interim analysis, 26.3% of patients in the ropeginterferon arm (n = 70) had discontinued with therapy and 25.0% of patients (n = 57) in the best available therapy arm had discontinued.

“Complete hematologic response [rates] for both agents are similar in the first year of treatment, but in my experience, interferon takes a little bit of time to work,” Verstovsek said. “So we see, after 12 months, interferon demonstrates superiority,” he continued.

The investigators reported that regarding the JAK2 V617F mutation, the median allele burden had declined from 37.3% at baseline to 7.3% over 5 years of treatment in the ropeginterferon arm, whereas the allele mutation had increased from 38.1% to 42.6% in the same period (P < .0001).3 “We have observed that allele burden goes down over time with ropeginterferon,” Verstovsek said.

Tolerability and safety associated with ropeginterferon are similar regardless of hydroxyurea status. In an analysis of patients who were hydroxyurea-naïve or pretreated with hydroxyurea, 93.8% vs 87.2%, respectively, experienced any adverse event (AE). Similar findings were reported for drug-related AEs (80.0% vs 76.6%, respectively), serious AEs (23.8% vs 23.4%), and drug-related AE leading to discontinuation (10.0% vs 10.6%).

Verstovsek said that non-driver mutations and/or chromosomal aberrations were detected at baseline in 34.8% of patients in the ropeginterferon arm and 38.6% in the control arm. These factors had no apparent influence on molecular response rates to ropeginterferon (64.5% vs 70.7%, respectively) in patients without these genetic abnormalities.

“This is something that is worth following to determine if we can push the limit of efficacy in cytoreductive therapy or does therapy only result in a decrease for thromboembolic risk?” Verstovsek asked. “Or can we aim for a molecular response in the near future?”

Verstovsek touched on the recommended dosage for ropeginterferon, which is dependent on hydroxyurea status. For patients who are hydroxyurea-naïve, the starting dose is 100 mcg every 2 weeks. For patients who are transitioning from hydroxyurea, the recommended starting dose is 50 mcg every 2 weeks in combination with hydroxyurea. For both groups, the maximum dosage is 500 mcg every 2 weeks, and hematologic parameters such as hematocrit level and leukocyte and platelet counts should be monitored.


For patients with PV who are being treated with hydroxyurea, the 5-year probability of thrombosis is 10%; that probability increases to 16% after 10 years, said Verstovsek. Poorly controlled hematocrit levels can contribute to the need for frequent phlebotomies. According to one study, factors that can predict thrombosis include being male, cardiovascular risk factors, the presence of thrombosis at the time of PV diagnosis, and treatment with hydroxyurea that results in more than 3 phlebotomies per year.4

“In my own practice, I would like to optimize the care and eliminate the need for phlebotomies,” Verstovsek said.

At the most recent American Society of Hematology Annual Meeting and Exposition, findings from the PTG-300-04 trial (NCT04057040) were presented evaluating rusfertide and its effect on hematocrit levels.5 The trial consisted of 3 portions: a 28-week dose finding, a 12-week blinded randomized withdrawal of rusfertide vs placebo, and a 52-week open-label extension portion.

When reviewing the effect of rusfertide on phlebotomy frequency, the investigators reported that during the first 28 weeks of treatment, 84% of patients did not require a phlebotomy, 14% required 1 phlebotomy, and 2% required 2 phlebotomies.5

Regarding the effect of rusfertide on platelets or white blood cell counts, Verstovsek said, “We see an immediate control of hematocrit in all the patients whether they’re treated with phlebotomy alone or phlebotomy with cytoreductive therapy; further, the agent does not have any influence on the platelets or the white blood cell count.”

Overall, patients reported improvement for symptoms including fatigue, concentration, and itching/pruritus. Regarding AEs, investigators reported that most drug-related AEs were grade 1 or 2 and no grade 4 or 5 AEs were observed. They noted that injection site reactions were most common and associated with 28.1% of injections; these were transient and no patients discontinued therapy because of it. The most common organ systems affected were the musculoskeletal and connective tissues, skin and subcutaneous tissues, and nervous system disorders.5

Verstovsek noted a 2-part phase 3 trial that compares the efficacy and safety of rusfertide compared with placebo when added on to current therapy for PV. The trial will randomize about 250 patients. Eligibility criteria include PV diagnosis and frequent phlebotomies with or without concurrent cytoreductive therapy to maintain hematocrit levels below 45% in the 6 months prior to enrollment in part 1. Part 2 of the study will evaluate PV therapy plus rusfertide.


1. Verstovsek S. Progress in polycythemia vera: ASH 2021. Presented at: 26th Annual International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas, and Myeloma. February 24-27, 2022; Miami, FL.

2. FDA approves treatment for rare blood disease. News release. FDA. November 12, 2021. Accessed February 27, 2022.

3. Gisslinger H, Klade C, Georgiev P, et al. Long-term use of ropeginterferon alpha-2b in polycythemia vera: 5-year results from a randomized controlled study and its extension. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 481. Accessed February 27, 2022.

4. Alvarez-Larrán A, Pérez-Encinas M, Ferrer-Marín F; Grupo Español de Neoplasias Mieloproliferativas Filadelfia Negativas. Risk of thrombosis according to need of phlebotomies in patients with polycythemia vera treated with hydroxyurea. Haematologica. 2017;102(1):103-109. doi:10.3324/haematol.2016.152769

5. Hoffman, Kemyanskaya M, Ginzburg Y, et al. Rusfertide (PTG-300) Controls Hematocrit Levels and Essentially Eliminates Phlebotomy Requirement in Polycythemia Vera Patients. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 388. Accessed February 27, 2022.