Pulmonary hypertension medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor(s)-in-Chief: Ralph Matar, Rim Halaby; José Eduardo Riceto Loyola Junior, M.D.[2]

Overview

The choice of treatment for pulmonary hypertension (PH) requires the assessment of the clinical severity of the disease and the identification of any underlying causes. Patients who have PH secondary to a medical condition such as left heart failure, lung diseases, or thromboembolic disease (PH group 2, 3, and 4 respectively) should receive treatment for the underlying cause. Patients who have pulmonary arterial hypertension (PAH) must undergo vasoreactivity testing in order to assist in the selection of the optimal therapy which includes calcium channel blockers, endothelin receptor antagonist, phosphodiesterase inhibitors, or prostanoids.

Medical Therapy

• If pulmonary hypertension is secondary to another disease, treatment is largely focused on treating the underlying disease.
• Oxygen is indicated for all causes of PH to maintain an oxygen saturation above 90% at exertion, rest or while sleeping. It is not effective in advanced Eisenmenger syndrome.
• Diuretics should be considered if there is important right heart dysfunction.

Treatment of PH due to Left Heart Disease

• Treatment must focus on left heart dysfunction;
• Prostacyclin analogues, phosphodiesterase type 5 (PDE5) inhibitors, endothelin-receptor antagonists, and soluble guanylate cyclase (SGC) stimulators.
• PH due to mitral valve dysfunction usually returns to normal after correction of the mitral valve disease.

Treatment of PH due to Lung Disease

• Only oxygen is proven to be effective;
• Avoid periods of hypoxia and treat underlying disease;
• There is no benefit in the use of pulmonary vasodilators in such cases.

Treatment of PH due to Chronic Thromboembolic Disease

• Pulmonary thromboendarterectomy (PTE) may be curative;
• Balloon pulmonary angioplasty may be recommended if patients are not candidates for (PTE) or if residual hypertension is still significant;
• Riociguat may be effective for refractory cases or cases unsuitable for surgical treatment.

Treatment Algorithm for PAH

• A right heart catheterization is essential to confirm the diagnosis of PH and should always be performed prior to the initiation of therapy.
• If left heart failure is excluded as a cause of PH, then vasodilator testing must be performed to assist in the selection of the optimal therapy.
• In the vasoreactivity test, a short acting vasodilator (prostanoids, inhaled NO, adenosine) is administered and the change in pulmonary arterial pressure (PAP) is assessed.
• A fall in the mean PAP by more than 10 and less than 40 mmHg is considered a positive result. Patients who have a positive vasodilator response are started on oral calcium channel blockers.
• Calcium channel blockers should not be administered to patients who are non-reactive to the vasoreactivity test. Calcium channel blocker should not be used in patients with Eisenmenger syndrome.
• Patients who do not have a positive vasodilator response require other specific medical therapy as described below.

Shown below is an algorithm depicting the optimal therapy for a patient with PAH.

Supportive treatment: Diuretics +/- Oxygen therapy +/- Oral anticoagulation therapy +/- Digoxin

What is the result of the acute vasoreactivity test?

Vasoreactive

Non vasoreactive

What is the WHO functional class (FC)?

What is the WHO functional class (FC)?

WHO FC I, II, or III

WHO FC II

WHO FC III

WHO FC IV

Administer: ❑ Calcium channel blocker

Administer: ❑ Endothelin receptor antagonist, or ❑ Phosphodiesterase 5 inhibitor ❑ Soluble guanylate cyclase stimulator

Administer: ❑ Endothelin receptor antagonist, or ❑ Phosphodiesterase 5 inhibitor, or ❑ Soluble guanylate cyclase stimulator, or ❑ Prostanoids

Administer: ❑ Prostanoids

Is there a sustained response?

Is there a sustained response?

Yes

No

If no, administer combination therapy

Continue with calcium channel blockerss

Is there a sustained response?

If no, lung transplantation

Supportive Therapy

The supportive therapy for patients with pulmonary hypertension includes:

• Diuretics: for right ventricular failure and fluid retention.
• Oxygen therapy: continuous oxygen therapy is needed for patients with oxygen saturation less than 90%.
• Oral anticoagulation therapy: to decrease the risk of venous thromboembolism in patients with idiopathic PAH, heritable PAH, anorexigenic related PH, and possibly in associated PAH.
• Digoxin: to improve cardiac muscle contractility in case of right heart failure and low cardiac output as well as to slow the ventricular rate in case of atrial tachycardia.

Specific Drug Therapies in Treatment-Naïve PAH Patients

WHO Functional Class I

Patients with WHO functional class I PAH or those at elevated risk of developing PAH, as in the case of systemic sclerosis, should be monitored for the occurrence of PAH-related symptoms.

WHO Functional Class II

• Symptomatic patients with positive acute vasoreactivity testing should be administered a trial of calcium channel blockers (amlodipine, nifedipine, or diltiazem) when no contraindications are present and in the absence of right heart failure.

• Patients among whom calcium channel blocker trial failed to improve the clinical status or those who are not candidates for calcium channel blockers should receive monotherapy with one of the following:
  • Endothelin receptor antagonist (bosentan, ambrisentan, macitentan)
  • Phosphodiesterase 5 inhibitors (sildenafil and tadalafil)
  • Soluble guanylate cyclase stimulator (riociguat)

• Prostanoids are not indicated for the treatment of patients with WHO functional class II PAH.

WHO Functional Class III

• Symptomatic patients with positive acute vasoreactivity testing should be administered a trial of calcium channel blockers (amlodipine, nifedipine, or diltiazem) when no contraindications are present and in the absence of right heart failure.

• Patients among whom calcium channel blocker trial failed to improve the clinical status or those who are not candidates for calcium channel blockers should receive monotherapy with one of the following:
  • Endothelin receptor antagonist (bosentan, ambrisentan, macitentan)
  • Phosphodiesterase 5 inhibitors (sildenafil and tadalafil)
  • Soluble guanylate cyclase stimulator (riociguat)

• Patients with WHO class III PAH whose disease is rapidly progressing and associated with poor prognostic markers, should be administered parenteral prostanoid as initial therapy instead of oral therapy.
  • IV epoprostenol
  • IV treprostinil
  • Continuous SC treprostinil

• Patients with WHO class III PAH whose symptoms are not improved on the initial therapy with either endothelin receptor antagonist or phosphodiesterase 5 inhibitors should receive any of the following as an add-on to their initial therapy:
  • Inhaled treprostinil (3 inhalations (18 μg) every 6 hours, can titrate up to 9 inhalations (54 μg) every 6 hours)
  • Inhaled Iloprost

• Patients with WHO class III PAH and rapid progression of the disease despite initial therapy with one or more oral medication should be administered parenteral or inhaled prostanoids.

WHO Functional Class IV

• The initial treatment for patients with WHO class IV PAH is a monotherapy with a parenteral prostanoid:
  • Continuous IV epoprostenol
  • Continuous IV treprostinil
  • Continuous SC treprostinil

• If the patient refuses or is unable to receive parenteral therapy, the alternative treatment is a combination of inhaled prostanoid (iloprost or treprostinil) and endothelin receptor antagonist (bosentan).

Combination Therapies in Patients on Established PAH Treatment

Patients with WHO functional class III or IV whose clinical status is unacceptable despite monotherapy should receive an add-on to their treatment:

• If already on endothelin receptor antagonist, add:
  • Inhaled iloprost, or
  • Inhaled treprostinil
  • Soluble guanylate cyclase stimulator riociguat (if already on either bosentan or ambrisentan)

• If already on phosphodiesterase 5 inhibitor, add:
  • Inhaled iloprost, or
  • Inhaled treprostinil, or
  • Macitentan

• If already on inhaled prostanoid, add:
  • Macitentan, or
  • Soluble guanylate cyclase stimulator ( riociguat)

• If already on IV epoprostenol:
  • Up titrate IV epoprostenol, or
  • Add sildenafil
  • Do not initiate bosentan simultaneously

Patients with WHO functional class III or IV whose clinical status is unacceptable despite dual therapy with two classes of PAH specific medications should receive a third class added on to their treatment.

List of All Specific Drug Therapies

Shown below is a table summarizing the class of recommendation and level of evidence for the different specific drug therapies by the WHO functional class of PAH according to the 2009 Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT).

Medication	WHO-FC II	WHO-FC III	WHO-FC IV
Calcium channel blockers	I-C	I-C	--
Endothelin receptor antagonsit
Ambrisentan	I-A	I-A	IIa-C
Bosentan	I-A	I-A	IIa-C
Sitaxentan	IIa-C	I-A	IIa-C
Phosphodiesterase 5 inhibitor
Sildenafil	I-A	I-A	IIa-C
Tadalafil	I-B	I-B	IIa-C
Prostanoids
Beraprost	--	IIb-B	--
Epoprostenol (IV)	--	I-A	I-A
Iloprost (inhaled)	--	I-A	IIa-C
Iloprost (IV)	--	IIa-C	IIa-C
Treprostinil (subcutaneous)	--	I-B	IIa-C
Treprostinil (IV)	--	IIa-C	IIa-C
Treprostinil (Inhaled)	--	I-B	IIa-C
Initial drugs combination therapy	--	--	IIa-C
Sequential drugs combination therapy	IIa-C	IIa-B	IIa-B

Endothelin Receptor Antagonist

There has been a clear role for endothelin system in the pathogenesis of PAH. Endothelin-1 exerts vasoconstrictor and mitogenic effects by binding to two different receptor isoforms: ET-A and ET-B. It is blocked by these antagonists at the vascular smooth muscle.

FDA approved endothelin receptor antagonists are bosentan, ambrisentan, and macitentan

• Bosentan: 62.5 mg PO bid for 4 weeks, then 125mg PO bid if there is no change in liver function tests;
  • Antagonizes both ET-A and ET-B receptors and was shown to improve haemodynamics, exercise capacity, functional class and delay progression of disease. It is started at 62.5 mg BID and up-titrated to 125 mg BID after 4 weeks.
• Macitentan: 10mg PO qd;
  • Antagonizes both ET-A and ET-B receptors.
• Ambrisentan: 5–10 mg PO qd;
  • Selective ET-A receptor antagonist. Proven to be efficacious on improving symptoms, exercise capacity, hemodynamics, and time to clinical worsening.
• Sitaxentan: 100mg PO qd;
  • Selectively orally active ET-A receptor antagonist was also shown to improve exercise capacity and hemodynamics.

Side effects:

• Hepatotoxicity, headache, edema, anemia.
• Do not use in pregnancy.

Phosphodiesterase Type-5 Inhibitors

Inhibiting cGMP-degrading enzymes leads to increased levels of cGMP and subsequently improved vasodilation. All phosphodiesterase inhibitors originally approved for the treatment of erectile dysfunction cause significant pulmonary vasodilation:

• Sildenafil:: 20 mg PO tid;
  • Daily Maximum effect is observed after 60min from administration of the drug. It's orally active, potent and a selective type-5 phosphodiesterase inhibitor. Favorable effects on symptoms, hemodynamics and exercise capacity were shown in several studies.
• Tadalafil: 40 mg PO qd;
  • Maximum effects observed after 75-90min. Single daily dose is available. Studies showed favorable results on symptoms, hemodynamics, exercise capacity, and times to clinical worsening when the largest dose was used.

Side effects:

• Headache, dyspepsia, flushing, epistaxis, hypotension.
• Do not use them with nitrates.

Prostanoids

Prostacyclins are potent vasodilators and potent inhibitors of platelet aggregation in vascular beds. Patients with PAH have been shown to have low levels prostacyclin levels, so stable analogues of prostacyclin have been made for that purpose. These drugs increase intracellular production of cAMP.

FDA approved prostanoids are epoprostenol, iloprost, and treprostinil.

• Epoprostenol: (start at 2ng/kg/min and titrate according patient symptoms and exercise capacity)
• Iloprost: 2.5-5mcg inhaled 6-9 times daily
• Treprostinil: different delivery methods are currently available.
• Selexipag: 200mcg PO bid up to maximum dose of 1600mcg bid or patients' tolerance.

Side effects:

• Headache, masticatory jaw pain, hypotension, flushing, nausea, diarrhea, rash.
• Cough may occur if inhaled;
• Risk of cellulitis.

Soluble Guanylate Cyclase Stimulator

• Riociguat: initiate 0.5-1mg PO tid, increase by 0.5mg every 2 weeks until 2.5mg tid is reached or up to the level where patient's tolerance allows.

Side effects:

• Hypotension, dyspepsia;
• Do not use in pregnancy.

Calcium Channel Blockers

Calcium channel blockers use must be limited to a few selected patients. These medications are effective for patients who present at the time of heart catheterization with a positive vasoreactivity response. Less than 10% of patients have any improvement and this response is a strong predictor of better prognosis. Their mode of action is characterized by a decrease in smooth muscle hypertrophy, hyperplasia and vasoconstriction. CCB should be started at a low dose and then progressively increase it:

• Nifedipine: Starting dose 30 mg bid; target dose: 120-240 mg/day
• Diltiazem: Starting dose 60 mg tid; target dose: 240-720 mg/day
• Amlodipine: Starting dose 2.5 mg qd; target dose: 20 mg/day

Nifedipine and amlodipine are preferred in cases of relative bradycardia, whereas diltiazem is preferred in cases of relative tachycardia.

Patients who are started on CCB should receive a follow up within the next 3 to 4 months to assess for CCB efficacy and tolerability.

Treatment Consideration in Other Types of PH

• There is no clear recommendations regarding the medical therapy in pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis. Caution should be taken with the administration of vasodilators, particularly prostanoids, due to the increased risk of pulmonary edema.

• Patients with PH secondary to left heart failure should receive an optimal therapy for their heart failure problem. The medications for PH are not contraindicated among these patients.

• Long term oxygen therapy is the treatment of choice among patients with PH secondary to lung diseases. These patients should not be administered vasodilators because they cause inhibit hypoxic vasoconstriction in the pulmonary circulation.

• Patients with chronic thromboembolic pulmonary hypertension require a life long administration of anticoagulation therapy.

General Measures

Exercise

• Rehabilitation of sedentary individuals is crucial. Patients must be encouraged to maintain physical activity despite PAH symptoms. Mild dyspnea is acceptable, but chest pain, near syncope, severe breathlessness should be avoided.
• Isometric exercises should be discouraged.

Pregnancy

• Patients with PAH should avoid pregnancy. Patients on PAH specific should receive dual contraceptive. Estrogen-containing contraceptives should be avoided because they increase the risk of venous thromboembolism.
• If pregnancy occurs, a multidisciplinary team should take care of the patients. Bosentan, ambrisentan, macitentan, and riociguat are contraindicated in pregnancy.

Altitude and Air Travel

• Patients with PAH should avoid high altitude. In case of exposure to high altitude or travel, patients should receive supplemental oxygen therapy (oxygen saturation >92%)

Vaccination

Patients with PAH should have an up-to-date vaccination against influenza and pneumococcus.

General anesthesia

• Epidural rather than general anesthesia should be administered for surgical procedures given the potential for hypotension.

Oxygen

• In-flight oxygen should be considered for those patients who have an oxygen saturation <12%.

Anticoagulation

• Anticoagulation should be considered in patients with pulmonary hypertension in the absence of hemoptysis.

Phlebotomy

• Phlebotomy should be used if the hemoglobin is greater than 20 and/or the hematocrit is greater than 65% or if symptoms of hyper viscosity develop.

Contraindicated medications

Pulmonary hypertension is considered an absolute contraindication to the use of the following medications:

• Esmolol

ESC/ERS (2009) Recommendations for the Treatment of Pulmonary Hypertension (DO NOT EDIT)

General Measures (DO NOT EDIT)

Class I

"1. It is recommended to avoid pregnancy in patients with PAH. (Level of Evidence: C) "

"2. Immunization of PAH patients against influenza and pneumococcal infections is recommended. (Level of Evidence: C) "

Class III

"1. Excessive physical activity that leads to distressing symptoms is not recommended in patients with PAH. (Level of Evidence: C) "

Class IIa

"1. Physically deconditioned PAH patients should be considered for supervised exercise rehabilitation. (Level of Evidence: B) "

"2. Psychosocial support should be considered in patients with PAH. (Level of Evidence: C) "

"3. In-flight oxygen administration should be considered for patients in WHO-FC III and IV and those with arterial oxygen pressure consistently less than 60mmHg coronary disease. (Level of Evidence: C) "

"4. Epidural anesthesia instead of general anesthesia should be utilized if possible for elective surgery. (Level of Evidence: C) "

Supportive Therapy (DO NOT EDIT)

Class I

"1. Diuretic treatment is indicated in PAH patients with signs of RV failure and fluid retention. (Level of Evidence: C) "

"2. Continuous long-term oxygen therapy is indicated in PAH patients when arterial oxygen pressure is consistently less than 60mmHg. (Level of Evidence: C) "

Class IIa

"1. Oral anticoagulant treatment should be considered in patients with IPAH, heritable PAH, and PAH due to use of anorexigens. (Level of Evidence: B) "

Class IIb

"1. Oral anticoagulant treatment should be considered in patients with APAH. (Level of Evidence: C) "

"2. Digoxin may be considered in patients with PAH who develop atrial tachyarrhythmias to slow ventricular rate. (Level of Evidence: C) "

PAH Associated with Congenital Cardiac Shunts (DO NOT EDIT)

Class I

"1. Bosentan (Endothelin receptor antagonist) is indicated in WHO-FC III patients with Eisenmenger syndrome. (Level of Evidence: B) "

Class III

"1. The use of CCB is not recommended in patients with Eisenmenger's syndrome. (Level of Evidence: C) "

Class IIa

"1. Other endothelin receptor antagonist, phosphodiesterase inhibitors, and prostanoids should be considered in patients with Eisenmenger's syndrome. (Level of Evidence: C) "

"2. In the absence of significant haemoptysis, oral coagulant treatment should be considered in patients with PA thrombosis or signs of heart failure. (Level of Evidence: C) "

"3. The use of supplemental oxygen therapy should be considered in cases in which it produces a consistent increase in arterial oxygen saturation and reduces symptoms. (Level of Evidence: C) "

"4. If symptoms of hyperviscosity are present, phlebotomy with isovolumic replacement should be considered usually when the haematocrit is > 65%. (Level of Evidence: C) "

Class IIb

"1. Combination therapy may be considered in patients with Eisenmenger's syndrome. (Level of Evidence: C) "

PAH Associated with Connective Tissue Diseases (CTD) (DO NOT EDIT)

Class I

"1. In patients with PAH associated with CTD the same treatment algorithm as in patients with IPAH is recommended. (Level of Evidence: A) "

"2. Echocardiographic screening for the detection of PH is recommended in symptomatic patients with scleroderma spectrum of diseases. (Level of Evidence: B) "

"3. Echocardiographic screening for the detection of PH is recommended in symptomatic patients with all other CTDs. (Level of Evidence: C) "

"4. Right heart catheterization is indicated in all cases of suspected PAH associated with CTDs, in particular if specific drug therapy is considered. (Level of Evidence: C) "

Class IIa

"1. Oral anticoagulation should be considered on an individual basis. (Level of Evidence: C) "

Class IIb

"1. Echocardiographic screening for the detection of PH is recommended in symptomatic patients with scleroderma spectrum of diseases. (Level of Evidence: C) "

PAH Associated with Portal Hypertension (DO NOT EDIT)

Class I

"1. Echocardiographic screening for the detection of PH is recommended in symptomatic patients with liver diseases and/or in candidates for liver transplantation. (Level of Evidence: B) "

Class III

"1. Anticoagulation is not recommended in patients with increased risk of bleeding. (Level of Evidence: C) "

"2. Significant PAH is a contraindication to liver transplantation if mean PAP is .35 mmHg and/or pulmonary vascular resistance is > 250 dynes.s.cm^-5 (Level of Evidence: C) "

Class IIa

"1. In patients with pulmonary arterial hypertension associated with portal hypertension the same treatment algorithm as in patients with idiopathic pulmonary hypertension should be considered, taking into consideration co-morbidities. (Level of Evidence: C) "

PAH Associated with Human Immunodeficiency Virus Infection (DO NOT EDIT)

Class I

"1. Echocardiography is indicated in patients with unexplained dyspnea to detect HIV-related cardiovascular complications. (Level of Evidence: C) "

Class III

"1. Anticoagulation is not recommended in patients with increased risk of bleeding. (Level of Evidence: C) "

Class IIa

"1. In patients with pulmonary arterial hypertension associated with HIV-infection the same treatment algorithm as in patients with idiopathic pulmonary hypertension should be considered, taking into consideration co-morbidities and drug-drug interactions. (Level of Evidence: C) "

PAH Associated with Pulmonary Veno-Occlusive Disease(PVOD) (DO NOT EDIT)

Class I

"1. Referral of patients with PVOD to a transplant center for evaluation is indicated as soon as the diagnosis is established. (Level of Evidence: C) "

Class IIa

"1. Patients with PVOD should be managed only in centers with extensive experience in pulmonary arterial hypertension due to the risk of lung edema after the initiation of PAH-specific drug therapy. (Level of Evidence: C) "

PH Associated with Left Heart Disease (DO NOT EDIT)

Class I

"1. The optimal treatment of the underlying left heart disease is recommended in patients with pulmonary hypertension due to left heart disease. (Level of Evidence: C) "

Class III

"1. The use of PAH specific drug therapy is not recommended in patients with pulmonary hypertension due to left heart disease. (Level of Evidence: C) "

Class IIa

"1. Patient with "out of proportion" pulmonary hypertension due to left heart disease should be enrolled in randomized controlled trials targeting pulmonary hypertension specific drugs. (Level of Evidence: C) "

Class IIb

"1. Increased left-sided filling pressures may be estimated by Doppler echocardiography. (Level of Evidence: C) "

"2. Invasive measurements of pulmonary wedge pressure of left ventricular end-diastolic pressure may be required to confirm the diagnosis of pulmonary hypertension due to left heart disease. (Level of Evidence: C) "

"3. Right heart catheterization may be considered in patients with echocardiographic signs suggesting severe pulmonary hypertension in patients with left heart disease. (Level of Evidence: C) "

PH Associated with Lung Disease (DO NOT EDIT)

Class I

"1. Echocardiography is recommended as a screening tool for the assessment of PH due to lung diseases. (Level of Evidence: C) "

"2. Right heart catheterization is recommended for a definite diagnosis of pulmonary hypertension due to lung diseases. (Level of Evidence: C) "

"3. The optimal treatment of the underlying lung disease including long-term oxygen therapy in patients with chronic hypoxemia is recommended in patients with pulmonary hypertension due to lung diseases. (Level of Evidence: C) "

Class III

"1. The use of PAH specific drug therapy is not recommended in patients with pulmonary hypertension due to lung diseases. (Level of Evidence: C) "

Class IIa

"1. Patients with "out of proportion" pulmonary hypertension due to lung diseases should be enrolled in randomized controlled trials targeting PAH-specific drugs. (Level of Evidence: C) "

PH Associated with Chronic Thromboembolic Pulmonary Hypertension(CTEPH) (DO NOT EDIT)

Class I

"1. The diagnosis of CTEPH is based on the presence of pre-capillary pulmonary hypertension(mean PAH>25mmHg,PWP<15mmHg,Pulmonary vascular resistance>2 Wood units) in patients with multiple chronic/organized occlusive thrombi/emboli in the elastic pulmonary arteries (main, lobar, segmental, subsegmental). (Level of Evidence: C) "

"2. In patients with CTEPH, lifelong anticoagulation is indicated. (Level of Evidence: C) "

"3. Surgical pulmonary endarterectomy is the recommended treatment for patients with CTEPH. (Level of Evidence: C) "

Class IIa

"1. Once perfusion scanning and/or CT angiography show signs compatible with CTEPH, the patient should be referred to a center with expertise in surgical pulmonary endarterectomy. (Level of Evidence: C) "

"2. The selection of patients for surgery should be based on the extent and location of the organized thrombi, on the degree of pulmonary hypertension, and on the presence of co-morbidities. (Level of Evidence: C) "

Class IIb

"1. PAH-specific drug therapy may be indicated in selected CTEPH patients such as patients not candidates for surgery or patients with residual pulmonary hypertension after pulmonary endarterectomy. (Level of Evidence: C) "

PAH Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death (DO NOT EDIT)

Class III (Harm)

"1. Prophylactic antiarrhythmic therapy generally is not indicated for primary prevention of SCD in patients with pulmonary arterial hypertension or other pulmonary conditions. (Level of Evidence: C) "