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ThomsonAn evidence-based approach to the management of pulmonaryarterial hypertensionStephen L. and Evangelos D. Michelakis Purpose of review Sponsorship: S.L.A. is supported by NIH-RO1-HL071115. Both authors are Evidence-based therapies and guidelines for pulmonary supported by the Canada Foundation for Innovation, the Alberta Heart and StrokeFoundation, the Canadian Institutes for Health Research (CIHR) and the Alberta arterial hypertension are critiqued.
Cardiovascular and Stroke Research Centre (ABACUS). E.D.M. is supported by the Alberta Heritage Foundation for Medical Research and holds a CRC in PulmonaryHypertension.
Morbidity and mortality in pulmonary arterial hypertensionreflects failure of right ventricular compensation for Conflicts of interest: S.L.A., none; E.D.M. has received consulting fees (Can$2000)from Pfizer and holds a non-reimbursed position on an Actelion-sponsored clinical increased afterload caused by obstructive pulmonary arterial remodeling. This predominantly reflects excessive Current Opinion in Cardiology 2006, 21:385–392 proliferation/impaired apoptosis of smooth muscle andendothelial cells, rather than vasoconstriction. To exclude confounding effects of cardiac output and left ventricular cyclic guanosine monophosphate European Cardiology Society end-diastolic pressure, the diagnosis of pulmonary arterial endothelin receptor blocker hypertension should require a pulmonary vascular Food and Drug Administration National Institutes of Health resistance >3 Wood-units, not simply a mean pulmonary arterial pressure >25 mmHg. A ‘positive' response (20% New York Heart Association pulmonary capillary wedge pressure fall in pulmonary arterial pressure/pulmonary vascular pulmonary arterial hypertension resistance PAP/PVR) to acute, selective, pulmonary pulmonary artery pressure pulmonary vascular resistance vasodilators (e.g. inhaled nitric oxide), occurs in 20% of randomized controlled trial patients, portends a favorable prognosis and justifies a trialof calcium channel blockers. Randomized controlled trials ß 2006 Lippincott Williams & Wilkins support treatment of NYHA class III pulmonary arterial hypertension with oral endothelin antagonists orphosphodiesterase-5 inhibitors. Prostacyclin analogues (inhaled/subcutaneous) are useful adjunctive therapies.
Pulmonary arterial hypertension (PAH) is increasingly Intravenous epoprostenol remains the therapeutic mainstay recognized as a disease of increased proliferation and for class IV PAH. Emerging antiproliferative-proapoptotic impaired apoptosis of cells in the small pulmonary therapies that merit investigator-initiated clinical trials arteries The resulting increase in the right ven- include: statins, Imatinib, NONO-ates, anti-survivin, tricular afterload results in right ventricular failure and potassium channel modulation, and dichloroacetate.
premature death. Although the morbidity and mortality of PAH remain high, recent advances in the biology of The diagnostic criteria for pulmonary arterial hypertension this disease have resulted in significant changes in the should be revised to include PVR. Sildenafil's efficacy and definition of PAH and an explosion of clinical research price recommend it as a first-line oral therapy. New that has completely transformed the field over the past pulmonary arterial hypertension-regression therapies and 5 years. A number of approved and investigational thera- therapeutic combinations offer the potential for cure of pies are now available for PAH patients. Here, we review pulmonary arterial hypertension.
the major advances in the treatment of PAH over the past5 years. We used, as much as possible, the standard principles of evidence-based medicine.
apoptosis, calcium antagonists, dichloroacetate,endothelin antagonists, phosphodiesterase 5 inhibitors Current definition of pulmonary arterialhypertension, its limitations and clinical Curr Opin Cardiol 21:385–392. ß 2006 Lippincott Williams & Wilkins.
aVascular Biology Group, Division of Cardiology and bPhysiology Department, Idiopathic PAH (iPAH) is now grouped with PAH syn- University of Alberta, Edmonton, Canada dromes that are associated with connective tissue disease, Correspondence to Stephen L. Archer, MD, FRCP, FAHA, Cardiology Division,Department of Medicine, University of Alberta, WMC 2C2.36, 8440 112th Street, cirrhosis, congenital heart shunts, HIV and anorexigen use.
Edmonton, Alberta, Canada T6G 2B7 This is based, at least partly, on the fact that the pathology Tel: +1 780 407 6353; fax: +1 780 407 6032; e-mail: of the pulmonary arteries in these diseases can be quitesimilar, suggesting a common pathogenetic mechanism.
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However, the results of several randomized controlled confirm the diagnosis, quantify the PAH and assess trials (RCTs) suggest that these syndromes are not homo- reversibility. Echocardiography is not specific enough geneous in their response to therapy or prognosis. For to diagnose PAH, particularly in cases of pulmonary example, scleroderma PAH patients often respond subop- hypertension resulting from left ventricular diastolic timally compared with iPAH patients. Congenital heart dysfunction and elevated PCWP. Acute vasodilator test- disease PAH patients, despite a better prognosis compared ing, during catheterization, defines the prognosis and with iPAH, often have a poor response to therapy.
guides therapy. Although the majority of centers useinhaled nitric oxide (NO) as a pulmonary vasodilator PAH is defined by the European Cardiology Society (10–80 ppm), many centers, particularly in Europe, use (ECS) guidelines simply as a resting mean pulmon- epoprostenol, inhaled iloprost or adenosine. Despite its ary artery pressure (PAP) greater than 25 mmHg recent increase in price, inhaled NO is the preferred (> 30 mmHg during exercise) The American vasodilator, because of its unique selectivity for the College of Chest Physicians definition, based on the National Institutes of Health (NIH) PAH registry,includes the requirement for a pulmonary capillary The definition of a ‘positive' response is controversial.
wedge pressure (PCWP) of less than 15 mmHg Both According to the ECS, a positive acute vasodilator definitions, however, do not explicitly require increased response requires both a fall of mean PAP of 10 mmHg pulmonary vascular resistance (PVR) and thus might or greater and final mean PAP of 40 mmHg or less, with result in the over-diagnosis of PAH, with important no decrease in cardiac output We believe that this clinical (unnecessary therapies) or research (inappro- definition is insensitive, and would miss the many priate inclusion of non-PAH patients in RCTs) implica- patients who respond with a 20% fall in PVR or mean tions. For example, consider an anemic or pregnant PAP, but whose mean PAP remains above 40 mmHg.
patient, with a ‘physiological' increase in cardiac output.
As pulmonary vasoconstriction is usually not the major This patient will have a ‘flow-induced' increase in the determinant of PVR, a dramatic decrease in mean PAP in mean PAP (say 35 mmHg), a normal PCWP (10 mmHg) response to acute vasodilators is quite rare. Because the and elevated cardiac output (10 l/m). The PVR in this ‘responders' have a much better prognosis when treated patient is (35–10)/10 ¼ 2.5 Wood units. Based on the with calcium antagonists the ECS definition would dis- current definitions, this hypothetical patient (who has qualify many PAH patients from the simple and cheap histologically normal pulmonary arteries) would be inap- calcium antagonist therapy In our practice responders propriately diagnosed with PAH, despite the normal who are class II–III merit a trial of calcium antagonists.
PVR. Another example of potential PAH misdiagnosis This dose titration is best initiated in a monitored hospi- is the patient with left ventricular diastolic dysfunction.
tal bed, rather than in the catheterization laboratory Consider such a patient with a mean PAP of 35 mmHg, because titration often requires prolonged observation PCWP of 20 mmHg and cardiac output of 5 l/m. The over 1–2 days. Doses of nifedipine or diltiazem are PVR in this patient will be (35–20)/5 ¼ 3 Wood units.
gradually increased as tolerated by systemic blood pres- Based on the current definition, this patient will be sure Alternative starting diagnosed with PAH (despite a PVR within normal medications are sildenafil, which we favor on the basis of limits), and despite the fact that the pulmonary arteries price, or bosentan. These medications are best initiated are probably normal and the increase in PAP only reflects in a monitored setting, and although invasive hemody- a transmission of the elevated left ventricular-end- namic monitoring is not usually required, we carefully diastolic pressure as a result of diastolic dysfunction.
monitor heart rate and systemic blood pressure. Non- Neither of these patients should be treated for PAH, responders who are class II–III are usually treated with or included in PAH RCTs; their mean PAP will normal- sildenafil or bosentan, progressing to inhaled iloprost or ize after treatment of the primary cause.
intravenous prostacyclin therapy if their status deterior-ates to class IV. In class IV patients, dose titration of flolan Only when PVR is increased (mean PAP > 25 mmHg and in a monitored setting, guided by a right heart catheter- PVR > 3 Wood units) can one diagnose pulmonary ization is required. As most patients in our programme are arterial hypertension. Even then, the diagnosis of PAH class II–III and are non-responders we treat the majority also requires the careful exclusion of secondary causes of them with sildenafil or bosentan plus warfarin.
of pulmonary hypertension, including thromboembolicdisease, left ventricular disease (restriction or diastolic It remains controversial whether echocardiographic dysfunction), pulmonary disease or hypoxia.
follow-up is adequate for chronic monitoring of PAHpatients. We ensure that each year all patients have Acute vasodilator testing one or more 6-min walk tests and an echocardiographic All patients who appear to have PAH after non-invasive measurement of PAP (using both tricuspid regurgitation testing should undergo a right heart catheterization to velocity and pulmonary artery acceleration time). In Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
An evidence-based approach to management of pulmonary arterial hypertension Archer and Michelakis Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
addition, yearly right heart catheterizations are indicated ing, headache, diarrhea, an erythematous rash and leg in most patients, and certainly in any patient showing pain). Acute tachyphylaxis occurs and frequent dose titrations are required Epoprostenol is the only drugthat has been shown to improve survival in PAH. The effect of epoprostenol (n ¼ 41) versus standard therapy A number of standard therapies (including oxygen, diu- (n ¼ 40) was assessed in a cohort of New York Heart retics, anticoagulant, digitalis, etc.) are commonly used Association (NYHA) class III–IV iPAH patients in a in PAH patients, despite the lack of support from 12-week prospective, randomized, multicenter open trial RCTs. These therapies and important general measures Compared with standard therapy, epoprostenol (the avoidance of pregnancy, exposure to high-altitude, improved hemodynamics (mean PAP 8% versus aerobic exercise) have recently been reviewed þ3%, PVR 21% versus þ9% and 6-min walk: þ47 mversus 64 m). Although there was less mortality in the Calcium antagonists epoprostenol arm (0 versus eight patients) the initial The calcium antagonists retain a role in PAH therapy 6-min walk was significantly longer than in the control because of their efficacy in selected patients and their group (315 versus 270 m). The small size of the study, low price In a non-randomized series of 64 coupled with this imbalance might have contributed to iPAH patients, 26% responded to high-dose calcium the apparent beneficial effects of epoprostenol. In antagonists with an acute decrease in the PVR of more another small RCT in scleroderma PAH, epoprostenol than 20% At 5 years, there was a clear survival also had beneficial hemodynamic and functional effects advantage to the initial responders versus non-responders but did not improve survival Two larger cohort (97 versus 55%). This prospective trial was, however, not studies suggest a survival benefit for epoprostenol-treated placebo controlled and it is unclear whether calcium patients at 1, 2 and 3 years (88, 76 and 63%) versus antagonist responsivity was primarily selecting a group historical controls (59, 46 and 35%) . These nonran- of PAH patients with a better prognosis (whether because domized studies may, however, say more about evolving of earlier presentation or unique pathophysiology). There excellence in PAH care than they do about epoprostenol is little science to guide the dosing of calcium antagonists.
The beneficial effects of epoprostenol can be In responders it is reasonable to start therapy with sustained for years, and as a result many patients have nifedipine 10 mg three times a day, and increase on a been removed from heart–lung transplantation lists daily basis to 30 mg three times a day, prior to converting Occasionally, the disease improves suffi- the patient to the long-acting form of the drug. If ciently that one can even replace epoprostenol with oral systemic blood pressure is not significantly lowered therapy Unfortunately, the use of epoprostenol is (< 10%) on this regimen, additional titrations into the limited by its cost (Can$60 000/year) and several ‘high-dose range' can be initiated with longer intervals of a week between dose changes Unfortunately,most PAH patients do not respond to vasodilators acutely, and are not candidates for calcium antagonist therapy.
Treprostinil is a prostacyclin analogue with a 3-h half-life Furthermore, the use of high-dose calcium antagonists is and stability at room temperature. It is delivered sub- limited by both symptomatic hypotension and edema, cutaneously by a continuous infusion. Unfortunately, a although lower doses may offer some benefit in PAH recent 12-week, RCT of 470 PAH patients randomly assigned to treprostinil or placebo (plus conventionaltherapy) found only modest efficacy (6-min walk: Prostaglandin analogues þ16 m), although several secondary endpoints improved The endothelium in PAH is characterized by the (hemodynamics and quality of life indices). The maxi- deficient production of vasodilator prostaglandins (pros- mum tolerable dose was often suboptimal, being limited tacyclin) providing the rationale for therapy with in 85% of patients by severe pain and erythema at the prostacyclin analogues injection site. This study included NYHA II patients(n ¼ 53). Perhaps the enrollment of healthier patients was detrimental to showing benefit (class II patients Because of its half-life of approximately 3 min, instability improved only by 2 m compared with 54 m for class IV at room temperature and irritating effects on veins, patients). In addition, the study included congenital heart epoprostenol must be refrigerated and administered disease PAH, and this subgroup did not improve, a intravenously by continuous infusion through tunneled, reminder that the lumping of diverse PAH subgroups central venous catheters. Therapy is initiated by a dose under a single rubric may be invalid. The recent intro- titration beginning at 2 ng/kg per minute, increasing until duction of intravenous treprostinil might prove to be symptoms occur. Most adverse effects relate to epopros- more convenient (no refrigeration and longer half-life) tenol's systemic vasodilator actions (e.g. jaw pain, flush- than epoprostenol Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
An evidence-based approach to management of pulmonary arterial hypertension Archer and Michelakis the temporal changes in PAH care between the 1980s Although this analogue has a half-life that is marginally and the present, the different definitions of PAH used, longer than that of epoprostenol (25 min), it can be and differences in patient characteristics. In a recent administered by inhalation. This preparation is approved single-center case series of 103 consecutive NYHA III– for the treatment of PAH in both Europe and the United IV iPAH patients treated with bosentan, the results were States, but is rarely used in North America. Iloprost is comparable to those in clinical trials, but 44% of patients administered in multiple 5-min sessions (6–9/day) using required the addition of prostanoid therapy during 1–2 ultrasonic nebulizers Airway nebulization delivers years of follow-up raising efficacy and economic iloprost to resistance pulmonary arteries with minimal issues. Bosentan offers some benefits to patients with systemic overflow. Two open-label studies of iloprost in moderate PAH, but suffers from a relative lack of efficacy, PAH for 3 months and one year and a 3-month, the need for chronic monitoring of liver function, and cost (Can$40 000/year).
efficacy. Iloprost (2.5 or 5 mg) six to nine times a day(total dose < 45 mg/day) prolonged the 6-min walk in 203 patients with severe PAH or chronic thromboembolic In contrast to bosentan, which is a non-selective ERB, pulmonary hypertension (NYHA functional class III–IV) sitaxsentan is a selective type A ERB, offering the without serious adverse effects Once again, the theoretical advantage of mitigating the endothelin-A therapeutic effect was greater in the iPAH subset than receptor-dependent vasoconstrictive and proliferative the population as a whole (þ59 versus þ36 m). Iloprost effects, while preserving the endothelin-B receptor- also improved pulmonary hemodynamics, and there was dependent NO-mediated vasodilatation and endothelin a trend towards improved survival (one death in the clearance. STRIDE-1 was a randomized, 12-week, iloprost group, four deaths in the placebo group).
placebo-controlled RCT that compared sitaxsentan[100 mg (n ¼ 55) or 300 mg (n ¼ 63) a day) with placebo Endothelin antagonists (n ¼ 60)]. Sitaxsentan improved 6-min walk, NYHA class, Endothelin levels are elevated in PAH, and some of this cardiac index and PVR in NYHA class II–IV patients vasoconstrictive, mitogenic peptide is synthesized in the with iPAH, scleroderma PAH or congenital heart disease pulmonary circulation , providing the rationale for the Sitaxsentan (100 mg) increased the 6-min walk by use of endothelin receptor blockers (ERBs) in PAH 35 m and the NYHA class improved in 29% of subjects.
Surprisingly, there was no incremental benefit from thehigher dose (just increased hepatotoxicity). When initi- ating sitaxsentan, warfarin doses should be reduced Bosentan was the first oral drug approved by the Food because inhibition of the CYP2C9 P450 enzyme will and Drug Administration (FDA) for use in class III–IV usually interfere with the metabolism of warfarin and PAH patients. The approval followed the publication of increase the international normalized ratio In the BREATHE-1 trial. In that placebo-controlled RCT, addition, ERBs decrease levels of sildenafil and may 213 class III–IV iPAH or scleroderma PAH patients were interfere with this therapy There are no prospective randomly assigned to bosentan (125 mg twice a day or data to indicate that sitaxsentan reduces mortality.
250 mg twice a day) compared with placebo for approxi-mately 16 weeks The primary endpoint, the 6-min walk, improved in the bosentan group compared with The two main endogenous stimuli for cyclic guanosine the placebo group (þ36 versus 8 m). Unfortunately, monophosphate (cGMP) production in the pulmonary although the improvement was greater at 250 versus circulation and right heart are brain natriuretic peptide 125 mg twice a day (þ54 versus þ35 m), an unacceptable and NO. Phosphodiesterase-5 inhibitors (sildenafil, var- incidence of abnormal liver function tests (14 versus 5%), denafil, tadalafil) amplify the effects of both brain brain syncope and flushing precludes the use of the higher natriuretic peptide and NO, increasing cGMP and pro- dose. Liver toxicity is an ERB class effect, resulting from moting a vasodilatory and antiproliferative effect in the bile salt accumulation The FDA requires monthly pulmonary circulation Phosphodiesterase-5 liver function tests in all patients treated with bosentan.
expression is preferentially expressed in the pulmonary No survival benefits have been demonstrated for bosen- and genital circulations, accounting for the relative lack of tan. A survival benefit was recently postulated for bosen- systemic hypotension when sildenafil is administered tan by comparing outcomes data from the open-label (providing exogenous nitrates are avoided).
extension trials following BREATH to that of the NIHregistry The validity of this type of retrospective comparison is, however, questionable because therapy in Several small trials and case reports showed that sildenafil the extension trials was not blinded. Moreover, compari- (50–100 mg three times a day) was similarly effective and son with the NIH registry is inappropriate because of selective as inhaled NO when administered acutely to Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
patients with PAH Sildenafil appears to offer equally beneficial in PAH Sildenafil is also useful in advantages over inhaled NO, increasing cardiac output preventing rebound in PAH during withdrawal of chronic and reducing PCWP, whereas inhaled NO tends to inhaled NO therapy and is beneficial in cor pulmo- increase PCWP and has little effect on cardiac output.
nale and pediatric PAH .
In 2003, a small open-label series showed that 3 months ofsildenafil (50 mg three times a day by mouth) produced Combination therapies sustained increases in 6-min walk (þ110 m) and resulted Following the model that has been successfully used to in some regression of right ventricular hypertrophy .
treat tuberculosis, HIV infections or cancer, practitioners In addition, it was shown that phosphodiesterase-5 is have begun the search for combinations of drugs for abundant in pulmonary arteries of PAH patients.
PAH. Adding bosentan to epoprostenol has, in our view,yielded disappointing results In contrast, the In 2005, the SUPER trial reported 278 patients from 53 addition of sildenafil to inhaled iloprost or subcu- centers in a 3-month, placebo-controlled, RCT that taneous treprostinil is well tolerated and appears to be tested the addition of sildenafil (20, 40 or 80 mg) to effective RCTs are required prospectively to com- conventional therapy The primary endpoint was pare de novo combination therapy with monotherapy, improvement in the 6-min walk. Subsequently, most and it appears the combination of phosphodiesterase-5 patients underwent an additional 9 months of therapy inhibitors and prostaglandin analogues should be tested (sildenafil 80 mg). Sildenafil caused a þ50 m increase in early in this process.
6-min walk that was sustained at one year. Although theauthors suggest that there was no dose response to Emerging therapies sildenafil (based on 6-min walk), there was a statistically It has recently been recognized that a decrease of significant, dose-dependent decrease in PVR, without proliferation and induction of apoptosis in the wall of toxicity The main adverse effects of sildenafil pulmonary arteries causes regression of established PAH.
were flushing, diarrhea and heartburn. Although theauthors claim equivalency to bosentan and epoprostenol, it is our opinion that the efficacy, convenience and cost Monocrotaline-induced PAH in rodents was reduced by (particularly if 100 mg pills are split, < Can$5000/year) simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A suggests an advantage of sildenafil as a first-line therapy reductase inhibitor. Simvastatin caused benefit by induc- for NYHA III patients. Following the 2005 approval by ing the apoptosis of neointimal smooth muscle cells the FDA, sildenafil is marketed at a low-dose under a Subsequently, an open-label observational study was different name (Revatio; Pfizer, New York, NY, USA).
performed on 16 PAH patients, World Health Organi- One can only hope that the low dose is associated with a zation class I–IV. Simvastatin (20–80 mg/day) improved fair price. In our opinion/experience, patients can be 6-min walk and decreased right ventricular pressure in safely treated with 50–100 mg doses of sildenafil. The some subjects without adverse events A large RCT relative value of bosentan compared with sildenafil is required to assess efficacy.
requires examination. The SERAPH study comparedthe two treatments in 26 class III PAH patients with iPAH or scleroderma PAH. Subjects were randomly In monocrotaline-induced PAH, disease progression is assigned in a double-blind fashion to receive sildenafil associated with increased lung expression of the seroto- (50 mg twice a day for 4 weeks, then 50 mg three times a nin transporter, which promotes the proliferation of pul- day) or bosentan (62.5 mg twice a day for 4 weeks, then monary artery smooth muscle cells. The selective 125 mg twice a day) over 16 weeks There was a serotonin transporter inhibitor fluoxetine prevented or trend towards a greater increase in 6-min walk with reversed PAH in this model Considering the good sildenafil (þ114 m) versus bosentan (þ59 m). In addition, safety profile and wide use of fluoxetine in humans as an only sildenafil reduced right ventricular mass. One silde- antidepressant, a PAH RCT is justified, However, a nafil patient did die suddenly, although it is uncertain if recent trial suggested that maternal fluoxetine (taken this was related to therapy.
in the third trimester) increases the risk of primarypulmonary hypertension of the newborn In an acute trial in 60 class II–IV PAH patients, all threephosphodiesterase-5 inhibitors caused similar PVR reductions; however, only sildenafil and tadalafil avoided Platelet-derived growth factor can drive smooth muscle changing the pulmonary/systemic vascular resistance cell proliferation, and dietary fish oil, which antagonizes ratio Only sildenafil, the least selective for phos- this pathway, reduces experimental PAH It has been phodiesterase-5, improved systemic oxygenation. That suggested that endothelial damage and exposure of the study suggested that all phosphodiesterase-5 inhibitors media to circulating platelet-derived growth factor might are not equally selective for the pulmonary circulation nor contribute to obstructive vascular remodeling. A recent Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
An evidence-based approach to management of pulmonary arterial hypertension Archer and Michelakis case report and a rodent study suggested that ima- Michelakis ED. Spatio-temporal diversity of apoptosis within the vascular wallin pulmonary arterial hypertension: heterogeneous BMP signaling may have tinib, a platelet-derived growth factor-antagonist may therapeutic implications. Circ Res 2006; 98:172–175.
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A large multicentre RCT shows sildenafil to be beneficial in class III PAH. Despite alack of dose effect in terms of 6-min walk, there was a dose effect of sildenafil on Gene therapy inhibiting endogenous survivin functional class and hemodynamics with 80 mg better than 20 mg. The rationale Suppression of apoptosis in the pulmonary vasculature for choosing sildenafil doses other than those used for erectile dysfunctionis unclear. Our clinic has had success with managing patients with sildenafil occurs partly because of the de-novo expression of survi- 50–100 mg three times a day by mouth.
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shown that survivin is expressed in the pulmonary Sildenafil offers an advatage over bosentan in its ability to cause a regression ofRVH. Interestingly, the large cost advantage of sildenafil over bosentan is not arteries of PAH patients and survivin inhibition causes examined. There was one unexplained sudden death in the sildenafil group. This the regression of experimental PAH was not seen in the other small studies or the SUPER trial.
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The American Journal of Pathology, Vol. 176, No. 4, April 2010 Copyright © American Society for Investigative Pathology Cardiovascular, Pulmonary and Renal Pathology Therapeutic Targeting of Classical and LectinPathways of Complement Protects fromIschemia-Reperfusion-Induced Renal Damage Giuseppe Castellano,* Rita Melchiorre,* of classical and lectin pathways of complement in a