Vascular Assessment and Management of Heel Ulcers

Initial Vascular Assessment

• A heel ulcer with absent pedal pulses requires immediate objective vascular assessment with ankle-brachial index (ABI), toe-brachial index (TBI), and pedal Doppler waveform analysis, as absent pulses alone are insufficient to confirm or exclude significant peripheral artery disease (PAD), according to the American Diabetes Association 1, 2
• The American College of Cardiology recommends measuring bilateral ankle systolic pressures and calculating ABI; values <0.9 indicate PAD 1, 2
• ABI may be falsely elevated (≥1.3) due to arterial calcification from medial wall sclerosis (Mönckeberg sclerosis), particularly in diabetic patients, rendering the test unreliable, as noted by the American Heart Association 1, 3
• If ABI is >1.3 or unreliable, the American Diabetes Association recommends measuring TBI; values <0.75 suggest significant PAD 1, 3

Clinical Examination and Advanced Imaging

• Cool lower limb temperature compared to contralateral side is an indicator of PAD, according to the American College of Cardiology 1, 2
• Femoral bruits on auscultation are a sign of PAD, as noted by the American Heart Association 1, 2
• Prolonged venous filling time (>20 seconds) is a predictor of poor healing, according to the American Diabetes Association 1, 2
• Ulcer location: heel ulcers are more commonly ischemic or neuro-ischemic rather than purely neuropathic, as reported by the American College of Cardiology 4
• The American Heart Association recommends proceeding to vascular imaging if any of the following are present: non-healing ulcer despite optimal wound care, absent or monophasic Doppler waveforms 1, 2, 4

Management Priorities

• Up to 50% of patients with foot ulcers have coexisting PAD, and these patients face significantly increased risk of amputation and mortality, according to the American Diabetes Association 1, 2
• The American College of Cardiology recommends offloading the heel completely, assessing for infection and osteomyelitis, and not debriding ischemic heel ulcers without infection 4
• Revascularization should be strongly considered when ankle pressure <50 mmHg or ABI <0.5, or when patent posterior tibial artery to the ankle is critical for heel perfusion, as noted by the American Heart Association 5
• The American Diabetes Association recommends aggressive cardiovascular risk reduction, including smoking cessation support, statin therapy, low-dose aspirin or clopidogrel, blood pressure control, and glycemic control in diabetic patients, which reduces 5-year mortality from 58% to 36% in patients with neuro-ischemic foot ulcers 5

Common Pitfalls to Avoid

• Never assume PAD is absent based solely on palpable pulses, as even skilled examiners can detect pulses despite significant ischemia, according to the American College of Cardiology 1, 3
• Never rely on ABI alone in diabetic patients, as arterial calcification causes falsely elevated readings; always obtain TBI or waveform analysis, as recommended by the American Heart Association 1, 3
• Never delay vascular assessment, as clinical examination sensitivity is too low to rule out PAD; objective testing is mandatory in all heel ulcers, according to the American Diabetes Association 1, 2

Peripheral Artery Disease Diagnosis and Management

Epidemiology and Risk Factors

• Peripheral artery disease (PAD) can occur in patients without diabetes, although diabetes significantly increases the risk and severity of PAD, according to the American Diabetes Association 6, 7
• PAD is defined as any atherosclerotic arterial occlusive disease below the level of the inguinal ligament, resulting in reduced blood flow to the lower extremity, as stated by the American Heart Association 7
• Approximately 50% of patients with diabetic foot ulcers have coexisting PAD, while the remaining 50% develop PAD without diabetes, as reported by the American Diabetes Association 6, 7

Clinical Presentation Differences

• PAD in patients without diabetes tends to present with more typical symptoms like claudication, as noted by the American College of Cardiology 7
• Diabetic patients with PAD often lack typical symptoms such as claudication or rest pain, even with severe tissue loss, according to the American Diabetes Association 6, 7
• Diagnostic testing is more straightforward in non-diabetic patients as they have less arterial calcification that can interfere with measurements, as stated by the American Heart Association 8

Diagnostic Approach

• All patients (diabetic and non-diabetic) should be evaluated for PAD with medical history and foot pulse palpation, ankle or pedal Doppler arterial waveforms, and ankle systolic pressure and ankle brachial index (ABI), as recommended by the American College of Cardiology 9
• An ABI <0.9 is useful for detecting PAD in non-diabetic patients, according to the American Heart Association 8
• The presence of triphasic pedal Doppler arterial waveforms strongly excludes PAD in both diabetic and non-diabetic patients, as noted by the European Society of Cardiology 10
• Toe brachial index ≥0.75 largely excludes PAD, as stated by the American Heart Association 8

Management Considerations

• All patients with PAD (diabetic and non-diabetic) should receive aggressive cardiovascular risk management, smoking cessation support, treatment of hypertension, statin therapy, and low-dose aspirin or clopidogrel, as recommended by the American College of Cardiology 11
• Revascularization decisions should be based on morphological distribution of PAD, availability of autogenous vein, patient co-morbidities, and local expertise, according to the American Heart Association 11

Clinical Pitfalls to Avoid

• Don't assume PAD is absent just because pulses are palpable - even skilled examiners can detect pulses despite significant ischemia, as warned by the American Heart Association 8
• Don't attribute poor wound healing to microangiopathy in diabetic patients - macrovascular disease (PAD) is typically the cause, as noted by the American Diabetes Association 12
• Don't delay vascular imaging in patients with non-healing ulcers who have ankle pressure <50 mmHg or ABI <0.5, as recommended by the American College of Cardiology 12
• Don't overlook PAD in patients with exertional leg symptoms but normal ABI - consider additional testing, according to the European Society of Cardiology 10

Diagnostic Challenges in Diabetic Neuropathy

Limitations of Ankle-Brachial Index (ABI)

• A normal ABI (0.91-1.40) in a diabetic patient with neuropathy does not reliably exclude peripheral artery disease (PAD) and requires additional vascular testing, particularly toe-brachial index (TBI) or post-exercise ABI, because arterial calcification from diabetes frequently produces falsely normal or elevated readings despite significant ischemia 13, 14
• ABI sensitivity is significantly lower in diabetic patients compared to the general population, particularly when neuropathy or end-stage chronic kidney disease coexist 15, 14

Arterial Calcification and Diagnostic Accuracy

• Medial arterial calcification (Mönckeberg sclerosis) is highly prevalent in diabetic patients and causes falsely elevated or normal ABI readings despite the presence of significant stenotic disease 16, 13
• When ABI is >1.30-1.40, it indicates noncompressible vessels from calcification, not absence of PAD—in fact, 50% of patients with ABI >1.40 have coexisting PAD 13

Additional Testing and Diagnostic Protocols

• If clinical suspicion for PAD persists despite normal ABI, proceed immediately to post-exercise ABI and/or TBI measurement 13, 15
• TBI should be performed because digital arteries are rarely affected by medial calcification; TBI <0.70-0.75 confirms PAD 16, 13
• Exercise ABI unmasks moderate stenoses that may not be apparent at rest—a post-exercise ankle systolic blood pressure decrease >30 mmHg or ABI decrease >20% is diagnostic for PAD 15, 14

Clinical Context and Risk Stratification

• Diabetic patients with neuropathy often lack typical PAD symptoms (claudication, rest pain) even with severe tissue loss because concomitant neuropathy decreases pain sensitivity 17, 18
• PAD in diabetes is frequently diagnosed at later stages (non-healing ulcers) due to this sensory deficit, increasing infection and amputation risk 17, 18
• Up to 50-70% of patients with chronic limb-threatening ischemia (CLTI) have diabetes 13, 18
• Even when PAD is excluded, an abnormal ABI (<0.90 or >1.40) identifies patients at very high cardiovascular risk requiring aggressive risk factor modification 13
• ABI >1.30-1.40 is associated with increased risk of death and cardiovascular events, independent of stenotic disease presence 17, 13

Diagnostic Approach to Peripheral Artery Disease

Introduction to PAD Diagnosis

• A normal resting ankle-brachial index (ABI) does not reliably exclude peripheral artery disease (PAD) causing claudication, and patients with exertional leg symptoms require exercise ABI testing even when resting ABI is normal or borderline (0.91-1.40) 19, 20

Diagnostic Recommendations

• The American College of Cardiology (ACC) and American Heart Association (AHA) guidelines recommend exercise treadmill ABI testing for patients with exertional non-joint-related leg symptoms and normal or borderline resting ABI (>0.90 and ≤1.40) 19, 21
• A drop in ABI of ≥0.15 after exercise, or a post-exercise ankle pressure decrease >30 mmHg, is diagnostic for at least moderate arterial occlusive disease even when resting ABI is normal 22, 20

Special Patient Populations

• Patients with isolated iliac artery occlusive disease may have normal resting ABI because collateral flow maintains ankle pressures at rest, and exercise ABI is specifically recommended to objectively evaluate functional limitations in these patients 20

Clinical Algorithm

• Measure resting ABI after 10 minutes of supine rest, and interpret as: abnormal (≤0.90), borderline (0.91-0.99), normal (1.00-1.40), or noncompressible (>1.40) 19, 21, 22
• Proceed immediately to exercise treadmill ABI testing if patient has exertional leg symptoms and normal or borderline resting ABI (0.91-1.40) 19, 21

Diagnostic Testing

• If resting ABI is >1.40 (noncompressible), measure toe-brachial index (TBI); values <0.70-0.75 confirm PAD 19, 21
• Consider pulse volume recordings or Doppler waveform analysis for noncompressible ABI 22, 21
• If exercise ABI is positive, duplex ultrasound, CTA, or MRA to localize disease and plan revascularization if symptoms warrant intervention 19, 21

Management of Ankle-Brachial Index 0.9 to 1.1

Understanding the ABI Range 0.9-1.1

• The American College of Cardiology and the American Heart Association recommend that patients with an ABI of 0.9 to 1.1 undergo further vascular evaluation with exercise treadmill ABI testing if they have exertional leg symptoms, or cardiovascular risk factor optimization and clinical surveillance if asymptomatic 23, 24
• The American College of Cardiology classifies an ABI of 0.91-0.99 as "borderline" and indicates patients who warrant further evaluation for subclinical peripheral artery disease (PAD) and increased cardiovascular risk 23, 24, 25
• An ABI exactly 0.90 is the diagnostic threshold for PAD, so values at or just above this cutoff require careful clinical interpretation 23, 24

Immediate Next Steps Based on Symptoms

• The American College of Cardiology recommends exercise treadmill ABI testing for patients with exertional non-joint-related leg symptoms and ABI 0.91-1.40, as a Class I, Level B-NR recommendation 24, 25
• A post-exercise ankle pressure decrease >30 mmHg or ABI decrease >20% confirms PAD even when resting ABI appears normal 23

Special Considerations for High-Risk Populations

• The European Heart Journal recommends exercising extreme caution interpreting ABI in diabetic patients, as arterial calcification frequently produces falsely normal or elevated readings despite significant ischemia 26
• If ABI is 0.9-1.1 in a diabetic patient with any foot symptoms, non-healing wounds, or absent pulses, the American College of Cardiology recommends immediately obtaining toe-brachial index (TBI) 24, 26
• TBI <0.70-0.75 confirms PAD when ABI is unreliable 24, 26

Cardiovascular Risk Stratification and Management

• The European Heart Journal recommends implementing aggressive cardiovascular risk reduction regardless of PAD symptoms, including statin therapy, antiplatelet therapy, smoking cessation, blood pressure control, and glycemic control 26
• The American College of Cardiology recommends considering combination therapy with low-dose rivaroxaban and aspirin for patients with symptomatic PAD confirmed by exercise testing and without high bleeding risk, as a Class IIa, Level B recommendation 26

Common Clinical Pitfalls to Avoid

• The American College of Cardiology recommends never assuming PAD is absent based solely on a single resting ABI measurement in the 0.9-1.1 range if the patient has exertional leg symptoms 24
• The European Heart Journal recommends never relying on ABI alone in diabetic patients without also assessing TBI or obtaining Doppler waveforms 26
• The American Heart Association recommends never using a single-leg ABI measurement for risk stratification, and always measuring bilateral ABI and using the lower value for cardiovascular risk assessment 23

Follow-Up and Monitoring

• The European Heart Journal recommends establishing a surveillance protocol based on initial findings, including repeat ABI annually for patients with borderline values (0.91-0.99) and cardiovascular risk factors 26
• The American College of Cardiology recommends immediate vascular referral if exercise ABI confirms PAD or if symptoms progress 24

Guideline for Vascular Assessment in High‑Risk Diabetic Patients

Patient Preparation and Equipment

• Position the patient supine for at least 10 minutes before any measurement to allow hemodynamic stabilization. [27][28]
• Use a handheld continuous‑wave Doppler probe with appropriate gel and a standard blood‑pressure cuff for all measurements. [27][28]

Brachial Pressure Measurement

• Obtain brachial systolic pressures first, locating the brachial artery with the Doppler probe at a 45°–60° angle to the skin. 28
• Inflate the cuff to 20 mm Hg above the pressure at which the Doppler flow signal disappears (maximum 300 mm Hg), then deflate slowly to identify the pressure at which the signal reappears. 28
• Measure both arms in a consistent sequence, repeat the first‑arm measurement at the end of the series, and average the two values unless they differ by >10 mm Hg, in which case use the second measurement. 28

Ankle Pressure Measurement

• Place the cuff just above the ankle and locate both the dorsalis pedis and posterior tibial arteries with the Doppler probe at a 45°–60° angle. [27][28]
• Record systolic pressures at each ankle artery using the same inflation/deflation protocol as for the brachial measurement. [27][28]
• Document the Doppler waveform at each ankle artery: a triphasic waveform essentially excludes peripheral arterial disease (PAD), whereas monophasic or absent waveforms suggest significant disease. 27

Ankle‑Brachial Index (ABI) Calculation and Interpretation

• Use the higher of the two brachial systolic pressures as the denominator for ABI calculation. [27][28]29
• Use the higher ankle systolic pressure (either dorsalis pedis or posterior tibial) from each leg as the numerator to maximize specificity and reduce false‑positive diagnoses. [28][29]
• Compute ABI for each leg separately: ABI = higher ankle pressure ÷ higher brachial pressure. [27][28]

• Evidence: ABI ≤ 0.90 is a diagnostic threshold for PAD. [27][28]29

Limitations of ABI in Diabetes

• Medial arterial calcification is highly prevalent in diabetic patients and frequently yields falsely elevated or normal ABI values despite underlying stenotic disease. 27

Toe‑Brachial Index (TBI) Protocol

• Measure TBI immediately in diabetic patients with chronic limb‑threatening ischemia, irrespective of the ABI result. 27
• Place a small cuff around the base of the great toe and record toe systolic pressure using photoplethysmography or Doppler. 27
• Calculate TBI = toe systolic pressure ÷ higher brachial pressure. 27
• Interpretation: TBI < 0.70 confirms PAD; a threshold of < 0.75 may be used as an alternative cutoff for significant disease. 27

Additional Vascular Assessments (when ABI/TBI are inconclusive)

• Transcutaneous oxygen pressure (TcPO₂): Values > 30 mm Hg predict favorable wound‑healing potential. 27
• Skin perfusion pressure (SPP): Values > 40 mm Hg predict favorable wound‑healing potential. 27
• Pulse volume recordings (PVR): Can corroborate ABI findings and reveal non‑compressible arteries when results are discordant. 27
• Segmental pressures with waveform analysis: Useful for precise anatomic localization to guide revascularization planning. 27

Technical Considerations for Incongruent or Non‑Detectable Ankle Signals

• If no arterial flow is detected at one ankle but the ABI calculated from the opposite ankle is normal, obtain duplex ultrasound to evaluate for PAD rather than assuming arterial agenesis. [28][29]
• When repeat measurements are required, perform them in the reverse order of the initial sequence to minimize systematic bias. 28

Management Based on TBI and Adjunctive Testing

• If TBI confirms PAD (TBI < 0.70–0.75):

  • Consider revascularization when ankle pressure < 50 mm Hg or ABI < 0.5, or when a patent posterior tibial artery is essential for heel perfusion. 27
  • Proceed with imaging (duplex ultrasound, CT angiography, or MR angiography) to delineate anatomy and plan revascularization. 27

• If results are equivocal or discordant:

  • Obtain TcPO₂ and/or SPP to assess the likelihood of wound healing with or without revascularization. 27
  • Refer to vascular surgery for comprehensive evaluation and possible catheter angiography. 27

Guidelines for Ordering and Interpreting Ankle‑Brachial Index (ABI) and Toe‑Brachial Index (TBI)

Order Components and Documentation

• The order should be titled “Bilateral ankle‑brachial index with toe‑brachial index and Doppler waveform analysis.” Including this exact name ensures the comprehensive measurement set is requested. [30][31]
• Patient demographics (age, sex) and all major vascular risk factors (smoking history, diabetes, hypertension, hyperlipidemia, chronic kidney disease) must be recorded in the order to aid interpretation. 31

Measurement Protocol

Brachial Pressures

• Measure bilateral brachial systolic pressures in a standardized sequence: first arm measured at the start of the session and repeated on the same arm after completing the lower‑extremity measurements. [30][32]
• If the two brachial measurements differ by more than 10 mm Hg, use the higher value as the denominator for all ABI calculations. [30][32]

Ankle Pressures

• Obtain bilateral dorsalis pedis (DP) and posterior tibial (PT) artery systolic pressures using continuous‑wave Doppler. [30][32]
• For each leg, use the higher of the DP or PT pressure as the numerator when calculating the ABI; this approach maximizes specificity, although using the lower pressure may identify additional at‑risk patients. [30][32]

Toe Pressures (High‑Risk Patients)

• Measure bilateral great‑toe systolic pressures (photoplethysmography or Doppler) in patients with diabetes, chronic kidney disease, age > 70 years, or any suspicion of arterial calcification. 31

Calculation and Reporting

• ABI formula: higher ankle pressure ÷ higher brachial pressure. [30][32]
• Calculate ABI separately for each leg and report both values. [33][31]

Interpretation Thresholds

All thresholds are supported by evidence from the American Heart Association. [30][31]32

Patient Preparation

• Position the patient supine for at least 10 minutes before any measurements to allow hemodynamic stabilization. 30
• Instruct the patient to avoid caffeine, smoking, and exercise for ≥ 2 hours prior to testing. 30

Exercise ABI Testing

• Add post‑exercise ABI measurement when the patient has exertional leg symptoms but a resting ABI of 0.91‑1.40. [30][32]
• Also add post‑exercise testing when clinical suspicion for PAD remains high despite a normal resting ABI. [30][32]
• Diagnostic criteria after exercise: a decrease in ankle pressure > 30 mm Hg or a decrease in ABI > 20 % confirms PAD. [30][32]

Clinical Decision‑Making

• In patients with chronic kidney disease or age > 70 years, arterial calcification is common and ABI sensitivity declines markedly; therefore, TBI should be obtained routinely. 31
• Always measure both legs; unilateral measurement can miss PAD and underestimate cardiovascular risk. [30][32]
• If ABI ≤ 0.90 or TBI < 0.70 in a symptomatic patient, proceed directly to anatomic imaging (duplex ultrasound, CT angiography, or MR angiography) for lesion localization. American College of Cardiology recommendation. 33

ABI Testing and Management in Older Adults with Peripheral Artery Disease

Guideline Recommendation

• The American College of Cardiology/American Heart Association (ACC/AHA) gives a Class I recommendation that an ankle‑brachial index (ABI) with toe‑brachial index (TBI) and Doppler waveform analysis be ordered for older adults with peripheral vascular disease to establish baseline PAD severity and guide safe selection of alternative rate‑control agents for atrial fibrillation. 34, 35

Baseline Assessment of PAD

• ACC/AHA guidelines require bilateral ABI measurement in all patients with PAD of any severity to confirm diagnosis and create a baseline reference. 34, 35
• The severity of PAD determines which alternative rate‑control agents are appropriate; for example, the safety of vasodilatory β‑blockers (carvedilol, labetalol) versus calcium‑channel blockers depends on PAD severity. 36
• An ABI ≤ 0.90 confirms hemodynamically significant PAD, whereas an ABI 0.91–0.99 denotes borderline disease that warrants additional testing. 34, 35

Age‑Based Screening Recommendation

• The 2011 ACC/AHA focused update lowered the screening age threshold to ≥ 65 years for all patients, irrespective of symptoms, based on epidemiologic data showing a 21 % PAD prevalence in this age group. 34, 35
• Consequently, patients aged 65 years or older qualify for ABI testing even without a prior PAD diagnosis. 34, 35

Interpretation of ABI Values and Medication Selection

ABI 1.00–1.40 (Normal Range)

• Full‑dose calcium‑channel blockers (e.g., diltiazem, verapamil) are considered safe alternatives for rate control in atrial fibrillation. 34, 35

ABI 0.91–0.99 (Borderline)

• Use caution when selecting vasodilating agents; start calcium‑channel blockers at lower initial doses. 34, 35
• If the patient reports exertional leg symptoms, add an exercise treadmill ABI test to evaluate functional PAD despite borderline resting values. 34

ABI ≤ 0.90 (Confirmed PAD)

• Initiate aggressive cardiovascular risk‑reduction measures, including statin therapy, antiplatelet therapy (aspirin or clopidogrel), smoking cessation, and blood‑pressure control. 36

General Management Steps

• Interpret ABI/TBI/Doppler results using the outlined algorithm to choose the safest rate‑control strategy for atrial fibrillation. 34, 35
• Regardless of ABI outcome, optimize statin therapy, antiplatelet therapy, and overall cardiovascular risk‑factor management because PAD is a coronary‑heart‑disease risk equivalent. 36

Assessment and Management of Borderline‑High Ankle‑Brachial Index (>1.3) in High‑Risk Patients

Diagnostic Evaluation

• In older adults who smoke and have diabetes and hypertension, a borderline‑high ABI (>1.3) should prompt immediate measurement of the toe‑brachial index (TBI) because the elevated ABI reflects non‑compressible vessels from medial arterial calcification, making the standard ABI unreliable and potentially masking significant peripheral artery disease. (American College of Cardiology/American Heart Association) 37
• An ABI > 1.40 (and values > 1.3 approaching this threshold) indicates non‑compressible vessels due to medial arterial calcification (Mönckeberg sclerosis), a condition that is highly prevalent in diabetic patients and invalidates the ABI test. (American College of Cardiology/American Heart Association) 38
• The combination of diabetes, smoking, hypertension, and advanced age creates an extremely high risk for both peripheral artery disease (PAD) and major cardiovascular events, necessitating accurate vascular assessment. (American College of Cardiology/American Heart Association) 39

Interpretation of Toe‑Brachial Index

• A TBI < 0.70–0.75 confirms significant PAD and warrants further diagnostic evaluation. (American College of Cardiology/American Heart Association) 37

Additional Vascular Testing

• Pulse‑volume recordings (PVR) are recommended when available because they are not affected by arterial calcification and provide qualitative assessment of limb perfusion. (American College of Cardiology/American Heart Association) 38

Comprehensive Cardiovascular Risk Management

• PAD is considered a coronary heart disease risk equivalent, so aggressive cardiovascular risk reduction is required regardless of TBI results. (American College of Cardiology/American Heart Association) 39

Smoking Cessation (Highest Priority)

• Clinicians should advise smoking cessation at every visit and document tobacco‑use status. (American College of Cardiology/American Heart Association) 39
• Comprehensive smoking‑cessation programs should combine behavioral modification therapy with pharmacotherapy. (American College of Cardiology/American Heart Association) 39
• Varenicline is recommended as the first‑line pharmacologic agent because it yields higher quit rates than nicotine‑replacement therapy or bupropion; bupropion or nicotine replacement may be used if varenicline is contraindicated. (American College of Cardiology/American Heart Association) 39
• Smoking is the single most important modifiable risk factor for PAD; observational studies show markedly increased risks of death, myocardial infarction, and amputation among patients who continue to smoke. (American College of Cardiology/American Heart Association) 39

Medical Therapy

• Statin therapy should be instituted for lipid management. (American College of Cardiology/American Heart Association) 39
• Antiplatelet therapy with aspirin or clopidogrel is recommended. (American College of Cardiology/American Heart Association) 39
• Blood‑pressure control should follow guideline‑recommended targets. (American College of Cardiology/American Heart Association) 39
• Optimized glycemic control is essential in diabetic patients. (American College of Cardiology/American Heart Association) 39

Indications for Further Imaging and Revascularization (TBI < 0.70–0.75)

• Critical limb‑threatening ischemia (rest pain, non‑healing wounds, or gangrene) warrants consideration of revascularization. (American College of Radiology) 38
• Severe lifestyle‑limiting claudication that persists despite optimal medical therapy also supports revascularization. (American College of Cardiology/American Heart Association) 39

Guideline Recommendations

• ACC/AHA guidelines specifically recommend performing TBI in patients with diabetes and advanced age who present with a high ABI (>1.3–1.4) because of the high likelihood of non‑compressible vessels. (American College of Cardiology/American Heart Association) 37

Evidence strength for the above statements is derived from guideline consensus and observational data; specific class or level designations were not provided in the source material.