Author + information
- Received December 3, 2015
- Revision received April 5, 2016
- Accepted April 12, 2016
- Published online July 12, 2016.
- Greg C. Flaker, MDa,∗ (, )
- Paul Theriot, BSBAb,
- Lea G. Binder, MAb,
- Paul P. Dobesh, PharmDc,
- Adam Cuker, MDd and
- John U. Doherty, MDe
- aUniversity of Missouri School of Medicine, Columbia, Missouri
- bAmerican College of Cardiology, Washington, DC
- cCollege of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska
- dPerelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- eSidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
- ↵∗Reprint requests and correspondence:
Dr. Greg C. Flaker, Department of Cardiovascular Medicine, University of Missouri-Columbia, CE 351 University Hospital, CE351, One Hospital Drive, Columbia, Missouri 65212.
Interruption of oral anticoagulation (AC) for surgery or an invasive procedure is a complicated process. Practice guidelines provide only general recommendations, and care of such patients occurs across multiple specialties. The availability of direct oral anticoagulants further complicates decision making and guidance here is limited. To evaluate current practice patterns in the United States for bridging AC, a survey was developed by the American College of Cardiology Anticoagulation Work Group. The goal of the survey was to assess how general and subspecialty cardiologists, internists, gastroenterologists, and orthopedic surgeons currently manage patients who receive AC and undergo surgery or an invasive procedure. The survey was completed by 945 physicians involved in the periprocedural management of AC. The results provide a template for educational and research projects geared toward the development of clinical pathways and point-of-care tools to improve this area of health care.
Annually, 10% to 15% of patients who receive oral anticoagulation (AC) therapy require treatment interruption for surgery or an invasive procedure (1,2). Parenteral AC, typically with unfractionated heparin or low molecular weight heparin, is thought to prevent thromboembolic events (TE) during the time when patients do not receive oral AC. The safety and efficacy of this practice of “bridging anticoagulation” has been called into question with several developments in AC therapy.
First, it has been difficult to show that bridging AC prevents TE. A systematic review and meta-analysis in patients who required interruption of vitamin K antagonist (VKA) therapy showed no significant differences in TE between those patients who received parenteral AC and those who did not. A significant excess of major bleeding was noted in those receiving parenteral AC (3). In the recently published, randomized, double-blind BRIDGE (Bridging Anticoagulation in Patients who Require Temporary Interruption of Warfarin Therapy for an Elective Procedure or Surgery) study, patients receiving VKAs for atrial fibrillation, who were at moderate risk for TE and who were undergoing surgery, were randomized to dalteparin or placebo. A low rate of TE, not significantly different between placebo and dalteparin, was noted. Significantly higher rates of major bleeding occurred with dalteparin (4).
Second, a number of surgical procedures with a lower risk for bleeding can be performed with brief or no interruption of warfarin. These include pacemaker and implantable cardioverter-defibrillator implantation, dental extraction, and cataract surgery (5–9). The ability to perform procedures at lower risk of bleeding without interruption of oral AC reduces the need for parenteral AC and the additional risk of bleeding.
Third, direct-acting oral anticoagulants (DOACs) have been incorporated into clinical practice. Unlike warfarin, which inhibits the synthesis of several clotting factors, DOACs directly inhibit selected components of the clotting cascade and have a much more rapid onset and offset of action than VKAs. On the basis of these pharmacological properties, many have questioned the need for the administration of parenteral AC when DOACs are interrupted. However, an increased frequency of stroke after cessation of DOACs has been reported (10–13), leading to the inclusion of a Food and Drug Administration recommendation in the prescribing information, stating that coverage with another AC should be considered if dabigatran, rivaroxaban, apixaban, or edoxaban are discontinued. In point of fact, this recommendation arose from the observation of excess stroke rates at the end of pivotal clinical trials, when patients were transitioned from a DOAC back to warfarin. This was not meant to endorse bridging when patients were taken off a DOAC for a procedure, but the impact of this recommendation in clinical practice is uncertain.
Finally, there is the realization that management of AC in a patient requiring surgery or an invasive procedure is complex. The interruption and reinstitution of oral AC, and the initiation and discontinuation of parenteral AC requires coordination between a number of health care providers (14).
Because of these developments, and to better understand current practice patterns for patients requiring interruption of AC therapy, a survey was developed by members of the American College of Cardiology (ACC) Anticoagulation Initiative Work Group and completed by a variety of health care providers in the United States who care for patients receiving AC.
The ACC’s Anticoagulation Initiative Work Group was formed in 2013 to improve the delivery of AC care. Members of this work group developed a survey, approved by the ACC, which was sent to physicians who care for patients on AC who undergo a procedure. Initially, the online survey was distributed to 9,165 members of the ACC who agreed to participate. General cardiologists (n = 158, response rate 6.5%), interventional cardiologists (n = 161, response rate 3.3%), and electrophysiologists (n = 163, response rate 8.8%) completed the survey.
Internal medicine primary care physicians, gastroenterologists, and orthopedic surgeons were identified through the Medical Panel of Research Now, Inc. The proprietary Research Now Medical panel is actively managed and updated with weekly verification. The Research Now Medical panel uses a “by invitation only” methodology, including online recruitment, as well as a direct mail enrollment campaign. The Research Now Medical panel is American Medical Association verified to ensure that all members enrolled in the panel are physicians, and therefore provides accurate targeting across all medical specialties. The survey was distributed to 3,054 physicians and was completed by internists (n = 152, response rate 13.9%), gastroenterologists (n = 160, response rate 13.0%), and orthopedic surgeons (n = 153, response rate 21.0%). For participation in this survey, each panelist from the Research Now Medical panel received $35.
The ACC provided financial support to Research Now, which conducted the survey for the noncardiologists. The survey was performed between July 22, 2015, and August 27, 2015. The complete survey is available in the Online Appendix. The respondents represented both private and academic practices across the United States. Of the cardiologists surveyed, 85% had primary board certification in internal medicine and 99% were board certified in cardiovascular diseases. Detailed profile information about the respondents is also available in the Online Appendix.
Who manages periprocedural AC?
When asked who manages AC during and after surgical or invasive procedures, the survey respondents said that cardiologists are extensively involved in decision-making processes, more commonly than the physician performing the procedure (Figure 1). A number of other health care professionals, including primary care physicians, pharmacists, and nurses, are involved in the periprocedural management of the patient who receives oral AC.
Identification of patients at high risk for TE
Patients at higher risk for TE may benefit from parenteral AC. Most respondents (82%) consider the presence of a mechanical heart valve to be of sufficient risk to warrant parenteral AC. A prior stoke or transient ischemic attack is sufficient to warrant parenteral AC by 74% of the respondents. However, there are significant variations in specialties as to which patient is at high enough risk to warrant parenteral AC (Table 1). A greater percentage of general cardiologists, electrophysiologists, and interventional cardiologists identified the presence of a mechanical heart valve, or a history of a stroke or transient ischemic attack as a marker of increased risk for perioperative TE than survey respondents as a whole.
When asked what criteria are used for a patient with atrial fibrillation without a mechanical heart valve who undergoes surgery with a high risk of bleeding, nearly one-half (44%) of the respondents reported that they use the CHA2DS2-VASc score to decide who should receive parenteral AC. Fewer (11%) report the use of the CHADS2 score. However, there was no consensus as to what score is high enough to warrant bridging (Figure 2). Of note is that 27% of respondents indicate that a CHADS2 score of 2 is sufficient to warrant bridging, despite the fact that the BRIDGE study, published in June 2015 (a month before the survey), demonstrated that for patients at moderately increased risk for stroke (mean CHADS2 score 2.3) no bridging was noninferior to bridging for preventing TE and was superior to bridging for preventing major bleeding (4).
Identification of surgical procedures at low risk for bleeding
A number of surgical procedures with a low risk for bleeding can be performed with brief or no interruption of warfarin. These include pacemaker and implantable cardioverter-defibrillator implantation, dental extraction, and cataract surgery. Despite these data, the perceived need to interrupt AC therapy and to use parenteral AC among respondents was substantial. Depending on the procedure, 17% to 37% of the respondents would typically or sometimes interrupt VKA therapy and administer parenteral AC for procedures generally safe to be performed without interruption (Figure 3). Differences between specialties are noted in Table 2. General cardiologists, interventional cardiologists, and electrophysiologists were more comfortable performing procedures at lower risk of bleeding without AC interruption than were noncardiologists.
Use of parenteral AC with DOACs
Given the rapid onset and offset of the anticoagulant effect with DOACs, parenteral AC might be unnecessary in patients undergoing temporary interruption of anticoagulant therapy for surgical procedures. However, when asked about periprocedural management of a patient with atrial fibrillation at increased risk of TE (CHA2DS2-VASc ≥2), the number of respondents who would bridge with a parenteral AC was similar, irrespective of whether the patient was taking warfarin or a DOAC (Figure 4). As noted subsequently in the Variation of Periprocedural Management section, it appears that the pharmacokinetics of warfarin may have been extrapolated by the respondents to the DOACs, and DOACs are interrupted too early before a procedure. The addition of a parental agent because the interruption is so long then compounds this “unforced error,” causing a second error because the pharmacokinetics of LMWH are similar to those of DOACs.
Device implantations in patients receiving VKAs and DOACs
When the survey results are restricted only to electrophysiologists who are implanting devices, nearly 9 of 10 (89%) are the sole or major decision makers regarding perioperative AC. Published studies have demonstrated the safety and efficacy of performing device surgery without the interruption of VKA antagonists (5–7). Most electrophysiologists (69%) would not interrupt warfarin for device implantation (Online Figure 1). Nearly 8 of 10 electrophysiologists (78%) would not stop warfarin for device replacement.
However, there remains uncertainty on the part of electrophysiologists concerning the safety and efficacy of performing device implantation surgery in the patient receiving a DOAC. A substantial minority (34%) of electrophysiologists would perform an initial implant without interruption of a DOAC, and 38% would perform device replacement without interruption. When asked about a specific case scenario for device implantation involving a hypothetical patient with normal renal function who receives apixaban 5 mg twice daily (b.i.d.), the duration of interruption of the DOAC varied. Nearly 1 in 5 of electrophysiologists (21%) omit 1 dose, but others recommend stopping DOAC therapy for 1 day (25%) or 2 days (25%) (Online Figure 2). Electrophysiologists uncommonly (12%) use parenteral AC in this situation.
Variation in periprocedural management between specialties
There are differences of opinion between the general cardiologist, the internist, and physicians performing procedures about the management of periprocedural AC, as illustrated in the following section. Two hypothetical patients were presented including: 1) a 70-year-old with a mechanical mitral valve prosthesis on warfarin; and 2) a patient with a CHA2DS2-VASc score of 5 and normal renal function (creatinine clearance 90 ml/min) who is treated with apixaban. Each patient undergoes an elective procedure, including colonoscopy, hip replacement, and coronary angiography (by a femoral approach).
For colonoscopy, general cardiologists consider themselves to be either the sole or major decision maker for the patient on warfarin 88% of the time. In contrast, the gastroenterologists consider themselves to be the sole or major decision maker for the patient on warfarin 67% of the time. This underscores the importance of a team approach in these patients and of assuring that someone is actively directing management.
In the case of a patient with a mechanical mitral valve, nearly 8 of 10 clinicians (79%) stop warfarin prior to colonoscopy. A similar percentage of general cardiologists (74%), internists (77%), and gastroenterologists (83%) stop warfarin 3 to 5 days prior to colonoscopy.
Enoxaparin or another low molecular weight heparin is the preferred parenteral anticoagulant for cardiologists (78%), internists (70%), and gastroenterologists (70%). However, the duration of post-procedure enoxaparin differed. More than 3 of 5 (63%) general cardiologists, internists, and gastroenterologists continue enoxaparin until the international normalized ratio (INR) is above a threshold value. The remaining respondents arbitrarily wait several days before discontinuing enoxaparin, irrespective of the INR. This likely reflects the fact that these patients are now outpatients not getting daily INR monitoring, and the duration of enoxaparin is on the basis of the pharmacokinetics of warfarin. Cardiologists (81%) preferred to continue enoxaparin until the INR was ≥2.0. An arbitrary 2 or more days was preferred by internists (50%) and gastroenterologists (48%) (Online Figure 3).
For the hypothetical patient with normal renal function on apixaban who undergoes elective colonoscopy, the majority of cardiologists (67%) stop apixaban 1 to 2 days prior to colonoscopy, compared with 37% of internists and 42% of gastroenterologists. Forty percent of gastroenterologists stop apixaban 3 to 5 days prior to the procedure. A comparison of survey responses for periprocedural management with warfarin and apixaban is illustrated in Table 3. Interestingly, a substantial minority of respondents would not interrupt warfarin or apixaban prior to elective colonoscopy.
In this situation, most clinicians (89%) do not use parenteral AC, but would simply start apixaban either 24 h (56%) or 48 h (33%) after the colonoscopy.
The responsibility for periprocedural management in a person with a mechanical heart valve who is undergoing hip replacement surgery is shared. The orthopedic surgeon considers himself/herself to be either the sole or major decision maker 53% of the time. The decision making is shared 31% of the time. The orthopedic surgeon has no influence or a minor influence only 15% of the time.
In this case scenario, almost 9 of 10 orthopedic surgeons (87%) stop warfarin at least 3 days prior to hip replacement. If parenteral AC is used, enoxaparin or some other low molecular weight heparin is preferred by 72% of orthopedic surgeons. Unfractionated heparin is preferred by 19% of orthopedic surgeons. If enoxaparin is used for parenteral AC, 44% of orthopedic surgeons favored 1 mg/kg daily. Another 22% favored a dose of 1.5 mg/kg daily. Others preferred a non–weight-based dosing schedule. Varying dosing schedules may reflect bleeding concerns or a reversion to prophylactic dosing. Enoxaparin is restarted on the day of the procedure by 24% and 24 h after the procedure by 70% of orthopedic surgeons. The majority of orthopedic surgeons (64%) continue the parenteral agent until the INR is above a threshold value. The remaining orthopedic surgeons arbitrarily wait several days before discontinuing enoxaparin (Online Figure 4).
For the hypothetical patient with normal renal function who receives apixaban and who undergoes elective hip replacement, there is no consensus of opinion as to the number of days apixaban should to be discontinued. The largest number (31%) stop apixaban 5 days prior to the procedure. Others stop apixaban 1 day (9%), 2 days (23%), 3 days (22%), or 4 days (9%) prior to surgery (Online Figure 5).
In this situation, most orthopedic surgeons (84%) do not use parenteral AC and simply start apixaban within 24 h (53%) or 48 h (48%) after the procedure.
Periprocedural management at the time of elective coronary angiography via femoral approach in the patient with a mechanical heart valve is primarily by the interventional cardiologist. Interventional cardiologists consider themselves either the sole or major decision maker 92% of the time.
For the patient receiving warfarin, more than 4 of 5 interventional cardiologists (83%) stop warfarin at least 3 days prior to coronary angiography. Warfarin is stopped 5 days, 4 days, and 3 days prior to the procedure by 27%, 15%, and 41% of interventional cardiologists, respectively.
Nearly 9 of 10 interventional cardiologists (88%) administer parenteral AC in the patient with a mechanical heart valve. Enoxaparin or another low molecular weight heparin is preferred by 73% of interventional cardiologists and 14% prefer unfractionated heparin.
The dose of enoxaparin is 1 mg/kg b.i.d. for 86% of interventional cardiologists. Enoxaparin is restarted, either on the day of the procedure (51%) or 24 h after the procedure (40%). Most interventional cardiologists (71%) continue enoxaparin until the INR is ≥2.0. Of the remaining interventional cardiologists, 21% prefer an arbitrary period of time before enoxaparin is discontinued, irrespective of the INR (Online Figure 6).
In the hypothetical patient with normal renal function who is receiving apixaban, there is no consensus of opinion as to the number of days apixaban needs to be discontinued. Almost all interventional cardiologists (96%) stop apixaban prior to the procedure. The duration of interruption of apixaban is variable. Some stop apixaban for 1 dose (21%), others for 1 day (25%), and others for 2 days (25%) prior to coronary angiography. A comparison of when warfarin and apixaban are stopped prior to elective coronary angiography is shown in Online Figure 7.
If a patient receives apixaban, a parenteral agent is not used by 84% of interventional cardiologists. Instead, nearly 9 of 10 (89%) simply begin apixaban within 24 h of coronary angiography.
More than 3 of 4 survey respondents believed that a standardized process or protocol is either extremely or very important for the periprocedural management of AC. However, 70% of respondents said that a standardized protocol for guidance of periprocedural management of AC is not available in their practice, and an additional 13% were not aware of whether a protocol was in place.
Bridging AC is a complicated undertaking (Central Illustration). The periprocedural management of patients who receive AC and who undergo surgery or invasive procedures involves a number of health care providers, including physicians who perform procedures, the primary care physician, nurses, and pharmacists. Although a decision maker is usually identified, this role varies, depending on the procedure. Given the number of health care providers involved in this process, standardized protocols or pathways of care make sense. However, only a minority of respondents reported the existence of standardized periprocedural protocols at their institutions. It has been shown that when AC protocols are devised and implemented, low TE and low rates of major bleeding are observed (15). Cardiologists were over-represented in this survey (approximately one-half of the respondents were cardiologists). In addition, the overall response rate was only 7.8%, which might bias the validity of the study. Regardless, a key message is that cardiologists are heavily involved in the management of AC in patients undergoing surgery or invasive procedures.
The survey highlighted that the CHA2DS2-VASc score is frequently used to identify patients for parenteral AC. This score was originally designed to identify risk factors for stroke in patients not receiving AC. The score is currently used to identify patients who receive AC who might receive parenteral AC when oral AC is interrupted. Although this makes clinical sense, the approach has never been validated. Furthermore, there is disagreement as to what score constitutes a high enough risk to justify bridging with parenteral AC. Given the excess risk of parenteral AC, clarification of risk factors in this population would allow clinicians to provide parenteral AC only to patients at appropriately high risk. The double-blind, randomized controlled trial of post-operative low molecular weight heparin bridging versus placebo bridging for patients who are at high risk for arterial thromboembolism (PERIOP2 [Safety and Effectiveness Study of LMWH Bridging Therapy for Patients on Long Term Warfarin and Require Temporary Interruption of Their Warfarin]) will help address the efficacy of parenteral AC in patients at high risk of TEs, including those with mechanical heart valves.
Previous studies have shown that the risk of TE is low in selected patients who have AC interrupted for surgical procedures (4,16). Surgical procedures at low risk for bleeding that do not require interruption of AC have also been defined (5–9). Although many lower-risk patients are undergoing procedures with a lower risk of bleeding without interruption of VKA, there are still many physicians who prefer to interrupt oral AC and provide parenteral AC. This puts patients at increased bleeding risk. The survey demonstrated that a considerable number of low-risk patients receive parenteral AC and a considerable number of low-risk procedures are being performed with parenteral AC. More education for physicians caring for these patients is warranted.
The survey confirmed the wide variability in dose and duration of parenteral AC, consistent with what has been reported in previous publications. Fixed, weight-based doses (4), a weight-based initial dose followed by reduced doses closer to surgery (17–19), and once a day or b.i.d. dosing (20) have been studied or advocated. Parenteral agents are administered only before the procedure, only after the procedure, or both before and after the procedure (17). Although the most common parenteral agent was enoxaparin, several dosing strategies were noted and tended to vary depending on profession. These differences may be explained by the philosophy of the clinician. For example, less than one-half of orthopedic surgeons use enoxaparin 1 mg/kg b.i.d. in the perioperative period for hip replacement. In contrast, nearly 9 of 10 interventional cardiologists use a dose of 1 mg/kg b.i.d. in the perioperative period for coronary angiography. The orthopedic surgeon, concerned about post-operative bleeding, favors a lower dose. The interventional cardiologist, more concerned about thrombus formation, favors the higher dose. After the BRIDGE study, parenteral AC will likely be used less often for patients at lower risk. Until additional data are obtained, patients at the highest TE risk (most mechanical heart valves, patients with CHADS scores >4) might continue to receive b.i.d. parenteral AC; others might receive once-daily parenteral AC, as previously recommended in high-volume institutions (19). In most patients, a reduction of the daily dose by 50% on the morning prior to the procedure can be considered.
The survey also demonstrated that the duration of parenteral AC was highly variable. For a patient treated with warfarin, most survey respondents favored continuation of parenteral AC until a therapeutic level of warfarin AC was reached. This approach is labor intensive and requires repeated post-operative measurements. This strategy is optimal for ensuring continuous adequate AC coverage for a patient at risk for TE. A number of other survey respondents favored a more practical approach, estimating the days required to reach a therapeutic INR and continuing parenteral AC for several days without repeated blood sampling. Given the fact that 22% of AC errors involve parenteral AC (21), additional studies to define the optimal dose and duration of parenteral AC are needed. Guidance for common AC-related management issues by expert consensus in the United States was published in 2012 (20) and needs updating.
The survey also highlights confusion about periprocedural management of AC in the patient treated with a DOAC. In the survey, management questions related to a patient taking apixaban were posed. It may not be valid to extrapolate these responses to other DOACs. Although it would have been ideal to include questions about dabigatran, rivaroxaban, and edoxaban as well, the survey would have been unwieldy. Apixaban was selected due to its general familiarity and growing use in the cardiac community. The purpose of the questions was to help define if respondents thought that procedures could safely be performed without DOAC interruption and, if not, how long should the DOAC be interrupted? Should parenteral AC be used during DOAC interruption? Guidance in this area is available (22) and derived from post hoc analyses of clinical trials and from registries. It appears that selected procedures with low risk for bleeding can be performed without interruption of the DOAC (apixaban) (23). Catheter ablation is now safely performed without interruption of DOACs (24,25). If procedures have sufficient bleeding risks, brief interruption of DOACs is associated with a low rate of TE, comparable to warfarin (23,26). The duration of AC interruption is shorter with a DOAC than with warfarin (24). In patients receiving predominantly rivaroxaban or dabigatran, the use of heparin bridging is associated with a higher risk of major bleeding compared with those who did not receive major bleeding, emphasizing concern about the use of parenteral AC with DOAC interruption (27). In a prospective study with time of discontinuation and resumption of dabigatran on the basis of pharmacokinetic information and the type of surgery or invasive procedure, a low risk of TE and major bleeding has been reported (28).
The role of parenteral AC with DOACs was difficult to understand in the survey. Some of the findings can be explained by a deficit in knowledge of the pharmacokinetic properties of DOACs.
Although the overall results suggested a similar rate of use of parenteral AC in warfarin-treated and in DOAC-treated patients who undergo surgery or an invasive procedure, the case scenarios do suggest that groups of individual clinicians, who perform procedures at lower risk in patients at moderate risk, infrequently use parental AC in DOAC-treated patients. The role of parenteral AC in higher-risk patients treated with DOACs undergoing surgeries or invasive procedures with higher bleeding risks, and who likely require interruption of AC for longer periods of time, remains uncertain.
Given this complex clinical scenario involving multiple health care professionals, it makes sense to develop consistently applied clinical pathways with standardized institutional protocols. Most respondents thought that this would be important.
This represents an important opportunity for professional societies and guidelines committees to work together to provide meaningful suggestions on the basis of current data. There are areas in the periprocedural management of AC where clinical evidence is clear-cut, and others where guidance needs to be tempered by clinical judgment. Guidelines, unfortunately, do not chart a clear path in all circumstances. For the present, consensus documents, clinical pathways, and point-of-care tools have enormous potential to improve care in this area. Coordination among specialties, pharmacists, nursing, and other health professionals has great potential for enhancement of care.
There is also an opportunity for professional societies to use these data to support research to address unanswered questions in the clinical space, as well as to promote strong educational programs to improve AC care.
For an expanded Methods section as well as supplemental tables and figures, please see the online version of this article.
The American College of Cardiology provided funds for this project. Dr. Flaker is a consultant for Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, and Daiichi-Sankyo. Dr. Dobesh is a consultant for Janssen, Daiichi-Sankyo, Pfizer, Bristol-Myers Squibb, and Boehringer-Ingelheim. Dr. Cuker is a consultant for Amgen, Biogen-Idec, Bracco, and Genzyme; and receives grant support from Spark Therapeutics and T2 Biosystems. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- American College of Cardiology
- twice daily
- direct-acting oral anticoagulant
- international normalized ratio
- thromboembolic event
- vitamin K antagonist
- Received December 3, 2015.
- Revision received April 5, 2016.
- Accepted April 12, 2016.
- American College of Cardiology Foundation
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