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Clinical Update on Pulmonary Hypertension J Investig Med: First Published As 10.1136/Jim-2020-001291 on 1 April 2020

Clinical Update on Pulmonary Hypertension J Investig Med: First Published As 10.1136/Jim-2020-001291 on 1 April 2020

Review

Clinical update on pulmonary J Investig Med: first published as 10.1136/jim-2020-001291 on 1 April 2020. Downloaded from Salim Yaghi, Anastasia Novikov, Theo Trandafirescu ‍ ‍

Queens Hospital Center, Abstract at least 25 mm Hg was chosen somewhat arbi- Medicine, Mount Sinai (PH) is a chronic, complex trarily and does not represent the upper limit of Medical Center, Queens, normal mPAP in the general population.2 3 New York, USA and challenging . Advances in treatment are for the subset of patients with pulmonary arterial The prior assessment of PAP at is Correspondence to hypertension. Selected review of the literature was not recommended with the current definitions Dr Theo Trandafirescu, conducted incorporating the European Society of due to lack of reliable data that precisely define Queens Hospital Center, /European Respiratory Society 2015 which levels of exercise-induced­ changes in PAP Medicine, Mount Sinai guidelines and recommendations from the Sixth or pulmonary have prog- Medical Center, Queens, nostic implications.2 3 NYC 11432, USA; World Symposium on Pulmonary Hypertension. ttrandaf@​ ​gmail.com​ PH is classified into five groups based on WHO Hemodynamic definitions of PH which classification. remains the initial include more than just the PAP during right Accepted 6 February 2020 test of choice, and careful assessment of the right catheterization (RHC) are probably more system aids in the diagnosis and prognosis of useful clinically as they have prognostic and the disease. Right heart catheterization remains therapeutic implications and can help with the gold standard of diagnosis and key guidance further classification of the disease. The major of treatment. Multidisciplinary approach is players here are pulmonary vascular resis- recommended for the care of patients with PH. tance and pulmonary wedge pressure Treatment selection is based on individual risk (table 1).1–3 stratification of patients, and early referral to specialized PH centers improves outcomes of Classifications patients. Treating PH is complex and is best carried The WHO classification1 2 categorizes multiple out in PH centers and with multidisciplinary clinical conditions into five groups according to approach. Early diagnosis and referral to those similarities in clinical presentation, patholog- centers are key not to delay treatment. ical findings, hemodynamic characteristics and treatment approach. These subtypes of PH are agreed on by the ESC in 2016 and the Sixth World Symposium (box 1 and tables 2–4). Introduction

Pulmonary hypertension (PH) has remained a http://jim.bmj.com/ challenging chronic progressive disease since the Diagnosis First World Symposium meeting in 1973, which ECG findings opened the era to groundbreaking discoveries An ECG may provide supportive evidence of about its pathophysiology and various treatment PH, but a normal ECG does not exclude the options. In this review, we try to summarize the diagnosis.4 An abnormal ECG is more likely in latest evidence about the disease, its definition, severe rather than mild PH. ECG abnormalities classification, diagnosis and treatment, focusing may include P pulmonale, right axis deviation, on October 1, 2021 by guest. Protected copyright. mainly on group 1 pulmonary arterial hyperten- RV , RV strain, right bundle branch sion (PAH). block, and QTc prolongation. Prolongation of the QRS complex and QTc suggests severe 4 Definitions disease. Supraventricular arrhythmias may occur in Pulmonary hypertension is defined as a mean advanced disease, in particular , but pulmonary arterial pressure (mPAP) greater also , with a cumulative inci- than 20 mm Hg at rest as per the Sixth World dence of 25% in patients after 5 years.5 Ventric- Symposium on Pulmonary Hypertension in 1 ular arrhythmias are rare. © American Federation for 2018, and greater than 25 mm Hg at rest as per Medical Research 2020. the guidelines issued by the European Society Re-­use permitted under of Cardiology (ESC)/European Respiratory Echocardiography CC BY-­NC. No commercial 2 re-use­ . Published by BMJ. Society (ERS) in 2015. A subset of patients Echocardiography remains the first test of with pulmonary arterial pressure (PAP) of choice when PH is suspected,6 not only because To cite: Yaghi S, between 21 and 24 mm Hg are considered high-­ it estimates systolic PAP but also because it can Novikov A, Trandafirescu T. risk patients with possible poor outcomes if left assess for signs of right ventricular (RV) dysfunc- J Investig Med Epub 7 ahead of print: [please unfollowed, which is why they were included in tion as well as left ventricular (LV) dysfunction. 1 include Day Month Year]. the Sixth World Symposium definition. Reading and interpreting echocardiographic doi:10.1136/jim-2020- The authors based this recommendation on imaging in respect to PH and its related 001291 the fact that the original definition of mPAP of effects on the right cardiac side is challenging;

Yaghi S, et al. J Investig Med 2020;0:1–7. doi:10.1136/jim-2020-001291 1 Review

Table 1 Hemodynamicdefinitions of pulmonary hypertension Box 1 updated clinical classification of pulmonary J Investig Med: first published as 10.1136/jim-2020-001291 on 1 April 2020. Downloaded from types hypertension (PH) Mean pulmonary Pulmonary capillary Pulmonary vascular Definition pressure (mm Hg) wedge pressure (mm Hg) resistance (Wood units) 1. Pulmonary arterial hypertension (PAH). Isolated precapillary PH 20 <15 3 (formerly pulmonary ►► Idiopathic. arterial hypertension) ► Heritable. Combined postcapillary 15 3 ► and precapillary pulmonary ►► Drug-­induced and toxin-­induced (see table 2). hypertension (PH) ► Isolated postcapillary PH 15 <3 ► Associated with the following: –– Connective tissue disease. –P– ortal hypertension. –– Congenital heart disease. therefore, the ESC guidelines issued a probability score for –– . PH based on echocardiographic features. ►► PAH long-­term responders to channel blockers The ESC/ERS and the Sixth World Symposium do not (see table 3). recommend using estimated systolic PAP anymore given ►► PAH with overt features of pulmonary veno-­occlusive inaccuracies of right atrial pressure (RAP) estimation and disease/or pulmonary capillary hemangiomatosis (see the amplification of measurement errors using derived vari- table 4). ables; thus, continuous-wave­ Doppler measurement of peak ►► Persistent PH of the newborn syndrome. tricuspid regurgitation velocity (TRV) is the main variable 2. Pulmonary hypertension due to left heart disease. 1 2 8 9 for assigning echocardiographic probability of PH ►► PH due to with preserved left ventricular (tables 5 and 6). ejection fraction. The algorithm in figure 1 summarizes how to use ►► PH due to heart failure with reduced left ventricular echocardiography and the probability score for PH to ejection fraction. determine further testing and whether RHC for defin- ►► . itive diagnosis is indicated. It can be said that patients ►► Congenital/acquired cardiovascular conditions leading with symptoms plus intermediate or high echocardio- to postcapillary PH. graphic probability score should go for RHC, and only 3. Pulmonary hypertension due to disease and/ patients with high probability should go or . for RHC; otherwise, follow-­up with repeat echocardiog- ►► Obstructive pulmonary . raphy is reasonable (figure 1). ►► Restrictive pulmonary diseases. ►► Other lung disease with mixed restrictive/obstructive Cardiac MRI pattern. Cardiac MRI (CMR) is accurate and reproducible in the ►► Hypoxia without lung disease. assessment of RV size, morphology and function, and ►► Developmental lung disorders. allows non-­invasive assessment of flow, including 4. Pulmonary hypertension due to http://jim.bmj.com/ volume, (CO), pulmonary arterial obstruction. distensibility and RV mass.10 ►► Chronic thromboembolic PH. In patients with suspected PH, the presence of late gado- ►► Other pulmonary artery obstructions. linium enhancement, reduced pulmonary arterial distensi- –– Sarcoma (high or intermediate grade) or bility and retrograde flow has high predictive value in the .

identification of PH; however, no single CMR measure- –– Other malignant tumors (renal, uterine, germ cell on October 1, 2021 by guest. Protected copyright. ment can exclude PH.2 In patients with PH, CMR may also tumor of the testis, other tumors). be useful in cases with suspected congenital heart disease if –– Non-malignant­ tumors (uterine leiomyoma). echocardiography is not conclusive. –– without connective tissue disease. Contrast-­enhanced and unenhanced magnetic resonance –– Congenital pulmonary stenoses. angiography has potential in the study of the pulmonary –P– arasites (hydatidosis). vasculature in patients with suspected chronic thromboem- 5.Pulmonary hypertension with unclear and/or bolic PH, particularly in clinical scenarios such as suspected multifactorial mechanisms. chronic in pregnant women, young patients or ►► Hematological disorders: chronic and when iodine-based­ contrast media injection is contraindi- myeloproliferative disorders. cated.2 10 ►► Systemic and metabolic disorders: pulmonary CMR provides useful prognostic information for patients Langerhans cell , Gaucher disease, glycogen with PAH both at baseline and at follow-up.­ 2 10 storage disease, and . ►► Others: fibrosing , chronic renal failure Severity and prognosis of disease (with/without dialysis), pulmonary tumorous thrombotic There is no single variable that provides sufficient diag- and HIV. nostic and prognostic value for patients with PH11 12; therefore, a comprehensive assessment of multiple vari- ables at regular intervals is strongly recommended by them into low, intermediate or high risk.2 Most of the the ESC to be done in expert PH centers. This complex proposed variables and cut-off­ values are based on expert assessment is used to define patients’ status and classify opinion.

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Table 2 Classification of drugs and toxins associated with Table 6 Echocardiographic signs of PH J Investig Med: first published as 10.1136/jim-2020-001291 on 1 April 2020. Downloaded from pulmonary arterial hypertension C. Inferior vena cava Definite Possible A. Ventricles B. Pulmonary artery and right Right /left Right ventricular Inferior vena cava ventricle basal diameter outflow Doppler diameter >21 mm with L-­ ratio >1.0. acceleration time decreased inspiratory <105 ms and/or mid-­ collapse (<50% with Benfluorex St John’s wort systolic notching. inspiration). Flattening of Early diastolic Right atrial area (end-­ Interferon alpha and beta interventricular septum pulmonary regurgitation ) >18 cm2. Toxic rapeseed oil Alkylating agents (left ventricular velocity >2.2 m/s.  eccentricity index >1.1 in systole and/or ).  Direct-­acting antiviral agents against hepatitis C virus  Pulmonary artery   diameter >25 mm.  Indirubin (Chinese herb Qing-­Dai) At least two from different categories (A, B or C) should be present to alter the probability of echocardiographic PH score. PH, pulmonary hypertension.

Table 3 Definitions of acute and long-­term response Mortality numbers are crude rates that were studied in Acute pulmonary vasoreactivity Reduction of mPAP >10 mm Hg to reach an patients with idiopathic PAH (IPAH) only; therefore, indi- for patients with idiopathic, absolute value of mPAP <40 mm Hg. vidualization of assessment is needed. The individual risk heritable or drug-­induced PAH. is modified by other factors, such as the rate of disease  Increased or unchanged cardiac output. progression and the presence or absence of signs of right Long-­term response to CCBs. New York Heart Association functional heart failure, or , and also by the presence of comor- class I/II. bidities, age, sex, background therapy, and PAH subtype, With sustained hemodynamic improvement among others (table 7). (same or better than achieved in the acute An important note to take from these variables is that test) after at least 1 year on CCBs only. functional class and exercise capacity are vital in the assess- CCBs, blockers; mPAP, mean pulmonary arterial pressure; ment process. The WHO Functional Class (WHO-FC)­ PAH, pulmonary arterial hypertension. remains one of the most powerful predictors of survival, and 6 min test remains the most widely used exer- cise test in PH centers (table 8).1 2 11–13 We can note as well that RV function is a key determi- nant of exercise capacity, and in contrast to common belief

Table 4 Signs suggestive of venous and capillary (pulmonary http://jim.bmj.com/ the estimated systolic PAP at rest is usually not prognostic veno-­occlusive disease/pulmonary capillary hemangiomatosis) 2 14 involvement and not relevant for therapeutic decision making. It is reasonable to say that the effects of this high pressure, Pulmonary function tests Decreased DLCO (<50%). especially on the right cardiac system, determine exercise Severe . capacity and predict survival. High-­resolution chest CT Septal lines, centrilobular ground glass opacities, and mediastinal lymphadenopathy. on October 1, 2021 by guest. Protected copyright. Response to PAH therapy Possible pulmonary . Genetic background Biallelic EIF2AK4 mutations. Occupational exposure Organic solvent (trichloroethylene). DLCO, of the for carbon monoxide; PAH, pulmonary arterial hypertension.

Table 5 Echocardiographic probability of pulmonary hypertension (PH) in symptomatic patients with suspicion of pulmonary hypertension Peak tricuspid Presence of other Echocardiographic regurgitation echocardiographic probability of pulmonary velocity (m/s) signs of PH hypertension <2.8 or not measurable No Low <2.8 or not measurable Yes Intermediate 2.9–3.4 No 2.9–3.4 Yes High >3.4 Not required Figure 1 ECHO probability score diagnostic algorithm

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Table 7 Risk stratification of PH patients Evolution of PAH therapy J Investig Med: first published as 10.1136/jim-2020-001291 on 1 April 2020. Downloaded from 1-­year mortality Intermediate risk prognosis factors Low risk (<5%) (5%–10%) High risk (>10%) ►► Epoprostenol intravenously (Flolan): approved in 1995. Clinical right heart Absent Absent Present failure ►► orally: approved in 2001. Symptom progression No Slow Rapid ►► subcutaneously: approved in 2002. Syncope No Occasional syncope Repeated syncope, ►► inhaled: approved in 2004. with heavy exercise or especially at rest orthostatic change ►► Treprostinil intravenously: approved in 2005. WHO Functional Class I and III III IV ►► orally: approved in 2005. 6MWD (m) 440 165–440 <165 ►► Ambrisentan orally: approved in 2007.

Cardiopulmonary Peak VO2 >15 mL/min/kg Peak VO2 11–15 mL/min/ Peak VO2 <11 mL/min/kg ►► Tadalafil orally: approved in 2009. exercise testing (>65% pred) kg (35%–65% pred) (<35% pred) ► Treprostinil inhaled: approved in 2009. VE/VCO2 slope <36 VE/VCO2 slope 36–44.9 VE/VCO2 slope >45 ► NT-proBNP­ (ng/L) <300 300–1400 1400 ►► Epoprostenol intravenously (Veletri): approved in 2010. Imaging RA area <18 cm2 RA area 18–26 cm2 RA area >26 cm2 ►► orally: approved in 2013. (echocardiography No pericardial effusion Minimal pericardial Pericardial effusion and/or cardiac MRI) effusion ►► orally: approved in 2013. Hemodynamics RAP <8 mm Hg RAP 8–14 mm Hg RAP >14 mm Hg ►► Treprostinil orally: approved in 2013. 2 2 2 CI >2.5 L/min/m CI 2.0–2.4 L/min/m CI <2.0 L/min/m ►► Selexipag orally: approved in 2015. SvO2 >65% SvO2 60%–65% SvO2 <60%

With advances in biological, molecular and genetic medi- Treatment and management of PH cine, we now have 14 FDA drugs for PAH. Historical background Treatment of WHO group 1 PAH by targeting the nitric Despite PH being recognized as early as 1891 by German oxide, and pathways has been 15 physician Ernst von Romberg, it took nearly 100 years standard since the 2003 World Symposium on Pulmo- for the first disease-­specific intravenous epopro- nary Hypertension (WSPH) guidelines. In the following 15 16 stenol to be approved in 1995. PH remains an orphan lines and algorithms, we try to summarize the treatments disease that has received little clinical attention possibly due proposed by the the Sixth WSPH task force and the ESC to lack of solid scientific understanding, and even after the 2018 guidelines. introduction of right heart catheterization by Werner Forss- General measures and supportive therapy should be initi- mann in 1929 and direct measurement of PAP no drugs have ated to all patients with confirmed diagnosis of PAH. been available for chronic treatment. It was not until the appetite-­suppressant, aminorex-­induced PAH epidemic in General measures 1973 when WHO held its first meeting in Geneva to assess ►► Avoid . what is known and not known about PH and PAH.15 16 ►► and pneumococcal . After this, significant interest from the scientific community ►► Psychosocial support. rapidly ensued, with advances in the understanding of the http://jim.bmj.com/ ►► Supervised exercise training and avoid excessive phys- mechanisms involved in the pathophysiology and biology of ical activity that leads to distressing symptoms. PAH and IPAH and with clinical trials being conducted in ►► Inflight (O ) therapy for partial pressure of the 1980s and early 1990s. 2 oxygen (PO ) less than 60 mm Hg or class III–IV. In 1982, the first treatment for primary PH was published 2 ►► Avoid general anesthesia and use epidural instead, if in the form of heart-­ by Norm Shumway feasible. and colleagues.17 The first medical therapy was not realized until the Nobel Prize winning work on by Vane, on October 1, 2021 by guest. Protected copyright. Supportive therapy Bergstrom and Samuelson. Even after demonstrating the for RV failure and fluid overload. beneficial effects of intravenous prostacyclin in 1982, 13 Long-­term O if PO is consistently less than 60 mm Hg. years have passed before epoprostenol was finally approved 2 2 Consider oral for IPAH and heritable by the and Drug Administration (FDA) in 1995 for the PAH (no strong evidence to support low therapeutic range treatment of IPAH (formerly known as primary pulmonary warfarin therapy that targets international normalized ratio hypertension). (INR) 1.5–2.5).18 19 Bosentan, an endothelin ETA/ETB receptor antagonist, Correct anemia and/or iron deficiency. was the first oral therapy approved for the treatment of Use of ACE, angiotensin receptor blockers (ARBs), beta PAH. blockers (BB) and ivabradine is not recommended in PAH unless there is a compelling indication. All patients with a diagnosis of group 1 PAH according to Table 8 WHO functional classes WHO should be referred to a PH center to guide treatment WHO Functional and ongoing management. Class Description Intravenous epoprostenol received the strongest recom- Class I Can perform ordinary physical activity without symptoms. mendation for therapy in high-risk­ patients due to its Class II Ordinary activity causes symptoms of dyspnea, , or near syncope. Comfortable at rest. proven mortality benefit in patients with PAH even as a 20 Class III Marked limitation of activity. Less than ordinary activity causes symptoms. monotherapy. Comfortable at rest. Vasoreactivity testing is indicated in patients with IPAH, Class IV Cannot perform any activity without symptoms. Dyspnea and/or fatigue at rest. heritable pulmonary arterial hypertension (HPAH) and

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PAH due to toxins or drugs. Vasoactive patients should be 7. Combination therapy unavailable or contraindicated. J Investig Med: first published as 10.1136/jim-2020-001291 on 1 April 2020. Downloaded from treated with high doses of CCB (, or In non-vasoactive­ and high-risk­ patients, combina- ) and reassessed in 3–4 months. If no adequate tion therapy including intravenous prostacyclin analog, response, then patients can be treated like non-­vasoactive especially intravenous epoprostenol (decreases 3-­month patients. mortality in high-­risk patients), is recommended.20 Calcium channel blockers (CCBs). It has been increas- In case of inadequate clinical response to initial combina- ingly recognized that only a small number of patients with tion or monotherapy, sequential double or triple combination IPAH who demonstrate favorable response to acute vasodi- therapy is recommended (riociguat and lator testing at the time of RHC do well with CCBs.1 2 21 type 5 inhibitor (PDE-­5i) are contraindicated). The CCBs that have been predominantly used in reported In case of inadequate clinical response with sequential studies are nifedipine, diltiazem and amlodipine, with partic- double combination therapy, triple combination should be ular emphasis on nifedipine and diltiazem. The choice of attempted. CCB is based on the patient’s at baseline, with a Refer to lung transplant if there is inadequate response relative bradycardia favoring nifedipine and amlodipine and to combination therapy. Balloon (decom- a relative favoring diltiazem. The daily doses of presses the right heart chambers by creating interatrial right these drugs that have shown efficacy in IPAH are relatively to left shunt; this will improve LV and CO, and also

high: 120–240 mg for nifedipine, 240–720 mg for diltiazem improve systemic O2 transport despite arterial O2 desatura- and up 20 mg for amlodipine. Factors that limit dose increase tion) should be considered as palliative or bridging proce- are usually systemic and lower limb peripheral dure in patients who are deteriorating despite maximal edema. Patients with IPAH who meet the criteria for a posi- medical therapy. tive vasodilator response and are treated with CCBs should be The following dual combination therapies are recom- followed closely both for safety and efficacy, with a complete mended on the basis of evidence: reassessment after 3–4 months of therapy including RHC. If 1. Macitentan and sildenafil. the patient does not show an adequate response, defined as 2. Riociguat and bosentan. being in WHO-FC­ I or II and with a marked hemodynamic 3. and endothelin receptor antagonist or PDE-­ improvement (near normalization), additional PAH therapy 5i, or both. should be instituted. In some cases the combination of CCB with the approved PAH drugs is required due to further clin- Endothelin receptor antagonists (ERA). Activation of the ical deterioration in case of CCB withdrawal attempts. endothelin system has been demonstrated in both plasma Vasodilator responsiveness does not appear to predict a and lung tissue of patients with PAH. Endothelin-1 exerts favorable long-term­ response to CCB therapy in patients vasoconstrictor and mitogenic effects by binding to two with PAH in the setting of connective tissue disease (CTD), distinct receptor isoforms in the pulmonary vascular smooth HIV, portopulmonary hypertension and pulmonary veno-­ muscle cells, endothelin receptors types A and B. occlusive disease. . Ambrisentan is an ERA that preferentially Patients who have not undergone a vasoreactivity study binds with endothelin receptor type A. The incidence of http://jim.bmj.com/ or those with a negative study and at low or intermediate abnormal function tests ranges from 0.8% to 3%. risk should not be started on CCBs due to potential severe Monthly liver function assessment is not mandated in the side effects (eg, hypotension, syncope and RV failure), and USA. An increased incidence of has been can be treated with either disease-­specific monotherapy or reported with ambrisentan use. oral combination therapy. Bosentan. Bosentan is an oral active dual endothelin No data for any specific monotherapy over the other, so receptor type A and B antagonist and the first molecule of

choice is individualized. its class to be synthesized. Increases in hepatic aminotrans- on October 1, 2021 by guest. Protected copyright. Monotherapy from any class based on suitability has been ferases occurred in approximately 10% of patients and were 1 relegated a ‘residual role’ in the following patients : found to be dose-­dependent and reversible after dose reduc- 1. Vasoreactive patients with PH who maintain reactivity tion or discontinuation. For these reasons, liver function and functional class I/II with sustained hemodynamic testing should be performed monthly in patients receiving improvement after at least 1 year on CCBs only. bosentan. 2. Patients with a low-risk­ profile who have historically Macitentan. Dual ERA macitentan has shown benefits to been stable on monotherapy. both patients who had not received treatment previously 3. Patients with IPAH more than 75 years old with multi- and those receiving additional therapy for PAH. While no ple risk factors for left heart disease. liver toxicity was shown, reduction in blood hemoglobin 4. Patients with PAH with suspicion or high probability of ≤8 g/dL was observed in 4.3% of patients receiving 10 mg pulmonary veno-­occlusive disease or pulmonary capil- of macitentan. lary hemangiomatosis. 5. Patients with PAH associated with HIV, portopulmonary hypertension, or uncorrected congenital heart disease, PDE-5i and stimulators as they were not included in randomized controlled tri- Inhibition of the cyclic guanosine monophosphate (cGMP) als of upfront combination therapy. degrading the phosphodiesterase type 5 enzyme results in 6. Patients with very mild disease defined on the basis of through the nitic oxide (NO)/cGMP pathway WHO-­FC I, pulmonary vascular resistance of 3–4 Wood at sites expressing this enzyme. Since the pulmonary vascu- units (WU), mPAP of less than 30 mm Hg, and normal lature contains substantial amounts of phosphodiesterase right ventricle on echocardiography. type 5, the potential clinical benefit of PDE-5is­ has been

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investigated in PAH. In addition, PDE-­5is exert anti- combination of riociguat and PDE-5i­ is contraindicated J Investig Med: first published as 10.1136/jim-2020-001291 on 1 April 2020. Downloaded from proliferative effects. All three PDE-5is­ approved for the due to hypotension. treatment of —sildenafil, and vardenafil—cause significant pulmonary vasodilation, with Prostacyclin analogs and agonists maximum effects observed after 60, 75–90 and 40–45 min, Prostacyclin is produced predominantly by endothelial respectively. cells and induces potent vasodilation of all vascular beds. This compound is the most potent endogenous inhibitor Sildenafil of aggregation and also appears to have both cyto- Sildenafil is an orally active, potent and selective inhibitor protective and antiproliferative activities. Dysregulation of phosphodiesterase type 5. Most side effects of sildenafil of the prostacyclin metabolic pathways has been shown in are mild to moderate and mainly related to vasodilation patients with PAH as assessed by a reduction of prostacyclin (, , epistaxis). synthase expression in the pulmonary arteries and of pros- Based on pharmacokinetic data, an intravenous formula- tacyclin urinary metabolites. The clinical use of prostacyclin tion of sildenafil has been proposed as a bridge for patients in patients with PAH has been extended by the synthesis with PAH on long-term­ oral treatment who are temporarily of stable analogs that possess different pharmacokinetic unable to ingest tablets. properties but share qualitatively similar pharmacodynamic effects. Tadalafil Tadalafil is a once-­daily dispensed selective PDE-­5i. The Epoprostenol profile is similar to that of sildenafil. Epoprostenol (synthetic prostacyclin) has a short half-­life (3–5 min) and is stable at room temperature for only 8 hours; Vardenafil it requires cooling and continuous administration by means Vardenafil is a twice-daily­ dispensed PDE-­5i. The side effect of an infusion pump and a permanent tunneled catheter. profile is similar to that of sildenafil. Epoprostenol improves symptoms, exercise capacity and hemodynamics and is the only treatment shown to reduce Riociguat mortality. Treatment with epoprostenol is initiated at a dose While PDE-­5is such as sildenafil, tadalafil and varde- of 2–4 ng/kg/min, with doses increasing at a rate limited by nafil enhance the NO/cGMP pathway, slowing cGMP side effects (flushing, headache, diarrhea, leg pain). The degradation, soluble guanylate cyclase (sGC) stimula- optimal dose varies between individual patients, ranging in tors enhance cGMP production. Moreover, preclinical the majority between 20 and 40 ng/kg/min. Serious adverse studies show sGC stimulators have antiproliferative and events related to the delivery system include pump malfunc- antiremodeling properties in various animal models. The tion, local site infection, catheter obstruction and . most common serious adverse event was syncope. The Guidelines for the prevention of http://jim.bmj.com/ on October 1, 2021 by guest. Protected copyright.

Figure 2 RHC, right heart catheterization; CCB, calcium channel blockers; NYHA, New York Heart Association; ERA, endothelin receptor antagonists; PDE5, phosphodiesterase type 5 inhibitor.

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made, and the use is non-­commercial. See: http://​creativecommons.​org/​ bloodstream infections have been proposed. Abrupt inter- J Investig Med: first published as 10.1136/jim-2020-001291 on 1 April 2020. Downloaded from ruption of the epoprostenol infusion should be avoided licenses/by-​ ​nc/4.​ ​0/. because in some patients this may lead to a PH rebound ORCID iD with symptomatic deterioration and even . Theo Trandafirescu http://orcid.​ ​org/0000-​ ​0002-5953-​ ​9516

Iloprost References Iloprost is a chemically stable prostacyclin analog available 1 Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions for intravenous, oral or aerosol administration. The effects and updated clinical classification of pulmonary hypertension. Eur Respir J of oral iloprost have not been assessed in PAH. 2019;53:1801913. 2 Galiè N, Humbert M, Vachiery J-­L, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint Task force for the Treprostinil diagnosis and treatment of pulmonary hypertension of the European Society Treprostinil is a tricyclic benzidine analog of epopros- of cardiology (ESC) and the European respiratory Society (ERS): endorsed tenol, with sufficient chemical stability to be adminis- by: association for European paediatric and congenital cardiology (AEPC), tered at ambient temperature. These characteristics allow International Society for heart and lung transplantation (ISHLT). Eur Respir J 2015;46:903–75. administration of the compound by intravenous and 3 Kovacs G, Berghold A, Scheidl S, et al. Pulmonary arterial pressure during subcutaneous routes. The subcutaneous administration of rest and exercise in healthy subjects: a systematic review. Eur Respi J treprostinil can be accomplished by a microinfusion pump 2009;34:888–94. and a small subcutaneous catheter. Infusion site pain is 4 Bossone E, Paciocco G, Iarussi D, et al. The prognostic role of the ECG in primary pulmonary hypertension. Chest 2002;121:513–8. the most common of treprostinil, leading to 5 Olsson KM, Nickel NP, Tongers J, et al. Atrial flutter and fibrillation in patients discontinuation of treatment in 8% of cases on active drug with pulmonary hypertension. Int J Cardiol 2013;167:2300–5. and limiting dose increases in an additional proportion 6 Frost A, Badesch D, Gibbs JSR, et al. Diagnosis of pulmonary hypertension. Eur of patients. Treatment with subcutaneous treprostinil is Respir J 2019;53:1801904. 7 Jacobs W, Konings TC, Heymans MW, et al. Noninvasive identification of initiated at a dose of 1–2 ng/kg/ min, with doses increasing left-sided­ heart failure in a population suspected of pulmonary arterial at a rate limited by side effects (local site pain, flushing, hypertension. Eur Respir J 2015;46:422–30. headache). The optimal dose varies between individual 8 Fisher MR, Forfia PR, Chamera E, et al. Accuracy of patients, ranging in the majority between 20 and 80 ng/ in the hemodynamic assessment of pulmonary hypertension. Am J Respir Crit kg/min (figure 2). Care Med 2009;179:615–21. 9 Rich JD, Shah SJ, Swamy RS, et al. Inaccuracy of Doppler echocardiographic estimates of pulmonary artery pressures in patients with pulmonary hypertension: implications for clinical practice. Chest 2011;139:988–93. Conclusion 10 Lewis R, Cogliano M, Johns CS, et al. Cardiac MRI: identifying thresholds This overview emphasizes the complexity of PH and PAH to predict mortality in pulmonary arterial hypertension. B27. Heartbreaker: or group 1 PH. We encourage early referral to tertiary care heart failure and pulmonary hypertension. Am Thorac Soc 2019;99:A2809. 11 Benza RL, Miller DP, Foreman AJ, et al. Prognostic implications of serial PH centers to coordinate management between cardiolo- risk score assessments in patients with pulmonary arterial hypertension: a gists, pulmonologist and internists. Despite advances in Registry to evaluate early and long-­term pulmonary arterial hypertension therapies for PAH, individualization of care is essential disease management (reveal) analysis. J Heart Lung Transplant to choosing between various options. Sequential dual or 2015;34:356–61. http://jim.bmj.com/ tertiary therapy for patients with PAH who fail mono- 12 Benza RL, Miller DP, Barst RJ, et al. An evaluation of long-term­ survival from time of diagnosis in pulmonary arterial hypertension from the reveal registry. therapy is recommended by the ESC/ERS. We suggest that Chest 2012;142:448–56. upfront dual or even tertiary therapy in selected patients 13 Hoeper MM, Ghofrani H, Grunig E, et al. Pulmonary hypertension. Deutsches with moderate-­risk to high-­risk features might be helpful Ärzteblatt International 2017;114.5:73. in improving prognosis in these subsets of patients. Subse- 14 Raymond RJ, Hinderliter AL, Willis PW, et al. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol quent studies addressing this question will be needed. 2002;39:1214–9. on October 1, 2021 by guest. Protected copyright. 15 Barst RJ. Pulmonary hypertension: past, present and future. Ann Thorac Med Funding The authors have not declared a specific grant for this research from 2008;3:1–4. any funding agency in the public, commercial or not-­for-­profit sectors. 16 Humbert M. Pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: pathophysiology. Eur Respir Rev 2010;19:59–63. Competing interests None declared. 17 Norman Shumway. BMJ 2006;332:553. Patient consent for publication Not required. 18 Preston IR, Roberts KE, Miller DP, et al. Effect of warfarin treatment on survival Provenance and peer review Commissioned; externally peer reviewed. of patients with pulmonary arterial hypertension (PAH) in the registry to evaluate early and long-term­ PAH disease management (reveal). Circulation Author note Pulmonary arterial hypertension (PAH) carries a poor prognosis 2015;132:2403–11. if not promptly diagnosed and appropriately treated. The development and 19 Olsson KM, Delcroix M, Ghofrani HA, et al. Anticoagulation and survival in approval of 14 over the last several decades have led to a rapidly pulmonary arterial hypertension: results from the comparative, prospective evolving approach to therapy, and have necessitated periodic updating of registry of newly initiated therapies for pulmonary hypertension (COMPERA). Circulation 2014;129:57–65. evidence-­based treatment guidelines. 20 Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous Open access This is an open access article distributed in accordance with epoprostenol (prostacyclin) with conventional therapy for primary pulmonary the Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, hypertension. N Engl J Med 1996;334:296–301. which permits others to distribute, remix, adapt, build upon this work non-­ 21 Sitbon O, Humbert M, Jaïs X, et al. Long-­term response to calcium commercially, and license their derivative works on different terms, provided channel blockers in idiopathic pulmonary arterial hypertension. Circulation the original work is properly cited, an indication of whether changes were 2005;111:3105–11.

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