The Saudi clinical practice guideline for the prophylaxis of venous thromboembolism in medical and critically ill patients

 [bib_ref] Heparin thromboprophylaxis in medical-surgical critically ill patients: a systematic review and meta-analysis..., Alhazzani [/bib_ref] [bib_ref] Does ambulation modify venous thromboembolism risk in acutely ill medical patients?, Amin [/bib_ref] [bib_ref] Use of intermittent pneumatic compression and not graduated compression stockings is associated..., Arabi [/bib_ref] [bib_ref] Heparin thromboprophylaxis in medical-surgical critically ill patients: a systematic review and meta-analysis..., Alhazzani [/bib_ref] [bib_ref] Rivaroxaban for thromboprophylaxis in acutely ill medical patients, Cohen [/bib_ref] [bib_ref] Heparin thromboprophylaxis in medical-surgical critically ill patients: a systematic review and meta-analysis..., Alhazzani [/bib_ref] [bib_ref] Prevalence of deep venous thrombosis among patients in medical intensive care, Hirsch [/bib_ref] [bib_ref] Meta-analysis of venous thromboembolism prophylaxis in medically Ill patients, Kanaan [/bib_ref] [bib_ref] Meta-analysis of low molecular weight heparin in the prevention of venous thromboembolism..., Mismetti [/bib_ref] [bib_ref] Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE..., Cohen [/bib_ref] [bib_ref] Venous thromboembolism-related mortality and morbidity in King Fahd General Hospital, Essam [/bib_ref] [bib_ref] Venous thromboembolism-related mortality and morbidity in King Fahd General Hospital, Essam [/bib_ref] [bib_ref] Venous thromboembolism-related mortality and morbidity in King Fahd General Hospital, Essam [/bib_ref] [bib_ref] Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, Kahn [/bib_ref] [bib_ref] Clinical Guidelines Committee of the American College of P. Venous thromboembolism prophylaxis..., Qaseem [/bib_ref] [bib_ref] Clinical Practice Guideline on Prophylaxis of VTE in Medical Patients and Long..., Al-Hameed [/bib_ref] [bib_ref] Guidelines 2.0: systematic development of a comprehensive checklist for a successful guideline..., Schunemann [/bib_ref] [bib_ref] Heparin thromboprophylaxis in medical-surgical critically ill patients: a systematic review and meta-analysis..., Alhazzani [/bib_ref] [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] [bib_ref] GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to..., Alonso-Coello [/bib_ref] [bib_ref] GRADE Evidence to Decision frameworks: 2. Clinical practice guidelines, Alonso-Coello [/bib_ref] [bib_ref] Development of the GRADE Evidence to Decision (EtD) frameworks for tests in..., Schuenemann [/bib_ref] [bib_ref] Venous thromboembolism-related mortality and morbidity in King Fahd General Hospital, Essam [/bib_ref] [fig_ref] Table 1 -: Interpretation of strong and conditional [/fig_ref] [bib_ref] GRADE guidelines: 14. Going from evidence to recommendations: the significance and presentation..., Andrews [/bib_ref] 

## Thromboprophylaxis in acutely ill medical patients.

## Question 1: should heparin versus no heparin be used for vte prophylaxis in acutely ill medical patients?
Summary of findings. We updated the 2014 systematic review by Alikhan et al, 1 but did not identify new studies. The overall quality of evidence was judged to be low. The studies included in the systematic review typically defined acutely ill patients as patients hospitalized for acute medical illness (for example, heart failure, chronic obstructive pulmonary disease), with a decrease in mobility. The summary of findings are shown in [fig_ref] Table 2 -: Heparin compared to no heparin for deep venous thrombosis prophylaxis of in... [/fig_ref].The baseline risks for deep vein thrombosis (DVT) and pulmonary embolism (PE) outcomes for the low-risk and high-risk subgroups are based on a risk assessment model by The baseline risk for mortality is based on the findings of a systematic review by Benefits and harms of the option. The meta-analysis of 6 trials (5,944 participants) found very low-quality evidence of a reduction in DVT with heparin use compared to no heparin for thromboprophylaxis. The meta-analysis of 7 trials (5939 participants) found low-quality evidence of a reduction in non-fatal PE with heparin use compared to no heparin for thromboprophylaxis in acutely ill hospitalized medical patients. The meta-analysis of 8 trials found low-quality evidence that did not rule out a reduction or an increase in all-cause mortality with heparin compared to no heparin for thromboprophylaxis in acutely ill hospitalized medical patients. The meta-analysis of 8 trials (13804 participants) found moderate quality evidence of an increase in major bleeding with heparin compared to no heparin for thromboprophylaxis in acutely ill hospitalized medical patients. The meta-analysis of 6 trials (13434 participants) found moderate quality evidence of an increase in minor bleeding with the use of heparin compared to no heparin for prophylaxis of DVT in acutely ill hospitalized medical patients. The metaanalysis of 5 trials (13349 participants) found moderate quality evidence that did not rule out a reduction or an increase in thrombocytopenia with heparin compared to no heparin for thromboprophylaxis in acutely ill hospitalized medical patients.
Resource use. The panel judged heparin cost to be low but to only be cost-effective in high-risk patients.
Feasibility, acceptability and equity considerations. The panel judged heparin use for thromboprophylaxis in acutely ill hospitalized medical patients to be both feasible and acceptable by all relevant stakeholders because of patient safety. Additionally, the panel judged heparin use in this population to unlikely impact health inequity.

## 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.
The majority of individuals in this situation would want the suggested course of action, but many would not.
For clinicians Most individuals should receive the intervention. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator.
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.

## For policy makers
The recommendation can be adapted as policy in most situations Policy making will require substantial debate and involvement of various stakeholders.
Balance between desirable and undesirable consequences. The panel judged heparin benefits to clearly outweigh its harms in high-risk patients, but less clearly in low-risk patients. Evidence certainty was considered moderate in high-risk patients and low in low-risk patients. The panel deemed the intervention to be of low-cost, cost-effective (in high-risk patients), feasible, and acceptable.

## Recommendation 1.
1a) In acutely ill hospitalized medical patients at high risk of VTE the panel recommends heparin unfractionated heparin (UFH)/low molecular weight heparin over no heparin for VTE prophylaxis (strong recommendation, moderate quality evidence).
1b) In acutely ill hospitalized medical patients at low risk of VTE, the panel suggests against heparin for VTE prophylaxis (conditional recommendation, low quality evidence).

## Remarks
- Risk stratification should be based on a validated risk stratification tool (for example, Padua Prediction Score). [bib_ref] A risk assessment model for the identification of hospitalized medical patients at..., Barbar [/bib_ref] - Decision to provide thromboprophylaxis should consider the patients' risk of bleeding.

## Monitoring and evaluation.
Monitoring the frequency of risk stratification and the compliance with heparin thromboprophylaxis is recommended.
Research priorities. The panel highlighted the need for studies addressing the following research priorities in KSA: impact of guideline implementation on clinical practice, VTE incidence and major bleeding in acutely ill hospitalized medical patients, values and preferences for giving heparin in different subgroups of acutely ill medical patients, and economic evaluation, including cost effectiveness. a reduction or an increase in all-cause mortality with LMWH compared to UFH for thromboprophylaxis in acutely ill hospitalized medical patients.
The meta-analysis of 7 trials (6028 participants) found moderate quality evidence of a reduction in major bleeding with the use of LMWH compared to UFH for thromboprophylaxis in acutely ill hospitalized medical patients. The meta-analysis of 4 trials (3962 participants) found moderate quality evidence of a reduction in minor bleeding with the use of LMWH compared to UFH for Thromboprophylaxis in acutely ill hospitalized medical patients. The meta-analysis of 4 trials (3962 participants) found moderate quality evidence that did not rule out a reduction or an increase in thrombocytopenia with the use of LMWH compared to UFH for Thromboprophylaxis in acutely ill hospitalized medical patients.
Resource use. The panel thought that there would be a variation in the cost across different hospital settings and deemed the nursing costs to be higher with UFH because it is given 3 times daily. The panel judged LMWH to be cost-effective.

## Question 2: should low molecular weight heparin versus ufh be used for vte prophylaxis in acutely ill medical patients?
Summary of findings. The findings are primarily derived from a 2014 systematic review by Alikhan et al,The updated literature search identified a 2013 randomized controlled trial (RCT) by Ishi et al. [bib_ref] Randomised controlled trial for efficacy of unfractionated heparin (UFH) versus low molecular..., Ishi [/bib_ref] The overall quality of evidence was deemed to be moderate. The summary of evidence is shown in .
Benefits and harms of the option. The meta-analysis of 7 trials (5983 participants) found low-quality evidence that did not rule out a reduction or an increase in DVT with low molecular weight heparin (LMWH) compared to UFH for thromboprophylaxis in acutely ill hospitalized medical patients. The meta-analysis of 7 trials (5485 participants) found low-quality evidence that did not rule out a reduction or an increase in non-fatal PE with LMWH compared to UFH for thromboprophylaxis in acutely ill hospitalized medical patients.The meta-analysis of 7 trials (5605 participants) found moderate quality evidence that did not rule out -Low molecular weight heparin compared to unfractionated heparin for deep venous thrombosis prophylaxis in acutely ill medical patients. Feasibility, acceptability and equity considerations. The panel judged LMWH use for thromboprophylaxis in acutely ill hospitalized medical patients to be both feasible and acceptable by patients and nurses. The panel also considered LMWH in this population to unlikely impact health inequity.

## Studies/ study design

## Quality assessment n (%) of patients effect quality

## Risk of bias
Balance between desirable and undesirable consequences. The panel considered LMWH benefits to probably outweigh its harms in acutely ill medical patients.

## Recommendation 2:
In acutely ill hospitalized medical patients the panel suggests using low molecular weight heparin over UFH for VTE prophylaxis (conditional recommendation, low quality evidence)
Remark. In case of renal failure, UFH use is preferred.
Implementation considerations. Consider having anti-factor Xa assay made available for LMWH monitoring in pregnant and renal impairment subpopulations.
Research priorities. Studies on cost effectiveness are needed.

## Question 3: should extended duration (that is up to 30 or 40 days) versus a regular duration (up to 10 days) be used for the thromboprophylaxis in acutely ill hospitalized medical patients?
Summary of findings. The definition of extended duration thromboprophylaxis is prophylaxis that is extends beyond the regular course of 10 days, and up to 30-40 days in total. We updated the systematic review by Sharma et al, [bib_ref] Extended thromboprophylaxis for medically ill patients with decreased mobility: does it improve..., Sharma [/bib_ref] but did not identify new studies. The overall evidence quality was moderate. The summary of evidence is shown in [fig_ref] Table 4 -: Extended duration compared to regular duration for the thromboprophylaxis of VTE in... [/fig_ref].
Benefits and harms of the option. The meta-analysis of 3 trials (20362 participants) found moderate quality evidence of an increase in major bleeding with the use of extended thromboprophylaxis duration compared to no extended thromboprophylaxis duration for acutely ill hospitalized medical patients. The meta-analysis of 3 trials (17542 participants) found moderate quality evidence that did not rule out a reduction or an increase in PE with the use of extended thromboprophylaxis duration compared to no extended thromboprophylaxis duration for acutely ill hospitalized medical patients. The meta-analysis of 2 trials (12552 participants) found moderate quality evidence that did not rule out a reduction or an increase in VTE-related mortality with the use of extended thromboprophylaxis duration compared to no extended thromboprophylaxis duration for acutely ill hospitalized medical patients. The metaanalysis of 3 trials (17547 participants) found moderate quality evidence that did not rule out a reduction or an increase in symptomatic DVT with the use of extended thromboprophylaxis duration compared to no extended thromboprophylaxis duration for acutely ill hospitalized medical patients. The meta-analysis of 3 trials (16723 participants) found high-quality evidence that did not rule out a reduction or an increase in all-cause mortality with the use of extended thromboprophylaxis duration compared to no extended thromboprophylaxis duration for acutely ill hospitalized medical patients.
Resource use. The panel judged the cost of heparin to be probably high because of the cost required to educate patients and the cost of the medication itself. The panel judged the intervention to probably not be cost-effective.
Feasibility, acceptability, and equity considerations. The panel judged the use of extended thromboprophylaxis duration to be probably not acceptable or feasible as health educators are needed.
Balance between desirable and undesirable consequences. The panel judged the harms of extended thromboprophylaxis duration to clearly outweigh its benefits in acutely ill hospitalized patients. Evidence certainty was considered to be moderate. The panel judged the intervention to be probably of high cost, not cost-effective, not feasible and not acceptable.

## Recommendation 3:
In acutely ill hospitalized medical patients the panel recommends a regular duration (that is, up to 10 days) over an extended duration (that is, up to 30 or 40 days) for the thromboprophylaxis. (strong recommendation, moderate quality evidence)
Research priorities. Studies that identify the subpopulations that would benefit from extended thromboprophylaxis and determine a risk stratification tool are needed.

## Question 4: should gcs versus no gcs be used for hospitalized medical patients?
Summary of findings. Our systematic search of the literature did not identify studies other than a RCT by Muir et al 30 and a 2009 RCT by Dennis et al.The summary of findings is shown in [fig_ref] Table 5 -: Graduated compression stockings versus no graduated compression stockings in hospitalized medical patients [/fig_ref].
Benefits and harms of the option. One trial 9 (2518 participants) provided low-quality evidence that did not rule out a reduction or an increase in symptomatic DVT (follow up: 1-30 days) with GCS use compared to no GCS in hospitalized medical patients. One trial 9 (2518 participants) provided low-quality evidence that did not rule out a reduction or an increase in PE (follow up: 1-30 days) with GCS use compared to no GCS in hospitalized medical patients. The meta-analysis of 2 trials 9,30 (2615 participants) found moderate quality evidence that did not rule out a reduction or an increase in mortality (follow up: 1-30 days) with GCS use compared to no GCS in hospitalized medical patients.
One trial 9 (2518 participants) provided very low-quality evidence of an increase in skin breaks/ ulcers/blisters/skin necrosis (follow up: 1-30 days) with GCS use compared to no GCS in hospitalized medical patients. One trial 9 (2518 participants) provided very low-quality evidence that did not rule out a reduction or an increase in Lower limb ischemia/amputation (follow up: 1-30 days) with GCS use compared to no GCS in hospitalized medical patients.
Resource use. The panel judged the cost of GCS to be low. But there was no evidence on whether GCS was cost-effective.
Feasibility, acceptability, and equity considerations. The panel judged GCS use to be probably feasible or acceptable. The panel was uncertain about the impact of GCS use on health inequity.

## Balance between desirable and undesirable consequences.
The panel judged the harms of GCS to outweigh the benefits in acutely ill hospitalized medical patients at low-risk of VTE. They judged this balance to be uncertain in acutely ill hospitalized medical patients at high-risk of VTE. Evidence certainty was considered to be low. The panel was uncertain about cost effectiveness, and judged the intervention to be probably feasible and acceptable.

## Recommendation 4:
4a) In acutely ill hospitalized medical patients at low risk of VTE the panel recommends against using GCS for VTE prophylaxis (strong recommendation, low quality evidence). 4b) In acutely ill hospitalized medical patients at high risk of VTE and bleeding (who cannot receive pharmacological prophylaxis), the panel suggests using GCS for VTE prophylaxis (conditional recommendation, low quality evidence).

## Remarks:
1. Consider monitoring for skin lesions and ischemia 2. Physician must ensure proper fitting

## Monitoring and evaluations.
Monitoring GCS use in acutely ill low-and high-risk medical patients is advocated.
Research priorities. More trials in non-stroke medical patients are needed.

## Question 5: should ipc versus no ipc be used for hospitalized medical patients?
Summary of findings. We updated a systematic review by Roderick et al, [bib_ref] Towards evidence-based guidelines for the prevention of venous thromboembolism: systematic reviews of..., Roderick [/bib_ref] which was on surgical patients and thus was considered as indirect evidence, [bib_ref] Towards evidence-based guidelines for the prevention of venous thromboembolism: systematic reviews of..., Roderick [/bib_ref] but we did not identify new studies. The overall quality of evidence was judged to be low. The summary of evidence is shown in [fig_ref] Table 6 -: Intermittent pneumatic compression devices versus no intermittent pneumatic compression devices in hospitalized... [/fig_ref].
Benefits and harms of the option. The meta-analysis of 19 trials found moderate quality evidence of a reduction in symptomatic DVT (follow up of 30 days) with the use of IPC compared to no IPC in hospitalized medical patients. The meta-analysis of 8 trials found low-quality evidence that did not rule out a reduction or an increase in PE (follow-up of 30 days) with IPC use compared to no IPC in hospitalized medical patients. The meta-analysis of 2 trials (2518 participants) found low-quality evidence that could not estimate the absolute effect of IPC use compared to no IPC use in hospitalized medical patients.
There were no studies that reported skin breaks/ ulcers/blisters/skin necrosis as an outcome and therefore we could not estimate the absolute effect of IPC use compared to no IPC use in hospitalized medical patients related to this outcome.
Resource use. The panel judged IPC cost to probably not be low and was uncertain whether IPC use is costeffective because of lacking evidence.
Feasibility, acceptability, and equity considerations. The panel judged IPC use to be probably feasible, but feasibility may vary between hospitals and that IPC use is less acceptable by patients. The panel judged IPC use to impact health inequity and noted that its cost and availability need to be considered.
Balance between desirable and undesirable consequences. The panel judged the harms of IPC/ [bib_ref] Venous thromboembolism-related mortality and morbidity in King Fahd General Hospital, Essam [/bib_ref] sequential compression device (SCD) to probably outweigh the benefits in acutely ill hospitalized medical patients at low-risk of VTE. The balance was uncertain in patients at high-risk of VTE. Evidence certainty was considered to be low. The panel was uncertain about the intervention cost effectiveness and acceptability. It judged the intervention to probably increase inequity and to be probably feasible.

## Recommendation 5:
5a) In acutely ill hospitalized medical patients at low risk of VTE, the panel recommends against using intermittent IPC for VTE prophylaxis (conditional recommendation, low quality evidence). 5b) In acutely ill hospitalized medical patients at high risk of VTE and bleeding (who should not receive pharmacological prophylaxis), the panel suggests using intermittent IPC for VTE prophylaxis (conditional recommendation, low quality evidence).
Remarks. The choice between mechanical prophylaxis options (GCS over intermittent pneumatic compression/sequential compression device) will depend on the local availability and patient preference. Implementation considerations. Administrators considering the use of SCD, need to take into account for both its capital and operational costs.
Monitoring and evaluation. The panel advocated that hospitals monitor adherence of IPC use and that compressive lower extremity ultrasound should be considered in patients who have been hospitalized for >72 hours without any thromboprophylaxis.
Research priorities. Additional studies on IPC effectiveness are needed.

## Thromboprophylaxis in critically ill medical patients

## Question 6: should heparin versus placebo be used for critically ill patients?
Summary of findings. We updated a systematic review by Alhazzani et al, 2 but did not identify new studies. The overall quality of evidence was judged to be low. In the systematic review, critically ill patients were defined as those being cared for in an intensive care unit (ICU) setting. The summary of evidence is shown in .
Benefits and harms of the option. One trial (1935 participants) provided moderate quality evidence that did not rule out a reduction or an increase in symptomatic DVT with the use of heparin compared to placebo in critically ill patients. The meta-analysis of 2 trials (2895 participants) found moderate quality evidence of a reduction in PE with the use of heparin compared to placebo in critically ill patients. The metaanalysis of 2 trials (2156 participants) found low-quality evidence that did not rule out a reduction or an increase in major bleeding with the use of heparin compared to placebo in critically ill patients. The meta-analysis of 2 trials (2148 participants) found moderate quality evidence that did not rule out a reduction or an increase in ICU mortality with heparin use compared to placebo in critically ill patients. Resource use. The panel judged heparin cost to be small and to probably be cost-effective, as appropriate prophylaxis provides better value in terms of costs and health gains than routine DVT screening.
Feasibility, acceptability and equity considerations. The panel judged heparin use to be both feasible and acceptable. The panel were uncertain about the impact of heparin use on health inequity in critically ill patients. Balance between desirable and undesirable consequences: The panel judged heparin benefits to probably outweigh its harms in critically ill medical patients. Evidence certainty was considered to be low. The panel judged the intervention to be low-cost, probably cost-effective, feasible and acceptable.

## Recommendation 6:
In critically ill medical patients the panel recommends heparin over no heparin for VTE prophylaxis (strong recommendation, low quality evidence).
Remark. Decision to provide thromboprophylaxis should consider the patients' risk of bleeding Implementation considerations and monitoring. Monitoring percentage of critically ill medical patients receiving heparin should be considered Research priorities. Additional research on this topic in critically ill patient population is needed.

## Question 7: should lmwh versus ufh be used for critically ill patients?
Summary of findings. We updated a systematic review by Alhazzani et al, 2 but did not identify new studies. The overall quality of evidence was judged to be moderate. The summary of evidence is shown in [fig_ref] Table 8 -: Low molecular weight heparin versus unfractionated heparin for critically ill patients [/fig_ref].

## Benefits and harms of the option.
The meta-analysis of 2 trials (4722 participants) found moderate quality evidence that did not rule out a reduction or an increase in symptomatic DVT with LMWH compared to UFH in critically ill patients. The meta-analysis of 2 trials (4722 participants) found low-quality evidence that did not rule out a reduction or an increase in PE with the use of LMWH compared to UFH in critically ill patients. The meta-analysis of 3 trials (4212 participants) found moderate quality evidence that did not rule out a reduction or an increase in major bleeding with the use of LMWH compared to UFH in critically ill patients. The meta-analysis of 4 trials (5184 participants) found moderate quality evidence that did not rule out a reduction or an increase in ICU mortality with the use of LMWH compared to UFH in critically ill patients.
Resource use. The panel judged LMWH cost to be small and to probably be cost-effective, as appropriate prophylaxis provides better value in terms of costs and health gains than routine DVT screening. 32 -Heparin compared to placebo for critically ill patients. Feasibility, acceptability, and equity considerations. The panel judged LMWH use to be both feasible and acceptable. The panel were uncertain about the impact of LMWH on health inequity in critically ill patients.

## Studies
Balance between desirable and undesirable consequences. The panel judged the LMWH benefits to probably outweigh its harms in critically ill medical patients. Evidence certainty was considered to be low. The panel judged the intervention to be low-cost, probably cost-effective, feasible, and acceptable.

## Recommendation 7:
In critically ill medical patients, the panel suggests low molecular weight heparin over UFH for the VTE prophylaxis (conditional recommendation, low quality evidence).
Remark. In case of renal failure, use of UFH is preferred.
Implementation considerations and monitoring. Consider having anti-factor Xa for LMWH monitoring made available for pregnant and renal impairment subpopulations.
Research priorities. Conducting cost effectiveness studies should be considered.

## Question 8: should gcs versus no gcs be used for critically ill patients?
Summary of findings. We identified a prospective cohort study by Arabi et al, [bib_ref] Use of intermittent pneumatic compression and not graduated compression stockings is associated..., Arabi [/bib_ref] and did not identify any other new studies. The overall quality of evidence was considered very low. Summary of evidence is shown in [fig_ref] Table 9 -: Graduated compression stockings compared to no graduated compression stockings for critically ill... [/fig_ref].
Benefits and harms of the option. One observational study (569 participants) provided very low-quality evidence that did not rule out a reduction or an increase in VTE with GCS use compared to no GCS in critically ill patients. One observational study (569 participants) provided very low-quality evidence that did not rule out a reduction or an increase in hospital mortality with GCS use compared to no GCS in critically ill patients.
One trial (2518 participants) provided very low-quality evidence that did not rule out a reduction or an increase in skin breaks/ ulcers/ blisters/ skin necrosis (follow up: 30 days) with GCS use compared to no GCS in critically ill patients. One trial (2518 participants) provided very low-quality evidence that did not rule out a reduction or an increase in lower limb ischemia/amputation (follow up: 30 days) with GCS use compared to no GCS in critically ill patients.
Resource use. The panel judged the cost of GCS to be small and to probably not be cost-effective, as appropriate prophylaxis provides better value in terms of costs and health gains than routine screening for DVT. 32 Balance between desirable and undesirable consequences. The panel judged the harms of GCS for thromboprophylaxis to probably outweigh the benefits in critically ill medical patients. Evidence certainty was considered to be low. The panel judged the intervention to be low-cost and probably feasible, and acceptable.

## Recommendation 8:
8a) In critically ill medical patients, the panel suggests against GCS for VTE prophylaxis (conditional recommendation, very low quality evidence). 8b) In critically ill medical patients at high risk of bleeding and in whom pharmacological prophylaxis is not feasible and in settings where intermittent, IPC is not available the panel suggests using GCS for VTE prophylaxis (conditional recommendation, very low quality evidence).
Remarks: 1. Consider monitoring for skin lesions and ischemia 2. Physician must ensure proper fitting 3. Ensure appropriate use of GCS (thigh length versus knee length) Implementation considerations. The hospital should acquire different sizes of high-quality GCS.

## Monitoring and evaluation.
Monitoring GCS use should be considered.
Research priorities. Studies on the benefits, harms and cost effectiveness of GCS use in ICU populations are needed.

## Question 9: should ipc versus no ipc be used for critically ill patients?
Summary of findings. We identified a prospective cohort study by Arabi et al, [bib_ref] Use of intermittent pneumatic compression and not graduated compression stockings is associated..., Arabi [/bib_ref] and did not identify any other new studies. The overall evidence quality was deemed very low. The summary of evidence is shown in [fig_ref] Table 1 -: Interpretation of strong and conditional [/fig_ref].
Benefits and harms of the option. One study (618 participants) provided very low-quality evidence that showed a reduction in VTE with IPC use compared to no IPC use in critically ill patients. One study found very low-quality evidence that did not rule out a reduction or an increase in hospital mortality with IPC compared to no IPC in critically ill patients.
There were no studies that reported skin breaks/ ulcers/blisters/skin necrosis as an outcome. Hence, we could not estimate the related IPC effect in hospitalized medical patients.
Resource use. The panel judged the cost of IPC to be small and to probably be cost effective, as appropriate prophylaxis provides better value in terms of costs and health gains than routine DVT screening. [bib_ref] Screening and prevention of venous thromboembolism in critically ill patients: a decision..., Sud [/bib_ref] Feasibility, acceptability, and equity considerations. The panel judged the feasibility of the use of IPC Very low CI -confidence interval, GCS -graduated compression stockings, HR -hazard ratio may vary among hospitals across the Kingdom of Saudi Arabia and judged that the intervention is probably acceptable. The panel judged IPC impact on health inequity is probably increased due to cost and availability. Balance between desirable and undesirable consequences. The panel judged the benefits of IPC/ SCD for the thromboprophylaxis to probably outweigh the harms in critically ill medical patients who are bleeding or at high risk of bleeding. Evidence certainty was considered to be very low. The panel judged the intervention to be low-cost, probably cost-effective, and probably acceptable.

## Recommendation 9:
9a) In critically ill medical patients who are bleeding, or at high risk of bleeding, the panel suggests using intermittent IPC for VTE prophylaxis (conditional recommendation, very low quality evidence). 9b) In critically ill medical patients at high risk of VTE receiving pharmacological prophylaxis, the panel suggests adding intermittent IPC for VTE prophylaxis (conditional recommendation, very low quality evidence).
Monitoring and evaluation. Monitoring IPC use adherence should be considered.
Research priorities. Additional studies on IPC in ICU populations are needed.

## Thromboprophylaxis in chronically ill patients
Question 10: Should thromboprophylaxis be used in chronically ill medical patients?
Summary of findings. Our literature search did not identify any eligible trial.
Benefits and harms of the option. There were no studies that reported DVT, PE, major bleeding, minor bleeding, thrombocytopenia, and all-cause mortality as outcomes. Therefore, we could not estimate thromboprophylaxis effect compared to no thromboprophylaxis in chronically ill medical patients.
Resource use. The panel were uncertain about the cost, or cost-effectiveness of thromboprophylaxis in chronically ill medical patients.
Feasibility, acceptability, and equity considerations. The panel deemed thromboprophylaxis to probably not be feasible, or acceptable in chronically ill medical patients. The panel were uncertain about thromboprophylaxis impact on health inequity in chronically ill patients.
Balance between desirable and undesirable consequences. The panel judged thromboprophylaxis harms to probably outweigh its benefits in chronically ill medical patients. Evidence certainty was considered very low. The panel members were uncertain regarding the intervention cost and cost-effectiveness and judged it to probably be neither feasible nor acceptable.

## Recommendation 10:
In chronically ill medical patients the panel suggests not using over using prophylaxis for VTE (conditional recommendation, very low quality evidence).
Research priorities. Trials testing thromboprophylaxis efficacy and safety in chronically ill patients are needed.
Discussion. This clinical practice guideline provides guidance on thromboprophylaxis in hospitalized medical and critically ill patients in KSA. Although other thromboprophylaxis guidelines exist, [bib_ref] Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, Kahn [/bib_ref] [bib_ref] Clinical Guidelines Committee of the American College of P. Venous thromboembolism prophylaxis..., Qaseem [/bib_ref] it takes into consideration more recent evidence (up to December (from 0 fewer to 0 fewer) Very low MD -mean difference, RR -relative risk, CI -confidence interval, HR -hazard ratio, IPC -intermittent pneumatic compression 2014), and is tailored for the Saudi context. Moreover, the Saudi recommendations are more elaborate than those of the American College of Physicians, 13 but more concise than those of American College of Chest Physicians. [bib_ref] Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, Kahn [/bib_ref] Certain recommendations in this guideline are similar to those in other guidelines, but others are different. For instance, the 2011 American College of Physicians', [bib_ref] Clinical Guidelines Committee of the American College of P. Venous thromboembolism prophylaxis..., Qaseem [/bib_ref] the 2012 American College of Chest Physicians' 12 and the Saudi guidelines recommended pharmacologic thromboprophylaxis using a heparin for hospitalized medical patients. Additionally, the 3 guidelines recommended against GCS use in these patients. On the other hand, the Saudi guideline recommended pharmacologic prophylaxis in critically ill patients and favored LMWH over UFH, whereas the 2012 American College of Chest Physicians' guideline only suggested LMWH or UFH thromboprophylaxis. [bib_ref] Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, Kahn [/bib_ref] The target audience of this guideline includes internists of various subspecialties and intensivists working in KSA. The guideline may benefit other healthcare professionals like public health officers and policy makers. However, clinicians, patients, third-party payers, institutional review committees, other stakeholders and courts should not view the guideline recommendations as dictating binding standards. Indeed, the recommendations do not take into consideration the specific features of individual clinical cases. The remarks following each recommendation are intended to facilitate its interpretation and be given due attention. The Saudi Expert Panel suggested local research on the values and preferences of the Saudi population regarding VTE in general, and studies on the effectiveness of the various modalities of VTE treatment and their potential side effects.
The dissemination of this guideline to healthcare providers in KSA is crucial, and the MOH has a particularly important role to achieve this goal. More crucial is the implementation of the guideline recommendations. Several interventions have been suggested and include order sets that incorporated thromboprophylaxis orders, computer alerts, and continuing medical education with or without quality assurance. [bib_ref] Changing clinical practice. Prospective study of the impact of continuing medical education..., Anderson [/bib_ref] [bib_ref] The effect of a continuing medical education program on Venous thromboembolism prophylaxis..., Al-Hameed [/bib_ref] Multifaceted strategies seem to be more effective than any single approach in improving VTE prophylaxis in hospitals. [bib_ref] Implementing guidelines for venous thromboembolism prophylaxis in a large Italian teaching hospital:..., Scaglione [/bib_ref] [bib_ref] Improved use of thromboprophylaxis for deep vein thrombosis following an educational intervention, Cohn [/bib_ref] [bib_ref] Improving the use of venous thromboembolism prophylaxis in an Australian teaching hospital, Gallagher [/bib_ref] [bib_ref] Improving adherence to venous thromoembolism prophylaxis using multiple interventions, Al-Tawfiq [/bib_ref] [bib_ref] A systematic review of strategies to improve prophylaxis for venous thromboembolism in..., Tooher [/bib_ref] In conclusions, the appropriate choice of thromboprophylaxis modality should be a cornerstone in the management of hospitalized medical and critically ill patients. This evidence-based guideline provides assistance for healthcare providers working in KSA. Healthcare authorities should take the extra step of ensuring its implementation.
[table] Table 1 -: Interpretation of strong and conditional (weak) recommendations according to the Grading of Recommendations, Assessment, Development and Evaluation approach. [/table]
[table] Table 2 -: Heparin compared to no heparin for deep venous thrombosis prophylaxis of in acutely ill medical patients. [/table]
[table] Table 4 -: Extended duration compared to regular duration for the thromboprophylaxis of VTE in acutely ill hospitalized medical patients [/table]
[table] Table 5 -: Graduated compression stockings versus no graduated compression stockings in hospitalized medical patients. [/table]
[table] Table 6 -: Intermittent pneumatic compression devices versus no intermittent pneumatic compression devices in hospitalized medical patients. [/table]
[table] Table 8 -: Low molecular weight heparin versus unfractionated heparin for critically ill patients. The panel judged GCS use to probably be both feasible and acceptable. The panel were uncertain about the impact of LMWH on health inequity in critically ill patients. [/table]
[table] Table 9 -: Graduated compression stockings compared to no graduated compression stockings for critically ill patients [/table]
[table] Table 10 -: Intermittent pneumatic compression compared to no intermittent pneumatic compression for critically ill patients. [/table]