今日の臨床サポート

肺性心

著者: 波多野将 東京大学 循環器内科/高度心不全治療センター

監修: 今井靖 自治医科大学 薬理学講座臨床薬理学部門・内科学講座循環器内科学部門

著者校正済:2021/09/01
現在監修レビュー中
参考ガイドライン:
  1. 日本循環器学会肺高血圧症治療ガイドライン(2017年改訂版)
  1. 日本肺高血圧・肺循環学会/厚生労働科学研究費補助金 難治性疾患政策研究事業「難治性呼吸器疾患・肺高血圧症に関する調査研究」班:特発性/遺伝性肺動脈性肺高血圧症(IPAH/HPAH)診療ガイドライン
  1. 日本肺高血圧・肺循環学会/厚生労働科学研究費補助金 難治性疾患政策研究事業「難治性呼吸器疾患・肺高血圧症に関する調査研究」班:慢性血栓塞栓性肺高血圧症(CTEPH)診療ガイドライン
患者向け説明資料

概要・推奨   

  1. 心エコーで三尖弁逆流速度が3.4m/sを超える場合には肺高血圧が疑われ、2.8m/s以下の場合には肺高血圧の可能性は低い(推奨度1)
  1. 肺高血圧症の患者には在宅酸素療法が適応となる。特にCOPDによる肺性心の患者では、酸素投与による目標PaO2は60Torr(SpO2 90%)以上とする(推奨度1)
  1. COPDの患者には強く禁煙を勧めるべきである(推奨度1)
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約
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  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
波多野将 : 講演料(ヤンセンファーマ,バイエル薬品),企業などが提供する寄付講座(日本新薬,持田製薬)[2021年]
監修:今井靖 : 講演料(第一三共株式会社)[2021年]

改訂のポイント:
  1. 定期レビューを行った(患者数についてアップデートを行った。また、肺動脈性肺高血圧症を呈する膠原病に原発性シェーグレン症候群を加えた)。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 肺性心とは、「肺、肺血管または肺のガス交換を一次的に障害して肺高血圧を引き起こす疾患により、右室肥大あるいは右室不全を生じた状態」と定義される。
  1. 肺高血圧が生じる主な機序には、肺血管そのものが閉塞もしくは狭小化することにより起こる血管性のものと、換気障害あるいはガス交換障害を生じるような呼吸器疾患により起こるものがある。
    前者に分類される疾患には肺動脈性肺高血圧症(PAH)や肺血栓塞栓症などがあり、後者に分類される疾患には慢性閉塞性肺疾患(COPD)、肺線維症、肺結核後遺症、睡眠時無呼吸症候群(SAS)、原発性肺胞低換気症候群などがある。
  1. 「平均肺動脈圧25mmHg以上」により定義される肺高血圧症とほとんどの部分でオーバーラップするが、先天性心疾患や左心疾患による肺高血圧症は含まれない。
  1. 肺高血圧の診断基準は2018年にフランスのニースで開催された第6回世界肺高血圧症シンポジウムにより「平均肺動脈圧>20mmHg」に変更となった。今後わが国のガイドラインにおいてもこれに合わせて診断基準が変更になる可能性がある[1]
 
 
  1. 肺性心の主要な原因疾患はCOPDであり、中等度以上のCOPDの約半数に肺性心を合併するという報告もある。PAHのうち、特発性もしくは遺伝性肺動脈性肺高血圧症(IPAH/HPAH)の患者は2013年現在で1,377人が登録されている。全身性強皮症、混合性結合組織病(MCTD)、全身性エリテマトーデスなどの膠原病の患者には、5~10%の頻度でPAHが合併するとされている。また、頻度は不明であるが、原発性シェーグレン症候群においてもPAHを合併することがある。慢性血栓塞栓症性肺高血圧症(CTEPH)の患者は、2016年現在で3,200人が登録されている。
  1. 肺性心の多くは慢性の経過で起こるものであるが、急性肺血栓塞栓症のように急性の経過で起こる肺性心もある。
 
  1. 肺性心を来す疾患の多くは難病として厚生労働省の定めるところの特定疾患であり、特定疾患の受給者は患者自己負担額の全額もしくは一部が自己負担となる。(参考文献:[2]
  1. まとめ:肺性心を来す疾患の多くは難病として厚生労働省の定めるところの特定疾患であり、特定疾患の受給者は患者自己負担額の全額もしくは一部が自己負担となる。肺動脈性肺高血圧症の治療薬をはじめとして、肺性心の治療薬は高額であるものが多いため、患者の負担軽減のためにも基準を満たす患者に対しては本制度を受給させるようにする。肺性心に関する主な特定疾患については図を参照されたい(<図表>)。
  1. 追記:各疾患の認定基準等の詳細については、難病情報センターのホームページを参照されたい。
 
肺高血圧症に関する主な厚生労働省特定疾患(2007年7月現在)

肺性心を来す疾患の多くは表のように厚生労働省が指定する特定疾患に指定されている。

出典

問診・診察のポイント  
  1. 肺性心を引き起こすような背景(喫煙歴、肺結核の既往、肺高血圧症の家族歴、膠原病の合併など)がないかどうかを確認する。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

著者: Nazzareno Galiè, Marc Humbert, Jean-Luc Vachiery, Simon Gibbs, Irene Lang, Adam Torbicki, Gérald Simonneau, Andrew Peacock, Anton Vonk Noordegraaf, Maurice Beghetti, Ardeschir Ghofrani, Miguel Angel Gomez Sanchez, Georg Hansmann, Walter Klepetko, Patrizio Lancellotti, Marco Matucci, Theresa McDonagh, Luc A Pierard, Pedro T Trindade, Maurizio Zompatori, Marius Hoeper, Victor Aboyans, Antonio Vaz Carneiro, Stephan Achenbach, Stefan Agewall, Yannick Allanore, Riccardo Asteggiano, Luigi Paolo Badano, Joan Albert Barberà, Hélène Bouvaist, Héctor Bueno, Robert A Byrne, Scipione Carerj, Graça Castro, Çetin Erol, Volkmar Falk, Christian Funck-Brentano, Matthias Gorenflo, John Granton, Bernard Iung, David G Kiely, Paulus Kirchhof, Barbro Kjellstrom, Ulf Landmesser, John Lekakis, Christos Lionis, Gregory Y H Lip, Stylianos E Orfanos, Myung H Park, Massimo F Piepoli, Piotr Ponikowski, Marie-Pierre Revel, David Rigau, Stephan Rosenkranz, Heinz Völler, Jose Luis Zamorano
雑誌名: Eur Heart J. 2016 Jan 1;37(1):67-119. doi: 10.1093/eurheartj/ehv317. Epub 2015 Aug 29.
Abstract/Text
PMID 26320113  Eur Heart J. 2016 Jan 1;37(1):67-119. doi: 10.1093/eurh・・・
著者: Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC), European Respiratory Society (ERS), International Society of Heart and Lung Transplantation (ISHLT), N Galiè, M M Hoeper, M Humbert, A Torbicki, J-L Vachiery, J A Barbera, M Beghetti, P Corris, S Gaine, J S Gibbs, M A Gomez-Sanchez, G Jondeau, W Klepetko, C Opitz, A Peacock, L Rubin, M Zellweger, G Simonneau
雑誌名: Eur Respir J. 2009 Dec;34(6):1219-63. doi: 10.1183/09031936.00139009. Epub 2009 Sep 12.
Abstract/Text
PMID 19749199  Eur Respir J. 2009 Dec;34(6):1219-63. doi: 10.1183/0903・・・
著者: N Nagaya, T Nishikimi, M Uematsu, T Satoh, S Kyotani, F Sakamaki, M Kakishita, K Fukushima, Y Okano, N Nakanishi, K Miyatake, K Kangawa
雑誌名: Circulation. 2000 Aug 22;102(8):865-70.
Abstract/Text BACKGROUND: Plasma brain natriuretic peptide (BNP) level increases in proportion to the degree of right ventricular dysfunction in pulmonary hypertension. We sought to assess the prognostic significance of plasma BNP in patients with primary pulmonary hypertension (PPH).
METHODS AND RESULTS: Plasma BNP was measured in 60 patients with PPH at diagnostic catheterization, together with atrial natriuretic peptide, norepinephrine, and epinephrine. Measurements were repeated in 53 patients after a mean follow-up period of 3 months. Forty-nine of the patients received intravenous or oral prostacyclin. During a mean follow-up period of 24 months, 18 patients died of cardiopulmonary causes. According to multivariate analysis, baseline plasma BNP was an independent predictor of mortality. Patients with a supramedian level of baseline BNP (>/=150 pg/mL) had a significantly lower survival rate than those with an inframedian level, according to Kaplan-Meier survival curves (P<0.05). Plasma BNP in survivors decreased significantly during the follow-up (217+/-38 to 149+/-30 pg/mL, P<0. 05), whereas that in nonsurvivors increased (365+/-77 to 544+/-68 pg/mL, P<0.05). Thus, survival was strikingly worse for patients with a supramedian value of follow-up BNP (>/=180 pg/mL) than for those with an inframedian value (P<0.0001).
CONCLUSIONS: A high level of plasma BNP, and in particular, a further increase in plasma BNP during follow-up, may have a strong, independent association with increased mortality rates in patients with PPH.

PMID 10952954  Circulation. 2000 Aug 22;102(8):865-70.
著者: Olivier Sanchez, Ludovic Trinquart, Isabelle Colombet, Pierre Durieux, Menno V Huisman, Gilles Chatellier, Guy Meyer
雑誌名: Eur Heart J. 2008 Jun;29(12):1569-77. doi: 10.1093/eurheartj/ehn208. Epub 2008 May 21.
Abstract/Text AIMS: To determine the prognostic value of right ventricular (RV) dysfunction assessed by echocardiography or spiral computed tomography (CT), or by increased levels of cardiac biomarkers [troponin, brain natriuretic peptide (BNP) and pro-BNP] in patients with haemodynamically stable pulmonary embolism (PE).
METHODS AND RESULTS: We included all studies published between January 1985 and October 2007 estimating the relationship between echocardiography, CT or cardiac biomarkers and the risk of death in patients with haemodynamically stable PE. Twelve of 722 potentially relevant studies met inclusion criteria. The unadjusted risk ratio of RV dysfunction as assessed by echocardiography (five studies) or by CT (two studies) for predicting death was 2.4 [95% confidence interval (CI) 1.3-4.4]. The unadjusted risk ratio for predicting death was 9.5 (95% CI 3.2-28.6) for BNP (five studies), 5.7 (95% CI 2.2-15.1) for pro-BNP (two studies) and 8.3 (95% CI 3.6-19.3) for cardiac troponin (three studies). Threshold values differed substantially between studies for all markers.
CONCLUSION: RV dysfunction assessed by CT, echocardiography, or by cardiac biomarkers are all associated with an increased risk of mortality in patients with haemodynamically stable PE. These findings should be interpreted with caution because of the clinical and methodological diversity of studies.

PMID 18495689  Eur Heart J. 2008 Jun;29(12):1569-77. doi: 10.1093/eurh・・・
著者: Hanno H Leuchte, Rainer A Baumgartner, Michal El Nounou, Michael Vogeser, Claus Neurohr, Michael Trautnitz, Juergen Behr
雑誌名: Am J Respir Crit Care Med. 2006 Apr 1;173(7):744-50. doi: 10.1164/rccm.200510-1545OC. Epub 2006 Jan 13.
Abstract/Text RATIONALE: The detection of pulmonary hypertension in patients with chronic lung disease has prognostic implications. The brain natriuretic peptide (BNP) has been suggested as a noninvasive marker for the presence and severity of pulmonary hypertension.
OBJECTIVES: We evaluated circulating BNP levels as a parameter for the presence and severity of pulmonary hypertension in patients with chronic lung disease.
METHODS: BNP levels were measured in 176 consecutive patients with various pulmonary diseases. Right heart catheterization, lung functional testing, and a 6-min walk test were performed. The mean follow-up time was nearly 1 yr.
MEASUREMENTS AND MAIN RESULTS: Significant pulmonary hypertension (mean pulmonary artery pressure > 35 mm Hg) was diagnosed in more than one-fourth of patients and led to decreased exercise tolerance and life expectancy. Elevated BNP concentrations identified significant pulmonary hypertension with a sensitivity of 0.85 and specificity of 0.88 and predicted mortality. Moreover, BNP served as a risk factor of death independent of lung functional impairment or hypoxemia in uni- and multivariate analysis.
CONCLUSION: We suggest BNP as a prognostic marker and as screening parameter for significant pulmonary hypertension in chronic lung disease.

PMID 16415273  Am J Respir Crit Care Med. 2006 Apr 1;173(7):744-50. do・・・
著者: Marius M Hoeper, Christian Apitz, Ekkehard Grünig, Michael Halank, Ralf Ewert, Harald Kaemmerer, Hans-Joachim Kabitz, Christian Kähler, Hans Klose, Hanno Leuchte, Silvia Ulrich, Karen M Olsson, Oliver Distler, Stephan Rosenkranz, H Ardeschir Ghofrani
雑誌名: Int J Cardiol. 2018 Dec 1;272S:37-45. doi: 10.1016/j.ijcard.2018.08.082. Epub 2018 Aug 25.
Abstract/Text In the summer of 2016, delegates from the German Respiratory Society, the German Society of Cardiology and the German Society of Pediatric Cardiology met in Cologne, Germany, to define consensus-based practice recommendations for the management of patients with pulmonary arterial hypertension (PAH). These recommendations were built on the 2015 European Pulmonary Hypertension guidelines and included new evidence, where available. The treatment algorithm for PAH was modified based on the observation that there are now many patients diagnosed with IPAH who are at an advanced age and have significant cardiopulmonary comorbidities. For patients newly diagnosed with classic forms of PAH, i.e. younger patients without significant cardiopulmonary comorbidities, the consensus-based recommendation was to use initial combination therapy as the standard approach. The use of monotherapies was no longer considered appropriate in such patients. The choice of treatment strategies should be based on the risk assessment as proposed in the European guidelines. In patients presenting with a low or intermediate risk, oral combination therapy with endothelin receptor antagonists and phosphodiesterase-5 inhibitors or soluble guanylate cyclase stimulators, respectively, should be used. In high-risk patients, triple combination therapy including a subcutaneous or intravenous prostacyclin analogue should be considered. For patients who suffer from PAH and significant cardiopulmonary comorbidities, initial monotherapy is recommended and the use of combination therapies should be considered on an individual basis. The latter recommendations are based on the scarcity of evidence supporting the use of combination therapy and the higher risk of drug-related adverse events in such patients.

Copyright © 2018 Elsevier B.V. All rights reserved.
PMID 30190158  Int J Cardiol. 2018 Dec 1;272S:37-45. doi: 10.1016/j.ij・・・
著者: Robyn J Barst, J Simon R Gibbs, Hossein A Ghofrani, Marius M Hoeper, Vallerie V McLaughlin, Lewis J Rubin, Olivier Sitbon, Victor F Tapson, Nazzareno Galiè
雑誌名: J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S78-84. doi: 10.1016/j.jacc.2009.04.017.
Abstract/Text Uncontrolled and controlled clinical trials with different compounds and procedures are reviewed to define the risk-benefit profiles for therapeutic options in pulmonary arterial hypertension (PAH). A grading system for the level of evidence of treatments based on the controlled clinical trials performed with each compound is used to propose an evidence-based treatment algorithm. The algorithm includes drugs approved by regulatory agencies for the treatment of PAH and/or drugs available for other indications. The different treatments have been evaluated mainly in idiopathic PAH, heritable PAH, and in PAH associated with the scleroderma spectrum of diseases or with anorexigen use. Extrapolation of these recommendations to other PAH subgroups should be done with caution. Oral anticoagulation is proposed for most patients; diuretic treatment and supplemental oxygen are indicated in cases of fluid retention and hypoxemia, respectively. High doses of calcium-channel blockers are indicated only in the minority of patients who respond to acute vasoreactivity testing. Nonresponders to acute vasoreactivity testing or responders who remain in World Health Organization (WHO) functional class III, should be considered candidates for treatment with either an oral phosphodiesterase-5 inhibitor or an oral endothelin-receptor antagonist. Continuous intravenous administration of epoprostenol remains the treatment of choice in WHO functional class IV patients. Combination therapy is recommended for patients treated with PAH monotherapy who remain in WHO functional class III. Atrial septostomy and lung transplantation are indicated for refractory patients or where medical treatment is unavailable.

PMID 19555861  J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S78-84. doi:・・・
著者:
雑誌名: Lancet. 1981 Mar 28;1(8222):681-6.
Abstract/Text A controlled trial of long term domiciliary oxygen therapy has been carried out in three centres in the U.K. The 87 patients, all under 70 years of age, who took part had chronic bronchitis or emphysema with irreversible airways obstruction, severe arterial hypoxaemia, carbon dioxide retention, and a history of congestive heart failure. The patients were randomised to oxygen therapy (treated) or no oxygen (controls). Oxygen was given by nasal prongs for at least 15 h daily, usually at 2 1/min. The two groups were well matched, both clinically and in terms of lung function and other laboratory findings. 19 of the 42 oxygen treated patients died in the five years of survival follow-up compared with 30 out of 45 controls: in the 66 men in this trial the survival advantage of oxygen did not emerge until 500 days had elapsed. Survival for the 12 female controls was surprisingly poor, 8 of them being dead at 3 years. Mortality was not easy to predict, though a summation of arterial carbon dioxide tension and red cell mass was helpful. Neither time spent in hospital because of exacerbations of respiratory failure nor work attendance were affected by oxygen therapy, but these patients were very ill at the start of the trial and many had already retired on grounds of age or ill-health. Physiological measurements suggested that oxygen did not slow the progress of respiratory failure in those who died early. However, in longer term survivors on oxygen, arterial oxygenation did seem to stop deterioration.

PMID 6110912  Lancet. 1981 Mar 28;1(8222):681-6.
著者:
雑誌名: Ann Intern Med. 1980 Sep;93(3):391-8.
Abstract/Text At six centers, 203 patients with hypoxemic chronic obstructive lung disease were randomly allocated to either continuous oxygen (O2) therapy or 12-hour nocturnal O2 therapy and followed for at least 12 months (mean, 19.3 months). The two groups were initially well matched in terms of physiological and neuropsychological function. Compliance with each oxygen regimen was good. Overall mortality in the nocturnal O2 therapy group was 1.94 times that in the continuous O2 therapy group (P = 0.01). This trend was striking in patients with carbon dioxide retention and also present in patients with relatively poor lung function, low mean nocturnal oxygen saturation, more severe brain dysfunction, and prominent mood disturbances. Continuous O2 therapy also appeared to benefit patients with low mean pulmonary artery pressure and pulmonary vascular resistance and those with relatively well-preserved exercise capacity. We conclude that in hypoxemic chronic obstructive lung disease, continuous O2 therapy is associated with a lower mortality than is nocturnal O2 therapy. The reason for this difference is not clear.

PMID 6776858  Ann Intern Med. 1980 Sep;93(3):391-8.
著者: Nazzareno Galiè, Joan A Barberà, Adaani E Frost, Hossein-Ardeschir Ghofrani, Marius M Hoeper, Vallerie V McLaughlin, Andrew J Peacock, Gérald Simonneau, Jean-Luc Vachiery, Ekkehard Grünig, Ronald J Oudiz, Anton Vonk-Noordegraaf, R James White, Christiana Blair, Hunter Gillies, Karen L Miller, Julia H N Harris, Jonathan Langley, Lewis J Rubin, AMBITION Investigators
雑誌名: N Engl J Med. 2015 Aug 27;373(9):834-44. doi: 10.1056/NEJMoa1413687.
Abstract/Text BACKGROUND: Data on the effect of initial combination therapy with ambrisentan and tadalafil on long-term outcomes in patients with pulmonary arterial hypertension are scarce.
METHODS: In this event-driven, double-blind study, we randomly assigned, in a 2:1:1 ratio, participants with World Health Organization functional class II or III symptoms of pulmonary arterial hypertension who had not previously received treatment to receive initial combination therapy with 10 mg of ambrisentan plus 40 mg of tadalafil (combination-therapy group), 10 mg of ambrisentan plus placebo (ambrisentan-monotherapy group), or 40 mg of tadalafil plus placebo (tadalafil-monotherapy group), all administered once daily. The primary end point in a time-to-event analysis was the first event of clinical failure, which was defined as the first occurrence of a composite of death, hospitalization for worsening pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response.
RESULTS: The primary analysis included 500 participants; 253 were assigned to the combination-therapy group, 126 to the ambrisentan-monotherapy group, and 121 to the tadalafil-monotherapy group. A primary end-point event occurred in 18%, 34%, and 28% of the participants in these groups, respectively, and in 31% of the pooled-monotherapy group (the two monotherapy groups combined). The hazard ratio for the primary end point in the combination-therapy group versus the pooled-monotherapy group was 0.50 (95% confidence interval [CI], 0.35 to 0.72; P<0.001). At week 24, the combination-therapy group had greater reductions from baseline in N-terminal pro-brain natriuretic peptide levels than did the pooled-monotherapy group (mean change, -67.2% vs. -50.4%; P<0.001), as well as a higher percentage of patients with a satisfactory clinical response (39% vs. 29%; odds ratio, 1.56 [95% CI, 1.05 to 2.32]; P=0.03) and a greater improvement in the 6-minute walk distance (median change from baseline, 48.98 m vs. 23.80 m; P<0.001). The adverse events that occurred more frequently in the combination-therapy group than in either monotherapy group included peripheral edema, headache, nasal congestion, and anemia.
CONCLUSIONS: Among participants with pulmonary arterial hypertension who had not received previous treatment, initial combination therapy with ambrisentan and tadalafil resulted in a significantly lower risk of clinical-failure events than the risk with ambrisentan or tadalafil monotherapy. (Funded by Gilead Sciences and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073.).

PMID 26308684  N Engl J Med. 2015 Aug 27;373(9):834-44. doi: 10.1056/N・・・
著者: Lewis J Rubin, David B Badesch, Robyn J Barst, Nazzareno Galie, Carol M Black, Anne Keogh, Tomas Pulido, Adaani Frost, Sebastien Roux, Isabelle Leconte, Michael Landzberg, Gerald Simonneau
雑誌名: N Engl J Med. 2002 Mar 21;346(12):896-903. doi: 10.1056/NEJMoa012212.
Abstract/Text BACKGROUND: Endothelin-1 is a potent vasoconstrictor and smooth-muscle mitogen. In a preliminary study, the orally administered dual endothelin-receptor antagonist bosentan improved exercise capacity and cardiopulmonary hemodynamics in patients with pulmonary arterial hypertension. The present trial investigated the effect of bosentan on exercise capacity in a larger number of patients and compared two doses.
METHODS: In this double-blind, placebo-controlled study, we randomly assigned 213 patients with pulmonary arterial hypertension (primary or associated with connective-tissue disease) to receive placebo or to receive 62.5 mg of bosentan twice daily for 4 weeks followed by either of two doses of bosentan (125 or 250 mg twice daily) for a minimum of 12 weeks. The primary end point was the degree of change in exercise capacity. Secondary end points included the change in the Borg dyspnea index, the change in the World Health Organization (WHO) functional class, and the time to clinical worsening.
RESULTS: At week 16, patients treated with bosentan had an improved six-minute walking distance; the mean difference between the placebo group and the combined bosentan groups was 44 m (95 percent confidence interval, 21 to 67; P<0.001). Bosentan also improved the Borg dyspnea index and WHO functional class and increased the time to clinical worsening.
CONCLUSIONS: The endothelin-receptor antagonist bosentan is beneficial in patients with pulmonary arterial hypertension and is well tolerated at a dose of 125 mg twice daily. Endothelin-receptor antagonism with oral bosentan is an effective approach to therapy for pulmonary arterial hypertension.

PMID 11907289  N Engl J Med. 2002 Mar 21;346(12):896-903. doi: 10.1056・・・
著者: Nazzareno Galiè, Horst Olschewski, Ronald J Oudiz, Fernando Torres, Adaani Frost, Hossein A Ghofrani, David B Badesch, Michael D McGoon, Vallerie V McLaughlin, Ellen B Roecker, Michael J Gerber, Christopher Dufton, Brian L Wiens, Lewis J Rubin, Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies (ARIES) Group
雑誌名: Circulation. 2008 Jun 10;117(23):3010-9. doi: 10.1161/CIRCULATIONAHA.107.742510. Epub 2008 May 27.
Abstract/Text BACKGROUND: Ambrisentan is a propanoic acid-based, A-selective endothelin receptor antagonist for the once-daily treatment of pulmonary arterial hypertension.
METHODS AND RESULTS: Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study 1 and 2 (ARIES-1 and ARIES-2) were concurrent, double-blind, placebo-controlled studies that randomized 202 and 192 patients with pulmonary arterial hypertension, respectively, to placebo or ambrisentan (ARIES-1, 5 or 10 mg; ARIES-2, 2.5 or 5 mg) orally once daily for 12 weeks. The primary end point for each study was change in 6-minute walk distance from baseline to week 12. Clinical worsening, World Health Organization functional class, Short Form-36 Health Survey score, Borg dyspnea score, and B-type natriuretic peptide plasma concentrations also were assessed. In addition, a long-term extension study was performed. The 6-minute walk distance increased in all ambrisentan groups; mean placebo-corrected treatment effects were 31 m (P=0.008) and 51 m (P<0.001) in ARIES-1 for 5 and 10 mg ambrisentan, respectively, and 32 m (P=0.022) and 59 m (P<0.001) in ARIES-2 for 2.5 and 5 mg ambrisentan, respectively. Improvements in time to clinical worsening (ARIES-2), World Health Organization functional class (ARIES-1), Short Form-36 score (ARIES-2), Borg dyspnea score (both studies), and B-type natriuretic peptide (both studies) were observed. No patient treated with ambrisentan developed aminotransferase concentrations >3 times the upper limit of normal. In 280 patients completing 48 weeks of treatment with ambrisentan monotherapy, the improvement from baseline in 6-minute walk at 48 weeks was 39 m.
CONCLUSIONS: Ambrisentan improves exercise capacity in patients with pulmonary arterial hypertension. Improvements were observed for several secondary end points in each of the studies, although statistical significance was more variable. Ambrisentan is well tolerated and is associated with a low risk of aminotransferase abnormalities.

PMID 18506008  Circulation. 2008 Jun 10;117(23):3010-9. doi: 10.1161/C・・・
著者: Nazzareno Galiè, Hossein A Ghofrani, Adam Torbicki, Robyn J Barst, Lewis J Rubin, David Badesch, Thomas Fleming, Tamiza Parpia, Gary Burgess, Angelo Branzi, Friedrich Grimminger, Marcin Kurzyna, Gérald Simonneau, Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group
雑誌名: N Engl J Med. 2005 Nov 17;353(20):2148-57. doi: 10.1056/NEJMoa050010.
Abstract/Text BACKGROUND: Sildenafil inhibits phosphodiesterase type 5, an enzyme that metabolizes cyclic guanosine monophosphate, thereby enhancing the cyclic guanosine monophosphate-mediated relaxation and growth inhibition of vascular smooth-muscle cells, including those in the lung.
METHODS: In this double-blind, placebo-controlled study, we randomly assigned 278 patients with symptomatic pulmonary arterial hypertension (either idiopathic or associated with connective-tissue disease or with repaired congenital systemic-to-pulmonary shunts) to placebo or sildenafil (20, 40, or 80 mg) orally three times daily for 12 weeks. The primary end point was the change from baseline to week 12 in the distance walked in six minutes. The change in mean pulmonary-artery pressure and World Health Organization (WHO) functional class and the incidence of clinical worsening were also assessed, but the study was not powered to assess mortality. Patients completing the 12-week randomized study could enter a long-term extension study.
RESULTS: The distance walked in six minutes increased from baseline in all sildenafil groups; the mean placebo-corrected treatment effects were 45 m (+13.0 percent), 46 m (+13.3 percent), and 50 m (+14.7 percent) for 20, 40, and 80 mg of sildenafil, respectively (P<0.001 for all comparisons). All sildenafil doses reduced the mean pulmonary-artery pressure (P=0.04, P=0.01, and P<0.001, respectively), improved the WHO functional class (P=0.003, P<0.001, and P<0.001, respectively), and were associated with side effects such as flushing, dyspepsia, and diarrhea. The incidence of clinical worsening did not differ significantly between the patients treated with sildenafil and those treated with placebo. Among the 222 patients completing one year of treatment with sildenafil monotherapy, the improvement from baseline at one year in the distance walked in six minutes was 51 m.
CONCLUSIONS: Sildenafil improves exercise capacity, WHO functional class, and hemodynamics in patients with symptomatic pulmonary arterial hypertension.

Copyright 2005 Massachusetts Medical Society.
PMID 16291984  N Engl J Med. 2005 Nov 17;353(20):2148-57. doi: 10.1056・・・
著者: Nazzareno Galiè, Bruce H Brundage, Hossein A Ghofrani, Ronald J Oudiz, Gerald Simonneau, Zeenat Safdar, Shelley Shapiro, R James White, Melanie Chan, Anthony Beardsworth, Lyn Frumkin, Robyn J Barst, Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group
雑誌名: Circulation. 2009 Jun 9;119(22):2894-903. doi: 10.1161/CIRCULATIONAHA.108.839274. Epub 2009 May 26.
Abstract/Text BACKGROUND: Treatment options for pulmonary arterial hypertension target the prostacyclin, endothelin, or nitric oxide pathways. Tadalafil, a phosphodiesterase type-5 inhibitor, increases cGMP, the final mediator in the nitric oxide pathway.
METHODS AND RESULTS: In this 16-week, double-blind, placebo-controlled study, 405 patients with pulmonary arterial hypertension (idiopathic or associated), either treatment-naive or on background therapy with the endothelin receptor antagonist bosentan, were randomized to placebo or tadalafil 2.5, 10, 20, or 40 mg orally once daily. The primary end point was the change from baseline to week 16 in the distance walked in 6 minutes. Changes in World Health Organization functional class, clinical worsening, and health-related quality of life were also assessed. Patients completing the 16-week study could enter a long-term extension study. Tadalafil increased the distance walked in 6 minutes in a dose-dependent manner; only the 40-mg dose met the prespecified level of statistical significance (P<0.01). Overall, the mean placebo-corrected treatment effect was 33 m (95% confidence interval, 15 to 50 m). In the bosentan-naive group, the treatment effect was 44 m (95% confidence interval, 20 to 69 m) compared with 23 m (95% confidence interval, -2 to 48 m) in patients on background bosentan therapy. Tadalafil 40 mg improved the time to clinical worsening (P=0.041), incidence of clinical worsening (68% relative risk reduction; P=0.038), and health-related quality of life. The changes in World Health Organization functional class were not statistically significant. The most common treatment-related adverse events reported with tadalafil were headache, myalgia, and flushing.
CONCLUSIONS: In patients with pulmonary arterial hypertension, tadalafil 40 mg was well tolerated and improved exercise capacity and quality of life measures and reduced clinical worsening.

PMID 19470885  Circulation. 2009 Jun 9;119(22):2894-903. doi: 10.1161/・・・
著者: Robyn J Barst, Michael McGoon, Vallerie McLaughlin, Victor Tapson, Stuart Rich, Lewis Rubin, Karlman Wasserman, Ronald Oudiz, Shelley Shapiro, Ivan M Robbins, Richard Channick, David Badesch, Barry K Rayburn, Robin Flinchbaugh, Jeff Sigman, Carl Arneson, Roger Jeffs, Beraprost Study Group
雑誌名: J Am Coll Cardiol. 2003 Jun 18;41(12):2119-25.
Abstract/Text OBJECTIVES: The purpose of this study was to assess the safety and efficacy of the oral prostacyclin analogue beraprost sodium during a 12-month double-blind, randomized, placebo-controlled trial in patients with pulmonary arterial hypertension (PAH).
BACKGROUND: Pulmonary arterial hypertension is a progressive disease that ultimately causes right heart failure and death. Despite the risks from its delivery system, continuous intravenous epoprostenol remains the most efficacious treatment currently available.
METHODS: A total of 116 patients with World Health Organization (WHO) functional class II or III primary pulmonary hypertension or PAH related to either collagen vascular diseases or congenital systemic to pulmonary shunts were enrolled. Patients were randomized to receive the maximal tolerated dose of beraprost sodium (median dose 120 microg four times a day) or placebo for 12 months. The primary end point was disease progression; i.e., death, transplantation, epoprostenol rescue, or >25% decrease in peak oxygen consumption (VO(2)). Secondary end points included exercise capacity assessed by 6-min walk test and peak VO(2), Borg dyspnea score, hemodynamics, symptoms of PAH, and quality of life.
RESULTS: Patients treated with beraprost exhibited less evidence of disease progression at six months (p = 0.002), but this effect was not evident at either shorter or longer follow-up intervals. Similarly, beraprost-treated patients had improved 6-min walk distance at 3 months by 22 m from baseline and at 6 months by 31 m (p = 0.010 and 0.016, respectively) compared with placebo, but not at either 9 or 12 months. Drug-related adverse events were common and were related to the disease and/or expected prostacyclin adverse events.
CONCLUSIONS: These data suggest that beneficial effects may occur during early phases of treatment with beraprost in WHO functional class II or III patients but that this effect attenuates with time.

PMID 12821234  J Am Coll Cardiol. 2003 Jun 18;41(12):2119-25.
著者: Takeyoshi Kunieda, Norifumi Nakanishi, Hiromi Matsubara, Tohru Ohe, Yoshiaki Okano, Hirobumi Kondo, Masaharu Nishimura, Kunio Shirato, Nobuhiro Tanabe, Satoshi Homma, Shunji Yoshida, Shigeko Inokuma, Makoto Kodama, Takao Koike, Hitoshi Hishida
雑誌名: Int Heart J. 2009 Jul;50(4):513-29.
Abstract/Text The long-acting beraprost preparation TRK-100STP is formulated to provide sustained release of an orally active prostacyclin derivative to maintain the optimal plasma concentration for a longer period of time compared with the currently used conventional beraprost sodium. In the present study, we evaluated the efficacy of this newly developed formulation for pulmonary arterial hypertension (PAH).An open-label, 12-week multicenter clinical trial was performed in 46 patients with PAH. They were initially treated with 120 microg of TRK-100STP divided into 60 microg twice daily, followed by a stepwise increase to 360 microg given as 180 microg twice daily. The 6-minute walking distance showed a significant increase by 33.4+/-66.0 m (95% confidence interval [CI], 13.4 to 53.5) from the baseline measurement. Mean pulmonary artery pressure, total pulmonary vascular resistance, and pulmonary vascular resistance decreased by -2.8+/-5.5 mmHg (95% CI, -4.6 to -1.0), by -0.92+/-2.63 mmHg*L(-1)*min (95% CI, -1.78 to -0.05), and by -0.89+/-2.81 mmHg*L(-1)*min (95% CI, -1.84 to 0.06), respectively, from the baseline measurements. A higher efficacy was observed in patients with a maximum tolerated dose of 360 microg daily than those of 240 microg daily or less.Treatment with TRK-100STP for a 12-week period improved the exercise capacity, mean pulmonary artery pressure, and total pulmonary vascular resistance. TRK-100STP was effective for Japanese patients with PAH.

PMID 19609055  Int Heart J. 2009 Jul;50(4):513-29.
著者: Tomás Pulido, Igor Adzerikho, Richard N Channick, Marion Delcroix, Nazzareno Galiè, Hossein-Ardeschir Ghofrani, Pavel Jansa, Zhi-Cheng Jing, Franck-Olivier Le Brun, Sanjay Mehta, Camilla M Mittelholzer, Loïc Perchenet, B K S Sastry, Olivier Sitbon, Rogério Souza, Adam Torbicki, Xiaofeng Zeng, Lewis J Rubin, Gérald Simonneau, SERAPHIN Investigators
雑誌名: N Engl J Med. 2013 Aug 29;369(9):809-18. doi: 10.1056/NEJMoa1213917.
Abstract/Text BACKGROUND: Current therapies for pulmonary arterial hypertension have been adopted on the basis of short-term trials with exercise capacity as the primary end point. We assessed the efficacy of macitentan, a new dual endothelin-receptor antagonist, using a primary end point of morbidity and mortality in a long-term trial.
METHODS: We randomly assigned patients with symptomatic pulmonary arterial hypertension to receive placebo once daily, macitentan at a once-daily dose of 3 mg, or macitentan at a once-daily dose of 10 mg. Stable use of oral or inhaled therapy for pulmonary arterial hypertension, other than endothelin-receptor antagonists, was allowed at study entry. The primary end point was the time from the initiation of treatment to the first occurrence of a composite end point of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension.
RESULTS: A total of 250 patients were randomly assigned to placebo, 250 to the 3-mg macitentan dose, and 242 to the 10-mg macitentan dose. The primary end point occurred in 46.4%, 38.0%, and 31.4% of the patients in these groups, respectively. The hazard ratio for the 3-mg macitentan dose as compared with placebo was 0.70 (97.5% confidence interval [CI], 0.52 to 0.96; P=0.01), and the hazard ratio for the 10-mg macitentan dose as compared with placebo was 0.55 (97.5% CI, 0.39 to 0.76; P<0.001). Worsening of pulmonary arterial hypertension was the most frequent primary end-point event. The effect of macitentan on this end point was observed regardless of whether the patient was receiving therapy for pulmonary arterial hypertension at baseline. Adverse events more frequently associated with macitentan than with placebo were headache, nasopharyngitis, and anemia.
CONCLUSIONS: Macitentan significantly reduced morbidity and mortality among patients with pulmonary arterial hypertension in this event-driven study. (Funded by Actelion Pharmaceuticals; SERAPHIN ClinicalTrials.gov number, NCT00660179.).

PMID 23984728  N Engl J Med. 2013 Aug 29;369(9):809-18. doi: 10.1056/N・・・
著者: Olivier Sitbon, Richard Channick, Kelly M Chin, Aline Frey, Sean Gaine, Nazzareno Galiè, Hossein-Ardeschir Ghofrani, Marius M Hoeper, Irene M Lang, Ralph Preiss, Lewis J Rubin, Lilla Di Scala, Victor Tapson, Igor Adzerikho, Jinming Liu, Olga Moiseeva, Xiaofeng Zeng, Gérald Simonneau, Vallerie V McLaughlin, GRIPHON Investigators
雑誌名: N Engl J Med. 2015 Dec 24;373(26):2522-33. doi: 10.1056/NEJMoa1503184.
Abstract/Text BACKGROUND: In a phase 2 trial, selexipag, an oral selective IP prostacyclin-receptor agonist, was shown to be beneficial in the treatment of pulmonary arterial hypertension.
METHODS: In this event-driven, phase 3, randomized, double-blind, placebo-controlled trial, we randomly assigned 1156 patients with pulmonary arterial hypertension to receive placebo or selexipag in individualized doses (maximum dose, 1600 μg twice daily). Patients were eligible for enrollment if they were not receiving treatment for pulmonary arterial hypertension or if they were receiving a stable dose of an endothelin-receptor antagonist, a phosphodiesterase type 5 inhibitor, or both. The primary end point was a composite of death from any cause or a complication related to pulmonary arterial hypertension up to the end of the treatment period (defined for each patient as 7 days after the date of the last intake of selexipag or placebo).
RESULTS: A primary end-point event occurred in 397 patients--41.6% of those in the placebo group and 27.0% of those in the selexipag group (hazard ratio in the selexipag group as compared with the placebo group, 0.60; 99% confidence interval, 0.46 to 0.78; P<0.001). Disease progression and hospitalization accounted for 81.9% of the events. The effect of selexipag with respect to the primary end point was similar in the subgroup of patients who were not receiving treatment for the disease at baseline and in the subgroup of patients who were already receiving treatment at baseline (including those who were receiving a combination of two therapies). By the end of the study, 105 patients in the placebo group and 100 patients in the selexipag group had died from any cause. Overall, 7.1% of patients in the placebo group and 14.3% of patients in the selexipag group discontinued their assigned regimen prematurely because of adverse events. The most common adverse events in the selexipag group were consistent with the known side effects of prostacyclin, including headache, diarrhea, nausea, and jaw pain.
CONCLUSIONS: Among patients with pulmonary arterial hypertension, the risk of the primary composite end point of death or a complication related to pulmonary arterial hypertension was significantly lower with selexipag than with placebo. There was no significant difference in mortality between the two study groups. (Funded by Actelion Pharmaceuticals; GRIPHON ClinicalTrials.gov number, NCT01106014.).

PMID 26699168  N Engl J Med. 2015 Dec 24;373(26):2522-33. doi: 10.1056・・・
著者: R J Barst, L J Rubin, W A Long, M D McGoon, S Rich, D B Badesch, B M Groves, V F Tapson, R C Bourge, B H Brundage, S K Koerner, D Langleben, C A Keller, S Murali, B F Uretsky, L M Clayton, M M Jöbsis, S D Blackburn, D Shortino, J W Crow, Primary Pulmonary Hypertension Study Group
雑誌名: N Engl J Med. 1996 Feb 1;334(5):296-301. doi: 10.1056/NEJM199602013340504.
Abstract/Text BACKGROUND: Primary pulmonary hypertension is a progressive disease for which no treatment has been shown in a prospective, randomized trial to improve survival.
METHODS: We conducted a 12-week prospective, randomized, multicenter open trial comparing the effects of the continuous intravenous infusion of epoprostenol (formerly called prostacyclin) plus conventional therapy with those of conventional therapy alone in 81 patients with severe primary pulmonary hypertension (New York Heart Association functional class III or IV).
RESULTS: Exercise capacity was improved in the 41 patients treated with epoprostenol (median distance walked in six minutes, 362 m at 12 weeks vs. 315 m at base line), but it decreased in the 40 patients treated with conventional therapy alone (204 m at 12 weeks vs. 270 m at base line; P < 0.002 for the comparison of the treatment groups). Indexes of the quality of life were improved only in the epoprostenol group (P < 0.01). Hemodynamics improved at 12 weeks in the epoprostenol-treated patients. The changes in mean pulmonary-artery pressure for the epoprostenol and control groups were -8 percent and +3 percent, respectively (difference in mean change, -6.7 mm Hg; 95 percent confidence interval, -10.7 to -2.6 mm Hg; P < 0.002), and the mean changes in pulmonary vascular resistance for the epoprostenol and control groups were -21 percent and +9 percent, respectively (difference in mean change, -4.9 mm Hg/liter/min; 95 percent confidence interval, -7.6 to -2.3 mm Hg/liter/min; P < 0.001). Eight patients died during the study, all of whom had been randomly assigned to conventional therapy (P = 0.003). Serious complications included four episodes of catheter-related sepsis and one thrombotic event.
CONCLUSIONS: As compared with conventional therapy, the continuous intravenous infusion of epoprostenol produced symptomatic and hemodynamic improvement, as well as improved survival in patients with severe primary pulmonary hypertension.

PMID 8532025  N Engl J Med. 1996 Feb 1;334(5):296-301. doi: 10.1056/N・・・
著者: V V McLaughlin, D E Genthner, M M Panella, S Rich
雑誌名: N Engl J Med. 1998 Jan 29;338(5):273-7. doi: 10.1056/NEJM199801293380501.
Abstract/Text BACKGROUND: Primary (idiopathic) pulmonary hypertension is a progressive, fatal disease. Conventional therapy with anticoagulant and vasodilator drugs may improve symptoms and survival among selected patients, but there is no evidence that the disease can be reversed.
METHODS: We evaluated the effects of long-term therapy (i.e., for more than one year) with intravenous epoprostenol (prostacyclin) in patients with advanced primary pulmonary hypertension. The base-line evaluation included an assessment of pulmonary vascular dilation in response to intravenous adenosine. The epoprostenol dose was increased monthly to the maximum tolerated. Long-term therapy was evaluated by measuring improvement in symptoms, exercise capacity, and hemodynamic measures.
RESULTS: We evaluated 27 patients with primary pulmonary hypertension over a mean (+/-SD) period of 16.7+/-5.2 months. Intravenous adenosine had a variable effect on pulmonary vascular resistance (mean reduction, 27 percent; range, 0 to 56; P<0.001). Epoprostenol therapy was initiated and the rate of infusion was increased by an average of 2.4 ng per kilogram of body weight per minute each month. Twenty-six of the 27 patients had improvement in symptoms and hemodynamic measures, and overall, pulmonary vascular resistance declined by 53 percent to 7.9+/-3.8 resistance units (P<0.001) at the time of restudy. The long-term effects of epoprostenol exceeded the short-term pulmonary vasodilator response to adenosine in all but one patient. Seven of the eight patients who had minimal pulmonary vasodilation in response to adenosine (mean reduction in resistance units, <20 percent) still had a significant reduction in pulmonary vascular resistance when treated with epoprostenol (mean, 39+/-14 percent; P=0.002).
CONCLUSIONS: In primary pulmonary hypertension, long-term therapy with epoprostenol lowers pulmonary vascular resistance beyond the level achieved in the short term with intravenous adenosine. Epoprostenol appears to have sustained efficacy in this disorder.

PMID 9445406  N Engl J Med. 1998 Jan 29;338(5):273-7. doi: 10.1056/NE・・・
著者: Satoshi Akagi, Kazufumi Nakamura, Katsumasa Miyaji, Aiko Ogawa, Kengo Fukushima Kusano, Hiroshi Ito, Hiromi Matsubara
雑誌名: Circ J. 2010 Oct;74(10):2200-5. Epub 2010 Aug 6.
Abstract/Text BACKGROUND: The appropriate dose range of epoprostenol is thought to be 25-40 ng · kg(-1) · min(-1) based on the results of previous studies showing that epoprostenol therapy reduced mean pulmonary artery pressure (mPAP) by 12-22% and pulmonary vascular resistance (PVR) by 32-53% compared with baseline values in patients with idiopathic pulmonary arterial hypertension (IPAH). However, the efficacy of treatment of IPAH patients with epoprostenol >40 ng · kg(-1) · min(-1) has not been determined and this was the aim of the present study.
METHODS AND RESULTS: The study group comprised 16 consecutive patients, none of whom died; 2 dropped out because they could not be titrated up as needed to the highest effective epoprostenol dose. Hemodynamics were evaluated in 14 IPAH patients who received high-dose epoprostenol monotherapy. The mean epoprostenol dosage was 107 ± 40 ng · kg(-1) · min(-1) (range, 54-190 ng · kg(-1) · min(-1)) and the mean duration of high-dose epoprostenol therapy was 1,355 ± 627 days (range, 582-2,410 days). Significant decreases from baseline values were seen in mPAP (from 66 ± 16 to 47 ± 12 mmHg, P<0.001) and PVR (from 21.6 ± 8.3 to 6.9 ± 2.9 Wood units, P<0.001). Compared with the baseline state, high-dose epoprostenol therapy reduced mPAP by 30% and PVR by 68%.
CONCLUSIONS: The present study suggests high-dose epoprostenol therapy is a new treatment strategy for IPAH.

PMID 20697180  Circ J. 2010 Oct;74(10):2200-5. Epub 2010 Aug 6.
著者: Xavier Jais, David Launay, Azzedine Yaici, Jérôme Le Pavec, Colas Tchérakian, Olivier Sitbon, Gérald Simonneau, Marc Humbert
雑誌名: Arthritis Rheum. 2008 Feb;58(2):521-31. doi: 10.1002/art.23303.
Abstract/Text OBJECTIVE: To describe the response to first-line immunosuppressive therapy with or without pulmonary vasodilators in pulmonary arterial hypertension (PAH) associated with systemic lupus erythematosus (SLE) or mixed connective tissue disease (MCTD).
METHODS: Twenty-three consecutive patients with SLE- or MCTD-associated PAH treated with first-line immunosuppressive therapy either alone (n = 16) or in combination with pulmonary vasodilators (n = 7) were evaluated according to clinical and hemodynamic criteria before and after immunosuppressive therapy. Responders were defined as patients in New York Heart Association (NYHA) functional class I or II with hemodynamic improvement after the last pulse of cyclophosphamide.
RESULTS: Among the 16 patients treated with first-line immunosuppressive therapy alone, 8 (50%) were responders. These patients had a significantly improved NYHA functional class, 6-minute walking distance, and mean pulmonary artery pressure. Patients in NYHA functional class I or II and/or a cardiac index >3.1 liters/minute/m(2) at baseline were more likely to benefit from immunosuppressive therapy. Six of the 8 nonresponders subsequently improved with pulmonary vasodilators. Among the 7 patients who were initially treated with immunosuppressive therapy and pulmonary vasodilators, 4 (57.1%) were responders.
CONCLUSION: PAH associated with SLE or MCTD may respond to a treatment combining cyclophosphamide and glucocorticoids. Patients who could benefit from this immunosuppressive therapy could be those who have less severe disease at baseline. For patients with more severe disease, pulmonary vasodilators should be started, possibly in combination with immunosuppressants. In any case, clinical and hemodynamic evaluations are mandatory to monitor the response and adapt the treatment. These retrospective and uncontrolled data need to be confirmed by randomized controlled trials.

PMID 18240255  Arthritis Rheum. 2008 Feb;58(2):521-31. doi: 10.1002/ar・・・
著者: J A Feinstein, S Z Goldhaber, J E Lock, S M Ferndandes, M J Landzberg
雑誌名: Circulation. 2001 Jan 2;103(1):10-3.
Abstract/Text BACKGROUND: Although pulmonary thromboendarterectomy is increasingly successful for the definitive treatment of chronic thromboembolic pulmonary hypertension (CTEPH), not all patients have surgically accessible disease. Others are poor surgical candidates because of comorbid illness. Therefore, for selected patients, we defined and implemented an alternative interventional strategy of balloon pulmonary angioplasty (BPA).
METHODS AND RESULTS: Eighteen patients (mean age, 51.8 years; range, 14 to 75 years) with CTEPH underwent BPA; they averaged 2.6 procedures (range, 1 to 5) and 6 dilations (range, 1 to 12). Selection of pulmonary artery segments for dilation required (1) complete occlusion, (2) filling defects, or (3) signs of intravascular webs. After an average of 36 months of follow-up (range, 0.5 to 66 months), the average New York Heart Association class improved from 3.3 to 1.8 (P:<0.001), and 6-minute walking distances increased from 209 to 497 yards (P:<0.0001). Pulmonary artery mean pressures decreased from 43.0+/-12.1 to 33. 7+/-10.2 mm Hg (P:=0.007). Eleven patients developed reperfusion pulmonary edema; 3 required mechanical ventilation.
CONCLUSIONS: BPA reduces pulmonary artery hypertension in patients with CTEPH and is associated with long-term improvement in New York Heart Association class and 6-minute walking distances. BPA is a promising interventional technique that warrants randomized comparison with medical therapy in CTEPH patients who are not surgical candidates.

PMID 11136677  Circulation. 2001 Jan 2;103(1):10-3.
著者: Koichiro Sugimura, Yoshihiro Fukumoto, Kimio Satoh, Kotaro Nochioka, Yutaka Miura, Tatsuo Aoki, Shunsuke Tatebe, Saori Miyamichi-Yamamoto, Hiroaki Shimokawa
雑誌名: Circ J. 2012;76(2):485-8. Epub 2011 Dec 15.
Abstract/Text BACKGROUND: Distal-type chronic thromboembolic pulmonary hypertension (CTEPH) is a fatal disease for which a new therapeutic strategy needs to be developed. We examined the effects of percutaneous transluminal pulmonary angioplasty (PTPA).
METHODS AND RESULTS: We prospectively enrolled 12 patients with distal-type CTEPH. After stabilizing their condition with pulmonary vasodilators, we then performed PTPA, which markedly improved pulmonary hemodynamics and pulmonary artery structure, as confirmed by angiography and optical coherence tomography, and also significantly improved their long-term prognosis compared with 39 historical controls.
CONCLUSIONS: PTPA is a promising therapeutic option for distal-type CTEPH.

PMID 22185711  Circ J. 2012;76(2):485-8. Epub 2011 Dec 15.
著者: Masaharu Kataoka, Takumi Inami, Kentaro Hayashida, Nobuhiko Shimura, Haruhisa Ishiguro, Takayuki Abe, Yuichi Tamura, Motomi Ando, Keiichi Fukuda, Hideaki Yoshino, Toru Satoh
雑誌名: Circ Cardiovasc Interv. 2012 Dec;5(6):756-62. doi: 10.1161/CIRCINTERVENTIONS.112.971390. Epub 2012 Nov 6.
Abstract/Text BACKGROUND: Chronic thromboembolic pulmonary hypertension leads to pulmonary hypertension and right-sided heart failure. The purpose of this study was to investigate the efficacy of percutaneous transluminal pulmonary angioplasty (PTPA) for the treatment of chronic thromboembolic pulmonary hypertension.
METHODS AND RESULTS: Twenty-nine patients with chronic thromboembolic pulmonary hypertension underwent PTPA. One patient had a wiring perforation as a complication of PTPA and died 2 days after the procedure. In the remaining 28 patients, PTPA did not produce immediate hemodynamic improvement at the time of the procedure. However, after follow-up (6.0 ± 6.9 months), New York Heart Association functional classifications and levels of plasma B-type natriuretic peptide significantly improved (both P<0.01). Hemodynamic parameters also significantly improved (mean pulmonary arterial pressure, 45.3 ± 9.8 versus 31.8 ± 10.0 mm Hg; cardiac output, 3.6 ± 1.2 versus 4.6 ± 1.7 L/min, baseline versus follow-up, respectively; both P<0.01). Twenty-seven of 51 procedures in total (53%), and 19 of 28 first procedures (68%), had reperfusion pulmonary edema as the chief complication. Patients with severe clinical signs and/or severe hemodynamics at baseline had a high risk of reperfusion pulmonary edema.
CONCLUSIONS: PTPA improved subjective symptoms and objective variables, including pulmonary hemodynamics. PTPA may be a promising therapeutic strategy for the treatment of chronic thromboembolic pulmonary hypertension.
CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp. Unique identifier: UMIN000001572.

PMID 23132237  Circ Cardiovasc Interv. 2012 Dec;5(6):756-62. doi: 10.1・・・
著者: Hiroki Mizoguchi, Aiko Ogawa, Mitsuru Munemasa, Hiroshi Mikouchi, Hiroshi Ito, Hiromi Matsubara
雑誌名: Circ Cardiovasc Interv. 2012 Dec;5(6):748-55. doi: 10.1161/CIRCINTERVENTIONS.112.971077. Epub 2012 Nov 27.
Abstract/Text BACKGROUND: Although balloon pulmonary angioplasty (BPA) for inoperable patients with chronic thromboembolic pulmonary hypertension was first reported over a decade ago, its clinical application has been restricted because of limited efficacy and complications. We have refined the procedure of BPA to maximize its clinical efficacy.
METHODS AND RESULTS: Sixty-eight consecutive patients with inoperable chronic thromboembolic pulmonary hypertension underwent BPA. We evaluated pulmonary artery diameters and determined the appropriate balloon size by using intravascular ultrasound. We performed BPA in a staged fashion over multiple, separate procedures to maximize efficacy and reduce the risk of reperfusion pulmonary injury. A total of 4 (2-8) sessions were performed in each patient, and the number of vessels dilated per session was 3 (1-14). The World Health Organization functional class improved from 3 to 2 (P<0.01), and mean pulmonary arterial pressure was decreased from 45.4 ± 9.6 to 24.0 ± 6.4 mm Hg (P<0.01). One patient died because of right heart failure 28 days after BPA. During follow-up for 2.2 ± 1.4 years after the final BPA, another patient died of pneumonia, and the remaining 66 patients are alive. In 57 patients who underwent right heart catheterization at follow-up, improvement of mean pulmonary arterial pressure was maintained (24.0 ± 5.8 mm Hg at 1.0 ± 0.9 years). Forty-one patients (60%) developed reperfusion pulmonary injury after BPA, but mechanical ventilation was required in only 4 patients.
CONCLUSIONS: Our refined BPA procedure improves clinical status and hemodynamics of inoperable patients with chronic thromboembolic pulmonary hypertension, with a low mortality. A refined BPA procedure could be considered as a therapeutic approach for patients with inoperable chronic thromboembolic pulmonary hypertension.

PMID 23192917  Circ Cardiovasc Interv. 2012 Dec;5(6):748-55. doi: 10.1・・・

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