Nick H. Kim

Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension

BACKGROUND Riociguat, a member of a new class of compounds (soluble guanylate cyclase stimulators), has been shown in previous clinical studies to be beneficial in the treatment of chronic thromboembolic pulmonary hypertension. METHODS In this phase 3, multicenter, randomized, double-blind, placebo-controlled study, we randomly assigned 261 patients with inoperable chronic thromboembolic pulmonary hypertension or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy to receive placebo or riociguat. The primary end point was the change from baseline to the end of week 16 in the distance walked in 6 minutes. Secondary end points included changes from baseline in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) level, World Health Organization (WHO) functional class, time to clinical worsening, Borg dyspnea score, quality-of-life variables, and safety. RESULTS By week 16, the 6-minute walk distance had increased by a mean of 39 m in the riociguat group, as compared with a mean decrease of 6 m in the placebo group (least-squares mean difference, 46 m; 95% confidence interval [CI], 25 to 67; P<0.001). Pulmonary vascular resistance decreased by 226 dyn·sec·cm(-5) in the riociguat group and increased by 23 dyn·sec·cm(-5) in the placebo group (least-squares mean difference, -246 dyn·sec·cm(-5); 95% CI, -303 to -190; P<0.001). Riociguat was also associated with significant improvements in the NT-proBNP level (P<0.001) and WHO functional class (P=0.003). The most common serious adverse events were right ventricular failure (in 3% of patients in each group) and syncope (in 2% of the riociguat group and in 3% of the placebo group). CONCLUSIONS Riociguat significantly improved exercise capacity and pulmonary vascular resistance in patients with chronic thromboembolic pulmonary hypertension. (Funded by Bayer HealthCare; CHEST-1 and CHEST-2 ClinicalTrials.gov numbers, NCT00855465 and NCT00910429, respectively.)

The right ventricle in pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a term used to classify a variety of conditions that share in common an injury to the pulmonary vasculature that produces elevations in pulmonary arterial pressure. However, it is the integrity of right ventricular function, rather than the degree of vascular injury, that is the major determinant of symptoms and survival in PAH. The article will review the normal structure and function of the right ventricle and summarize the impact of PAH and its treatments on right ventricular function.

Pulmonary Endarterectomy: Recent Changes in a Single Institution's Experience of More Than 2,700 Patients

BACKGROUND Chronic thromboembolic pulmonary hypertension (CTEPH) is a known sequela of acute pulmonary embolic disease and yet remains underdiagnosed. Although nonsurgical options for patients with CTEPH have become increasingly available, including pulmonary artery hypertensive medical therapy, surgical endarterectomy provides the most appropriate intervention as a potential cure for this debilitating disorder. This article summarizes the most recent outcomes of pulmonary endarterectomy at a single institution over the past 12 years, with emphasis on the surgical approach to segmental-level chronic thromboembolic disease. METHODS More than 2,700 pulmonary endarterectomy operations have been performed at the University of California, San Diego Medical Center. Because of recent changes in the patient population and in surgical results, 1,500 patients with symptomatic chronic thromboembolic disease who underwent pulmonary endarterectomy between March 1999 and December 2010 were analyzed. The outcomes for the more recent 500 patients, compared with the previous 1,000 were studied. RESULTS In-hospital mortality for the cohort of 1,000 patients (group 1) was 5.2% compared with 2.2% for the last 500 operations (group 2) (p < 0.01). There was no mortality in the last 260 consecutive patients undergoing isolated pulmonary endarterectomy. More patients presented with segmental type III disease in the more recent 500 patients (21.4% versus 13.1%; p < 0.001). Between the 2 patient groups, there was a comparable decline in pulmonary vascular resistance (PVR) (group 1: 861.2 ± 446.2 to 94.8 ± 204.2 dynes/sec/cm(-5); group 2: 719.0 ± 383.2 to 253.4 ± 148.6 dynes/sec/cm(-5)) and mean pulmonary artery (PA) pressures (group 1: 46.1 ± 11.4 to 28.7 ± 10.1 mm Hg; group 2: 45.5 ± 11.6 to 26.0 ± 8.4 mm Hg) after endarterectomy. CONCLUSIONS Despite a patient population with more distal disease, results continue to improve. Pulmonary endarterectomy for patients with CTEPH results in significant pulmonary hemodynamic improvement, with favorable outcomes achievable even in patients with distal segmental-level chronic thromboembolic disease.

End points and clinical trial design in pulmonary arterial hypertension.

New and emerging therapies might provide benefit in patients with pulmonary arterial hypertension. Their efficacy and safety will be compared with existing combination therapies in randomized clinical trials. Appropriate end points for these trials need to be identified: these will include exercise testing, the composite end point of time to clinical worsening, and hemodynamic markers, including advanced imaging modalities and biomarkers. Quality-of-life questionnaires are useful and important secondary end points; pulmonary arterial hypertension-specific questionnaires are currently being developed. Advantages and disadvantages of various trial designs, including placebo-controlled monotherapy or add-on trials, noninferiority studies, and withdrawal trials are also discussed.

Interventional and surgical modalities of treatment in pulmonary hypertension.

Most patients with chronic thromboembolic pulmonary hypertension are operable, and pulmonary endarterectomy is the treatment of choice. Pulmonary endarterectomy should not be delayed for medical therapy, and risk stratification helps to define patients likely to achieve the best outcome. Inoperable patients should be referred for trials of medical agents. Atrial septostomy is promising but underutilized, although better ways of ensuring an adequate, lasting septostomy still need to be determined. Indications for the procedure are unchanged, and it should be considered more frequently. Bilateral sequential lung or heart-lung transplantation is an important option for selected patients, and potential candidates who are class IV or III but not improving should be referred early to a transplantation center. Currently, there is a need for right ventricular assist devices with flow characteristics suited to the circulation of patients with pulmonary arterial hypertension. Right ventricular synchronization therapy has not yet been tested. Novel shunts (e.g., Potts anastomosis) also hold promise. All surgery for pulmonary hypertension should be performed in centers with experience in these techniques.

Preoperative Partitioning of Pulmonary Vascular Resistance Correlates With Early Outcome After Thromboendarterectomy for Chronic Thromboembolic Pulmonary Hypertension

Background—Pulmonary thromboendarterectomy (PTE) is the preferred treatment for chronic thromboembolic pulmonary hypertension (CTEPH), but persistent pulmonary hypertension after PTE, as a result of either inaccessible distal thrombotic material or coexistent intrinsic small-vessel disease, remains a major determinant of poor outcome. Conventional preoperative evaluation is unreliable in identifying patients at risk for persistent pulmonary hypertension or predicting postoperative hemodynamic outcome. We postulated that pulmonary arterial occlusion pressure waveform analysis, a technique that has been used for partitioning pulmonary vascular resistance, might identify CTEPH patients with significant distal, small-vessel disease. Methods and Results—Twenty-six patients underwent preoperative right heart catheterization before PTE. Pulmonary artery occlusion waveform recordings were performed in triplicate. Postoperative hemodynamics after PTE were compared with preoperative partitioning of pulmonary vascular resistance derived from the occlusion data. Preoperative assessment of upstream resistance (R up) correlated with both postoperative total pulmonary resistance index (R2=0.79, P <0.001) and postoperative mean pulmonary artery pressure (R2=0.75, P <0.001). All 4 postoperative deaths occurred in patients with a preoperative R up <60%. Conclusions—Pulmonary arterial occlusion pressure waveform analysis may identify CTEPH patients at risk for persistent pulmonary hypertension and poor outcome after PTE. Patients with CTEPH and R up value <60% appear to be at highest risk.

Pulmonary Hypertensive Medical Therapy in Chronic Thromboembolic Pulmonary Hypertension Before Pulmonary Thromboendarterectomy

Background— The currently recommended treatment for chronic thromboembolic pulmonary hypertension is pulmonary thromboendarterectomy (PTE). No convincing evidence for the use of pulmonary hypertensive medical therapy (PHT) exists in operable candidates. We sought to determine the prevalence of the use of PHT on referral for PTE and the effects on pre-PTE hemodynamics and post-PTE outcomes/hemodynamics. Methods and Results— We performed a retrospective analysis of chronic thromboembolic pulmonary hypertension patients referred for PTE during 2005–2007. The prevalence of PHT was determined for all patients referred to our institution. Hemodynamic and outcomes analysis involved only those undergoing PTE. Data included baseline demographics, PHT medication(s), dosage, duration of therapy, and time to referral. Hemodynamic data were acquired from the time of diagnosis, the time of referral visit, and after PTE. Outcomes included intensive care unit, hospital, and ventilator days; bleeding and infection rates; incidence of reperfusion lung injury; and in-hospital mortality. The control group (n=244) was compared with the PHT group (n=111); subgroups included monotherapy with bosentan, sildenafil, or epoprostenol and combination therapy. The prevalence of PHT significantly increased from 19.9% in 2005 to 37% in 2007. There was minimal benefit of treatment with PHT on pre-PTE mean pulmonary artery pressure, but its use was associated with a significant delay in time to referral for PTE. Both groups experienced significant improvements in hemodynamic parameters after PTE. The 2 groups did not differ significantly in any post-PTE outcome. Similar results were obtained for each subgroup. Conclusions— Our results suggest that PHT use has minimal effect on pre-PTE hemodynamics and no effect on post-PTE outcomes/hemodynamics.

Chronic thromboembolic pulmonary hypertension.

Over the past 4 decades, chronic thromboembolic pulmonary hypertension has evolved from an autopsy curiosity to a potentially correctable form of pulmonary hypertension. Advances in surgical techniques along with the introduction of pulmonary hypertension disease-modifying therapies provide a therapeutic option for the majority of patients afflicted with the disease. Approximately 5,000 thromboendarterectomy procedures have now been performed worldwide with mortality rates reported by established programs experienced in the management of this disease process falling to a range of 4 to 7%. A mortality rate of 1.3% has been reported in patients at low risk based on their preoperative hemodynamic profile. After a successful pulmonary thromboendarterectomy, substantial improvement and often normalization can be achieved in right ventricular function, gas exchange, exercise capacity, and quality of life. For patients not candidates for thromboendarterectomy, or for those with persistent post-thromboendarterectomy pulmonary hypertension, disease-modifying medical therapies have been demonstrated to stabilize and improve pulmonary hemodynamics, albeit not to the same extent as primary thromboendarterectomy. The current review focuses on the diagnostic approach to chronic thromboembolic pulmonary hypertension and the available surgical and medical therapeutic options. Additional research is necessary to more accurately predict postoperative hemodynamic outcome and to define the optimal therapeutic approach, especially in patients with involvement of the distal vasculature.

Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: a long-term extension study (CHEST-2)

Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of inoperable and persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH). In the 16-week CHEST-1 study, riociguat showed a favourable benefit–risk profile and improved several clinically relevant end-points in patients with CTEPH. The CHEST-2 open-label extension evaluated the long-term safety and efficacy of riociguat. Eligible patients from CHEST-1 received riociguat individually adjusted up to a maximum dose of 2.5 mg three times daily. The primary objective was the safety and tolerability of riociguat; exploratory efficacy end-points included 6-min walking distance (6MWD) and World Health Organization (WHO) functional class (FC). Overall, 237 patients entered CHEST-2 and 211 (89%) were ongoing at this interim analysis (March 2013). The safety profile of riociguat in CHEST-2 was similar to CHEST-1, with no new safety signals. Improvements in 6MWD and WHO FC observed in CHEST-1 persisted for up to 1 year in CHEST-2. In the observed population at 1 year, mean±sd 6MWD had changed by +51±62 m (n=172) versus CHEST-1 baseline (n=237), and WHO FC had improved/stabilised/worsened in 47/50/3% of patients (n=176) versus CHEST-1 baseline (n=236). Long-term riociguat had a favourable benefit–risk profile and apparently showed sustained benefits in exercise and functional capacity for up to 1 year. Riociguat shows favourable benefit–risk profile in CTEPH patients, with benefits in 6MWD and WHO FC for up to 1 year http://ow.ly/Co04L

Chronic thromboembolic pulmonary hypertension: role of medical therapy

Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease with poor prognosis if not treated. The treatment of choice is surgery with pulmonary endarterectomy. However, a significant percentage of patients are deemed non-operable due to distal distribution of the disease and arteriopathy in the non-occluded areas that is indistinguishable from pulmonary arterial hypertension (PAH). The overlap in clinical presentation, pathological features and pathogenesis between PAH and CTEPH provides a compelling rationale for exploring the efficacy of PAH-targeted therapies in CTEPH. These therapies are often considered for non-operable patients and are also used in operable patients as a bridge to surgery or as post-pulmonary endarterectomy therapy for persistent pulmonary hypertension, despite the fact they are not licensed for CTEPH. Two randomised clinical trials have been performed in non-operable CTEPH patients. The BENEFiT study, with the endothelin receptor antagonist bosentan, did not show improvement in walking distance. Recently, the CHEST-1 trial, with the soluble guanylate cyclase stimulator riociguat, met study end-point and demonstrated significant improvement in walking distance in patients with non-operable CTEPH. There is an urgent need for more randomised clinical trials designed to clarify whether administration of PAH-targeted therapies improves clinically meaningful end-points in various CTEPH populations.