ASH Draft Recommendations for SCD Related Cardiopulmonary and Kidney Disease

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1 ASH Draft Recommendations for SCD Related Cardiopulmonary and Kidney Disease 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 ends November 5, RECOMMENDATIONS Question 1: Should right-sided cardiac catheterization vs. serial non-invasive monitoring be used for patients with sickle cell disease suspected to have pulmonary hypertension and abnormal ECHO? 1.1 The ASH guideline panel recommends against right-heart catheterization in asymptomatic patients with SCD and isolated TRJV 2.5 to 2.9 m/sec. (Conditional recommendation, low quality evidence) 1.2 The ASH guideline panel suggests right heart catheterization in patients with SCD and TRJV 2.5 m/sec who also have reduced 6MWD or elevated NT-proBNP. (Conditional recommendation, low quality evidence) Technical Remarks: 1. Decisions about the need for right-heart catheterization should be based on ECHOs obtained at steady state and not during illness such as hospitalization for pain or acute chest syndrome. 2. ECHOs should be repeated in the setting of elevated TRJV prior to referral for right-heart catheterization given the suboptimal reproducibility of TRJV measurements. 3. In the setting of severe anemia, consider transfusion and repeating ECHO prior to referring for right-heart catheterization given the influence of anemia and increased cardiac output on TRJV. 4. Consult with cardiology about other findings on ECHO, in addition to elevated TRJV, which could suggest significant pulmonary vascular disease such as right ventricular failure or septal flattening. 5. For patients with TRJV 2.5 m/sec who are asymptomatic, other non-invasive evaluation (NT-proBNP or 6MWD) is suggested to increase the diagnostic accuracy for pulmonary vascular disease (Mehari et al., 2013). 6. Abnormal cutoff values for NT-proBNP and 6MWD have not been firmly determined for patients with SCD. However, NT-proBNP values of 160 pg/ml (Machado, 2006) and 6MWD 500 meters (Parent, 2011; Fonseca, 2012) represent reasonable thresholds for adults with SCD based on previously published in this population.

2 7. Use clinical judgment or consult with expert in pulmonary hypertension regarding need for right-heart catheterization for patients who report symptoms suggestive of pulmonary vascular disease but have normal 6MWD and NT-proBNP. 8. Consult with expert in pulmonary hypertension regarding results of right-heart catheterization and therapeutic options based on type of pulmonary vascular disease and presumed pathophysiology. Question 2: Should angiotensin inhibition (renin-angiotensin-aldosterone system blockade) vs. no angiotensin inhibition be used for patients with sickle cell disease and albuminuria? 2.0 The ASH guideline panel suggests the use of angiotensin converting enzyme inhibitors or angiotensin II receptor blockers (ACEI/ARB) in patients with SCD and albuminuria. (Conditional recommendation, low quality evidence) Technical Remarks: 1. The initiation of ACEi and ARBs for patients with SCD requires adequate follow-up and monitoring of side effects (i.e. hyperkalemia, cough, hypotension). 2. Similar to the general population, patients with SCD whose renal function depends on the activity of the renin angiotensin system should be monitored for change in kidney function while on ACEi or ARBs. 3. Albuminuria should be confirmed by either a first am urine sample or 2 consecutive untimed urine samples. Question 3: Should screening echocardiography vs. no screening be performed to identify pulmonary hypertension for asymptomatic patients with sickle cell disease? 3.0 The ASH guideline panel suggests against performing routine screening echocardiogram to identify pulmonary hypertension in asymptomatic children and adults with SCD. (Conditional recommendation, low quality evidence) Technical Remarks: 1. The panel acknowledges the potential value of TRJV on ECHO as a general biomarker of disease severity, given the relationship between elevated TRJV and increased mortality in adults with SCD. In this way, baseline TRJV may inform a greater understanding of disease severity in adults with SCD and influence shared decision making regarding general management strategies, including initiation or optimization of disease-modifying therapies such as hydroxyurea or chronic transfusions. 2. The panel acknowledges that there is considerable variability in how much patients value knowing about abnormal findings on a screening ECHO. This may influence individual provider decisions about screening given the known limitations of TRJV measurements and unclear impact on subsequent changes in management. 3. Although the panel suggests no screening ECHO in asymptomatic patients, the following signs or symptoms may warrant an ECHO to evaluate for pulmonary vascular disease: Dyspnea at rest or with exertion that is out of proportion to known condition, increased compared to baseline or that is unexplained

3 Chest pain at rest or with exertion that is out of proportion to known condition, increased compared to baseline or that is unexplained Increase in exercise limitation compared to baseline unexplained by other factors Evidence of decreased 6-minute walk test distance Evidence for increased NT-proBNP History of recurrent hypoxemia at rest or with exertion Evidence for sleep disordered breathing with or without hypoxemia History of syncope or pre-syncope Evidence for loud P2 component of second heart sound or unexpected or new murmur on exam Signs of right-sided heart failure such as lower extremity or pedal edema, elevated jugular venous distention, hypotension or hepatomegaly History of pulmonary embolism Question 4: Should targeted therapy for pulmonary hypertension OR chronic transfusion therapy vs. no targeted therapy OR transfusions be used for patients with sickle cell disease and right heart catheterization-defined pulmonary hypertension? 4.1 The ASH guideline panel recommends against the use of pulmonary arterial hypertension-specific therapies in patients who do not have pulmonary arterial hypertension confirmed by right-heart catheterization. (Conditional recommendation, low quality evidence) 4.2 The ASH guideline panel suggests the use of pulmonary arterial hypertension-specific therapies under the care of a pulmonary hypertension specialist in patients with a diagnosis of pulmonary arterial hypertension confirmed by right-heart catheterization given the lack of alternative treatment options and high morbidity and mortality. (Conditional recommendation, low quality evidence) Good practice statement: The panel suggests a multidisciplinary* (hematology, pulmonary hypertension specialist, pulmonary) approach when considering pulmonary arterial hypertension-specific therapies in patients who have pulmonary arterial hypertension confirmed by right-heart catheterization. Technical Remarks: 1. Improvements in hemodynamics by right-heart catheterization and change in diuretic requirements (for right heart failure) should be considered as endpoints for clinical trials investigating patients with pulmonary arterial hypertension confirmed by right-heart catheterization treated with pulmonary arterial hypertension specific therapy.

4 2. Patients with pulmonary arterial hypertension confirmed by right-heart catheterization should be referred to pulmonary hypertension treatment centers given the possibility of increased side effects (e.g. pain) with pulmonary arterial hypertension-specific therapy such as sildenafil. 3. Initiation and/or optimization for disease-modifying therapy such as hydroxyurea or chronic transfusions should be considered for patients with pulmonary arterial hypertension confirmed by right-heart catheterization. 4. Potential differences in the pathophysiologic basis (e.g. contribution of anemia) and differences in side effect profile (e.g. pain) should be considered when determining treatment options for pulmonary arterial hypertension confirmed by right-heart catheterization in SCD. 5. This recommendation applies to patients with SCD who have no other clear reason for their pulmonary arterial hypertension confirmed by right-heart catheterization (e.g. obstructive sleep apnea, significant lung diseases, left heart failure). 6. Treatment options may differ based on the subtype of pulmonary hypertension as classified by findings on rightheart catheterization and clinical evaluation. Question 5: Should routine monitoring of pulmonary function vs. no monitoring be used for asymptomatic patients with sickle cell disease? 5.0 The ASH guideline panel suggests against performing routine screening pulmonary function testing in asymptomatic patients with SCD. (Conditional recommendation, low quality evidence) Technical Remarks: 1. This recommendation is limited to asymptomatic individuals with sickle cell disease. A comprehensive respiratory history and review of systems should be performed to identify patients with SCD for whom a low threshold should be considered for pulmonary function testing. Whenever appropriate, validated tools should be used to further identify which patients should be considered for pulmonary function testing. 2. The following signs or symptoms may warrant pulmonary function testing at steady state (i.e. healthy) to evaluate for lung disease: Wheezing or increased cough at rest or with exertion Wheezing or increased cough during episode of acute upper respiratory infection Wheezing or increased cough during episode of acute chest syndrome Dyspnea at rest or with exertion that is increased compared to baseline or that is unexplained Chest pain at rest or with exertion that is out of proportion to known condition, increased compared to baseline or that is unexplained Increase in exercise limitation compared to baseline Evidence of abnormal 6-minute walk test distance History of recurrent hypoxemia at rest or with exertion History of syncope or pre-syncope History of recurrent acute syndrome

5 History of pulmonary embolism 3. Providers should understand the importance of educating patients, discussing patient/caregiver priorities and incorporating shared decision making when considering obtaining pulmonary function testing. Question 6: In adults with sickle cell disease, what are the effects of targeting a BP goal of 130/80 compared to a goal of 140/90? 6.0 The ASH guideline panel recommends for targeting a BP goal of 130/80 compared to a goal of 140/90 in adults with sickle cell disease. (Strong recommendation, moderate quality evidence) Technical Remarks: 1. The impact of hypertension on patient-important outcomes is significant for the African American individuals and therefore, requires adherence to general population guidelines independent of having sickle cell disease. Question 7: Should proceeding with renal transplant vs. remaining on dialysis be used for patients with sickle cell disease and end stage renal disease? 7.0 The panel suggests referral for renal transplant in patients with sickle cell disease and end stage renal disease or advanced chronic kidney disease. (Conditional recommendation, low quality evidence) Technical Remarks: 1. Providers should adhere closely to general guidelines and recommendations for peri-operative transfusion requirements for surgery in adults with SCD. 2. There should be judicious use of corticosteroids as part of post-transplant immunosuppression given the potential relationship between steroid exposure and vaso-occlusive pain in SCD. Question 8: Should screening for sleep-disordered breathing vs. no screening be used for patients with sickle cell disease? 8.0 The ASH guideline panel suggests against screening with formal polysomnography (sleep study) for sleepdisordered breathing in asymptomatic* patients with SCD. (Conditional recommendation, low quality evidence) Technical Remarks: 1. Sleep-disordered breathing should be defined as follows for children and adults: abnormal respiratory patterns (e.g. apneas and/or hypopneas, insufficient ventilation) during sleep resulting in daytime sleepiness or fatigue that interferes with an individual s ability to function and reduces quality of life. 2. Formal sleep should be conducted in a certified sleep center that meets standards as required by accreditation groups (The Joint Commission, American Academy of Sleep Medicine).

6 3. A thorough review of systems should be performed to identify patients with SCD for whom a low threshold should be considered for obtaining a formal sleep study. Whenever appropriate, validated tools should be used to further identify which patients should be considered for formal sleep testing. 4. The following signs and symptoms may raise suspicion that a sickle cell patient might have sleep-disordered breathing and for whom formal sleep testing might be appropriate: Snoring or loud snoring Early morning headaches Daytime hypersomnolence or non-restorative sleep Observed apnea or respiratory pauses during sleep Unexplained desaturation or hypoxemia during sleep, while awake or with exertion Abnormal score on validated sleep symptom screening survey Carbon dioxide retention on arterial blood gas History of poorly controlled hypertension or congestive heart failure History of nocturnal enuresis in an older child (e.g. 10 years old) History of recurrent priapism or nocturnal vaso-occlusive pain History of pulmonary arterial hypertension by right-heart catheterization History of ischemic stroke without evidence for vasculopathy Symptoms of ADHD in children Question 9A: Should indefinite anticoagulation vs. short term ( 6 months) anticoagulation be used for adults with sickle cell disease who have their first unprovoked VTE? 9A.1 The ASH guideline panel suggests indefinite anticoagulation over shorter periods for adults with SCD and first, non-surgical, unprovoked VTE. (Conditional recommendation, low quality evidence) Technical Remarks: 1. Edoxaban should be avoided in adults with SCD due to the concerns of its use in patients with renal hyperfiltration. 2. The decision to remain on anticoagulation should be made through shared decision making based on patient values/preferences and subject to regular re-evaluation of these parameters.

7 Question 9B: Should long term (> 6 months) vs. short term (either 3 or 6 months) anticoagulation be used for adults with sickle cell disease who have their first provoked VTE? 9B.1. The ASH guideline panel suggests indefinite anticoagulation over shorter periods for adults with SCD and first, non-surgical, provoked VTE. (Conditional recommendation, low quality evidence) Technical Remarks: 1. The panel considers SCD a chronic underlying risk factor for venous thromboembolism. 2. The type, strength and duration of the provoking event should be considered when considering indefinite anticoagulation in this setting. 3. The decision to remain on anticoagulation should be made through shared decision making based on patient values/preferences and subject to regular re-evaluation of these parameters. 4. Indefinite anticoagulation is not recommended for central venous line-associated venous thromboembolism 5. Edoxaban should be avoided in SCD due to the concerns of its use in patients with renal hyperfiltration. Question 10: Should combination therapy with hydroxyurea and erythropoietin vs. erythropoietin or hydroxyurea alone be used for patients with sickle cell disease and nephropathy? 10.0 The ASH guideline panel suggests combination therapy with hydroxyurea and erythropoietin in patients with sickle cell disease and worsening anemia associated with chronic kidney disease. (Conditional recommendation, low quality evidence) Technical Remarks: 1. Need to optimize adherence to hydroxyurea therapy while on erythropoietin to maximize increasing fetal hemoglobin. 2. Consider narrow therapeutic window for erythropoietin and hemoglobin. The panel suggests not going above a ceiling of 10 g/dl to decrease the risk of vaso-occlusion, stroke and venous thromboembolism. 3. Consider initiating erythropoietin when there is a simultaneous drop in hemoglobin and absolute reticulocyte count, due to chronic kidney disease, while on steady state hydroxyurea

8 QUESTION 1 Should Right-sided cardiac catheterization vs. Serial non-invasive monitoring be used for patients with sickle cell disease suspected to have pulmonary hypertension and abnormal ECHO? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: Patients with sickle cell disease suspected to have pulmonary hypertension and abnormal ECHO. Right-sided cardiac catheterization Serial non-invasive monitoring Mortality; Catheterization side effects; Accuracy of ECHO as a screening tool for PH SETTING: PERSPECTIVE: BACKGROUND: Elevated tricuspid regurgitant velocity (TRJV) is a common finding on Doppler echocardiogram (ECHO) among individuals with SCD and may predict the presence of pulmonary arterial hypertension. Although right-heart catheterization represents the gold standard for diagnosing pulmonary arterial hypertension, the utility of serial monitoring by non-invasive measures such as TRJV in individuals suspected to have pulmonary arterial hypertension based on an abnormal ECHO is not clear. The impact of serial monitoring by Doppler ECHO versus right-heart catheterization is also unknown. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Desirable Effects How substantial are the desirable anticipated effects? Trivial Small The desirable effects are small when using TRJV 2.5 m/sec as sole criterion for determining next step but moderate when combining TRJV 2.5 m/sec with other signs (e.g. reduced 6MWD or 8

9 Moderate Large increased NT-proBNP) or symptoms suggestive of pulmonary vascular disease. This is based on the suboptimal accuracy of TRJV on screening ECHO as the sole criterion for pulmonary vascular disease in SCD. Undesirable Effects How substantial are the undesirable anticipated effects? Large Moderate Small Trivial The undesirable effects are moderate to large given the high false positive rate of using 2.5 m/sec on screening ECHO as a sole criterion for pulmonary vascular disease. However, the undesirable effect associated with complications is small since the complication rate for right-heart catheterization in adults is low. Certainty of evidence What is the overall certainty of the evidence of effects? Very low Low Moderate High No included The overall certainty of evidence of effects is very low given that there are no direct head to head comparisons of the (e.g. right-heart catheterization versus serial ECHO) on patient important outcomes. Other reasons for low certainty included the following: 1) variability in criteria (i.e. TRJV alone versus other signs/symptoms) used to determine which patients underwent rightheart catheterization, 2) diagnostic limitations of TRJV by ECHO as a screening test (i.e. high false positive rates), 3) inability to determine if the decision to proceed with right-heart catheterization or its results led to change in management that affected outcomes, and 4) evidence for death by causes other than pulmonary vascular disease in the majority of patients regardless of whether or not they underwent right-heart catheterization. 9

10 Values Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Balance of effects Does the balance between desirable and undesirable effects favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the The balance of effects favors not performing right-heart catheterization for asymptomatic patients with TRV 2.5 to 2.9 m/sec alone on screening ECHO. However, the balance of effects favors performing right-heart catheterization for patients with TRV 2.5 on screening ECHO accompanied by signs (reduced 6MWD or increased NT-proBNP) or signs and symptoms of pulmonary vascular disease. Resources required How large are the resource requirements (costs)? 10

11 Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)? Very low Low Moderate High No included Cost effectiveness Does the cost-effectiveness of the favor the or the comparison? 11

12 Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased Acceptability Is the acceptable to key stakeholders? No Probably no Probably yes Yes Feasibility Is the feasible to implement? No Probably no 12

13 Probably yes Yes Varies 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 Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included 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 13

14 TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the Conditional recommendation for the or the comparison Strong recommendation for the CONCLUSIONS Recommendation The panel recommends against right-heart catheterization in asymptomatic patients with SCD isolated TRJV 2.5 to 2.9 m/sec. The panel suggests right heart catheterization in patients with SCD and TRJV 2.5 m/sec who also have reduced 6MWD or elevated NT-proBNP. Technical remarks: 9. Decisions about the need for right-heart catheterization should be based on ECHOs obtained at steady state and not during illness such as hospitalization for pain or acute chest syndrome. 10. ECHOs should be repeated in the setting of elevated TRJV prior to referral for right-heart catheterization given the suboptimal reproducibility of TRJV measurements. 11. In the setting of severe anemia, consider transfusion and repeating ECHO prior to referring for right-heart catheterization given the influence of anemia and increased cardiac output on TRJV. 12. Consult with cardiology about other findings on ECHO, in addition to elevated TRJV, which could suggest significant pulmonary vascular disease such as right ventricular failure or septal flattening. 13. For patients with TRJV 2.5 m/sec who are asymptomatic, other non-invasive evaluation (NT-proBNP or 6MWD) is suggested to increase the diagnostic accuracy for pulmonary vascular disease (Mehari et al., 2013). 14. Abnormal cutoff values for NT-proBNP and 6MWD have not been firmly determined for patients with SCD. However, NT-proBNP values of 160 pg/ml (Machado, 2006) and 6MWD 500 meters (Parent, 2011; Fonseca, 2012) represent reasonable thresholds for adults with SCD based on previously published in this population. 15. Use clinical judgment or consult with expert in pulmonary hypertension regarding need for right-heart catheterization for patients who report symptoms suggestive of pulmonary vascular disease but have normal 6MWD and NT-proBNP. 16. Consult with expert in pulmonary hypertension regarding results of right-heart catheterization and therapeutic options based on type of pulmonary vascular disease and presumed pathophysiology. Justification Subgroup considerations 14

15 Implementation considerations Monitoring and evaluation Research priorities 1. Prospective study evaluating the utility of adding NT-proBNP and 6MWD to ECHO to improve diagnostic yield for patients with SCD undergoing evaluation for pulmonary vascular disease. 2. Prospective study to better characterize the risk factors for development and natural history of pulmonary vascular disease in children and adults with SCD. 3. Prospective study to determine the prognostic implications of various subtypes and severity of pulmonary vascular disease with or without treatment. GRADE Evidence Profile Question 1: Right-sided cardiac catheterization compared to serial non-invasive monitoring in patients with sickle cell disease suspected to have pulmonary hypertension and abnormal ECHO. Certainty assessment of patients Effect of Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Right-sided cardiac catheterization Serial noninvasive monitoring Relative (95% CI) Absolute (95% CI) Certainty Importance Mortality 15

16 Certainty assessment of patients Effect of Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Right-sided cardiac catheterization Serial noninvasive monitoring Relative (95% CI) Absolute (95% CI) Certainty Importance 3 observational not serious not serious serious a not serious none There were no direct prospective, head to head comparisons of mortality in children or adults with SCD who underwent right-heart catheterization versus serial ECHO for suspected pulmonary hypertension based on an abnormal ECHO. However, 3 (Mehari, Parent, Fonseca) examined mortality among selected patients with elevated TRJV who underwent right-heart catheterization for suspected pulmonary hypertension. Mortality rates were compared in this group versus those patients who did not undergo right-heart catheterization regardless of TRJV elevation: VERY LOW CRITICAL Only patients with TRVJ 2.5 m/s underwent right-heart catheterization Total number of patients received right-heart catheterization = 206, in whom 87 (42%) had pulmonary hypertension Total number of deaths in patients who underwent right-heart catheterization = 29 (14%) Total number of patients continued with noninvasive monitoring = 795, in whom 54 died (6.8%) Catheterization side effects 1 observational not serious not serious serious a not serious none Only 1 study (Parent) reported side effects of right-heart catheterization in SCD patients. In this study, 96 out of 398 underwent right heart catheterization. Three episodes of vaso-occlusive crisis occurred in three patients shortly after catheterization (3.12%), necessitating brief hospitalizations. There were no permanent sequelae related to these events. VERY LOW CRITICAL Accuracy of ECHO as a screening tool for PH 4 observational not serious not serious serious a not serious none Four reported data on accuracy of ECHO to screen for pulmonary hypertension (Mehari, Parent, Fonseca, Fitzgerald). Among these, the total number patients screened with ECHO = 1,007. Of those who underwent screening, 104 with elevated TRVJ underwent right-heart catheterization to confirm pulmonary hypertension. Pulmonary hypertension was confirmed by right-heart catheterization in 87/1007 patients (8.6%). The remaining patients did not proceed with further investigation to confirm or rule out pulmonary hypertension. VERY LOW IMPORTANT 16

17 Explanations a. Observational study downgraded due to indirectness due to no head to head comparison of the on the important outcomes. References 1. Mehari et al. Hemodynamic predictors of mortality in adults with sickle cell disease. American Journal of Respiratory and Critical Care Medicine. 2013;187(8): Parent et al. A hemodynamic study of pulmonary hypertension in sickle cell disease. New England Journal of Medicine. 2011;365(1): Fonseca et al. Pulmonary hypertension diagnosed by right heart catheterisation in sickle cell disease. European Respiratory Journal. 2012;39(1): Fitzgerald et al. Misclassification of pulmonary hypertension in adults with sickle hemoglobinopathies using doppler echocardiography. Southern Medical Journal. 2012;105(6): QUESTION 2 Should Angiotensin inhibition (renin-angiotensin-aldosterone system blockade) vs. No angiotensin inhibition be used for patients with sickle cell disease and albuminuria? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: Patients with sickle cell disease and albuminuria. Angiotensin inhibition (renin-angiotensin-aldosterone system blockade) No angiotensin inhibition RCT-Urine albumin; RCT-Blood pressure; RCT-K level; Urine albumin; Blood pressure; K level; Renal function; SETTING: PERSPECTIVE: BACKGROUND: Albuminuria is a common finding among adults, and some children, with SCD and may be associated with progression to chronic kidney disease. The exact pathophysiology, natural history and optimal therapy of albuminuria in individuals with SCD, however, remain unclear. Angiotensin inhibition, with angiotensin converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB), represents a treatment strategy adopted in other conditions. The impact of angiotensin inhibition on patient-important outcomes in SCD is not known. CONFLICT OF INTEREST: ASSESSMENT Problem 17

18 Is the problem a priority? No Probably no Probably yes Yes Up to 12% of people with sickle cell disease will develop end stage renal disease (ESRD) Cochrane Database Syst Rev Jul 3;7. Decreasing the progression of proteinuria to ESRD is important for decreasing morbidity and mortality. Little is known about the natural history of proteinuria in this patient population so risk of progression is drawn from data in other populations (i.e. those with diabetes). Desirable Effects How substantial are the desirable anticipated effects? Trivial Small Moderate Large The desirable anticipated effects are moderate for the effect of angiotensin converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) on severe albuminuria (macro) but trivial for the effect on moderate albuminuria (micro). This is based on data from 8 (See Evidence Table) in which 83/114 subjects treated with an ACEi or ARB had improvement in proteinuria. The majority of subjects in these had macroalbuminuria at the time of enrollment. There are no data in patients with sickle cell disease about the effect of angiotensin inhibition on long term kidney function and whether the use of these agents slows progression of chronic kidney disease. Limitations of the available data include short follow-up, limited data on side effects, variability in classification of proteinuria, and unknown quality assurance with measurements of urine albumin. The panel also suggested that it is unclear whether or not short term reduction in proteinuria results in long term benefits (better kidney function, etc.). Undesirable Effects How substantial are the undesirable anticipated effects? 18

19 Large Moderate Small Trivial The undesirable anticipated effects are trivial based on the absence of significant hypotension or hyperkalemia seen in published (See Evidence Table). In 6, 0/72 and 0/30 subjects had hypotension from ACEi or ARBs, respectively. In 5, 8/62 and 4/30 subjects had hyperkalemia from ACEi or ARBs, respectively. In these, no angioedema was reported. However, it is reasonable to expect the same rate of angioedema as that seen in the general African American population undergoing treatment with ACEi or ARBs. The panel believes that the risks of taking ACEi or ARBs is similar for patients with sickle cell disease versus the general population Certainty of evidence What is the overall certainty of the evidence of effects? Very low Low Moderate High No included The overall certainty of effects is very low based on the following: 1) imprecision due to limited data with small sample size, 2) indirectness of the outcome (i.e. surrogate outcome) with only short follow up, 3) suboptimal study design and reliance on non-rct, and 4) potential for selective reporting. The panel agreed not to use indirect evidence from diabetes as the pathophysiology for proteinuria is likely different when compared to that proposed for sickle cell disease. Values Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability Balance of effects No evidence identified The panel, including patient representatives, agreed that there is likely little variability in patients' desire to decrease the risk of end stage renal disease. 19

20 Does the balance between desirable and undesirable effects favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings The resource requirements, including some cost associated with medication and monitoring, are expected to be negligible. The effect of using ACEi and ARBs to reduce the risk of end stage renal disease (i.e. prevention of end stage renal disease and dialysis) could not be discussed because it is unknown. Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)? 20

21 Very low Low Moderate High No included Cost effectiveness Does the cost-effectiveness of the favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased The panel, including patient representatives, felt that in general patients with SCD are likely to have access to ACEi and ARBs given the widespread availability of generic formulations. 21

22 Acceptability Is the acceptable to key stakeholders? No Probably no Probably yes Yes The panel, including patient representatives, felt that taking ACEi and ARBCs will likely be acceptable given the availability of once daily dosing of these medications. Feasibility Is the feasible to implement? No Probably no Probably yes Yes The panel, including patient representatives, felt that it would be feasible to implement this as costs of the medication are low, generic formulations are available and most providers are familiar with prescribing these medications. 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 Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included 22

23 JUDGEMENT VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included 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 TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the or the comparison Conditional recommendation for the Strong recommendation for the CONCLUSIONS Recommendation 23

24 The ASH guideline panel suggests the use of angiotensin converting enzyme inhibitors or angiotensin II receptor blockers (ACEI/ARB) in patients with SCD and albuminuria. Technical remarks 1. The initiation of ACEi and ARBs for patients with SCD requires adequate follow-up and monitoring of side effects (i.e. hyperkalemia, cough, hypotension). 2. Similar to the general population, patients with SCD whose renal function depends on the activity of the renin angiotensin system should be monitored for change in kidney function while on ACEi or ARBs.. 3. Albuminuria should be confirmed by either a first am urine sample or 2 consecutive untimed urine samples. Justification The possibility of deceasing the risk of progression to ESRD was highly valued by the panel. Decreasing albuminuria was considered valuable as a way of potentially decreasing the risk of progression to ESRD. Data and outcomes from both observational and the one randomized controlled trial uniformly demonstrated a decrease in albuminuria associated with ACEi and ARBs in patients with SCD. This benefit, along with minimal side effects and monitoring burden, supported a recommendation for the. This recommendation is based on stronger evidence of a reduction in albuminuria in patients with higher levels of albuminuria. Subgroup considerations The panel believes that it is important to consider stage of chronic kidney disease and degree of proteinuria when considering this. Implementation considerations Monitoring and evaluation The initiation of ACEi and ARBs requires follow-up and monitoring of side effects related to angiotensin inhibition therapy with specific warnings for patients with impaired renal function, electrolyte imbalances, and volume depletion. Research priorities 24

25 1. Prospective to study the association between moderate albuminuria (30-300mg/g) and progression to severe albuminuria (>300mg/g) in patients with SCD. 2. Prospective to understand natural history of progression of albuminuria to end stage renal disease in patients with SCD. 3. Randomized controlled trials of renal protective medications to determine the appropriate therapy for patients with SCD identified with severe albuminuria. 4. Randomized controlled trials of placebo vs renal protective medications for patients identified with moderate albuminuria to evaluate progression to severe albuminuria or end stage renal disease. 25

26 GRADE Evidence Profile Question 2: Angiotensin inhibition (RAS blockade aldosterone) compared to No angiotensin inhibition in patients with sickle cell disease and albuminuria. Certainty assessment of patients Effect of Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Angiotensin inhibition (RAS blockade aldosterone) No angiotensin inhibition Relative (95% CI) Absolute (95% CI) Certainty Importance RCT-Urine albumin 1 randomised trials not serious not serious not serious serious a none MD 63 mg/day higher (40 higher to 86 higher) MODERATE IMPORTANT RCT-Blood pressure 1 randomised trials not serious not serious not serious serious a none MD 82 mg/day higher (0 to 0 ) MODERATE IMPORTANT RCT-K level 1 randomized trials not serious not serious not serious serious b none Only 1 RCT study (Foucan) reported potassium levels in patients undergoing treatment: The initial dose was 6.25 mg/day during the first month, 12.5 mg/day during the second and the third months, and 25 mg/day after the third month. After 6 months, potassium remained constant throughout the study in both groups (data not shown in the study). VERY LOW IMPORTANT Urine albumin 26

27 Certainty assessment of patients Effect of Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Angiotensin inhibition (RAS blockade aldosterone) No angiotensin inhibition Relative (95% CI) Absolute (95% CI) Certainty Importance 8 observational serious c not serious not serious not serious none A total of 8 observational (Foucan, McKie, Aoki, Fitzhugh, Falk, Quinn, Yee, Haymann) reported the effect of treatment on urine albumin: In 6, 53 of 84 (63%) patients who received ACEi therapy showed improvement in the urine albumin. Of these, 18 (34%) had severe albuminuria (macroalbuminuria), 6 (11%) had moderate albuminuria (microalbuminuria), and the rest were not specified. In 2, 30 patients received ARBs (losartan) and all of them (100%) showed improvement in urine albumin level. Of these, 18 (60%) had moderate albuminuria (microalbuminuria) and 12 (40%) had severe albuminuria (macroalbuminuria). VERY LOW IMPORTANT Blood pressure 6 observational serious d not serious not serious not serious none There were 6 observational (Foucan, Aoki, Falk, Quinn, Yee, Haymann) that reported treatment effect on blood pressure: In 4, 8 out of total 72 (11%) who received ACEi showed improvement in the blood pressure. The rest showed either no difference in BP compared to placebo group, or no difference in BP before and after ACEi treatment. No hypotension was reported in all. In 2, 30 patients received ARBs (losartan) with no significant change in BP reported before and after losartan. No hypotension was reported in both. VERY LOW IMPORTANT K level 5 observational serious e not serious not serious not serious none A total of 5 observational (Foucan, Aoki, Quinn, Yee, Haymann) reported potassium levels with treatment: In 3 with a total of 62 patients who received ACEi, 8 patients (13%) showed an increase in K level from 5 +/- 0.6 meq/l to 5.5+/-1, and the rest did not show changes in K either before and after ACEi or compared to placebo group. In 2, 30 patients received ARBs (losartan), 4 had grade 1 hyperkalemia (13%), and the rest showed no increase in K level. VERY LOW IMPORTANT Renal function 27

28 Certainty assessment of patients Effect of Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Angiotensin inhibition (RAS blockade aldosterone) No angiotensin inhibition Relative (95% CI) Absolute (95% CI) Certainty Importance 2 observational serious f not serious not serious not serious none In 2 observational (Yee, Haymann) with a total of 54 patients who received ACEi/ARBs, there was no significant change in renal function before and after treatment. VERY LOW IMPORTANT CI: Confidence interval; MD: Mean difference Explanations a. Moderate (imprecision due to small sample size). b. Imprecision due to small sample size and surrogate outcome c. Small sample size 102 patients and non-rct d. Small sample size 90 patients and non-rct e. Small sample size 80 patients and non-rct f. Small sample size 54 patients and non-rct References 1. Foucan L et al. A randomized trial of captopril for microalbuminuria in normotensive adults with sickle cell anemia. Am J Med. 1998;104(4): McKie et al. Prevalence, prevention, and treatment of microalbuminuria and proteinuria in children with sickle cell disease. J Pediatr Hematol Oncol. 2007;29(3): Aoki et al. Enalapril reduces the albuminuria of patients with sickle cell disease. Am J Med. 1995;98(5): Fitzhugh et al. Enalapril and hydroxyurea therapy for children with sickle nephropathy. Pediatr Blood Cancer. 2005;45(7): Falk et al. Prevalence and pathologic features of sickle cell nephropathy and response to inhibition of angiotensin-converting enzyme. N Engl J Med. 1992;326(14): Quinn et al. Losartan for the Nephropathy of Sickle Cell Anemia: A Phase 2, Multi Center Trial. Am J Hematol Yee et al. Losartan therapy decreases albuminuria with stable glomerular filtration and permselectivity in sickle cell anemia. Blood Cells, Molecules, and Diseases Haymann et al. Renin angiotensin system blockade promotes a cardio renal protection in albuminuric homozygous sickle cell patients. Br J Haematol. 2017;179(5):

29 QUESTION 3 Should screening echocardiography vs. no screening be performed to identify pulmonary hypertension for asymptomatic patients with sickle cell disease? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: In asymptomatic patients with sickle cell disease. Screening echocardiography No screening Mortality-Adults; Mortality-Adults and children/adolescent; Mortality-Unknown age/not reported; Ejection fraction; NYHA classification; 6-MWT; SETTING: PERSPECTIVE: BACKGROUND: Elevated tricuspid regurgitant velocity (TRJV), as measured by Doppler echocardiogram (ECHO), is common among adults with SCD and is associated with an increased risk of mortality. Elevated TRJV may also predict pulmonary arterial hypertension, which is confirmed by right-heart catheterization. Despite the utility of Doppler ECHO as a screening tool for individuals with signs and symptoms suggestive of pulmonary arterial hypertension, its utility as a screening tool for asymptomatic individuals with SCD is not clear. The impact of results from screening on patientimportant outcomes is also unknown. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Desirable Effects How substantial are the desirable anticipated effects? 29

30 Trivial Small Moderate Large Possible desirable effects include the ability to determine the true prevalence of pulmonary vascular disease, the potential to use TRJV as a prognostication biomarker, and the potential to discuss optimizing disease-modifying therapy with patients (small to moderate for adults, trivial for children) based on results of screening. Screening ECHOs may provide additional information beyond TRJV measurements, such as that gained from parameters that reflect diastolic dysfunction. Moreover, the utility of TRJV may extend beyond its ability to screen for pulmonary vascular disease and instead may represent a general prognostic indicator for mortality. Obtaining ECHOs for these indications, however, should be considered separately from its use as a screening tool for pulmonary vascular disease in SCD but may be reasonable in patients with signs, symptoms or a clinical course that warrants evaluation. Undesirable Effects How substantial are the undesirable anticipated effects? Large Moderate Small Trivial Possible undesirable effects include the inability to know how to use information from screening, the potential for anxiety in patients as a result of the information, the potential for no change in management, the risks associated with inappropriate referral for right-heart catheterization due to high false positive rate, and the potential adverse effects associated with inappropriate treatment with pulmonary hypertension therapy (moderate for adults, moderate to large for children). Certainty of evidence What is the overall certainty of the evidence of effects? 30

31 Very low Low Moderate High No included The overall certainty of evidence of effects is very low given that there are no direct head to head comparisons of the (e.g. screening versus no screening for pulmonary hypertension) on patient important outcomes such as mortality. The majority of instead only evaluated the relationship between mortality and TRJV in those undergoing ECHO screening. Other reasons for low certainty included the following: 1) diagnostic limitations of TRJV by ECHO as a screening test (i.e. high false positive rates) for pulmonary vascular disease, 2) inability to determine how results from ECHO determined subsequent changes in management decisions (i.e. right-heart catheterization), 3) lack of sufficient evidence for which therapies constitute appropriate management of elevated TRJV and/or pulmonary vascular disease in SCD, 4) inability to determine if changes in management based on ECHO results affect outcomes, and 5) evidence for death by causes other than pulmonary vascular disease in the majority of patients who underwent ECHO with the intent to screen for pulmonary hypertension. Accuracy of ECHO to screen for pulmonary hypertension: A total of 4 were analyzed for diagnostic accuracy. Total patients screened with ECHO = 1,007. Of these patients, 104 had an elevated TRVJ and underwent right-hear catheterization to confirm pulmonary hypertension. Pulmonary hypertension was confirmed by right-heart catheterization in 87/1,007 (8.6%) patients. The rest of the patients did not proceed with further investigation to confirm or rule out pulmonary hypertension. Causes of death: A total of 4 reported causes of death for a total of 57 patients with TRV 2.5: 1 was due to right ventricular dysfunction with pneumonia, 1 was due to right ventricular dysfunction, 2 were due to cardiac failure, and the rest were not related to cardiopulmonary causes. Values Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability The panel anticipates there is variability in patient versus provider desire for knowledge of abnormal results and that this may be influenced by differences in acceptance of potential management based on culture, age and other factors. Balance of effects Does the balance between desirable and undesirable effects favor the or the comparison? 31

32 Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the In children, the balance of effects probably favors the comparison (i.e. no screening ECHO) based on low quality of evidence in the pediatric SCD population. In adults, the balance of effects also probably favors the comparison (i.e. no screening ECHO) based on a vote that was taken among members of the panel with the final results being: 5 members in favor of screening, 8 members not in favor of screening, and 1 member in favor of either screening or no screening. It is important to note that the discussion of balance of effects was focused primarily on evidence and outcomes related to ECHO in the setting of screening for pulmonary hypertension alone. Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)? 32

33 Very low Low Moderate High No included Cost effectiveness Does the cost-effectiveness of the favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased The panel believes that equity may be reduced for adults not currently insured if screening by ECHO was suggested. 33

34 Acceptability Is the acceptable to key stakeholders? No Probably no Probably yes Yes Feasibility Is the feasible to implement? No Probably no Probably yes Yes Varies The panel believes that feasibility of screening by ECHO may vary given the lack of standardization of ECHO protocols as well as the technical aspects and skills required for accurate measurement of TRJV. 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 Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability 34

35 JUDGEMENT BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included 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 TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the Conditional recommendation for the or the comparison Strong recommendation for the CONCLUSIONS Recommendation 35

36 The panel suggests against performing routine screening echocardiogram to identify pulmonary hypertension in asymptomatic children and adults with SCD. Technical remarks: 4. The panel acknowledges the potential value of TRJV on ECHO as a general biomarker of disease severity, given the relationship between elevated TRJV and increased mortality in adults with SCD. In this way, baseline TRJV may inform a greater understanding of disease severity in adults with SCD and influence shared decision making regarding general management strategies, including initiation or optimization of disease-modifying therapies such as hydroxyurea or chronic transfusions. 5. The panel acknowledges that there is considerable variability in how much patients value knowing about abnormal findings on a screening ECHO. This may influence individual provider decisions about screening given the known limitations of TRJV measurements and unclear impact on subsequent changes in management. 6. Although the panel suggests no screening ECHO in asymptomatic patients, the following signs or symptoms may warrant an ECHO to evaluate for pulmonary vascular disease: Dyspnea at rest or with exertion that is out of proportion to known condition, increased compared to baseline or that is unexplained Chest pain at rest or with exertion that is out of proportion to known condition, increased compared to baseline or that is unexplained Increase in exercise limitation compared to baseline unexplained by other factors Evidence of decreased 6-minute walk test distance Evidence for increased NT-proBNP History of recurrent hypoxemia at rest or with exertion Evidence for sleep disordered breathing with or without hypoxemia History of syncope or pre-syncope Evidence for loud P2 component of second heart sound or unexpected or new murmur on exam Signs of right-sided heart failure such as lower extremity or pedal edema, elevated jugular venous distention, hypotension or hepatomegaly History of pulmonary embolism Justification Subgroup considerations Implementation considerations 36

37 Monitoring and evaluation Research priorities 1. Prospective study to evaluate the relationship between all findings on ECHO, including TRVJ and parameters for diastolic function, and patient important outcomes 2. Study to further standardize and validate findings on ECHO, including determining the range of "normal" versus "abnormal" findings for children and adults with SCD. 37

38 GRADE Evidence Profile Question 3: Screening echocardiography compared to no screening in asymptomatic patients with sickle cell disease. of Mortality Certainty assessment Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Impact Certainty Importance 17 observational not serious not serious serious a not serious none There were no direct head to head comparisons of mortality rates in children and adults who underwent ECHO screening versus no screening for pulmonary vascular disease. However, several examined the relationship between mortality and TRJV elevation measured on screening ECHO: VERY LOW CRITICAL Twelve performed on adult age group with total number of patients = 2,985. Total number of deaths in adults = 212 (7.1%), divided by TRJV (Fonseca, Cabrita, Upadhya, Al-Sukun, Bachir, Ataga, Mehari, Gladwin, Parent, Billy-Brissac, Damy, Upadhya): 2.5 m/s = 48 (22.6%) 2.5 m/s = 77 (36.3%) m/s = 4 (1.9%) 3 m/s = 13 (0.43%) Non-specified TRV = 70 (2.3%) Four performed on mixed age groups of adults and children/adolescent with total number of patients = 645. Total deaths in mixed age group = 54 (8.6%), divided by TRJV (Pashankar, Al- Khoufi, Ansari, Lobo): 2.5 m/s = 5 (9.2%). 2.5 m/s = 8 (14.8%). Non-specified TRV = 35 (64.8%). Pulmonary- arterial systolic pressure (PASP) 25 mmhg = 8 (14.8%). One study did not report the age group of their cohort = 397. This study reported 2 deaths with non-specified high TRVJ (Gorbett). Accuracy of ECHO as a screening tool for pulmonary hypertension 38

39 of Certainty assessment Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Impact Certainty Importance 4 observational not serious not serious serious b not serious none Four reported data on accuracy of ECHO to screen for pulmonary hypertension (Fitzgerald, Fonseca, Mehari, Parent). Among these, the total number patients screened with ECHO = 1,007. Of those who underwent screening, 104 with elevated TRVJ underwent right-heart catheterization to confirm pulmonary hypertension. Pulmonary hypertension was confirmed by right-heart catheterization in 87/1007 patients (8.6%). The remaining patients did not proceed with further investigation to confirm or rule out pulmonary hypertension. VERY LOW IMPORTANT Quality of life and functional capacity 1 observational not serious not serious serious b not serious none There were no direct head to head comparisons of quality of life or functional capacity in children and adults who underwent ECHO screening versus no screening for pulmonary vascular disease. However, 1 study with 398 patients examined the relationship of TRJV elevation measured on screening ECHO to NYHA classification and 6-minute walk distance (Parent): VERY LOW IMPORTANT The whole cohort was divided into three groups based on TRJV and rightheart catheterization results and excluded a group of 13 patients with a TRJV of at least 2.5 m/sec who declined to undergo right heart catheterization. The groups were as follows: Group 1 (TRJV < 2.5 m/sec) (n=289) Group 2 (TRJV >/= 2.5 m/sec & mean PA pressure < 25 mm Hg) (n=72) Group 3 (TRJV >/= 2.5 m/sec & mean PA pressure 25 mm Hg) (n= 24) The distribution of groups classified as NYHA class I or II versus III or IV was significantly different (p value < 0.001) as follows: 94 patients in group 1, 93 patients in group 2, and 62 patients in group 3 classified as I or II on NYHA 6 patients in group 1, 7 patients in group 2, and 38 patients in group 3 classified as III or IV on NYHA 6-minute walk distance (mean +/- SD) was also significant different by group (p value < 0.001) as follows: 520 +/- 88 in group /- 62 in group /- 94 in group 3 Other outcomes: Anxiety related to abnormal test, patient desire to know about abnormal screening, rate of cardiac catheterization, change in patient management 39

40 of Certainty assessment Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Impact Certainty Importance 0 observational not serious not serious serious b not serious none No direct head to head data were available for patients undergoing ECHO screening versus no screening VERY LOW CRITICAL Explanations a. Observational study downgraded due to indirectness due to no head to head comparison of the on the important outcomes b. Observational study downgraded due to indirectness due to no head to head comparison of the on the important outcomes References 1. Fonseca et al. Pulmonary hypertension diagnosed by right heart catheterisation in sickle cell disease. European Respiratory Journal. 2012;39(1): Cabrita et al. The association between tricuspid regurgitation velocity and 5-year survival in a North West London population of patients with sickle cell disease in the United Kingdom. British Journal of Haematology. 2013;162(3): Upadhya et al. Identification of high risk patient with sickle cell disease using echocardiography. Journal of the American Society of Echocardiography. 2012;Conference:23rd Annual Scientific Sessions of the American Society of Echocardiography - Cardiovascular Imaging: A Disease and a Patient-Based Approach, ASE National Harbor, MD United States. Conference Publication: (var.pagings). 25 (6) (pp B6). 4. Al-Sukhun S et al, editors. Pulmonary hypertension is present in 10-30% of adult patients with sickle cell disease. Blood; 2000: AMER SOC HEMATOLOGY 1900 M STREET. NW SUITE 200, WASHINGTON, DC USA. 5. Bachir et al. Prospective multicentric survey on pulmonary hypertension (PH) in adults with sickle cell disease. Am Soc Hematology; Ataga et al. Pulmonary hypertension in patients with sickle cell disease: a longitudinal study. British journal of haematology. 2006;134(1): Mehari et al. Mortality in adults with sickle cell disease and pulmonary hypertension. JAMA Journal of the American Medical Association. 1254;307(12): Gladwin et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. New England Journal of Medicine. 2004;350(9): Parent et al. A hemodynamic study of pulmonary hypertension in sickle cell disease. New England Journal of Medicine. 2011;365(1): Billy-Brissac et al. Pulmonary hypertension in an adult sickle cell population in Guadeloupe. Int J Cardiol. 2009;135(1): Damy et al. Haematological determinants of cardiac involvement in adults with sickle cell disease. European heart journal. 2015;37(14): Upadhya et al. Echocardiography-derived tricuspid regurgitant jet velocity is an important marker for the progression of sickle-cell disease. Acta haematologica. 2014;132(2): Pashankar et al. Longitudinal natural history study of tricuspid regurgitant jet velocity in untreated children with sickle cell disease. Pediatric Blood and Cancer. 2013;Conference:26th Annual Meeting of the American Society of Pediatric Hematology/Oncology, ASPHO Miami, FL United States. Conference Publication: (var.pagings). 60 (pp S24). 14. Al-Khoufi et al. Prevalence of pulmonary arterial hypertension among sickle cell disease patients in Al Hassa. Global journal of health science. 2013;5(5): Lobo et al. Echocardiographic evaluation of patients with sickle cell disease. Chest. 2011;Conference:CHEST Honolulu, HI United States. Conference Publication: (var.pagings). 140 (4 MEETING ABSTRACT) (no pagination). 16. de Castro et al. Risk factors of pulmonary hypertension in brazilian patients with sickle cell anemia. PLoS ONE. 2015;10(9):e Gorbett D et al. An Evaluation of Serial Tricuspid Regurgitant (TR) Jet Velocities on 2D Echocardiography as an Independent Predictor of Mortality in Sickle Cell Disease. CHEST Journal. 2010;138(4_MeetingAbstracts):354A-A. 18. Fitzgerald et al. Misclassification of pulmonary hypertension in adults with sickle hemoglobinopathies using doppler echocardiography. Southern Medical Journal. 2012;105(6): Mehari et al. Hemodynamic predictors of mortality in adults with sickle cell disease. American Journal of Respiratory and Critical Care Medicine. 2013;187(8):

41 QUESTION 4 Should Targeted therapy for pulmonary hypertension OR chronic transfusion therapy vs. No targeted therapy OR transfusions be used for patients with sickle cell disease and right heart catheterization defined pulmonary hypertension? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: Patients with sickle cell disease and right heart catheterization defined pulmonary hypertension. Targeted therapy for pulmonary hypertension OR chronic transfusion therapy No targeted therapy OR transfusions Exercise Intolerance & 6-MWD; Exercise Intolerance & 6-MWD; Side effects; Mortality; Blood pressure changes; NYHA classification; O2 requirements; Quality of life SETTING: PERSPECTIVE: BACKGROUND: Pulmonary arterial hypertension, confirmed by right-heart catheterization, is associated with increased mortality among adults with SCD. However, several aspects of pulmonary arterial hypertension in the SCD population remain unclear, including its exact pathophysiology, natural history and optimal treatment. Treatment of pulmonary arterial hypertension in individuals with a diagnosis confirmed by right-heart catheterization may include therapy targeted specifically at pulmonary arterial hypertension or disease-modifying therapy in SCD such as monthly transfusions. The impact of either strategy on patient-important outcomes is not known. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Desirable Effects How substantial are the desirable anticipated effects? Trivial Small The desirable effects are trivial due to the following: 1) the paucity of direct evidence from RCTs for the use of therapy specific for pulmonary arterial hypertension (1 for sildenafil, Machado, 2011, and 1 for bosentan, Barst, 2009) or disease-modifying therapy In the only completed RCT of sildenafil (Machado, 2011) in patients with SCD, the drug 41

42 Moderate Large (hydroxyurea or chronic transfusions, 2) the reliance of several on surrogate endpoints such as 6-minute walk distance and oxygen requirement (see Evidence Table for data) without evidence for improvement in right-heart catheterization-defined hemodynamics or mortality associated with pulmonary arterial hypertension, 3) the inclusion of patients in several with elevated TRJV rather than confirmed pulmonary arterial hypertension by right-heart catheterization, and 4) the absence of data on effects in different subtypes of pulmonary hypertension. The applicability of indirect evidence from other PAH populations to SCD is controversial due to lack of evidence 1) confirming similar pathophysiology as well as 2) harms/benefits of pulmonary arterial hypertension therapy in the SCD population with RHCconfirmed PAH. Given the high mortality related to pulmonary arterial hypertension in SCD, however, we relied on the following indirect evidence on various classes of therapies targeted at pulmonary arterial hypertension to guide decision-making (Jain, 2017): was administered to patients with SCD based on TRJV screening and stopped early due to higher percentage of participants experiencing serious adverse events on the treatment arm. Undesirable Effects How substantial are the undesirable anticipated effects? Large Moderate Small Trivial The undesirable effects are moderate based on data from 1 RCT (Machado, 2011) and 5 observation investigating therapy specific for pulmonary arterial hypertension (sildenafil, bosentan and prostacyclin and non-specific therapy, L-arginine) as well as 1 observational study on chronic transfusion (See Evidence Table for data) for patients with SCD. The applicability of indirect evidence from other populations to SCD is controversial due to lack of evidence 1) confirming similar pathophysiology as well as 2) harms/benefits of pulmonary arterial hypertension therapy in the SCD population with right heart catheterization-confirmed PAH. Given the high mortality related to pulmonary arterial hypertension in SCD, however, we relied on the following indirect evidence on various classes of therapies targeted at pulmonary arterial hypertension to guide decision-making (Jain, 2017): 42

43 Certainty of evidence What is the overall certainty of the evidence of effects? Very low Low Moderate High No included The overall certainty of the evidence of effects is low for sildenafil and very low for other pulmonary arterial hypertension specific therapies or disease-modifying therapies based on the following: 1) only 2 RCTs of therapies specific for pulmonary arterial hypertension (1 for sildenafil, Machado, 2011, and 1 for bosentan, Barst, 2009) in the SCD population and the rest observational, 2) inconsistency by which pulmonary arterial hypertension is diagnosed by right heart catheterization in these, 3) imprecision due to small sample size in, 4) reliance on surrogate endpoints such as functional capacity (e.g. 6-minute walk distance or NYHA class), quality of life or oxygen requirement without evidence for improvement in right-heart catheterizationdefined hemodynamics or mortality associated with pulmonary arterial hypertension, and 5) reliance on indirect evidence of the effects in other patient populations, which may also be confounded by the fact that the pathophysiology of pulmonary arterial hypertension is poorly understood in SCD. The reliance on surrogate endpoints is common to of pulmonary arterial hypertension treatment in the general population and thus, represents a standard limitation. Values Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty There is probably some variability in patient perceptions of some of the side effects related to therapies specific for pulmonary arterial hypertension. 43

44 or variability Probably no important uncertainty or variability No important uncertainty or variability Balance of effects Does the balance between desirable and undesirable effects favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the The balance between desirable and undesirable effects probably favors the based on a vote taken by members of the panel with the results being: 10 members probably in favor of and 3 members stating they did not know if they favored or did not favor the. It is important to note that the high morbidity and mortality associated with pulmonary arterial hypertension in SCD and the lack of alternative therapies influenced the panel s decision-making. 3. Need to consider all subtypes of PH for balance of effects Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Mayo to add data for costs of drugs Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)? 44

45 Very low Low Moderate High No included Cost effectiveness Does the cost-effectiveness of the favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased 45

46 Increased Acceptability Is the acceptable to key stakeholders? No Probably no Probably yes Yes Varies Feasibility Is the feasible to implement? No Probably no Probably yes Yes Varies 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 Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability 46

47 JUDGEMENT BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included 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 TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the Conditional recommendation for the or the comparison Strong recommendation for the CONCLUSIONS Recommendation The panel recommends against the use of pulmonary arterial hypertension-specific therapies in patients who do not have pulmonary arterial hypertension confirmed by right-heart catheterization. The panel suggests the use of pulmonary arterial hypertension-specific therapies under the care of a pulmonary hypertension specialist in patients with a diagnosis of pulmonary arterial hypertension confirmed by right-heart catheterization given the lack of alternative treatment options and high morbidity and mortality. 47

48 Good practice statement: The panel suggests a multidisciplinary* (hematology, pulmonary hypertension specialist, pulmonary) approach when considering pulmonary arterial hypertension-specific therapies in patients who have pulmonary arterial hypertension confirmed by right-heart catheterization Technical remarks: 7. Improvements in hemodynamics by right-heart catheterization and change in diuretic requirements (for right heart failure) should be considered as endpoints for clinical trials investigating patients with pulmonary arterial hypertension confirmed by right-heart catheterization treated with pulmonary arterial hypertension specific therapy. 8. Patients with pulmonary arterial hypertension confirmed by right-heart catheterization should be referred to pulmonary hypertension treatment centers given the possibility of increased side effects (e.g. pain) with pulmonary arterial hypertension-specific therapy such as sildenafil. 9. Initiation and/or optimization for disease-modifying therapy such as hydroxyurea or chronic transfusions should be considered for patients with pulmonary arterial hypertension confirmed by right-heart catheterization. 10. Potential differences in the pathophysiologic basis (e.g. contribution of anemia) and differences in side effect profile (e.g. pain) should be considered when determining treatment options for pulmonary arterial hypertension confirmed by right-heart catheterization in SCD. 11. This recommendation applies to patients with SCD who have no other clear reason for their pulmonary arterial hypertension confirmed by right-heart catheterization (e.g. obstructive sleep apnea, significant lung diseases, left heart failure). 12. Treatment options may differ based on the subtype of pulmonary hypertension as classified by findings on right-heart catheterization and clinical evaluation. Justification Subgroup considerations Implementation considerations 48

49 Monitoring and evaluation Research priorities 1. Prospective study to evaluate the effect of chronic transfusion and/or hydroxyurea, either as primary therapy or as an adjuvant to targeted therapy, in pulmonary arterial hypertension confirmed by rightheart catheterization. 2. Well-designed randomized controlled trials for pulmonary arterial hypertension-specific therapy in patients with SCD and pulmonary arterial hypertension confirmed by right-heart catheterization, which examine relevant patient-important outcomes, including benefits versus harms. 3. Registry study of patients with SCD and pulmonary arterial hypertension confirmed by right-heart catheterization and patient-important outcomes, including functional capacity, quality of life and mortality, as well as the impact of treatment on these outcomes. 4. Prospective study of other adjuvant therapies (e.g. oxygen, anticoagulation) on patient-important outcomes in patients with SCD and pulmonary arterial hypertension confirmed by right-heart catheterization. GRADE Evidence Profile Question 4. Targeted therapy for pulmonary hypertension OR chronic transfusion therapy compared to No targeted therapy OR transfusions in patients with sickle cell disease and right heart catheterization defined pulmonary hypertension. Certainty assessment of patients Effect of Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Targeted therapy for pulmonary hypertension OR chronic transfusion therapy No targeted therapy OR transfusions Relative (95% CI) Absolute (95% CI) Certainty Importance Exercise Intolerance & 6-MWD 1 randomised trials not serious not serious not serious very serious a,b none Only 1 RCT on Bosentan (n=26) examined the effect of treatment on exercise tolerance and 6-MWD in adults with pulmonary arterial hypertension (PAH) confirmed by right-heart catheterization (Barst): In the PAH group, the median difference in 6MWD pre-andpost Bosentan was -9 (-18,-5) vs. 38 (3, 52) in placebo. In pulmonary venous hypertension (PH) group, the median difference in 6MWD pre-and-post Bosentan was 0 (-9,0) vs. 17 (-24, 80) in placebo. LOW IMPORTANT 49

50 Certainty assessment of patients Effect of Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Targeted therapy for pulmonary hypertension OR chronic transfusion therapy No targeted therapy OR transfusions Relative (95% CI) Absolute (95% CI) Certainty Importance Exercise Intolerance & 6-MWD 5 observational not serious not serious not serious serious c none A total of 5 observational on PAH-specific therapy: In 2 observational on sildenafil (total n=36) (Little, Machado): o Combined means for 6-MWD before sildenafil ± o Combined means for 6-MWD after sildenafil ± VERY LOW IMPORTANT In 1 observational study (n=24 patients, given 13 courses of L-arginine) (Little): o 6-MW distances did not change with L-arginine therapy from ± m to ± m, P = n.s.) In 1 observational study on arginine (n=10) (Morris): o Two patients described improved exercise tolerance and energy level after therapy. In 1 observational study on prostacyclin (n=11) (Weir): o Mean 6MWD pre prostacyclin therapy was 329 m, with SEM 26 o Mean after prostacyclin therapy was 369 m with SEM 12 In 1 observational study on Endothelin receptor antagonists agents (bosentan or ambrisentan) (n=14) (Minniti): o 6-MWD increased significantly (baseline 357 ± 22 to 398 ± 18 m at 5 6 months, P < 0.05) Side effects 50

51 Certainty assessment of patients Effect of Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Targeted therapy for pulmonary hypertension OR chronic transfusion therapy No targeted therapy OR transfusions Relative (95% CI) Absolute (95% CI) Certainty Importance 5 randomised trials and observational not serious not serious not serious very serious a none Side effects of PAH-specific therapy for treatment of pulmonary hypertension was examined in the following : In 1 RCT and 2 observational, the total patients received sildenafil (n=63) (Machado, Little, Machado): o headaches (n=11), acute chest syndrome (n=1), anemia (n=2), bronchitis (n=1), lower respiratory tract infection (n=1), hyperkalemia (n=0), hypertension (n=0), hypotension (n=1), atrial fibrillation (n=1), cardiac failure congestive (n=1), pyrexia (n=1), traumatic brain injury (n=1), suicide attempt (n=1), acute pulmonary edema (n=1), hospitalization for SCD pain episodes (n=13), priapism (n=1), facial or peripheral swelling (n=8), ocular complications (n=6) LOW IMPORTANT In 1 observational study (n=24 patients) given 13 courses of L- arginine) (Little): o leg edema (n=4), and ocular complications (n=2) In 1 observational study on prostacyclin (n=11) (Weir): o 10 patients reported inguinal swelling, headaches, dizziness, pharyngeal symptoms, jaw pain, painful injection sites, bacteremia and line sepsis In 1 observational study on endothelin receptor antagonists agents (bosentan or ambrisentan) (n=14) (Minniti): o lower extremities edema (n=4), headache (n=3), skin rash (n=1), increase LFTs (n=2), decreased Hb (n=3), subarachnoid haemorrhage (n=1), and hypotension attributed primarily to progressive cirrhosis and hypoadrenalism (n=1) Side effects of chronic transfusions for the treatment of PAH was examined in the following study: In 1 observational study (n=25) patients received IV transfusion (Detterich): o no episodes of pain crisis attributable to the forearm occlusion Mortality 51

52 Certainty assessment of patients Effect of Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Targeted therapy for pulmonary hypertension OR chronic transfusion therapy No targeted therapy OR transfusions Relative (95% CI) Absolute (95% CI) Certainty Importance 1 observational not serious not serious not serious serious d none Mortality was reported in 3 : In 1 RCT on Bosentan (n=26) (Barst): 1 death happened in bosentan arm (9%) In 1 observational study on prostacyclin (n=11) (Weir): 2 deaths reported (18%) In 1 observational study on sildenafil (n=74) (Machado): 1 death occurred in the placebo group due to acute chest syndrome VERY LOW CRITICAL Blood pressure changes 1 observational not serious not serious not serious serious d none Blood pressure changes were reported in 1 study (Machado): The acute systemic hemodynamic effects of sildenafil administration were evaluated in five patients with sickle cell disease. Mean arterial pressure did not statistically change - 13% change. 95% CI: 2 to 28. VERY LOW IMPORTANT NYHA classification 1 observational not serious not serious not serious serious c none Change in NYHA classification was reported in 1 study (Minniti): Improved NYHA by at least one classification n=7 Worsened NYHA classification by at least one classification n=3 No change n=3 VERY LOW IMPORTANT O2 requirements 52

53 Certainty assessment of patients Effect of Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Targeted therapy for pulmonary hypertension OR chronic transfusion therapy No targeted therapy OR transfusions Relative (95% CI) Absolute (95% CI) Certainty Importance 3 observational not serious not serious not serious serious d none Changes in oxygen requirements were reported in 3 : In 1 observational study on endothelin receptor antagonists agents (bosentan or ambrisentan) (n=14) (Minniti): o pulse oximeter mean values were 95.8% before ETR blocking therapy and 97% after 6 months VERY LOW CRITICAL In 1 observational study on arginine therapy (n=10) (Morris): o venous oxygen saturation increased from /-18 to /-9% after l-arginine supplementation (n = 6, p = 0.066) In 1 case series on Automated red cell exchange transfusion (ARCET) (n=2) (Tsitsikas): o Patient 1: ARCET led to rapid symptomatic improvement and a SaO2 of 97% breathing room air that did not drop for 5 weeks and after exertion o Patient 2: first ARCET cycle improved her symptoms and O2 requirements SaO2 from 84% to 96% on air until 4-5 weeks Quality of life 1 randomised trials not serious not serious not serious very serious a none Quality of life was reported in 1 study (Machado): Brief Pain Inventory at 10 weeks: (5.1 +/- 3.68) in sildenafil group, and (1.3 +/- 2.18) in placebo group Pain that interfered with the ability to walk at week 10: (4.6 +/- 3.57) in sildenafil group, and (1.4 +/- 1.19) in placebo group Enjoyment of life at week 10: (4.9 +/- 3.97) in sildenafil group, and (2.4 +/- 3.88) in placebo group LOW CRITICAL Explanations a. Small sample size b. Surrogate outcome c. Non-RCT, imprecision due to small sample size & surrogate outcome d. Non-RCT, imprecision due to small sample size 53

54 References 1. Barst et al. Exercise capacity and haemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosentan: Results of the ASSET. British Journal of Haematology. 2010;149(3): Machado et al. Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity. Blood. 2011;118(4): Tsitsikas et al. Regular automated red cell exchange transfusion in the management of pulmonary hypertension in sickle cell disease. British Journal of Haematology. 2014;167(5): Detterich et al. Chronic transfusion therapy improves but does not normalize systemic and pulmonary vasculopathy in sickle cell disease. Blood. 2015;126(6). 5. Weir et al. Prostacyclin-analog therapy in sickle cell pulmonary hypertension. Haematologica. 2017;102(5):e163-e5. 6. Little et al. Hematologic, biochemical, and cardiopulmonary effects of l arginine supplementation or phosphodiesterase 5 inhibition in patients with sickle cell disease who are on hydroxyurea therapy. European journal of haematology. 2009;82(4): Machado et al. Sildenafil therapy in patients with sickle cell disease and pulmonary hypertension. British journal of haematology. 2005;130(3): Minniti et al. Endothelin receptor antagonists for pulmonary hypertension in adult patients with sickle cell disease. British journal of haematology. 2009;147(5): Morris et al. Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease? American Journal of Respiratory and Critical Care Medicine. 2003;168(1):63-9. QUESTION 5 Should Routine monitoring of pulmonary function vs. No monitoring be used for asymptomatic patients with sickle cell disease? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: Asymptomatic patients with sickle cell disease. Routine monitoring of pulmonary function No monitoring Pain; Acute chest syndrome; Mortality; FEV1; FVC; FEV1/FVC; RV & TLC; SETTING: PERSPECTIVE: BACKGROUND: Abnormal lung function or chronic lung disease, diagnosed by pulmonary function testing (PFT), is relatively common among children and adults with SCD. However, several aspects of chronic lung disease remain unclear in SCD, including its prevalence, natural history, relationship to disease severity and optimal therapy. Despite the utility of PFT as a screening tool for individuals with signs and symptoms suggestive of chronic lung disease or abnormal lung function, its utility as a screening tool for asymptomatic individuals with SCD is not clear. The impact of results from screening on patient-important outcomes is also unknown. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? 54

55 No Probably no Probably yes Yes Desirable Effects How substantial are the desirable anticipated effects? Trivial Small Moderate Large The desirable anticipated effects in patients with SCD who are asymptomatic are trivial and include knowledge about lung function gained from performing the test, the ability to determine the true prevalence of chronic lung disease in the SCD population and the ability to better understand the natural history of chronic lung disease in the SCD population. Some evidence is available only for the decline in lung function as a result of pulmonary function test screening (see Evidence Table for data). Undesirable Effects How substantial are the undesirable anticipated effects? Large Moderate Small Trivial The undesirable anticipated effects are trivial and may include the potential for missing school or work for patients with SCD or their providers and the potential for increased anxiety in patients and their providers as a result of being given information about abnormal lung function. Direct evidence is not available for any undesirable effect as a result of pulmonary function test screening. Certainty of evidence What is the overall certainty of the evidence of effects? 55

56 Very low Low Moderate High No included The overall certainty of the evidence of effects is very low given that there are no direct head to head comparisons of the (e.g. screening versus no screening of lung function) on patient important outcomes such as pain, acute chest syndrome or mortality. Other reasons for low certainty included the following: 1) inability to determine how results from pulmonary function testing determine subsequent changes in management decisions in asymptomatic patients (i.e. further testing or initiation of treatment), 2) inconsistent data on relationship between abnormal lung function and outcomes such as pain, acute chest syndrome or mortality (see Evidence table for data), 3) lack of sufficient evidence for which therapies constitute appropriate management of abnormal findings on screening in asymptomatic patients, and 4) inability to determine if changes or no changes in management based on screening itself results affect outcomes (see below). The relationship between FEV1% predicted and mortality in Kassim 2015 study was confounded by the lack of inclusion of TRJV or NT-pro BNP data, both of which represent strong predictors of mortality in adults with SCD. Pulmonary function testing in the analyzed did not include bronchoprovocation, which are useful for demonstrating airway hyperreactivity in the absence of airway obstruction. Limited data comparing pain, acute chest syndrome and mortality in patients who did versus did not undergo pulmonary function testing (PFT) (Kassim, 2015): Pain and acute chest syndrome rates did not significantly differ in patients who did versus did not undergo PFT Despite a significant relationship between decrease in FEV1% predicted and higher mortality, mortality rates did not differ in patients who did versus did not undergo PFT Values Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability There may be variability in patient or caregiver feelings of helplessness, knowledge gaps, anxiety or desire to know information gained from screening. Balance of effects Does the balance between desirable and undesirable effects favor the or the comparison? 56

57 Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the The balance between desirable and undesirable effects probably favors the comparison (i.e. no screening pulmonary function testing) in asymptomatic children and adults with SCD. It is important to note that the discussion of the balance between desirable and undesirable effects was driven primarily by insufficient evidence that screening asymptomatic patients leads to changes in management that would directly result in improvement in patient-importance outcomes such as pain, acute chest syndrome or mortality. Resources required How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)? 57

58 Very low Low Moderate High No included Cost effectiveness Does the cost-effectiveness of the favor the or the comparison? Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the No included Equity What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increased Increased Rather than being universally available, pulmonary function testing may only be available at tertiary care centers with a pulmonary function laboratory or at practices with pulmonary function testing equipment (i.e. office-based spirometry), which is not currently standard of care for primary care or hematology offices. 58

59 Acceptability Is the acceptable to key stakeholders? No Probably no Probably yes Yes Feasibility Is the feasible to implement? No Probably no Probably yes Yes 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 Large Moderate Small Trivial Varies Don't know CERTAINTY OF EVIDENCE Very low Low Moderate High No included VALUES Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty or variability No important uncertainty or variability 59

60 JUDGEMENT BALANCE OF EFFECTS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies Don't know RESOURCES REQUIRED Large costs Moderate costs Negligible costs and savings Moderate savings Large savings Varies Don't know CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Very low Low Moderate High No included COST EFFECTIVENESS Favors the comparison Probably favors the comparison Does not favor either the or the comparison Probably favors the Favors the Varies No included 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 TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the Conditional recommendation for the or the comparison Strong recommendation for the CONCLUSIONS Recommendation The panel suggests against performing routine screening pulmonary function testing in asymptomatic patients with SCD. Technical remarks: 7. This recommendation is limited to asymptomatic individuals with sickle cell disease. A comprehensive respiratory history and review of systems should be performed to identify patients with SCD for whom a low threshold should be considered for pulmonary function testing. Whenever appropriate, validated tools should be used to further identify which patients should be considered for pulmonary function testing. 8. The following signs or symptoms may warrant pulmonary function testing at steady state (i.e. healthy) to evaluate for lung disease: 60

61 Wheezing or increased cough at rest or with exertion Wheezing or increased cough during episode of acute upper respiratory infection Wheezing or increased cough during episode of acute chest syndrome Dyspnea at rest or with exertion that is increased compared to baseline or that is unexplained Chest pain at rest or with exertion that is out of proportion to known condition, increased compared to baseline or that is unexplained Increase in exercise limitation compared to baseline Evidence of abnormal 6-minute walk test distance History of recurrent hypoxemia at rest or with exertion History of syncope or pre-syncope History of recurrent acute syndrome History of pulmonary embolism 9. Providers should understand the importance of educating patients, discussing patient/caregiver priorities and incorporating shared decision making when considering obtaining pulmonary function testing. Justification Subgroup considerations Implementation considerations Monitoring and evaluation 61

62 Research priorities 1. Well-designed prospective, longitudinal multicenter study to evaluate the natural history of lung function across the lifespan in patients with SCD 2. Prospective study to evaluate the factors that contribute to decline in lung function among patients with SCD 3. Prospective study to evaluate the relationship between lung function and clinical and patient important outcomes in SCD 4. Prospective study to assess the utility of screening and it impact on patient important outcomes, including change in management and its influence on clinical endpoints as well as overall mortality GRADE Evidence Profile Question 5. Routine monitoring of pulmonary function compared to No monitoring in asymptomatic patients with sickle cell disease. of Pain Certainty assessment Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Impact Certainty Importance 2 observational not serious not serious serious a not serious none There were 2 that examined pain and pulmonary function testing (Kassim, Cohen): In 1 prospective cohort study on adults (n=1295), the pain rate in patients received PFT was lower than patients who didn t, but the difference was insignificant In 1 prospective cohort study with mixed age group (adults and children) (n=147), no observable relationship between pain events rate and lung function VERY LOW CRITICAL Acute chest syndrome 62

63 of Certainty assessment Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Impact Certainty Importance 3 observational not serious not serious serious a not serious none There were 3 that examined acute chest syndrome and pulmonary function testing (Kassim, Intzes, Cohen): In 1 prospective cohort study on adults (n=1295), the ACS rate in patients received PFT was almost similar to patients who didn t In 1 prospective cohort study on children (n=122): o Combined restrictive and obstructive lung disease has significant relation to ACS o Asthma is strongly related to ACS o No significant relation between obstructive lung disease and ACS In 1 prospective cohort study with mixed age group (adults and children) (n=147), no observable relationship between ACS rate and lung function VERY LOW CRITICAL Mortality 2 observational not serious not serious serious a not serious none In 2 observational on adult age group (total n=1484) (Kassim, Chaturvedi): low PFTs were significantly associated with increased hazard of death PFTs were lower in patients who died compared to patients who stayed alive during follow up VERY LOW CRITICAL Decline in lung function 8 observational not serious not serious serious a not serious none There were 8 that examined decline in lung function and pulmonary function testing: In 4 observational on children and adolescents age groups (total n=169) (Koumbourlis, Arteta, Koumbourlis, De Souza), there was an observable trend of decreased PFTs parameters overtime between baseline and follow up measurements In 2 observational on adults (total n=127) (Lunt, Field)), there was an observable trend of decreased PFTs parameters overtime between baseline and follow up measurements In 2 observational on children (total n=462) (Lunt, MacLean), there was an observable trend of decreased PFTs parameters overtime between baseline and follow up measurements VERY LOW IMPORTANT 63

64 Explanations a. Downgraded due to indirectness due to no head to head comparison of the on the important outcomes References 1. Kassim et al. Low forced expiratory volume is associated with earlier death in sickle cell anemia. Blood. 1544;126(13): Koumbourlis et al. Lung function and somatic growth in patients with hemoglobin SC sickle cell disease. Pediatric pulmonology. 2008;43(2): Arteta et al. Longitudinal change in pulmonary function in children with sickle cell disease and associated factors. American Journal of Respiratory and Critical Care Medicine. 2010;Conference:American Thoracic Society International Conference, ATS New Orleans, LA United States. Conference Publication: (var.pagings). 181 (1 MeetingAbstracts) (no pagination). 4. Lunt et al. Pulmonary vascular and interstitial morphological abnormalities and lung function in adults with sickle cell disease. American Journal of Respiratory and Critical Care Medicine. 2013;Conference:American Thoracic Society International Conference, ATS Philadelphia, PA United States. Conference Publication: (var.pagings). 187 (no pagination). 5. Field et al. Longitudinal analysis of pulmonary function in adults with sickle cell disease. American journal of hematology. 2008;83(7): Koumbourlis et al. Longitudinal changes in lung function and somatic growth in children with sickle cell disease. Pediatric pulmonology. 2007;42(6): Lunt et al. Longitudinal assessment of lung function in children with sickle cell disease. Pediatric pulmonology. 2016;51(7): MacLean JE, Atenafu E, Kirby-Allen M, MacLusky IB, Stephens D, Grasemann H, et al. Longitudinal decline in lung volume in a population of children with sickle cell disease. American journal of respiratory and critical care medicine. 2008;178(10): De Souza et al. Quality of sleep and pulmonary function in clinically stable adolescents with sickle cell anemia. Jornal Brasileiro de Pneumologia. 2007;33(3): Intzes et al. Lung function abnormalities and asthma are associated with acute chest syndrome in children. Pediatric Blood and Cancer. 2011;Conference:24th Annual Meeting of the American Society of Pediatric Hematology Oncology, ASPHO Baltimore, MD United States. Conference Publication: (var.pagings). 56 (6) (pp 909). 11. Chaturvedi et al. Elevated tricuspid regurgitant jet velocity, reduced forced expiratory volume in 1 second, and mortality in adults with sickle cell disease. American Journal of Hematology. 2017;92(2): Cohen et al. Pattern of lung function is not associated with prior or future morbidity in children with sickle cell anemia. Annals of the American Thoracic Society. 1314;13(8): QUESTION 6 In adults with sickle cell disease, what are the effects of targeting a BP goal of 130/80 compared to a goal of 140/90? POPULATION: INTERVENTION: COMPARISON: MAIN OUTCOMES: Adults with sickle cell disease. the effects of targeting a BP goal of a goal of Overall outcomes; SETTING: PERSPECTIVE: BACKGROUND: Treatment of hypertension and maintenance of optimal blood pressure control are important for previously healthy individuals as well as individuals with co-morbid conditions such as SCD. Several aspects of blood pressure control in the SCD population remain unclear, including the pathophysiologic basis for lower baseline blood pressures, contributors to blood pressure elevation, natural history of blood pressure elevation and relationship of elevated blood pressures to disease severity and other complications. The optimal treatment of elevated blood pressures, including optimal 64

65 blood pressure target, and its impact on patient-important outcomes are also unknown. CONFLICT OF INTEREST: ASSESSMENT Problem Is the problem a priority? No Probably no Probably yes Yes Higher blood pressure is associated with worse outcomes, including all-cause mortality, in individuals with SCD (Pegelow, 1997). However, there are no data from a contemporary cohort and no data on treatment effect. The panel chose therefore to evaluate indirect data from the general population on outcomes related to intensive versus standard blood pressure targets. Desirable Effects How substantial are the desirable anticipated effects? Trivial Small Moderate Large The desirable anticipated effects are large based on indirect data from the general population that intensive blood pressure targets (i.e. initiation of therapy at blood pressure of 130/80) result in a decrease in cardiovascular mortality, stroke, major cardiovascular events and heart failure (see Table below). The panel has no reason to believe that people with sickle cell disease would have outcomes related to blood pressure management different from the general population in regards to blood pressure management. There are no direct data on the effect of lowering blood pressure to any specific threshold in patients with sickle cell disease. However, data from 2 suggest an association between higher blood pressures and adverse outcomes in patients with SCD: 1. In the Cooperative Study of Sickle Cell Disease cohort, there was an association between higher blood pressure and all cause mortality (Pegelow, 1997). The combined survival of male subjects in the low and above average blood pressure groups was significantly better than the survival of subjects in the high blood pressure group for both systolic (P = 0.012) and diastolic (P = 0.007) blood pressure. For females, subjects in the low and above average groups had better survival than those in the high BP group although the difference did not reach statistical significance. 2. Finding from another study (Gordeuk, 2008) suggest that systemic SBP mmhg or DBP mmhg defines a category of relative systemic hypertension in patients with sickle cell disease that is associated with increased risk of renal dysfunction. 65

66 Table of Outcomes from Systematic Review Comparing Intensive versus Standard Blood Pressure Targets in the General Population Undesirable Effects How substantial are the undesirable anticipated effects? 66