Clinical Practice Guideline on Prevention of VTE in surgical patients

Prevention of VTE in surgical patients i

Prevention of venous thromboembolism in general abdominal-pelvic surgery and major orthopedic surgery Guideline Panel Members Saudi Expert Panel       

Dr. Ali Alaklabi* Dr. Mohamad Abdelaal* Dr. Hasan Al Dorzi* Dr. Fawzi Al Jassir* Dr. Tarig Al Khuwaitir* Dr. Yousef Alomi Dr. Saleh Alqarni

*Saudi Association for Venous Thrombo-Embolism (SAVTE) (www.savte.com)

McMaster University Working Group Mrs. Rebecca Morgan, MPH, Dr. Itziar Etxeandia, Dr. Ignacio Neumann, Dr. Jan Brozek, and Dr. Holger Schünemann, on behalf of the McMaster Guideline Working Group

Acknowledgements We acknowledge Dr. Fahad Al-Hameed, Dr. Essam Aboelnazar, Dr. Mohammed Addar, Prof. Mohammed AlHajjaj, Dr. Nasr Ibrahim Dafalla, and Dr. Abdulelah Qadi for their contribution to this work. We gratefully acknowledge Dr. Yasser Sami Amer, from King Saud University for peer reviewing this final report. Disclosure of potential conflict of interest: Dr. Al Dorzi declares he has received speaker honoraria from Sanofi Aventis. Dr. Alaklabi declares he has received travel sponsorship from Sanofi Aventis and Bayer. Other co-authors have no conflict of interest to declare. Funding: This clinical practice guideline was funded by the Ministry of Health, Saudi Arabia. Address for correspondence: Saudi Center for Evidence Based Health Care

Prevention of VTE in surgical patients ii

E-mail: [email protected] Web: http://www.moh.gov.sa/endepts/Proofs/Pages/home.aspx

Prevention of VTE in surgical patients iii

Contents The Saudi Center for Evidence Based Health Care (EBHC) ..................................................................... v Executive Summary................................................................................................................................. 1 Introduction ........................................................................................................................................ 1 Methodology....................................................................................................................................... 1 How to use these guidelines ............................................................................................................... 1 Key questions ...................................................................................................................................... 2 Recommendations .............................................................................................................................. 4 Scope and purpose.................................................................................................................................. 5 Introduction ............................................................................................................................................ 5 Methodology........................................................................................................................................... 5 How to use these guidelines ................................................................................................................... 6 Key questions .......................................................................................................................................... 7 Recommendations .................................................................................................................................. 8 Question 1: Should LMWH rather than no prophylaxis be used in surgical patients in patients at low risk of VTE (e.g. Caprini score ≤ 2)? .............................................................................................. 9 Question 2: Should unfractionated heparin rather than no prophylaxis be used in surgical patients in patients at low risk of VTE (e.g. Caprini ≤ 2)? ............................................................................... 10 Question 3: Should intermittent pneumatic compression devices (IPC) rather than no prophylaxis be used in surgical patients in patients at low risk of VTE (e.g. Caprini score ≤ 2)? ......................... 10 Question 4: Should LMWH rather than no prophylaxis be used in surgical patients in patients at moderate risk of VTE (e.g. Caprini score 3-4)? ................................................................................. 11 Question 5: Should unfractionated heparin rather than no prophylaxis be used in surgical patients in patients at moderate risk of VTE (e.g. Caprini score 3-4)? ........................................................... 12 Question 6: Should intermittent pneumatic compression devices (IPC) rather than no prophylaxis be used in surgical patients in patients at moderate risk of VTE (e.g. Caprini score 3-4)? .............. 12 Question 7: Should LMWH rather than no prophylaxis be used in surgical patients in patients at moderate risk of VTE (e.g. Caprini score 3-4) and high risk of bleeding? ......................................... 13 Question 8: Should unfractionated heparin rather than no prophylaxis be used in surgical patients in patients at moderate risk of VTE (e.g. Caprini score, 3-4) and high risk of bleeding? .................. 14 Question 9: Should intermittent pneumatic compression devices (IPC) rather than no prophylaxis be used in surgical patients in patients at moderate risk of VTE (e.g. Caprini score 3-4) and high risk of bleeding? ................................................................................................................................ 15 Question 10: Should LMWH rather than no prophylaxis be used in surgical patients in patients at high risk of VTE (e.g. Caprini score ≥ 5)? ........................................................................................... 16 Question 11: Should unfractionated heparin rather than no prophylaxis be used in surgical patients in patients at high risk of VTE (e.g. Caprini score ≥ 5)?....................................................... 16 Question 12: Should intermittent pneumatic compression devices (IPC) rather than no prophylaxis be used in surgical patients in patients at high risk of VTE (e.g. Caprini score ≥ 5)? ........................ 17 Question 13: Should LMWH rather than no prophylaxis be used in surgical patients in patients at high risk of VTE (e.g. Caprini score ≥ 5) and high risk of bleeding? .................................................. 18 Question 14: Should unfractionated heparin rather than no prophylaxis be used in surgical patients in patients at high risk of VTE (e.g. Caprini score ≥ 5) and high risk of bleeding? .............. 19

Prevention of VTE in surgical patients iv

Question 15: Should intermittent pneumatic compression devices (IPC) rather than no prophylaxis be used in surgical patients in patients at high risk of VTE (e.g. Caprini score ≥ 5) and high risk of bleeding?........................................................................................................................................... 19 Question 16: Should LMWH rather than no prophylaxis be used in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery)? ........ 20 Question 17: Should LMWH rather Vitamin K Antagonists (VKA) be used in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery)? .......................................................................................................................................................... 21 Question 18: Should extended prophylaxis (up to 35 days) with LMWH rather than short-term prophylaxis (7-14 days) be used in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery)? ....................................................... 23 References ............................................................................................................................................ 24 Appendices............................................................................................................................................ 25 Appendix 1: Evidence to Decision Frameworks ................................................................................ 26 Evidence to Decision Framework 1: LMWH compared to no prophylaxis in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery ....... 26 Evidence to Decision Framework 2: Unfractionated Heparin compared to no prophylaxis in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery .......................................................................................................................................... 36 Evidence to Decision Framework 3: Intermittent pneumatic compression (IPC) compared to no prophylaxis in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery .................................................................................................................. 47 Evidence to Decision Framework 4: LMWH compared to no prophylaxis in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery) ...................................................................................................................................................... 57 Evidence to Decision Framework 5: LMWH compared to Vitamin K Antagonists in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery) ........................................................................................................................... 62 Evidence to Decision Framework 6: Extended prophylaxis (up to 35 days) with LMWH compared to short prophylaxis (7-14 days) in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery) ..................................................... 66 Appendix 2: Search Strategies and Results ....................................................................................... 70

Prevention of VTE in surgical patients v

The Saudi Center for Evidence Based Health Care (EBHC) The Saudi Centre for Evidence Based Health Care has managed and supported the coordination of the process of clinical practice guideline (CPG) development between the methodological team from McMaster University and the local clinical expert panel members in Saudi Arabia. The EBHC staff members recruited local clinical experts through contacting Saudi specialist societies and also independent experts interested in developing reliable and most up-to-date CPGs to harmonize the treatment and provide the highest quality of health care in the kingdom of Saudi Arabia. These experts were health care professionals of multidisciplinary backgrounds. As much as possible, patient’s representatives were also included in panels. In an effort to make national recommendations, the participating experts were professionals from the Ministry of Health (MoH), National Guard Hospitals, King Faisal Specialist Hospital and Research Centre (KFSHRC), University Hospitals, Security Forces Hospitals, Prince Sultan Military Medical City (PSMMC) and from some private hospitals. Based on a preselection of available evidence syntheses, the EBHC provided a list of potential topics to be addressed in CPGs after thorough consultations with the local stakeholders. These topics were further discussed with the McMaster University team for important selection criteria and agreed on 12 topics for the second wave of guidelines. The guideline panel meetings were held in Riyadh on 15th-18th March 2015 where about 96 local experts working in Saudi Arabia participated with the methodological support from 20 experts from McMaster University and its partners from the American University of Beirut, Lebanon, and the University of Freiburg, Germany, in providing high quality recommendations for common and important clinical conditions in the Kingdom. The Saudi Centre for EBHC supports the efforts for dissemination of the CPGs by publishing online the full reports of the CPGs, facilitates writing concise versions of the CPGs for publication in peer reviewed medical journals, sending hard copies to hospitals and health care centers. Finally, a mobile App has been introduced in KSA to facilitate the dissemination efforts of the completed practice guidelines. The staff members at the Saudi Centre for EBHC: Dr Zulfa Al Rayess, Consultant Family Medicine, Head of Saudi Center for EBHC Dr Yaser Adi, Scientific Advisor for the Saudi Centre for EBHC Miss Nourah Al Moufarreh, Project Manager, Saudi Center for EBHC

Prevention of VTE in surgical patients 1

Executive Summary Introduction Venous thromboembolism (VTE) is an important cause of death in surgical patients in the Kingdom of Saudi Arabia, especially when appropriate prophylaxis is not used.1 Given the importance of this topic, the Ministry of Health of the Kingdom of Saudi Arabia with the methodological support of the McMaster University working group produced practice guidelines to assist health care providers in evidence-based decision-making on the prevention of VTE in patients undergoing general and abdominal-pelvic surgery and major orthopedic surgery. Methodology This practice guideline is a part of the larger initiative of the Ministry of Health of the Kingdom of Saudi Arabia (KSA) to establish a program of rigorous development of guidelines. The ultimate goals are to provide guidance for clinicians and other healthcare decision makers and reduce unnecessary variability in clinical practice across the Kingdom. The Saudi expert guideline panel selected the topic of this guideline and all healthcare questions addressed herein using a formal prioritization process. For all the selected questions we updated existing systematic reviews.2,3 We also conducted systematic searches for information that was required to develop full guidelines for the KSA, including searches for information about patients’ values and preferences, and costs and resource use specific to the Saudi context. Based on the systematic reviews we prepared summaries of available evidence supporting each recommendation following the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach.4 We used this information to prepare GRADE evidence-to-decision frameworks that served the guideline panel to follow the structured consensus process and transparently document all decisions made

during the meeting (see Appendix 1). The guideline panel met in Riyadh on March 17 & 18, 2015 and formulated all recommendations during this meeting. Potential conflicts of interests of all panel members were managed according to the World Health Organization (WHO) rules.5 As a quality measure prior to publication, the final report has been externally peer reviewed by a methodological expert who has not been involved in this guideline development. How to use these guidelines The guideline-working group developed and graded the recommendations and assessed the quality of the supporting evidence according to the GRADE approach.6 Quality of evidence (confidence in the estimates of effects) is categorized as: high, moderate, low, or very low based on consideration of risk of bias, indirectness, inconsistency, imprecision and publication bias of the estimates as well as factors that lead to upgrading the quality of the evidence. High quality evidence indicates that we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality evidence indicates moderate confidence, and that the true effect is likely close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality evidence indicates that our confidence in the effect estimate is limited, and that the true effect may be substantially different. Finally, very low quality evidence indicates that the estimate of effect of interventions is very uncertain, the true effect is likely to be substantially different from the effect estimate and further research is likely to have important potential for reducing the uncertainty. The strength of recommendations is expressed as either strong (‘guideline panel recommends…’) or conditional (‘guideline panel suggests…’) and has explicit implications (see Table 1).7 Understanding the interpretation of these two grades is essential for sagacious clinical decision-making.

Prevention of VTE in surgical patients ii

Table 1: Interpretation of strong and conditional (weak) recommendations Implications

Strong recommendation

Conditional (weak) recommendation

For patients

Most individuals in this situation would want the recommended course of action and only a small proportion would not. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences. Most individuals should receive the intervention. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator.

The majority of individuals in this situation would want the suggested course of action, but many would not.

For clinicians

For policy makers

Recognize that different choices will be appropriate for individual patients and that you must help each patient arrive at a management decision consistent with his or her values and preferences. Decision aids may be useful helping individuals making decisions consistent with their values and preferences. The recommendation can be adapted Policy making will require substantial as policy in most situations debate and involvement of various stakeholders.

Key questions I. Recommendations in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery Question 1: Should LMWH rather than no prophylaxis be used in surgical patients at low risk of VTE (e.g. Caprini score ≤ 2)? Question 2: Should unfractionated heparin rather than no prophylaxis be used in surgical patients at low risk of VTE (e.g. Caprini ≤ 2)? Question 3: Should intermittent pneumatic compression devices (IPC) rather than no prophylaxis be used in surgical patients at low risk of VTE (e.g. Caprini score ≤ 2)? Question 4: Should LMWH rather than no prophylaxis be used in surgical patients at moderate risk of VTE (e.g. Caprini score 3-4)?

Question 5: Should unfractionated heparin rather than no prophylaxis be used in surgical patients at moderate risk of VTE (e.g. Caprini score 3-4)? Question 6: Should intermittent pneumatic compression devices (IPC) rather than no prophylaxis be used in surgical patients at moderate risk of VTE (e.g. Caprini score 3-4)? Question 7: Should LMWH rather than no prophylaxis be used in surgical patients at moderate risk of VTE (e.g. Caprini score 3-4) and high risk of bleeding? Question 8: Should unfractionated heparin rather than no prophylaxis be used in surgical patients at moderate risk of VTE (e.g. Caprini score, 3-4) and high risk of bleeding? Question 9: Should intermittent pneumatic compression devices (IPC) rather than no prophylaxis be used in surgical patients at moderate risk of VTE (e.g. Caprini score 3-4) and high risk of bleeding?


Question 10: Should LMWH rather than no prophylaxis be used in surgical patients at high risk of VTE (e.g. Caprini score ≥ 5)? Question 11: Should unfractionated heparin rather than no prophylaxis be used in surgical patients at high risk of VTE (e.g. Caprini score ≥ 5)? Question 12: Should intermittent pneumatic compression devices (IPC) rather than no prophylaxis be used in surgical patients at high risk of VTE (e.g. Caprini score ≥ 5)? Question 13: Should LMWH rather than no prophylaxis be used in surgical patients at high risk of VTE (e.g. Caprini score ≥ 5) and high risk of bleeding? Question 14: Should unfractionated heparin rather than no prophylaxis be used in surgical patients at high risk of VTE (e.g. Caprini score ≥ 5) and high risk of bleeding? Question 15: Should intermittent pneumatic compression devices (IPC) rather than no prophylaxis be used in surgical patients at high risk of VTE (e.g. Caprini score ≥ 5) and high risk of bleeding? II. Recommendations in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery) Question 16: Should LMWH rather than no prophylaxis be used in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery)? Question 17: Should LMWH rather Vitamin K Antagonists (VKA) be used in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery)? Question 18: Should extended prophylaxis (up to 35 days) with LMWH rather than short-

term prophylaxis (7-14 days) be used in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery)?


Recommendations I. Recommendations in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery Recommendations 1-3: For patients undergoing general and abdominal-pelvic surgery at low risk of VTE (e.g. Caprini score ≤ 2), the panel suggests using LMWH (conditional recommendation, moderate quality evidence), unfractionated heparin (conditional recommendation, moderate quality evidence) or intermittent pneumatic compression devices (conditional recommendation, low quality evidence) rather than no prophylaxis. Recommendations 4-6: For patients undergoing general and abdominal-pelvic surgery at moderate risk of VTE (e.g. Caprini score 3-4), the panel recommends using unfractionated heparin rather than no prophylaxis (strong recommendation, moderate quality evidence), and suggests using LMWH (conditional recommendation, moderate quality evidence) or intermittent pneumatic compression devices (conditional recommendation, low quality evidence) rather than no prophylaxis. Recommendations 7-9: For patients undergoing general and abdominal-pelvic surgery at moderate risk of VTE (e.g. Caprini score 3-4) and high risk of bleeding, the panel recommends using unfractionated heparin rather than no prophylaxis (strong recommendation, moderate quality evidence), and suggests using LMWH (conditional recommendation, moderate quality evidence) or intermittent pneumatic compression devices (conditional recommendation, low quality evidence) rather than no prophylaxis. Recommendations 10-12: For patients undergoing general and abdominal-pelvic surgery at high risk of VTE (e.g. Caprini score ≥ 5), the panel recommends using LMWH (strong recommendation, moderate quality evidence)

or unfractionated heparin (strong recommendation, moderate quality evidence) rather than no prophylaxis, and suggests using intermittent pneumatic compression devices (conditional recommendation, low quality evidence) rather than no prophylaxis. Recommendations 13-15: For patients undergoing general and abdominal-pelvic surgery at high risk of VTE (e.g. Caprini score ≥ 5) and high risk of bleeding, the panel recommends using LMWH (strong recommendation, moderate quality evidence), unfractionated heparin (strong recommendation, moderate quality evidence) or intermittent pneumatic compression devices (strong recommendation, low quality evidence) rather than no prophylaxis.

II. Recommendations in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery)? Recommendation 16: In patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery), the panel suggests using LMWH rather than no prophylaxis (conditional recommendation, low quality evidence). Recommendation 17: In patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery), the panel suggests using LMWH rather than Vitamin K Antagonists (VKA) (conditional recommendation, low quality evidence). Recommendation 18: In patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery), the panel recommends extended prophylaxis (up to 35 days) with LMWH rather than short-term prophylaxis (7-14 days) (strong recommendation, moderate quality evidence).


Scope and purpose The purpose of this document is to provide guidance about the thromboprophylaxis in patients undergoing general and abdominalpelvic surgery and major orthopedic surgery. The target audience of this guideline includes general surgeons and orthopedic surgeons in the Kingdom of Saudi Arabia (KSA). Other health care professionals and policy makers may also benefit from this guideline. Given the importance of this topic, the Ministry of Health (MoH) of Saudi Arabia with the support of the McMaster University guideline working group produced practice guideline to assist health care providers in evidence-based decision-making. This practice guideline is a part of the larger initiative of the Saudi MoH to establish a program of rigorous adaptation and de novo development of guidelines in KSA; the ultimate goal being to provide guidance for clinicians and other healthcare decision makers and reduce unnecessary variability in clinical practice across the Kingdom.

Introduction Venous thromboembolism (VTE) is an important cause of death in surgical patients in the Kingdom of Saudi Arabia.1,8 Prophylaxis with low doses of anticoagulants can effectively reduce the risk of mortality, pulmonary embolism (PE) and symptomatic deep venous thrombosis (DVT). However, these interventions are not properly implemented in the Kingdom, and thromboprophylaxis is typically underused.9 Previous guidelines addressed issues around diagnosis of VTE and were produced in the first phase of this project. 10 Given the importance of this topic, the Saudi MoH with the methodological support of the McMaster University guideline working group produced practice guidelines to assist health care providers in evidence-based decisionmaking on the prevention of VTE in patients undergoing general and abdominal-pelvic

surgery and major orthopedic surgery.

Methodology To facilitate the interpretation of these guidelines; we briefly describe the methodology we used to develop and grade recommendations and quality of the supporting evidence. The Saudi expert guideline panel selected the topic of this guideline and all healthcare questions addressed herein using a formal prioritization process. For the selected questions we updated existing systematic reviews, several conducted for the 9th edition of the Antithrombotic Guidelines (AT9).2,3 For each question, the McMaster guideline working group updated the search strategy to identify new studies and/or new systematic reviews. When relevant, the meta-analyses were updated. We also conducted systematic searches for information that was required to develop full guidelines for the KSA, including searches for information about patients’ values and preferences, and costs and resource use specific to the Saudi context (see Appendix 2). Next, we developed for each question an evidence profile and an evidence-to-decision (EtD) table following the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and shared them with the panel members (see Appendix 1).4,11 The guideline panel was invited to provide additional information, particularly when published evidence was lacking. The final step consisted of an in-person meeting of the guideline panel in Riyadh on March or 17 & 18, 2015 to formulate the final recommendations. We used the GRADE evidence-todecision frameworks to follow a structured consensus process and transparently document all decisions made during the meeting. Given the absence of evidence for several of the EtD criteria discussion of the panel was held to come to consensus (e.g. on drug prices and resource requirements) or reverted to indirect evidence from other settings. Poten-


tial conflicts of interests of all panel members were managed according to the World Health Organization (WHO) rules.5 Grading of the quality of evidence The GRADE working group defines the quality of evidence as the extent of our confidence that the estimate of an effect is adequate to support a particular decision or recommendation.6 We assessed the quality of evidence using the GRADE approach. Quality of evidence is classified as “high”, “moderate”, “low”, or “very low” based on decisions about methodological characteristics of the available evidence for a specific health care problem. The definition of each category is as follows:  





High: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Very low: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

Grading of the strength of recommendations The GRADE working group defines the strength of recommendation as the extent to which we can be confident that desirable effects of an intervention outweigh undesirable effects. According to the GRADE approach, the strength of a recommendation is either strong or conditional (also known as or called weak) and has explicit implications.7 Understanding the interpretation of these two grades – either strong or conditional – of the strength of recommendations is essential for sagacious clinical decision-making (see Table 1).

As a quality measure prior to publication, the final report has been externally peer reviewed by a methodological expert who has not been involved in this guideline development.

How to use these guidelines The MoH of Saudi Arabia and McMaster University Practice Guidelines provide clinicians and their patients with a basis for rational decisions about the thromboprophylaxis in patients undergoing general and abdominalpelvic surgery and major orthopedic surgery. Clinicians, patients, third-party payers, institutional review committees, other stakeholders, or the courts should never view these recommendations as dictates. As described in other guidelines following the GRADE approach, no guideline or recommendation can take into account all of the often-compelling unique features of individual clinical circumstances. Therefore, no one charged with evaluating clinicians’ actions should attempt to apply the recommendations from these guidelines by rote or in a blanket fashion. Statements about the underlying values and preferences, resources, feasibility, equity, acceptability as well as other qualifying remarks accompanying each recommendation are its integral parts and serve to facilitate an accurate interpretation. They should never be omitted when quoting or translating recommendations from these guidelines if they influence the strength or direction of the recommendation. The guideline panel did not specify doses for medications in its recommendations as they differ by product. The reader should base dosing on product specific doses and factors that require dose adjustments (e.g. renal insufficiency, etc).


Key questions The following is a list of the clinical questions selected by the Saudi expert panel and addressed in this guideline. I. Recommendations in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery Question 1: Should LMWH rather than no prophylaxis be used in surgical patients at low risk of VTE (e.g. Caprini score ≤ 2)? Question 2: Should unfractionated heparin rather than no prophylaxis be used in surgical patients at low risk of VTE (e.g. Caprini ≤ 2)? Question 3: Should intermittent pneumatic compression devices (IPC) rather than no prophylaxis be used in surgical patients at low risk of VTE (e.g. Caprini score ≤ 2)? Question 4: Should LMWH rather than no prophylaxis be used in surgical patients at moderate risk of VTE (e.g. Caprini score 3-4)? Question 5: Should unfractionated heparin rather than no prophylaxis be used in surgical patients at moderate risk of VTE (e.g. Caprini score 3-4)? Question 6: Should intermittent pneumatic compression devices (IPC) rather than no prophylaxis be used in surgical patients at moderate risk of VTE (e.g. Caprini score 3-4)? Question 7: Should LMWH rather than no prophylaxis be used in surgical patients at moderate risk of VTE (e.g. Caprini score 3-4) and high risk of bleeding? Question 8: Should unfractionated heparin rather than no prophylaxis be used in surgical patients at moderate risk of VTE (e.g. Caprini score, 3-4) and high risk of bleeding? Question 9: Should intermittent pneumatic compression devices (IPC) rather than no

prophylaxis be used in surgical patients at moderate risk of VTE (e.g. Caprini score 3-4) and high risk of bleeding? Question 10: Should LMWH rather than no prophylaxis be used in surgical patients at high risk of VTE (e.g. Caprini score ≥ 5)? Question 11: Should unfractionated heparin rather than no prophylaxis be used in surgical patients at high risk of VTE (e.g. Caprini score ≥ 5)? Question 12: Should intermittent pneumatic compression devices (IPC) rather than no prophylaxis be used in surgical patients at high risk of VTE (e.g. Caprini score ≥ 5)? Question 13: Should LMWH rather than no prophylaxis be used in surgical patients at high risk of VTE (e.g. Caprini score ≥ 5) and high risk of bleeding? Question 14: Should unfractionated heparin rather than no prophylaxis be used in surgical patients at high risk of VTE (e.g. Caprini score ≥ 5) and high risk of bleeding? Question 15: Should intermittent pneumatic compression devices (IPC) rather than no prophylaxis be used in surgical patients at high risk of VTE (e.g. Caprini score ≥ 5) and high risk of bleeding? II. Recommendations in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery)? Question 16: Should LMWH rather than no prophylaxis be used in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery)? Question 17: Should LMWH rather Vitamin K Antagonists (VKA) be used in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery)?


Question 18: Should extended prophylaxis (up to 35 days) with LMWH rather than shortterm prophylaxis (7-14 days) be used in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery)?

Recommendations I. Recommendations in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery Risk stratification The recommendations for general and abdominal-pelvic surgery presented in this guideline are categorized by the risk of VTE and the risk of bleeding. Risk of VTE

The Caprini score provides a relatively simple model to estimate the risk of VTE by adding points for various VTE risk factors (table 2).12 This model has been validated in samples of general, vascular, and urological surgery patients.13 For the purpose of this guideline, we have categorized patients in 3 groups: low risk of VTE (Caprini score ≤ 2); moderate risk of VTE (Caprini score 3-4); and high risk if VTE (Caprini score ≥ 5) Risk of bleeding There is no formal model to identify patients at high risk for thromboprophylaxis-related bleeding in general or abdominal-pelvic surgery. General risk factors for bleeding complications are described in the table 3, however, this list is not exhaustive and clinicians should evaluate risk of bleeding considering the specific patient’s circumstances.

Table 2: The Caprini score is shown here and adapted from reference 12 1 point

2 points

3 points

5 points

❑ Age 41-60 years ❑ BMI > 25 Kg/m2 ❑ Minor surgery ❑ Edema in the lower extremities ❑ Varicose veins ❑ Sepsis (in the previous month) ❑ Serious lung disease such as pneumonia (in the previous month) ❑ Abnormal pulmonary function test ❑ Acute myocardial infarction ❑ Congestive heart failure (in the previous month) ❑ Bed rest ❑ Inflammatory bowel disease For women only: ❑ Pregnancy ❑ Post-partum ❑ Oral contraceptive ❑ Hormonal therapy ❑ Unexplained or recurrent abortion

❑ Age: 61-74 years ❑ Arthroscopic surgery ❑ Laparoscopy lasting more than 45 minutes ❑ General surgery lasting more than 45 minutes ❑ Cancer ❑ Plaster cast ❑ Bed bound for more than 72 hours ❑ Central venous access

❑ Age≥ 75 years ❑ Prior episodes of VTE ❑ Positive family history for VTE ❑ Prothrombin 20210 A ❑ Factor V Leiden ❑ Lupus anticoagulants ❑ Anticardiolipin antibodies ❑ High homocysteine in the blood ❑ Heparin induced thrombocytopenia ❑ Other congenital or acquired thrombophilia

❑ Stroke (in the previous month) ❑ Fracture of the hip, pelvis, or leg ❑ Elective arthroplasty ❑ Acute spinal cord injury (in the previous month)


Table 3: General risk factors for bleeding complications3 Evidence of active bleeding Previous major bleeding Known, untreated bleeding disorder Severe renal or hepatic failure Thrombocytopenia Acute stroke Uncontrolled systemic hypertension Lumbar puncture, epidural, or spinal anesthesia within previous 4 h or next 12 h Concomitant use of anticoagulants, antiplatelet therapy, or thrombolytic drugs

Values and Preferences: A recent systematic review14 found 3 studies evaluating the disutility associated with VTE prophylaxis. None of these studies was conducted in surgical patients. We identified no new studies in our values and preferences literature search and no evidence specific to the KSA healthcare setting. The results of the 3 studies suggested that the disutility associated with one episode of DVT was greater, on average, than the disutility associated with bleeding. The panel recognized that values and preferences probably do not vary substantially among patients in the KSA.

Question 1: Should LMWH rather than no prophylaxis be used in surgical patients in patients at low risk of VTE (e.g. Caprini score ≤ 2)? Summary of Findings: We updated a metaanalysis of 7 randomized trials, but found no new studies. The overall quality of evidence was judged as moderate. Benefits of the Option: The use of LMWH rather than no prophylaxis in patients at low risk of VTE probably produces 1 fewer fatal PE per 1000 patients (95% CI from 2 to 0 fewer; moderate quality evidence) and 10 fewer symptomatic VTEs per 1000 patients (95% CI from 13 to 3 fewer; moderate quality evidence).

Harms of the Option: In patients at low risk of bleeding, the use of LMWH rather than no prophylaxis leads to 12 more non-fatal major bleeding events (95% CI from 4 to 23 more; high quality evidence). The risk of fatal bleeding could not be estimated due to absence of events in the identified trials. However, this probably reflects a very low risk of fatal bleeding in patients using LMWH. Acceptability: It was considered that the use of LMWH is likely acceptable, since adverse effects are infrequent and the intervention is used for a limited period of time. Feasibility: No obvious barriers were identified regarding implementation of LMWH. The intervention is generally available. Resource Use: LMWH is a relatively cheap intervention, costing around 5$ (USD) per patients day. This incremental cost was considered probably small relative to the net benefit. Balance between desirable and undesirable consequences: The panel considered that the desirable consequences probably outweigh undesirable consequences in most settings for patients at low risk of VTE. This recommendation places more value in the reduction of mortality (1 fewer events per 1000 patients) and symptomatic VTE events (10 fewer events per 1000 patients; 95% CI from 13 to 3 fewer; moderate quality evidence) rather than in the


risk of bleeding (12 more non-fatal major bleeding events; 95% CI from 4 to 23 more; high quality evidence) or cost.

Question 2: Should unfractionated heparin rather than no prophylaxis be used in surgical patients in patients at low risk of VTE (e.g. Caprini ≤ 2)? Summary of Findings: We updated a systematic review and meta-analysis of 44 randomized trials, but identified no new studies. The overall quality of evidence was judged as moderate. Benefits of the Option: The use of unfractionated heparin rather than no prophylaxis in patients at low risk of VTE reduces the risk of fatal PE in 1 fewer event per 1000 patients (95% CI from 2 to 0 fewer; high quality evidence) and probably produces 8 fewer symptomatic VTEs per 1000 patients (95% CI from 10 to 5 fewer; moderate quality evidence). Harms of the Option: In patients at low risk of bleeding using unfractionated heparin, the risk of fatal bleeding seems to be the same than in patients not using the intervention. However, the 95% CI includes the possibility of an increase of 2 events per 1000 patients (moderate quality evidence). Also, unfractionated heparin probably increases the risk of non-fatal major bleeding in 7 events per 1000 patients (95% CI from 4 to 10 more; moderate quality evidence) Acceptability: The use of unfractionated heparin is likely acceptable, since adverse effects are infrequent and the intervention is used for a limited period of time. Feasibility: The panel did not identify any barriers regarding implementation of unfractionated heparin. The intervention is generally available in the KSA setting. Resource Use: The updated systematic review did not identify any literature relevant to cost in the KSA setting. Indirect cost was not con-

sidered. The panel discussed the price of unfractionated heparin as ranging from $8 to $10 USD per day. The panel recognized that additional resources required for implementation would be for nursing staff and time. Balance between desirable and undesirable consequences: The panel considered that the desirable consequences probably outweigh undesirable consequences in most settings for patients at low risk of VTE. This recommendation places more value in the reduction of symptomatic VTE events (8 fewer symptomatic VTEs per 1000 patients; 95% CI from 10 to 5 fewer; moderate quality evidence) rather than in the risk of bleeding (7 more events per 1000 patients; 95% CI from 4 to 10 more; moderate quality evidence) or cost. Question 3: Should intermittent pneumatic compression devices (IPC) rather than no prophylaxis be used in surgical patients in patients at low risk of VTE (e.g. Caprini score ≤ 2)? Summary of Findings: We updated a systematic review and meta-analysis that included 9 randomized trials. We found no additional trials in the update of the literature search. The overall quality of evidence was judged as low. Benefits of the Option: The use of intermittent pneumatic compression devices (IPC) rather than no prophylaxis in patients at low risk of VTE may reduce the risk of symptomatic VTE in 8 fewer events per 1000 patients (95% CI from 12 to 4 fewer; low quality evidence) Harms of the Option: Although not reported in the identified trials, the use of IPC has been associated with the incidence of skin lesions such as skin breaks, blisters, ulcers and necrosis. IPC may be less effective than other alternatives: A meta-analysis of 8 trials (a total of 3134 participants) comparing LMWH vs. mechanical prophylaxis found low quality evidence suggesting an increased risk of symp-


tomatic VTE with IPC (RR 1.8; 95% CI 1.16 to 2.79).3

be used to estimate patients’ risk of VTE. The Caprini score is an example of such tools.

Acceptability: The use of IPC is likely acceptable; however variability was noted among the panelists.

Research Priorities: Studies assessing local data are needed in order to define the KSA population’s VTE baseline risk.

Feasibility: Intermittent pneumatic compression devices might not be available in some settings or hospitals. Nurses and other health care professionals will require training on how to apply the devices.

Question 4: Should LMWH rather than no prophylaxis be used in surgical patients in patients at moderate risk of VTE (e.g. Caprini score 3-4)?

Resource Use: The updated systematic review did not identify any literature relevant to IPC cost in the KSA setting. IPC costs are not exactly known in KSA. The consumables are about $50 USD per patient, but there are several other indirect costs. Mechanical prophylaxis seems to be less effective than pharmacological prophylaxis. Therefore, it may not be the most cost-effective alternative. Balance between desirable and undesirable consequences: The panel considered that the desirable consequences probably outweigh undesirable consequences in most settings for patients at low risk of VTE. This recommendation places more value in the reduction of symptomatic VTE events (8 fewer events per 1000 patients; 95% CI from 12 to 4 fewer; low quality evidence) rather than in the risk of skin lesions or cost.

Recommendations 1-3: For patients undergoing general and abdominal-pelvic surgery at low risk of VTE (e.g. Caprini score ≤ 2), the panel suggests using LMWH (conditional recommendation, moderate quality evidence), unfractionated heparin (conditional recommendation, moderate quality evidence) or intermittent pneumatic compression devices (conditional recommendation, low quality evidence) rather than no prophylaxis. Implementation Considerations and Monitoring: Appropriate stratification tools have to

Summary of Findings: We updated a systematic review and meta-analysis that included 7 randomized trials. We found no additional trials in the update of the literature search. The overall quality of evidence was judged as moderate. Benefits of the Option: The use of LMWH rather than no prophylaxis in patients at moderate risk of VTE probably leads to 3 fewer fatal PEs per 1000 patients (95% CI from 4 fewer to 1 more; moderate quality evidence) and 21 fewer non-fatal symptomatic VTEs per 1000 patients (95% CI from 26 to 6 fewer; moderate quality evidence). Harms of the Option: In patients at low risk of bleeding, the use of LMWH rather than no prophylaxis produces 12 more non-fatal major bleeds (95% CI from 4 to 23 more; high quality evidence). The risk of fatal bleeding could not be estimated due to absence of events in the identified trials. However, this probably reflects a very low risk of fatal bleeding in patients using LMWH. Acceptability: It was considered that the use of LMWH is likely acceptable, since adverse effects are infrequent and the intervention is used for a limited period of time Feasibility: No obvious barriers were identified regarding implementation of LMWH. The intervention is generally available. Resource Use: LMWH is a relatively cheap intervention, costing around 5$ (USD) per patients day. This incremental cost was con-


sidered probably small relative to the net benefit. Balance between desirable and undesirable consequences: The panel considered that the desirable consequences probably outweigh undesirable consequences in most settings for patients at moderate risk of VTE. This recommendation places more value in the reduction fatal PEs (3 fewer fatal PEs per 1000 patients; 95% CI from 4 fewer to 1 more; moderate quality evidence) and of symptomatic VTE events (21 fewer non-fatal symptomatic VTEs per 1000 patients; 95% CI from 26 to 6 fewer; moderate quality evidence)) rather than in the risk of bleeding (12 more non-fatal major bleeding events; 95% CI from 4 to 23 more; high quality evidence) or cost.

Question 5: Should unfractionated heparin rather than no prophylaxis be used in surgical patients in patients at moderate risk of VTE (e.g. Caprini score 3-4)? Summary of Findings: We updated a systematic review and meta-analysis that included 44 randomized trials. We found no additional trials in the update of the literature search. The overall quality of evidence was judged as moderate. Benefits of the Option: The use of unfractionated heparin rather than no prophylaxis in patients at moderate risk of VTE decreases the risk of fatal PE in 3 fewer events per 1000 patients (95% CI from 4 to 1 fewer; high quality evidence) and probably reduces the risk of non-fatal symptomatic VTE in 17 fewer events per 1000 patients (95% CI from 21 to 11 fewer; moderate quality evidence). Harms of the Option: In patients at low risk of bleeding using unfractionated heparin, the risk of fatal bleeding seems to be the same than in patients not using the intervention. However, the 95% CI includes the possibility of an increase of 2 events per 1000 patients (moderate quality evidence). Also, unfractionated heparin probably increases the risk of

non-fatal major bleeding in 7 events per 1000 patients (95% CI from 4 to 10 more; moderate quality evidence) Acceptability: The use of unfractionated heparin is likely acceptable, since adverse effects are infrequent and the intervention is used for a limited period of time. Feasibility: The panel did not identify any barriers regarding implementation of unfractionated heparin. The intervention is generally available in the KSA setting. Resource Use: The updated systematic review did not identify any literature relevant to cost in the KSA setting. Indirect cost was not considered. The panel suggested and discussed the price of unfractionated heparin as ranging from $8 to $10 USD per day. The panel recognized that additional resources required for implementation would be for nursing staff and time. Balance between desirable and undesirable consequences: The panel considered that the desirable consequences clearly outweigh undesirable consequences in all or almost all settings for patients at moderate risk of VTE. This recommendation places more value in the reduction of fatal PE (3 fewer events per 1000 patients; 95% CI from 4 to 1 fewer; high quality evidence) and symptomatic VTE events (17 fewer events per 1000 patients; 95% CI from 21 to 11 fewer; moderate quality evidence) rather than in the risk of bleeding (7 more events per 1000 patients; 95% CI from 4 to 10 more; moderate quality evidence) or cost.

Question 6: Should intermittent pneumatic compression devices (IPC) rather than no prophylaxis be used in surgical patients in patients at moderate risk of VTE (e.g. Caprini score 3-4)? Summary of Findings: We updated a systematic review and meta-analysis that included 9 randomized trials. We found no additional


trials in the update of the literature search. The overall quality of evidence was judged as low.

tomatic VTEs per 1000 patients; 95% CI from 23 to 8 fewer; low quality evidence) rather than in the risk of skin lesions or cost.

Benefits of the Option: The use of intermittent pneumatic compression devices (IPC) rather than no prophylaxis in patients at moderate risk of VTE may produce 15 fewer symptomatic VTEs per 1000 patients (95% CI from 23 to 8 fewer; low quality evidence)

Recommendations 4-6: For patients undergoing general and abdominal-pelvic surgery at moderate risk of VTE (e.g. Caprini score 3-4), the panel recommends using unfractionated heparin rather than no prophylaxis (strong recommendation, moderate quality evidence), and suggests using LMWH (conditional recommendation, moderate quality evidence) or intermittent pneumatic compression devices (conditional recommendation, low quality evidence) rather than no prophylaxis.

Harms of the Option: Although not reported in the identified trials, the use of IPC has been associated with the incidence of skin lesions such as skin breaks, blisters, ulcers and necrosis. IPC may be less effective than other alternatives: A meta-analysis of 8 trials (a total of 3134 participants) comparing LMWH vs. mechanical prophylaxis found low quality evidence suggesting an increased risk of symptomatic VTE with IPC (RR 1.8; 95% CI 1.16 to 2.79).3

Implementation Considerations and Monitoring: Appropriate stratification tools have to be used to estimate patients’ risk of VTE, as for example the Caprini score.

Acceptability: The use of IPC is likely acceptable; however variability was noted among the panelists.

Research Priorities: Studies assessing local data are needed in order to define the KSA population’s VTE baseline risk.

Feasibility: Intermittent pneumatic compression devices might not be available in some settings or hospitals. Nurses and other health care professionals will require training on how to apply the devices.

Question 7: Should LMWH rather than no prophylaxis be used in surgical patients in patients at moderate risk of VTE (e.g. Caprini score 3-4) and high risk of bleeding?

Resource Use: The updated systematic review did not identify any literature relevant to cost in the KSA setting. IPC costs are not exactly known in KSA. The consumables are about $50 USD per patient, but there are several other indirect costs. Mechanical prophylaxis seems to be less effective than pharmacological prophylaxis. Therefore, it may not be the most cost-effective alternative. Balance between desirable and undesirable consequences: The panel considered that the desirable consequences probably outweigh undesirable consequences in most settings for patients at moderate risk of VTE. This recommendation places more value in the reduction of symptomatic VTE events (15 fewer symp-

Summary of Findings: We updated a systematic review and meta-analysis that included 7 randomized trials. We found no additional trials in the update of the literature search. The overall quality of evidence was judged as moderate. Benefits of the Option: The use of LMWH rather than no prophylaxis in patients at moderate risk of VTE probably reduces the risk of fatal PEs in 3 fewer events per 1000 patients (95% CI from 4 fewer to 1 more; moderate quality evidence) and the risk of non-fatal symptomatic VTEs in 21 fewer events per 1000 patients (95% CI from 26 to 6 fewer; moderate quality evidence).


Harms of the Option: In patients at high risk of bleeding, the use of LMWH rather than no prophylaxis increases the risk of non-fatal major bleeding in 22 more events per 1000 (95% CI from 8 to 41 more; high quality evidence). The risk of fatal bleeding could not be estimated due to absence of events in the identified trials. However, this probably reflects a very low risk of fatal bleeding in patients using LMWH. Acceptability: It was considered that the use of LMWH is likely acceptable, since adverse effects are infrequent and the intervention is used for a limited period of time Feasibility: no obvious barriers were identified regarding implementation of LMWH. The intervention is generally available. Resource Use: LMWH is a relatively cheap intervention, costing around 5$ (USD) per patients day. This incremental cost was considered probably small relative to the net benefit. Balance between desirable and undesirable consequences: The panel considered that the desirable consequences probably outweigh undesirable consequences in most settings for patients at moderate risk of VTE and high risk of bleeding. This recommendation places more value in the reduction fatal PEs (3 fewer fatal PEs per 1000 patients; 95% CI from 4 fewer to 1 more; moderate quality evidence) and of symptomatic VTE events (21 fewer non-fatal symptomatic VTEs per 1000 patients; 95% CI from 26 to 6 fewer; moderate quality evidence) rather than in the risk of bleeding (22 more events per 1000; 95% CI from 8 to 41 more; high quality evidence) or cost. Question 8: Should unfractionated heparin rather than no prophylaxis be used in surgical patients in patients at moderate risk of VTE (e.g. Caprini score, 3-4) and high risk of bleeding?

Summary of Findings: We updated a systematic review and meta-analysis that included 44 randomized trials. We found no additional trials in the update of the literature search. The overall quality of evidence was judged as moderate. Benefits of the Option: The use of unfractionated heparin rather than no prophylaxis in patients at moderate risk of VTE produces 3 fewer fatal PEs per 1000 patients (95% CI from 4 to 1 fewer; high quality evidence) and probably reduces the risk of non-fatal symptomatic VTE in 17 fewer events per 1000 patients (95% CI from 21 to 11 fewer; moderate quality evidence). Harms of the Option: In patients at high risk of bleeding using unfractionated heparin, the risk of fatal bleeding seems to be the same than in patients not using the intervention. However, the 95% CI includes the possibility of an increase of 6 events per 1000 patients (moderate quality evidence). Also, unfractionated heparin probably increases the risk of non-fatal major bleeding in 12 events per 1000 patients (95% CI from 7 to 18 more; moderate quality evidence) Acceptability: The use of unfractionated heparin is likely acceptable, since adverse effects are infrequent and the intervention is used for a limited period of time. Feasibility: The panel did not identify any barriers regarding implementation of unfractionated heparin. The intervention is generally available in the KSA setting. Resource Use: Our systematic review did not identify any literature relevant to cost in the KSA setting. Indirect cost was not considered. Panel discussed the price of unfractionated heparin as ranging from $8 to $10 USD per day. The panel recognized that additional resources required for implementation would be for nursing staff and time. Balance between desirable and undesirable consequences: The panel considered that the


desirable consequences clearly outweigh undesirable consequences in all or almost all the settings for patients at moderate risk of VTE and high risk of bleeding. This recommendation places more value in the reduction of fatal PE (3 fewer events per 1000 patients; 95% CI from 4 to 1 fewer; high quality evidence) and symptomatic VTE events (17 fewer events per 1000 patients; 95% CI from 21 to 11 fewer; moderate quality evidence) rather than in the risk of bleeding (12 events per 1000 patients; 95% CI from 7 to 18 more; moderate quality evidence) or cost.

Question 9: Should intermittent pneumatic compression devices (IPC) rather than no prophylaxis be used in surgical patients in patients at moderate risk of VTE (e.g. Caprini score 3-4) and high risk of bleeding? Summary of Findings: We updated a systematic review and meta-analysis that included 9 randomized trials. We found no additional trials in the update of the literature search. The overall quality of evidence was judged as low. Benefits of the Option: The use of intermittent pneumatic compression devices (IPC) rather than no prophylaxis in patients at moderate risk of VTE may lead to 15 fewer symptomatic VTE events per 1000 patients (95% CI from 23 to 8 fewer; low quality evidence) Harms of the Option: Although not reported in the identified trials, the use of IPC has been associated with the incidence of skin lesions such as skin breaks, blisters, ulcers and necrosis. IPC may be less effective than other alternatives: A meta-analysis of 8 trials (a total of 3134 participants) comparing LMWH vs. mechanical prophylaxis found low quality evidence suggesting an increased risk of symptomatic VTE with IPC (RR 1.8; 95% CI 1.16 to 2.79).3

Acceptability: The use of IPC is likely acceptable; however variability was noted among the panelists. Feasibility: Intermittent pneumatic compression devices might not be available in some settings or hospitals. Nurses and other health care professionals will require training on how to apply the devices. Resource Use: Our systematic review did not identify any literature relevant to cost in the KSA setting. IPC costs are not exactly known in KSA. The consumables are about $50 USD per patient, but there are several other indirect costs. Mechanical prophylaxis seems to be less effective than pharmacological prophylaxis. Therefore, it may not be the most costeffective alternative. Balance between desirable and undesirable consequences: The panel considered that the desirable consequences probably outweigh undesirable consequences in most settings for patients at moderate risk of VTE and high risk of bleeding. This recommendation places more value in the reduction of symptomatic VTE events (15 fewer symptomatic VTEs per 1000 patients; 95% CI from 23 to 8 fewer; low quality evidence) rather than in the risk of skin lesions or cost. Recommendations 7-9: For patients undergoing general and abdominal-pelvic surgery at moderate risk of VTE (e.g. Caprini score 3-4) and high risk of bleeding, the panel recommends using unfractionated heparin rather than no prophylaxis (strong recommendation, moderate quality evidence), and suggests using LMWH (conditional recommendation, moderate quality evidence) or intermittent pneumatic compression devices (conditional recommendation, low quality evidence) rather than no prophylaxis. Implementation Considerations and Monitoring: Appropriate stratification tools have


to be used to estimate patients’ risk of VTE, as for example the Caprini score. Research Priorities: Studies assessing local data are needed in order to define the KSA population’s VTE baseline risk Question 10: Should LMWH rather than no prophylaxis be used in surgical patients in patients at high risk of VTE (e.g. Caprini score ≥ 5)? Summary of Findings: We updated a systematic review and meta-analysis that included 7 randomized trials. We found no additional trials in the update of the literature search. The overall quality of evidence was judged as moderate. Benefits of the Option: The use of LMWH rather than no prophylaxis in patients at high risk of VTE probably decrease the risk of fatal PE in 5 fewer events per 1000 patients (95% CI from 9 fewer to 1 more; moderate quality evidence) and the risk of non-fatal symptomatic VTE in 41 fewer events per 1000 patients (95% CI from 58 to 11 fewer; moderate quality evidence). Harms of the Option: In patients at low risk of bleeding, the use of LMWH rather than no prophylaxis produces 12 more non-fatal major bleeds (95% CI from 4 to 23 more; high quality evidence). The risk of fatal bleeding could not be estimated due to absence of events in the identified trials. However, this probably reflects a very low risk of fatal bleeding in patients using LMWH. Acceptability: It was considered that the use of LMWH is likely acceptable, since adverse effects are infrequent and the intervention is used for a limited period of time. Feasibility: No obvious barriers were identified regarding implementation of LMWH. The intervention is generally available.

Resource Use: indirect evidence coming from high-risk patients in orthopaedic surgery suggests that the use of LMWH is cost effective compared to aspirin (ICER 1,200-7,200 USD per VTE avoided, in standard 10 days prophylaxis regimen)15 Balance between desirable and undesirable consequences: The panel considered that the desirable consequences clearly outweigh undesirable consequences in all or almost all the settings for patients at high risk of VTE. This recommendation places more value in the reduction fatal PEs (5 fewer events per 1000 patients; 95% CI from 9 fewer to 1 more; moderate quality evidence) and of symptomatic VTE events (41 fewer events per 1000 patients; 95% CI from 58 to 11 fewer; moderate quality evidence) rather than in the risk of bleeding (12 more non-fatal major bleeds; 95% CI from 4 to 23 more; high quality evidence) or cost. Question 11: Should unfractionated heparin rather than no prophylaxis be used in surgical patients in patients at high risk of VTE (e.g. Caprini score ≥ 5)? Summary of Findings: We updated a systematic review and meta-analysis that included 44 randomized trials. We found no additional trials in the update of the literature search. The overall quality of evidence was judged as moderate. Benefits of the Option: The use of unfractionated heparin rather than no prophylaxis in patients at high risk of VTE leads to 6 fewer fatal PEs per 1000 patients (95% CI from 8 to 1 fewer; high quality evidence) and probably to 33 fewer non-fatal symptomatic VTE events per 1000 patients (95% CI from 41 to 21 fewer; moderate quality evidence). Harms of the Option: In patients at low risk of bleeding using unfractionated heparin, the risk of fatal bleeding seems to be the same than in patients not using the intervention. However, the 95% CI includes the possibility of an increase of 2 events per 1000 patients


(moderate quality evidence). Also, unfractionated heparin probably increases the risk of non-fatal major bleeding in 7 events per 1000 patients (95% CI from 4 to 10 more; moderate quality evidence) Acceptability: The use of unfractionated heparin is likely acceptable, since adverse effects are infrequent and the intervention is used for a limited period of time. Feasibility: The panel did not identify any barriers regarding implementation of unfractionated heparin. The intervention is generally available in the KSA setting. Resource Use: Our systematic review did not identify any literature relevant to cost in the KSA setting. Indirect cost was not considered. Panel discussed the price of unfractionated heparin as ranging from $8 to $10 USD per day. The panel recognized that additional resources required for implementation would be for nursing staff and time. Balance between desirable and undesirable consequences: The panel considered that the desirable consequences clearly outweigh undesirable consequences in all or almost all the settings for patients at high risk of VTE. This recommendation places more value in the reduction of fatal PEs (6 events per 1000 patients; 95% CI from 8 to 1 fewer; high quality evidence) and symptomatic VTE events (33 fewer non-fatal symptomatic VTE events per 1000 patients (95% CI from 41 to 21 fewer; moderate quality evidence) rather than in the risk of bleeding (7 more non-fatal major bleedings per 1000 patients; 95% CI from 4 to 10 more; moderate quality evidence) or cost.

Question 12: Should intermittent pneumatic compression devices (IPC) rather than no prophylaxis be used in surgical patients in patients at high risk of VTE (e.g. Caprini score ≥ 5)? Summary of Findings: We updated a systematic review and meta-analysis that included 9

randomized trials. We found no additional trials in the update of the literature search. The overall quality of evidence was judged as low. Benefits of the Option: The use of intermittent pneumatic compression devices (IPC) rather than no prophylaxis in patients at moderate risk of VTE may decrease the risk of symptomatic VTE in 30 fewer events per 1000 patients (95% CI from 46 to 15 fewer; low quality evidence) Harms of the Option: Although not reported in the identified trials, the use of IPC has been associated with the incidence of skin lesions such as skin breaks, blisters, ulcers and necrosis. IPC may be less effective than other alternatives: A meta-analysis of 8 trials (a total of 3134 participants) comparing LMWH vs. mechanical prophylaxis found low quality evidence suggesting an increased risk of symptomatic VTE with IPC (RR 1.8; 95% CI 1.16 to 2.79).3 Acceptability: The use of IPC is likely acceptable; however variability was noted among the panelists. Feasibility: Intermittent pneumatic compression devices might not be available in some settings or hospitals. Nurses and other health care professionals will require training on how to apply the devices. Resource Use: Our systematic review did not identify any literature relevant to cost in the KSA setting. IPC costs are not exactly known in KSA. The consumables are about $50 USD per patient, but there are several other indirect costs. Mechanical prophylaxis seems to be less effective than pharmacological prophylaxis. Therefore, it may not be the most costeffective alternative. Balance between desirable and undesirable consequences: The panel considered that the desirable consequences probably outweigh undesirable consequences in most settings for patients at moderate risk of VTE. This recom-


mendation places more value in the reduction of symptomatic VTE events (30 fewer events per 1000 patients; 95% CI from 46 to 15 fewer; low quality evidence) rather than in the risk of skin lesions or cost. Recommendations 10-12: For patients undergoing general and abdominal-pelvic surgery at high risk of VTE (e.g. Caprini score ≥ 5), the panel recommends using LMWH (strong recommendation, moderate quality evidence) or unfractionated heparin (strong recommendation, moderate quality evidence) rather than no prophylaxis, and suggests using intermittent pneumatic compression devices (conditional recommendation, low quality evidence) rather than no prophylaxis. Implementation Considerations and Monitoring: Appropriate stratification tools have to be used to estimate patients’ risk of VTE, as for example the Caprini score. Research Priorities: Studies assessing local data are needed in order to define the KSA population’s VTE baseline risk.

Question 13: Should LMWH rather than no prophylaxis be used in surgical patients in patients at high risk of VTE (e.g. Caprini score ≥ 5) and high risk of bleeding? Summary of Findings: We updated a systematic review and meta-analysis that included 7 randomized trials. We found no additional trials in the update of the literature search. The overall quality of evidence was judged as moderate. Benefits of the Option: The use of LMWH rather than no prophylaxis in patients at high risk of VTE probably leads to 5 fewer fatal PEs per 1000 patients (95% CI from 9 fewer to 1 more; moderate quality evidence) and probably to 41 fewer non-fatal symptomatic VTE events per 1000 patients (95% CI from 58 to 11 fewer; moderate quality evidence).

Harms of the Option: In patients at high risk of bleeding, the use of LMWH rather than no prophylaxis increases the risk of non-fatal major bleeding in 22 more events per 1000 (95% CI from 8 to 41 more; high quality evidence). The risk of fatal bleeding could not be estimated due to absence of events in the identified trials. However, this probably reflects a very low risk of fatal bleeding in patients using LMWH. Acceptability: It was considered that the use of LMWH is likely acceptable, since adverse effects are infrequent and the intervention is used for a limited period of time. Feasibility: No obvious barriers were identified regarding implementation of LMWH. The intervention is generally available. Resource Use: Indirect evidence coming from high-risk patients in orthopaedic surgery suggests that the use of LMWH is cost effective compared to aspirin (ICER 1,200-7,200 USD per VTE avoided, in standard 10 days prophylaxis regimen).15 Balance between desirable and undesirable consequences: The panel considered that the desirable consequences clearly outweigh undesirable consequences in all or almost all the settings for patients at high risk of VTE and high risk of bleeding. This recommendation places more value in the reduction fatal PEs (5 fewer events per 1000 patients; 95% CI from 9 fewer to 1 more; moderate quality evidence) and of symptomatic VTE events (41 fewer events per 1000 patients; 95% CI from 58 to 11 fewer; moderate quality evidence) rather than in the risk of bleeding (22 more events per 1000; 95% CI from 8 to 41 more; high quality evidence) or cost.


Question 14: Should unfractionated heparin rather than no prophylaxis be used in surgical patients in patients at high risk of VTE (e.g. Caprini score ≥ 5) and high risk of bleeding? Summary of Findings: We updated a systematic review and meta-analysis that included 44 randomized trials. We found no additional trials in the update of the literature search. The overall quality of evidence was judged as moderate. Benefits of the Option: The use of unfractionated heparin rather than no prophylaxis in patients at high risk of VTE leads to 6 fewer fatal PEs per 1000 patients (95% CI from 8 to 1 fewer; high quality evidence) and probably to 33 fewer non-fatal symptomatic VTE events per 1000 patients (95% CI from 41 to 21 fewer; moderate quality evidence). Harms of the Option: In patients at high risk of bleeding using unfractionated heparin, the risk of fatal bleeding seems to be the same than in patients not using the intervention. However, the 95% CI includes the possibility of an increase of 6 events per 1000 patients (moderate quality evidence). Also, unfractionated heparin probably increases the risk of non-fatal major bleeding in 12 events per 1000 patients (95% CI from 7 to 18 more; moderate quality evidence) Acceptability: The use of unfractionated heparin is likely acceptable, since adverse effects are infrequent and the intervention is used for a limited period of time. Feasibility: The panel did not identify any barriers regarding implementation of unfractionated heparin. The intervention is generally available in the KSA setting. Resource Use: Our systematic review did not identify any literature relevant to cost in the KSA setting. Indirect cost was not considered. Panel discussed the price of unfractionated heparin as ranging from $8 to $10 USD per day. The panel recognized that additional

resources required for implementation would be for nursing staff and time. Balance between desirable and undesirable consequences: The panel considered that the desirable consequences clearly outweigh undesirable consequences in all or almost all the settings for patients at high risk of VTE and high risk of bleeding. This recommendation places more value in the reduction of fatal PEs (6 events per 1000 patients; 95% CI from 8 to 1 fewer; high quality evidence) and symptomatic VTE events (33 fewer non-fatal symptomatic VTE events per 1000 patients (95% CI from 41 to 21 fewer; moderate quality evidence) rather than in the risk of bleeding in 12 events per 1000 patients (95% CI from 7 to 18 more; moderate quality evidence) or cost. Question 15: Should intermittent pneumatic compression devices (IPC) rather than no prophylaxis be used in surgical patients in patients at high risk of VTE (e.g. Caprini score ≥ 5) and high risk of bleeding? Summary of Findings: We updated a systematic review and meta-analysis that included 9 randomized trials. We found no additional trials in the update of the literature search. The overall quality of evidence was judged as low. Benefits of the Option: The use of intermittent pneumatic compression devices (IPC) rather than no prophylaxis in patients at moderate risk of VTE may lead to 30 fewer symptomatic VTE events per 1000 patients (95% CI from 46 to 15 fewer; low quality evidence) Harms of the Option: Although not reported in the identified trials, the use of IPC has been associated with the incidence of skin lesions such as skin breaks, blisters, ulcers and necrosis. IPC may be less effective than other alternatives: A meta-analysis of 8 trials (a total of 3134 participants) comparing LMWH vs. mechanical prophylaxis found low quality evidence suggesting an increased risk of symp-


tomatic VTE with IPC (RR 1.8; 95% CI 1.16 to 2.79).3 Acceptability: The use of IPC is likely acceptable; however variability was noted among the panelists. Feasibility: Intermittent pneumatic compression devices might not be available in some settings or hospitals. Nurses and other health care professionals will require training on how to apply the devices. Resource Use: Our systematic review did not identify any literature relevant to cost in the KSA setting. IPC costs are not exactly known in KSA. The consumables are about $50 USD per patient, but there are several other indirect costs. Mechanical prophylaxis seems to be less effective than pharmacological prophylaxis. Therefore, it may not be the most costeffective alternative. Balance between desirable and undesirable consequences: The panel considered that the desirable consequences clearly outweigh undesirable consequences in all or almost all the settings for patients at high risk of VTE and high risk of bleeding. This recommendation places more value in the reduction of symptomatic VTE events (30 fewer events per 1000 patients; 95% CI from 46 to 15 fewer; low quality evidence) rather than in the risk of skin lesions or cost. Also, IPC may be a good alternative for when the high risk of bleeding precludes the use of LMWH or unfractionated heparin. Recommendations 13-15: For patients undergoing general and abdominal-pelvic surgery at high risk of VTE (e.g. Caprini score ≥ 5) and high risk of bleeding, the panel recommends using LMWH (strong recommendation, moderate quality evidence), unfractionated heparin (strong recommendation, moderate quality evidence) or intermittent pneumatic compression devices (strong recommendation, low quality evidence) rather than no prophylaxis.

Implementation Considerations and Monitoring: Appropriate stratification tools have to be used to estimate patients’ risk of VTE, as for example the Caprini score. Research Priorities: Studies assessing local data are needed in order to define the KSA population’s VTE baseline risk. II. Recommendations in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery)? Values and Preferences: A recent systematic review14 found 3 studies evaluating the disutility associated with VTE prophylaxis. None of these studies was conducted in surgical patients. We identified no new studies in our values and preferences literature search and no evidence specific to the KSA healthcare setting. The results of the 3 studies suggested that the disutility associated with one episode of DVT was greater, on average, than the disutility associated with bleeding. The panel recognized that values and preferences probably do not vary substantially Question 16: Should LMWH rather than no prophylaxis be used in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery)? Summary of Findings: We updated a systematic review and meta-analysis that included 14 randomized trials. We found no additional trials in the update of the literature search. The overall quality of evidence was judged as low. Benefits of the Option: The use of LMWH rather than no prophylaxis in patients undergoing major orthopedic surgery probably reduces the risk of mortality (1 fewer event per 1000 patients; 95% CI from 10 fewer to 23 more; moderate quality evidence), the risk of non-fatal pulmonary embolism (4 fewer events per 1000 patients; 95% CI from 8 fewer


to 5 more; moderate quality evidence) and the risk of symptomatic DVT (9 fewer events per 1000 patients; 95% CI from 10 to 7 fewer; moderate quality evidence). Harms of the Option: In patients undergoing major orthopedic surgery using LMWH, the risk of major bleeding seems to be the same than in patients not using the intervention. However, the 95% CI includes the possibility of an increase of 11 events per 1000 patients (low quality evidence). Acceptability: It was considered that the use of LMWH is likely acceptable, since adverse effects are infrequent and the intervention is used for a limited period of time. Feasibility: No obvious barriers were identified regarding implementation of LMWH. The intervention is generally available. Resource Use: Indirect evidence coming from high-risk patients in orthopaedic surgery suggests that the use of LMWH is cost effective compared to aspirin (ICER 1,200-7,200 USD per VTE avoided, in standard 10 days prophylaxis regimen)15 Balance between desirable and undesirable consequences: The panel considered that the desirable consequences probably outweigh undesirable consequences in most settings for patients undergoing major orthopedic surgery. This recommendation places more value in the reduction of non-fatal pulmonary embolism (4 fewer events per 1000 patients; 95% CI from 8 fewer to 5 more; moderate quality evidence) and of the risk of symptomatic DVT (9 fewer events per 1000 patients; 95% CI from 10 to 7 fewer; moderate quality evidence) rather than the potential increment of the risk of bleeding or cost.

Recommendation 16: In patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery), the panel suggests using LMWH rather than no prophylaxis (conditional recommendation, low quality evidence). Implementation Considerations and Monitoring:  Although LMWH has an easy administration, clinicians must ensure that patients who are discharged with LMWH receive appropriate information and education about the selfadministration of the injectable medication.  Clinicians should look carefully at the risk of bleeding in patients elective to surgery, paying special attention in elderly patients.  It is difficult to assess the risk of bleeding in trauma patients due to the urgent nature of the intervention. Research Priorities: Further research studies are needed to evaluate the effectiveness in patients at different risk strata.

Question 17: Should LMWH rather Vitamin K Antagonists (VKA) be used in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery)? Summary of Findings: We updated a systematic review and meta-analysis that included 8 randomized trials. We found no additional trials in the update of the literature search. The overall quality of evidence was judged as low. Benefits of the Option: The use of LMWH rather than VKA in patients undergoing major orthopedic surgery probably leads to 1 fewer death per 1000 patients (95% CI from 2 fewer to 2 more; moderate quality evidence) and 1


fewer non-fatal pulmonary embolism per 1000 patients (95% CI from 2 fewer to 2 more; moderate quality evidence). Also LMWH may decrease the risk of symptomatic DVT in 2 fewer events per 1000 patients (95% CI from 2 to 1 fewer; low quality evidence) Harms of the Option: In patients undergoing major orthopedic surgery, the use of LMWH rather than VKA may increase the risk of major bleeding in 4 more events per 1000 patients (95% CI from 1 fewer to 11 more; low quality evidence) Values and Preferences: The use of VKA involves changes in diet and lifestyle that patient may want to avoid. LMWH, on the other hand, requires daily injections. Acceptability: Although LMWH requires daily injections, it was considered that its use is likely more acceptable for patients, since adverse effects are infrequent and the intervention is used for a limited period of time. The use of Vitamin K Antagonists requires laboratory monitoring and more disruptive life-style changes. Feasibility: It was considered that both interventions are generally available. However given that Vitamin K Antagonists require follow-up and laboratory monitoring, it might not be feasible to implement them in some places. No obvious barriers were identified regarding implementation of LMWH. Resource Use: The evidence from economic evaluations is inconsistent. In some studies the use of LMWH is cost-effective, while in other Vitamin K Antagonists dominate. This large variability may be explained in part due to differences in the assumptions regarding the indirect costs of the intervention. In the KSA setting, Vitamin K Antagonists cost around 12 USD per month (including the cost of the drug and INR measurement). 10-days regimen of LMWH cost around 50 USD; nevertheless, the use of Vitamin K Antagonists probably implies a higher net cost due to the follow-up and laboratory monitoring required.

Balance between desirable and undesirable consequences: The panel considered that the desirable consequences probably outweigh undesirable consequences in most settings for patients undergoing major orthopedic surgery. This recommendation places more value in the potential reduction of symptomatic DVTs with LMWH (2 fewer events per 1000 patients; 95% CI from 2 to 1 fewer; low quality evidence) rather than in the potential increment of the risk of bleeding (4 more events per 1000 patients; 95% CI from 1 fewer to 11 more; low quality evidence) Recommendation 17: In patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery), the panel suggests using LMWH rather than Vitamin K Antagonists (VKA) (conditional recommendation, low quality evidence). Implementation Considerations and Monitoring:  Although LMWH has an easy administration, clinicians must ensure that patients who are discharged with LMWH receive appropriate information and education about the selfadministration of the injectable medication.  Clinicians must ensure that patients who are discharged with vitamin K antagonist receive appropriate information regarding the importance of strict compliance and the need of follow-up and INR monitoring. Research Priorities:  Cost effectiveness studies in the KSA setting  Studies that compare LMWH with new anticoagulant oral medications


Question 18: Should extended prophylaxis (up to 35 days) with LMWH rather than short-term prophylaxis (7-14 days) be used in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery)? Summary of Findings: We updated a systematic review and meta-analysis that included 8 randomized trials. We found 4 additional trials in the update of the literature search. The overall quality of evidence was judged as moderate. Benefits of the Option: Extended prophylaxis (up to 35 days) with LMWH probably avoids 1 death per 1000 patients (95% CI from 2 fewer to 3 more; moderate quality evidence) in comparison to short-term prophylaxis (7-14 days). Also, on contemporary populations (current surgical techniques, early mobilization, etc.) extended prophylaxis probably leads to 3 fewer non-fatal PEs (95% CI from 4 fewer to 0 more; moderate quality evidence) and 5 fewer symptomatic DVT events (95% CI from 7 to 3 fewer; high quality evidence).

Feasibility: No obvious barriers were identified regarding implementation of the different schemes of LMWH. Resource Use: The evidence from economic evaluations is somewhat inconsistent. However, extended prophylaxis with LMWH appears to be cost-effective compared with short duration therapy.15 Balance between desirable and undesirable consequences: The panel considered that the desirable consequences probably outweigh undesirable consequences in all or almost all the settings for patients undergoing major orthopedic surgery. This recommendation places more value in the potential reduction of non-fatal PEs (3 fewer non-fatal PEs; 95% CI from 4 fewer to 0 more; moderate quality evidence) and of symptomatic DVT events (5 fewer events; 95% CI from 7 to 3 fewer; high quality evidence) rather than in the potential increment of the risk of bleeding or cost. Recommendation 18:

Harms of the Option: The use of extended prophylaxis with LMWH in patients undergoing major orthopedic surgery does not seem to increase the risk of bleeding. However, the 95% CI includes the possibility of an increment of 5 bleeds per 1000 patients (moderate quality evidence).

In patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery), the panel recommends extended prophylaxis (up to 35 days) with LMWH rather than shortterm prophylaxis (7-14 days) (strong recommendation, moderate quality evidence).

Acceptability: It was considered that the use of LMWH is likely acceptable, since adverse effects are infrequent. Nevertheless it should be noted that extended prophylaxis may not be acceptable for some patients and that some physicians are reluctant to prescribe injections for long time.

Implementation Considerations and Monitoring: Clinicians must ensure that patients receive appropriate information and education about the self-administration of the injectable medication in order to improve the adherence to the treatment.


References 1. Essam AE, Sharif G, Al-Hameed F. Venous thromboembolism-related mortality and morbidity in King Fahd General Hospital, Jeddah, Kingdom of Saudi Arabia. Annals of thoracic medicine 2011;6:193-8. 2. 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:e278S-325S. 3. Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e227S-77S. 4. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ (Clinical research ed) 2008;336:924-6. 5. WHO Handbook for Guideline Development. World Health Organization, 2012. (Accessed February 7, 2014, at http://apps.who.int/iris/bitstream/10665/75146/1/9789241548441_eng.pdf.) 6. Balshem H, Helfand M, Schunemann HJ, et al. GRADE guidelines: 3. Rating the quality of evidence. Journal of clinical epidemiology 2011;64:401-6. 7. Andrews J, Guyatt G, Oxman AD, et al. GRADE guidelines: 14. Going from evidence to recommendations: the significance and presentation of recommendations. Journal of clinical epidemiology 2013;66:719-25. 8. Abo-El-nazar Y, F. Al-Hameed, et al. Prevalence of Venous Thrombo-Embolism & Related Morbidity and Mortality among hospitalized patients in Saudi Arabia (SAVTE Registry).". JOURNAL OF THROMBOSIS AND HAEMOSTASIS 2013;11:Abstract. 9. Rehmani RS, Memon JI, Alaithan A, et al. Venous thromboembolism risk and prophylaxis in a Saudi hospital. Saudi medical journal 2011;32:1149-54. 10.Al-Hameed F, Al-Dorzi HM, Shamy A, et al. The Saudi clinical practice guideline for the diagnosis of the first deep venous thrombosis of the lower extremity. Annals of thoracic medicine 2015;10:3-15. 11.Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. Journal of clinical epidemiology 2011;64:383-94. 12.Caprini JA, Arcelus JI, Hasty JH, Tamhane AC, Fabrega F. Clinical assessment of venous thromboembolic risk in surgical patients. Seminars in thrombosis and hemostasis 1991;17 Suppl 3:304-12. 13.Bahl V, Hu HM, Henke PK, Wakefield TW, Campbell DA, Jr., Caprini JA. A validation study of a retrospective venous thromboembolism risk scoring method. Annals of surgery 2010;251:344-50. 14.MacLean S, Mulla S, Akl EA, et al. Patient values and preferences in decision making for antithrombotic therapy: a systematic review: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e1S-23S. 15.Kapoor A, Chuang W, Radhakrishnan N, et al. Cost effectiveness of venous thromboembolism pharmacological prophylaxis in total hip and knee replacement: a systematic review. PharmacoEconomics 2010;28:521-38.


Appendices 1. Appendix 1: Evidence-to-Decision Frameworks 2. Appendix 2: Search Strategies and Results


Appendix 1: Evidence to Decision Frameworks Evidence to Decision Framework 1: LMWH compared to no prophylaxis in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery Criteria

Problem

Judgements

○ No ○ Probably no ○ Uncertain Is there a problem priority? ○ Probably yes ● Yes ○ Varies

What is the overall certainty of this evidence?

Research evidence No specific information about the risk of VTE in Saudi context has been identified.

Additional considerations VTE is a frequent medical complication on surgical patients. Priority might differ because the event risks are different for low, moderate or high-risk populations.

○ No included studies ○ Very low ○ Low ● Moderate ○ High The benefit of the intervention varies with the baseline risk for VTE (low, moderate or high risk)

Benefits & harms of the options

Is there important uncertainty about how much people value the main outcomes?

Are the desirable anticipated effects large?

○ Important uncertainty or variability ○ Possibly important uncertainty or variability ● Probably no important uncertainty of variability ○ No important uncertainty of variability ○ No known undesirable Low risk of VTE ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies Moderate risk of VTE ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes

In the same way, the magnitude of the potential harm varies with the baseline risk for bleeding.


Criteria

Judgements

Research evidence

Additional considerations

○ Varies High risk of VTE ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies Low risk of bleeding ○ No ● Probably no ○ Uncertain ○ Probably yes ○ Yes ○ Varies Are the undesirable anticipated effects small?

Are the desirable effects large relative to undesirable effects?

High risk of bleeding ○ No ● Probably no ○ Uncertain ○ Probably yes ○ Yes ○ Varies Low risk of VTE ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies Moderate risk of VTE ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies Moderate risk of VTE / High risk of bleeding

A recent systematic review (MacLean et al.) found 3 studies evaluating the disutility associated with VTE prophylaxis. None of these studies was conducted in surgical patients. The results suggested that the disutility associated with one episode of DVT was greater, on average, than the disutility associated with bleeding

The panel judged that most patients in the KSA setting would value these outcomes similarly.


Criteria

Judgements

Research evidence


○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies High risk of VTE ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies High risk of VTE / High risk of bleeding ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies

Are the resources required small?

Resource use Is the incremental cost small relative to the net benefits?

○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies

Indirect evidence: In high risk patients (e.g. orthopedic surgery) the use of LMWH is cost effective compared to aspirin (ICER 1200-7200 USD per VTE avoided)

Low risk of VTE ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies

No information specific to Saudi context has been identified.

Moderate risk of VTE ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes

The cost of LMWH in the KSA setting is approximate 50 USD per patient (standard 10-days regimen)


Criteria

Judgements

Research evidence


○ Varies Moderate risk of VTE / High risk of bleeding ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies High risk of VTE ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies High risk of VTE / High risk of bleeding ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies

Equity

Acceptability

Feasibility


What would be the impact on health inequities?

○ Increased ○ Probably increased ○ Uncertain ● Probably reduced ○ Reduced ○ Varies

Likely not relevant, since cost is relatively low.


Is the option acceptable to key stakeholders?


The use of LMWH is likely acceptable, since adverse effects are infrequent and the intervention is used for a limited period of time.


Is the option feasible to implement?


No obvious barriers regarding implementation identified. The intervention is generally available.


Evidence profile: LMWH compared to no prophylaxis in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery Author(s): I Neumann, I. Etxeandia, R. Morgan, H Schünemann Question: LMWH compared to no prophylaxis in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery (1.1 Low Risk VTE) Setting: Kingdom of Saudi Arabia Health System Bibliography: 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:e278S-325S. Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e227S-77S. Quality assessment № of studies

Study design

Risk of bias

Inconsistency

№ of patients Indirectness

Imprecision

not serious

serious

Other considerations

LMWH

Effect

no prophylaxis

Quality

Relative (95% CI)

Absolute (95% CI)

OR 0.54 (0.27 to 1.10)

1 fewer per 1000 (from 0 fewer to 2 fewer)

⨁⨁⨁ ◯ MODERATE

Importance

Fatal Pulmonary Embolism (follow up: range 7-270 days to) 1 5

randomised trials

not serious

not serious

2

none

11/2553 (0.4%)

0.3%

3

0.6%

3

3 fewer per 1000 (from 1 more to 4 fewer)

1.2%

3


CRITICAL

2

Fatal bleeding (follow up: range 21-270 days to) 4

randomised trials

not serious

not serious

not serious

not serious

none

4

0.1%

⨁⨁⨁⨁

not estimable

CRITICAL

HIGH

0.2% Nonfatal symptomatic VTE (follow up: range 21-270 days to) 3

randomised trials

serious

5

not serious

not serious

not serious

none

5/611 (0.8%)


⨁⨁⨁ ◯

6


MODERATE

6.0%

6


1.2%

7

1.5%

6

3.0%

OR 0.31 (0.12 to 0.81)

CRITICAL

5

Nonfatal major bleeding (follow up: range 7-270 days to) 7

randomised trials

not serious

not serious

not serious

not serious

none

39/670 (5.8%)

2.2%

7

OR 2.03 (1.37 to 3.01)

12 more per 1000 (from 4 more to 23 more) 22 more per 1000 (from 8 more to 41 more)

⨁⨁⨁⨁ HIGH

CRITICAL


MD – mean difference, RR – relative risk

Explanations 1. 2. 3. 4. 5. 6. 7.

Inferred from all-cause mortality The 95% CI includes the possibility of both no effect and substantial benefit. Pooled risk of death from any cause was 24 of 2,589 (0.9%) in the control groups. Risk of fatal PE in low-, moderate-, and high-VTE risk groups was calculated under the assumption that the ratio of death from any cause to symptomatic VTE did not vary across risk categories. No events recorded in 5078 patient in either group One study was not blinded, and one study had unclear concealment of allocation sequence; nonfatal symptomatic VTE was not objectively confirmed in one large study. Baseline risk of VTE in moderate-, high-, and very-high-risk patients after adjustment for prophylaxis received. Data from Bahl et al. In low-risk patients, rate of symptomatic VTE was 0%. In seven studies of LMWH vs no prophylaxis in abdominal surgery (Mismetti et al), the weighted pooled (random-effects model) risk of major bleeding in the control groups was 1.2%. In 36 studies of LMWH vs unfractionated heparin in abdominal surgery, the pooled risk of major bleeding in the unfractionated heparin groups was 3.2% but was only 2.7% in noncancer surgery and 8.1% in cancer surgery. After adjustment for prophylaxis, the risks for noncancer and cancer surgery were 1.7% and 5.1%, respectively. In a more-recent comparison of LMWH vs fondaparinux, the risk of bleeding requiring reoperation or intervention was 1.0% in the LMWH group. In a secondary analysis of RCT data (Cohen et al), the odds of major bleeding were 1.8 times greater in patients with cancer.


Recommendation 1 – Low risk for VTE Should LMWH vs. no prophylaxis be used in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery? Balance of consequences

Undesirable consequences clearly outweigh desirable consequences in most settings

Undesirable consequences probably outweigh desirable consequences in most settings

The balance between desirable and undesirable consequences is closely balanced or uncertain

Desirable consequences probably outweigh undesirable consequences in most settings

Desirable consequences clearly outweigh undesirable consequences in most settings

○

○

○

●

○

Type of recommendation

We recommend against offering this option

We suggest not offering this option

We suggest offering this option

We recommend offering this option

○

○

●

○

Recommendation

For patients undergoing general and abdominal-pelvic surgery at low risk of VTE (e.g. Caprini score ≤ 2), the panel suggests using LMWH rather than no prophylaxis (conditional recommendation, moderate quality evidence)

Justification

Voting: Consequences closely balanced/Uncertain – 2; Desirable consequences probably outweigh undesirable consequences– 4; Desirable consequences clearly outweigh undesirable consequences - 1

Subgroup considerations

This recommendation is unlikely to apply to patients who are undergoing bariatric surgery

Implementation considerations

Appropriate stratification tools have to be used to estimate patients’ risk of VTE, as for example the Caprini score.

Monitoring and evaluation

None

Research possibilities

Studies assessing local data are needed in order to define the KSA population’s VTE baseline risk


Recommendation 4 – Moderate risk for VTE Should LMWH vs. no prophylaxis be used in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery? Balance of consequences






○

○

○

●

○






○

○

●

○

Recommendation

For patients undergoing general and abdominal-pelvic surgery at moderate risk of VTE (e.g. Caprini score 3-4), the panel suggests using LMWH rather than no prophylaxis (conditional recommendation, moderate quality evidence)

Justification

Voting: Consequences Closely balanced/Uncertain – 2; Desirable consequences probably outweigh undesirable consequences – 4; Desirable consequences clearly outweigh undesirable consequences - 1






None




Recommendation 7 – Moderate risk for VTE / High risk of bleeding Should LMWH vs. no prophylaxis be used in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery? Balance of consequences






○

○

○

●

○






○

○

●

○

Recommendation

For patients undergoing general and abdominal-pelvic surgery at moderate risk of VTE (e.g. Caprini score 3-4) and high risk of bleeding, the panel suggests using LMWH rather than no prophylaxis (conditional recommendation, moderate quality evidence)

Justification

Voting: Consequences closely balanced/Uncertain – 2; Desirable consequences probably outweigh undesirable consequences– 4; Desirable consequences clearly outweigh undesirable consequences - 1





Monitoring and evaluation None Research possibilities


Recommendation 10 – High risk for VTE


Should LMWH vs. no prophylaxis be used in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery? Balance of consequences






○

○

○

○

●






○

○

○

●

Recommendation

For patients undergoing general and abdominal-pelvic surgery at high risk of VTE (e.g. Caprini score ≥ 5), the panel recommends using LMWH rather than no prophylaxis (strong recommendation, moderate quality evidence)

Justification

Voting: Desirable consequences probably outweigh undesirable consequences – 1; Desirable consequences clearly outweigh undesirable consequences - 6






None



Recommendation 13 – High risk for VTE / High risk of bleeding


Should LMWH vs. no prophylaxis be used in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery? Balance of consequences






○

○

○

○

●






○

○

○

●

Recommendation

For patients undergoing general and abdominal-pelvic surgery at high risk of VTE (e.g. Caprini score ≥ 5) and high risk of bleeding, the panel recommends using LMWH rather than no prophylaxis (strong recommendation, moderate quality evidence)

Justification

Voting: Desirable consequences probably outweigh undesirable consequences – 1; Desirable consequences clearly outweigh undesirable consequences - 6






None



Evidence to Decision Framework 2: Unfractionated Heparin compared to no prophylaxis in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery


Criteria

Problem

Judgements



Is there important uncertainty about how much people value the main outcomes?


Additional considerations VTE is a frequent medical complication on surgical patients. Therefore, this problem is likely a priority.

○ No included studies ○ Very low ○ Low ● Moderate ○ High

○ Important uncertainty or variability ○ Possibly important uncertainty or variability ● Probably no important uncertainty of variability ○ No important uncertainty of variability ○ No known undesirable Low risk of VTE ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies

Benefits & harms of the options


Moderate risk of VTE ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies High risk of VTE ○ No ○ Probably no ○ Uncertain

The panel judged that most patients in the KSA setting would


Criteria

Judgements ○ Probably yes ● Yes ○ Varies

Are the undesirable anticipated effects small?

Low risk of bleeding ○ No ● Probably no ○ Uncertain ○ Probably yes ○ Yes ○ Varies High risk of bleeding ○ No ● Probably no ○ Uncertain ○ Probably yes ○ Yes ○ Varies Low risk of VTE ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies


Moderate risk of VTE ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies Moderate risk of VTE / High risk of bleeding ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies

Research evidence

Additional considerations value these outcomes similarly



Criteria

Judgements

Research evidence


High risk of VTE ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies High risk of VTE / High risk of bleeding ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies


Resource use Is the incremental cost small relative to the net benefits?


No specific information about the risk of VTE in Saudi context has been identified.

Panel discussed the price of unfractionated heparin: $8 to 10 per day. Additional resources are required for nursing staff.

Low risk of VTE ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies

No specific information about the risk of VTE in Saudi context has been identified. Indirect evidence suggests that VTE prophylaxis is likely cost-effective in high-risk patients.

The panel noted that there is residual uncertainty.

Moderate risk of VTE ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies Moderate risk of VTE / High risk of bleeding ○ No ○ Probably no ○ Uncertain


Criteria

Judgements

Research evidence


● Probably yes ○ Yes ○ Varies High risk of VTE ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies High risk of VTE / High risk of bleeding ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies

Equity

Acceptability

Feasibility




○ Increased ○ Probably increased ○ Uncertain ○ Probably reduced ● Reduced ○ Varies




The use of unfractionated heparin is likely acceptable, since adverse effects are infrequent and the intervention is used for a limited period of time.




No obvious barriers regarding implementation identified. The intervention is generally available


Evidence profile: Unfractionated Heparin compared to no prophylaxis in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery Author(s): Neumann, I. Etxeandia, R. Morgan, H. Schünemann Date: Question: Unfractionated heparin compared to no prophylaxis in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery Setting: Kingdom of Saudi Arabia Health System Bibliography: 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:e278S-325S. Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e227S-77S. Quality assessment № of studies

Study design

№ of patients

Risk of bias

Inconsistency

Indirectness

Imprecision

not serious

not serious

not serious

not serious


unfractionated heparin

Effect no prophylaxis

Relative (95% CI)

Absolute (95% CI)

Quality

Importance

Fatal Pulmonary Embolism 20

randomised trials

none

19/6809 (0.3%)

0.3%

1

OR 0.53 (0.31 to 0.91)

2


0.6%

1


1.2%

1


0.1%

4

⨁⨁⨁⨁

CRITICAL

HIGH

Fatal bleeding 7

randomised trials

Nonfatal symptomatic VTE 22

not serious

not serious

not serious

serious

3

none

7/6703 (0.1%)

0.2%

4

1.5%

9

OR 1.14 (0.41 to 3.15)

2

0 fewer per 1000 (from 1 fewer to 2 more)

⨁⨁⨁◯ MODERATE

CRITICAL

3


5

randomised trials

serious

6

not serious

7

not serious

not serious

none

8

OR 0.44 (0.31 to 0.63)

2


3.0%

9


6.0%

9


1.2%

11


CRITICAL

67

Nonfatal major bleeding 10 44

randomised trials

serious

6

not serious

not serious

not serious

none

388/6524 (5.9%)

2.2%

11

OR 1.57 (1.32 to 1.87)

7 more per 1000 (from 4 more to 10 more) 12 more per 1000 (from 7 more to 18 more)


6

CRITICAL



Explanations 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Pooled risk of fatal PE was 55 of 6,683 (0.8%) in the control groups. Risk of fatal PE in low-, moderate-, and high-risk groups calculated under the assumption that the ratio of PE to fatal PE did not vary across risk categories. Relative risk estimates based on reanalysis of data reported in meta-analysis by Collins et al, using a random-effects statistical model. Duration of follow-up varied, but usually to hospital discharge. Pooled effect includes possibility of both substantial benefit and serious harm. Pooled risk of fatal bleeding was 0.1% in the control groups. Risk of fatal bleeding in low- and high-risk groups calculated under the assumption that the ratio of clinically important bleeding to fatal bleeding did not vary across risk categories. Inferred from nonfatal PE Many studies were not blinded, and allocation concealment was not adequately described. There was mild heterogeneity across surgical specialties. OR for nonfatal PE was 0.44 (95% CI, 0.31-0.63) in 22 trials of general surgery, 0.29 (95% CI, 0.03-2.24) in two trials of urological surgery and 4.66 (95% CI, 0.53-40.8) in two trials of orthopedic trauma. No events in intervention group and 5.1% of patients with events in control group from a total population of 12,698 patients included in 22 studies Baseline risk of VTE in moderate-, high-, and very-high-risk patients, after adjustment for prophylaxis received. Data from Bahl et al. In low-risk patients, rate of symptomatic VTE was 0%. Inferred from excessive intraoperative bleeding or need for transfusion In seven studies of LMWH vs no prophylaxis in abdominal surgery (Mismetti et al), the weighted pooled (random-effects model) risk of major bleeding in the control groups was 1.2%. In 36 studies of LMWH vs unfractionated heparin in abdominal surgery, the pooled risk of major bleeding in the unfractionated heparain groups was 3.2%, including 2.7% of patients without cancer and 8.1% of patients with cancer. After adjustment for prophylaxis, the risks for noncancer and cancer surgery were 1.7% and 5.1%, respectively. In a more-recent comparison of LMWH vs fondaparinux, the risk of bleeding requiring reoperation or intervention was 1.0% in the LMWH group (Agnelli et al). In a secondary analysis of RCT data (Cohen et al), the odds of major bleeding were 1.8 times greater in patients with cancer.


Recommendation 2 – Low risk for VTE Should unfractionated heparin vs. no prophylaxis be used in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery? Balance of consequences






○

○

○

●

○






○

○

●

○

Recommendation

For patients undergoing to general and abdominal-pelvic surgery at low risk of VTE (e.g. Caprini score ≤ 2), the panel suggests using unfractionated heparin rather than no prophylaxis (conditional recommendation, moderate quality evidence)

Justification

Voting: Consequences closely balanced/Uncertain – 1; Desirable consequences probably outweigh undesirable consequences– 5


None




Evaluation of major bleeding events




Recommendation 5 – Moderate risk for VTE Should unfractionated heparin vs. no prophylaxis be used in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery? Balance of consequences






○

○

○

○

●






○

○

○

●

Recommendation

For patients undergoing general and abdominal-pelvic surgery at moderate risk of VTE (e.g. Caprini score 3-4), the panel recommends using unfractionated heparin rather than no prophylaxis (strong recommendation, moderate quality evidence)

Justification

Balance of benefits and harms clear.


None








Recommendation 8 – Moderate risk for VTE / High risk of bleeding Should unfractionated heparin vs. no prophylaxis be used in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery? Balance of consequences






○

○

○

○

●






○

○

○

●

Recommendation

For patients undergoing general and abdominal-pelvic surgery at moderate risk of VTE (e.g. Caprini score 3-4) and high risk of bleeding, the panel recommends using unfractionated heparin rather than no prophylaxis (strong recommendation, moderate quality evidence)

Justification


Subgroup considerations None Implementation considerations







Recommendation 11 – High risk for VTE Should unfractionated heparin vs. no prophylaxis be used in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery? Balance of consequences






○

○

○

○

●






○

○

○

●

Recommendation

For patients undergoing general and abdominal-pelvic surgery at high risk of VTE (e.g. Caprini score ≥ 5), the panel recommends using unfractionated heparin rather than no prophylaxis (strong recommendation, moderate quality evidence)

Justification



None

Implementation consideraAppropriate stratification tools have to be used to estimate patients’ risk of VTE, as for example the Caprini score. tions Monitoring and evaluation





Recommendation 14 – High risk for VTE / High risk of bleeding Should unfractionated heparin vs. no prophylaxis be used in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery? Balance of consequences






○

○

○

○

●






○

○

○

●

Recommendation

For patients undergoing general and abdominal-pelvic surgery at high risk of VTE (e.g. Caprini score ≥ 5) and high risk of bleeding, the panel recommends using unfractionated heparin rather than no prophylaxis (strong recommendation, moderate quality evidence)

Justification



None







Evidence to Decision Framework 3: Intermittent pneumatic compression (IPC) compared to no prophylaxis in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery


Criteria

Problem

Judgements

○ No ○ Probably no ○ Uncertain Is there a problem priority? ○ Probably yes ○ Yes ● Varies


Is there important uncertainty about how much people value the main outcomes? Benefits & harms of the options

○ No included studies ○ Very low ● Low ○ Moderate ○ High

○ Important uncertainty or variability ○ Possibly important uncertainty or variability ● Probably no important uncertainty of variability ○ No important uncertainty of variability ○ No known undesirable Low risk of VTE ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies


Moderate risk of VTE ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies High risk of VTE


Additional considerations VTE is a frequent medical complication on surgical patients. Therefore, this problem is likely a priority Some panel members thought that the intervention has less relevance compared with LMWH.


Criteria

Judgements

Research evidence


○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies


○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies Low risk of VTE ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies



Moderate risk of VTE ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies High risk of VTE ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies

Resource use




IPC cost is not exactly known in KSA. The consumables are about $50 USD per patient. However, there are other indirect costs. Mechanical prophylaxis seems to


Criteria

Equity

Acceptability

Feasibility

Judgements

Research evidence



Is the incremental cost small relative to the net benefits?


be less effective than pharmacological prophylaxis. Therefore, it may not be the most costeffective alternative.



○ Increased ● Probably increased ○ Uncertain ○ Probably reduced ○ Reduced ○ Varies

IPCs may not be available for patients in rural areas, since distribution of devices may not be guaranteed and maintenance of devices/service is questionable.




The panel noted variability around acceptance by patients.



○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies

Intermittent pneumatic compression devices might not be available in some places. Nurses and other health care professionals will require training on how to use the devices


Evidence profiles: Intermittent pneumatic compression (IPC) compared to no prophylaxis in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery Author(s): Neumann, I. Etxeandia, R. Morgan, H. Schünemann Question: Intermittent pneumatic compression devices (IPC) compared to no prophylaxis in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery Setting: Kingdom of Saudi Arabia Health System Bibliography: 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:e278S-325S. Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e227S-77S. Quality assessment № of studies

Study design

№ of patients

Risk of bias

Inconsistency

Indirectness

Imprecision


serious

not serious

serious

not serious

none

Effect

intermittent pneumatic compression devices (IPC)

no prophylaxis

45/755 (6.0%)

1.5%

Relative (95% CI)

Absolute (95% CI)

OR 0.48 (0.22 to 0.74)


Quality

Importance

⨁⨁◯◯

CRITICAL

Symptomatic VTE 1 9

randomised trials

2

3

3.0%


6.0%


LOW

23

Skin breaks, blisters, ulcers, necrosis - not reported -

-

-

-

-

-

-


Explanations 1. 2. 3.

Inferred from proximal DVT Unblinded assessment of DVT in most studies Relative risk estimate based on surrogate outcome of uncertain relationship to symptomatic VTE

-

see comment

not estimable

see comment

-

CRITICAL


Additional Evidence profile: Mechanical prophylaxis compared to LMWH in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery Author(s): Neumann, I. Etxeandia, R. Morgan, H. Schünemann Question: Mechanical prophylaxis compared to LMWH in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery Setting: Kingdom of Saudi Arabia Health System Bibliography: 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:e278S-325S. Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e227S-77S. Quality assessment № of studies Symptomatic VTE 8

Study design

Risk of bias

Inconsistency


Imprecision


Effect

mechanical prophylaxis

LMWH

4

0.5%

Relative (95% CI)

Absolute (95% CI)

RR 1.80 (1.16 to 2.79)

4 more per 1000 (from 1 more to 9 more)

Quality

Importance

1

randomised trials

serious

2

not serious

serious

3

not serious

none

0.9%


1.9%


⨁⨁◯◯ LOW

CRITICAL

23

Major bleeding 7

randomised trials

not serious

not serious

not serious

not serious

none

5

2.4%

RR 0.51 (0.40 to 0.64)

4.5%


⨁⨁⨁⨁

CRITICAL

⨁⨁◯◯

CRITICAL

HIGH


Skin breaks, ulcers, blisters, necrosis 1

randomised trials

serious

6

not serious

serious

7

not serious

none

16/1362 (1.2%)

5.1%

RR 0.25 (0.14 to 0.43)


Explanations 1. 2. 3. 4. 5. 6. 7.

Inferred from proximal or distal DVT Unblinded assessment of DVT in most studies Relative risk estimate based on surrogate outcome of uncertain relationship to symptomatic VTE Number of events in control group were not reported. Estimated number at risk , assuming equal numbers in intervention and control groups, with a total population of 3,134 patients Baseline risk pf bleeding estimated from control groups in trials of LMWH vs. no prophylaxis adjusted to reflect use of LMWH in all 5,457 patients. Unblinded assessment of the outcome Data from CLOTS1 study in patients with stroke and prophylaxis with graduated compression stockings


LOW

67


Recommendation 3 – Low risk for VTE IPC vs. no prophylaxis be used in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery? Balance of consequences






○

○

○

●

○






○

○

●

○

Recommendation

For patients undergoing general and abdominal-pelvic surgery at low risk of VTE (e.g. Caprini score ≤ 2), the panel suggests using intermittent pneumatic compression devices (IPC) rather than no prophylaxis (conditional recommendation, low quality evidence)

Justification

Voting: Desirable consequences probably outweigh undesirable consequences– 5; Desirable consequences clearly outweigh undesirable consequences in most settings - 1


Patients at low risk of VTE and high risk of bleeding are likely to be the subgroup benefiting most.


Ultrasound before IPC is useful to rule out DVT before applying the device. Training about use of IPC is required and distribution will require special efforts.


None


Studies assessing local data are needed in order to define the KSA population’s VTE baseline risk and effectiveness of IPC


Recommendation 6 – Moderate risk for VTE IPC vs. no prophylaxis be used in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery? Balance of consequences






○

○

○

●

○






○

○

●

○

Recommendation

For patients undergoing general and abdominal-pelvic surgery at moderate risk of VTE (e.g. Caprini score 3-4), the panel suggests using intermittent pneumatic compression devices (IPC) rather than no prophylaxis (conditional recommendation, low quality evidence)

Justification



None




None




Recommendation 9 – Moderate risk for VTE / High risk of bleeding IPC vs. no prophylaxis be used in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery? Balance of consequences






○

○

○

●

○






○

○

●

○

Recommendation

For patients undergoing general and abdominal-pelvic surgery at moderate risk of VTE (e.g. Caprini score 3-4) and high risk of bleeding, the panel suggests using intermittent pneumatic compression devices (IPC) rather than no prophylaxis (conditional recommendation, low quality evidence)

Justification



None




None




Recommendation 12 – High risk for VTE IPC vs. no prophylaxis be used in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery? Balance of consequences






○

○

○

●

○


Recommendation





○

○

●

○

For patients undergoing general and abdominal-pelvic surgery at high risk of VTE (e.g. Caprini score ≥ 5), the panel suggests using intermittent pneumatic compression devices (IPC) rather than no prophylaxis (conditional recommendation, low quality evidence) Voting: Desirable consequences probably outweigh undesirable consequences– 5; Desirable consequences clearly outweigh undesirable consequences in most settings – 1

Justification The indirect evidence comparing LMWH and IPC was considered by the panel. That created some uncertainty about the relative efficacy of IPC vs LMWH in terms of reduction of non-fatal PE. Subgroup considerations Implementation considerations

None



None




Recommendation 15 – High risk for VTE / High risk of bleeding IPC vs. no prophylaxis be used in general and abdominal-pelvic surgery, including bariatric, vascular, plastic and reconstructive surgery? Balance of consequences






○

○

○

○

●


Recommendation





○

○

○

●

For patients undergoing general and abdominal-pelvic surgery at high risk of VTE (e.g. Caprini score ≥ 5) and high risk of bleeding, the panel recommends using intermittent pneumatic compression devices (IPC) rather than no prophylaxis (strong recommendation, low quality evidence) Voting: Desirable consequences probably outweigh undesirable consequences– 1; Desirable consequences clearly outweigh undesirable consequences in most settings – 5

Justification

Subgroup considerations Implementation considerations

The indirect evidence comparing LMWH and IPC was considered by the panel. That created some uncertainty about the relative efficacy of IPC vs LMWH in terms of reduction of nonfatal PE.

None



None



Evidence to Decision Framework 4: LMWH compared to no prophylaxis in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery)


Criteria

Problem

Judgements



Is there important uncertainty about how much people value the main outcomes? Benefits & harms of the options Are the desirable anticipated effects large?





○ Important uncertainty or variability ○ Possibly important uncertainty or variability ● Probably no important uncertainty of variability ○ No important uncertainty of variability ○ No known undesirable ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies ○ No ○ Probably no ○ Uncertain


Additional considerations VTE is the most frequent medical complication in orthopedic surgical patients. Therefore, this problem is likely a priority


Criteria

Judgements

Research evidence


● Probably yes ○ Yes ○ Varies



Indirect evidence: In orthopedic surgical patients the use of LMWH is cost effective compared to aspirin (ICER 1200-7200 USD per VTE avoided)







○ Increased ○ Probably increased ○ Uncertain ● Probably reduced ○ Reduced ○ Varies




LMWH is likely acceptable, since adverse effects are infrequent and the intervention is used for a limited period.




No obvious barriers regarding implementation identified. The intervention is generally available

Resource use

Equity

Acceptability

Feasibility


Evidence profile: LMWH compared to no prophylaxis in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery) Author(s): Neumann, I. Etxeandia, R. Morgan, H. Schünemann Question: LMWH compared to no prophylaxis in major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery) Setting: Kingdom of Saudi Arabia Health System Bibliography: 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:e278S-325S. Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e227S-77S. Quality assessment № of studies

Study design

Risk of bias

Inconsistency

№ of patients

Indirectness

Imprecision


Effect

LMWH

no prophylaxis

5/488 (1.0%)

1.4%

Quality

Importance

Relative (95% CI)

Absolute (95% CI)

RR 0.90 (0.30 to 2.67)


⨁⨁⨁◯

RR 0.58 (0.22 to 1.47)


⨁⨁⨁◯

RR 0.50 (0.43 to 0.59)


⨁⨁⨁◯

RR 0.81 (0.38 to 1.72)


⨁⨁◯◯

Mortality 1 6

randomised trials

not serious

not serious

not serious

serious

none

2

MODERATE

CRITICAL

2

Nonfatal Pulmonary Embolism 11

randomised trials

Symptomatic DVT 14

not serious

not serious

not serious

serious

none

2

6/1115 (0.5%)

1.0%

3

MODERATE

CRITICAL

2

4

randomised trials

not serious

not serious

serious

4

not serious

none

282/1202 (23.5%)

1.8%

3

MODERATE

CRITICAL

4

Major nonfatal bleeding 11

randomised trials

not serious

not serious

not serious

very serious

25

none

17/1092 (1.6%)

1.5%


Explanations 1. 2. 3. 4. 5.

Deaths placebo: two from VTE, none from bleeding, one from unexplained causes, and four from other causes. Deaths LMWH: one from VTE, none from bleeding, none from unexplained causes, and four from other causes. 95% CI does not exclude substancial benefits and harms. Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc). Inferred from asymptomatic DVT Point estimate suggests an apparent reduction with LMWH

LOW

25

CRITICAL


Recommendation 16 Should LMWH compared to no prophylaxis be used patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery)? Balance of consequences






○

○

○

●

○


Recommendation





○

○

●

○

In patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery), the panel suggests using LMWH rather than no prophylaxis (conditional recommendation, low quality evidence).

Justification Subgroup considerations

Assessing the risk of bleeding in trauma patients may be challenging due to the urgent nature of the intervention


Clinicians should look carefully the risk of bleeding in patients undergoing elective surgery, paying special attention in elderly patients.


None


Further research studies are need to evaluate the effectiveness in patients at different risk strata


Evidence to Decision Framework 5: LMWH compared to Vitamin K Antagonists in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery) Criteria

Problem

Judgements






○ Important uncertainty or variability ○ Possibly important uncertainty or variability ● Probably no important uncertainty of variability ○ No important uncertainty of variability ○ No known undesirable ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies



Are the desirable effects

○ No




Criteria large relative to undesirable effects?

Acceptability

Feasibility

Research evidence


○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies




○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies







Resource use

Equity

Judgements

In the KSA setting, Vitamin K The evidence from economic evaluations is inconsistent. In some studies the use of LMWH is Antagonists cost around 12 USD cost-effective, while in other Vitamin K Antagonists dominate. per month (including the cost of This large variability may be explained in part due to differences in the assumptions regarding the the drug and INR measurement) indirect costs of the intervention. 10-days regimen of LMWH cost of approximately 50 USD Nevertheless, the use of Vitamin K Antagonists probably implies a higher net cost due to the followup and laboratory monitoring required. No specific information about the risk of VTE in Saudi context has been identified.

Likely not relevant, since direct cost of both options is relatively low.


Use of Vitamin K Antagonists requires laboratory monitoring and life-style changes. Use of LMWH requires daily injections. The panel considered that this latter option is likely more acceptable to patients.


Both interventions are generally available Given that Vitamin K Antagonists require follow-up and laboratory monitoring, it might not be feasible to implement them in some places.


Evidence profile: LMWH compared to Vitamin K Antagonists in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery) Author(s): Neumann, I. Etxeandia, R. Morgan, H. Schünemann Date: Question: LMWH compared to Vitamin K antagonists in major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery) Setting: Kingdom of Saudi Arabia Health System Bibliography: 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:e278S-325S. Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e227S-77S. Quality assessment № of studies

Study design

Risk of bias

Inconsistency

not serious

not serious


Imprecision


Effect

LMWH

Vitamin K antagonists

3/3584 (0.1%)

0.2%

Quality

Importance

Relative (95% CI)

Absolute (95% CI)

RR 0.50 (0.14 to 1.82)


⨁⨁⨁◯

RR 0.68 (0.22 to 2.10)


⨁⨁⨁◯

RR 0.68 (0.60 to 0.78)


⨁⨁◯◯

RR 1.36 (0.95 to 1.96)

4 more per 1000 (from 1 fewer to 11 more)

⨁⨁◯◯

Mortality 1 7

randomised trials

not serious

serious

2

none

MODERATE

CRITICAL

2

Nonfatal Pulmonary Embolism 8

randomised trials

not serious

not serious

not serious

serious

2

none

5/5100 (0.1%)

0.2%

3

MODERATE

CRITICAL

2

Symptomatic DVT 4 8

randomised trials

not serious

serious

5

serious

not serious

4

none

614/2898 (21.2%)

0.5%

3

LOW

CRITICAL

45

Major bleeding 5

randomised trials

not serious

serious

5

not serious

6

serious

7

none

99/2428 (4.1%)

1.1%

8

MD – mean difference, RR – relative risk 1. 2. 3. 4. 5. 6. 7. 8.

Deaths VKA: none from VTE, two from bleeding, one from unexplained causes, and three from other causes. Deaths LMWH: none from VTE, none from bleeding, one from unexplained causes, and two from other causes. Although 95% CI around relative effect is wide, the difference is very small in absolute terms and likely not relevant for patients Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc) Inferred from asymptomatic DVT Substancial heterogeneity was observed on the meta-analysis Estimate excludes studies that administered enoxaparin close to surgery (< 12 h perioperatively), making the true bleeding risk increase with LMWH less certain CI includes beneficial effects for both treatment arms. The average bleeding rate for LMWH in trials enrolling patients since 2003 is 1.5%.

LOW

567

CRITICAL


Recommendation 17 Should LMWH compared to Vitamin K Antagonists be used patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery)? Balance of consequences






○

○

○

●

○


Recommendation





○

○

●

○

In patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery), the panel suggests using LMWH rather than Vitamin K Antagonists (VKA) (conditional recommendation, low quality evidence).



Patient that are not feasible to take LMWH should use vitamin K antagonist over no prophylaxis - Although current LMWH has an easy administration, clinicians must ensure that patients who are discharged with LMWH receive appropriate information and education about the self-administration of the injectable medication. - Clinicians must ensure that patients who are discharged with vitamin K antagonist receive appropriate information regarding the importance of strict compliance and the need of follow-up and INR monitoring


None


- Cost effectiveness studies in the KSA setting. - Studies which comparing LMWH with new oral anticoagulant


Evidence to Decision Framework 6: Extended prophylaxis (up to 35 days) with LMWH compared to short prophylaxis (7-14 days) in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery) Criteria

Problem

Judgements






○ No included studies ○ Very low ○ Low ● Moderate ○ High

○ Important uncertainty or variability ○ Possibly important uncertainty or variability ● Probably no important uncertainty of variability ○ No important uncertainty of variability ○ No known undesirable ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies




Criteria


Acceptability

Feasibility

Research evidence






○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies No specific information about the risk of VTE in Saudi context has been identified.



Likely not relevant, since direct cost of both options is relatively low.




Since the use of LMWH requires daily injections, extended therapy may not be acceptable for some patients.




No obvious barriers regarding implementation identified. Both options are generally available

Resource use

Equity

Judgements

No specific information about the risk of VTE in Saudi context has been identified. The evidence from economic evaluations is somewhat inconsistent. However, extended prophylaxis with LMWH appears to be cost-effective compared with short duration therapy.


Evidence profile: Extended prophylaxis (up to 35 days) with LMWH compared to short prophylaxis (7-14 days) in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery) Author(s): I. Neumann, I. Etxeandia, R. Morgan, H. Schünemann Question: Extended prophylaxis (up to 35 days) with LMWH compared to prophylaxis (7-14 days) in patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery) Setting: Kingdom of Saudi Arabia Health System Bibliography: 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:e278S-325S. Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e227S-77S. Quality assessment № of studies

Study design

Risk of bias

№ of patients

Inconsistency

Indirectness

Imprecision

not serious

not serious

not serious

serious

not serious

not serious


Effect

Extended prophylaxis (up to 35 days) with LMWH

prophylaxis (7-14 days)

Relative (95% CI)

Absolute (95% CI)

3/2603 (0.1%)

5/2415 (0.2%)

RR 0.59 (0.14 to 2.44)


RR 0.46 (0.22 to 0.96)


Quality

Importance

Mortality 11

randomised trials

1

none


CRITICAL

1

Symptomatic Pulmonary Embolism 12

randomised trials

not serious

serious

2

none

3

8/2555 (0.3%)

21/2351 (0.9%)

0.5%

4


CRITICAL

23


4

Symptomatic DVT 11

randomised trials

not serious

not serious

not serious

not serious

none

27/2246 (1.2%)

61/2192 (2.8%)

1.0%

4

RR 0.46 (0.29 to 0.74)


⨁⨁⨁⨁

CRITICAL

⨁⨁⨁◯

CRITICAL

HIGH


4

Major bleeding 9

randomised trials

not serious

not serious

not serious

serious

1

none

6/2325 (0.3%)

7/2211 (0.3%)


Explanations 1. 2. 3. 4.

The 95% CI around the absolute estimate does not exclude substantial harm with extended prophylaxis The 95% CI around the absolute estimate includes the possibility of a very small difference, likely irrelevant for patients. Funnel plot might suggest absence of small trials showing an advantage of short-term prophylaxis Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc

RR 0.85 (0.30 to 2.41)


MODERATE

1


Recommendation 18 Should Extended prophylaxis (up to 35 days) with LMWH compared to short prophylaxis (7-14 days) be used patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery)? Undesirable consequences clearly Balance of outweigh desirable consequences consequences in most settings ○ Type of recommendation

Recommendation





○

○

○

●





○

○

○

●

In patients undergoing major orthopedic surgery (total hip arthroplasty, total knee arthroplasty or hip fracture surgery), the panel recommends extended prophylaxis (up to 35 days) with LMWH rather than short-term prophylaxis (7-14 days) (strong recommendation, moderate quality evidence).



None

Although current LMWH has an easy administration, clinicians must ensure that patients who are discharged with LMWH receive appropriate information and education about the self-administration of the injectable medication.


Monitoring of this recommendation could be considered a quality indicator


None


Appendix 2: Search Strategies and Results

Effect Estimates: Database: MEDLINE (via OVID) Search strategy:

Date of search: 11/2014

1. exp Venous Thrombosis/ 2. deep venous thromb$.mp. 3. Venous Thromboembolism/ 4. Pulmonary embolism/ 5. ((Pulmon$ or vein or venous) adj3 (Emboli$ or thromb$)).mp. 6. 1 or 2 or 3 or 4 or 5 7. Primary Prevention.mp. or Primary Prevention/ 8. Thromboprophylax$.mp. 9. prophylax$.mp. 10. 7 or 8 or 9 11. 6 and 10 12. Stocking$, Compression/ or stocking.mp. 13. pneumatic compression.mp. 14. mechanical compression.mp. 15. mechanical thromboprophylaxis.mp. 16. Mechanical Thrombolysis.mp. or Mechanical Thrombolysis/ 17. intermittent pneumatic compression device.mp. or Intermittent Pneumatic Compression Devices/ 18. 12 or 13 or 14 or 15 or 16 or 17 19. anticoagulant$.mp. or exp Anticoagulants/ 20. exp Heparin/ or heparin.mp. 21. exp Heparin, Low-Molecular-Weight/ 22. (LMW or low molecular weight heparin or nadroparin or fraxiparin or enoxaparin or clexane or lovenox or dalteparin or fragmin or ardeparin or normiflo or tinzaparin or logiparin or innohep or certoparin or sandoparin or reviparin or clivarin or danaproid or orgaran).mp. 23. 19 or 20 or 21 or 22 24. exp Coumarins/ 25. warfarin/ 26. warfarin$.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] 27. 24 or 25 or 26 28. 18 or 23 or 27 29. randomized controlled trial.pt. 30. random allocation/ 31. double-blind method/ 32. Single-Blind Method/ 33. randomi?ed control* trial*.mp. 34. randomi?ed clinical trial*.mp. 35. controlled clinical trial.pt. 36. ((singl* or doubl* or tripl* or trebl*) adj25 (blind* or mask*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]


37. random*.mp. 38. placebo*.mp. 39. cross-over studies.sh. 40. cross-over studies/ 41. latin square.tw. 42. 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 43. animals/ not humans/ 44. 42 not 43 45. 11 and 28 and 44 46. limit 45 to (english language and yr="2010-current") Date limit: 01/2010 - 11/2014 Study Types: RCTs Records retrieved

378

Database: Cochrane Central Register of Controlled Trials (via OVID) Search strategy:


1. exp Venous Thrombosis/ 2. deep venous thromb$.mp. 3. Venous Thromboembolism/ 4. Pulmonary embolism/ 5. ((Pulmon$ or vein or venous) adj3 (Emboli$ or thromb$)).mp. 6. 1 or 2 or 3 or 4 or 5 7. Primary Prevention.mp. or Primary Prevention/ 8. Thromboprophylax$.mp. 9. prophylax$.mp. 10. 7 or 8 or 9 11. 6 and 10 12. Stocking$, Compression/ or stocking.mp. 13. pneumatic compression.mp. 14. mechanical compression.mp. 15. mechanical thromboprophylaxis.mp. 16. Mechanical Thrombolysis.mp. or Mechanical Thrombolysis/ 17. intermittent pneumatic compression device.mp. or Intermittent Pneumatic Compression Devices/ 18. 12 or 13 or 14 or 15 or 16 or 17 19. anticoagulant$.mp. or exp Anticoagulants/ 20. exp Heparin/ or heparin.mp. 21. exp Heparin, Low-Molecular-Weight/ 22. (LMW or low molecular weight heparin or nadroparin or fraxiparin or enoxaparin or clexane or lovenox or dalteparin or fragmin or ardeparin or normiflo or tinzaparin or logiparin or innohep or certoparin or sandoparin or reviparin or clivarin or danaproid or orgaran).mp. 23. 19 or 20 or 21 or 22 24. exp Coumarins/ 25. warfarin/ 26. warfarin$.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] 27. 24 or 25 or 26 28. 18 or 23 or 27


29. 11 and 28 30. Limit 29 to (english language and yr="2010-current") Date limit: 01/2010 - 11/2014 Study Types: RCTs Records retrieved

131

SEARCH SUMMARY: EFFECT ESTIMATES

Nº Total-Retrieved:

509

MEDLINE

378

CENTRAL

131

Nº Total without duplicates:

389

Screening (Title and Abstract) Excluded

359

Selection (Full text) Excluded

30

Not the comparison of interests: 10 Not a Randomized trial: 18 Trials included in the update

2

Trials identified through other sources

2


Values and Preferences: Database: MEDLINE (via OVID) Search strategy:


1. patient$ participation.mp. or exp patient participation/ 2. patient$ satisfaction.mp. or exp patient satisfaction/ 3. attitude to health.mp. or exp Attitude to health/ 4. (patient$ preference$ or patient$ perception$ or patient$ decision$ or patient$ perspective$ or user$ view$ or patient$ view$ or patient$ value$).mp. 5. (patient$ utilit$ or health utilit$).mp. 6. health related quality of life.mp. or exp "quality of life"/ 7. (health stat$ utilit$ or health stat$ indicator$ or (health stat$ adj 2 valu$)).mp. or exp Health Status Indicators/ 8. 1 or 2 or 3 or 4 or 5 or 6 or 7 9. exp Venous Thrombosis/ 10. deep venous thromb$.mp. 11. Venous Thromboembolism/ 12. Pulmonary embolism/ 13. ((Pulmon$ or vein or venous) adj3 (Emboli$ or thromb$)).mp. 14. 9 or 10 or 11 or 12 or 13 15. Primary Prevention.mp. or Primary Prevention/ 16. Thromboprophylax$.mp. 17. prophylax$.mp. 18. 15 or 16 or 17 19. 14 and 18 20. Stocking$, Compression/ or stocking.mp. 21. pneumatic compression.mp. 22. mechanical compression.mp. 23. mechanical thromboprophylaxis.mp. 24. Mechanical Thrombolysis.mp. or Mechanical Thrombolysis/ 25. intermittent pneumatic compression device.mp. or Intermittent Pneumatic Compression Devices/ 26. 20 or 21 or 22 or 23 or 24 or 25 27. anticoagulant$.mp. or exp Anticoagulants/ 28. exp Heparin/ or heparin.mp. 29. exp Heparin, Low-Molecular-Weight/ 30. (LMW or low molecular weight heparin or nadroparin or fraxiparin or enoxaparin or clexane or lovenox or dalteparin or fragmin or ardeparin or normiflo or tinzaparin or logiparin or innohep or certoparin or sandoparin or reviparin or clivarin or danaproid or orgaran).mp. 31. 27 or 28 or 29 or 30 32. exp Coumarins/ 33. warfarin/ 34. warfarin$.mp. [mp=ti, ab, sh, hw, tn, ot, dm, mf, dv, kw, nm, kf, px, rx, ui] 35. 32 or 33 or 34 36. 26 or 31 or 35 37. 8 and 19 and 36 38. limit 37 to (english language and yr="2010-current") Date limit: 01/2010 - 11/2014 Study Types: Any Records retrieved

74


Database: EMBASE (via OVID) Search strategy:


1. patient$ participation.mp. or exp patient participation/ 2. patient$ satisfaction.mp. or exp patient satisfaction/ 3. attitude to health.mp. or exp Attitude to health/ 4. (patient$ preference$ or patient$ perception$ or patient$ decision$ or patient$ perspective$ or user$ view$ or patient$ view$ or patient$ value$).mp. 5. (patient$ utilit$ or health utilit$).mp. 6. health related quality of life.mp. or exp "quality of life"/ 7. (health stat$ utilit$ or health stat$ indicator$ or (health stat$ adj 2 valu$)).mp. or exp Health Status Indicators/ 8. 1 or 2 or 3 or 4 or 5 or 6 or 7 9. exp Venous Thrombosis/ 10. deep venous thromb$.mp. 11. Venous Thromboembolism/ 12. Pulmonary embolism/ 13. ((Pulmon$ or vein or venous) adj3 (Emboli$ or thromb$)).mp. 14. 9 or 10 or 11 or 12 or 13 15. Primary Prevention.mp. or Primary Prevention/ 16. Thromboprophylax$.mp. 17. prophylax$.mp. 18. 15 or 16 or 17 19. 14 and 18 20. Stocking$, Compression/ or stocking.mp. 21. pneumatic compression.mp. 22. mechanical compression.mp. 23. mechanical thromboprophylaxis.mp. 24. Mechanical Thrombolysis.mp. or Mechanical Thrombolysis/ 25. intermittent pneumatic compression device.mp. or Intermittent Pneumatic Compression Devices/ 26. 20 or 21 or 22 or 23 or 24 or 25 27. anticoagulant$.mp. or exp Anticoagulants/ 28. exp Heparin/ or heparin.mp. 29. exp Heparin, Low-Molecular-Weight/ 30. (LMW or low molecular weight heparin or nadroparin or fraxiparin or enoxaparin or clexane or lovenox or dalteparin or fragmin or ardeparin or normiflo or tinzaparin or logiparin or innohep or certoparin or sandoparin or reviparin or clivarin or danaproid or orgaran).mp. 31. 27 or 28 or 29 or 30 32. exp Coumarins/ 33. warfarin/ 34. warfarin$.mp. [mp=ti, ab, sh, hw, tn, ot, dm, mf, dv, kw, nm, kf, px, rx, ui] 35. 32 or 33 or 34 36. 26 or 31 or 35 37. 8 and 19 and 36 38. limit 37 to (english language and yr="2010-current") Date limit: 01/2010 - 11/2014 Study Types: Any Records retrieved

171


SEARCH SUMMARY: VALUES AND PREFERENCES Nº Total-Retrieved: MEDLINE EMBASE: Nº Total without duplicates: Screening (Title and Abstract) Excluded Selection (Full text) Excluded Included in the update

245 74 171 224 224 0


Cost-Effectiveness: Database: MEDLINE (via OVID) Search strategy:


1. exp Venous Thrombosis/ 2. deep venous thromb$.mp. 3. Venous Thromboembolism/ 4. Pulmonary embolism/ 5. ((Pulmon$ or vein or venous) adj3 (Emboli$ or thromb$)).mp. 6. 1 or 2 or 3 or 4 or 5 7. Primary Prevention.mp. or Primary Prevention/ 8. Thromboprophylax$.mp. 9. prophylax$.mp. 10. 7 or 8 or 9 11. 6 and 10 12. Stocking$, Compression/ or stocking.mp. 13. pneumatic compression.mp. 14. mechanical compression.mp. 15. mechanical thromboprophylaxis.mp. 16. Mechanical Thrombolysis.mp. or Mechanical Thrombolysis/ 17. intermittent pneumatic compression device.mp. or Intermittent Pneumatic Compression Devices/ 18. 12 or 13 or 14 or 15 or 16 or 17 19. anticoagulant$.mp. or exp Anticoagulants/ 20. exp Heparin/ or heparin.mp. 21. exp Heparin, Low-Molecular-Weight/ 22. (LMW or low molecular weight heparin or nadroparin or fraxiparin or enoxaparin or clexane or lovenox or dalteparin or fragmin or ardeparin or normiflo or tinzaparin or logiparin or innohep or certoparin or sandoparin or reviparin or clivarin or danaproid or orgaran).mp. 23. 19 or 20 or 21 or 22 24. exp Coumarins/ 25. warfarin/ 26. warfarin$.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] 27. 24 or 25 or 26 28. 18 or 23 or 27 29. economics/ or exp economics, hospital/ or exp economics, medical/ or economics, nursing/ or economics, pharmaceutical/ 30. exp "Costs and Cost Analysis"/ 31. Value-Based Purchasing/ 32. exp "Fees and Charges"/ 33. budget$.mp. or Budgets/ 34. (low adj cost).mp. 35. (high adj cost).mp. 36. (health?care adj cost$).mp. 37. (cost adj estimate$).mp. 38. (cost adj variable$).mp. 39. (unit adj cost$).mp.


40. (fiscal or funding or financial or finance).tw. 41. (economic$ or pharmacoeconomic$ or price$ or pricing).tw. 42. 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 43. 11 and 28 and 42 44. limit 43 to (english language and yr="2010-current") Date limit: 01/2010 - 11/2014 Study Types: Any Records retrieved

118

Database: EMBASE (via OVID) Search strategy:


1. exp Venous Thrombosis/ 2. deep venous thromb$.mp. 3. Venous Thromboembolism/ 4. Pulmonary embolism/ 5. ((Pulmon$ or vein or venous) adj3 (Emboli$ or thromb$)).mp. 6. 1 or 2 or 3 or 4 or 5 7. Primary Prevention.mp. or Primary Prevention/ 8. Thromboprophylax$.mp. 9. prophylax$.mp. 10. 7 or 8 or 9 11. 6 and 10 12. Stocking$, Compression/ or stocking.mp. 13. pneumatic compression.mp. 14. mechanical compression.mp. 15. mechanical thromboprophylaxis.mp. 16. Mechanical Thrombolysis.mp. or Mechanical Thrombolysis/ 17. intermittent pneumatic compression device.mp. or Intermittent Pneumatic Compression Devices/ 18. 12 or 13 or 14 or 15 or 16 or 17 19. anticoagulant$.mp. or exp Anticoagulants/ 20. exp Heparin/ or heparin.mp. 21. exp Heparin, Low-Molecular-Weight/ 22. (LMW or low molecular weight heparin or nadroparin or fraxiparin or enoxaparin or clexane or lovenox or dalteparin or fragmin or ardeparin or normiflo or tinzaparin or logiparin or innohep or certoparin or sandoparin or reviparin or clivarin or danaproid or orgaran).mp. 23. 19 or 20 or 21 or 22 24. exp Coumarins/ 25. warfarin/ 26. warfarin$.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] 27. 24 or 25 or 26 28. 18 or 23 or 27 29. fee$.mp. or exp fee/ 30. health care cost$.mp. or exp "health care cost"/ 31. hospital cost$.mp. or exp "hospital cost"/ 32. pharmacoeconomics.mp. or exp pharmacoeconomics/ 33. health economics.mp. or health economics/ 34. budget$.mp. or budget/ 35. socioeconomics.mp. or socioeconomics/


36. (low adj cost).mp. 37. (high adj cost).mp. 38. (health?care adj cost$).mp. 39. (cost adj estimate$).mp. 40. (cost adj variable$).mp. 41. (unit adj cost$).mp. 42. (fiscal or funding or financial or finance).tw. 43. (economic$ or pharmacoeconomic$ or price$ or pricing).tw. 44. 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 45. 11 and 28 and 44 46. limit 45 to (english language and yr="2011-current") Date limit: 01/2010 - 11/2014 Study Types: Any Records retrieved

327

SEARCH SUMMARY: COST EFFECTIVENESS Nº Total-Retrieved: MEDLINE: EMBASE: Nº Total without duplicates: Screening (Title and Abstract) Excluded Selection (Full text) Excluded Not the comparison of interest: 5 Included in the update

445 118 327 369 363 5 1


SYNTAX GUIDE /

At the end of a phrase, searches the phrase as a subject heading

.sh

At the end of a phrase, searches the phrase as a subject heading

MeSH

Medical Subject Heading

fs

Floating subheading

exp

Explode a subject heading

*

Before a word, indicates that the marked subject heading is a primary topic; or, after a word, a truncation symbol (wildcard) to retrieve plurals or varying endings

#

Truncation symbol for one character

?

Truncation symbol for one or no characters only

ADJ

Requires words are adjacent to each other (in any order)

ADJ#

Adjacency within # number of words (in any order)

.ti

Title

.ab

Abstract

.hw .mp

Heading Word; usually includes subject headings and controlled vocabulary Protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier

.pt

Publication type

.rn

CAS registry number