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PULMONARY HYPERTENSION NEWER INSIGHTS

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					      Pulmonary HyPertension: newer insigHts




4:4   S Bhandari, PS Sandhu, New Delhi
      INTRODUCTION
      Most practicing cardiologists see patients with pulmonary hypertension (PH) on a regular basis. The
      explosion in knowledge of and treatment for PH over the past decade obligates cardiologists to be
      more cognizant of this disorder.
      PH has been defined as a resting mean pulmonary arterial pressure (mPAP) >25 mm Hg, or >30 mm
      Hg with exercise. The subgroup of PH known as pulmonary arterial hypertension (PAH) adds the
      criterion that the pulmonary arterial wedge pressure must be ≤15 mm Hg.1
      CLASSIFICATION
      The clinical classification of PH has gone through a series of changes since the first version was
      proposed in 1973 at the first international conference on primary pulmonary hypertension endorsed by
      the WHO (Table 1).2 The initial classification designated only 2 categories, PPH or secondary PH. 25
      years later, the 2nd World Symposium on PAH was held in Evian, France. The “Evian classification”
      attempted to create categories of PH that shared pathologic and clinical features as well as similar
      therapeutic options 3
      The 3rd World Symposium on PAH was held in Venice, Italy, 5 years after the Evian conference. At
      this conference modest changes were made. The most notable change was to abandon the term PPH in
      favor of idiopathic pulmonary arterial hypertension (IPAH); familial PAH if there is a family history
      of PAH; or associated PAH if another cause, such as CTD or HIV, is present. The term “secondary
      PH” was abandoned since it did not help with diagnosis or in directing treatment.4
      During the 4th World Symposium on PH held in 2008 in Dana Point, California, the general philosophy
      and organization of the Evian-Venice classifications was maintained, but modified it to clarify some
      areas that were unclear.
      PAThOPhySIOLOgy OF Ph
      Different pathological5,6,8–10 features characterize the diverse clinical PH groups.
      •   Group 1, PAH: The increase in PVR is related to different mechanisms, including vasoconstric-
          tion, proliferative and obstructive remodeling of the pulmonary vessel wall, inflammation, and
          thrombosis.
      •   Group 1′: includes mainly PVOD which involves septal veins and pre-septal venules with oc-
          clusive fibrotic lesions, venous muscularization, capillary proliferation (patchy), pulmonary
          oedema, occult alveolar haemorrhage, lymphatic dilatation and lymph node enlargement (vas-
          cular transformation of the sinus), and inflammatory infiltrates.
      •   Group 2, PH due to left heart disease.
      •   Group 3, PH due to lung diseases and/or hypoxia. The pathophysiological mechanisms involved
          in this setting are hypoxic vasoconstriction, mechanical stress of hyperinflated lungs, loss of
          capillaries, and inflammation.

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    Table 1 Updated clinical classification of Ph (Dana Point,                 •    Group 5, PH with unclear and/or multifactorial mecha-
                              2008)                                                 nisms.
1 Pulmonary arterial hypertension (PAH)
                                                                               NATURAL hISTORy AND PROgNOSTIC FACTORS
    1.1 Idiopathic
                                                                               The natural history of IPAH was well described by the NIH
    1.2 Heritable
                                                                               registry in 1985 before the availability of any disease-specific
        1.2.1 BMPR2
                                                                               therapy.11 The median survival was 2.8 years, with 1, 3, and
        1.2.2 ALK1, endoglin (with or without hereditary haemorrhagic          5-year survival rates of 68%, 48%, and 34%, respectively.12
              telangiectasia)
                                                                               Associated conditions influence outcomes: Patients with CTD
        1.2.3 Unknown
                                                                               and HIV-associated PAH tend to have a worse prognosis,
    1.3 Drugs and toxins induced                                               whereas those with congenital heart disease–associated PAH
    1.4 Associated with (APAH)                                                 tend to have a better prognosis.
        1.4.1 Connective tissue diseases(CTD)
                                                                               Important prognostic indicators in PAH include symptoms,
        1.4.2 HIV infection                                                    exercise endurance, and hemodynamics.13Most of these
        1.4.3 Portal hypertension                                              prognostic variables are related to RV function. In the NIH
        1.4.4 Congenital heart disease                                         registry, the median survival among patients presenting with
        1.4.5 Schistosomiasis                                                  class I and II symptoms was ~ 6 years versus 2.5 years for patients
        1.4.6 Chronic haemolytic anaemia                                       with class III symptoms and just 6 months for patients who
    1.5 Persistent pulmonary hypertension of the newborn
                                                                               presented with class IV symptoms.12 Two large retrospective
                                                                               series have confirmed the importance of functional class
        1′ Pulmonary veno-occlusive disease and/or pulmonary capillary
        haemangiomatosis                                                       as a prognostic variable, even during treatment.14,15 Among
                                                                               IPAH patients treated with epoprostenol, prognosis was worse
2 Pulmonary hypertension due to left heart disease
                                                                               for patients who commenced therapy with more advanced
    2.1 Systolic dysfunction
                                                                               symptoms. Moreover, in both series, patients who improved
    2.2 Diastolic dysfunction                                                  to class I or II status after 3 to 17 months of epoprostenol
    2.3 Valvular disease                                                       therapy had a better prognosis than patients who remained
3 Pulmonary hypertension due to lung diseases and/or hypoxia                   in class III or IV.
    3.1 Chronic obstructive pulmonary disease                                  Exercise tolerance in PAH is commonly assessed by means
    3.2 Interstitial lung disease                                              of the 6-minute-walk distance (6MWD). In one of the first
    3.3 Other pulmonary diseases with mixed restrictive and obstructive        controlled trials, a 6MWD of <150 m was associated with a
        pattern                                                                very poor prognosis. 16 In a series of 178 IPAH patients treated
    3.4 Sleep-disordered breathing                                             with epoprostenol, those who walked further than the median
    3.5 Alveolar hypoventilation disorders                                     value of 380 m after 3 months of therapy had a better prognosis
    3.6 Chronic exposure to high altitude                                      than those who did not.16
    3.7 Developmental abnormalities                                            PROgReSS OF meDICAL TReATmeNT IN PUL-
4 Chronic thromboembolic pulmonary hypertension                                mONARy ARTeRIAL hyPeRTeNSION
5 PH with unclear and/or multifactorial mechanisms                             In 1891, Ernst von Romberg, a German physician, described
    5.1 Haematological disorders: myeloproliferative disorders, splenec-       an autopsy subject as having “pulmonary vascular sclerosis”;
        tomy.
                                                                               however, it is only since 1995 with the introduction of
    5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell his-        epoprostenol that disease-specific targeted medical therapies
        tiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vascu-
        litis
                                                                               for PAH have become available. Furthermore, significant
                                                                               advances in the treatment of PAH have occurred during the
    5.3 Metabolic disorders: glycogen storage disease, Gaucher disease,
        thyroid disorders                                                      past 15 years. Currently 9 medical therapies have received
                                                                               regulatory approval. These agents target the prostacyclin
    5.4 Others: tumoural obstruction, fibrosing mediastinitis, chronic re-
        nal failure on dialysis                                                pathway, the nitric oxide pathway, and the endothelin pathway.
                                                                               Combination trials have demonstrated additive or synergistic
ALK-1 = activin receptor-like kinase 1; BMPR2 = bone morphogenetic pro-
tein receptor 2, HIV = human immunodeficiency virus.                           benefit by targeting 2 or all 3 of these pathways (Figs. 1 and 2).
                                                                               CONveNTIONAL TReATmeNTS
•     Group 4, CTEPH: non-resolution of acute embolic
      masses which later undergo fibrosis leading to mechani-                  Diuretics role has been limited to patients manifesting RV
      cal obstruction of pulmonary arteries.                                   failure. However, patients with advanced PAH can have
                                                                               increased left ventricular filling pressures that contribute

                                                                             182
                                                                                   Pulmonary Hypertension: Newer Insights

                                 Terbogrel                                  STEP
                                                                                                                 its vasodilator and antithrombotic effects. Patients may have
                               Treprostinil                               Sildenafil
                                   AIR              Sildenafil            STRIDE2      ARIES
                                                                                                                 a reduction in PVR of ≥50%, even if no acute hemodynamic
          Epoprostenol           BREATHE1           BREATHE2
                                                                 SUPER
                                                                           COMBI       EARLY
                                                                                               PHIRST
                                                                                                                 effects are noted. Epoprostenol is administered through
   Epoprostenol                                                  SERAPH                               TRIUMPH

Epoprostenol          Bosentan
                                 ALPHABET
                                         Beraprost
                                                     STRIDE1              BREATHE5 PACES
                                                                                                                 a central venous catheter that is surgically implanted and
                                                                                                                 delivered by an ambulatory infusion system.
1990   1996    2000      ‘01       ’02        ‘03      ’04        ‘05       ’06        ‘08      ’09      ‘10
                                                                                                                 Most complications are due to the delivery system and include
Monotherapy                                                                                                      catheter-related infections and temporary interruption of the
Monotherapy and/or sequential combination                                                                        infusion because of pump malfunction, which causes rebound
Upfront combination
                                                                                                                 pulmonary hypertension. Side effects related to epoprostenol
Colour code identifies the design of the study: monotherapy (black): in-                                         are flushing, headache, nausea, diarrhea, and a jaw discomfort
vestigational drug vs. placebo in patients naive for PAH approved drugs.
                                                                                                                 that occurs with eating. In most patients, these symptoms are
Monotherapy and/or sequential combination (red): investigational drug vs.
placebo in patients either naive for, or treated with PAH approved drugs.                                        minimal and well tolerated.
Upfront combination (light blue): single drug vs. combination of two drugs
in patients naive for pulmonary arterial hypertension approved drugs.
                                                                                                                 The experience with epoprostenol in patients with IPAH
                                                                                                                 for more than 10 years has been reported by two large
  Fig. 1: Time-course of 25 published RCT in pulmonary arterial                                                  centers.14,15 Survival rates markedly improved; predictors of
                           hypertension
                                                                                                                 survival included NYHA class, exercise tolerance, and acute
                                                                                                                 vasodilator responsiveness. Both studies provided important
to the symptoms of dyspnea and orthopnea, which can be
                                                                                                                 data for identifying patients who would do well over the
relieved with diuretics.
                                                                                                                 long term, versus those in whom transplantation should be
Because hypoxemia is a potent pulmonary vasoconstrictor,                                                         considered.
oxygen supplementation is given to maintain SPO2 > 90%.
                                                                                                                 Treprostinil is a stable prostacyclin analogue that has
Anticoagulants The evidence for favorable effects of oral                                                        pharmacological actions similar to those of epoprostenol,
anticoagulant treatment is based on retrospective analyses from                                                  but differs in that it is chemically stable at room temperature
7 studies, of which 5 were positive and 2 were negative.18,20,22                                                 and neutral pH and has a longer half-life. It is administered
The survival of anticoagulated patients selected on the basis                                                    through continuous S/C infusion. In a large RCT in patients
of clinical judgment was improved from 21% to 49%. Most                                                          with PH, it was effective in increasing 6MWD, decreasing
experts recommend warfarin anticoagulation targeted to an                                                        dyspnea, and hemodynamics.25
INR of 2.0 to 3.0.
                                                                                                                 Iloprost, an inhalational analogue of prostacyclin. In RCT,
Short-term IV digoxin in IPAH produces a modest increase                                                         inhaled iloprost was shown to have an acute effect on
in cardiac output and a significant reduction in circulating                                                     hemodynamics similar to those of inhaled nitric oxide and
norepinephrine21; no data is available on the effects of long-                                                   when given chronically, causes improvement in 6MWD, and
term treatment. Therefore, the use is based primarily on the                                                     in hemodynamics.26 Because of the short half-life of iloprost,
judgment of the physician.                                                                                       however, it requires frequent (up to 12/day) inhalations.
CCBs Favorable clinical and prognostic effects of high doses                                                     Beraprost is an orally active prostacyclin analogue that has
of oral CCB drugs in acutely vasoreactive patients with                                                          been evaluated in RCT trials in patients with PAH. In one
IPAH have been shown in single-center, nonrandomized,                                                            large European trial (ALPHABET study), beraprost improved
uncontrolled studies.17, 22                                                                                      exercise capacity and symptoms over a 12-week period but
Acute vasodilator testing is recommended for all PAH                                                             had no significant effect on hemodynamics or functional
patients, even though patients with IPAH and anorexigen                                                          class. A similar trial conducted in the United States, however,
induced PAH are more likely to respond. Empirical treatment                                                      showed similar efficacy at 12 weeks, only to document the
with CCBs without a positive response with acute vasodilator                                                     loss of effectiveness over 1 year.27 At present, beraprost is only
testing using either inhaled nitric oxide or IV epoprostenol is                                                  approved for use in Japan.
contraindicated.23                                                                                               eNDOTheLIN ReCePTOR BLOCkeRS (eRA)
SyNTheTIC PROSTACyCLIN AND PROSTACyC-                                                                            ET-1 exerts vasoconstrictor and mitogenic effects and is
LIN ANALOgUeS                                                                                                    activated in PAH. Three endothelin receptor blockers have
Prostacyclins have been found to be effective in the therapy                                                     been approved for PAH. Although there have never been direct
of PAH.15 Continuous IV infusion of epoprostenol has been                                                        comparative trials, all three appear to have similar efficacy.28
shown in RCT to improve quality of life and symptoms related                                                     Bosentan is a non-selective ET receptor blocker. 9 RCTs
to PH. The long-term effects of epoprostenol in PH include                                                       using 1 of 3 ERAs as monotherapy have been performed


                                                                                                               183
                                                  Medicine Update 2012  Vol. 22


                                                                               Vasodilator and
                 Vasodilator Therapies                                       Antiplatelet Therapies

             Oxygen                                                      Prostacyclin analogues
             Calcium-channel blockers                                    Nitric oxide donors
             Endothelin-receptor antagonists                             L-arginine
             Brain natriuretic peptide                                   Phosphodiesterase inhibitors              Anticoagulant
             Calcitonin gene-related peptide                             Prostacyclin synthase                      Therapies

                                                                                                                   Warfarin


      Antiinflammatory Therapies

    Prostacyclin analogues                                   Smooth
    Nitric oxide donors                                     muscle cells         Platelets                                      Fibrin
    Endothelin-receptors antagonists
    Statins
    5-lipoxygenase inhibitors
    Monocyte-macrophage
        chemoattractant protein-1




                                                                                                      Inhalation Therapies

                                        Endothelium                                               Oxygen
                                                                                                  Prostacyclin analogues
                                                                                                  Nitric oxide donors
                                                                                                  Ethyl nitrite




      Leukocytes
                                                                  Remodeling Therapies

                                                             Nitric oxide donors
                                                             Endothelin-receptor antagonists




                                       Fig. 2 : Therapeutic Approaches to Pulmonary Hypertension 24

in PAH patients, bosentan was evaluated in 4 RCTs in PAH               receptor blocker that can be given once daily at a 100 mg
patients,29-31 including 1 RCT performed in a cohort of patients       dose. It has been assessed in PAH patients in 2 RCTs, both of
with the Eisenmenger syndrome31 and 1 RCT performed in                 which demonstrated improvement in exercise capacity and
a cohort of patients with only mildly symptomatic PAH.32               hemodynamic status.33,34
Overall, bosentan improved exercise capacity, functional
                                                                       Ambrisentan is an orally active ETA-selective endothelin
class, hemodynamic status, echocardiographic and Doppler
                                                                       receptor blocker that can be given once daily at a 5-mg dose,
variables, and time to clinical worsening. The approved
                                                                       which can be increased to 10 mg if the drug is well tolerated. It
dosage of bosentan is 125 mg twice daily.
                                                                       has been evaluated in RCTs.35 Results showed improvements
Sitaxsentan is an orally active ETA-selective endothelin

                                                                 184
                                                 Pulmonary Hypertension: Newer Insights

                             ALgORIThm FOR The meDICAL TReATmeNT OF PAh.42

 Oral anticoagulants (E/B)-IPAH/HPAH             Supportive therapy and general measures                     Avoid excessive physical exertion (E/A)
 Diuretics (E/A)                                                                                             Birth control (E/A)
 Oxygen* (E/A)                                                                                               Psychological and social support (E/C)
 Digoxin (E/C)                                                Expert referral (E/A)                          Infection prevention (E/A)
 Supervised rehabilitation (E/B)
                                                   Acute vasoreactivity test (A for IPAH)
                                                             (E/C for APAH)
               ACUTE RESPONDER
                                                                             NON-RESPONDER

    WHO Class I-IV                Strength of
  Amlodipine, diltiazem,        Recommendation             WHO Class II                        WHO Class III                    WHO Class IV
     nifedipine (B)                                 Ambrisentan, Bosentan,             Ambrisentan, Bosentan,           Epoprostenol IV
                                       A            Sildenafil                         Epoprostenol IV, Iloprost inh,
                                                                                       Sildenafil
                                                    Sitaxsentan, Tadalafil             Sitaxsentan, Tadalafil,          Iloprost inh
                                       B
   Sustained response                                                                  Treprostinil SC
       (WHO I-II)                      C                                               Beraprost                        Treprostinil SC
                                                                                       Iloprost IV, Treprostinil IV     Iloprost IV, Treprostinil IV
                                       E/B                                                                              Initial combination therapy (see
                                                                                                                        below)
                                                                                                                        Ambrisentan, Bosentan,
                                       E/C
     YES           NO                                                                                                   Sildenafil, Sitaxsentan, Tadalafil
                                  Not approved                                         Treprostinil inh+                Treprostinil inh+
                                                                             INADEQUATE CLINICAL RESPONSE
  Amlodipine, diltiazem,
     nifedipine (B)                                  Sequential combination therapy


                                                                 Prostanoids                                  INADEQUATE CLINICAL RESPONSE
                                                      + (B)                           + (B)
                                                                                                                 Atrial septostomy (E/B) and/or
                                             PDE-5 I                 + (B)                ERA                         lung transplant (E/A)


in exercise capacity and clinical events that seem similar to                In the pivotal tadalafil RCT, ~50% of the patients had oral
the results observed with the other 2 ERAs.                                  tadalafil added to background oral bosentan; it improved
                                                                             exercise capacity, hemodynamic status, and clinical
On the basis of the results of RCTs using ERAs, the incidence
                                                                             events. Inhaled treprostinil has also been studied as add-on
of elevated hepatic transaminases >3 times the upper limit of
                                                                             therapy to either background bosentan or sildenafil; in both
normal seems to be ~10, 4, 2% with bosentan, sitaxsentan,
                                                                             combinations, the addition of inhaled treprostinil improved
and ambrisentan respectively. They have interactions with
                                                                             exercise capacity.39 These studies support the efficacy of
warfarin that require careful monitoring of the INR and dose
                                                                             combination treatment in patients who remain symptomatic
adjustments when used together.
                                                                             on monotherapy. The optimal combination on the basis of
COmBINATION TheRAPy                                                          overall risk-benefit considerations remains unknown.
Combination treatment has been evaluated to address the                      eARLy INTeRveNTION
multiple pathobiologic mechanisms of PH. The combination
                                                                             For functional class II or III patients, the role of early
of oral bosentan and IV epoprostenol was investigated in
                                                                             aggressive intervention, either as monotherapy or in
1 small study, with inconclusive results.35,36The addition of
                                                                             conjunction with either a PDE-5 inhibitor and/or an ERA,
inhaled iloprost to background oral bosentan demonstrated
                                                                             remains unknown. Although the first RCTs in PAH focused
improved hemodynamic status and clinical events in 1 RCT40;
                                                                             primarily on functional class III and IV patients, results from
however, these results were not confirmed in an open trial.37
                                                                             a more recent RCT evaluating the efficacy of bosentan in only
In another study, the addition of oral sildenafil to background
                                                                             mildly symptomatic PAH patients support early intervention.35
IV epoprostenol demonstrated improved exercise capacity,
                                                                             In addition, prespecified subgroup analyses of the sildenafil,
hemodynamic status, and clinical events; furthermore, the
                                                                             tadalafil, and ambrisentan RCTs did not show any significant
addition of oral sildenafil to background IV epoprostenol
                                                                             differences in the therapeutic efficacy of these drugs between
increased survival versus IV epoprostenol alone.38
                                                                             patients in WHO functional classes II and III.35

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                                                     Medicine Update 2012  Vol. 22

INvASIve TeChNIQUeS                                                        6.   Tuder RM et.al. Pulmonary circulation: development and patholo-
                                                                                gy. JACC 2009; 54:S3–S9.
Atrial septostomy is a palliative procedure, the rationale of
                                                                           7.   Fedullo PF, et al. CTEPH. NEJM 2001; 345:1465–1472.
which is based on experimental and clinical observations
suggesting that intraatrial defect allowing right-to-left                  8.   Humbert M et.al. Cellular and molecular pathobiology of PAH.
shunting in the setting of severe PH might be of benefit.19                     JACC 2004; 43:S13–S24.
Indications for the procedure include recurrent syncope and/               9.   Hassoun PM et.al. Inflammation, growth factors, and pulmonary
or RV failure, despite maximum medical therapy, as a bridge                     vascular remodeling. JACC 2009; 54:S10–S19.
to transplantation, or when no other option exists.                        10. Morrell N et.al. Cellular and molecular basis of PAH. JACC 2009;
                                                                               54:S20–S31.
Heart-Lung And Lung Transplantation has been performed
                                                                           11. Rich S. Primary pulmonary hypertension. A national prospective
successfully in patients with PH since 1981. Currently, bilateral              study. Ann Intern Med 1987; 107:216–223.
lung transplantation has become the procedure of choice.41
                                                                           12. D’Alonzo GE et al. Survival in patients with primary pulmonary
Hemodynamic studies have shown a moderate reduction in                         hypertension: results from a national prospective registry. Ann In-
PAP and PVR associated with improvement in RV function.                        tern Med 1991; 115:343–349.
The 1-year survival rate is 70-75%, the 2-year survival rate
                                                                           13. McLaughlin VV. et al. American College of Chest Physicians.
is 55-60%, and the 5-year survival rate is between 40-45%.                     Prognosis of pulmonary arterial hypertension: ACCP evidence-
Transplantation should be reserved for patients with PH when                   based clinical practice guidelines. Chest 2004; 126:78S–92S.
they are in NYHA functional Class III/IV despite therapy with              14. McLaughlin VV. et al. Survival in primary pulmonary hyperten-
a prostacyclin.                                                                sion: the impact of epoprostenol therapy. Circulation 2002; 106:
                                                                               1477–1482.
meTA-ANALySIS TO ASSeSS eFFeCT ON mOR-                                     15. Sitbon O et al. Long-term intravenous epoprostenol infusion in
TALITy                                                                         primary pulmonary hypertension: prognostic factors and survival.
Meta-analysis of 25 RCTs in 3363 PH patients showed a                          JACC 2002; 40:780 –788.
reduction in mortality ranging 38-43% after an average                     16. Barst RJ et al. A comparison of continuous intravenous epoproste-
treatment period of 14.3 weeks.43 A subgroup analysis showed                   nol with conventional therapy for primary pulmonary hypertensi-
that all three classes of PH-approved drugs achieved a similar                 on. NEJM 1996; 334:296 –301.
favorable reduction in mortality, although no statistical                  17. Sitbon O.et al. Long-term response to calcium channel blockers
significance was achieved individually.                                        in idiopathic pulmonary arterial hypertension. Circulation 2005;
                                                                               111:3105–11.
CONCLUSIONS                                                                18. Fuster V. PPH: natural history and the importance of thrombosis.
The epidemiology of PAH is changing. Remarkable advances                       Circulation 1984; 70:580 –7.
in understanding the pathobiology and clinical care in PAH                 19. Klepetko W et al. Interventional and surgical modalities of treat-
have resulted in improved exercise capacity and survival.                      ment for PAH. JACC 2004; 43:73S– 80.
Despite such important progress, however, neither exercise                 20. Johnson SR. Anticoagulation in PAH: a qualitative systematic re-
capacity nor survival is normal. Controlled studies have only                  view. Eur Respir J 2006; 28:999 –1004.
just begun to evaluate the role of combinations of therapies, as           21. Rich S et al. The short-term effects of digoxin in patients with
well as the utility of genetic and other biomarkers. It is hoped               right ventricular dysfunction from pulmonary hypertension. Chest
that such studies will allow for better targeting of therapy to                1998;114:787–92
individual patients who have PH.                                           22. Rich S. The effect of high doses of calcium channel blockers
                                                                               on survival in primary pulmonary hypertension. NEJ M 1992;
ReFeReNCeS                                                                     327:76–81.
1.   Kovacs G et.al. . Pulmonary arterial pressure during rest and exer-   23. McLaughlin VM et al. ACCF/AHA clinical expert consensus do-
     cise in healthy control subjects: a systematic review. Eur Respir J       cument on pulmonary hypertension: a report of the ACC Foun-
     2009.                                                                     dation Task Force on Expert Consensus Documents. JACC 2009;
2.   Hatano S et.al. Primary Pulmonary Hypertension. Report on a               53:1573– 619.
     WHO Meeting. October 15–17, 1973, Geneva: World Health Or-            24. Harrison WF et al. Pulmonary Arterial Hypertension NEJM 2004;
     ganization, 1975.                                                         351:1655-65.
3.   Fishman AP. Clinical classification of PH. Clin Chest Med 2001;       25. Simonneau G et al. Continuous subcutaneous infusion of trepro-
     22:385–91.                                                                stinil, a prostacyclin analogue, in patients with PAH: A double-
4.   Simonneau G et.al. Clinical classification of PH. JACC 2004;              blind, RCT. Am J Respir Crit Care Med 2002; 165:800.
     43:5S–12S.                                                            26. Olschewski H et al. Inhaled iloprost for severe pulmonary hyper-
5.   Pietra GG et.al. Pathologic assessment of vasculopathies in PH.           tension. NEJM 2002; 347:322.
     JACC 2004; 43:S25–S32.                                                27. Barst RJ et al. Beraprost therapy for PAH. JACC 2003; 41:2119.


                                                                       186
                                                  Pulmonary Hypertension: Newer Insights

28. Dupuis J et al. Endothelin receptor antagonist in PAH. Eur Respir    36. Humbert M, Barst RJ, Robbins IM, et al. Combination of bosen-
    J 2008; 31:407.                                                          tan with epoprostenol in pulmonary arterial hypertension: BREA-
29. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual           THE-2. Eur Respir J 2004; 24:353–9.
    endothelin-receptor antagonist bosentan in patients with pulmona-    37. Hoeper MM et al. Combining inhaled iloprost with bosentan in
    ry hypertension: a randomised placebo-controlled study. Lancet           patients with IPAH. Eur Respir J 2006; 28:691– 4.
    2001; 358:1119 –23.                                                  38. Simonneau G et al., for the PACES Study Group. Addition of sil-
30. Rubin LJ et al., for the Bosentan Randomized Trial of Endothe-           denafil to long-term intravenous epoprostenol therapy in patients
    lin Antagonist Therapy Study Group. Bosentan therapy for PAH.            with PAH: a randomized trial. Ann Intern Med 2008; 149:521–30.
    NEJM 2002; 346: 896–903.                                             39. McLaughlin V et al. TRIUMPH I: efficacy and safety of inhaled
31. Galiè N et al. Bosentan therapy in patients with Eisenmenger syn-        treprostinil sodium in patients with PAH. Am J Respir Crit Care
    drome (BREATHE-5): a multicenter, double-blind, randomized,              Med 2008; 177:A965.
    placebo controlled study. Circulation 2006; 114:48–54.               40. McLaughlin VV et al. Randomized study of adding inhaled ilo-
32. Galiè N et al. Treatment of patients with mildly symptomatic PAH         prost to existing bosentan in PAH. Am J Respir Crit Care Med
    with bosentan (EARLY study): a double-blind, RCT. Lancet 2008;           2006; 174:1257– 63.
    371: 2093–100.                                                       41. Orens JB: General overview of lung transplantation and review of
33. Barst RJ et al. Sitaxsentan therapy for PAH. Am J Respir Crit Care       organ allocation. Proc Am Thorac Soc 2009; 6:13.
    Med 2004; 169:441–7.                                                 42. Robyn JB et al. Updated Evidence-Based Treatment Algorithm in
34. Barst RJ. Treatment of PAH with the selective endothelin-A recep-        PAH. JACC 2009; 54:S78–84.
    tor antagonist sitaxsentan. JACC 2006; 47:2049 –56.                  43. Macchia A, et al. Systematic review of trials using vasodilators in
35. Galiè N et al. Ambrisentan therapy for PAH. JACC 2005; 46:529            pulmonary arterial hypertension: why a new approach is needed.
    –35.                                                                     Am Heart J 2010; 159:245–257.




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