ASH Draft Recommendations for Heparin-Induced Thrombocytopenia. Draft

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1 ASH Recommendations for Heparin-Induced Thrombocytopenia INTRODUCTION American Society of Hematology (ASH) guidelines are based on a systematic review of available evidence. Through a structured process, a guideline panel makes judgements about the evidence and forms recommendations. The public comment period occurs after recommendations are formed but before a manuscript report of the guidelines has been finalized and before ASH organizational approval of the guidelines. Comments collected during the open comment period are provided to the guideline panel for review prior to finalizing the guidelines. These draft recommendations are not final and therefore are not intended for use or citation. To submit comments on the draft recommendations, please visit Only comments submitted via the online survey will be reviewed by the guideline panel. The public comment period for these draft recommendations is September 1 October 2, RECOMMENDATIONS Section 1: Screening asymptomatic patients for HIT 1.1a. For patients receiving heparin in whom the risk of HIT is considered to be intermediate ( %) or high (> 1.0%), the panel suggests platelet count monitoring to screen for HIT. (Conditional recommendation, very low certainty of the evidence) 1.1b. For patients receiving heparin in whom the risk of HIT is considered to be low (< 0.1%), the panel suggests against platelet count monitoring to screen for HIT. (Conditional recommendation, very low certainty in the evidence) Remarks: High risk populations include surgical and trauma patients receiving postoperative UFH thromboprophylaxis. Intermediate risk populations include medical and obstetrical patients receiving UFH thromboprophylaxis and surgical and trauma patients receiving LMWH thromboprophylaxis. Low risk patients include medical and obstetrical patients receiving LMWH thromboprophylaxis and any patients receiving fondaparinux. In patients in whom platelet count monitoring is considered appropriate, the platelet count should be measured at least every other day from initiation of heparin until day 14 or until heparin is stopped, whichever occurs first. It is acceptable not to begin monitoring the platelet count until day 4 unless the patient has received heparin in the 30 days prior to the current course of heparin. Section 2: Diagnosis and initial management of patients with suspected HIT Recommendations 2.1 to 2.10 should be considered together when testing and treating patients with suspected HIT. The recommendations sequence of tests and treatment are illustrated in figure In patients with suspected HIT, the panel recommends using the 4Ts score to estimate the probability of HIT rather than a gestalt approach. If there is an intermediate or high probability 4Ts score, the panel recommends an immunoassay. If the immunoassay is positive and functional assay is available, the panel recommends a functional assay. (Strong recommendation, moderate certainty of evidence) Remarks: Missing or inaccurate information may lead to a faulty 4Ts score and inappropriate management decisions. Every effort should be made to obtain accurate and complete information necessary to calculate the 4Ts score. If key information is missing, it may be prudent to err on the side of a higher 4Ts score. Patients should be reassessed frequently. If there is a change in the clinical picture, the 4Ts score should be recalculated.

2 Different immunoassays and functional assays are available. The choice of assay may be influenced by diagnostic accuracy, availability, cost, feasibility, and turnaround time. If an enzyme linked immunoassay is used, a low threshold is preferred over a high threshold. In some settings, the functional assay may not be available and decisions may need to be made based on the results of the 4Ts score and immunoassay. A functional assay may not be necessary in patients with a high 4Ts score and strongly positive immunoassay. In some centers, a functional assay may be performed in tandem with an immunoassay for quality assurance or efficiency In patients with suspected HIT and a low probability 4Ts score, the panel recommends against HIT laboratory testing. (Strong recommendation, moderate certainty of evidence) 2.3. In patients with suspected HIT and a low probability 4Ts score, the panel recommends against empiric treatment for HIT (i.e. against discontinuation of heparin and initiation of a non-heparin anticoagulant). (Strong recommendation, moderate certainty of evidence) 2.4. In patients with suspected HIT and an intermediate probability 4Ts score who have no other indication for therapeutic intensity anticoagulation, the panel recommends discontinuation of heparin. (Strong recommendation, moderate certainty of evidence) The panel suggests initiation of a non-heparin anticoagulant at prophylactic intensity if the patient is at high bleeding risk and at therapeutic intensity if the patient is not at high bleeding risk. (Strong recommendation, moderate certainty of evidence) 2.5. In patients with suspected HIT and an intermediate probability 4Ts score who have another indication for therapeutic intensity anticoagulation, the panel recommends discontinuation of heparin. (Strong recommendation, moderate certainty of evidence) The panel suggests initiation of a non-heparin anticoagulant at therapeutic intensity. (Conditional recommendation, moderate certainty of evidence) 2.6. In patients with suspected HIT and a high probability 4Ts score, the panel recommends discontinuation of heparin and initiation of a non-heparin anticoagulant at therapeutic intensity. (Strong recommendation, moderate certainty of evidence) 2.7. In patients with an intermediate probability 4Ts score and a negative immunoassay, the panel recommends discontinuation of the non-heparin anticoagulant and resumption of heparin, if indicated. (Strong recommendation, moderate certainty of evidence) 2.8. In patients with a high probability 4Ts score and a negative immunoassay, the panel recommends discontinuation of the non-heparin anticoagulant and resumption of heparin, if indicated. (Strong recommendation, moderate certainty of evidence) 2.9. In patients with an intermediate probability 4Ts score and a positive immunoassay, the panel recommends continued avoidance of heparin and continued administration of a non-heparin anticoagulant at therapeutic intensity. For those patients who were receiving prophylactic intensity therapy, the panel recommends providing therapeutic intensity therapy. (Strong recommendation, moderate certainty of evidence) In patients with a high probability 4Ts score and a positive immunoassay, the panel recommends continued avoidance of heparin and continued administration of a non-heparin anticoagulant. (Strong recommendation, moderate certainty of evidence) Section 3: Management of the acute phase of HIT 3.1. In patients with acute HITT or acute isolated HIT, the panel recommends discontinuation of heparin and initiation of a non-heparin anticoagulant. (Strong recommendation, moderate certainty of evidence) 3.2. In patients with acute HITT or acute isolated HIT, the panel recommends treatment with a non-heparin anticoagulant at therapeutic intensity dosing rather than prophylactic intensity dosing. (Strong recommendation, very low certainty in the evidence)

3 3.3. In patients with acute HITT or acute isolated HIT and no other indication for antiplatelet therapy, the panel suggests treatment with a non-heparin anticoagulant alone rather than in combination with an antiplatelet agent. (Conditional recommendation, low certainty of the evidence) 3.4. In patients with acute HITT or acute isolated HIT, the panel suggests treatment with argatroban, bivalirudin, danaparoid, fondaparinux, or a direct oral anticoagulant. (Conditional recommendation, very low certainty in the evidence) Remarks: The choice of agent may be influenced by drug factors (availability, cost, ability to monitor the anticoagulant effect, route of administration, half-life), patient factors (kidney function, liver function, bleeding risk, clinical stability), and experience of the clinician. In patients with critical illness, increased bleeding risk, or increased potential need for urgent procedures, argatroban, bivalirudin, and danaparoid may be preferred. These patients may require close monitoring. Fondaparinux and the direct oral anticoagulants are reasonable options in clinically stable patients at average bleeding risk. The same contraindications to their use in the treatment of acute venous thromboembolism should be applied in determining their appropriateness for patients with HIT. In patients with HIT complicated by arterial thromboembolism, a parenteral non-heparin anticoagulant may be preferred because few such patients have been treated with a direct oral anticoagulant. If a direct oral anticoagulant is to be used, the panel prefers rivaroxaban because most of the published experience in HIT is with this agent. Various dosing regimens have been reported. For patients with acute HITT, the panel prefers rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg daily. For patients with acute isolated HIT, the panel prefers rivaroxaban 15 mg twice daily until platelet count recovery followed by 20 mg daily if there is an indication for ongoing anticoagulation In patients with acute HITT or acute isolated HIT, the panel recommends against routine insertion of an inferior vena cava filter. (Strong recommendation, moderate certainty of the evidence) 3.6. In patients with acute HITT or acute isolated HIT, the panel recommends against initiation of a VKA prior to platelet count recovery (usually a platelet count of /L). (Strong recommendation, moderate certainty of the evidence) Remarks: This recommendation also applies to patients who are taking a VKA at the onset of acute HITT or acute isolated HITT. In these patients VKA would be discontinued and vitamin K administered In patients with acute HITT or acute isolated HIT who are at average bleeding risk, the panel suggests against routine platelet transfusion. (Conditional recommendation, low certainty in the evidence) Remarks: Platelet transfusion may be an option for patients with active bleeding or at high bleeding risk. 3.8a. In patients with acute isolated HIT, the panel suggests bilateral lower-extremity compression ultrasonography to screen for asymptomatic proximal deep vein thrombosis. (Conditional recommendation, very low certainty in the evidence) 3.8b. In patients with acute isolated HIT and an upper-extremity central venous catheter, the panel suggests upperextremity compression ultrasonography in the limb with the catheter to screen for asymptomatic deep vein thrombosis. The panel suggests against upper-extremity compression ultrasonography in limbs without central venous catheters to screen for asymptomatic deep vein thrombosis. (Conditional recommendation, very low certainty in the evidence) Remark: These recommendations do not apply to patients with symptoms suggestive of DVT, who would require diagnostic imaging In patients with acute isolated HIT and no asymptomatic deep vein thrombosis identified by screening compression ultrasonography, the panel suggests that anticoagulation be continued, at a minimum, until platelet count recovery (usually a platelet count of /L). The panel suggests against continuing treatment 3 months unless the patient has persistent HIT without platelet count recovery. (Conditional recommendation, very low certainty of evidence) In patients with subacute HIT, the panel suggests treatment with a direct oral anticoagulant (dabigatran, rivaroxaban, apixaban, edoxaban) rather than VKA. (Conditional recommendation, moderate certainty in the evidence)

4 Remarks: The choice of agent may be influenced by drug factors (availability, cost, ability to monitor the anticoagulant effect, route of administration, half-life), patient factors (kidney function, liver function, bleeding risk, clinical stability), and experience of the clinician. Direct oral anticoagulants are reasonable options in clinically stable patients at average bleeding risk. The same contraindications to their use in the treatment of acute venous thromboembolism should be applied in determining their appropriateness for patients with HIT. Section 4: Cardiovascular surgery 4.1. In patients with acute HIT or subacute HIT A, who require cardiovascular surgery, the panel recommends delaying surgery until the patient has subacute HIT B or remote HIT (see recommendation 4.2), if feasible. (Best practice statement) If delaying surgery is not feasible, the panel suggests intraoperative anticoagulation with bivalirudin or preoperative plasma exchange and heparin or heparin and an antiplatelet agent. (Conditional recommendation, low certainty in the evidence) Remarks: Choice of strategy may be influenced by availability, cost, and clinician experience. If the strategy of preoperative plasma exchange and heparin or heparin and an antiplatelet agent is used, treatment with heparin would be limited to the intraoperative setting and avoided before and after surgery In patients with subacute HIT B or remote HIT who require cardiovascular surgery, the panel suggests intraoperative anticoagulation with heparin rather than treatment with a non-heparin anticoagulant or preoperative plasma exchange and heparin or heparin and an antiplatelet agent. (Conditional recommendation, very low certainty in the evidence) Remarks: Treatment with heparin would be limited to the intraoperative setting and avoided before and after surgery. Section 5: Percutaneous cardiovascular intervention 5.1. In patients with acute HIT or subacute HIT A who require percutaneous cardiovascular intervention, the panel suggests treatment with bivalirudin rather than a different non-heparin anticoagulant. (Conditional recommendation, low certainty of evidence) Remarks: If bivalirudin is not available or there is a lack of institutional experience, argatroban might be a suitable substitute. Choice of drug may be influenced by drug availability, cost, ability to monitor the anticoagulant effect, and clinician experience In patients with subacute HIT B or remote HIT who require percutaneous cardiovascular intervention, the panel suggests treatment with bivalirudin rather than UFH. (Conditional recommendation, very low certainty of evidence) Remarks: Heparin is an acceptable alternative in patients with subacute HIT B or remote HIT if a suitable non-heparin anticoagulant is not available or clinician experience is lacking. If heparin is used, exposure should be limited to the intraprocedural setting and should be avoided before and after the procedure. If bivalirudin is not available or there is a lack of institutional experience, argatroban might be a suitable substitute. Choice of drug may be influenced by drug availability, cost, ability to monitor the anticoagulant effect, and clinician experience. Section 6: Renal replacement therapy 6.1. In patients with acute HIT who are on renal replacement therapy and require anticoagulation to prevent thrombosis of the dialysis circuitry, the panel suggests treatment with argatroban, danaparoid, or bivalirudin rather than other nonheparin anticoagulants. (Conditional recommendation; very low certainty in the evidence). Remark: Choice of agent may be influenced by drug factors (availability, cost), patient factors (liver function), and experience of the clinician In patients with subacute HIT A or subacute HIT B or remote HIT who are on renal replacement therapy, are not otherwise on anticoagulation, and require anticoagulation to prevent thrombosis of the dialysis circuit, the panel suggests regional citrate rather than heparin or other non-heparin anticoagulants. (Conditional recommendation; very low certainty in the evidence).

5 Section 7: Venous thromboembolism treatment and prophylaxis in patients with remote HIT 7.1. In patients with remote HIT who require venous thromboembolism treatment or prophylaxis, the panel recommends administration of a non-heparin anticoagulant (e.g. apixaban, dabigatran, edoxaban, fondaparinux, rivaroxaban, vitamin K antagonist) rather than UFH or LMWH. (Strong recommendation, very low certainty in the evidence) Remark: Apart from the recommendation to avoid heparin anticoagulants, these patients should be treated similarly to those without a history of HIT. For recommendations on choice of non-heparin anticoagulant for VTE prophylaxis, please refer to the American Society of Hematology Guidelines on Prevention of Venous Thromboembolism in Surgical Hospitalized Patients and Prevention of Venous Thromboembolism in Medical Hospitalized Patients. For recommendations on choice of agent for VTE treatment, please refer to the American Society of Hematology Guidelines on Treatment of Acute VTE. Section 8: Emergency identification 8.1a. In patients with a history of HIT in the last 3 months, the panel suggests carrying or wearing an emergency identifier (e.g. an emergency pendant or bracelet). (Conditional recommendation, very low certainty of evidence) Remarks: The emergency identifier should include the drug (heparin), the reaction to the drug (HIT), and the date HIT was diagnosed. 8.1b. In patients with a history of HIT more than 3 months ago, the ASH panel suggests against carrying or wearing an emergency identifier. (Conditional recommendation, very low certainty of evidence)

6 Recommendations 1.1a & 1.1b Should platelet count monitoring to screen for HIT vs. no platelet count monitoring be used for asymptomatic patients who are receiving UFH or LMWH or fondaparinux? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: SETTING: PERSPECTIVE: Assessment PROBLEM Is the problem a priority? No Probably no Probably yes Yes asymptomatic patients receiving UFH, LMWH, or fondaparinux platelet count monitoring no platelet count monitoring Pulmonary Embolism; Limb Amputation; Ischemic Stroke; Deep Venous Thrombosis in the Upper Leg; Pulmonary Embolism; Deep Venous Thrombosis in the Lower Leg; Deep Venous Thrombosis in the Upper Arm; Inpatient and outpatient Clinical recommendation - population perspective BACKGROUND: Approximately 12 million hospitalized patients each year are exposed to heparin for thromboprophylaxis. Heparininduced thrombocytopenia (HIT) is a potential complication of heparin therapy in which there is a low blood platelet count (thrombocytopenia). There may be risk factors to consider when estimating a patient s baseline risk of HIT. Early detection of HIT may lead to timely initiation of appropriate treatment. Panel members recused as a result of risk of conflicts of interest: None JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS Approximately 12 million hospitalized patients each year are exposed to heparin for thromboprophylaxis. Heparin-induced thrombocytopenia (HIT) is a potential complication of heparin therapy caused by either unfractionated heparin or low molecular-weight heparin (LMWH). Results from a meta-analysis suggest that the absolute risk for HIT for patients treated with LMWH is 0.2% (95% CI, 0.1%-0.4%), and 2.6% (95% CI, 1.5%-3.8%) if treated with UFH 1.

7 How substantial are the desirable anticipated effects? Trivial Small Moderate Large No randomized controlled trials or non-randomized studies compared the frequency and timing of monitoring of platelet counts. One retrospective cohort study reported on 127 patients with confirmed HIT over 14 years 2. The risk of thrombosis did not differ between patients who were treated with heparin cessation alone or heparin cessation and initiation of warfarin. Approximately 50% of patients experienced a thrombotic event in the 30 days following HIT diagnosis. Treating HIT can result in better outcomes (reduction of thrombotic events). Patients with a greater risk of HIT will receive greater benefits from screening and early diagnosis. The guideline panel agreed to use baseline risk to inform this question. DESIRABLE EFFECTS In a meta-analysis of trials to assess the value of parenteral treatment with lepirudin, the combined risk for the combined incidence of death, new thromboembolic complications, and limb amputation was highest in the period between diagnosis of HIT and the start of therapy (combined event rate per patient per day of 6.1%) 3. The baseline risk of HIT in various populations is provided below. We included studies with >500 people when available; when not available smaller studies provided data. One meta-analysis identified the following incidence of HIT in postoperative (orthopedic and cardiac) populations based on treatment with either UFH or LMWH: UFH: 2.6%; LMWH: 0.2% 1. Baseline risks of HIT Population Reference Predictive factors Postoperative (orthopaedic and cardiac) UFH 2.6% LMWH 0.2% Martel % Sun 2016 Greater BMI, and lower preoperative platelet count; not associated with previous cardiac procedure Postoperative with heparin or with (cardiac) heparin within 48 hours 1.1% Cegarra- Sanmartin 2014 Two major determinants of risk of HIT are type of heparin and patient population. UFH places patients at greater risk than LMWH. LMWH places patients at greater risk than fondaparinux. Based on the evidence, the panel identified high risk populations (greater than 1% risk of HIT) who would have a large benefit from being screened and include surgical and trauma patients receiving postoperative UFH thromboprophylaxis. Intermediate risk populations (0.1-1%) would have a moderate benefit from being screened for HIT and include medical and obstetrical patients receiving UFH thromboprophylaxis and surgical and trauma patients receiving LMWH thromboprophylaxis. Low risk patients (<0.1%) would have a trivial benefit of screening and include medical or obstetrical patients receiving LMWH and any patients receiving fondaparinux.

8 UNDESIRABLE EFFECTS CERTAINTY OF EVIDENCE How substantial are the undesirable anticipated effects? Large Moderate Small Trivial What is the overall certainty of the evidence of effects? Very low Low Moderate High No included studies With suspected HIT (surgical, medical, critically ill) Critically ill (UFH primarily) HIT with thrombosis (percent with HIT) Timing of monitoring: 0.6% Kuitunen % Kerendi % Walls % Cuker 2012 (CI 7 to 17%) 0.5% Crowther % Warkentin % Joseph % Tardy % Wan % Perry % Altuntas % Sun % Radaideh 2012 previous percutaneous coronary interventions; infectious endocarditis; class IV NYHA heart failure The typical window for HIT development is 5-14 days after heparin initiation. An exception is patients who have had previous heparin exposure in the last 30 days; these patients may be at risk for rapid onset of HIT beginning within hours of re-exposure 2,4. No research evidence was identified. Delays in treatment can result in poorer outcomes. The panel agreed that over diagnosis of HIT and subsequent inappropriate treatment is common and can be harmful and can be exacerbated by monitoring of asymptomatic patients. The magnitude of the harms does not appear to be related to the baseline risk of HIT in patients, likely because the timing and magnitude of drop in platelet count is not related to the risk factors. The panel agreed that the harms are moderate because the sequence of diagnosis and treatment events may results in inappropriate testing and changes in treatment. Some panelists placed a higher value on avoiding over diagnosis which could results from early monitoring prior to day 4, in particular in patients who may develop thrombocytopenia for reasons other than HIT (e.g., cardiac surgery). Other panelists placed a higher value on recording a platelet count trend beginning at day 1 until day 4 to assist in the interpretation of platelet counts between day 4 and day 14. The evidence for baseline risk is moderate to high quality but was rated down to very low because this evidence is indirectly providing evidence of the harms of not monitoring patients. The panel agreed to not include studies that only used diagnosis of thrombocytopenia as an indicator for HIT in estimating baseline risk, as it

9 may overestimate the number of patients with true HIT. VALUES BALANCE OF EFFECTS Is there important uncertainty about or in how much people value the main outcomes? Important uncertainty or Possibly important uncertainty or Probably no important uncertainty or No important uncertainty or Does the balance between desirable and undesirable effects favor the intervention or the comparison? Favors the comparison Probably favors the comparison (<0.1%) Does not favor either the intervention or the comparison Probably favors the intervention (0.1-1% or >1%) Favors the intervention No research evidence was identified. No research evidence was identified. The panel agreed that patients may have different values and preferences for screening based on whether they are at low or high risk and treated with UFH. The panel placed greater value on preventing the consequences due to HIT, (e.g., thrombosis, amputation, or mortality) than major bleeding.

10 RESOURCES REQUIRED CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES COST EFFECTIVENESS How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings What is the certainty of the evidence of resource requirements (costs)? Very low Low Moderate High No included studies Does the cost-effectiveness of the intervention favor the intervention or the comparison? Favors the comparison Probably favors the comparison (<0.1%) Does not favor either the intervention or the comparison Probably favors the intervention (0.1-1% or >1%) Favors the intervention No included studies No research evidence was identified. No research evidence was identified. No research evidence was identified. The panel agreed that the cost of obtaining a platelet count is small. Per patient the cost is small; however, there are many patients that would need to be monitored given the frequency of heparin use. Considerations of the panel include the cost of over-monitoring, cost incurred by harms of stopping anticoagulation or starting non-heparin anticoagulation. High baseline risk: The panel agreed that the harms of monitoring are probably less costly than the benefits of monitoring. Moderate baseline risk: The panel agreed that the harms of monitoring are probably less costly than the benefits of monitoring. Low baseline risk: The panel agreed that the costs of the harms of not monitoring are probably less than the costs of monitoring.

11 What would be the impact on health equity? No research evidence was identified. Platelet tests are widely available. EQUITY Reduced Probably reduced Probably no impact Probably increased Increased ACCEPTABILITY FEASIBILITY Is the intervention acceptable to key stakeholders? No Probably no Probably yes Yes Is the intervention feasible to implement? No Probably no Probably yes Yes No research evidence was identified. No research evidence was identified. Acceptability of over monitoring may vary among different patients and physicians. Most stakeholders would be accepting of platelet count monitoring. Most patients with moderate and high baseline risk are receiving platelet count monitoring for reasons other than HIT screening. Platelet count testing is feasible. The panel agreed that bringing outpatients back to the clinic to monitor platelet count might be less practical. If the patient is in the hospital then platelet count monitoring is more feasible.

12 Summary of judgments JUDGEMENT IMPLICATIONS PROBLEM No Probably no Probably yes Yes Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS CERTAINTY OF EVIDENCE VALUES BALANCE OF EFFECTS RESOURCES REQUIRED CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Large Moderate Small Trivial Varies Don't know Very low Low Moderate High Important uncertainty or Favors the comparison Large costs Possibly important uncertainty or Probably favors the comparison Moderate costs Probably no important uncertainty or Does not favor either the intervention or the comparison Negligible costs and savings No important uncertainty or Probably favors the intervention Very low Low Moderate High Favors the intervention Varies No included studies Don't know Moderate savings Large savings Varies Don't know No included studies Probably favors the comparison (<0.1%) Probably favors the intervention (0.1-1% or >1%) COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies No included studies

13 JUDGEMENT IMPLICATIONS EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know Conclusions TYPE OF RECOMMENDATION RECOMMENDATION Strong recommendation against the intervention Conditional recommendation against the intervention Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention Strong recommendation for the intervention 1.1a. For patients receiving heparin in whom the risk of HIT is considered to be intermediate ( %) or high (> 1.0%), the panel suggests platelet count monitoring to screen for HIT. (Conditional recommendation, very low certainty of the evidence) 1.1b. For patients receiving heparin in whom the risk of HIT is considered to be low (< 0.1%), the panel suggests against platelet count monitoring to screen for HIT. (Conditional recommendation, very low certainty in the evidence) Remarks: High risk populations include surgical and trauma patients receiving postoperative UFH thromboprophylaxis. Intermediate risk populations include medical and obstetrical patients receiving UFH thromboprophylaxis and surgical and trauma patients receiving LMWH thromboprophylaxis. Low risk patients include medical and obstetrical patients receiving LMWH thromboprophylaxis and any patients receiving fondaparinux. In patients in whom platelet count monitoring is considered appropriate, the platelet count should be measured at least every other day from initiation of heparin until day 14 or until heparin is stopped, whichever occurs first. It is acceptable not to begin monitoring the platelet count until day 4 unless the patient has received heparin in the 30 days prior to the current course of heparin.

14 JUSTIFICATION The benefits from early detection among high and moderate risk patients would probably outweigh the harms from over diagnosis and inappropriate treatment. The costs, acceptability, and feasibility also favored monitoring of high and moderate risk patients. The harms of over diagnosis and inappropriate treatment among low risk patients would probably outweigh the benefits of early detection. SUBGROUP CONSIDERATIONS IMPLEMENTATION CONSIDERATIONS MONITORING AND EVALUATION RESEARCH PRIORITIES References of Cited Studies: Studies examining reduced monitoring in moderate risk patients could provide higher quality evidence; however, it was not seen as a high priority by the panel. 1. Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood. 2005;106(8): Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. The American journal of medicine. 1996;101(5): Greinacher A, Eichler P, Lubenow N, Kwasny H, Luz M. Heparin-induced thrombocytopenia with thromboembolic complications: Meta-analysis of 2 prospective trials to assess the value of parenteral treatment with lepirudin and its therapeutic aptt range. Blood. 2000;96(3): Lubenow N, Kempf R, Eichner A, Eichler P, Carlsson LE, Greinacher A. Heparin-induced thrombocytopenia: temporal pattern of thrombocytopenia in relation to initial use or reexposure to heparin. CHEST Journal. 2002;122(1):37-42.

15 EtD Platelet monitoring: Question 1.1a and 1.1b No randomized controlled trials or non-randomized studies compared the frequency and timing of monitoring of platelet counts. The risk of HIT in various populations is provided below. We included studies with >500 people when available; when not available smaller studies provided data. Baseline risks of HIT Population Reference Predictive factors Postoperative (orthopaedic and cardiac) UFH 2.6% LMWH 0.2% Martel % Sun 2016 Greater BMI, and lower preoperative platelet count; not associated with previous cardiac procedure with heparin or with heparin within 48 hours 1.1% Cegarra-Sanmartin 2014 Postoperative (cardiac) 0.6% Kuitunen % Kerendi 2007 previous percutaneous coronary interventions; infectious endocarditis; class IV NYHA heart failure 1.9% Walls 1995 With suspected HIT (surgical, medical, 11% Cuker 2012 critically ill) (CI 7 to 17%) Critically ill (UFH primarily) 0.5% Crowther % Warkentin % Joseph % Tardy 2006 HIT with thrombosis (percent with HIT) 55% Wan % Perry % Altuntas % Sun % Radaideh 2012

16 Time intervals to diagnosis and platelet recovery Study Time to diagnosis Platelet recovery Warkentin /243 had typical onset (70%) within 4 or more days after start of heparin (usually 5 to 10) how quickly not dependent on previous course of heparin. 73 (30%) had rapid less than 4 days - median 10.5 hours (IQR 2.1 to 18.1) all received heparin in last 100 days (usually last 3 weeks). Tardy 2006 HIT occurred after a median of 10.7 days (range 7.6 to 14.3) of hep treatment Sturtevant 2006 The time from commencement of heparin to the positive HIT screen (reflecting when the diagnosis was first suspected) ranged from 4 to 30 days (mean 14 days). Grouzi 2010 Days on heparin until HIT screen: range 2-16, median 7.2 (3.3 SD) Cegarra-Sanmartín 2014 The interval from the start of heparin therapy to diagnosis of HIT ranged from 4 to 32 days. Wan 2006 Joseph 2014 The mean time to clinical suspicion of HIT was 5.42 days. There were 22 cases that occurred earlier than 5 days after surgery, with a peak of 9 cases at 4 days and subsequent rapid decline and only 6 cases after 7 days (5 people from 10 to 15). Duration of exposure 7 days (3 to 10) before diagnosis For those treated for HIT who survived, the time for recovery of platelet count (> /L) was 3 12 days (mean 6 days). Days of platelet recovery 1-9, Median 4.1 (2 SD) (on lepirudin or fondaparinux) Mean time to recovery of platelet count after stopping heparin was 2.1 days (range: 1-5). Ali /100 had drop at day 3 and 4 On day 5-7 (the post op returned to normal at day 5) Martel 2005 References of Included Studies Systematic review UFH vs LMWH - from 9 to 11 days (one study after 30 days) 1. Ali N, Moiz B, Rehman Y, Salman M, Sami SA. The frequency of heparin induced thrombocytopenia in patients undergoing elective cardiac bypass surgeries. Journal of the Pakistan Medical Association. 2009;59(6): Althaus K, Strobel U, Fuerll B, Greinacher A. Improving the capability of the anti-pf4/heparin enzyme immunosorbent assay to rule out platelet activating PF4/heparin antibodies. Journal of Thrombosis and Haemostasis. 2009;7(S2): Cegarra-Sanmartin V, Gonzalez-Rodriguez R, Paniagua-Iglesias P, et al. Fondaparinux as a safe alternative for managing heparin-induced thrombocytopenia in postoperative cardiac surgery patients. Journal of Cardiothoracic and Vascular Anesthesia. 2014;28(4): Crowther MA, Cook DJ, Albert M, et al. The 4Ts scoring system for heparin-induced thrombocytopenia in medical-surgical intensive care unit patients. Journal of critical care. 2010;25(2): Cuker A, Gimotty PA, Crowther MA, Warkentin TE. Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: A systematic review and meta-analysis. Blood. 2012;120(20): Grouzi E, Kyriakou E, Panagou I, Spiliotopoulou I. Fondaparinux for the treatment of acute heparin-induced thrombocytopenia: A single-center experience. Clinical and Applied Thrombosis/Hemostasis. 2010;16(6):

17 7. Joseph L, Casanegra A, Dhariwal M, et al. Bivalirudin for the treatment of heparin-induced thrombocytopenia: A 9 year, 461 patient experience. Journal of the American College of Cardiology. 2014;1):A Kerendi F, Thourani VH, Puskas JD, et al. Impact of heparin-induced thrombocytopenia on postoperative outcomes after cardiac surgery. The Annals of thoracic surgery. 2007;84(5): Kuitunen A, Suojaranta-Ylinen R, Raivio P, Kukkonen S, Lassila R. Heparin-induced thrombocytopenia following cardiac surgery is associated with poor outcome. Journal of cardiothoracic and vascular anesthesia. 2007;21(1): Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood. 2005;106(8): Radaideh SM, Frenkel EP, Dowell JE, Sarode R, Shen YM. Incidence of isolated heparin-induced thrombocytopenia and risk of thrombosis by IgGspecific anti-pf4/heparin ELISA. Clinical and Applied Thrombosis/Hemostasis. 2012;18(2): Sturtevant JM, Pillans PI, Mackenzie F, Gibbs HH. Heparin-induced thrombocytopenia: Recent experience in a large teaching hospital. Internal Medicine Journal. 2006;36(7): Sun L, Gimotty PA, Lakshmanan S, Cuker A. Diagnostic accuracy of rapid immunoassays for heparin-induced thrombocytopenia. A systematic review and meta-analysis. Thrombosis and haemostasis. 2016;115(5): Tardy B, Lecompte T, Boelhen F, et al. Predictive factors for thrombosis and major bleeding in an observational study in 181 patients with heparin-induced thrombocytopenia treated with lepirudin. Blood. 2006;108(5): Wan C, Warner M, De Varennes B, Ergina P, Cecere R, Lachapelle K. Clinical Presentation, Temporal Relationship, and Outcome in Thirty-Three Patients with Type 2 Heparin-Induced Thrombocytopenia After Cardiotomy. Annals of Thoracic Surgery. 2006;82(1): Warkentin TE. Platelet count monitoring and laboratory testing for heparin-induced thrombocytopenia. Archives of pathology & laboratory medicine. 2002;126(11):

18 Recommendations 2.1 & 2.2 Should the following test strategy be used to diagnose HIT in patients who have received heparin and are suspected of heparin-induced thrombocytopenia (HIT): intermediate or high 4Ts score then immunoassay then functional assay when positive immunoassay? POPULATION: patients who have received heparin and are suspected of HIT INTERVENTION: a diagnostic test strategy (intermediate or high 4Ts score then immunoassay then functional assay when positive immunoassay) PURPOSE OF THE TEST: LINKED TREATMENTS: ANTICIPATED OUTCOMES: SETTING: PERSPECTIVE: SUBGROUPS: detection of HIT antibodies heparin or non-heparin anticoagulants for patients diagnosed with HIT Mortality; Major bleeding; Thromboembolic events; Limb amputation; Heparin-induced thrombocytopenia (recurrent acute); True positive; False positive; False negative; True negative; in-patient population BACKGROUND: Approximately 12 million hospitalized patients each year are exposed to heparin for thromboprophylaxis. Heparin-induced thrombocytopenia (HIT) is a potential complication of heparin therapy caused by either unfractionated heparin or low molecular-weight heparin (LMWH). Accurate diagnosis of HIT is needed to inform treatment decisions and may consist of a gestalt evaluation of risk based on clinical experience, a 4Ts score, an immunoassay and/or a functional assay. The 4Ts score is a risk assessment tool to determine the risk of developing HIT. The 4T score measures 1) magnitude of thrombocytopenia (2) timing of thrombocytopenia with respect to heparin exposure; (3) thrombosis or other sequelae of HIT; and (4) likelihood of other causes of thrombocytopenia. There are three categories of the 4Ts scoring system: High (score of 6-8); Intermediate (score of 4-5); Low (score of 0-3). HIT immunoassay tests have been developed to detect HIT antibodies by targeting complexes of platelet factor 4 (PF4) bound to heparin. HIT immunoassays vary by detection threshold and result time. Multiple types of immunoassays have been used to detect HIT: Enzyme-linked immunosorbent assay (ELISA) to detect immunoglobulin G (IgG) antibodies ELISA to detect polyspecific antibodies IgG-specific chemiluminescent assay (IgG-CA) Polyspecific chemiluminescent assay (Poly-CA) Particle gel immunoassay (PaGIA) Particle immunofiltration assay (PIFA) Lateral flow immunoassay (LFIA) Latex agglutination assay/latex particle-enhanced assay (HemosIL-Ab) Functional assays include the serotonin release assay (SRA), heparin-induced platelet activation (HIPA) test, platelet aggregation test (PAT), and flow cytometry-based assays. There has been some debate about the sequence of tests that should be used to diagnose HIT: - gestalt or 4Ts score followed by immunoassay followed by functional assay - gestalt or 4Ts score followed by functional assay - gestalt or 4Ts score followed by immunoassay When a sequence of tests has been used, treatment decisions are also made at various points when results are received. Treatments may include stopping or continuing heparin, and starting or stopping non-heparin anticoagulants. ASH conflict of interest declaration and management policies were applied and the following panel members were voting panel members (determining the direction and strength of the recommendation): [Information redacted for public review] Panel members recused as a result of risk of conflicts of interest: [Information redacted for public review]

19 Assessment JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS PROBLEM TEST ACCURACY DESIRABLE EFFECTS Is the problem a priority? No Probably no Probably yes Yes How accurate is the test? Very inaccurate Inaccurate Accurate Very accurate How substantial are the desirable anticipated effects? Trivial Small Moderate Large Varies Accurate diagnosis of HIT is needed to inform treatment decisions to prevent serious complications of HIT. The sequence of tests to identify patients is unclear. There are questions about whether a gestalt approach or the 4Ts score could be used to first identify patients at high risk and potentially treat; whether immunoassay tests could then be used; and whether functional assays are necessary. Washed platelet functional assays are considered the gold standard because of their specificity for the confirmation of HIT. However, there remains some uncertainty around the true sensitivity and specificity of functional assays. We found no systematic reviews or primary studies in which patients received a test or sequence of tests to diagnose HIT and then patient important outcomes were measured. Instead, we searched for systematic reviews and studies reporting the test accuracy of a gestalt approach, the 4Ts score, immunoassay tests and functional assay tests, and then calculated the number of patients correctly or incorrectly diagnosed (absolute effects) and their outcomes. We found one systematic review of studies assessing the accuracy of the 4Ts score (Cuker 2012). We updated this review but did not find additional studies, and then calculated sensitivity and specificity of the 4Ts score based on the included studies. We found two recent systematic reviews of the test accuracy of immunoassays (Nagler 2016 and Sun 2016). See Evidence Tables 1, 2, and 3 following the Evidence to Decision Framework for details of test accuracy of each strategy and the calculated absolute effects. When calculating the absolute effects, we assumed the prevalence of HIT among patients with suspected HIT as 11% (Cuker 2012); we used both an intermediate and high threshold for the 4Ts score; we used the low threshold with the IgG and Poly ELISAs immunoassays because of common use; and assumed the functional assay had 100% sensitivity and specificity. However, the panel acknowledged that the accuracy of the functional assay varies due to the technical complexity. Results for a sequence of tests including when immunoassays were negative have also been modeled but are not summarized below. See additional details of assumptions in the Tables). The intervention strategy, or strategy against which all other strategies were compared was a sequence of tests: an intermediate or high 4Ts score, followed by an immunoassay, followed by a functional assay when the immunoassay was positive. Absolute effects are shown for 1000 patients suspected of HIT. Although the intervention strategy only misclassified approximately 10/1000 suspected HIT patients, the panel noted that the calculated numbers are based on an assumption that the functional assay is 100% sensitive and specific and therefore the accuracy may be overestimated. The accuracy of the data for the immunoassays was modeled and most data were similar, with the exception of the high threshold for ELISAs (i.e. greater false negatives). Because of their common use in clinical practice, the ELISAs at low threshold were modeled with the

20 UNDESIRABLE EFFECTS How substantial are the undesirable anticipated effects? Large Moderate Small Trivial Varies 4Ts (intermediate and high), immunoassay, functional assay (when immunoassay is positive) In 1000 patients with suspected HIT who received this sequence of tests (intervention strategy), approximately people received the immunoassay test after the 4Ts score people received a functional assay test after a positive immunoassay test people were correctly identified as having HIT (true positives) - 10 cases of HIT were missed (false negatives) people were correctly identified as not having HIT (true negatives) - 0 people were incorrectly identified as having HIT (false positives) - in total, 410 people who do not have HIT would receive non-heparin anti-coagulants unnecessarily for varying periods of time depending on timing of laboratory tests 4Ts (intermediate and high) followed by immunoassay only Compared to the intervention strategy, if the functional assay is not performed, approximately fewer functional assay tests would be performed - 55 more people would be incorrectly identified as having HIT (false positives) 4Ts (intermediate and high) followed by functional assay only Compared to the intervention strategy, if no immunoassay test is used and people identified at immediate or high risk with a 4Ts score received a functional assay test, approximately fewer people would receive a immunoassay test more people would receive a functional assay test 4Ts (high) followed by immunoassay and followed by functional assay for positive immunoassay Compared to the intervention strategy, if a high threshold 4Ts score is used, approximately fewer people would receive a immunoassay test fewer people would receive a functional assay test - 50 more people with HIT would be missed (more false negatives) fewer people who do not have HIT would receive non-heparin anti-coagulants unnecessarily for varying periods of time depending on timing of laboratory tests Gestalt followed by immunoassay and followed by functional assay for positive immunoassay Compared to the intervention strategy, if the 4Ts score is not used before an immunoassay test followed by functional assay test, approximately more people would have an immunoassay - 80 more people would have a functional assay test - 5 fewer people with HIT would be missed (fewer false negatives) more people who do not have HIT would receive non-heparin anti-coagulants unnecessarily for varying periods of time depending on timing of laboratory tests functional assay. The panel agreed that there may be patients who have a high 4Ts score and a strongly positive immunoassay test in whom it may not be necessary to do a functional assay. This is because there would be no patients incorrectly identified as having HIT (i.e., no false positives). Diagnostic test accuracy outcomes based on evidence for recommendations 3.1 to 3.11: True positives - Patients will appropriately be treated and/or have more testing (reduced risk of thrombosis by 55% - 70%) False negatives - Patients will be missed and may experience serious consequences of HIT, e.g. thrombosis (300/1000 more people with HIT if not treated), amputation (60/1000 more people with HIT if not treated), death (60/1000 more people with HIT if not treated) True negatives - Patients will appropriately not have further testing and will appropriately not be treated for HIT

21 False positives - Patients will continue with unnecessary testing and/or may experience serious consequences of unnecessary treatment for HIT (e.g. bleeding ~8 to 35% over treatment duration), and may be falsely labeled as having HIT over the long term CERTAINTY OF THE EVIDENCE OF TEST ACCURACY CERTAINTY OF THE EVIDENCE OF TEST'S EFFECTS What is the overall certainty of the evidence of test accuracy? Very low Low Moderate High No included studies What is the overall certainty of the evidence for any critical or important direct benefits, adverse effects or burden of the test? Very low Low Moderate High No included studies Overall, there was high heterogeneity for specificity of the 4Ts score; and heterogeneity was not calculated but is expected to be high across the other tests. There are more studies assessing accuracy data for the ELISAs, in particular, for low threshold. The risk of bias was assessed in the reviews, and there was serious concern with selection bias and with the reference standard. No research evidence was identified. Although no research evidence was identified, the guideline panel agreed based on observations that patients would likely not experience direct harm or benefits from the tests.

22 CERTAINTY OF THE EVIDENCE OF MANAGEMENT'S EFFECTS CERTAINTY OF THE EVIDENCE OF TEST RESULT/MANAGEMENT CERTAINTY OF EFFECTS What is the overall certainty of the evidence of effects of the management that is guided by the test results? Very low Low Moderate High No included studies How certain is the link between test results and management decisions? Very low Low Moderate High No included studies What is the overall certainty of the evidence of effects of the test? Very low Low Moderate High No included studies Evidence comparing starting non-heparin anti-coagulants to staying on heparin (or discontinuing heparin alone) was overall moderate quality. See evidence for recommendations 3.1 to The panel agreed that the link between how patients would be managed and the consequences of the false and true negatives and positives was moderate, due to some practice variation..

23 VALUES BALANCE OF EFFECTS Is there important uncertainty about or in how much people value the main outcomes? Important uncertainty or Possibly important uncertainty or Probably no important uncertainty or No important uncertainty or Does the balance between desirable and undesirable effects favor the intervention or the comparison? Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the Utility values were identified for the outcomes of thrombotic events and bleeding: - DVT (utility): Most people find DVT probably has a small impact on lives. There is likely important for this assessment 23,24. (Moderate certainty of evidence due to inconsistency) - Pulmonary embolism (utility): People find pulmonary embolism probably a small impact on lives. There is likely important for this assessment 23. (Moderate certainty of evidence due to inconsistency) - Gastrointestinal tract bleeding event (utility): People find gastrointestinal tract bleeding event probably has a small impact on lives. There is likely important for this assessment 25. (Moderate certainty of evidence due to indirectness) - Muscular bleeding (utility): People find muscular bleeding event probably has a small impact on lives. There is likely important for this assessment 25. (Moderate certainty of evidence due to indirectness) - Central nervous system bleeding (including intracranial bleeding) (utility): People find central nervous system appears to have a moderate impact on their lives. There is likely no important for this assessment 26,27. (Very low certainty of evidence due to inconsistency, indirectness, and imprecision) - Major intracranial bleeding event (utility): People find major intracranial bleeding has a large impact on their lives. There is likely important for this assessment. (High certainty of evidence) - Minor intracranial bleeding event: People find minor intracranial bleeding has a large impact on their lives. There is likely important for this assessment. (High certainty of evidence) No research evidence was identified for the outcomes of mortality or limb amputation. Desirable and undesirable effects of the comparison strategies compared to the intervention strategy Comparison strategy Size of benefits with comparison Size of harms with comparison Implications of the comparison per 1000 patients 4Ts + IA (no FA) Trivial Small 55 more false positives (incorrectly diagnosed with HIT 4 19 more bleeds) Balance Probably favoring the intervention strategy 4Ts + FA (no IA) Trivial Trivial Does not favor either 4Ts High + IA + FA Moderate Large harms 50 more false negatives (missed cases - 15 more thromboses, 3 more amputations, 3 more deaths) 370 fewer people without HIT would discontinue heparin and receive non-heparin anticoagulants while awaiting laboratory testing Probably favoring the intervention strategy The guideline panel put higher value on avoiding false negatives (i.e. missing true HIT cases) than false positives (i.e. treating patients who do not have true HIT). This is because delay in initiation of appropriate treatment for true HIT cases may be associated with high risk of thrombosis, amputation, and death. These risks may be greater than the consequences of overtreating with non-heparin anti-coagulants in people without true HIT or labeling people inappropriately with HIT. On this basis, the panel equated the value of 10 false positives with 1 false negative.

24 RESOURCES REQUIRED intervention How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Gestalt + IA + FA Small Moderate 5 fewer false negatives (missed cases fewer thromboses, 0.3 fewer amputations, 0.3 fewer deaths) 490 more people without HIT would discontinue heparin and receive non-heparin anticoagulants while awaiting laboratory testing IA, immunoassay; FA, functional assay. Probably favoring the intervention strategy We calculated the costs of performing the tests in each strategy (not including costs of treatment or consequences; clinical hours or facilities, or benefits and harms of treatment). Estimated costs are per 1000 patients suspected with HIT. Costs of one IA test is 75 USD and FA test 325 USD (Pierce 2013). Strategy No. of IA tests performed (n) No. of FA tests performed (n) Estimated cost of tests No. of patients without HIT treated with nonheparin anticoagulants (short term) No. of patients without HIT treated with nonheparin anticoagulants (long term) No. of patients with HIT but not treated 4Ts + IA + FA Ts + IA (no FA) large cost in long term Relative costs compared to intervention strategy (4Ts + IA + FA) (downstream treatment effects not included) 10 Moderate costs 4Ts + FA (no IA) Negligible 4Ts High + IA + FA Moderate savings) Gestalt + IA + FA Large costs The guideline panel agreed that immunoassays typically take 1 day or more to receive results. Availability of the functional assays varies by institution, therefore costs may differ if the test needs to be sent to another institution. Quality assurance may also incur costs. IA, immunoassay; FA, functional assay.

25 CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES COST EFFECTIVENESS What is the certainty of the evidence of resource requirements (costs)? Very low Low Moderate High No included studies Does the costeffectiveness of the intervention favor the intervention or the comparison? Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies No included studies. Judgments of costs and benefits and harms described above were used to determine the overall cost effectiveness Strategy 4Ts + IA + FA Relative cost compared to 4Ts + IA + FA Benefits of the comparison Harms of the comparison Cost effectiveness compared to 4Ts + IA + FA 4Ts + IA (no FA) Moderate costs Trivial Small Less cost effective probably favors intervention strategy due to variable costs of treatments 4Ts + FA (no IA) Negligible Trivial Trivial Does not favor either intervention strategy or comparison 4Ts High + IA + FA Moderate savings Moderate Large harms Probably favors intervention strategy Gestalt + IA + FA Large costs Small Moderate Favors intervention strategy EQUITY What would be the impact on health equity? Reduced Probably reduced Probably no No research evidence identified. The panel agreed that some centers may not have access to the functional assays or the opportunity to send out the tests. Any strategy that includes a functional assay would probably

26 impact Probably increased Increased reduce health equity. For institutions that could not perform a functional assay, there will be more patients identified as incorrectly having HIT (i.e. false-positives). ACCEPTABILITY FEASIBILITY Is the intervention acceptable to key stakeholders? No Probably no Probably yes Yes Is the intervention feasible to implement? No Probably no Probably yes Yes No research evidence identified. No research evidence identified. The laboratory tests and the test strategy are currently being performed at many institutions. Currently, some physicians are not using the 4Ts, which may be due to lack of awareness, lack of trust, and beliefs that a gestalt approach is better than the 4Ts. The guideline panel agreed that all the information needed to calculate a 4Ts score is not always available and efforts should be made to obtain this information. Guidance is also available about how to conduct the 4Ts in the absence of complete information. The panel agreed that the accuracy of the gestalt assessment is highly dependent on the expertise of the clinician, whereas the 4Ts is likely less dependent on operator expertise. Time needed to perform the tests needs to be considered.

27 The panel noted that some centres may not have access to the functional assays or the opportunity to send out the tests. This could result either in delays of treatment and possible serious consequences, or the functional assay will not be possible to perform. SRA functional assay is more widely used in the USA, whereas many parts of Europe use a HIPA or PAT assay. HIPA or PAT is used in different centers based on feasibility.

28 Summary of judgments JUDGEMENT IMPLICATIONS PROBLEM No Probably no Probably yes Yes Varies Don't know TEST ACCURACY Very inaccurate Inaccurate Accurate Very accurate Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF THE EVIDENCE OF TEST ACCURACY CERTAINTY OF THE EVIDENCE OF TEST'S EFFECTS CERTAINTY OF THE EVIDENCE OF MANAGEMENT'S EFFECTS CERTAINTY OF THE EVIDENCE OF TEST RESULT/MANAGEMENT Very low Low Moderate High Very low Low Moderate High Very low Low Moderate High Very low Low Moderate High CERTAINTY OF EFFECTS Very low Low Moderate High VALUES Important uncertainty or Possibly important uncertainty or Probably no important uncertainty or No important uncertainty or No included studies No included studies No included studies No included studies No included studies BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know

29 JUDGEMENT IMPLICATIONS CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included studies COST EFFECTIVENESS EQUITY Favors the comparison Reduced Probably favors the comparison Probably reduced Does not favor either the intervention or the comparison Probably no impact Probably favors the intervention Probably increased Favors the intervention Varies No included studies Increased Varies Don't know ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know Conclusions TYPE OF RECOMMENDATION RECOMMENDATION Strong recommendation against the intervention Conditional recommendation against the intervention Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention Strong recommendation for the intervention Recommendations 2.1 to 2.10 should be considered together when testing and treating patients with suspected HIT. The sequence of tests and treatment are described in figure In patients with suspected HIT, the panel recommends using the 4Ts score to estimate the probability of HIT rather than a gestalt approach. If there is an intermediate or high probability 4Ts score, the panel recommends an immunoassay. If the immunoassay is positive and functional assay is available, the panel recommends a functional assay. (Strong recommendation, moderate certainty of evidence) Remarks: Missing or inaccurate information may lead to a faulty 4Ts score and inappropriate management decisions. Every effort should be made to obtain accurate and complete information necessary to calculate the 4Ts score. If key information is missing, it may be prudent to err on the side of a higher 4Ts score. Patients should be reassessed frequently. If there is a change in the clinical picture, the 4Ts score should be recalculated.

30 Different immunoassays and functional assays are available. The choice of assay may be influenced by diagnostic accuracy, availability, cost, feasibility, and turnaround time. If an enzyme linked immunoassay is used, a lower threshold is preferred over a high threshold. In some settings, the functional assay may not be available and decisions may need to be made based on the results of the 4Ts and immunoassay. A functional assay may not be necessary in patients with a high 4Ts score and strongly positive immunoassay. In some centers, a functional assay may be performed in tandem with an immunoassay for quality assurance or efficiency. JUSTIFICATION SUBGROUP CONSIDERATIONS IMPLEMENTATION CONSIDERATIONS 2.2. In patients with suspected HIT and a low probability 4Ts score, the panel recommends against HIT laboratory testing. (Strong recommendation, moderate certainty of evidence) The panel reviewed the evidence for five strategies: 4Ts (intermediate and high) followed by immunoassay then functional assay (when immunoassay is positive); 4Ts (intermediate and high) followed by immunoassay only; 4Ts (intermediate and high) followed by functional assay only; 4Ts (high) followed by immunoassay then functional assay for positive immunoassay; and, a gestalt approach followed by immunoassay then functional assay. Studies were not available that followed patients suspected with HIT from testing to patient important outcomes such as thrombosis, bleeds, death or amputation. However, there was moderate certainty evidence from test accuracy data and moderate to low certainty evidence from treatment studies which were used to model the outcomes. These models were based on the data for IgG and poly specific enzyme linked immunosorbent assays at low thresholds given their widespread use and abundance of evidence. Based on these modeled effects, the recommended strategy likely results in few false negatives and little to no false positives. It is currently in use, and feasible in most settings either on site or as a send out to a reference laboratory. However, some settings may not have access to the tests which may reduce equity across populations. Overall, desirable consequences clearly outweighed undesirable consequences. Using the functional assay may however not be necessary and would be costly in patients who had a high 4Ts score and a strongly positive immunoassay, as there were likely no false positives after the immunoassay. 4Ts at intermediate and high risk followed by immunoassay (no functional assay): Compared to the recommended strategy, there are trivial benefits and greater harms due to the additional false positives which lead to unnecessary treatment and increased bleeds and costs. 4Ts at intermediate and high risk followed by functional assay (no immunoassay): Compared to the recommended strategy, there are trivial differences in benefits and harms. However, this strategy increases costs of testing and reduces feasibility and equity. 4Ts at high risk only followed by immunoassay and then functional assay: Compared to the recommended strategy, in the short term fewer patients without HIT would receive inappropriate treatment. However, this benefit is outweighed by the greater number of missed cases of HIT which may result in serious consequences such as thrombosis, amputation and death. Gestalt followed by immunoassay and functional assay: Compared to the recommended strategy, there were small benefits as there were fewer false negatives. However, this small benefit is outweighed by the large number of people without HIT who receive unnecessary treatment in the short term, which may increase costs and risks of bleeds. Greater clinical decision support may be needed at point-of-care regarding the use of and management decisions based on the 4Ts score.

31 MONITORING AND EVALUATION RESEARCH PRIORITIES Research priorities include implementation analyses, adherence and identification of barriers to use of the recommended strategy and in particular the use of the 4Ts score. Assessment of other immunoassays currently available should be conducted. Research should also include the development of novel assays that overcome the limitations of the currently available immunoassays, such as immunoassays with enhanced specificity and functional assays with enhanced feasibility.

32 EVIDENCE TABLES Table 1: Test accuracy outcomes for 1000 people suspected to have HIT using a gestalt suspicion, the 4Ts score, or using 4Ts score followed by functional assay Pooled sensitivity and specificity was calculated using raw data from 13 studies identified in Cuker 2012 and converted to true positive, false negative, true negative and false positive based on 1000 patients who are suspected to have HIT. We assumed the gestalt method was clinical suspicion of HIT, i.e. all patients suspected of HIT who were identified in the 13 studies. These patients included patients with low, intermediate or high risk on the 4Ts score. We assumed that the prevalence of HIT is 11% (CI 7% to 17%) based on a pooled weighted mean across the 13 studies in Cuker The range of prevalence is 4 to 42%. Because these studies did not consistently show higher prevalence in particular populations, we did not calculate test accuracy outcomes based on different prevalence. We assumed that the functional assay was 100% sensitive and specific conducted on the positive patients identified as intermediate or high risk by the 4Ts score. Reference: Cuker A, Gimotty PA, Crowther MA, Warkentin TE. Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and metaanalysis. Blood Nov 15;120(20): doi: /blood Ts High 4Ts High and GESTALT 4Ts High and threshold Intermediate 4Ts High (all Intermediate followed by a threshold followed Consequences threshold suspected) threshold functional assay by a functional assay Sensitivity Specificity TP FN TN FP Total Prevalence (%) Out of Patients will appropriately be treated or have more testing (reduced risk of thrombosis by 55% - 70%) Patients will be missed and may experience serious consequences of HIT, e.g. thrombosis (300/1000 more people with HIT if not treated), amputation (60/1000 more people with HIT if not treated), death (60/1000 more people with HIT if not treated) Patients will appropriately not have further testing and will appropriately not be treated for HIT Patients will continue with unnecessary testing and/or may experience serious consequences of unnecessary treatment for HIT (e.g. bleeding ~8 to 35% over treatment duration), and may be falsely labelled as having HIT over the long term

33 Table 2: Test accuracy outcomes for 1000 people suspected to have HIT based on a gestalt assessment or at intermediate or high risk using the 4Ts score and who received an immunoassay test Sensitivity (95% CI) Specificity (95% CI) PaGIA 0.98 (0.94, 1.00) 0.88 (0.81, 0.96) HemosIL -Ab 1 (NR) 0.84 (NR) IgG-CA Poly-CA LFIA PIFA 0.95 (0.90, 1.00) 0.94 (0.89, 0.99) 0.97 (0.85, 1.00) 0.82 (0.77, 0.87) 0.97 (0.92, 1.00) 0.91 (0.86, 0.96) 1 (NR) 0.7 (NR) IgG ELISA (LT) 0.98 (0.95, 0.99) 0.85 (0.78, 0.91) IgG ELISA (IT) 0.91 (0.86, 0.95) 0.94 (0.89, 0.96) GESTALT FOLLOWED BY IMMUNOASSAY (positives by gestalt receive immunoassay test approximately 993 people) True positive False negative True negative False positive IgG ELISA (HT) 0.61 (0.60, 0.62) 0.99 (0.98, 1.00) Poly ELISA (LT) 0.97 (0.90, 0.99) 0.87 (0.82, 0.91) Poly ELISA (IT) 0.98 (0.91, 1.00) 0.95 (0.91, 0.97) Poly ELISA (HT) 0.15 (0.15, 0.16) 1.00 (0.99, 1.00) T THRESHOLD HIGH FOLLOWED BY IMMUNOASSAY (approximately 89 people have test) True positive False negative True negative False positive T THRESHOLD HIGH/INTERMEDIATE FOLLOWED BY IMMUNOASSY (approximately 509 people have test) True positive False negative True negative False positive Diagnostic test accuracy outcomes based on evidence for recommendations 3.1 to 3.11: True positives - Patients will appropriately be treated and/or have more testing (reduced risk of thrombosis by 55% - 70%) False negatives - Patients will be missed and may experience serious consequences of HIT, e.g. thrombosis (300/1000 more people with HIT if not treated), amputation (60/1000 more people with HIT if not treated), death (60/1000 more people with HIT if not treated) True negatives - Patients will appropriately not have further testing and will appropriately not be treated for HIT

34 False positives - Patients will continue with unnecessary testing and/or may experience serious consequences of unnecessary treatment for HIT (e.g. bleeding ~8 to 35% over treatment duration), and may be falsely labelled as having HIT over the long term References Cuker A, Gimotty PA, Crowther MA, Warkentin TE. Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood Nov 15;120(20): doi: /blood Nagler M, Bachmann LM, ten Cate H, ten Cate-Hoek A. Diagnostic value of immunoassays for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood Feb 4;127(5): Sun L, Gimotty PA, Lakshmanan S, Cuker A. Diagnostic accuracy of rapid immunoassays for heparin-induced thrombocytopenia. A systematic review and meta-analysis. Thromb Haemost May 2;115(5):

35 Table 3: Test accuracy outcomes for 1000 people suspected to have HIT who received a screening test (including a gestalt assessment) followed by the IgG ELISA (low threshold) and Poly ELISA (low threshold) immunoassay tests and followed by a functional assay We assumed that the functional assay was 100% sensitive and specific. sequence of screen and IgG (LT) for positives GESTALT FOLLOWED BY IMMUNOASSAY All who received an IgG ELISA (LT) have FA IgG ELISA (LT) positive have FA IgG ELISA (LT) negatives have FA sequence of screen and Poly (LT) for positives All who received a poly ELISA (LT) have FA Poly ELISA (LT) positive have FA Poly ELISA (LT negative have FA True positive False negative True negative False positive IgG tests 993 FA tests 238 tests 755 FA tests *993 poly tests 993 FA tests 238 FA tests *774 FA tests 4T THRESHOLD HIGH FOLLOWED BY IMMUNOASSAY True positive False negative True negative False positive IgG tests 89 FA tests 54 tests 35 FA tests *89 poly tests 89 FA tests 54 FA tests *36 FA tests 4T THRESHOLD HIGH/INTERMEDIATE FOLLOWED BY IMMUNOASSY 885 True positive False negative True negative False positive IgG tests 509 FA tests 160 tests 349 FA tests 509 poly tests 509 FA tests 160 FA tests *358 FA tests Diagnostic test accuracy outcomes based on evidence for recommendations 3.1 to 3.11: True positives - Patients will appropriately be treated and/or have more testing (reduced risk of thrombosis by 55% - 70%) False negatives - Patients will be missed and may experience serious consequences of HIT, e.g. thrombosis (300/1000 more people with HIT if not treated), amputation (60/1000 more people with HIT if not treated), death (60/1000 more people with HIT if not treated) True negatives - Patients will appropriately not have further testing and will appropriately not be treated for HIT False positives - Patients will continue with unnecessary testing and/or may experience serious consequences of unnecessary treatment for HIT (e.g. bleeding ~8 to 35% over treatment duration), and may be falsely labelled as having HIT over the long term

36 Recommendations Should treatment for HIT be provided to patients who are suspected of HIT and have an intermediate or high probability 4Ts score? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: SETTING: PERSPECTIVE: patients who are suspected of HIT and have an intermediate or high probability 4Ts score discontinuation of heparin and initiation of a nonheparin anticoagulant Continued used of heparin Mortality; Thromboembolic complications; Limb Amputation; Major bleed Inpatient Clinical recommendation - population perspective BACKGROUND: Approximately 12 million hospitalized patients each year are exposed to heparin for thromboprophylaxis. Heparin-induced thrombocytopenia (HIT) is a potential complication of heparin therapy caused by either unfractionated heparin or low molecular-weight heparin (LMWH). Diagnosis of HIT consists of a sequence of tests which take time to yield results. Therefore, guidance is needed about how to treat patients after the result of each test is received. The sequence of tests recommended by the panel is to conduct a 4Ts score, then perform an immunoassay on patients identified at intermediate and high risk, and then perform a functional assay on patients with a positive immunoassay. The 4Ts score is a risk assessment tool to determine the risk of developing HIT. The 4T score measures 1) magnitude of thrombocytopenia (2) timing of thrombocytopenia with respect to heparin exposure; (3) thrombosis or other sequelae of HIT; and (4) likelihood of other causes of thrombocytopenia. There are three categories of the 4Ts scoring system: High (score of 6-8); Intermediate (score of 4-5); Low (score of 0-3). Multiple HIT immunoassay tests have been developed to detect HIT antibodies that target complexes of platelet factor 4 (PF4) bound to heparin. HIT immunoassays vary by detection threshold and turnaround time. Treatments may include stopping or continuing heparin, and starting or stopping nonheparin anti-coagulants. ASH conflict of interest declaration and management policies were applied and the following panel members were voting panel members (determining the direction and strength of the recommendation): [Information redacted for public review] Panel members recused as a result of risk of conflicts of interest: [Information redacted for public review]

37 Assessment JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS PROBLEM DESIRABLE EFFECTS UNDESIRABLE EFFECTS Is the problem a priority? No Probably no Probably yes Yes How substantial are the desirable anticipated effects? Trivial Small Moderate Large How substantial are the undesirable anticipated effects? Large Moderate Small Trivial Approximately 12 million hospitalized patients each year are exposed to heparin for thromboprophylaxis. Heparin-induced thrombocytopenia (HIT) is a potential complication of heparin therapy caused by either unfractionated heparin or low molecular-weight heparin (LMWH). Results from a meta-analysis suggest that the absolute risk for HIT for patients treated with LMWH is 0.2% (95% CI, 0.1%-0.4%), and 2.6% (95% CI, 1.5%-3.8%) if treated with UFH 1. Studies addressing this question were not identified. Instead, we used the calculations of absolute numbers of patients who would be correctly or incorrectly diagnosed with HIT after the use of the 4Ts score. We used the evidence from Table 1 in Recommendation 2.1 and 2.2 (see Table 1 following this Evidence to Decision Framework). In 1000 patients assessed with the 4Ts score at high and intermediate threshold, there are approximately true positives (patients with HIT identified at high and intermediate risk) - 9 false negatives (patients with HIT identified at low risk) true negatives (patients without HIT identified at low risk) false positives (patients without HIT identified at high and intermediate risk) In these patients, we estimated the following effects with the discontinuation of heparin and initiation of non-heparin anti-anticoagulant: Benefits patients with HIT are treated appropriately (reduced risk of thrombosis by 55% - 70%); patients without HIT who were identified at low risk would be managed appropriately (i.e. not treated for HIT) Harms - 9 patients with HIT will be missed and not be treated appropriately which may lead to serious consequences, e.g. thrombosis (30% more patients with HIT if not treated), amputation (6% more patients with HIT if not treated), death (6% more patients with HIT if not treated) patients without HIT will receive unnecessary treatment for HIT which may result in increased bleeds in the short term until further laboratory testing is performed (e.g. 1% per day). Therapeutic versus prophylactic intensity of non-heparin anti-coagulant Evidence is provided in the Evidence to Decision framework for Recommendation 3.2. Overall, in patients who have a high probability 4Ts score, there are large benefits with reductions in thrombosis when providing therapeutic intensity versus prophylactic, and small harms due to bleeding. The guideline panel noted that in many situations, if a patient is suspected of HIT, heparin is discontinued while confirmatory testing occurs. However, it is unclear whether heparin should be discontinued and a non-heparin anti-coagulant started. It is also unclear if the intensity of the nonheparin anti-coagulant should be prophylactic or therapeutic. The panel agreed that the benefits are large for those who are correctly identified as having HIT (101/1000), and the harms are small for the people without HIT (408/1000) who would receive unnecessary treatment for HIT in the short term (false positives). Conversely, for those patients with a low probability 4Ts, if we discontinued heparin and initiated a non-heparin anti-coagulant, 9 patients would be appropriately treated which is a small benefit. If we treated, 482 patients would receive unnecessary treatment which would lead to bleeds for a short period of time which is a small harm. In patients with high bleeding risk and intermediate probability of 4Ts, the difference in harms between therapeutic and prophylactic intensity is moderate with respect to bleeds. The difference in benefits of reduced risk of thrombosis between therapeutic and prophylactic intensity are small (because relatievly fewer people with an intermediate 4Ts score have true HIT).

38 In patients who have intermediate probability 4Ts score, there would be fewer people with true HIT (i.e. more false positives). In people with high bleeding risk, treatment with therapeutic intensity may lead to greater bleeds. Overall, there would be fewer benefits with therapeutic intensity and greater harms due to the risk of bleeding; and with prophylactic intensity, there may be fewer bleeds. CERTAINTY OF EVIDENCE VALUES What is the overall certainty of the evidence of effects? Very low Low Moderate High No included studies Is there important uncertainty about or in how much people value the main outcomes? Important uncertainty or Possibly important uncertainty or Probably no important uncertainty or No important uncertainty or Moderate certainty of evidence for treatment effects. Low certainty for comparisons between prophylactic and therapeutic intensity. Finding related to the outcomes: - DVT (utility): Most people find DVT probably has a small impact on lives. There is likely important for this assessment 2,3. (Moderate certainty of evidence due to inconsistency) - Pulmonary embolism (utility): People find pulmonary embolism probably has a small impact on lives. There is likely important for this assessment 2. (Moderate certainty of evidence due to inconsistency) - Gastrointestinal tract bleeding event (utility): People find gastrointestinal tract bleeding event probably has a small impact on lives. There is likely important for this assessment 4. (Moderate certainty of evidence due to indirectness) - Muscular bleeding (utility): People find muscular bleeding event probably has a small impact on lives. There is likely important for this assessment 4. (Moderate certainty of evidence due to indirectness) - Central nervous system bleeding (including intracranial bleeding) (utility): People find central nervous system appears to have a moderate impact on their lives. There is likely no important for this assessment 5,6. (Very low certainty of evidence due to inconsistency, indirectness, and imprecision) - Major intracranial bleeding event (utility): People find major intracranial bleeding has a large impact on their lives. There is likely important for this assessment. (High certainty of evidence) - Minor intracranial bleeding event: People find minor intracranial bleeding has a large impact on their lives. There is likely important for this assessment. (High certainty of evidence) The panel placed greater value on preventing thrombosis than preventing major bleeding.

39 BALANCE OF EFFECTS RESOURCES REQUIRED CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Does the balance between desirable and undesirable effects favor the intervention or the comparison? Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings What is the certainty of the evidence of resource requirements (costs)? Very low Low Moderate High No included studies In patients with high or intermediate probability of 4Ts score, treating for HIT is favored (favors intervention). In patients with low probability of 4Ts score, treating for HIT is not favored (favors comparison). In patients with high bleeding risk and an intermediate probability 4Ts score, prophylactic intensity anticoagulation is probably favored. Compared with the comparison, 509 more patients would be treated with a non-heparin anticoagulant under the intervention strategy. 408 of these 509 would likely be treated for a relatively short time until HIT laboratory assay results returned. Treatment of these patients would entail moderate costs because of the cost of non-heparin anticoagulants. Therapeutic versus prophylactic intensity: negligible cost differences

40 COST EFFECTIVENESS EQUITY ACCEPTABILITY Does the cost-effectiveness of the intervention favor the intervention or the comparison? Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention No included studies What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased Is the intervention acceptable to key stakeholders? No Probably no Probably yes Yes In patients with high or intermediate probability of 4Ts score, the cost savings from preventing thrombosis probably outweighs the costs of the treatment and the bleeds that may occur. In patients with a low probability 4Ts score, the cost savings of avoiding unnecessary treatment and possible bleeds in a large number of patients without HIT probably outweighs the costs of reducing thrombosis in the few patients with true HIT. In patients with high bleeding risk and an intermediate probability 4Ts score, the costs of harms with therapeutic intensity (i.e. bleeds) would probably outweigh the cost savings from preventing thrombosis in the relatively few patients with HIT. No research evidence identified. No research evidence identified. The panel agreed that there is no reason that non-heparin anticoagulants would not be prescribed or provided to any subgroup of populations when indicated. The panel agreed that clinicians would find providing prophylactic intensity to patients at high bleeding risk treatment acceptable. The panel agreed that some clinicians may not find it acceptable to not treat patients suspected of HIT at low probability 4Ts score due to fear of litigation. Clinicians may need to be reminded that treating patients with a low probability 4Ts will result in more bleeds and greater costs and only rarely prevent adverse consequences of HIT. FEASIBIL ITY Is the intervention feasible to implement? No Probably no No research evidence identified. The panel agreed that some drugs are not available in some countries; however, there is at least one non-

41 Probably yes Yes heparin anticoagulant available in most countries. Summary of judgements JUDGEMENT PROBLEM No Probably no Probably yes Yes Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS CERTAINTY OF EVIDENCE VALUES BALANCE OF EFFECTS RESOURCES REQUIRED CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES COST EFFECTIVENESS Large Moderate Small Trivial Varies Don't know Very low Low Moderate High Important uncertainty or Favors the comparison Large costs Possibly important uncertainty or Probably favors the comparison Moderate costs Probably no important uncertainty or Does not favor either the intervention or the comparison Negligible costs and savings No important uncertainty or Probably favors the intervention Very low Low Moderate High Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Favors the intervention Varies No included studies Don't know Moderate savings Large savings Varies Don't know Probably favors the intervention Favors the intervention Varies No included studies No included studies IMPLICATIONS EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know

42 Conclusions TYPE OF RECOMMENDATION Strong recommendation against the intervention Conditional recommendation against the intervention Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention Strong recommendation for the intervention RECOMMENDATION JUSTIFICATION 2.3. In patients with suspected HIT and a low probability 4Ts score, the panel recommends against empiric treatment for HIT (i.e. against discontinuation of heparin and initiation of a non-heparin anticoagulant). (Strong recommendation, moderate certainty of evidence) 2.4. In patients with suspected HIT and an intermediate probability 4Ts score who have no other indication for therapeutic intensity anticoagulation, the panel recommends discontinuation of heparin. (Strong recommendation, moderate certainty of evidence) The panel suggests initiation of a non-heparin anticoagulant at prophylactic intensity if the patient is at high bleeding risk and at therapeutic intensity if the patient is not at high bleeding risk. (Strong recommendation, moderate certainty of evidence) 2.5. In patients with suspected HIT and an intermediate probability 4Ts score who have another indication for therapeutic intensity anticoagulation, the panel recommends discontinuation of heparin. (Strong recommendation, moderate certainty of evidence) The panel suggests initiation of a non-heparin anticoagulant at therapeutic intensity. (Conditional recommendation, moderate certainty of evidence) 2.6. In patients with suspected HIT and a high probability 4Ts score, the panel recommends discontinuation of heparin and initiation of a non-heparin anticoagulant at therapeutic intensity. (Strong recommendation, moderate certainty of evidence) When treating compared to not treating for HIT in patients with high or intermediate probability 4Ts score, the benefits and costs savings from preventing thrombosis outweigh the harms (e.g. bleeds) and costs of treatment. In addition, treating for HIT is probably acceptable, feasible and equitable. When treating compared to not treating for HIT in patients with a low probability 4Ts score, there may be greater harms due to bleeds in a large number of patients who do not have HIT, and there would be few thromboses prevented in the few patients with true HIT. There would also be additional costs. Some clinicians may not find this acceptable due to fear of litigation. However, the benefits of not treating outweigh the harms. In patients with high bleeding risk and an intermediate probability of 4Ts, although the costs are negligible between therapeutic and prophylactic intensity therapy, there would be greater harms with therapeutic intensity (bleeds), and the benefits are small because most patients will not have true HIT. SUBGROUP CONSIDERATIONS IMPLEMENTATION CONSIDERATIONS Greater clinical decision support may be needed at point-of-care regarding the use of and management decisions based on the 4Ts score. MONITORING AND EVALUATION

43 RESEARCH PRIORITIES Research priorities include implementation analyses, adherence and identification of barriers to use and management of patients according to the 4Ts score. References 1. Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: A meta-analysis. Blood. 2005;106(8): Hogg K, Shaw J, Coyle D, Fallah P, Carrier M, Wells P. Validity of standard gamble estimated quality of life in acute venous thrombosis. Thrombosis research. 2014;134(4): Marvig CL, Verhoef TI, De Boer A, et al. Quality of life in patients with venous thromboembolism and atrial fibrillation treated with coumarin anticoagulants. Thrombosis research. 2015;136(1): Locadia M, Stalmeier PF, Oort FJ, Prins MH, Sprangers MA, Bossuyt PM. A comparison of 3 valuation methods for temporary health states in patients treated with oral anticoagulants. Medical decision making. 2004;24(6): Lenert LA, Soetikno RM. Automated computer interviews to elicit utilities. Journal of the American Medical Informatics Association. 1997;4(1): O'Meara JJ, McNutt RA, Evans AT, Moore SW, Downs SM. A decision analysis of streptokinase plus heparin as compared with heparin alone for deep-vein thrombosis. New England Journal of Medicine. 1994;330(26):

44 EVIDENCE TABLE Table 1: Test accuracy outcomes for 1000 people suspected to have HIT using a gestalt suspicion, the 4Ts score, or using 4Ts score followed by functional assay Pooled sensitivity and specificity was calculated using raw data from 13 studies identified in Cuker 2012 and converted to true positive, false negative, true negative and false positive based on 1000 patients who are suspected to have HIT. We assumed the gestalt method was clinical suspicion of HIT, i.e. all patients suspected of HIT who were identified in the 13 studies. These patients included patients with low, intermediate or high risk on the 4Ts score. We assumed that the prevalence of HIT is 11% (CI 7% to 17%) based on a pooled weighted mean across the 13 studies in Cuker The range of prevalence is 4 to 42%. Because these studies did not consistently show higher prevalence in particular populations, we did not calculate test accuracy outcomes based on different prevalence. Reference: Cuker A, Gimotty PA, Crowther MA, Warkentin TE. Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and metaanalysis. Blood Nov 15;120(20): doi: /blood Ts High and Intermediate Consequences threshold Sensitivity Specificity TP Patients will appropriately be treated or have more testing (reduced risk of thrombosis 101 by 55% - 70%) FN Patients will be missed and may experience serious consequences of HIT, e.g. thrombosis (300/1000 more people with HIT if not treated), amputation (60/ more people with HIT if not treated), death (60/1000 more people with HIT if not treated) TN Patients will appropriately not have further testing and will appropriately not be treated 482 for HIT FP Patients will continue with unnecessary testing and/or may experience serious 408 consequences of unnecessary treatment for HIT (e.g. bleeding ~8 to 35% over treatment duration), and may be falsely labelled as having HIT over the long term Total 1000 Prevalence (%) 11 Out of

45 Recommendations Should non-heparin anti-coagulants be continued, or stopped and heparin resumed if indicated, in patients with an intermediate or high probability 4Ts score and a positive or negative immunoassay? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: SETTING: PERSPECTIVE: patients with an intermediate or high probability 4Ts score and positive or negative immunoassay continuation of non-heparin anti-coagulants discontinuation of non-heparin anticoagulants and resumption of heparin, if indicated Mortality; Thromboembolic complications; Limb Amputation; Major bleed Inpatient Clinical recommendation - population perspective BACKGROUND: Approximately 12 million hospitalized patients each year are exposed to heparin for thromboprophylaxis. Heparin-induced thrombocytopenia (HIT) is a potential complication of heparin therapy caused by either unfractionated heparin or low molecular-weight heparin (LMWH). Diagnosis of HIT consists of a sequence of tests, the results of which take time to return. Therefore, guidance is needed about how to treat patients after the result of each test is received. The sequence of tests recommended by the panel is to conduct a 4Ts score, then perform an immunoassay on patients identified at intermediate and high risk, and then perform a functional assay on patients with a positive immunoassay. The 4Ts score is a risk assessment tool to determine the risk of developing HIT. The 4T score measures 1) magnitude of thrombocytopenia (2) timing of thrombocytopenia with respect to heparin exposure; (3) thrombosis or other sequelae of HIT; and (4) likelihood of other causes of thrombocytopenia. There are three categories of the 4Ts scoring system: High (score of 6-8); Intermediate (score of 4-5); Low (score of 0-3). Multiple HIT immunoassay tests have been developed to detect HIT antibodies that target complexes of platelet factor 4 (PF4) bound to heparin. HIT immunoassays vary by detection threshold and result time. After patients have been assessed at intermediate or high probability of HIT using the 4Ts score, heparin is discontinued and a non-heparin anti-coagulant started (see more details in Recommendations ). Patients will receive an immunoassay test and, depending on the result, non-heparin anti-coagulants may need to be continued, or stopped and heparin restarted if indicated. Non-heparin anticoagulants include argatroban, danaparoid, bivalirudin, and fondaparinux. Treatment with DOACs is addressed in Recommendation 3.4 DOAC) ASH conflict of interest declaration and management policies were applied and the following panel members were voting panel members (determining the direction and strength of the recommendation): [Information redacted for public review] Panel members recused as a result of risk of conflicts of interest: [Information redacted for public review]

46 Assessment JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS PROBLEM DESIRABLE EFFECTS Is the problem a priority? No Probably no Probably yes Yes How substantial are the desirable anticipated effects? Trivial Small Moderate Large Approximately 12 million hospitalized patients each year are exposed to heparin for thromboprophylaxis. Heparin-induced thrombocytopenia (HIT) is a potential complication of heparin therapy caused by either unfractionated heparin or low molecular-weight heparin (LMWH). Results from a meta-analysis suggest that the absolute risk for HIT for patients treated with LMWH is 0.2% (95% CI, 0.1%-0.4%), and 2.6% (95% CI, 1.5%-3.8%) if treated with UFH 1. Studies directly addressing this question were not identified. Instead, we used the calculations of absolute numbers of patients who would be correctly or incorrectly diagnosed with HIT after the use of the 4Ts score (at intermediate or high probability) and a positive or negative immunoassay test. We used the evidence from Table 2 in Recommendations 2.1 and 2.2 for people at high or intermediate risk of HIT and a positive or negative IgG low threshold ELISA (see Table 1 following this Evidence to Decision Framework). Out of 1000 patients with suspected HIT, 89 patients had a high probability 4Ts score and received an IgG low threshold ELISA. The test accuracy for this sequence of tests for those 89 patients is reported below: True positives 48 False negatives 1 True negatives 34 False positives 6 The guideline panel noted that in many situations clinicians will need to wait for the results of a functional assay test to confirm a HIT diagnosis. The consequences of continuing or discontinuing nonheparin anti-coagulants in patients with a positive or negative immunoassay could be serious and include bleeding, thrombosis, death and other complications. Continuation of non-heparin anticoagulants after a positive immunoassay (and discontinuation after a negative immunoassay): For patients that had a high probability 4Ts score: The panel agreed that the benefits are large for the patients who would receive the appropriate treatment: 48 who have HIT and 34 who don't have HIT. There would be small harms for the 1 patient with HIT who had treatment inappropriately stopped (possible thrombosis, death, and amputation) and for the 6 patients without HIT in whom treatment was continued in the short term (bleeds). If the non-heparin anti-coagulant is continued: Benefits - 48 out of 54 patients who test positive by IgG ELISA will have HIT and will be appropriately treated (reduced risk of thrombosis by 55% - 70%); For patients that had an intermediate 4Ts score: The panel agreed that the benefits are large for the patients who would receive the appropriate treatment: 51 who have HIT and 313 who don't have

47 - 34 out of 35 who test negative by IgG ELISA will have their treatment discontinued appropriately. Harms - 6 out of 54 patients who test positive by IgG ELISA will not have HIT and will be inappropriately treated (resulting in increased bleeds in the short term e.g., 1% per day); HIT. There would be small harms for the 1 patient with HIT who had treatment inappropriately stopped (possible thrombosis, death, and amputation) and for the 55 patients without HIT in whom treatment was continued in the short term (bleeds). UNDESIRABLE EFFECTS How substantial are the undesirable anticipated effects? Large Moderate Small Trivial - 1 out of 35 patients who test negative by IgG ELISA will have HIT and will have treatment inappropriately discontinued, which may lead to serious consequences, e.g. thrombosis (30% more people), amputation (6%more people), death (6%more people). Out of 1000 patients with suspected HIT, 420 patients had an intermediate probability 4Ts score and received an IgG low threshold ELISA. The test accuracy for this sequence of tests for those 420 patients is reported below: True positives 51 False negatives 1 True negatives 313 False positives 55 If the non-heparin anti-coagulant is continued: Benefits - 51 out of 106 patients who test positive by IgG ELISA will have HIT and will be appropriately treated (reduced risk of thrombosis by 55% - 70%); out of 314 who test negative by IgG ELISA will have their treatment discontinued appropriately. In patients with high bleeding risk, no other indication for therapeutic intensity anticoagulation, and an intermediate probability 4Ts score who are receiving prophylactic intensity non-heparin anticoagulants (per Recommendation 2.4), if treatment was changed to therapeutic intensity, the harms of therapeutic therapy may be small when compared with prophylactic intensity treatment: 55/106 who have a positive immunoassay test do not have HIT and they may have more bleeds. However, for 51/106 people with HIT the benefits would be large, as they may have a reduced risk of thrombosis with therapeutic intensity. Overall, changing to therapeutic intensity may mean large benefits and small harms. Harms: - 55 out of 106 patients who test positive by IgG ELISA will not have HIT and will be inappropriately treated (resulting in increased bleeds in the short term e.g., 1% per day); - 1 out of 314 patients who test negative by IgG ELISA will have HIT and will be inappropriately discontinued from treatment, which may lead to serious consequences, e.g. thrombosis (30% more people), amputation (6% more people), death (6% more people).

48 Therapeutic versus prophylactic intensity Based on Recommendation 2.4, patients with an intermediate probability 4Ts score who have no other indication for therapeutic intensity anticoagulation and are judged to be at high bleeding risk are suggested to receive prophylactic intensity non-heparin anti-coagulants. CERTAINTY OF EVIDENCE VALUES What is the overall certainty of the evidence of effects? Very low Low Moderate High No included studies Is there important uncertainty about or in how much people value the main outcomes? Important uncertainty or Possibly important uncertainty or Probably no important uncertainty or No important uncertainty or The same test accuracy data from above was used to determine the number of patients with a positive immunoassay who were true positive (51/106) and false positive (55/106). Therapeutic intensity therapy may increase the risk of bleeds unnecessarily in patients without HIT, but reduce the risk of thrombosis in patients with HIT. Moderate certainty of evidence for treatment effects. Low certainty for comparisons between prophylactic and therapeutic intensity treatment with non-heparin anticoagulants. Finding related to the outcomes: - DVT (utility): Most people find DVT probably has a small impact on lives. There is likely important for this assessment 2,3. (Moderate certainty of evidence due to inconsistency) - Pulmonary embolism (utility): People find pulmonary embolism probably has a small impact on lives. There is likely important for this assessment 2. (Moderate certainty of evidence due to inconsistency) - Gastrointestinal tract bleeding event (utility): People find gastrointestinal tract bleeding event probably has a small impact on lives. There is likely important for this assessment 4. (Moderate certainty of evidence due to indirectness) - Muscular bleeding (utility): People find muscular bleeding event probably has a small impact on lives. There is likely important for this assessment 4. (Moderate certainty of evidence due to indirectness) The panel placed greater value on preventing thrombosis or clotting than major bleeding. In principle, the panel valued false negatives 10 times more than false positives. - Central nervous system bleeding (including intracranial bleeding) (utility): People find central nervous system appears to have a moderate impact on their lives. There is likely no important

49 for this assessment 5,6. (Very low certainty of evidence due to inconsistency, indirectness, and imprecision) - Major intracranial bleeding event (utility): People find major intracranial bleeding has a large impact on their lives. There is likely important for this assessment. (High certainty of evidence) BALANCE OF EFFECTS RESOURCES REQUIRED Does the balance between desirable and undesirable effects favor the intervention or the comparison? Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings - Minor intracranial bleeding event: People find minor intracranial bleeding has a large impact on their lives. There is likely important for this assessment. (High certainty of evidence) In patients with a high or intermediate probability 4Ts score and a positive immunoassay, there may be large benefits and small harms when continuing non-heparin anti-coagulants compared to discontinuing (i.e. favors intervention). In patients judged to be at high bleeding risk and intermediate probability of 4Ts score and a positive immunoassay, there may be large benefits and small harms to changing from prophylactic to therapeutic intensity (intervention) treatment with a non-heparin anticoagulant. Therefore, therapeutic intensity is favored over continuing prophylactic intensity (comparison). There would be costs of continuing non-heparin anti-coagulants versus heparin for 160 patients. Moderate costs due to the cost of non-heparin anticoagulants and numbers of patients. Therapeutic versus prophylactic intensity: negligible cost differences

50 CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES COST EFFECTIVENESS EQUITY What is the certainty of the evidence of resource requirements (costs)? Very low Low Moderate High No included studies Does the cost-effectiveness of the intervention favor the intervention or the comparison? Favors the comparison Probably favors the comparison Does not favor either the intervention or the comparison Probably favors the intervention Favors the intervention No included studies What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased In patients with high or intermediate probability of 4Ts score and positive immunoassay, the cost savings from preventing thrombosis outweighs the drug costs and the costs of the bleeds that may occur. In patients with high bleeding risk and intermediate probability of 4Ts score and positive immunoassay, the cost savings from preventing thrombosis in patients with HIT would be greater than the drug costs and the cost of harms with therapeutic intensity (i.e. bleeds). No research evidence identified. The panel agreed that there is no reason that non-heparin anticoagulants would not be prescribed or provided to any subgroup of populations when indicated.

51 Is the intervention acceptable to key stakeholders? No research evidence identified. ACCEPTABILITY FEASIBILITY No Probably no Probably yes Yes Is the intervention feasible to implement? No Probably no Probably yes Yes Summary of judgements No research evidence identified. JUDGEMENT PROBLEM No Probably no Probably yes Yes Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know The panel agreed that some drugs are not available in some countries; however, there is at least one nonheparin anticoagulant available in most countries. IMPLICATIONS UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included studies

52 JUDGEMENT IMPLICATIONS VALUES Important uncertainty or Possibly important uncertainty or Probably no important uncertainty or No important uncertainty or BALANCE OF EFFECTS RESOURCES REQUIRED CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES COST EFFECTIVENESS EQUITY Favors the comparison Large costs Probably favors the comparison Moderate costs Does not favor either the intervention or the comparison Negligible costs and savings Probably favors the intervention Moderate savings Very low Low Moderate High Favors the comparison Reduced Probably favors the comparison Probably reduced Does not favor either the intervention or the comparison Probably no impact Probably favors the intervention Favors the intervention Varies Don't know Large savings Varies Don't know Favors the intervention Probably increased Varies No included studies No included studies Increased Varies Don't know ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know

53 Conclusions TYPE OF RECOMMENDATION Strong recommendation against the intervention Conditional recommendation against the intervention Conditional recommendation for either the intervention or the comparison Conditional recommendation for the intervention Strong recommendation for the intervention RECOMMENDATION JUSTIFICATION SUBGROUP CONSIDERATIONS IMPLEMENTATION CONSIDERATIONS 2.7. In patients with an intermediate probability 4Ts score and a negative immunoassay, the panel recommends discontinuation of the non-heparin anticoagulant and resumption of heparin, if indicated. (Strong recommendation, moderate certainty of evidence) 2.8. In patients with a high probability 4Ts score and a negative immunoassay, the panel recommends discontinuation of the non-heparin anticoagulant and resumption of heparin, if indicated. (Strong recommendation, moderate certainty of evidence) 2.9. In patients with an intermediate probability 4Ts score and a positive immunoassay, the panel recommends continued avoidance of heparin and continued administration of a non-heparin anticoagulant at therapeutic intensity. For those patients who were receiving prophylactic intensity therapy, the panel recommends providing therapeutic intensity therapy. (Strong recommendation, moderate certainty of evidence) In patients with a high probability 4Ts score and a positive immunoassay, the panel recommends continued avoidance of heparin and continued administration of a non-heparin anticoagulant. (Strong recommendation, moderate certainty of evidence) When continuing non-heparin anti-coagulants for patients with high or intermediate probability 4Ts score and a positive immunoassay, the benefits from preventing thrombosis outweigh the harms (e.g. bleeds) and drug costs. In addition, continuing non-heparin anti-coagulants is probably acceptable, feasible and equitable. In patients with high bleeding risk and intermediate probability of 4Ts and positive immunoassay, the costs are negligible and there may be large benefits from preventing thrombosis and small harms (bleeds) when changing to therapeutic intensity. Greater clinical decision support may be needed at point-of-care regarding how to use test results to inform management. MONITORING AND EVALUATION RESEARCH PRIORITIES Implementation analyses, adherence and identification of barriers to use and management of patients according to the 4Ts score.

54 References of Cited Studies: 1. Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: A meta-analysis. Blood. 2005;106(8): Hogg K, Shaw J, Coyle D, Fallah P, Carrier M, Wells P. Validity of standard gamble estimated quality of life in acute venous thrombosis. Thrombosis research. 2014;134(4): Marvig CL, Verhoef TI, De Boer A, et al. Quality of life in patients with venous thromboembolism and atrial fibrillation treated with coumarin anticoagulants. Thrombosis research. 2015;136(1): Locadia M, Stalmeier PF, Oort FJ, Prins MH, Sprangers MA, Bossuyt PM. A comparison of 3 valuation methods for temporary health states in patients treated with oral anticoagulants. Medical decision making. 2004;24(6): Lenert LA, Soetikno RM. Automated computer interviews to elicit utilities. Journal of the American Medical Informatics Association. 1997;4(1): O'Meara JJ, McNutt RA, Evans AT, Moore SW, Downs SM. A decision analysis of streptokinase plus heparin as compared with heparin alone for deep-vein thrombosis. New England Journal of Medicine. 1994;330(26):

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