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There is no substitute for experience: Lessons learned from CHEST-1 (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase Stimulator Trial-1) for future clinical trial design

  • Jonathan D'Cunha
    Correspondence
    Address for reprints: Jonathan D'Cunha, MD, PhD, Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, UPMC Presbyterian Suite C-900, 200 Lothrop St, Pittsburgh, PA 15213.
    Affiliations
    Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa
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Open ArchivePublished:June 01, 2016DOI:https://doi.org/10.1016/j.jtcvs.2016.05.040
      The study design of CHEST-1 (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase Stimulator Trial-1) sets a new standard for clinical trials, especially as they relate to complex and relatively infrequent, highly specialized disease processes.
      See Articles page 669, 763, and 872.
      See Editorial Commentaries page 771 and 879.
      See Editorial page 656.
      Chronic thromboembolic pulmonary hypertension (CTEPH) is an obstructive process of the pulmonary vasculature by residual organized thrombi that leads to increased pulmonary vascular resistance, progressive pulmonary hypertension (PH), and eventual right ventricular failure.
      • Humbert M.
      Pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: pathophysiology.
      • Lang I.M.
      • Klepetko W.
      Chronic thromboembolic pulmonary hypertension: an updated review.
      • Moser K.M.
      • Bloor C.M.
      Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension.
      • Peacock A.
      • Simonneau G.
      • Rubin L.
      Controversies, uncertainties and future research on the treatment of chronic thromboembolic pulmonary hypertension.
      • Simonneau G.
      • Robbins I.M.
      • Beghetti M.
      • Channick R.N.
      • Delcroix M.
      • Denton C.P.
      • et al.
      Updated clinical classification of pulmonary hypertension.
      Prognosis is poor, and early diagnosis key to outcomes. Pulmonary endarterectomy (PEA) is the gold standard for treatment of chronic thromboembolic pulmonary hypertension.
      • Jenkins D.
      • Mayer E.
      • Screaton N.
      • Madani M.
      State-of-the-art chronic thromboembolic pulmonary hypertension diagnosis and management.
      In some patients, PEA is potentially curative and the key is identification of those patients who will benefit from intervention.
      Medical therapy is reserved for those patients with inoperable disease. Those patients with distal disease or persistent/recurrent PH after PEA should undergo medical treatment. Thus, appropriate assessment of operability is critical to success. The assessment of patients who would benefit from operability is subjective and challenging and poses a significant problem for risk assessment, clinical practice, and clinical trials for those patients with CTEPH.
      In this issue of the Journal, Jenkins and colleagues
      • Jenkins D.P.
      • Biederman A.
      • D'Armini A.M.
      • Dartevelle P.
      • Gan H.
      • Klepetko W.
      • et al.
      Operability assessment in CTEPH: lessons from the CHEST-1 study.
      present an expert opinion article in which they evaluate the operability assessment of patients in the CHEST-1 (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase Stimulator Trial-1) study. This work is interesting and timely in that it has broader implications for methodology as it relates to clinical trial design and execution. This expert opinion article demonstrates that CTEPH remains an underdiagnosed and underappreciated condition. There are patients missing out on potentially curative surgery because of variability in operative assessment.
      The authors seek to emphasize the importance of seeking an expert second opinion and introduce the possibility of remote assessment by expert high-volume surgeons during the evaluation process. CHEST-1 evaluated riociguat for the treatment of inoperable chronic thromboembolic PH or persistent/recurrent PH after PEA. It was a phase III pivotal trial that demonstrated significant efficacy for pharmacotherapy in CTEPH. Screened patients underwent independent adjudication by a committee of experienced surgeons or local adjudication in collaboration with an experienced surgeon. Following the methodology in this study, 69 of 312 patients had their “inoperable” label reversed. This process of misclassifying patients has the potential to deny patient of receiving curative surgery. An uncommon disease with a potentially significant morbidity deserves quality standards as described in this trial.
      The operability assessment in CTEPH is a complex and subjective process that is based on experience, like so many of our problems in cardiothoracic surgery. This study sets the standards for evaluation, which should include operability assessment by an experienced PEA team. CHEST-1 included a rigorous prospective assessment of operability by expert PEA surgeons that essentially solidified the fact that only technically inoperable patients or those with persistent/recurrent PH after PEA were enrolled. This is the type of rigor that has led to the pivotal findings regarding the efficacy of riociguat in CTEPH. Further, this methodology also demonstrates the potential power of remote expert opinion. The demonstrated success of this unique approach has implications not only for future CTEPH work, but other clinical trials.
      The study design of CHEST-1 sets new standard for clinical trials especially as they relate to complex and relatively infrequent, highly specialized disease processes that benefit from multidisciplinary input/discussion. The process should be analyzed carefully, and its thought-provoking design should stimulate improved trial design through similar methodologies where feasible.

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      Linked Article

      • Operability assessment in CTEPH: Lessons from the CHEST-1 study
        The Journal of Thoracic and Cardiovascular SurgeryVol. 152Issue 3
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          Pulmonary endarterectomy is the gold standard treatment for chronic thromboembolic pulmonary hypertension and is potentially curative, although some patients are unsuitable for pulmonary endarterectomy and require alternative management. Lack of standardized assessment of pulmonary endarterectomy eligibility risks suboptimal treatment in some patients. We discuss the implications for future clinical trials and practice of a unique operability assessment in patients who have chronic thromboembolic pulmonary hypertension and were initially screened for inclusion in the CHEST-1 (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase Stimulator Trial-1) study.
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      • Understanding pathophysiologic changes occurring in chronic thromboembolic disease
        The Journal of Thoracic and Cardiovascular SurgeryVol. 152Issue 3
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          The pathophysiologic processes involved in the development of chronic pulmonary thromboembolic disease (CTED) from acute pulmonary embolism are poorly understood.1,2 In the most simplistic physiologic terms, one or more pulmonary emboli fail to resolve through fibrinolysis, leading to chronic obstruction of the pulmonary vascular bed and resulting in increasing right heart failure. There is substantial evidence, however, that the process may not be quite so simple. First, if simple obstruction were the only issue, pulmonary endarterectomy (PEA) should reliably lead to improvement or resolution of pulmonary hypertension in all cases—in fact, however, this does not occur.
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      • Hemodynamic and ventilatory responses during exercise in chronic thromboembolic disease
        The Journal of Thoracic and Cardiovascular SurgeryVol. 152Issue 3
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          Patients with chronic thromboembolic disease (CTED) may suffer from exercise intolerance without pulmonary hypertension at rest. Pulmonary endarterectomy (PEA) for symptomatic CTED results in improvement of symptoms and quality of life. Neither the pathophysiology of the exercise limitation nor the underlying mechanisms of the PEA-induced improvement have been studied previously.
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      • Midterm benefits of surgical pulmonary embolectomy for acute pulmonary embolus on right ventricular function
        The Journal of Thoracic and Cardiovascular SurgeryVol. 152Issue 3
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          Surgical pulmonary embolectomy has been used for the successful treatment of massive and submassive pulmonary emboli. The purpose of this study is to document the short- and midterm echocardiographic follow-up of right ventricular function after surgical pulmonary embolectomy for acute pulmonary embolus.
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      • Surgical pulmonary embolectomy: Should we extend its role?
        The Journal of Thoracic and Cardiovascular SurgeryVol. 152Issue 3
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          In this issue of the Journal, Keeling and associates1 present their institutional experience and a retrospective analysis on the outcome of surgical pulmonary embolectomy (SPE). In their article, Keeling and associates1 emphasize the beneficial effect of surgical clot removal on right ventricular function, with the consequence of improved midterm survival.
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