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JOURNALSCAN | 3Managing PAHA Cardiologist’s PerspectiveA Pulmonologist’s PerspectivePulmonary arterial hypertension(PAH) is a rare disorder,but perhaps not as rare asonce believed. Historically,PAH epidemiology has often beencharacterized as 1 or 2 per million.However, evidence from a French registrysuggests the prevalence of aboutVallerie McLaughlin, MD15 per million. 1Professor of Medicine The more contemporary data onUniversity of MichiganPAH epidemiology makes twoAnn Arbor, MIkey points:• Far more people are affected by the condition than previouslyrecognized.• Clinicians should remain vigilant for the possibility ofPAH when evaluating patients for dyspnea.Even with the increased prevalence, PAH does not have a mandatefor routine screening in clinical practice. Screening mightbe appropriate for specific subgroups of patients who have anincreased risk of PAH, such as patients with scleroderma.RECOGNITIONDiagnosis, evaluation, and treatment of PAH overlap the medicalspecialties of cardiology and pulmonology. 2 Physicians inboth specialties have a role in the care of patients with PAH,and patients benefit from a collaborative approach to clinicalmanagement. The other categories included in the classificationsystem have features that require more or lessinvolvement of one specialty.Cardiologists are among the first physicians who seepatients with PAH during the initial evaluation. In thatrespect, cardiologists have a unique opportunity to identifythe patients earlier, after excluding more common potentialcauses of symptoms.Regardless of when cardiologists have their first patient contact,they have a prominent role in the workup for PAH.Echocardiography is a principal screening tool for the condition.It is often the initial study that leads to the considerationof this diagnosis. In addition to the anatomic and symptomaticinformation, pulmonary pressure values provide importantclues to PAH. More often than not, a cardiologist will performright heart catheterization, which is the definitive evaluationfor diagnosis of PAH.THERAPYA key consideration in constructing a clinical algorithm for PAHis the severity of the condition. Newly diagnosed patients withright heart failure, dyspnea at rest, and poor hemodynamics oftenThe largest category of pulmonaryhypertension ispulmonary arterial hypertension(PAH), which hasbeen the focus classification since thefirst system was approved in 1973. 1This category, often called group 1,includes idiopathic PAH, heritablePAH, and multiple conditions andrisk factors associated with PAH. Oneof the fastest growing subgroupswithin group 1 is PAH associatedRichard Channick, MDDirector, Pulmonary HypertensionProgram, Massachusetts GeneralHospital, Harvard Medical SchoolBoston, MAwith drugs and toxins. In particular, use of methamphetamineshas increased in prominence as a risk factor for PAH.RECOGNITION AND AWARENESSPulmonologists often are the first point of contact for patientswith PAH. Patients seek out pulmonary specialists becausethe principal symptom of PAH is dyspnea. The key to diagnosisis clinical suspicion. Although dyspnea has manypotential causes, including more common diseases such asasthma or chronic obstructive pulmonary disease (COPD), cliniciansshould remain aware of the possibility that PAH isthe underlying problem, particularly as other potential causesare excluded.Misdiagnosis poses a major challenge to effective clinical managementof PAH. Failure to diagnose PAH promptly hassignificant implications for a condition that already has a poorprognosis and high mortality. Emerging data have suggestedsubstantial delays between onset of symptoms and diagnosis ofPAH, causing patients to endure unnecessary morbidity and perhapsgiving the disease a window of opportunity for progression.EVIDENCE-BASED TREATMENTMore than a half-dozen therapies have approval for treatmentof PAH. Current clinical guidelines for management of thecondition emphasize the importance of an evidence-basedtreatment algorithm.Strength of clinical data should always have a key influence ontherapeutic decision-making related to PAH. Among currentlyavailable therapies, the endothelin receptor antagonist bosentanoffers an example of an agent that has accumulated considerabledata in clinical research and in clinical practice. Clinical studiesof bosentan have yielded short-term data (12-15 weeks),6-month data, and now long-term evidence of the drug’s safetyand efficacy in patients with PAH functional class II, III, IV. 2The evidence base for a therapy should not begin and endwith data from pivotal clinical trials. Experience gained fromContinued on page 4 Continued on page 4


JOURNALSCAN | 7Targeting Endothelin-1 in PAH With BosentanKey Point: This pivotal trial with bosentan was the first double-blind placebo controlled study to investigate the role of blockingendothelin in pulmonary arterial hypertension (PAH). The positive impact on exercise capacity, hemodynamics, and functionalclass built the foundation for further study with an oral endothelin receptor antagonist medication for the treatment of PAH.Based on Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endotheln-receptor antagonist bosentan in patients withpulmonary hypertension: a randomized placebo-controlled study. Lancet. 2001;358:1119-1123.Evidence that endothelin plays a key role in the developmentand progression of pulmonary arterialhypertension (PAH) provided a rationale for evaluatingendothelin inhibition as a therapeutic strategy forpatients with this disease. In an early test of the endothelinhypothesis, the dual endothelin-receptor antagonist bosentanwas evaluated in a randomized, placebo-controlled clinical trial. 1METHODSThe study included 32 patients with PAH or PAH associatedwith scleroderma. They were randomly assigned 1:2 to placeboor to bosentan at a dose of 62.5 mg BID for 4 weeks and then125 mg BID for a total of at least 12 weeks of therapy. The primaryendpoint was change in exercise capacity from baseline tothe end of treatment. Secondary endpoints included changes incardiopulmonary hemodynamics, Borg dyspnea index, WHOfunctional class, and withdrawal because of clinical worsening.RESULTSAt baseline the 6-minute walk distance averaged 360 metersin the bosentan group and 355 meters in the placebo group.After 12 weeks of treatment, bosentan-treated patients had a70-meter improvement in 6-minute walk distance comparedwith no change in the placebo group (P=0.021) (Figure 1). Allpatients were in functional class III at baseline. In the bosentangroup, nine of 21 patients improved to class II and the other12 remained stable in class III. In contrast, one of 11 patients inthe placebo group improved to class II, eight remained in classIII, and two deteriorated to class IV (P=0.019 versus bosentan).Treatment with bosentan significantly increased the time toclinical worsening compared with placebo (P=0.033). All sec-Table 1. Haemodynamic effects of placebo and bosentan atweek 12ChangeDifferencefrom baseline between treatmentsPlacebo Bosentan Difference(n=10) (n=20) (95% CI) pVariableCardiac index (mean [SE], L min–1m–2) 0·5 (0·1) 0·5 (0·1) 1·0 (0·6 to 1·4)


8 | JOURNALSCANTargeting Endothelin-1 in PAH With Bosentan (continued)Tracleer is indicated for the treatment of pulmonary arterial hypertension (PAH) in patients with WHO Class II-IV symptoms, toimprove exercise ability and decrease the rate of clinical worsening. Patients with WHO Class II symptoms showed reduction in therate of clinical deterioration and a trend for improvement in walk distance. Physicians should consider whether these potential benefitsare sufficient to offset the risk of liver injury in WHO Class II patients, which may preclude future use as their disease progresses.Important safety informationBecause of the associated risks, Tracleer may be prescribed only through the Tracleer Access Program.Potential for serious liver injury (including, after prolonged treatment, rare cases of liver failure and unexplained hepatic cirrhosis in asetting of close monitoring)—Liver monitoring of all patients is essential prior to initiation of treatment and monthly thereafter.High potential for major birth defects—Pregnancy must be excluded and prevented through the use of reliable forms of birth control;monthly pregnancy tests should be obtained.Contraindicated for use with cyclosporine A and glyburide.Please see accompanying full prescribing information on back cover and the safety profile information included on pages 15 and 16.REFERENCE1. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endotheln-receptor antagonist bosentan in patients with pulmonary hypertension: a randomized placebo-controlledstudy. Lancet. 2001;358:1119-1123.


10 | JOURNALSCANBosentan Therapy For Pulmonary Arterial Hypertension (continued)Subgroup analyses demonstrated significant improvementin the walk test with bosentan regardless of sex, cause of disease,associated congenital heart defect, time from diagnosis,baseline walk-test performance, and baseline hemodynamics.Bosentan had a similar effect in patients with primary PAHand those with PAH associated with connective tissue disease.There were no apparent differences in treatment effects amongsubgroups, as the study was not designed to detect such differences.However, the dual endothelin-receptor antagonistimproved 6-minute walk distance by 46 meters in 102 patientswith primary PAH compared with a 5-meter decline among 48patients with primary PAH in the placebo group. Bosentantherapy improved walk distance by 3 meters among 33 patientswith PAH associated with connective tissue disease, whereas 14similar patients in the placebo group had a 40-meter deteriorationin walk distance.The Borg dyspnea index decreased by an average of 0.1 inpatients assigned to the lower dosage of bosentan and by anaverage of 0.6 in patients assigned to 250 mg BID. The indexincreased by an average of 0.3 in the placebo group. Theplacebo-corrected improvement was statistically significantwith the higher dosage of bosentan (P=0.012), but not the125 mg BID dosage (Figure 2).For both doses of bosentan combined, 42% of patientshad improvement in WHO functional class compared with30% of placebo-treated patients. Bosentan significantlyincreased the time to clinical worsening compared withplacebo (P=0.002). The degree of improvement was similarwith both dosages of bosentan.Adverse events were similar and occurred in similar proportionsof patients in the bosentan groups and the placebogroups, with the exception of abnormal hepatic function,Figure 2. Kaplan–Meier Estimates of the Proportion of PatientsWith Clinical WorseningPatients Without Events (%)Number at riskPlaceboBosentan,125 mgBosentan,250 mg100755025Bosentan, 250 mgBosentan, 125 mgPlacebo00 4 8 12 16 20 24 28Week697470687270Source: Rubin et al. 2 Used with permission.637170which was more common in the 250mg group (14%).Abnormal hepatic function was observed in three out of theseventy four patients (4%) in the 125 mg bosentan group (seefull safety profile on pages 15-16).DISCUSSIONBoth dosages of bosentan proved superior to placebo.However, the increased frequency of abnormal liver functionwith the higher dosage suggests that 125 mg BID might bethe preferred dosage.Overall, the results confirmed the therapeutic potential ofendothelin-receptor blockade for primary PAH.62706848554810181371411376Tracleer is indicated for the treatment of pulmonary arterial hypertension (PAH) in patients with WHO Class II-IV symptoms, toimprove exercise ability and decrease the rate of clinical worsening. Patients with WHO Class II symptoms showed reduction in therate of clinical deterioration and a trend for improvement in walk distance. Physicians should consider whether these potential benefitsare sufficient to offset the risk of liver injury in WHO Class II patients, which may preclude future use as their disease progresses.Important safety informationBecause of the associated risks, Tracleer may be prescribed only through the Tracleer Access Program.Potential for serious liver injury (including, after prolonged treatment, rare cases of liver failure and unexplained hepatic cirrhosis in asetting of close monitoring)—Liver monitoring of all patients is essential prior to initiation of treatment and monthly thereafter.High potential for major birth defects—Pregnancy must be excluded and prevented through the use of reliable forms of birth control;monthly pregnancy tests should be obtained.Contraindicated for use with cyclosporine A and glyburide.Please see accompanying full prescribing information on back cover and the safety profile information included on pages 15 and 16.REFERENCES1. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: A randomised placebo-controlledstudy. Lancet. 2001;358:1119-1123.2. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896-903.


JOURNALSCAN | 13Treatment of Eisenmenger Syndrome with BosentanKey Point: Bosentan is the first and only PAH therapy to be studied in a clinical trial with an exclusively dedicated populationof PAH associated with congenital heart disease (Eisenmenger Syndrome).Based on Galiè N, Beghetti M, Gatzoulis MA, et al. Bosentan therapy in patients with Eisenmenger Syndrome: a multicenter,double-blind, randomized, placebo-controlled study. Circulation. 2006;114:48-54.Until recently, no evidence-based approach to treatmentexisted for advanced pulmonary arterialhypertension (PAH) associated with congenitalheart disease, or Eisenmenger Syndrome. The syndromemanifests as a multisystem disorder associated with avariety of life-threatening complications, including hemoptysis,cerebrovascular accidents, brain abscess, cardiacarrhythmias, and syncope.Eisenmenger Syndrome evolves as the congenital heartdefect causes a major left to right shunt, induces severe pulmonaryvascular disease and PAH, and finally results inreversal of the direction of shunting and development ofcyanosis. The structural abnormalities in lung circulation associatedwith Eisenmenger Syndrome are histologically similarto those caused by other forms of PAH.Endothelin 1 appears to have a key role in the pathogenesisof PAH, and elevated concentrations of endothelin 1 have beenobserved in patients with Eisenmenger Syndrome. Intuitively,inhibition of endothelin 1 would appear to offer a potentiallyeffective therapeutic approach.Bosentan is an oral dual endothelin-1 receptor antagonist thathas demonstrated efficacy in idiopathic PAH and PAH relatedto connective tissue disease. 1,2 Small, uncontrolled studies havesuggested that bosentan may improve exercise capacity andhemodynamics in patients with Eisenmenger Syndrome. 3-6The Bosentan Randomized Trial of Endothelin AntagonistTherapy-5 (BREATHE-5) was the first controlled study ofbosentan in patients with Eisenmenger Syndrome. 7METHODSBREATHE-5 included patients older than 12 years withEisenmenger Syndrome and associated World HealthOrganization (WHO) functional class III PAH. Presence ofthe syndrome was established by echocardiography andcardiac catheterization.Eligibility criteria included systemic pulse oximetry (SpO2)of 70% to 90% at rest with room air and a 6-minute walk distanceof 150 to 450 meters. Exclusion criteria included patentductus arteriosus, complex congenital heart defect, left ventriculardysfunction, restrictive lung disease, obstructive lungdisease, and coronary artery disease.Investigators at 15 centers in Europe, North America, andAustralia randomized patients 2:1 to bosentan or placebo.Bosentan therapy began at a dosage of 62.5 mg BID for4 weeks, followed by 125 mg BID for an additional 12 weeks.Patients who could not tolerate the 125 mg BID dosage couldbe downtitrated to the starting dosage.The trial had both a first and a second primary endpoint.The first was a safety endpoint in the form of change in SpO2from baseline to week 16. The second primary endpoint wasthe change in pulmonary vascular resistance index (PVRi)from baseline to week 16. Investigators conducted a noninferioritytest to compare bosentan and placebo. If the nullhypothesis related to SpO2 was rejected, a second test was performedto compare bosentan and placebo with respect to effecton PVRi, defined as (mean pulmonary arterial pressure minusleft atrial pressure)/systemic blood flow index X 80.RESULTSThe trial included 54 patients, 37 randomized to bosentanand 17 to placebo. The patient groups were well matched withrespect to baseline characteristics (Figure 1).Figure 1. Change From Baseline of 6-Minute Walk Distancein Placebo and Bosentan GroupsSix-Minute Walk Distance (m)Change From Baseline55453525155-5-15-25-35Placebo (n=17)TE=treatment effect.Source: Galiè et al. 7 Used with permission.Bosentan (n=37)TE=53.1 mP=0.008The baseline SpO2 averaged 83.6% in the placebo group and83.7% in the bosentan group. Direct measurement of SpO2 byleft-heart catheterization yielded baseline averages of 82.4% inthe placebo group and 80.2% in the bosentan group. Theplacebo-corrected effect was 1.0 (95% confidence interval [CI],


14 | JOURNALSCANTreatment of Eisenmenger Syndrome with Bosentan (continued)-0.7–2.8) >-5, which met the criteria for noninferiority andconfirmed that bosentan does not reduce systemic arterial bloodoxygen saturation. No patient in either group had as much as a10% decrease in SpO2 from baseline.The PVRi increased by 5.4% in the placebo group, butdecreased by 9.3% in bosentan-treated patients, resulting in astatistically significant treatment effect (P=0.0383). The systemicvascular resistance index increased by 10.4% in theplacebo group and declined by 11.5% in the bosentan group,but the difference did not achieve statistical significance.The 6-minute walk distance decreased by 9.7 meters in theplacebo group and increased by 43.4 meters in the bosentangroup. The net treatment effect of 53.1 meters was statisticallysignificant (P=0.008). The treatment effect remained significantin a robustness analysis (P=0.0176).Two placebo-treated patients improved to functional class IIcompared with 13 patients in the bosentan group. One patientin each group had deterioration to WHO class IV.Several adverse events occurred more often with bosentanthan with placebo: peripheral edema (19% vs 6%), headache(14% vs 12%), palpitations (11% vs 0%), dizziness (8% vs6%), and chest pain (8% vs 0%). Severe adverse events wereinfrequent (8% with bosentan and 18% with placebo). Twopatients in each group discontinued because of adverse events(see full safety profile on pages 15-16).A total of 37 patients (11 placebo, 26 bosentan) who completedrandomized therapy entered a 24-week open-labelextension study. At the end of the extension phase, placebotreatedpatients switched to bosentan had a 33.2-meterimprovement in the 6-minute walk distance, and patients originallytreated with bosentan maintained the initial effect,increasing the mean difference by 6.7 meters.DISCUSSIONIn this first-ever randomized, placebo-controlled trial foradults with Eisenmenger Syndrome, bosentan significantlyimproved hemodynamics and exercise capacity withoutadversely affecting systemic arterial oxygen saturation. Theresults indicate that bosentan may represent a treatmentoption for patients with the syndrome.Tracleer is indicated for the treatment of pulmonary arterial hypertension (PAH) in patients with WHO Class II-IV symptoms, toimprove exercise ability and decrease the rate of clinical worsening. Patients with WHO Class II symptoms showed reduction in therate of clinical deterioration and a trend for improvement in walk distance. Physicians should consider whether these potential benefitsare sufficient to offset the risk of liver injury in WHO Class II patients, which may preclude future use as their disease progresses.Important safety informationBecause of the associated risks, Tracleer may be prescribed only through the Tracleer Access Program.Potential for serious liver injury (including, after prolonged treatment, rare cases of liver failure and unexplained hepatic cirrhosis in asetting of close monitoring)—Liver monitoring of all patients is essential prior to initiation of treatment and monthly thereafter.High potential for major birth defects—Pregnancy must be excluded and prevented through the use of reliable forms of birth control;monthly pregnancy tests should be obtained.Contraindicated for use with cyclosporine A and glyburide.Please see accompanying full prescribing information on back cover and the safety profile information included on pages 15 and 16.REFERENCES1. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: A randomised placebo-controlled study.Lancet. 2001;358:1119-1123.2. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896-903.3. Christensen DD, McConnell ME, Book WM, Mahle WT. Initial experience with bosentan therapy in patients with the Eisenmenger syndrome. Am J Cardiol. 2004;94:261-263.4. Gatzoulis MA, Rogers P, Li W, et al. Safety and tolerability of bosentan in adults with Eisenmenger physiology. Int J Cardiol. 2005;98:147-151.5. Apostolopoulou SC, Manginas A, Cokkinos DV, Rammos S. Effect of the oral endothelin antagonist bosentan on the clinical, exercise, and haemodynamic status of patients withpulmonary arterial hypertension related to congenital heart disease. Heart. 2005;91:1447-1452.6. Schulze-Neick I, Gilbert N, Ewert R, et al. Adult patients with congenital heart disease and pulmonary arterial hypertension: First open prospective multicenter study of bosentantherapy. Am Heart J. 2005;150:716.e7-716.e12.7. Galiè N, Beghetti M, Gatzoulis MA, et al. Bosentan therapy in patients with Eisenmenger syndrome: A multicenter, double-blind, randomized, placebo-controlled study.Circulation. 2006;114:48-54.


JOURNALSCAN | 15SAFETY PROFILELiver and pregnancy warningsBecause of the risks associated with treatment, the useof Tracleer requires participation in the Tracleer AccessProgram (T.A.P. ® ), a restricted distribution program. In orderto receive Tracleer, prescribers and patients must enroll inT.A.P. and agree to comply with the requirements of thisprogram.Tracleer may cause liver damage In the Tracleer pivotal clinical trials, Tracleer caused atleast 3-fold (upper limit of normal; ULN) elevation of liveraminotransferases (ALT and AST) in about 11% of patients,accompanied by elevated bilirubin in a small number ofcases. Because these changes are a marker for potential seriousliver injury, liver monitoring of all patients is essential prior toinitiation of treatment and monthly thereafter. Elevations in aminotransferases require close attention. Discontinue Tracleer if aminotransferase elevations areaccompanied by signs or symptoms of liver dysfunction orinjury or increases in bilirubin ≥2 × ULN.Liver enzyme elevations: experience andmanagement Use of Tracleer should generally be avoided in patients withelevated aminotransferases (>3 × ULN) at baseline becausemonitoring liver injury may be more difficult. It is important to adhere strictly to the monthly monitoringschedule for the duration of treatment.— Changes in aminotransferases may occur early or late intreatment.— There have been rare postmarketing reports of liverfailure and unexplained hepatic cirrhosis in a setting ofclose monitoring; the contribution of Tracleer could notbe excluded.Pregnancy must be excluded and prevented Tracleer is very likely to produce major birth defects if usedby pregnant females, based on animal data. To prevent pregnancy, females of childbearing potentialmust use 2 reliable methods of contraception duringtreatment and for 1 month after stopping Tracleer.— No other contraception is needed for patients who have atubal sterilization or Copper T 380A IUD orLNg-20 IUS inserted. Hormonal contraceptives, including oral, injectable,transdermal, and implantable contraceptives, should not beused as the sole means of contraception because they maynot be effective in patients receiving Tracleer. Monthly pregnancy tests should be obtained.Tracleer aminotransferase (ALT/AST)management 1ALT/AST level1 to 3 × ULN>3 to ≤5 × ULN>5 to ≤8 × ULNTreatment and monitoring recommendationsContinue to monitor; no change in monitoringschedule or dosageConfirm by another test; if confirmed, reducethe dose or interrupt treatment and monitor LFTlevels every 2 weeksContinue or reintroduce Tracleer if levelsreturn to pretreatment levelsConfirm by another test; if confirmed, stoptherapy; monitor LFTs at least every 2 weeksConsider reintroduction of therapy if LFTsreturn to pretreatment levels>8 × ULN Stop therapy; do not reintroduceIf Tracleer is reintroduced, it should be at the starting dose;aminotransferase levels should be checked within 3 days andthereafter according to the recommendations above.If liver aminotransferase elevations are accompanied byclinical symptoms of liver injury (such as nausea, vomiting,fever, abdominal pain, jaundice, or unusual lethargy orfatigue) or increases in bilirubin ≥2 × ULN, treatment shouldbe stopped. There is no experience with the reintroduction ofTracleer in these circumstances.Safety profile: warnings, precautions, adverseevents, and drug interactionsAdverse events occurring in ≥3% of patients treatedwith Tracleer and morefrequently than theplacebo group 1Adverse eventRespiratorytract infectionTracleer: Indicated for PAH WHO functional class II, III, IVTracleer(n=258)Placebo(n=172)Adverse eventTracleer(n=258)Placebo(n=172)56 (22%) 30 (17%) Hypotension 10 (4%) 3 (2%)Headache 39 (15%) 25 (14%) Sinusitis 9 (4%) 4 (2%)Edema 28 (11%) 16 (9%) Arthralgia 9 (4%) 3 (2%)Chest pain 13 (5%) 8 (5%)Liver functiontest abnormal9 (4%) 3 (2%)Syncope 12 (5%) 7 (4%) Palpitations 9 (4%) 3 (2%)Flushing 10 (4%) 5 (3%) Anemia 8 (3%) –Please see accompanying full prescribing information on back cover

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