Journal of Marine Medical Society

REVIEW ARTICLE
Year
: 2019  |  Volume : 21  |  Issue : 1  |  Page : 9--14

Review of advances in management of pulmonary hypertension


Manjit Sharad Tendolkar1, Rahul Tyagi1, R Ananthakrishnan2, Ajay Handa1,  
1 Department of Pulmonary Medicine, INHS Asvini, Mumbai, Maharashtra, India
2 Department of Cardiology, INHS Asvini, Mumbai, Maharashtra, India

Correspondence Address:
Surg Lt Cdr Manjit Sharad Tendolkar
Department of Pulmonary Medicine, INHS Asvini, Mumbai, Maharashtra
India

Abstract

Pulmonary hypertension (PH) is characterized by an increased pulmonary artery pressure with subsequent increase in morbidity and mortality. Epidemiologically, one of the common causes of PH among serving soldier is chronic thromboembolic PH. There have been recent reports of PH among divers. There has been a lot of advancement in the management of PH in recent times. We review the management of this condition with special emphasis on recent advances.



How to cite this article:
Tendolkar MS, Tyagi R, Ananthakrishnan R, Handa A. Review of advances in management of pulmonary hypertension.J Mar Med Soc 2019;21:9-14


How to cite this URL:
Tendolkar MS, Tyagi R, Ananthakrishnan R, Handa A. Review of advances in management of pulmonary hypertension. J Mar Med Soc [serial online] 2019 [cited 2019 Jul 23 ];21:9-14
Available from: http://www.marinemedicalsociety.in/text.asp?2019/21/1/9/260671


Full Text



 Introduction



Pulmonary hypertension (PH) is defined as mean pulmonary arterial pressure (mPAP) >25 mmHg as assessed by a right-heart catheterization.[1] There are emerging studies of PH among divers due to venous gas embolism after recreational scuba diving.[2] Chronic exposure to high altitude is a known cause of PH. With a substantial number of serving personnel of the Indian army exposed to high altitudes, there is a documented risk of development of PH. The study of high-altitude PH in the Indian population has been done among residents of Spiti Valley and has been found to be 3.23%.[3]

Epidemiologically, one of the common causes of PH among serving soldier is chronic thromboembolic PH (CTEPH). This is a review of recent advances in PH diagnosis and management.

 Classification of Pulmonary Hypertension



The first classification of PH was given by the WHO in 1973 during the First World Symposium on Pulmonary Hypertension (WSPH) at Geneva where it was classified into two categories as primary PH and secondary PH according to the identification of causes or risk factors.[4] A landmark classification of PH was given in 1998 during the Second WSPH held in Evian, France, where PH was broadly classified into five subgroups according to the cause. Subsequent WSPH was held every 5 yearly at Venice, Dana Point, and Nice (2013 and 2018). The present classification was given in WSPH held at Nice in 2013[5] [Table 1] and [Table 2]. No fresh changes have been published till September 2018 after the WSPH held at Nice in February 2018.{Table 1}{Table 2}

 Recent Advances in Diagnosis of Pulmonary Hypertension



A diagnostic algorithm is given by the European Society of Cardiology/European Respiratory Society for the evaluation of PH [Figure 1]. The current guidelines emphasize on right-heart catheterization for the definite diagnosis of PH, as well as follow-up, especially when treatment modification is being planned.[1] Other investigations that have been contemporarily used in aiding the diagnosis of PH include chest radiography, echocardiography, and computed tomography (CT). This armamentarium is further enhanced by emerging modalities such as dual-energy CT, photon emission CT,[6] magnetic resonance (MR) imaging, three-dimensional MR perfusion mapping,[7] optical coherence tomography, and positron emission tomography.[8] Contrast-enhanced and unenhanced MR angiography can be particularly helpful in identifying chronic pulmonary thromboembolism in pregnancy women, young patients, and those with contraindication for iodine-based contrast injection.[9] Biomarkers have been studied for their role in PH; however, given their low specificity, none of them can be reliably used for the diagnosis of PH [Table 3].[6],[7] It is worth noting that low levels of serum caveolin-1 (cutoff: 17.17 pg/ml) have shown good specificity for the diagnosis of idiopathic pulmonary arterial hypertension (IPAH, sensitivity: 0.59; specificity: 1.0).[10] Serum chloride levels have been shown to be a strong and independent predictor of mortality in patients with IPAH and heritable pulmonary arterial hypertension (PAH).[11]{Figure 1}{Table 3}

 Recent Advances in Treatment of Pulmonary Arterial Hypertension



The treatment process of PAH patients cannot be limited to mere prescription of drugs but is characterized by a complex strategy that includes the initial evaluation of severity and the subsequent response to treatment.[1] The overall goal of treatment is to achieve a low-risk status whereby a patient is maintained in the WHO-FC II which is usually accompanied by near-normal 6-min walk distance (6MWD). Threshold of >440 m has been recommended by the Fifth WSPH.[12]

The treatment of PAH involves a three-pronged approach:

(1) general measures (2) specific drug therapy (3) reviewing the response to therapy.

 Advances in General Measures



General measures in the management of PH include avoiding pregnancy, immunization against influenza and pneumococcus, psychosocial support, supervised exercise, and preference to epidural anesthesia over general anesthesia. Recent data suggest that there is a significant improvement in outcomes of pregnancies associated with PAH which causes other idiopathic PAH, where the mortality continues to be high.[13]

 Advances in Drug Therapy for Pulmonary Arterial Hypertension



Ever since the first description of PH by Ernst Von Romberg in 1891, it took 104 years for the first drug to be approved by the Food and Drug Administration (FDA) for use in PAH. It is worth noting that calcium channel blockers which have been used for PAH in 1980 have not been approved by the FDA. The timeline of drugs introduced for use in PAH is shown in [Figure 2].{Figure 2}

The four classes of drugs including calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, and prostacyclin analogs have been widely used for the management of PAH. The recently approved drugs include macitentan, riociguat, oral treprostinil, and selexipag.

Macitentan

Newest endothelin receptor antagonist shows increased tissue penetration and greater affinity for and longer duration of blockade of endothelin receptors compared with bosentan. Macitentan was studied in SERAPHIN trial. SERAPHIN was the first event-driven PAH study, using a composite primary endpoint that included worsening of PAH, initiation of prostacyclin analog infusion, lung transplantation, and death. It has been studied that macitentan when used alone or in combination with other targeted therapies significantly reduced morbidity and mortality in patients with WHO-FC II–IV and also demonstrated the ability to improve functional status, delay disease progression, and decrease hospitalizations.[14] Optimal dosing of macitentan is 10 mg orally once daily. Most common adverse effects are anemia, nasopharyngitis, bronchitis, headache, influenza, and urinary tract infection. Unlike bosentan, macitentan has significantly less hepatotoxicity and does not require mandatory monitoring of liver function.[15]

Riociguat

It directly stimulates guanylate cyclase independently of nitric oxide. The PATENT-1 trial showed that riociguat significantly improves 6MWD, the primary endpoint, and also improvs secondary endpoints, including pulmonary vascular resistance, NT-proBNP levels, WHO-FC, and time to clinical worsening. PATENT-2, an extension trial of PATENT-1, showed additional increases in 6MWD at 1 year and 2 years of treatment, with >90% of patients achieving stable or improved functional capacity (FC).[13] Riociguat is used in a maximum dose of 2.5 mg orally three times daily. Hypotension is a serious adverse effect, and the use in combination with phosphodiesterase type 5 inhibitors is contraindicated. Other common adverse effects include headache, dizziness, dyspepsia, peripheral edema, nausea, vomiting, and diarrhea.[16]

Oral treprostinil

Treprostinil has been used for PAH since 2002 in subcutaneous and intravenous forms. Oral formulation of treprostinil was approved for use in PAH in December 2013. The FREEDOM-C1 and FREEDOM-M trials, treprostinil, used in treatment-naive patients as monotherapy (up to 12 mg twice daily) significantly improved 6MWD; however, no significant improvement in clinical worsening or symptoms was demonstrated. Adverse effects of treprostinil are headache, nausea, diarrhea, flushing, jaw pain, hypokalemia, and abdominal pain.[17]

Selexipag

Selexipag is a novel agent approved by the FDA in December 2015. It delays disease progression and reduces the risk of hospitalization for PAH. It selectively activates the prostaglandin I2 receptor resulting in significant vasodilation. In the Phase 3 GRIPHON study, selexipag at a dose of up to 1.6 mg twice daily reduced the risk of death (primary composite endpoint) or PAH-related complication. The effect was consistent across age, sex, PAH etiology, baseline FC, and background treatment with other PAH medications. Adverse effects include headache, diarrhea, nausea, jaw pain, myalgia, pain in extremities, flushing, and arthralgia.[18]

Combination therapy

AMBITION trial established a strong case for upfront combination therapy using ambrisentan and tadalafil compared with pooled monotherapy in WHO-FC II or III PAH patients. Combination therapy was associated with a significantly lower risk of death, hospitalization, disease progression, or unsatisfactory long-term clinical response. 6MWD, percentage of patients with a satisfactory clinical response, and NT-proBNP levels improved to a greater extent in patients who received combination therapy. Adverse events, including peripheral edema, headache, nasal congestion, and anemia, occurred more frequently in the combination therapy group than in monotherapy groups, but rates of drug discontinuation were low and serious adverse effects were similar across study groups.[19]

 Percutaneous Interventional Techniques



Atrial septostomy

It is deemed to be useful in patients having right ventricular (RV) failure with PH for whom medical therapy has failed. The physiological basis for improvements after atrial septostomy (AS) includes an improved cardiac output, RV decompression, and reduced sympathetic over-reactivity. Techniques include balloon AS, balloon-dilated AS, and fenestrated devices. Procedural complications include balloon rupture and embolization of balloon fragments, cardiac perforation or damage including rupture of the atrial appendage, failure to deflate the balloon, stroke, and vascular complications.[20] AS has shown to improve survival in patients with severe PH.[21]

Potts shunt

The right ventricle is decompressed by forming a direct anastomosis between the descending aorta (dAo) and the left pulmonary artery (LPA). This technique is very risky, as any misjudgment in the length of the stent to span the distance between the LPA and dAo can result in hemorrhage.[22] It can be theorized that the main advantage of a Potts shunt over an AS is the permanent post cardiac right-to-left shunt that does not lead to arterial oxygen desaturation in the upper part of the body, including the brain and the coronary circulation unlike AS.[23]

Pulmonary artery denervation

It works by reducing sympathetic stimulation of the pulmonary vasculature.[24] A pilot study in humans involving 21 patients with IPAH has reported significant improvements in mPAP after pulmonary artery denervation (PADN).[25] A clinical trial to study the effectiveness of PADN (ClinicalTrials.gov Identifier: NCT03282266) is underway and is expected to complete by 2021.

Futuristic management of pulmonary arterial hypertension

Drug therapy involving tacrolimus and ralinepag which act by promoting bone morphogenetic protein signaling and prostacyclin analog mechanism, respectively, is in Phase 2 of clinical trials. Sotatercept, which acts as a ligand trap for transforming growth factor-beta superfamily, is in Phase 2 of PULSAR trial which is expected to be completed in November 2021. Rituximab, a CD20 antibody, and ifetroban, a selective thromboxane receptor antagonist, being evaluated for effectiveness in systemic sclerosis-associated PAH, are presently in Phase 2 of clinical trials.

There is a growing interest in the use of stem cells in the management of PAH with initial reports of improvement in pulmonary hemodynamics. At present, studies are in Phase 2 of clinical trials and have a potential of unleashing a new era in the management of PH [Table 4]. There are clinical trials ongoing studying the use of inhalational SERCA2a gene therapy.{Table 4}

 Recent Advances in Management of Pulmonary Hypertension Due to Left Heart Disease



PADN has been shown to significantly increase exercise capacity in combined pre- and postcapillary PH associated with left heart failure, as studied in PADN-5 trial.[26]

 Recent Advances in Management of Pulmonary Hypertension Due to Lung Diseases



No drugs have been approved for the type of PH due to lung diseases. The problem with using vasodilators in Group 3 PH lies in the possibility of worsening the ventilation-perfusion mismatch leading to more hypoxemia as the blood flow gets directed to poorly ventilated areas of the lungs. Inhaled medications in theory can be used to circumvent this conundrum. Inhaled treprostinil has been studied to be well tolerated and has shown to improve exercise tolerance in Group 3 PH.[27]

 Recent Advances in Management of Pulmonary Hypertension Due to Chronic Thromboembolic Pulmonary Hypertension



In patients who are deemed operable, pulmonary endarterectomy (PEA) remains the gold standard for CTEPH. For patients who are not eligible for PEA, medical management with riociguat or balloon pulmonary angioplasty (BPA) can be considered apart from lifelong anticoagulation. Long-term medical therapy with riociguat was studied in CHEST-2 trial, which has shown improved 6MWD and improved survival.[28]

Pulmonary angioplasty for chronic thromboembolic pulmonary hypertension

Balloon pulmonary angioplasty (BPA) has been used in adults with CTEPH in whom distal disease is inaccessible and too high risk. It improved the pulmonary blood flow distribution and increased pulmonary vascular capacitance, decreasing RV afterload. Reperfusion pulmonary injury is a fatal complication that is known to occur with a reported incidence as high as 68% after BPA.[29]

RACE trial comparing riociguat to BPA in nonoperable cases of CTEPH is underway (ClinicalTrials.gov ID: NCT02634203).

 Conclusion



There are no specific studies documenting the incidence of high-altitude PH among serving personnel in India. PH remains a disease with significant morbidity, and our understanding of its pathogenesis and management continues to progress. With the future moving toward personalized medicine, the growing pharmaceutical market for PH, a significant progress in management, is expected over the coming decades.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: The joint 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: Association for European Paediatric and Congenital Cardiology (AEPC), international society for heart and lung transplantation (ISHLT). Eur Heart J 2016;37:67-119.
2Marabotti C, Scalzini A, Chiesa F. Increase of pulmonary arterial pressure in subjects with venous gas emboli after uncomplicated recreational SCUBA diving. Respir Med 2013;107:596-600.
3Negi PC, Marwaha R, Asotra S, Kandoria A, Ganju N, Sharma R, et al. Prevalence of high altitude pulmonary hypertension among the natives of Spiti Valley – A high altitude region in Himachal Pradesh, India. High Alt Med Biol 2014;15:504-10.
4Hatano S, Strasser T. Primary Pulmonary Hypertension: Report on a WHO Meeting 15-17 October, 1973. Geneva: World Health Organization; 1975.
5Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013;62:D34-41.
6Meng JJ, Zhang LJ, Wang Q, Fang W, Dai HJ, Yan J, et al. Acomparison of ventilation/perfusion single photon emission CT and CT pulmonary angiography for diagnosis of pulmonary embolism. Zhonghua Jie He He Hu Xi Za Zhi 2013;36:177-81.
7Rajaram S, Swift AJ, Telfer A, Hurdman J, Marshall H, Lorenz E, et al. 3D contrast-enhanced lung perfusion MRI is an effective screening tool for chronic thromboembolic pulmonary hypertension: Results from the ASPIRE registry. Thorax 2013;68:677-8.
8Johns CS, Wild JM, Rajaram S, Swift AJ, Kiely DG. Current and emerging imaging techniques in the diagnosis and assessment of pulmonary hypertension. Expert Rev Respir Med 2018;12:145-60.
9Swift AJ, Rajaram S, Condliffe R, Capener D, Hurdman J, Elliot CA, et al. Diagnostic accuracy of cardiovascular magnetic resonance imaging of right ventricular morphology and function in the assessment of suspected pulmonary hypertension results from the ASPIRE registry. J Cardiovasc Magn Reson 2012;14:40.
10Wang KY, Lee MF, Ho HC, Liang KW, Liu CC, Tsai WJ, et al. Serum caveolin-1 as a novel biomarker in idiopathic pulmonary artery hypertension. Biomed Res Int 2015;2015:173970.
11Naal T, Abuhalimeh B, Khirfan G, Dweik RA, Tang WH, Tonelli AR, et al. Serum chloride levels track with survival in patients with pulmonary arterial hypertension. Chest 2018;154:541-9.
12McLaughlin VV, Gaine SP, Howard LS, Leuchte HH, Mathier MA, Mehta S, et al. Treatment goals of pulmonary hypertension. J Am Coll Cardiol 2013;62:D73-81.
13Sliwa K, van Hagen IM, Budts W, Swan L, Sinagra G, Caruana M, et al. Pulmonary hypertension and pregnancy outcomes: Data from the registry of pregnancy and cardiac disease (ROPAC) of the European Society of Cardiology. Eur J Heart Fail 2016;18:1119-28.
14Bazan IS, Fares WH. Pulmonary hypertension: Diagnostic and therapeutic challenges. Ther Clin Risk Manag 2015;11:1221-33.
15Pulido T, Adzerikho I, Channick RN, Delcroix M, Galiè N, Ghofrani HA, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013;369:809-18.
16Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013;369:330-40.
17Tapson VF, Jing ZC, Xu KF, Pan L, Feldman J, Kiely DG, et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy (The FREEDOM-C2 study). Chest 2013;144:952-8.
18Sitbon O, Channick R, Chin KM, Frey A, Gaine S, Galiè N, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med 2015;373:2522-33.
19Galiè N, Barberà JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin VV, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med 2015;373:834-44.
20Bhamra-Ariza P, Keogh AM, Muller DW. Percutaneous interventional therapies for the treatment of patients with severe pulmonary hypertension. J Am Coll Cardiol 2014;63:611-8.
21Sandoval J, Gaspar J, Peña H, Santos LE, Córdova J, del Valle K, et al. Effect of atrial septostomy on the survival of patients with severe pulmonary arterial hypertension. Eur Respir J 2011;38:1343-8.
22Baruteau AE, Serraf A, Lévy M, Petit J, Bonnet D, Jais X, et al. Potts shunt in children with idiopathic pulmonary arterial hypertension: Long-term results. Ann Thorac Surg 2012;94:817-24.
23Sandoval J, Pulido T, Sandoval JP, Zayas N, Gaspar J. Balloon dilation atrial septostomy and Potts anastomosis for severe pulmonary arterial hypertension: Why, when, and how. Adv Pulm Hypertens 2016;15:19-25.
24Sandoval J. Interventional therapies in pulmonary hypertension. Rev Esp Cardiol (Engl Ed) 2018;71:565-74.
25Chen SL, Zhang FF, Xu J, Xie DJ, Zhou L, Nguyen T, et al. Pulmonary artery denervation to treat pulmonary arterial hypertension: The single-center, prospective, first-in-man PADN-1 study (first-in-man pulmonary artery denervation for treatment of pulmonary artery hypertension). J Am Coll Cardiol 2013;62:1092-100.
26Zhang H, Zhang J, Chen M, Xie DJ, Kan J, Yu W, et al. Pulmonary artery denervation significantly increases 6-min walk distance for patients with combined pre- and post-capillary pulmonary hypertension associated with left heart failure: The PADN-5 study. JACC Cardiovasc Interv 2019;12:274-84.
27Agarwal M, Waxman AB. Inhaled treprostinil in group-3 pulmonary hypertension. J Heart Lung Transplant 2015;34:S343.
28Simonneau G, D'Armini AM, Ghofrani HA, Grimminger F, Jansa P, Kim NH, et al. Predictors of long-term outcomes in patients treated with riociguat for chronic thromboembolic pulmonary hypertension: Data from the CHEST-2 open-label, randomised, long-term extension trial. Lancet Respir Med 2016;4:372-80.
29Sugimura K, Fukumoto Y, Satoh K, Nochioka K, Miura Y, Aoki T, et al. Percutaneous transluminal pulmonary angioplasty markedly improves pulmonary hemodynamics and long-term prognosis in patients with chronic thromboembolic pulmonary hypertension. Circ J 2012;76:485-8.