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Integrated Fragility Hip Fracture Program: A Model for High Quality Care
Hip fractures are a significant cause of morbidity and mortality among elderly patients. Patients with fragility hip fractures often carry multiple comorbid diagnoses with a significant risk of perioperative complications. After hip fracture, 30-day mortality has been reported as 3.3% to 17.2% with one-year mortality as high as 50%.1
Multidisciplinary care,2-5 surgery within 24 hours (h),6-12 use of regional peripheral nerve blocks,13-16 restrictive blood transfusion strategies,17,18 tranexamic acid (TXA) use,19 pharmacologic deep venous thrombosis (DVT) prophylaxis,20 surgical site infection prevention protocols,21 early mobilization,22 and nutritional optimization23-25 have been individually shown to improve outcomes in hip fracture patients.
Our program sought to define, standardize, and implement evidence-based best practices to improve clinical care and outcomes of patients with hip fractures. We convened a Center for Musculoskeletal Care (CMC) Hip Fracture Oversight Group that included surgeons and advanced practice providers from Orthopedics; physicians from Internal Medicine Hospitalist, Geriatrics, Emergency Medicine, and Anesthesia; and representatives from rehabilitation services, nursing, care management, pharmacy, and performance improvement. With clinical input from all involved services, we developed evidence-based protocols to standardize the care of patients with fragility hip fractures from the time of the patient’s evaluation in the emergency room to discharge and outpatient rehabilitation. The program was operationalized in February 2016.
This project was considered by the Yale University institutional review board (IRB) to be a quality improvement and, therefore, exempted from IRB approval.
MATERIALS AND METHODS
Yale-New Haven Hospital is composed of two main campuses. The York Street Campus (YSC) is the Level 1 Trauma Center. The St. Raphael’s Campus (SRC) houses the CMC nursing units for elective lower extremity arthroplasty and spine procedures. Prior to 2016, patients with hip fractures were cared for equally at both Yale-New Haven Hospital campuses. Patients were admitted to both medical and surgical services with no standardization of hip fracture care processes. Surgeons were assigned based on availability. Frequently, patients were added on to the operating room (OR) schedule and did not undergo surgery until off-hours and after a prolonged waiting period.
Medical comanagement of patients with fragility hip fractures at our institution predated the start of our CMC Integrated Fragility Hip Fracture Program (IFHFP). Comanagement was instituted in 2012 at YSC and in 2014 at SRC but without standardized protocols. The IFHFP began in February 2016 with the centralization of all patients with fragility hip fractures to the SRC at Yale-New Haven Hospital. Emergency medical services directed patients with suspected hip fractures to the designated campus. A dedicated hip fracture OR was allocated daily with a hip fracture surgeon assigned by a shared community and faculty surgeon call schedule. Patients were encouraged but not required to accept care from the on-call hip fracture surgical attending. Anesthesia was notified of the arrival of a patient with a hip fracture in the emergency department, and if the patient consented and qualified, a single-shot femoral nerve block was performed. Patients were screened for nasal staphylococcal colonization and treated with povidone-iodine nasal decolonization, chlorhexidine wash, and antibiotics determined by staphylococcal status and type of surgical procedure planned. Preoperative and postoperative order sets were implemented that dictated the care processes as outlined in Table 1. Surgeons determined the choice of operative intervention as per usual; this included internal fixation and partial or total hip replacement. Detailed medical and surgical protocols are included in Appendix A.
Since the initiation of the IFHFP on February 1, 2016, the program has continued to advance with our experience. We used the year preceding the start of the program as our baseline year (January 1, 2015, through December 31, 2015). The following years, 2016 and 2017, were a transition time during which our protocols were implemented. The intervention year was defined as January 1, 2018, through December 31, 2018. The outcomes during the intervention year were compared with the baseline year. It is important to note that our program has been in continuous evolution, including during the intervention year, with protocols created and refined as we gain experience.
Outcomes include 30-day mortality, transfusions, adverse effects of drugs, venous thromboembolic complications, sepsis, myocardial infarction, mechanical surgical fixation complications, length of stay, 30-day readmission rate, unexpected return to the OR, and time to operative intervention. Definitions of the outcome variables are reviewed in Appendix B.
RESULTS
There were 275 consecutive patients with hip fractures admitted to SRC in the baseline year (January 1, 2015 to December 31, 2015) and 434 patients with hip fractures admitted in the intervention year (January 1, 2018, to December 31, 2018) after consolidation of the program to the single Yale-New Haven Campus and implementation of standardized care processes. Patient demographic data including age, sex, ethnicity, body mass index, and American Society of Anesthesiologists physical status classification were evaluated for the baseline year and intervention year and reported in Table 2. There were no differences in the demographics of patients between baseline and intervention years.
From baseline year to intervention year, 30-day mortality, transfusion, adverse effects of drugs, length of stay, unexpected return to OR, and time to OR were all significantly reduced. Mortality within 30 days decreased from 8.0% to 2.8%. The results are displayed in Table 3. No significant difference was seen in the incidence of venous thromboembolism, sepsis, myocardial infarctions, readmission at 30 days, or mechanical surgical fixation complications.
The Figure shows the 30-day IFHFP mortality rate as reported on a monthly basis starting on January 1 of the baseline year, 2015, and continuing through December 31 of the intervention year, 2018. The process interventions are mapped according to the date of initiation. The median mortality rate (including all data from January 1, 2015, to December 31, 2018) is demonstrated as the dotted line. From May 2018 to December 2018, each monthly mortality rate was recorded below the four-year median, a visual demonstration of the statistical significance seen in our mortality reduction from 8.0% in the baseline year to 2.8% in the intervention year.
DISCUSSION
Patients with fragility hip fractures are a medically complex and vulnerable population. The goal of the CMC IFHFP was to standardize the care of these high-risk patients in an effort to reduce time to the OR, perioperative medical complications, time spent in the hospital, and ultimately mortality.
The barriers to implementing coordinated, multidisciplinary care are significant. In our case, we had a fragmented care model with fragility hip fracture patients cared for at two campuses, on different nursing units, with both community and faculty surgeons providing operative care, and with no predesignated primary team. We structured our program for equal sharing of call between community and faculty surgeons. However, there was distrust among the physician groups: Primary care physicians were concerned that their referral lines with orthopedic surgical colleagues would be fractured by the new shared call. Surgeons doubted that patients would be distributed equally among community and faculty practices. Hospitalists feared that comanagement would mean surgeons abdicating responsibility for care. Surgeons worried that routine medical involvement would delay surgery and prolong the length of stay with excessive testing. In order to achieve consensus, address concerns, and allay fears, we engaged the primary care and surgeon leadership for their support at the onset of the program and held monthly large group meetings and many smaller sessions to advance objectives. We meticulously tracked data and frequently reported out to the involved groups.
As it is well established that operative intervention on a hip fracture is best completed within 24 h to optimize a patient’s clinical outcomes, critical interventions were the designation of a hip fracture OR starting midday and expectation that surgery be performed the day after admission for medically cleared patients. Surgeons were able to book elective cases or outpatient clinic time in the morning. The morning hours prior to surgery allowed time for any final medical optimization, preoperative nursing care, and family discussions. Most surgeries were then completed by the primary OR staff during standard operating hours. Patients were out of the postanesthesia care unit and settled back on the orthopedic nursing unit in the early evening without a prolonged period of nil per os, bed rest, or sleep interruption.
While our protocol expected surgery the day after admission for medically cleared patients, we used surgery within 24 h as a simple metric to compare baseline with intervention outcomes. With our hip fracture OR block time beginning midday, the majority of our medically cleared hip fracture patients would receive surgical treatment within 24 h of admission. Our data show a significant improvement in timeliness of surgical intervention from 41.8% of patients to the OR within 24 h in 2015 to 55% in 2018. In 2017, we conducted an interval four-month audit involving a detailed chart review of all patients for whom surgery was delayed beyond 24 h from hospital admission. Chart review identified anticoagulation as the primary reason for surgical delay. Of patients who were eligible for surgery (medically stabilized and not therapeutically anticoagulated), 90% underwent surgery within 24 h during this four-month period in 2017. This compares to an overall rate of surgery within 24 h of 57% during the calendar year 2017. We did not perform a subgroup analysis of outcomes in patients with time to OR of 24-36 h. From this study, we are therefore unable to draw any conclusion regarding time to surgery and mortality.
Our dedicated OR hip fracture block time was changed from 7:30
Transfusion rate reduction from 46.6% to 28.1% was achieved primarily by the implementation and strict enforcement of a policy to avoid transfusing asymptomatic patients with hemoglobin >7.0 g/dL. In addition, we recommended TXA using standard perioperative arthroplasty dosing of 1 g intravenously (IV) at the time of incision followed by 1 g IV 3 h later in the postanaesthesia care unit. However, adherence to TXA recommendations was poor. A year-long audit (February 2017 to February 2018) demonstrated that only 29% of patients undergoing hip fracture surgery received the recommended TXA. After the conclusion of the study period of this review, we revised our TXA protocol to include an infusion at the time of admission and subsequent perioperative doses. The expanded TXA protocol (with clear exclusion criteria) has been “hard-wired” into our electronic perioperative order sets. We are tracking TXA compliance on a weekly basis. We anticipate that earlier TXA administration and improved compliance will further reduce transfusion rates.
We reduced the adverse effects of medications with two initiatives: First, dedicated hip fracture order sets with medications selected and dosed specifically for the geriatric population were launched at the onset of the IFHFP in 2016. Second, in coordination with our regional anesthesia team, patients who met criteria underwent a single-shot femoral nerve block upon diagnosis of the hip fracture. Patients reported up to 24 h of nonnarcotic pain relief with the femoral nerve block.
Prior to the introduction of the IFHFP, surgeons determined DVT prophylaxis based on their personal preference. Many of our surgeons were concerned that standardizing DVT prophylaxis to enoxaparin would increase the risk of surgical site bleeding, hematoma, infection, and reoperation. With data tracking and periodic reporting, we were able to reassure our surgeons: We demonstrated a reduction in the rate of patients unexpectedly requiring a return to the OR from 5.1% in 2015 to 0% in 2018.
We did not find a significant difference in mechanical complications due to surgical fixation during the index admission. Most mechanical complications do not present within the index admission and, therefore, would not be identified by this metric. Furthermore, in this phase of the program, we did not seek to change or standardize intraoperative surgical processes outside of surgical site infection prevention measures. Surgical technical quality and variation among surgeons is an area of ongoing evaluation within our program. We have begun a surgical quality review process with an expert review of postoperative radiography, beginning with fixation of nondisplaced femoral neck fractures, feedback to surgeons, and tracking of mechanical complications beyond the index admission. The surgical quality outcomes will be presented in a future manuscript.
Anticoagulation use is common in patients with hip fractures because of the high prevalence of comorbid conditions such as atrial fibrillation and venous thromboembolic disease. Direct oral anticoagulants (DOACs) are now commonly used in place of the vitamin K antagonist, warfarin. Our inability to efficiently reverse the DOACs compounded by surgeon unfamiliarity with these agents led to extreme caution in the timing of OR, with most patients delayed a full 48 h from the last dose of their prescribed DOAC. After recognizing the impact of anticoagulation on the timing of surgery, we convened a multidisciplinary group to determine rational guidelines for the timing of surgery in patients on chronic anticoagulation based on the bleeding risk of the planned operative procedure. These guidelines were instituted in December 2018, so their impact is not reflected in this review.
Our results showing a reduction in length of stay and mortality cannot be explained by any one intervention. We propose that the standardization of all processes and protocols, the establishment of clear expectations among all the medical and nursing personnel, and the shorter time spent waiting for surgery all contributed to the length of stay reduction. Likewise, the decrease in time to OR, reduction in time spent in the hospital, fewer transfusions, adverse effects of medication, and surgical complications requiring a return to the OR have all likely contributed to the significant reduction in mortality. The efforts of the orthopedic nursing team certainly contributed: The CMC nurses led the efforts to standardize surgical site infection bundle care, reduce indwelling bladder catheter use, and together with physical therapy, mobilize patients out of bed for meals postoperatively. The strong focus on teamwork, data tracking, feedback and accountability, and the desire for continued improvement may have been the strongest drivers in this program’s success.
Our results showed a nonsignificant increase in 30-day readmission from 9.1% to 12.5%. One limitation of this study is that we did not track specific readmission diagnoses to better understand trends in diagnoses or indications for hospital readmission. Going forward, we are reviewing readmissions to better understand opportunities to improve our inpatient processes and transitions of care.
This an evolving project. We have expanded our use of TXA in an effort to further reduce transfusion rates. We have adjusted our protocols for patients admitted on DOACs and warfarin to allow more rapid surgical intervention. We have initiated a surgical quality review process in which surgical fixation is reviewed with timely feedback to the operating surgeon. We are working closely with the skilled nursing facilities to extend our rehabilitation and nursing care protocols beyond the acute care setting. We are measuring patient engagement with a brief discharge survey specific to the CMC IFHFP. We continue to seek feedback from our referring primary care physicians to improve communication at times of care transition.
One of the limitations of a quality improvement project such as this one is the inability to identify the effect of each individual intervention. We can conclude that the totality of the multidisciplinary project reduced mortality in our hip fracture population, but we cannot report the relative effect of each process change. Another center seeking to replicate this success cannot determine from this research how to prioritize their resources to achieve a similar outcome.
How we care for the fragility hip fracture patient after hospital discharge is critical and unaddressed in this current study. A limitation of our current program is the lack of consistent postdischarge bone health management—which we are working to address. Also related to postdischarge management, we have partnered with a network of preferred skilled nursing facilities to standardize the care and decrease the length of stay. These data will be published separately.
We understand that our experience at the CMC is unique and specific to our care environment. This is a single site study and may not be generalizable to other centers. Nonetheless, the principles of multidisciplinary care, evidence-based protocol development, technological integration of protocols through order sets, and data tracking with feedback and accountability are the essential elements of our success that can be generalized to other institutions.
CONCLUSIONS
The CMC at Yale School of Medicine and Yale-New Haven Hospital IFHFP provides a model for implementing well-documented evidence-based interventions to standardize the care of patients with fragility hip fractures. The IFHFP yielded reduced mortality, length of stay, blood transfusion utilization, adverse effects of medications, unexpected return to the OR, and time to the OR.
Acknowledgments
The authors thank the work of the Center for Musculoskeletal Care Hip Fracture Oversight Group, program surgeons, and community primary care leaders: Olukemi Akande, MD, Mark Altman, MD, Diren Arsoy, MD, John Aversa, MD, Michael Connair, MD, Leo Cooney, MD, Kenneth Donohue, MD, David Gibson, MD, Gail Haesche, RN, MS, ACM-RN, Carol Just, MSN, NEA-BC, RN, Patricia Kenyon, RN, ACM, Francis Lee MD, Michael Leslie, MD, Michael Lucchini, MD, Christopher Lynch, MD, Rowland Mayor, MD, Tara Messina, PT, Lorraine Novella, RN, Paul Oliver, PA-C, Vivek Parwani, MD, Joseph Quaranta, MD, Lee Rubin, MD, Derek Shia, MD, Jeff Sumner, MD, John Tarutis, Arya Varthi, MD, Anuruddha Walaliyadda, MD, Daniel Wiznia, MD, Shirvinda Wijesekera, MD, Joseph Wu, MD, Brad Yoo, MD, and James Yue, MD.
1. Abrahamsen B, van Staa T, Ariely M, Olson M, Cooper C. Excess mortality following hip fracture: a systematic epidemiologic review. Osteoporos Int. 2009;20(10):1633-1650. https://doi.org/10.1007/s00198-009-0920-3.
2. DellaRocca GJ, Moylan KC, Crist BD, Volgas DA, Stannard JP, Mehr DR. Comanagement of geriatric patients with hip fractures: a retrospective, controlled cohort study. Geriatr Orthop Surg Rehabil. 2013;4(1):10-15. https://doi.org/10.1177/2151458513495238.
3. Wang Y, Tang J, Zhou F, Yang L, Wu J. Comprehensive geriatric care reduces acute perioperative delirium in elderly patients with hip fractures: a meta-analysis. Medicine. 2017; 96(26): e7361. https://doi.org/10.1097/MD.0000000000007361.
4. Liu VX, Rosas E, Hwang J, et al. Enhanced recovery after surgery program implementation in 2 surgical populations in an integrated health care delivery system. JAMA Surg. 2017;152(7):e171032. https://doi.org/10.1001/jamasurg.2017.1032.
5. Taraldsen K, Sletvold O, Thingstad P, et al. Physical behavior and function early after hip fracture surgery in patients receiving geriatric care or orthopedic care—a randomized controlled trial. J Gerontol A Biol Sci Med Sci. 2014;69(3):338-345. https://doi.org/10.1093/gerona/glt097.
6. Grimes JP, Gregory PM, Noveck H, Butler MS, Carson Jl. The effects of time-to-surgery on mortality and morbidity in patients following hip fracture. Am J Med. 2002;112(9):702-709. https://doi.org/10.1016/s0002-9343(02)01119-1.
7. Hamlet WP, Lieberman JR, Freedman EL, Dorey FJ, Fletcher A, Johnson EE. Influence of health status and the timing of surgery on mortality in hip fracture patients. Am J Orthop. 1997;26(9):621-627.
8. Hoenig H, Rubenstein LV, Sloane R, Honer R, Kahn K. What is the role of timing in the surgical and rehabilitative care of community-dwelling older persons with acute hip fracture? Arch Intern Med. 1997;157(5):513-520.
9. Orosz GM, Magaziner J, Hannan El, et al. Association of timing of surgery for hip fracture and patient outcomes. JAMA. 2004;291(14):1738-1743. https://doi.org/10.1001/jama.291.14.1738.
10. Gdalevich M, Cohen D, Yosef D, Tauber C. Morbidity and mortality after hip fracture: the impact of operative delay. Arch Orthop Trauma Surg. 2004:124(5):334-340. https://doi.org/10.1007/s00402-004-0662-9.
11. Doruk H, Mas MR, Yidiz C, Sonmez A, Kýrdemir V. The effect of the timing of hip fracture surgery on the activity of daily living and mortality in elderly. Arch Gerontol Geriatr. 2004;39(2):179-185.https://doi.org/10.1016/j.archger.2004.03.004.
12. Uzoigwe CE, Burnand HG, Cheesman CL, Aghedo DO, Faizi M, Middleton RG. Early and ultra-early surgery in hip fracture patients improves survival. Injury. 2013;44(6):726-729. https://doi.org/10.1016/j.injury.2012.08.025.
13. Guay J, Parker MJ, Griffiths R, Kopp SL. Peripheral nerve blocks for hip fractures. Cochrane Database Syst Rev. 2017;5: CD001159. https://doi.org/10.1002/14651858.CD001159.pub2.
14. Morrison RS, Dickman E, Hwang U, et al. Regional nerve blocks improve pain and functional outcomes in hip fracture: a randomized controlled trial. J Am Geriatr Soc. 2016;64(12):2433-2439. https://doi.org/10.1111/jgs.14386.
15. Beaudoin FL, Haran JP, Liebmann O. A comparison of ultrasound-guided three-in-one femoral nerve block versus parenteral opioids alone for analgesia in emergency deparment patients with hip fractures: a randomized controlled trial. Acad Emerg Med. 2013;20(6):584-591. https://doi.org/10.1111/acem.12154.
16. Dickman E, Pushkar I, Likourezos A, et al. Ultrasound-guided nerve blocks for intracapsular and extracapsular hip fractures. Am J Emerg Med. 2016;34(3):586-589. https://doi.org/10.1016/j.ajem.2015.12.016.
17. Carson JL, Terrin MI, Noveck H, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med. 2011;365(26):2453-2462. https://doi.org/10.1056/NEJMoa1012452.
18. Garcia-Alvarez F, Al-Ghanem R, García-Alvarez I, López-Baisson A, Bernal M. Risk factors for postoperative infections in patients with hip fracture treated by means of Thompson arthoplasty. Arch Gerontol Geriatr. 2010; 50(1):51-55. https://doi.org/10.1016/j.archger.2009.01.009.
19. Farrow LS, Smith TO, Ashcroft GP, Myint PK. A systematic review of tranexamic acid in hip fracture surgery. Br J Clin Pharmacol. 2016;82(6):1458-1470. https://doi.org/10.1111/bcp.13079.
20. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e278S-e325S. https://doi.org/10.1378/chest.11-2404.
21. Gillespie WJ, Walenkamp G. Antibiotic prophylaxis for surgery for proximal femoral and other closed long bone fractures. Cochrane Database Syst Rev. 2010;(3):CD000244. https://doi.org/10.1002/14651858.CD000244.pub2.
22. Kamel HK, Iqbal MA, Mogallapu R, Maas D, Hoffmann RG. Time to ambulation after hip fracture surgery: relation to hospitalization outcomes. J Gerontol A Biol Sci Med Sci. 2003;58(11):1042-1045. https://doi.org/10.1093/gerona/58.11.m1042.
23. Foster MR, Heppenstall RB, Friedenberg ZB, Hozack WJ. A prospective assessment of nutritional status and complications in patients with fractures of the hip. J Orthop Trauma. 1990;4(1):49-57. https://doi.org/10.1097/00005131-199003000-00009.
24. Bell JJ, Pulle RC, Crouch AM, Kuys SS, Ferrier RL, Whitehouse SL. Impact of malnutrition on 12-month mortality following acute hip fracture. ANZ J Surg. 2016;86(3):157-161. https://doi.org/10.1111/ans.13429.
25. Avenell A, Handoll HH. Nutritional supplementation for hip fracture aftercare in older people. Cochrane Database Syst Rev. 2010;(1):CD001880. https://doi.org/10.1002/14651858.CD001880.pub5.
Hip fractures are a significant cause of morbidity and mortality among elderly patients. Patients with fragility hip fractures often carry multiple comorbid diagnoses with a significant risk of perioperative complications. After hip fracture, 30-day mortality has been reported as 3.3% to 17.2% with one-year mortality as high as 50%.1
Multidisciplinary care,2-5 surgery within 24 hours (h),6-12 use of regional peripheral nerve blocks,13-16 restrictive blood transfusion strategies,17,18 tranexamic acid (TXA) use,19 pharmacologic deep venous thrombosis (DVT) prophylaxis,20 surgical site infection prevention protocols,21 early mobilization,22 and nutritional optimization23-25 have been individually shown to improve outcomes in hip fracture patients.
Our program sought to define, standardize, and implement evidence-based best practices to improve clinical care and outcomes of patients with hip fractures. We convened a Center for Musculoskeletal Care (CMC) Hip Fracture Oversight Group that included surgeons and advanced practice providers from Orthopedics; physicians from Internal Medicine Hospitalist, Geriatrics, Emergency Medicine, and Anesthesia; and representatives from rehabilitation services, nursing, care management, pharmacy, and performance improvement. With clinical input from all involved services, we developed evidence-based protocols to standardize the care of patients with fragility hip fractures from the time of the patient’s evaluation in the emergency room to discharge and outpatient rehabilitation. The program was operationalized in February 2016.
This project was considered by the Yale University institutional review board (IRB) to be a quality improvement and, therefore, exempted from IRB approval.
MATERIALS AND METHODS
Yale-New Haven Hospital is composed of two main campuses. The York Street Campus (YSC) is the Level 1 Trauma Center. The St. Raphael’s Campus (SRC) houses the CMC nursing units for elective lower extremity arthroplasty and spine procedures. Prior to 2016, patients with hip fractures were cared for equally at both Yale-New Haven Hospital campuses. Patients were admitted to both medical and surgical services with no standardization of hip fracture care processes. Surgeons were assigned based on availability. Frequently, patients were added on to the operating room (OR) schedule and did not undergo surgery until off-hours and after a prolonged waiting period.
Medical comanagement of patients with fragility hip fractures at our institution predated the start of our CMC Integrated Fragility Hip Fracture Program (IFHFP). Comanagement was instituted in 2012 at YSC and in 2014 at SRC but without standardized protocols. The IFHFP began in February 2016 with the centralization of all patients with fragility hip fractures to the SRC at Yale-New Haven Hospital. Emergency medical services directed patients with suspected hip fractures to the designated campus. A dedicated hip fracture OR was allocated daily with a hip fracture surgeon assigned by a shared community and faculty surgeon call schedule. Patients were encouraged but not required to accept care from the on-call hip fracture surgical attending. Anesthesia was notified of the arrival of a patient with a hip fracture in the emergency department, and if the patient consented and qualified, a single-shot femoral nerve block was performed. Patients were screened for nasal staphylococcal colonization and treated with povidone-iodine nasal decolonization, chlorhexidine wash, and antibiotics determined by staphylococcal status and type of surgical procedure planned. Preoperative and postoperative order sets were implemented that dictated the care processes as outlined in Table 1. Surgeons determined the choice of operative intervention as per usual; this included internal fixation and partial or total hip replacement. Detailed medical and surgical protocols are included in Appendix A.
Since the initiation of the IFHFP on February 1, 2016, the program has continued to advance with our experience. We used the year preceding the start of the program as our baseline year (January 1, 2015, through December 31, 2015). The following years, 2016 and 2017, were a transition time during which our protocols were implemented. The intervention year was defined as January 1, 2018, through December 31, 2018. The outcomes during the intervention year were compared with the baseline year. It is important to note that our program has been in continuous evolution, including during the intervention year, with protocols created and refined as we gain experience.
Outcomes include 30-day mortality, transfusions, adverse effects of drugs, venous thromboembolic complications, sepsis, myocardial infarction, mechanical surgical fixation complications, length of stay, 30-day readmission rate, unexpected return to the OR, and time to operative intervention. Definitions of the outcome variables are reviewed in Appendix B.
RESULTS
There were 275 consecutive patients with hip fractures admitted to SRC in the baseline year (January 1, 2015 to December 31, 2015) and 434 patients with hip fractures admitted in the intervention year (January 1, 2018, to December 31, 2018) after consolidation of the program to the single Yale-New Haven Campus and implementation of standardized care processes. Patient demographic data including age, sex, ethnicity, body mass index, and American Society of Anesthesiologists physical status classification were evaluated for the baseline year and intervention year and reported in Table 2. There were no differences in the demographics of patients between baseline and intervention years.
From baseline year to intervention year, 30-day mortality, transfusion, adverse effects of drugs, length of stay, unexpected return to OR, and time to OR were all significantly reduced. Mortality within 30 days decreased from 8.0% to 2.8%. The results are displayed in Table 3. No significant difference was seen in the incidence of venous thromboembolism, sepsis, myocardial infarctions, readmission at 30 days, or mechanical surgical fixation complications.
The Figure shows the 30-day IFHFP mortality rate as reported on a monthly basis starting on January 1 of the baseline year, 2015, and continuing through December 31 of the intervention year, 2018. The process interventions are mapped according to the date of initiation. The median mortality rate (including all data from January 1, 2015, to December 31, 2018) is demonstrated as the dotted line. From May 2018 to December 2018, each monthly mortality rate was recorded below the four-year median, a visual demonstration of the statistical significance seen in our mortality reduction from 8.0% in the baseline year to 2.8% in the intervention year.
DISCUSSION
Patients with fragility hip fractures are a medically complex and vulnerable population. The goal of the CMC IFHFP was to standardize the care of these high-risk patients in an effort to reduce time to the OR, perioperative medical complications, time spent in the hospital, and ultimately mortality.
The barriers to implementing coordinated, multidisciplinary care are significant. In our case, we had a fragmented care model with fragility hip fracture patients cared for at two campuses, on different nursing units, with both community and faculty surgeons providing operative care, and with no predesignated primary team. We structured our program for equal sharing of call between community and faculty surgeons. However, there was distrust among the physician groups: Primary care physicians were concerned that their referral lines with orthopedic surgical colleagues would be fractured by the new shared call. Surgeons doubted that patients would be distributed equally among community and faculty practices. Hospitalists feared that comanagement would mean surgeons abdicating responsibility for care. Surgeons worried that routine medical involvement would delay surgery and prolong the length of stay with excessive testing. In order to achieve consensus, address concerns, and allay fears, we engaged the primary care and surgeon leadership for their support at the onset of the program and held monthly large group meetings and many smaller sessions to advance objectives. We meticulously tracked data and frequently reported out to the involved groups.
As it is well established that operative intervention on a hip fracture is best completed within 24 h to optimize a patient’s clinical outcomes, critical interventions were the designation of a hip fracture OR starting midday and expectation that surgery be performed the day after admission for medically cleared patients. Surgeons were able to book elective cases or outpatient clinic time in the morning. The morning hours prior to surgery allowed time for any final medical optimization, preoperative nursing care, and family discussions. Most surgeries were then completed by the primary OR staff during standard operating hours. Patients were out of the postanesthesia care unit and settled back on the orthopedic nursing unit in the early evening without a prolonged period of nil per os, bed rest, or sleep interruption.
While our protocol expected surgery the day after admission for medically cleared patients, we used surgery within 24 h as a simple metric to compare baseline with intervention outcomes. With our hip fracture OR block time beginning midday, the majority of our medically cleared hip fracture patients would receive surgical treatment within 24 h of admission. Our data show a significant improvement in timeliness of surgical intervention from 41.8% of patients to the OR within 24 h in 2015 to 55% in 2018. In 2017, we conducted an interval four-month audit involving a detailed chart review of all patients for whom surgery was delayed beyond 24 h from hospital admission. Chart review identified anticoagulation as the primary reason for surgical delay. Of patients who were eligible for surgery (medically stabilized and not therapeutically anticoagulated), 90% underwent surgery within 24 h during this four-month period in 2017. This compares to an overall rate of surgery within 24 h of 57% during the calendar year 2017. We did not perform a subgroup analysis of outcomes in patients with time to OR of 24-36 h. From this study, we are therefore unable to draw any conclusion regarding time to surgery and mortality.
Our dedicated OR hip fracture block time was changed from 7:30
Transfusion rate reduction from 46.6% to 28.1% was achieved primarily by the implementation and strict enforcement of a policy to avoid transfusing asymptomatic patients with hemoglobin >7.0 g/dL. In addition, we recommended TXA using standard perioperative arthroplasty dosing of 1 g intravenously (IV) at the time of incision followed by 1 g IV 3 h later in the postanaesthesia care unit. However, adherence to TXA recommendations was poor. A year-long audit (February 2017 to February 2018) demonstrated that only 29% of patients undergoing hip fracture surgery received the recommended TXA. After the conclusion of the study period of this review, we revised our TXA protocol to include an infusion at the time of admission and subsequent perioperative doses. The expanded TXA protocol (with clear exclusion criteria) has been “hard-wired” into our electronic perioperative order sets. We are tracking TXA compliance on a weekly basis. We anticipate that earlier TXA administration and improved compliance will further reduce transfusion rates.
We reduced the adverse effects of medications with two initiatives: First, dedicated hip fracture order sets with medications selected and dosed specifically for the geriatric population were launched at the onset of the IFHFP in 2016. Second, in coordination with our regional anesthesia team, patients who met criteria underwent a single-shot femoral nerve block upon diagnosis of the hip fracture. Patients reported up to 24 h of nonnarcotic pain relief with the femoral nerve block.
Prior to the introduction of the IFHFP, surgeons determined DVT prophylaxis based on their personal preference. Many of our surgeons were concerned that standardizing DVT prophylaxis to enoxaparin would increase the risk of surgical site bleeding, hematoma, infection, and reoperation. With data tracking and periodic reporting, we were able to reassure our surgeons: We demonstrated a reduction in the rate of patients unexpectedly requiring a return to the OR from 5.1% in 2015 to 0% in 2018.
We did not find a significant difference in mechanical complications due to surgical fixation during the index admission. Most mechanical complications do not present within the index admission and, therefore, would not be identified by this metric. Furthermore, in this phase of the program, we did not seek to change or standardize intraoperative surgical processes outside of surgical site infection prevention measures. Surgical technical quality and variation among surgeons is an area of ongoing evaluation within our program. We have begun a surgical quality review process with an expert review of postoperative radiography, beginning with fixation of nondisplaced femoral neck fractures, feedback to surgeons, and tracking of mechanical complications beyond the index admission. The surgical quality outcomes will be presented in a future manuscript.
Anticoagulation use is common in patients with hip fractures because of the high prevalence of comorbid conditions such as atrial fibrillation and venous thromboembolic disease. Direct oral anticoagulants (DOACs) are now commonly used in place of the vitamin K antagonist, warfarin. Our inability to efficiently reverse the DOACs compounded by surgeon unfamiliarity with these agents led to extreme caution in the timing of OR, with most patients delayed a full 48 h from the last dose of their prescribed DOAC. After recognizing the impact of anticoagulation on the timing of surgery, we convened a multidisciplinary group to determine rational guidelines for the timing of surgery in patients on chronic anticoagulation based on the bleeding risk of the planned operative procedure. These guidelines were instituted in December 2018, so their impact is not reflected in this review.
Our results showing a reduction in length of stay and mortality cannot be explained by any one intervention. We propose that the standardization of all processes and protocols, the establishment of clear expectations among all the medical and nursing personnel, and the shorter time spent waiting for surgery all contributed to the length of stay reduction. Likewise, the decrease in time to OR, reduction in time spent in the hospital, fewer transfusions, adverse effects of medication, and surgical complications requiring a return to the OR have all likely contributed to the significant reduction in mortality. The efforts of the orthopedic nursing team certainly contributed: The CMC nurses led the efforts to standardize surgical site infection bundle care, reduce indwelling bladder catheter use, and together with physical therapy, mobilize patients out of bed for meals postoperatively. The strong focus on teamwork, data tracking, feedback and accountability, and the desire for continued improvement may have been the strongest drivers in this program’s success.
Our results showed a nonsignificant increase in 30-day readmission from 9.1% to 12.5%. One limitation of this study is that we did not track specific readmission diagnoses to better understand trends in diagnoses or indications for hospital readmission. Going forward, we are reviewing readmissions to better understand opportunities to improve our inpatient processes and transitions of care.
This an evolving project. We have expanded our use of TXA in an effort to further reduce transfusion rates. We have adjusted our protocols for patients admitted on DOACs and warfarin to allow more rapid surgical intervention. We have initiated a surgical quality review process in which surgical fixation is reviewed with timely feedback to the operating surgeon. We are working closely with the skilled nursing facilities to extend our rehabilitation and nursing care protocols beyond the acute care setting. We are measuring patient engagement with a brief discharge survey specific to the CMC IFHFP. We continue to seek feedback from our referring primary care physicians to improve communication at times of care transition.
One of the limitations of a quality improvement project such as this one is the inability to identify the effect of each individual intervention. We can conclude that the totality of the multidisciplinary project reduced mortality in our hip fracture population, but we cannot report the relative effect of each process change. Another center seeking to replicate this success cannot determine from this research how to prioritize their resources to achieve a similar outcome.
How we care for the fragility hip fracture patient after hospital discharge is critical and unaddressed in this current study. A limitation of our current program is the lack of consistent postdischarge bone health management—which we are working to address. Also related to postdischarge management, we have partnered with a network of preferred skilled nursing facilities to standardize the care and decrease the length of stay. These data will be published separately.
We understand that our experience at the CMC is unique and specific to our care environment. This is a single site study and may not be generalizable to other centers. Nonetheless, the principles of multidisciplinary care, evidence-based protocol development, technological integration of protocols through order sets, and data tracking with feedback and accountability are the essential elements of our success that can be generalized to other institutions.
CONCLUSIONS
The CMC at Yale School of Medicine and Yale-New Haven Hospital IFHFP provides a model for implementing well-documented evidence-based interventions to standardize the care of patients with fragility hip fractures. The IFHFP yielded reduced mortality, length of stay, blood transfusion utilization, adverse effects of medications, unexpected return to the OR, and time to the OR.
Acknowledgments
The authors thank the work of the Center for Musculoskeletal Care Hip Fracture Oversight Group, program surgeons, and community primary care leaders: Olukemi Akande, MD, Mark Altman, MD, Diren Arsoy, MD, John Aversa, MD, Michael Connair, MD, Leo Cooney, MD, Kenneth Donohue, MD, David Gibson, MD, Gail Haesche, RN, MS, ACM-RN, Carol Just, MSN, NEA-BC, RN, Patricia Kenyon, RN, ACM, Francis Lee MD, Michael Leslie, MD, Michael Lucchini, MD, Christopher Lynch, MD, Rowland Mayor, MD, Tara Messina, PT, Lorraine Novella, RN, Paul Oliver, PA-C, Vivek Parwani, MD, Joseph Quaranta, MD, Lee Rubin, MD, Derek Shia, MD, Jeff Sumner, MD, John Tarutis, Arya Varthi, MD, Anuruddha Walaliyadda, MD, Daniel Wiznia, MD, Shirvinda Wijesekera, MD, Joseph Wu, MD, Brad Yoo, MD, and James Yue, MD.
Hip fractures are a significant cause of morbidity and mortality among elderly patients. Patients with fragility hip fractures often carry multiple comorbid diagnoses with a significant risk of perioperative complications. After hip fracture, 30-day mortality has been reported as 3.3% to 17.2% with one-year mortality as high as 50%.1
Multidisciplinary care,2-5 surgery within 24 hours (h),6-12 use of regional peripheral nerve blocks,13-16 restrictive blood transfusion strategies,17,18 tranexamic acid (TXA) use,19 pharmacologic deep venous thrombosis (DVT) prophylaxis,20 surgical site infection prevention protocols,21 early mobilization,22 and nutritional optimization23-25 have been individually shown to improve outcomes in hip fracture patients.
Our program sought to define, standardize, and implement evidence-based best practices to improve clinical care and outcomes of patients with hip fractures. We convened a Center for Musculoskeletal Care (CMC) Hip Fracture Oversight Group that included surgeons and advanced practice providers from Orthopedics; physicians from Internal Medicine Hospitalist, Geriatrics, Emergency Medicine, and Anesthesia; and representatives from rehabilitation services, nursing, care management, pharmacy, and performance improvement. With clinical input from all involved services, we developed evidence-based protocols to standardize the care of patients with fragility hip fractures from the time of the patient’s evaluation in the emergency room to discharge and outpatient rehabilitation. The program was operationalized in February 2016.
This project was considered by the Yale University institutional review board (IRB) to be a quality improvement and, therefore, exempted from IRB approval.
MATERIALS AND METHODS
Yale-New Haven Hospital is composed of two main campuses. The York Street Campus (YSC) is the Level 1 Trauma Center. The St. Raphael’s Campus (SRC) houses the CMC nursing units for elective lower extremity arthroplasty and spine procedures. Prior to 2016, patients with hip fractures were cared for equally at both Yale-New Haven Hospital campuses. Patients were admitted to both medical and surgical services with no standardization of hip fracture care processes. Surgeons were assigned based on availability. Frequently, patients were added on to the operating room (OR) schedule and did not undergo surgery until off-hours and after a prolonged waiting period.
Medical comanagement of patients with fragility hip fractures at our institution predated the start of our CMC Integrated Fragility Hip Fracture Program (IFHFP). Comanagement was instituted in 2012 at YSC and in 2014 at SRC but without standardized protocols. The IFHFP began in February 2016 with the centralization of all patients with fragility hip fractures to the SRC at Yale-New Haven Hospital. Emergency medical services directed patients with suspected hip fractures to the designated campus. A dedicated hip fracture OR was allocated daily with a hip fracture surgeon assigned by a shared community and faculty surgeon call schedule. Patients were encouraged but not required to accept care from the on-call hip fracture surgical attending. Anesthesia was notified of the arrival of a patient with a hip fracture in the emergency department, and if the patient consented and qualified, a single-shot femoral nerve block was performed. Patients were screened for nasal staphylococcal colonization and treated with povidone-iodine nasal decolonization, chlorhexidine wash, and antibiotics determined by staphylococcal status and type of surgical procedure planned. Preoperative and postoperative order sets were implemented that dictated the care processes as outlined in Table 1. Surgeons determined the choice of operative intervention as per usual; this included internal fixation and partial or total hip replacement. Detailed medical and surgical protocols are included in Appendix A.
Since the initiation of the IFHFP on February 1, 2016, the program has continued to advance with our experience. We used the year preceding the start of the program as our baseline year (January 1, 2015, through December 31, 2015). The following years, 2016 and 2017, were a transition time during which our protocols were implemented. The intervention year was defined as January 1, 2018, through December 31, 2018. The outcomes during the intervention year were compared with the baseline year. It is important to note that our program has been in continuous evolution, including during the intervention year, with protocols created and refined as we gain experience.
Outcomes include 30-day mortality, transfusions, adverse effects of drugs, venous thromboembolic complications, sepsis, myocardial infarction, mechanical surgical fixation complications, length of stay, 30-day readmission rate, unexpected return to the OR, and time to operative intervention. Definitions of the outcome variables are reviewed in Appendix B.
RESULTS
There were 275 consecutive patients with hip fractures admitted to SRC in the baseline year (January 1, 2015 to December 31, 2015) and 434 patients with hip fractures admitted in the intervention year (January 1, 2018, to December 31, 2018) after consolidation of the program to the single Yale-New Haven Campus and implementation of standardized care processes. Patient demographic data including age, sex, ethnicity, body mass index, and American Society of Anesthesiologists physical status classification were evaluated for the baseline year and intervention year and reported in Table 2. There were no differences in the demographics of patients between baseline and intervention years.
From baseline year to intervention year, 30-day mortality, transfusion, adverse effects of drugs, length of stay, unexpected return to OR, and time to OR were all significantly reduced. Mortality within 30 days decreased from 8.0% to 2.8%. The results are displayed in Table 3. No significant difference was seen in the incidence of venous thromboembolism, sepsis, myocardial infarctions, readmission at 30 days, or mechanical surgical fixation complications.
The Figure shows the 30-day IFHFP mortality rate as reported on a monthly basis starting on January 1 of the baseline year, 2015, and continuing through December 31 of the intervention year, 2018. The process interventions are mapped according to the date of initiation. The median mortality rate (including all data from January 1, 2015, to December 31, 2018) is demonstrated as the dotted line. From May 2018 to December 2018, each monthly mortality rate was recorded below the four-year median, a visual demonstration of the statistical significance seen in our mortality reduction from 8.0% in the baseline year to 2.8% in the intervention year.
DISCUSSION
Patients with fragility hip fractures are a medically complex and vulnerable population. The goal of the CMC IFHFP was to standardize the care of these high-risk patients in an effort to reduce time to the OR, perioperative medical complications, time spent in the hospital, and ultimately mortality.
The barriers to implementing coordinated, multidisciplinary care are significant. In our case, we had a fragmented care model with fragility hip fracture patients cared for at two campuses, on different nursing units, with both community and faculty surgeons providing operative care, and with no predesignated primary team. We structured our program for equal sharing of call between community and faculty surgeons. However, there was distrust among the physician groups: Primary care physicians were concerned that their referral lines with orthopedic surgical colleagues would be fractured by the new shared call. Surgeons doubted that patients would be distributed equally among community and faculty practices. Hospitalists feared that comanagement would mean surgeons abdicating responsibility for care. Surgeons worried that routine medical involvement would delay surgery and prolong the length of stay with excessive testing. In order to achieve consensus, address concerns, and allay fears, we engaged the primary care and surgeon leadership for their support at the onset of the program and held monthly large group meetings and many smaller sessions to advance objectives. We meticulously tracked data and frequently reported out to the involved groups.
As it is well established that operative intervention on a hip fracture is best completed within 24 h to optimize a patient’s clinical outcomes, critical interventions were the designation of a hip fracture OR starting midday and expectation that surgery be performed the day after admission for medically cleared patients. Surgeons were able to book elective cases or outpatient clinic time in the morning. The morning hours prior to surgery allowed time for any final medical optimization, preoperative nursing care, and family discussions. Most surgeries were then completed by the primary OR staff during standard operating hours. Patients were out of the postanesthesia care unit and settled back on the orthopedic nursing unit in the early evening without a prolonged period of nil per os, bed rest, or sleep interruption.
While our protocol expected surgery the day after admission for medically cleared patients, we used surgery within 24 h as a simple metric to compare baseline with intervention outcomes. With our hip fracture OR block time beginning midday, the majority of our medically cleared hip fracture patients would receive surgical treatment within 24 h of admission. Our data show a significant improvement in timeliness of surgical intervention from 41.8% of patients to the OR within 24 h in 2015 to 55% in 2018. In 2017, we conducted an interval four-month audit involving a detailed chart review of all patients for whom surgery was delayed beyond 24 h from hospital admission. Chart review identified anticoagulation as the primary reason for surgical delay. Of patients who were eligible for surgery (medically stabilized and not therapeutically anticoagulated), 90% underwent surgery within 24 h during this four-month period in 2017. This compares to an overall rate of surgery within 24 h of 57% during the calendar year 2017. We did not perform a subgroup analysis of outcomes in patients with time to OR of 24-36 h. From this study, we are therefore unable to draw any conclusion regarding time to surgery and mortality.
Our dedicated OR hip fracture block time was changed from 7:30
Transfusion rate reduction from 46.6% to 28.1% was achieved primarily by the implementation and strict enforcement of a policy to avoid transfusing asymptomatic patients with hemoglobin >7.0 g/dL. In addition, we recommended TXA using standard perioperative arthroplasty dosing of 1 g intravenously (IV) at the time of incision followed by 1 g IV 3 h later in the postanaesthesia care unit. However, adherence to TXA recommendations was poor. A year-long audit (February 2017 to February 2018) demonstrated that only 29% of patients undergoing hip fracture surgery received the recommended TXA. After the conclusion of the study period of this review, we revised our TXA protocol to include an infusion at the time of admission and subsequent perioperative doses. The expanded TXA protocol (with clear exclusion criteria) has been “hard-wired” into our electronic perioperative order sets. We are tracking TXA compliance on a weekly basis. We anticipate that earlier TXA administration and improved compliance will further reduce transfusion rates.
We reduced the adverse effects of medications with two initiatives: First, dedicated hip fracture order sets with medications selected and dosed specifically for the geriatric population were launched at the onset of the IFHFP in 2016. Second, in coordination with our regional anesthesia team, patients who met criteria underwent a single-shot femoral nerve block upon diagnosis of the hip fracture. Patients reported up to 24 h of nonnarcotic pain relief with the femoral nerve block.
Prior to the introduction of the IFHFP, surgeons determined DVT prophylaxis based on their personal preference. Many of our surgeons were concerned that standardizing DVT prophylaxis to enoxaparin would increase the risk of surgical site bleeding, hematoma, infection, and reoperation. With data tracking and periodic reporting, we were able to reassure our surgeons: We demonstrated a reduction in the rate of patients unexpectedly requiring a return to the OR from 5.1% in 2015 to 0% in 2018.
We did not find a significant difference in mechanical complications due to surgical fixation during the index admission. Most mechanical complications do not present within the index admission and, therefore, would not be identified by this metric. Furthermore, in this phase of the program, we did not seek to change or standardize intraoperative surgical processes outside of surgical site infection prevention measures. Surgical technical quality and variation among surgeons is an area of ongoing evaluation within our program. We have begun a surgical quality review process with an expert review of postoperative radiography, beginning with fixation of nondisplaced femoral neck fractures, feedback to surgeons, and tracking of mechanical complications beyond the index admission. The surgical quality outcomes will be presented in a future manuscript.
Anticoagulation use is common in patients with hip fractures because of the high prevalence of comorbid conditions such as atrial fibrillation and venous thromboembolic disease. Direct oral anticoagulants (DOACs) are now commonly used in place of the vitamin K antagonist, warfarin. Our inability to efficiently reverse the DOACs compounded by surgeon unfamiliarity with these agents led to extreme caution in the timing of OR, with most patients delayed a full 48 h from the last dose of their prescribed DOAC. After recognizing the impact of anticoagulation on the timing of surgery, we convened a multidisciplinary group to determine rational guidelines for the timing of surgery in patients on chronic anticoagulation based on the bleeding risk of the planned operative procedure. These guidelines were instituted in December 2018, so their impact is not reflected in this review.
Our results showing a reduction in length of stay and mortality cannot be explained by any one intervention. We propose that the standardization of all processes and protocols, the establishment of clear expectations among all the medical and nursing personnel, and the shorter time spent waiting for surgery all contributed to the length of stay reduction. Likewise, the decrease in time to OR, reduction in time spent in the hospital, fewer transfusions, adverse effects of medication, and surgical complications requiring a return to the OR have all likely contributed to the significant reduction in mortality. The efforts of the orthopedic nursing team certainly contributed: The CMC nurses led the efforts to standardize surgical site infection bundle care, reduce indwelling bladder catheter use, and together with physical therapy, mobilize patients out of bed for meals postoperatively. The strong focus on teamwork, data tracking, feedback and accountability, and the desire for continued improvement may have been the strongest drivers in this program’s success.
Our results showed a nonsignificant increase in 30-day readmission from 9.1% to 12.5%. One limitation of this study is that we did not track specific readmission diagnoses to better understand trends in diagnoses or indications for hospital readmission. Going forward, we are reviewing readmissions to better understand opportunities to improve our inpatient processes and transitions of care.
This an evolving project. We have expanded our use of TXA in an effort to further reduce transfusion rates. We have adjusted our protocols for patients admitted on DOACs and warfarin to allow more rapid surgical intervention. We have initiated a surgical quality review process in which surgical fixation is reviewed with timely feedback to the operating surgeon. We are working closely with the skilled nursing facilities to extend our rehabilitation and nursing care protocols beyond the acute care setting. We are measuring patient engagement with a brief discharge survey specific to the CMC IFHFP. We continue to seek feedback from our referring primary care physicians to improve communication at times of care transition.
One of the limitations of a quality improvement project such as this one is the inability to identify the effect of each individual intervention. We can conclude that the totality of the multidisciplinary project reduced mortality in our hip fracture population, but we cannot report the relative effect of each process change. Another center seeking to replicate this success cannot determine from this research how to prioritize their resources to achieve a similar outcome.
How we care for the fragility hip fracture patient after hospital discharge is critical and unaddressed in this current study. A limitation of our current program is the lack of consistent postdischarge bone health management—which we are working to address. Also related to postdischarge management, we have partnered with a network of preferred skilled nursing facilities to standardize the care and decrease the length of stay. These data will be published separately.
We understand that our experience at the CMC is unique and specific to our care environment. This is a single site study and may not be generalizable to other centers. Nonetheless, the principles of multidisciplinary care, evidence-based protocol development, technological integration of protocols through order sets, and data tracking with feedback and accountability are the essential elements of our success that can be generalized to other institutions.
CONCLUSIONS
The CMC at Yale School of Medicine and Yale-New Haven Hospital IFHFP provides a model for implementing well-documented evidence-based interventions to standardize the care of patients with fragility hip fractures. The IFHFP yielded reduced mortality, length of stay, blood transfusion utilization, adverse effects of medications, unexpected return to the OR, and time to the OR.
Acknowledgments
The authors thank the work of the Center for Musculoskeletal Care Hip Fracture Oversight Group, program surgeons, and community primary care leaders: Olukemi Akande, MD, Mark Altman, MD, Diren Arsoy, MD, John Aversa, MD, Michael Connair, MD, Leo Cooney, MD, Kenneth Donohue, MD, David Gibson, MD, Gail Haesche, RN, MS, ACM-RN, Carol Just, MSN, NEA-BC, RN, Patricia Kenyon, RN, ACM, Francis Lee MD, Michael Leslie, MD, Michael Lucchini, MD, Christopher Lynch, MD, Rowland Mayor, MD, Tara Messina, PT, Lorraine Novella, RN, Paul Oliver, PA-C, Vivek Parwani, MD, Joseph Quaranta, MD, Lee Rubin, MD, Derek Shia, MD, Jeff Sumner, MD, John Tarutis, Arya Varthi, MD, Anuruddha Walaliyadda, MD, Daniel Wiznia, MD, Shirvinda Wijesekera, MD, Joseph Wu, MD, Brad Yoo, MD, and James Yue, MD.
1. Abrahamsen B, van Staa T, Ariely M, Olson M, Cooper C. Excess mortality following hip fracture: a systematic epidemiologic review. Osteoporos Int. 2009;20(10):1633-1650. https://doi.org/10.1007/s00198-009-0920-3.
2. DellaRocca GJ, Moylan KC, Crist BD, Volgas DA, Stannard JP, Mehr DR. Comanagement of geriatric patients with hip fractures: a retrospective, controlled cohort study. Geriatr Orthop Surg Rehabil. 2013;4(1):10-15. https://doi.org/10.1177/2151458513495238.
3. Wang Y, Tang J, Zhou F, Yang L, Wu J. Comprehensive geriatric care reduces acute perioperative delirium in elderly patients with hip fractures: a meta-analysis. Medicine. 2017; 96(26): e7361. https://doi.org/10.1097/MD.0000000000007361.
4. Liu VX, Rosas E, Hwang J, et al. Enhanced recovery after surgery program implementation in 2 surgical populations in an integrated health care delivery system. JAMA Surg. 2017;152(7):e171032. https://doi.org/10.1001/jamasurg.2017.1032.
5. Taraldsen K, Sletvold O, Thingstad P, et al. Physical behavior and function early after hip fracture surgery in patients receiving geriatric care or orthopedic care—a randomized controlled trial. J Gerontol A Biol Sci Med Sci. 2014;69(3):338-345. https://doi.org/10.1093/gerona/glt097.
6. Grimes JP, Gregory PM, Noveck H, Butler MS, Carson Jl. The effects of time-to-surgery on mortality and morbidity in patients following hip fracture. Am J Med. 2002;112(9):702-709. https://doi.org/10.1016/s0002-9343(02)01119-1.
7. Hamlet WP, Lieberman JR, Freedman EL, Dorey FJ, Fletcher A, Johnson EE. Influence of health status and the timing of surgery on mortality in hip fracture patients. Am J Orthop. 1997;26(9):621-627.
8. Hoenig H, Rubenstein LV, Sloane R, Honer R, Kahn K. What is the role of timing in the surgical and rehabilitative care of community-dwelling older persons with acute hip fracture? Arch Intern Med. 1997;157(5):513-520.
9. Orosz GM, Magaziner J, Hannan El, et al. Association of timing of surgery for hip fracture and patient outcomes. JAMA. 2004;291(14):1738-1743. https://doi.org/10.1001/jama.291.14.1738.
10. Gdalevich M, Cohen D, Yosef D, Tauber C. Morbidity and mortality after hip fracture: the impact of operative delay. Arch Orthop Trauma Surg. 2004:124(5):334-340. https://doi.org/10.1007/s00402-004-0662-9.
11. Doruk H, Mas MR, Yidiz C, Sonmez A, Kýrdemir V. The effect of the timing of hip fracture surgery on the activity of daily living and mortality in elderly. Arch Gerontol Geriatr. 2004;39(2):179-185.https://doi.org/10.1016/j.archger.2004.03.004.
12. Uzoigwe CE, Burnand HG, Cheesman CL, Aghedo DO, Faizi M, Middleton RG. Early and ultra-early surgery in hip fracture patients improves survival. Injury. 2013;44(6):726-729. https://doi.org/10.1016/j.injury.2012.08.025.
13. Guay J, Parker MJ, Griffiths R, Kopp SL. Peripheral nerve blocks for hip fractures. Cochrane Database Syst Rev. 2017;5: CD001159. https://doi.org/10.1002/14651858.CD001159.pub2.
14. Morrison RS, Dickman E, Hwang U, et al. Regional nerve blocks improve pain and functional outcomes in hip fracture: a randomized controlled trial. J Am Geriatr Soc. 2016;64(12):2433-2439. https://doi.org/10.1111/jgs.14386.
15. Beaudoin FL, Haran JP, Liebmann O. A comparison of ultrasound-guided three-in-one femoral nerve block versus parenteral opioids alone for analgesia in emergency deparment patients with hip fractures: a randomized controlled trial. Acad Emerg Med. 2013;20(6):584-591. https://doi.org/10.1111/acem.12154.
16. Dickman E, Pushkar I, Likourezos A, et al. Ultrasound-guided nerve blocks for intracapsular and extracapsular hip fractures. Am J Emerg Med. 2016;34(3):586-589. https://doi.org/10.1016/j.ajem.2015.12.016.
17. Carson JL, Terrin MI, Noveck H, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med. 2011;365(26):2453-2462. https://doi.org/10.1056/NEJMoa1012452.
18. Garcia-Alvarez F, Al-Ghanem R, García-Alvarez I, López-Baisson A, Bernal M. Risk factors for postoperative infections in patients with hip fracture treated by means of Thompson arthoplasty. Arch Gerontol Geriatr. 2010; 50(1):51-55. https://doi.org/10.1016/j.archger.2009.01.009.
19. Farrow LS, Smith TO, Ashcroft GP, Myint PK. A systematic review of tranexamic acid in hip fracture surgery. Br J Clin Pharmacol. 2016;82(6):1458-1470. https://doi.org/10.1111/bcp.13079.
20. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e278S-e325S. https://doi.org/10.1378/chest.11-2404.
21. Gillespie WJ, Walenkamp G. Antibiotic prophylaxis for surgery for proximal femoral and other closed long bone fractures. Cochrane Database Syst Rev. 2010;(3):CD000244. https://doi.org/10.1002/14651858.CD000244.pub2.
22. Kamel HK, Iqbal MA, Mogallapu R, Maas D, Hoffmann RG. Time to ambulation after hip fracture surgery: relation to hospitalization outcomes. J Gerontol A Biol Sci Med Sci. 2003;58(11):1042-1045. https://doi.org/10.1093/gerona/58.11.m1042.
23. Foster MR, Heppenstall RB, Friedenberg ZB, Hozack WJ. A prospective assessment of nutritional status and complications in patients with fractures of the hip. J Orthop Trauma. 1990;4(1):49-57. https://doi.org/10.1097/00005131-199003000-00009.
24. Bell JJ, Pulle RC, Crouch AM, Kuys SS, Ferrier RL, Whitehouse SL. Impact of malnutrition on 12-month mortality following acute hip fracture. ANZ J Surg. 2016;86(3):157-161. https://doi.org/10.1111/ans.13429.
25. Avenell A, Handoll HH. Nutritional supplementation for hip fracture aftercare in older people. Cochrane Database Syst Rev. 2010;(1):CD001880. https://doi.org/10.1002/14651858.CD001880.pub5.
1. Abrahamsen B, van Staa T, Ariely M, Olson M, Cooper C. Excess mortality following hip fracture: a systematic epidemiologic review. Osteoporos Int. 2009;20(10):1633-1650. https://doi.org/10.1007/s00198-009-0920-3.
2. DellaRocca GJ, Moylan KC, Crist BD, Volgas DA, Stannard JP, Mehr DR. Comanagement of geriatric patients with hip fractures: a retrospective, controlled cohort study. Geriatr Orthop Surg Rehabil. 2013;4(1):10-15. https://doi.org/10.1177/2151458513495238.
3. Wang Y, Tang J, Zhou F, Yang L, Wu J. Comprehensive geriatric care reduces acute perioperative delirium in elderly patients with hip fractures: a meta-analysis. Medicine. 2017; 96(26): e7361. https://doi.org/10.1097/MD.0000000000007361.
4. Liu VX, Rosas E, Hwang J, et al. Enhanced recovery after surgery program implementation in 2 surgical populations in an integrated health care delivery system. JAMA Surg. 2017;152(7):e171032. https://doi.org/10.1001/jamasurg.2017.1032.
5. Taraldsen K, Sletvold O, Thingstad P, et al. Physical behavior and function early after hip fracture surgery in patients receiving geriatric care or orthopedic care—a randomized controlled trial. J Gerontol A Biol Sci Med Sci. 2014;69(3):338-345. https://doi.org/10.1093/gerona/glt097.
6. Grimes JP, Gregory PM, Noveck H, Butler MS, Carson Jl. The effects of time-to-surgery on mortality and morbidity in patients following hip fracture. Am J Med. 2002;112(9):702-709. https://doi.org/10.1016/s0002-9343(02)01119-1.
7. Hamlet WP, Lieberman JR, Freedman EL, Dorey FJ, Fletcher A, Johnson EE. Influence of health status and the timing of surgery on mortality in hip fracture patients. Am J Orthop. 1997;26(9):621-627.
8. Hoenig H, Rubenstein LV, Sloane R, Honer R, Kahn K. What is the role of timing in the surgical and rehabilitative care of community-dwelling older persons with acute hip fracture? Arch Intern Med. 1997;157(5):513-520.
9. Orosz GM, Magaziner J, Hannan El, et al. Association of timing of surgery for hip fracture and patient outcomes. JAMA. 2004;291(14):1738-1743. https://doi.org/10.1001/jama.291.14.1738.
10. Gdalevich M, Cohen D, Yosef D, Tauber C. Morbidity and mortality after hip fracture: the impact of operative delay. Arch Orthop Trauma Surg. 2004:124(5):334-340. https://doi.org/10.1007/s00402-004-0662-9.
11. Doruk H, Mas MR, Yidiz C, Sonmez A, Kýrdemir V. The effect of the timing of hip fracture surgery on the activity of daily living and mortality in elderly. Arch Gerontol Geriatr. 2004;39(2):179-185.https://doi.org/10.1016/j.archger.2004.03.004.
12. Uzoigwe CE, Burnand HG, Cheesman CL, Aghedo DO, Faizi M, Middleton RG. Early and ultra-early surgery in hip fracture patients improves survival. Injury. 2013;44(6):726-729. https://doi.org/10.1016/j.injury.2012.08.025.
13. Guay J, Parker MJ, Griffiths R, Kopp SL. Peripheral nerve blocks for hip fractures. Cochrane Database Syst Rev. 2017;5: CD001159. https://doi.org/10.1002/14651858.CD001159.pub2.
14. Morrison RS, Dickman E, Hwang U, et al. Regional nerve blocks improve pain and functional outcomes in hip fracture: a randomized controlled trial. J Am Geriatr Soc. 2016;64(12):2433-2439. https://doi.org/10.1111/jgs.14386.
15. Beaudoin FL, Haran JP, Liebmann O. A comparison of ultrasound-guided three-in-one femoral nerve block versus parenteral opioids alone for analgesia in emergency deparment patients with hip fractures: a randomized controlled trial. Acad Emerg Med. 2013;20(6):584-591. https://doi.org/10.1111/acem.12154.
16. Dickman E, Pushkar I, Likourezos A, et al. Ultrasound-guided nerve blocks for intracapsular and extracapsular hip fractures. Am J Emerg Med. 2016;34(3):586-589. https://doi.org/10.1016/j.ajem.2015.12.016.
17. Carson JL, Terrin MI, Noveck H, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med. 2011;365(26):2453-2462. https://doi.org/10.1056/NEJMoa1012452.
18. Garcia-Alvarez F, Al-Ghanem R, García-Alvarez I, López-Baisson A, Bernal M. Risk factors for postoperative infections in patients with hip fracture treated by means of Thompson arthoplasty. Arch Gerontol Geriatr. 2010; 50(1):51-55. https://doi.org/10.1016/j.archger.2009.01.009.
19. Farrow LS, Smith TO, Ashcroft GP, Myint PK. A systematic review of tranexamic acid in hip fracture surgery. Br J Clin Pharmacol. 2016;82(6):1458-1470. https://doi.org/10.1111/bcp.13079.
20. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e278S-e325S. https://doi.org/10.1378/chest.11-2404.
21. Gillespie WJ, Walenkamp G. Antibiotic prophylaxis for surgery for proximal femoral and other closed long bone fractures. Cochrane Database Syst Rev. 2010;(3):CD000244. https://doi.org/10.1002/14651858.CD000244.pub2.
22. Kamel HK, Iqbal MA, Mogallapu R, Maas D, Hoffmann RG. Time to ambulation after hip fracture surgery: relation to hospitalization outcomes. J Gerontol A Biol Sci Med Sci. 2003;58(11):1042-1045. https://doi.org/10.1093/gerona/58.11.m1042.
23. Foster MR, Heppenstall RB, Friedenberg ZB, Hozack WJ. A prospective assessment of nutritional status and complications in patients with fractures of the hip. J Orthop Trauma. 1990;4(1):49-57. https://doi.org/10.1097/00005131-199003000-00009.
24. Bell JJ, Pulle RC, Crouch AM, Kuys SS, Ferrier RL, Whitehouse SL. Impact of malnutrition on 12-month mortality following acute hip fracture. ANZ J Surg. 2016;86(3):157-161. https://doi.org/10.1111/ans.13429.
25. Avenell A, Handoll HH. Nutritional supplementation for hip fracture aftercare in older people. Cochrane Database Syst Rev. 2010;(1):CD001880. https://doi.org/10.1002/14651858.CD001880.pub5.
© 2020 Society of Hospital Medicine
The role of adjuvant chemotherapy in early-stage and locally advanced non–small cell lung cancer
Despite surgery, 40% to 75% of patients with stage I to IIIA non–small cell lung cancer (NSCLC) will die within 5 years. After multiple trials showed no survival advantage to chemotherapy in the adjuvant setting for the treatment of locally advanced NSCLC, the first hint of benefit came in 1995 with the publication of a meta-analysis of 14 clinical trials, which showed a nonsignificant 5% improvement in 5-year survival with chemotherapy after surgery.1
A second meta-analysis, this one conducted by the Lung Adjuvant Cisplatin Evaluation (LACE) Collaborative Group, demonstrated a hazard ratio (HR) of 0.89 (P = .005) on the end point of overall survival with the use of postoperative cisplatin-based chemotherapy in patients with NSCLC; this translates to a 5-year absolute improvement of 5.4% from chemotherapy.2 The survival benefit was confined to patients with stage II and stage III disease.
Post hoc exploratory subgroup analyses of the Cancer and Leukemia Group B (CALGB) 96333 and Adjuvant Navelbine International Trialist Association (ANITA)4 trials revealed a significant survival benefit to four cycles of cisplatin-based adjuvant chemotherapy in patients with stage Ib disease who had tumors 4 cm or larger.
BIOMARKERS
Prognostic and predictive biomarkers beyond cancer stage are needed, as only 10% to 15% of patients with resected NSCLC who receive chemotherapy derive a benefit. Predictive markers can be used to guide therapeutic decision-making, and prognostic markers permit estimation of patient outcome independent of treatment modality.
As with ERCC1, expression of the DNA mismatch repair protein mutS homolog 2 (MSH2)7 is both prognostic and predictive after surgery. In a separate biomarker analysis from the IALT study, approximately two-thirds of patients with NSCLC had MSH2-negative tumors by immunohistochemistry, indicating lack of expression of MSH2 in tumors. Patients with expression of MSH2, who have intact mismatch repair, had a better prognosis and benefitted less from systemic chemotherapy than those with an absence of MSH2 expression.8
Individually, ERCC1 and MSH2 have similar power in predicting benefit from adjuvant chemotherapy in NSCLC; the HR for death was similar in patients with low expression of either gene.8 The two biomarkers combined, however, were more powerful than either alone in their ability to predict a survival advantage with chemotherapy.8 In an evaluation of 658 patients with NSCLC for whom both biomarkers were available, patients who expressed low tumor levels of both ERCC1 and MSH2 had an HR for death that was 35% lower with adjuvant chemotherapy compared with surgery alone after median follow-up of 7.5 years; the presence of two positive biomarkers was associated with an increase in the HR for death by 32%. Validation of these findings in a phase 3 setting will be necessary before these biomarkers can be used in the clinical setting.
The Southwest Oncology Group (SWOG) is conducting a trial (SWOG 0720) in patients with stage I NSCLC to determine whether a subset based on ERCC1 and ribonucleotide reductase M1 (RRM1) status will derive benefit from adjuvant therapy with gemcitabine together with cisplatin. Ribonucleotide reductase subunit 1 is the regulatory subunit of ribonuclease reductase, which is an enzyme that catalyzes the deoxynucleotide production required for DNA repair.
Two other clinical trials, under way but not completed, testing various forms of chemotherapy and targeted therapy based on ERCC1 and epidermal growth factor receptor (EGFR) mutation status are the Tailored Post-Surgical Therapy in Early Stage NSCLC (TASTE) and the International Tailored Chemotherapy Adjuvant (ITACA) trials. The TASTE trial is comparing standard chemotherapy (cisplatin plus pemetrexed) with customized adjuvant treatment based on EGFR and ERCC1 status in patients with stage II or IIIa nonsquamous NSCLC. The ITACA trial is a phase 3 study of pemetrexed, cisplatin, and radiotherapy determined by thymidylate synthase (TS) and ERCC1 gene expression levels in patients with stage II to III completely resected NSCLC. TS is an enzyme responsible for maintaining intracellular levels of thymidine, important for DNA synthesis and repair, and may serve as a predictor of response to pemetrexed.
GENE EXPRESSION PROFILING
Gene expression profiles, already used to predict benefit from chemotherapy in early-stage breast cancer, may inform treatment decisions in lung cancer as well. A15-gene signature that could predict risk of recurrence and death after surgery alone for stage Ib or II NSCLC was identified using fresh frozen tissue of patients from the National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG) JBR.10 trial of vinorelbine/cisplatin.9 The risk profile was subsequently validated with reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) in the same cases and in four independent sets of patients.9
Among those patients with stage Ib disease, the gene expression profile was both prognostic (HR of 13.22 for disease-specific survival in the high- vs low-risk population) and predictive (HR of 0.44 for the use of adjuvant chemotherapy in the high-risk patients but no survival benefit observed with chemotherapy in low-risk patients).9
USE OF BIOMARKERS TO SELECT TREATMENT
As alluded to earlier, the use of biomarker expression to guide treatment selection is an area of intense investigation. In the metastatic setting, therapy targeted to the EGFR mutation has proven to be remarkably beneficial in patients with EGFR-activating mutations. In the adjuvant setting, the NCIC CTG BR.19 trial enrolled an unselected population of patients with completely resected stage Ib to IIIa NSCLC; the patients were randomized to 2 years of treatment with the tyrosine kinase inhibitor gefitinib, which targets EGFR, or placebo. Tissue samples from trial participants were collected and revealed KRAS mutation in 27%, a high EGFR gene copy number by fluorescence in situ hybridization (FISH) in 41%, and an activating EGFR mutation in 21%.
The NCIC CTG BR.19 trial was greatly underpowered because enrollment was stopped at 503 patients when, in 2008, the SWOG 0023 investigators reported a worse overall median survival with maintenance gefitinib after definitive chemoradiation in patients with stage III NSCLC.10 As a result of the early termination of patient accrual, the median duration of adjuvant gefitinib in NCIC CTG BR.19 was less than 5 months. Further, only 20% were exposed to chemotherapy and only 21% of the final study population had an EGFR mutation. In the overall study population, the HR for overall survival among gefitinib recipients was 1.23, indicating harm, and there was a trend in favor of placebo on the end point of disease-free survival. Neither KRAS nor EGFR copy number was predictive or prognostic, and EGFR mutation status was not prognostic.11 Patients with wild-type EGFR had a trend toward detriment with maintenance gefitinib that was similar to that of the overall population, and those with EGFR mutation experienced no benefit with maintenance gefitinib.
In the Randomized Double-Blind Trial in Adjuvant NSCLC with Tarceva (RADIANT), patients with resected stage I to IIIa NSCLC, with the option for postoperative chemotherapy, were assessed for EGFR expression by immunohistochemistry or FISH and then randomized to erlotinib or placebo for 2 years. The trial completed accrual in 2010 and results are expected in 4 to 5 years.
Cleveland Clinic is currently accruing patients for a phase 2 trial of patients with resected stage I to IIIa NSCLC. All patients will have their tumors screened for activating EGFR mutations; those with activating mutations will receive adjuvant erlotinib for 2 years. starting within 6 months of surgery.
SUMMARY
Although adjuvant chemotherapy has been well established for patients with early-stage NSCLC, stage alone is not an ideal biomarker to predict the utility of chemotherapy, as the vast majority of patients derive no benefit from chemotherapy.
Biomarkers have been poorly validated and therefore are inappropriate for clinical use at this time. Validation of gene arrays has been disappointingly slow in lung cancer because of the absence of large tumor banks that are available in breast cancer and colon cancer.
It remains unclear whether targeted therapies improve outcomes over traditional chemotherapy in the adjuvant setting in NSCLC, as tumors in the metastatic and adjuvant settings are not the same.
- Non-Small-Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995; 311:899–909.
- Pignon J-P, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008; 26:3552–3559.
- Strauss GM, Herndon JE, Maddaus ME, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non–small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008; 26:5043–5051.
- Douillard JY, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 2006; 7:719–727.
- Gazdar AF. DNA repair and survival in lung cancer—the two faces of Janus. N Engl J Med 2007; 356:771–773.
- Olaussen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006; 355:983–991.
- Vilar E, Gruber SB. Microsatellite instability in colorectal cancer—the stable evidence. Nat Rev Clin Oncol 2010; 7:153–162.
- Fouret P, Planchard D, Mendiboure J, et al. MSH2 and adjuvant cisplatin-based chemotherapy in non-small cell lung cancer [ASCO abstract CRA7502]. J Clin Oncol 2009; 27 (suppl).
- Zhu C-Q, Ding K, Strumpf D, et al. Prognostic and predictive gene signature for adjuvant chemotherapy in resected non-small-cell lung cancer. J Clin Oncol 2010; 28:4417–4424.
- Kelly K, Chansky K, Gaspar LE, et al. Updated analysis of SWOG 0023: a randomized phase III trial of gefitinib versus placebo maintenance after definitive chemoradiation followed by docetaxel in patients with locally advanced stage III nonsmall cell lung cancer [ASCO abstract 7513]. J Clin Oncol 2007; 25 (suppl).
- Goss GD, Lorimer I, Taso S, et al. A phase III randomized, double-blind, placebo-controlled trial of the epidermal growth factor inhibitor gefitinib in completely resected stage IB-IIIA non-small cell lung cancer (NSCLC): NCIC CTG BR.19 [ASCO abstract LBA7005]. J Clin Oncol 2010; 28 (suppl).
Despite surgery, 40% to 75% of patients with stage I to IIIA non–small cell lung cancer (NSCLC) will die within 5 years. After multiple trials showed no survival advantage to chemotherapy in the adjuvant setting for the treatment of locally advanced NSCLC, the first hint of benefit came in 1995 with the publication of a meta-analysis of 14 clinical trials, which showed a nonsignificant 5% improvement in 5-year survival with chemotherapy after surgery.1
A second meta-analysis, this one conducted by the Lung Adjuvant Cisplatin Evaluation (LACE) Collaborative Group, demonstrated a hazard ratio (HR) of 0.89 (P = .005) on the end point of overall survival with the use of postoperative cisplatin-based chemotherapy in patients with NSCLC; this translates to a 5-year absolute improvement of 5.4% from chemotherapy.2 The survival benefit was confined to patients with stage II and stage III disease.
Post hoc exploratory subgroup analyses of the Cancer and Leukemia Group B (CALGB) 96333 and Adjuvant Navelbine International Trialist Association (ANITA)4 trials revealed a significant survival benefit to four cycles of cisplatin-based adjuvant chemotherapy in patients with stage Ib disease who had tumors 4 cm or larger.
BIOMARKERS
Prognostic and predictive biomarkers beyond cancer stage are needed, as only 10% to 15% of patients with resected NSCLC who receive chemotherapy derive a benefit. Predictive markers can be used to guide therapeutic decision-making, and prognostic markers permit estimation of patient outcome independent of treatment modality.
As with ERCC1, expression of the DNA mismatch repair protein mutS homolog 2 (MSH2)7 is both prognostic and predictive after surgery. In a separate biomarker analysis from the IALT study, approximately two-thirds of patients with NSCLC had MSH2-negative tumors by immunohistochemistry, indicating lack of expression of MSH2 in tumors. Patients with expression of MSH2, who have intact mismatch repair, had a better prognosis and benefitted less from systemic chemotherapy than those with an absence of MSH2 expression.8
Individually, ERCC1 and MSH2 have similar power in predicting benefit from adjuvant chemotherapy in NSCLC; the HR for death was similar in patients with low expression of either gene.8 The two biomarkers combined, however, were more powerful than either alone in their ability to predict a survival advantage with chemotherapy.8 In an evaluation of 658 patients with NSCLC for whom both biomarkers were available, patients who expressed low tumor levels of both ERCC1 and MSH2 had an HR for death that was 35% lower with adjuvant chemotherapy compared with surgery alone after median follow-up of 7.5 years; the presence of two positive biomarkers was associated with an increase in the HR for death by 32%. Validation of these findings in a phase 3 setting will be necessary before these biomarkers can be used in the clinical setting.
The Southwest Oncology Group (SWOG) is conducting a trial (SWOG 0720) in patients with stage I NSCLC to determine whether a subset based on ERCC1 and ribonucleotide reductase M1 (RRM1) status will derive benefit from adjuvant therapy with gemcitabine together with cisplatin. Ribonucleotide reductase subunit 1 is the regulatory subunit of ribonuclease reductase, which is an enzyme that catalyzes the deoxynucleotide production required for DNA repair.
Two other clinical trials, under way but not completed, testing various forms of chemotherapy and targeted therapy based on ERCC1 and epidermal growth factor receptor (EGFR) mutation status are the Tailored Post-Surgical Therapy in Early Stage NSCLC (TASTE) and the International Tailored Chemotherapy Adjuvant (ITACA) trials. The TASTE trial is comparing standard chemotherapy (cisplatin plus pemetrexed) with customized adjuvant treatment based on EGFR and ERCC1 status in patients with stage II or IIIa nonsquamous NSCLC. The ITACA trial is a phase 3 study of pemetrexed, cisplatin, and radiotherapy determined by thymidylate synthase (TS) and ERCC1 gene expression levels in patients with stage II to III completely resected NSCLC. TS is an enzyme responsible for maintaining intracellular levels of thymidine, important for DNA synthesis and repair, and may serve as a predictor of response to pemetrexed.
GENE EXPRESSION PROFILING
Gene expression profiles, already used to predict benefit from chemotherapy in early-stage breast cancer, may inform treatment decisions in lung cancer as well. A15-gene signature that could predict risk of recurrence and death after surgery alone for stage Ib or II NSCLC was identified using fresh frozen tissue of patients from the National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG) JBR.10 trial of vinorelbine/cisplatin.9 The risk profile was subsequently validated with reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) in the same cases and in four independent sets of patients.9
Among those patients with stage Ib disease, the gene expression profile was both prognostic (HR of 13.22 for disease-specific survival in the high- vs low-risk population) and predictive (HR of 0.44 for the use of adjuvant chemotherapy in the high-risk patients but no survival benefit observed with chemotherapy in low-risk patients).9
USE OF BIOMARKERS TO SELECT TREATMENT
As alluded to earlier, the use of biomarker expression to guide treatment selection is an area of intense investigation. In the metastatic setting, therapy targeted to the EGFR mutation has proven to be remarkably beneficial in patients with EGFR-activating mutations. In the adjuvant setting, the NCIC CTG BR.19 trial enrolled an unselected population of patients with completely resected stage Ib to IIIa NSCLC; the patients were randomized to 2 years of treatment with the tyrosine kinase inhibitor gefitinib, which targets EGFR, or placebo. Tissue samples from trial participants were collected and revealed KRAS mutation in 27%, a high EGFR gene copy number by fluorescence in situ hybridization (FISH) in 41%, and an activating EGFR mutation in 21%.
The NCIC CTG BR.19 trial was greatly underpowered because enrollment was stopped at 503 patients when, in 2008, the SWOG 0023 investigators reported a worse overall median survival with maintenance gefitinib after definitive chemoradiation in patients with stage III NSCLC.10 As a result of the early termination of patient accrual, the median duration of adjuvant gefitinib in NCIC CTG BR.19 was less than 5 months. Further, only 20% were exposed to chemotherapy and only 21% of the final study population had an EGFR mutation. In the overall study population, the HR for overall survival among gefitinib recipients was 1.23, indicating harm, and there was a trend in favor of placebo on the end point of disease-free survival. Neither KRAS nor EGFR copy number was predictive or prognostic, and EGFR mutation status was not prognostic.11 Patients with wild-type EGFR had a trend toward detriment with maintenance gefitinib that was similar to that of the overall population, and those with EGFR mutation experienced no benefit with maintenance gefitinib.
In the Randomized Double-Blind Trial in Adjuvant NSCLC with Tarceva (RADIANT), patients with resected stage I to IIIa NSCLC, with the option for postoperative chemotherapy, were assessed for EGFR expression by immunohistochemistry or FISH and then randomized to erlotinib or placebo for 2 years. The trial completed accrual in 2010 and results are expected in 4 to 5 years.
Cleveland Clinic is currently accruing patients for a phase 2 trial of patients with resected stage I to IIIa NSCLC. All patients will have their tumors screened for activating EGFR mutations; those with activating mutations will receive adjuvant erlotinib for 2 years. starting within 6 months of surgery.
SUMMARY
Although adjuvant chemotherapy has been well established for patients with early-stage NSCLC, stage alone is not an ideal biomarker to predict the utility of chemotherapy, as the vast majority of patients derive no benefit from chemotherapy.
Biomarkers have been poorly validated and therefore are inappropriate for clinical use at this time. Validation of gene arrays has been disappointingly slow in lung cancer because of the absence of large tumor banks that are available in breast cancer and colon cancer.
It remains unclear whether targeted therapies improve outcomes over traditional chemotherapy in the adjuvant setting in NSCLC, as tumors in the metastatic and adjuvant settings are not the same.
Despite surgery, 40% to 75% of patients with stage I to IIIA non–small cell lung cancer (NSCLC) will die within 5 years. After multiple trials showed no survival advantage to chemotherapy in the adjuvant setting for the treatment of locally advanced NSCLC, the first hint of benefit came in 1995 with the publication of a meta-analysis of 14 clinical trials, which showed a nonsignificant 5% improvement in 5-year survival with chemotherapy after surgery.1
A second meta-analysis, this one conducted by the Lung Adjuvant Cisplatin Evaluation (LACE) Collaborative Group, demonstrated a hazard ratio (HR) of 0.89 (P = .005) on the end point of overall survival with the use of postoperative cisplatin-based chemotherapy in patients with NSCLC; this translates to a 5-year absolute improvement of 5.4% from chemotherapy.2 The survival benefit was confined to patients with stage II and stage III disease.
Post hoc exploratory subgroup analyses of the Cancer and Leukemia Group B (CALGB) 96333 and Adjuvant Navelbine International Trialist Association (ANITA)4 trials revealed a significant survival benefit to four cycles of cisplatin-based adjuvant chemotherapy in patients with stage Ib disease who had tumors 4 cm or larger.
BIOMARKERS
Prognostic and predictive biomarkers beyond cancer stage are needed, as only 10% to 15% of patients with resected NSCLC who receive chemotherapy derive a benefit. Predictive markers can be used to guide therapeutic decision-making, and prognostic markers permit estimation of patient outcome independent of treatment modality.
As with ERCC1, expression of the DNA mismatch repair protein mutS homolog 2 (MSH2)7 is both prognostic and predictive after surgery. In a separate biomarker analysis from the IALT study, approximately two-thirds of patients with NSCLC had MSH2-negative tumors by immunohistochemistry, indicating lack of expression of MSH2 in tumors. Patients with expression of MSH2, who have intact mismatch repair, had a better prognosis and benefitted less from systemic chemotherapy than those with an absence of MSH2 expression.8
Individually, ERCC1 and MSH2 have similar power in predicting benefit from adjuvant chemotherapy in NSCLC; the HR for death was similar in patients with low expression of either gene.8 The two biomarkers combined, however, were more powerful than either alone in their ability to predict a survival advantage with chemotherapy.8 In an evaluation of 658 patients with NSCLC for whom both biomarkers were available, patients who expressed low tumor levels of both ERCC1 and MSH2 had an HR for death that was 35% lower with adjuvant chemotherapy compared with surgery alone after median follow-up of 7.5 years; the presence of two positive biomarkers was associated with an increase in the HR for death by 32%. Validation of these findings in a phase 3 setting will be necessary before these biomarkers can be used in the clinical setting.
The Southwest Oncology Group (SWOG) is conducting a trial (SWOG 0720) in patients with stage I NSCLC to determine whether a subset based on ERCC1 and ribonucleotide reductase M1 (RRM1) status will derive benefit from adjuvant therapy with gemcitabine together with cisplatin. Ribonucleotide reductase subunit 1 is the regulatory subunit of ribonuclease reductase, which is an enzyme that catalyzes the deoxynucleotide production required for DNA repair.
Two other clinical trials, under way but not completed, testing various forms of chemotherapy and targeted therapy based on ERCC1 and epidermal growth factor receptor (EGFR) mutation status are the Tailored Post-Surgical Therapy in Early Stage NSCLC (TASTE) and the International Tailored Chemotherapy Adjuvant (ITACA) trials. The TASTE trial is comparing standard chemotherapy (cisplatin plus pemetrexed) with customized adjuvant treatment based on EGFR and ERCC1 status in patients with stage II or IIIa nonsquamous NSCLC. The ITACA trial is a phase 3 study of pemetrexed, cisplatin, and radiotherapy determined by thymidylate synthase (TS) and ERCC1 gene expression levels in patients with stage II to III completely resected NSCLC. TS is an enzyme responsible for maintaining intracellular levels of thymidine, important for DNA synthesis and repair, and may serve as a predictor of response to pemetrexed.
GENE EXPRESSION PROFILING
Gene expression profiles, already used to predict benefit from chemotherapy in early-stage breast cancer, may inform treatment decisions in lung cancer as well. A15-gene signature that could predict risk of recurrence and death after surgery alone for stage Ib or II NSCLC was identified using fresh frozen tissue of patients from the National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG) JBR.10 trial of vinorelbine/cisplatin.9 The risk profile was subsequently validated with reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) in the same cases and in four independent sets of patients.9
Among those patients with stage Ib disease, the gene expression profile was both prognostic (HR of 13.22 for disease-specific survival in the high- vs low-risk population) and predictive (HR of 0.44 for the use of adjuvant chemotherapy in the high-risk patients but no survival benefit observed with chemotherapy in low-risk patients).9
USE OF BIOMARKERS TO SELECT TREATMENT
As alluded to earlier, the use of biomarker expression to guide treatment selection is an area of intense investigation. In the metastatic setting, therapy targeted to the EGFR mutation has proven to be remarkably beneficial in patients with EGFR-activating mutations. In the adjuvant setting, the NCIC CTG BR.19 trial enrolled an unselected population of patients with completely resected stage Ib to IIIa NSCLC; the patients were randomized to 2 years of treatment with the tyrosine kinase inhibitor gefitinib, which targets EGFR, or placebo. Tissue samples from trial participants were collected and revealed KRAS mutation in 27%, a high EGFR gene copy number by fluorescence in situ hybridization (FISH) in 41%, and an activating EGFR mutation in 21%.
The NCIC CTG BR.19 trial was greatly underpowered because enrollment was stopped at 503 patients when, in 2008, the SWOG 0023 investigators reported a worse overall median survival with maintenance gefitinib after definitive chemoradiation in patients with stage III NSCLC.10 As a result of the early termination of patient accrual, the median duration of adjuvant gefitinib in NCIC CTG BR.19 was less than 5 months. Further, only 20% were exposed to chemotherapy and only 21% of the final study population had an EGFR mutation. In the overall study population, the HR for overall survival among gefitinib recipients was 1.23, indicating harm, and there was a trend in favor of placebo on the end point of disease-free survival. Neither KRAS nor EGFR copy number was predictive or prognostic, and EGFR mutation status was not prognostic.11 Patients with wild-type EGFR had a trend toward detriment with maintenance gefitinib that was similar to that of the overall population, and those with EGFR mutation experienced no benefit with maintenance gefitinib.
In the Randomized Double-Blind Trial in Adjuvant NSCLC with Tarceva (RADIANT), patients with resected stage I to IIIa NSCLC, with the option for postoperative chemotherapy, were assessed for EGFR expression by immunohistochemistry or FISH and then randomized to erlotinib or placebo for 2 years. The trial completed accrual in 2010 and results are expected in 4 to 5 years.
Cleveland Clinic is currently accruing patients for a phase 2 trial of patients with resected stage I to IIIa NSCLC. All patients will have their tumors screened for activating EGFR mutations; those with activating mutations will receive adjuvant erlotinib for 2 years. starting within 6 months of surgery.
SUMMARY
Although adjuvant chemotherapy has been well established for patients with early-stage NSCLC, stage alone is not an ideal biomarker to predict the utility of chemotherapy, as the vast majority of patients derive no benefit from chemotherapy.
Biomarkers have been poorly validated and therefore are inappropriate for clinical use at this time. Validation of gene arrays has been disappointingly slow in lung cancer because of the absence of large tumor banks that are available in breast cancer and colon cancer.
It remains unclear whether targeted therapies improve outcomes over traditional chemotherapy in the adjuvant setting in NSCLC, as tumors in the metastatic and adjuvant settings are not the same.
- Non-Small-Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995; 311:899–909.
- Pignon J-P, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008; 26:3552–3559.
- Strauss GM, Herndon JE, Maddaus ME, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non–small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008; 26:5043–5051.
- Douillard JY, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 2006; 7:719–727.
- Gazdar AF. DNA repair and survival in lung cancer—the two faces of Janus. N Engl J Med 2007; 356:771–773.
- Olaussen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006; 355:983–991.
- Vilar E, Gruber SB. Microsatellite instability in colorectal cancer—the stable evidence. Nat Rev Clin Oncol 2010; 7:153–162.
- Fouret P, Planchard D, Mendiboure J, et al. MSH2 and adjuvant cisplatin-based chemotherapy in non-small cell lung cancer [ASCO abstract CRA7502]. J Clin Oncol 2009; 27 (suppl).
- Zhu C-Q, Ding K, Strumpf D, et al. Prognostic and predictive gene signature for adjuvant chemotherapy in resected non-small-cell lung cancer. J Clin Oncol 2010; 28:4417–4424.
- Kelly K, Chansky K, Gaspar LE, et al. Updated analysis of SWOG 0023: a randomized phase III trial of gefitinib versus placebo maintenance after definitive chemoradiation followed by docetaxel in patients with locally advanced stage III nonsmall cell lung cancer [ASCO abstract 7513]. J Clin Oncol 2007; 25 (suppl).
- Goss GD, Lorimer I, Taso S, et al. A phase III randomized, double-blind, placebo-controlled trial of the epidermal growth factor inhibitor gefitinib in completely resected stage IB-IIIA non-small cell lung cancer (NSCLC): NCIC CTG BR.19 [ASCO abstract LBA7005]. J Clin Oncol 2010; 28 (suppl).
- Non-Small-Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995; 311:899–909.
- Pignon J-P, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008; 26:3552–3559.
- Strauss GM, Herndon JE, Maddaus ME, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non–small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008; 26:5043–5051.
- Douillard JY, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 2006; 7:719–727.
- Gazdar AF. DNA repair and survival in lung cancer—the two faces of Janus. N Engl J Med 2007; 356:771–773.
- Olaussen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006; 355:983–991.
- Vilar E, Gruber SB. Microsatellite instability in colorectal cancer—the stable evidence. Nat Rev Clin Oncol 2010; 7:153–162.
- Fouret P, Planchard D, Mendiboure J, et al. MSH2 and adjuvant cisplatin-based chemotherapy in non-small cell lung cancer [ASCO abstract CRA7502]. J Clin Oncol 2009; 27 (suppl).
- Zhu C-Q, Ding K, Strumpf D, et al. Prognostic and predictive gene signature for adjuvant chemotherapy in resected non-small-cell lung cancer. J Clin Oncol 2010; 28:4417–4424.
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