Pulmonary arterial hypertension: tailoring treatment to risk in the current era

Gaine, Seán; McLaughlin, Vallerie V.

doi:10.1183/16000617.0095-2017

Cited by 33 publications

(38 citation statements)

References 57 publications

(82 reference statements)

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“…) is a progressive and incurable disease that occurs when the pulmonary arteries undergo pathological remodelling, causing the blood vessels to vasoconstrict, with a consequent increase in pulmonary vascular resistance. Continued high pressure in the pulmonary artery leads to right ventricular heart failure and death if left untreated (Gaine & McLaughlin, ). Although PAH is a rare disease with an incidence of 15–50 people per million in the population (Humbert et al .…”

Section: Introductionmentioning

confidence: 99%

Characterization and regulation of wild‐type and mutant TASK‐1 two pore domain potassium channels indicated in pulmonary arterial hypertension

Cunningham

Holden

Escribano

et al. 2018

The Journal of Physiology

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Key points The TASK‐1 channel gene (KCNK3) has been identified as a possible disease‐causing gene in heritable pulmonary arterial hypertension (PAH). In the present study, we show that novel mutated TASK‐1 channels, seen in PAH patients, have a substantially reduced current compared to wild‐type TASK‐1 channels. These mutated TASK‐1 channels are located at the plasma membrane to the same degree as wild‐type TASK‐1 channels. ONO‐RS‐082 and alkaline pH 8.4 both activate TASK‐1 channels but do not recover current through mutant TASK‐1 channels. We show that the guanylate cyclase activator, riociguat, a novel treatment for PAH, enhances current through TASK‐1 channels but does not recover current through mutant TASK‐1 channels. Abstract Pulmonary arterial hypertension (PAH) affects ∼15–50 people per million. KCNK3, the gene that encodes the two pore domain potassium channel TASK‐1 (K2P3.1), has been identified as a possible disease‐causing gene in heritable PAH. Recently, two new mutations have been identified in KCNK3 in PAH patients: G106R and L214R. The present study aimed to characterize the functional properties and regulation of wild‐type (WT) and mutated TASK‐1 channels and determine how these might contribute to PAH and its treatment. Currents through WT and mutated human TASK‐1 channels transiently expressed in tsA201 cells were measured using whole‐cell patch clamp electrophysiology. Localization of fluorescence‐tagged channels was visualized using confocal microscopy and quantified with in‐cell and on‐cell westerns. G106R or L214R mutated channels were located at the plasma membrane to the same degree as WT channels; however, their current was markedly reduced compared to WT TASK‐1 channels. Functional current through these mutated channels could not be restored using activators of WT TASK‐1 channels (pH 8.4, ONO‐RS‐082). The guanylate cyclase activator, riociguat, enhanced current through WT TASK‐1 channels; however, similar to the other activators investigated, riociguat did not have any effect on current through mutated TASK‐1 channels. Thus, novel mutations in TASK‐1 seen in PAH substantially alter the functional properties of these channels. Current through these channels could not be restored by activators of TASK‐1 channels. Riociguat enhancement of current through TASK‐1 channels could contribute to its therapeutic benefit in the treatment of PAH.

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Section: Introductionmentioning

confidence: 99%

Characterization and regulation of wild‐type and mutant TASK‐1 two pore domain potassium channels indicated in pulmonary arterial hypertension

Cunningham

Holden

Escribano

et al. 2018

The Journal of Physiology

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“… 5 , 6 As a result, combination therapy with ≥ 2 classes of PAH-approved drugs is becoming the standard of care. 2 , 7 In a meta-analysis of 18 randomized controlled trials including 4162 patients with PAH, combination therapy significantly reduced the risk of clinical worsening, significantly increased 6-min walking distance (6MWD) and functional class, and improved hemodynamic parameters compared with monotherapy, although there was no effect on mortality. 8 A second meta-analysis of 17 randomized controlled trials also found a reduction in clinical worsening events with combination therapy versus monotherapy.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of riociguat in combination therapy for patients with pulmonary arterial hypertension (PATENT studies)

Ghofrani

Grünig

Jansa³

et al. 2020

Pulm. circ.

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Many patients with pulmonary arterial hypertension do not achieve treatment goals with monotherapy, and therefore combination therapy is becoming the standard of care. The soluble guanylate cyclase stimulator riociguat is licensed for the treatment of pulmonary arterial hypertension; here we present findings from patients who were receiving combined riociguat plus endothelin receptor antagonists or non-intravenous prostanoids in the randomized, placebo-controlled PATENT-1 study and its open-label extension (PATENT-2). Moreover, we include new data from patients receiving early sequential combination therapy (three to six months of endothelin receptor antagonist treatment) or long-term background endothelin receptor antagonist therapy (>6 months). Patients were randomized to riociguat 2.5 mg–maximum ( N = 131 pretreated patients) and placebo ( N = 60 pretreated patients). Riociguat improved 6-min walking distance (PATENT-1 primary endpoint), functional capacity, and hemodynamics after 12 weeks in pretreated patients. The placebo-corrected changes in 6-min walking distance were +24 m in endothelin receptor antagonist-pretreated patients and +106 m in the small group of prostanoid-pretreated patients. In the early sequential combination and long-term background endothelin receptor antagonist groups, the placebo-corrected changes in 6-min walking distance were +65 m (95% CI: 17 to 113 m) and +13 m (95% CI: –8 to 33 m), respectively. In conclusion, these data suggest that early sequential combination of an endothelin receptor antagonist plus riociguat is a feasible treatment option. Both early sequential therapy and long-term background endothelin receptor antagonist plus riociguat were well tolerated in the PATENT studies.

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“…Combination therapy has been shown to be efficacious in the clinical trial setting, but it may also increase the practical challenges in clinical practice, and care must be taken to ensure that the benefit–risk ratio remains favorable for the patient. The robust clinical efficacy data supporting combination therapy and the role of risk stratification to guide clinical decision-making have recently been comprehensively reviewed [ 9 ]. However, practical advice for healthcare professionals regarding combination therapy management in the clinic is also required.…”

Section: Introductionmentioning

confidence: 99%

Pulmonary Arterial Hypertension: Combination Therapy in Practice

Burks

Stickel

Galiè

2018

Am J Cardiovasc Drugs

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Combination therapy is now regarded as the standard of care in pulmonary arterial hypertension (PAH) and is becoming widely used in clinical practice. Given the inherent complexities of combining medications, there is a need for practical advice on implementing this treatment strategy in the clinic. Drawing on our experience and expertise, within this review, we discuss some of the challenges associated with administration of combination therapy in PAH and how these can be addressed in the clinic. Despite their differing modes of action, all of the currently available classes of PAH therapy induce systemic vasodilation. In initial combination therapy regimens in particular, this may lead to additive side effects and reduced tolerability compared with monotherapy. However, approaches such as staggered treatment initiation and careful up-titration may reduce the risk of additive side effects and have been used successfully in clinical practice, as well as in clinical trials and registry studies. When combination therapy regimens are initiated, it is important that patients are monitored regularly for the presence of any side effects and that these are then managed promptly and appropriately. For patients to attain the best outcomes, the treatment regimen must be tailored to the individual’s specific needs, including consideration of PAH etiology, the presence of comorbidities and concomitant medications beyond PAH therapy, and patient lifestyle and preference. It is also vital that individuals are managed at expert care centers, where multidisciplinary teams have a wealth of specialist experience in treating PAH patients. Adherence to therapy can be a concern in a chronic disease such as PAH, and as treatment regimens become increasingly complex, maintaining good treatment adherence may become more challenging. It is essential that patients are educated on the importance of treatment adherence, and this is a key role for the PAH nurse specialist. For patients who are managed carefully in expert centers with combination therapy regimens that are tailored to their specific needs, a favorable benefit–risk ratio can be achieved. With individual and carefully managed approaches, the excellent results observed with combination therapy in clinical trials can be obtained by patients in a real-world setting.

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Pulmonary arterial hypertension: tailoring treatment to risk in the current era

Cited by 33 publications

References 57 publications

Characterization and regulation of wild‐type and mutant TASK‐1 two pore domain potassium channels indicated in pulmonary arterial hypertension

Characterization and regulation of wild‐type and mutant TASK‐1 two pore domain potassium channels indicated in pulmonary arterial hypertension

Efficacy and safety of riociguat in combination therapy for patients with pulmonary arterial hypertension (PATENT studies)

Pulmonary Arterial Hypertension: Combination Therapy in Practice

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