bay-63-2521 and Thromboembolism

Nitric oxide (NO) activates soluble guanylate cyclase (sGC) by binding its prosthetic heme group, thereby catalyzing cyclic guanosine monophosphate (cGMP) synthesis. cGMP causes vasodilation and may inhibit smooth muscle cell proliferation and platelet aggregation. The NO-sGC-cGMP pathway is disordered in pulmonary arterial hypertension (PAH), a syndrome in which pulmonary vascular obstruction, inflammation, thrombosis, and constriction ultimately lead to death from right heart failure. Expression of sGC is increased in PAH but its function is reduced by decreased NO bioavailability, sGC oxidation and the related loss of sGC's heme group. Two classes of sGC modulators offer promise in PAH. sGC stimulators (e.g., riociguat) require heme-containing sGC to catalyze cGMP production, whereas sGC activators (e.g., cinaciguat) activate heme-free sGC. Riociguat is approved for PAH and yields functional and hemodynamic benefits similar to other therapies. Its main serious adverse effect is dose-dependent hypotension. Riociguat is also approved for inoperable chronic thromboembolic pulmonary hypertension.

Topics: Animals; Benzoates; Chronic Disease; Cyclic GMP; Drug Design; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Nitric Oxide; Pyrazoles; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Thromboembolism

Chronic thromboembolic pulmonary hypertension (CTEPH) is an insidious, progressive disease with a poor prognosis. The treatment of choice is pulmonary thromboendarterectomy, although not all patients benefit from surgery at a specialized center. Riociguat, an oral soluble guanylate cyclase (sGC) stimulator is the first pharmacotherapeutic agent that has been shown to improve exercise capacity and hemodynamics in a large multicenter, double-blind, randomized placebo-controlled trial for the treatment of patients with inoperable or persistent CTEPH. Riociguat stimulates sGC directly in a nitric oxide (NO)-independent manner, thereby increasing the sensitivity of sGC to NO, and also in synergy with NO, leading to increased production of cyclic guanosine monophosphate, an intracellular messenger involved in regulating vascular tone, smooth muscle cell proliferation, fibrosis and inflammation. This review will summarize the pharmacodynamics, pharmacokinetics as well as safety and efficacy data of riociguat in inoperable or persistent CTEPH.

Topics: Animals; Chronic Disease; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Nitric Oxide; Pyrazoles; Pyrimidines; Thromboembolism

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but debilitating and life-threatening complication of acute pulmonary embolism. CTEPH results from persistent obstruction of pulmonary arteries and progressive vascular remodelling. Not all patients presenting with CTEPH have a history of clinically overt pulmonary embolism. The diagnostic work-up to detect or rule out CTEPH should include ventilation-perfusion scintigraphy, which has high sensitivity and a negative predictive value of nearly 100%. CT angiography usually reveals typical features of CTEPH, including mosaic perfusion, part or complete occlusion of pulmonary arteries, and intraluminal bands and webs. Patients with suspected CTEPH should be referred to a specialist centre for right-heart catheterisation and pulmonary angiography. Surgical pulmonary endarterectomy remains the treatment of choice for CTEPH and is associated with excellent long-term results and a high probability of cure. For patients with inoperable CTEPH, various medical and interventional therapies are being developed.

Topics: Angioplasty, Balloon; Bosentan; Chronic Disease; Endarterectomy; Endothelin Receptor Antagonists; Enzyme Activators; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Embolism; Purines; Pyrazoles; Pyrimidines; Sildenafil Citrate; Sulfonamides; Thromboembolism

The pharmacology, pharmacokinetics, clinical efficacy, safety, and role in therapy for riociguat are reviewed.. Riociguat is the first member of a new class of medications, soluble guanylate cyclase stimulators. Riociguat is indicated for patients with resistant or recurrent chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary endarterectomy who have World Health Organization (WHO) functional class IV pulmonary arterial hypertension (PAH) and in patients with inoperable CTEPH, regardless of WHO functional class, to improve exercise capacity and WHO functional class. Riociguat is indicated in patients with WHO functional class II PAH to improve exercise capacity, improve functional class, and delay clinical worsening. The mechanism of action of riociguat is within the nitric oxide pathway in the pulmonary vasculature. Clinical trials have demonstrated improvements in exercise capacity as measured by the six-minute walk distance test and in pulmonary arterial hemodynamics as measured by invasive pulmonary monitoring. Riociguat must be administered three times daily and requires dosage adjustments. Riociguat is a pregnancy category X drug and interacts with numerous medications. The two most serious adverse effects related to riociguat are hypotension and bleeding. Riociguat's role in the therapy of both PAH and CTEPH will be determined as more clinical experience and data are collected. Riociguat will likely cost approximately $90,000 annually.. Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of CTEPH and PAH. It can be considered first-line therapy for the treatment of CTEPH and should be considered as an alternative to phosphodiesterase type-5 inhibitors in patients with PAH.

Topics: Chronic Disease; Female; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Pregnancy; Pulmonary Embolism; Pyrazoles; Pyrimidines; Thromboembolism

Riociguat (Adempas(®)), a soluble guanylate cyclase stimulator, is a new, first-in-class drug approved for the treatment of patients with chronic thromboembolic pulmonary hypertension (CTEPH) [inoperable or persistent/recurrent following surgery] or pulmonary arterial hypertension (PAH). It has been designated an orphan medicine by the European Medicines Agency and the US FDA. This article reviews the available pharmacological properties of oral riociguat and its clinical efficacy and tolerability in adults with CTEPH or PAH. Riociguat is effective and well tolerated in patients with inoperable CTEPH or persistent/recurrent CTEPH following pulmonary endarterectomy, and in patients with PAH. It has a positive result on exercise capacity and pulmonary haemodynamics, and improves WHO functional class. Most adverse events can be attributed to the vasodilatory mechanism of riociguat; however, there is a potential for serious bleeding and fetal harm, and riociguat use is contraindicated in pregnant patients. Pulmonary endarterectomy remains the first treatment of choice for CTEPH, as it is potentially curative. Head-to-head trials comparing riociguat with the approved phosphodiesterase type 5 inhibitors in patients with PAH would be of value for the placement of riociguat in the management of this disease. Riociguat is a promising addition to the treatment options for patients with CTEPH or PAH.

Topics: Chronic Disease; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Thromboembolism

Topics: Animals; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Thromboembolism; Ventricular Dysfunction, Left

Current pulmonary hypertension treatment guidelines recommend use of a risk stratification model encompassing a range of parameters, allowing patients to be categorised as low, intermediate or high risk. Three abbreviated versions of this risk stratification model were previously evaluated in patients with pulmonary arterial hypertension (PAH) in the French, Swedish and COMPERA registries. Our objective was to investigate the three abbreviated risk stratification methods for patients with mostly prevalent PAH and chronic thromboembolic pulmonary hypertension (CTEPH), in patients from the PATENT-1/2 and CHEST-1/2 studies of riociguat.. Risk was assessed at baseline and at follow-up in PATENT-1 and CHEST-1. Survival and clinical worsening-free survival were assessed in patients in each risk group/strata.. With all three methods, riociguat improved risk group/strata in patients with PAH after 12 weeks. The French non-invasive and Swedish/COMPERA methods discriminated prognosis for survival and clinical worsening-free survival at both baseline and follow-up. Furthermore, patients achieving one or more low-risk criteria or a low-risk stratum at follow-up had a significantly reduced risk of death and clinical worsening compared with patients achieving no low-risk criteria or an intermediate-risk stratum. Similar results were obtained in patients with inoperable or persistent/recurrent CTEPH.. This analysis confirms and extends the results of the registry analyses, supporting the value of goal-oriented treatment in PAH. Further assessment of these methods in patients with CTEPH is warranted.

Topics: Adult; Aged; Chronic Disease; Europe; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Arterial Hypertension; Pyrazoles; Pyrimidines; Registries; Risk Assessment; Risk Factors; Survival Analysis; Thromboembolism

The REVEAL risk score (RRS) was developed to predict survival in patients with pulmonary arterial hypertension (PAH), based on multiple patient characteristics. Herein we calculated RRS for patients in the randomized CHEST-1 study and open-label CHEST-2 extension study of riociguat in inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH). We investigated the effect of riociguat vs placebo on RRS in the CHEST-1 study, and the relationship between RRS and long-term outcomes in the CHEST-2 study.. RRS was calculated post hoc for baseline and Week 16 of CHEST-1 and Week 12 of CHEST-2, based on 9 evaluable elements. Patients were grouped into risk strata by RRS. Relationships between RRS and both survival and clinical worsening-free survival were examined by Kaplan-Meier and Cox proportional hazards analyses.. Overall, 237 patients completed CHEST-1 and entered CHEST-2. In CHEST-1, riociguat significantly improved RRS (p < 0.0001) and risk stratum (p < 0.001) vs placebo from baseline to Week 16. RRS at baseline, and at Week 16, and change in RRS during CHEST-1 were significantly associated with survival (hazard ratios for a 1-point reduction in RRS: 0.702, 0.692, and 0.682, respectively) and clinical worsening-free survival (hazard ratios: 0.697, 0.719, and 0.754, respectively) over 2 years in CHEST-2.. Riociguat improved RRS in patients with inoperable and persistent/recurrent CTEPH. RRS at baseline and Week 16, and change in RRS from baseline, predicted survival and clinical worsening-free survival. This analysis of RRS in patients with inoperable or persistent/recurrent CTEPH suggests utility for the RRS in indications beyond PAH.

Topics: Chronic Disease; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pyrazoles; Pyrimidines; Risk Assessment; Survival Rate; Thromboembolism

Following positive results from the Phase III CHEST-1 study in patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), the Phase IIIb CTEPH early access study (EAS) was designed to assess the safety and tolerability of riociguat in real-world clinical practice, as well as to provide patients with early access to riociguat before launch. Riociguat is approved for the treatment of inoperable and persistent/recurrent CTEPH.. We performed an open-label, uncontrolled, single-arm, early access study in which 300 adult patients with inoperable or persistent/recurrent CTEPH received riociguat adjusted from 1 mg three times daily (tid) to a maximum of 2.5 mg tid. Patients switching from unsatisfactory prior pulmonary arterial hypertension (PAH)-targeted therapy (n = 84) underwent a washout period of at least 3 days before initiating riociguat. The primary aim was to assess the safety and tolerability of riociguat, with World Health Organization functional class and 6-min walking distance (6MWD) as exploratory efficacy endpoints.. In total, 262 patients (87%) completed study treatment and entered the safety follow-up (median treatment duration 47 weeks). Adverse events were reported in 273 patients (91%). The most frequently reported serious adverse events were syncope (6%), right ventricular failure (3%), and pneumonia (2%). There were five deaths, none of which was considered related to study medication. The safety and tolerability of riociguat was similar in patients switched from other PAH-targeted therapies and those who were treatment naïve. In patients with data available, mean ± standard deviation 6MWD had increased by 33 ± 42 m at Week 12 with no clinically relevant differences between the switched and treatment-naïve subgroups.. Riociguat was well tolerated in patients with CTEPH who were treatment naïve, and in those who were switched from other PAH-targeted therapies. No new safety signals were observed.. ClinicalTrials.org NCT01784562 . Registered February 4, 2013.

Topics: Aged; Antihypertensive Agents; Chronic Disease; Drug Administration Schedule; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pyrazoles; Pyrimidines; Syncope; Thromboembolism; Treatment Outcome

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.

Topics: Aged; Antihypertensive Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Exercise Test; Female; Follow-Up Studies; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pyrazoles; Pyrimidines; Respiratory Function Tests; Risk; Thromboembolism; Time Factors; Walking

We assessed the therapeutic potential of riociguat, a novel soluble guanylate cyclase stimulator, in adults with chronic thromboembolic pulmonary hypertension (CTEPH; n = 42) or pulmonary arterial hypertension (PAH; n = 33) in World Health Organization (WHO) functional class II/III. In this 12-week, multicentre, open-label, uncontrolled phase II study, patients received oral riociguat 1.0-2.5 mg t.i.d. titrated according to systemic systolic blood pressure (SBP). Primary end-points were safety and tolerability; pharmacodynamic changes were secondary end-points. Riociguat was generally well tolerated. Asymptomatic hypotension (SBP <90 mmHg) occurred in 11 patients, but blood pressure normalised without dose alteration in nine and after dose reduction in two. Median 6-min walking distance increased in patients with CTEPH (55.0 m from baseline (390 m); p<0.0001) and PAH (57.0 m from baseline (337 m); p<0.0001); patients in functional class II or III and bosentan pre-treated patients showed similar improvements. Pulmonary vascular resistance was significantly reduced by 215 dyn·s·cm(-5) from baseline (709 dyn·s·cm(-5); p<0.0001). 42 (56%) patients were considered to have experienced drug-related adverse events (AEs; 96% mild or moderate). Dyspepsia, headache and hypotension were the most frequent AEs. Study discontinuation because of AEs was 4%. These preliminary data show that riociguat has a favourable safety profile and improves exercise capacity, symptoms and pulmonary haemodynamics in CTEPH and PAH. Randomised controlled trials are underway.

Topics: Administration, Oral; Aged; Antihypertensive Agents; Exercise; Female; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Male; Middle Aged; Prospective Studies; Pyrazoles; Pyrimidines; Thromboembolism; Treatment Outcome

Riociguat, a soluble guanylate cyclase stimulator, induces pulmonary artery dilatation through blood flow and is effective in treating chronic thromboembolic pulmonary hypertension (CTEPH). There are two types of vasculopathies in CTEPH based upon its location, in other words, proximal or distal to the thrombus-medicated obstruction. Distal vasculopathy is characterized by intrapulmonary shunts due to diminished blood flow. While other therapeutic interventions for CTEPH including pulmonary endarterectomy and balloon pulmonary angioplasty achieve reperfusion to the distal vasculopathy vessels, the effects of riociguat on distal vasculopathy vessels remain undetermined. Herein, we describe a case of a 66-year-old woman who exhibited deterioration of mean pulmonary artery pressure and exercise tolerance after a 4-month treatment with riociguat. She received balloon pulmonary angioplasty prior to riociguat administration. Her lung perfusion scintigraphy and pulmonary angiography findings did not change over the course of treatment. Notably, after the discontinuation of riociguat, her clinical values returned to their levels prior to riociguat administration. Her intrapulmonary shunt ratio followed a similar course as her hemodynamic status. We demonstrate that riociguat can deteriorate hemodynamic status, which may mediate the dilatation of intrapulmonary shunts. We should perform close monitoring of symptoms and hemodynamic status after riociguat administration, especially in patients in whom the reperfused DVs occurred due to invasive treatment.

Topics: Aged; Angiography; Angioplasty, Balloon; Chronic Disease; Enzyme Activators; Exercise Tolerance; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Lung; Patient Outcome Assessment; Pulmonary Artery; Pulmonary Embolism; Pyrazoles; Pyrimidines; Radionuclide Imaging; Thromboembolism

Topics: Chronic Disease; Drug Design; Humans; Hypertension, Pulmonary; Patient Safety; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Thromboembolism; Treatment Outcome

When pulmonary hypertension results in marked limitation in activities of daily living (functional class III), the first-choice vasodilator is bosentan, despite its limitations. There is no proven advantage of adding another vasodilator. The adverse effects of vasodilators outweigh their uncertain efficacy in patients with only a slight limitation of physical activity (class II). When surgery is not feasible or when chronic thromboembolic pulmonary hypertension persists despite surgery, there are no vasodilators with a favourable harm-benefit balance. Riociguat (Adempas, Bayer) is a vasodilator that acts by enhancing the synthesis of cyclic guanosine monophosphate (cGMP), a mediator of vasodilation. This mechanism of action is similar to that of sildenafil, which inhibits cGMP catabolism. Riociguat has been authorised in the European Union in adult patients with class II or III pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Riociguat monotherapy has not been compared with another vasodilator in patients with pulmonary arterial hypertension. In a 12-week randomised, double-blind, placebo-controlled trial in 380 patients, riociguat had modest symptomatic efficacy, improving the functional class in 21% of patients (versus 14% in the placebo arm). There was no statistically significant difference in mortality. The symptomatic benefit appeared to be similar in patients who continued to take bosentan and in those who were not taking a vasodilator other than riociguat. In a 16-week, double-blind trial in 261 patients with chronic thromboembolic pulmonary hypertension in whom surgery was not feasible or had failed, riociguat was more effective than placebo on symptoms; there was improvement in functional class in respectively 33% and 15% of patients. There was no statistically significant change in mortality. In these two clinical situations, subgroup analyses showed no benefit of riociguat in patients who had only slight limitation of physical activity (class II). The main adverse effects of riociguat are related to its vasodilatory properties, and include headache, arterial hypotension, dizziness and peripheral oedema. Riociguat can also cause bleeding, including potentially severe pulmonary haemorrhage. More data are needed on its cardiac, renal and osseous adverse effects. Riociguat is subject to pharmacodynamic interactions with many other drugs. In particular, riociguat coadministration with a phosphodiesterase type 5 inhi

Topics: Activities of Daily Living; Adult; Animals; Chronic Disease; Cyclic GMP; Humans; Hypertension, Pulmonary; Motor Activity; Pyrazoles; Pyrimidines; Thromboembolism; Vasodilator Agents

Topics: Antihypertensive Agents; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Pulmonary Veno-Occlusive Disease; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides; Thromboembolism; Treatment Failure; Vasodilator Agents