Pulmonary Hypertension, July 2006
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Ghislaine SURREL
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Posted 08/14/2006
Steven D. Nathan, MD
The Pulmonary Hypertension Journal Scan is the clinician's guide to the latest clinical research findings from JAMA, The New England Journal of Medicine, CHEST, and other journals of interest. Short summaries of feature articles include links to the article abstracts when available. (Access to full-text articles usually requires registration at the specific journal's Web site.)
From
Chest
( Volume 130, Number 1 )
Becattini C, Agnelli G, Pesavento R, et al
Chest. 2006;130(1):172-175
When diagnosing pulmonary hypertension, one of the causes to exclude in the work- up algorithm of any patient presenting with the condition, is chronic thromboembolic disease (CTED). Exclusion of this World Health Organization group III etiology is important since the treatment algorithm is different in that patients might have surgically amenable disease. In addition, not all such patients have a prior history suggestive of an acute thromboembolic event. The Ventilation/Perfusion (V/Q) scan is traditionally relied upon to exclude this condition. But what about the other end of this equation, specifically, how many patients with acute pulmonary emboli (PE) are at risk of developing CTED? It has been variously estimated that this figure is between 0.1% to 3.8%.[1,2]
This group of investigators out of Italy sought to establish the incidence of CTED by prospectively studying 259 consecutive patients diagnosed with acute PE. To qualify for inclusion, all patients had their PEs objectively confirmed, required anticoagulation therapy for a period of 3 to 12 months, and could have no risk factors (or a temporary risk factor such as recent surgery) for thromboembolism. Patients with known persistent risk factors for thromboembolism were excluded. PE was "unprovoked " in 135 of the patients and was associated with a temporary risk factor in the remaining 124. The average follow-up period was 46 months during which time 21 patients died (8.1%) and 31 (12%) had recurrence of a thromboembolic event, with a second PE in half of these. Although persistent dyspnea was found in 37 of the patients, there were usually other causes for this. CTED was documented in only 2 of these cases for an incidence of 0.8%. Both cases occurred within 2 years of the initial PE event. Both patients did not have risk factors for PE and, therefore, the incidence in patients without temporary risk factors translated to 1.5% (2/135). The authors offer some possible explanations for this low incidence of CTED, including low severity of the initial PE event and the effects of appropriate anticoagulation thereafter. They also raise questions about the conventional wisdom of CTED, specifically that it occurs several years after the initial acute PE and that it doesn't occur after a single episode of acute PE.
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This program was supported by an independent educational grant from Actelion.
Sanchez O, Sitbon O, Jais X, et al
Chest. 2006;130(1):182-189
Pulmonary arterial hypertension (PAH) can complicate the course of various connective tissue disorders (CTD), and immune and/or inflammatory mechanisms likely do play a significant role in the genesis of PAH in some of these patients. The authors of this paper sought to evaluate the effects of immunosuppressive therapy in patients who were both immunosuppressive-therapy and PAH-therapy naïve. Importantly, patients with significant interstitial lung disease were excluded (total lung capacity [TLC] and forced vital capacity FVC] > 60%).The authors identified 28 patients over a 10-time span that constituted the cohort for this retrospective review. Of these, 13 patients had systemic lupus erythematosus (SLE), 8 had mixed connective tissue disease (MCTD), 6 had scleroderma, and one had rheumatoid arthritis (RA). The baseline 6-minute walk distance of the group was 256 meters, the mPAP was 50 ± 13 mm Hg, and the cardiac index was 2.7 ± 0.7 L/min/m2. Seven of the patients were NYHA class II, 16 class II, and 5 class IV at baseline. All patients received conventional therapy in the form of diuretics, anticoagulation, and oxygen, if needed. Immunosuppressive therapy was instituted using monthly pulsed intravenous cyclophosphamide at a dose of 600 mg/M2 for at least 3 months. Some 22 of 28 patients received oral steroids at 0.5-1.0 mg/kg/day.
A positive response to therapy was defined as patients in NYHA class I or II with sustained hemodynamic response after at least one year of immunosuppressive therapy without the need for any additional PAH-specific medications. 8/28 patients (29%) had such a response. Five of these patients had SLA and 3 had MCTD with none of the scleroderma patients manifesting a response. This represented 38% (5/13) and 37% (3/8) of the SLE and MCTD groups who were trialed on therapy. The fact that no scleroderma patients had a response is noteworthy and in keeping with a lack of reports in the literature on this subject. The responders had an associated increase in their mean 6-minute walk distance from 294 to 449 meters. Survival was also better in this group with a 5-year survival rate of 100% vs a 38% 5-year survival rate for the nonresponders. Only 1 patient in the responder group required PAH-specific medication after an initial response to therapy compared to 75% of the nonresponders. The patients who responded tended to be less sick than the nonresponders, based on their hemodynamic profiles, functional class, and 6-minute walk distance (294 for responders vs 240 meters for nonresponders). This suggests that the responders might have been at an earlier phase of their disease.
The authors did a nice job of highlighting the limitations and pitfalls of their retrospective study. Nonetheless, they do provide valuable insight into a subject where there is a paucity of literature. They end with their own recommendations based on their clinical practice. They suggest that patients with SLE or MCTD-associated PAH in NYHA class I or II should receive first-line steroids and cyclophosphamide for 3 to 6 months. If there is no improvement in their clinical and hemodynamic profile over this timeframe, then these therapies should be stopped. Patients with class III or IV symptoms should receive both immunosuppressive therapy in combination with PAH-specific therapy.
From
Circulation
July 2006 ( Volume 4, Number 114 )
Galie N, Beghetti M, Gatzoulis MA, et al
Circulation. 2006;4(114):48-54
A diagnosis of Eisenmenger's syndrome carries with it a prognosis that is better than that of idiopathic pulmonary arterial hypertension (IPAH) with a 1-year survival reported at 98% and 58% by 10 years.[1] Nonetheless, it is associated with significant exercise impairment and morbidity including hemoptysis, cerebrovascular accidents, brain abscesses, arrhythmias, and syncope. Like IPAH, endothelin has been shown to be upregulated in patients with Eisenmenger's.[2] This paper reports the results of the aptly named "BREATH-5" study, which was designed to investigate the effects of the dual endothelin antagonist, bosentan, in patients with Eisenmenger's syndrome.
This was a multicenter, prospective 16-week study of 54 patients with this condition. Patients were excluded if they had patent ductus arteriosus or other complex congenital heart disease. The first primary endpoint was safety, specifically the authors wanted to establish that gas exchange was not worsened by looking at the change in SpO2 from baseline to week 16 on room air at rest. The second primary endpoint was the change in the pulmonary vascular resistance index at the 2 time periods. A number of secondary endpoints were also assessed.
Patients received bosentan at the standard dose or a placebo in a 2:1 randomization. The 2 groups were well matched although the pulmonary vascular resistance index (PVRi) was slightly higher in the bosentan group. All patients were in World Health Organization (WHO) functional class III with baseline 6-minute walk distances (6MWD) and resting pulse oximetry (SpO2) of 332 meters and 82.4% vs 366 meters and 83.6% in the bosentan and placebo arms, respectively. The placebo-corrected effect on the SpO2 was 1.0 (c.i. -0.7 to 2.8) demonstrating noninferiority and, therefore, meeting the primary endpoint of the study. The PVRi increased in the placebo arm by 5.4% vs a decrease in the bosentan arm of 9.3%. There was also an associated significant decrease in the mean PAP in the bosentan group of 5.5 mm Hg. The 6MWD decreased in the placebo arm by 9.7 meters and increased in the bosentan group by 43.3 meters for a placebo-adjusted difference of 53.1 meters (P = .008 -- quite impressive!) Thirty-five percent of the bosentan patients improved to WHO class II vs 13% of the placebo patients. One patient in each group deteriorated to class IV and the rest remained in WHO class III.
An open-label extension included 11 patients who had previously been in the placebo arm and 26 of the treated patients. There was an increase in the 6MWD in the former group of 33.2 meters and maintenance of the salutary effect in the latter group (6MWD + 6.7 meters) at 24 weeks.
In summary, this trial demonstrates that bosentan improves hemodynamics and exercise capacity without compromising oxygenation in patients with Eisenmenger's syndrome. The magnitude of the effect, based on changes in the 6MWD and hemodynamics, appeared to be equivalent to that seen in other trials of bosentan for other forms of PAH.[3,4]
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From
European Respiratory Journal
July 2006 ( Volume 28, Number 1 )
Hughes RJ, Bonderman D, Suntharalingam J, et al
European Respiratory Journal. 2006;28(1):138-143
Chronic thromboembolic disease (CTED) is an important condition to differentiate in the work-up of patients with pulmonary hypertension as the treatment algorithm includes the possibility of surgical thromboendarterectomy which can be curative. It is thought to develop in patients with unresolved pulmonary emboli, although not all patients with this condition have a prior history of thromboembolic disease. In unobstructed vessels exposed to high flow and shear stresses, there is the development of a small vessel arteriopathy which perpetuates the resultant pulmonary hypertension. Not all patients are candidates for surgical intervention, especially if the embolic phenomenon involves more distal vessels.
There have been anecdotal reports of successful medical therapy of patients with CTED including with the use of bosentan.[1,2] Long-term follow-up (1 year) of the use of bosentan in such patients was the subject of this retrospective review from 3 European specialist centers. There were 47 patients with inoperable CTED disease who qualified for the analysis. Eight of these patients had previously undergone pulmonary endarterectomy (PEA) (17%). Stratification by World Health Organization (WHO) class included 10, 32, and 5 patients who were class II, III, and IV, respectively. The mean pulmonary artery pressure (mPAP) of the group was 50 ± 2 mm Hg. The primary outcome measures were the 6-minute walk distance (6MWD) and WHO classification. The baseline 6MWD of the group was 312 ± 17 meters.
Patients were treated with the standard dose of bosentan (125 mg twice a day) with provision to increase the dose. By 4 months, the 6MWD had increased by 49 ± 8.4 meters and at one year the 6MWD was 52 ± 10 meters compared to baseline. The WHO class improved in 1 (24%) of the patients, it remained stable in the remainder. Two patients had died by one year, 2 had commenced on alternative therapies for their disease, and 3 had their bosentan dose increased to 250 mg twice a day. The improvement in the 6MWD was most marked in those patients who had previously undergone PEA (102 vs 0 meters). This makes intuitive sense from the standpoint that this group was likely more limited from residual small vessel arteriopathy vs the other patients who still had a significant more proximal mechanical component to their pulmonary hypertension. The 1-year survival was 96% with 43 patients remaining on bosentan monotherapy. This compares very favorably with data from another study including a control group of patients with CTED in whom a mPAP > 50 mm Hg was associated with a 1-year survival of only 40%.[3] Two-year data was available in 18 patients, 15 of whom remained on bosentan monotherapy.
In conclusion, the authors note that bosentan was well tolerated and can result in sustained improvement in function and exercise capacity in patients with CTED and may also improve survival. The authors caution that all such patients should first be assessed as potential surgical candidates and all should receive long-term anticoagulation.
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http://www.medscape.com/viewarticle/541796_3
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