Sequential combination therapy with parenteral prostacyclin in BMPR2 mutations carriers

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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The role of combination therapy in managing pulmonary arterial hypertension

European Respiratory Review ◽

10.1183/09059180.00007314 ◽

2014 ◽

Vol 23 (134) ◽

pp. 469-475 ◽

Cited By ~ 35

Author(s):

Hossein-Ardeschir Ghofrani ◽

Marc Humbert

Keyword(s):

Pulmonary Arterial Hypertension ◽

Combination Therapy ◽

Arterial Hypertension ◽

Treatment Algorithm ◽

Supporting Evidence ◽

Potential Clinical Benefit ◽

Treatment Naïve ◽

Sequential Combination ◽

Pulmonary Arterial ◽

Randomised Controlled

Pulmonary arterial hypertension (PAH) is a complex, progressive disease with several pathobiological mechanisms, including the endothelin, nitric oxide and prostacyclin pathways. Current treatments for PAH target one of these pathways and, in more severe cases or instances of disease worsening, may be combined with a view to target multiple pathways in parallel. Treatment combination is performed sequentially (as an intensification from initial monotherapy) or upfront (use of two or more therapies in treatment-naïve patients). Whilst combination therapy has been historically considered to be an option for the treatment of PAH, supporting evidence was typically limited to expert opinion, clinical experience and registry data.Data from randomised controlled trials on sequential combination therapy in particular has grown in recent years, resulting in a change in the level of recommendations in the latest update to the PAH treatment algorithm. However, short-term trials have shown inconsistent results, and have not been powered to assess morbidity/mortality outcomes. More recent data from long-term trials suggest a potential clinical benefit associated with sequential combination therapy.In this review we will introduce the concept of combination therapy, consider the latest evidence for both sequential and upfront combination therapy, and discuss additional considerations when initiating combination therapy in clinical practice.

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Achieving glycemic goal with initial versus sequential combination therapy using metformin and pioglitazone in type 2 diabetes mellitus

Current Medical Research and Opinion ◽

10.1185/03007995.2010.536755 ◽

2010 ◽

Vol 27 (1) ◽

pp. 189-195 ◽

Cited By ~ 5

Author(s):

Bhavik J. Pandya ◽

Morgan Bron ◽

Therese McCall ◽

Andrew P. Yu ◽

Kristina S. Chen ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Combination Therapy ◽

Sequential Combination

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Successful Regeneration After Experimental Stroke by Granulocyte-Colony Stimulating Factor Is Not Further Enhanced by Constraint-Induced Movement Therapy Either in Concurrent or in Sequential Combination Therapy

Stroke ◽

10.1161/strokeaha.111.622159 ◽

2012 ◽

Vol 43 (1) ◽

pp. 185-192 ◽

Cited By ~ 23

Author(s):

Kai Diederich ◽

Verena Quennet ◽

Henrike Bauer ◽

Harald D. Müller ◽

Heike Wersching ◽

...

Keyword(s):

Combination Therapy ◽

Movement Therapy ◽

Experimental Stroke ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Constraint Induced Movement Therapy ◽

Sequential Combination ◽

Stimulating Factor

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A poly(ascorbyl acrylate)-containing nanoplatform with anticancer activity and the sequential combination therapy with its loaded paclitaxel

Journal of Materials Chemistry B ◽

10.1039/c6tb01818a ◽

2016 ◽

Vol 4 (40) ◽

pp. 6588-6596 ◽

Cited By ~ 1

Author(s):

Yufeng Song ◽

Yanqi Xie ◽

Junjiao Yang ◽

Ruiqiong Li ◽

Xu Jin ◽

...

Keyword(s):

Combination Therapy ◽

Anticancer Activity ◽

Therapeutic Agents ◽

Tumor Inhibition ◽

Sequential Combination

The complex nanocarriers combined with the loaded therapeutic agents to achieve synergistic tumor inhibition.

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Sequential Combination Therapy with Pegylated Interferon Leads to Loss of Hepatitis B Surface Antigen and Hepatitis B e Antigen (HBeAg) Seroconversion in HBeAg-Positive Chronic Hepatitis B Patients Receiving Long-Term Entecavir Treatment

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00249-15 ◽

2015 ◽

Vol 59 (7) ◽

pp. 4121-4128 ◽

Cited By ~ 31

Author(s):

Guo-Jun Li ◽

Yi-Qi Yu ◽

Shao-Long Chen ◽

Ping Fan ◽

Ling-Yun Shao ◽

...

Keyword(s):

Chronic Hepatitis ◽

Hepatitis B ◽

Combination Therapy ◽

Therapy Group ◽

Hepatitis B Surface Antigen ◽

Hbeag Seroconversion ◽

Pegylated Interferon ◽

Hepatitis B E Antigen ◽

Sequential Combination

ABSTRACTNucleos(t)ide analogues rarely result in a durable off-treatment response in chronic hepatitis B infection, whereas pegylated interferon (Peg-IFN) induces a long-lasting response only in a subset of patients. We assessed the effect of sequential combination therapy with Peg-IFN-α2a and entecavir in hepatitis B e antigen (HBeAg)-positive patients with prior long-term entecavir therapy and investigated the predictors of response to treatment. HBeAg-positive individuals who did not achieve HBeAg seroconversion during previous long-term entecavir therapy, receiving Peg-IFN-α2a added to ongoing entecavir therapy (sequential combination [S-C] therapy;n= 81) for 48 weeks or remaining on entecavir monotherapy (n= 116), were retrospectively included. A matched pair was created at a 1:1 ratio from each treatment group. The primary endpoint was HBeAg seroconversion at week 48. Subgroup analysis of response prediction was conducted for 81 patients with S-C therapy. More patients in the S-C therapy group achieved HBeAg seroconversion than those in the entecavir group (44% versus 6%;P< 0.0001). An HBeAg level of <200 signal-to-cutoff ratio (S/CO) at baseline was a strong predictor for higher HBeAg seroconversion than that achieved when HBeAg was ≥200 S/CO (64.2% versus 17.9%;P< 0.0001). Hepatitis B surface antigen (HBsAg) levels at baseline and the decrease in HBsAg levels predicted HBsAg loss in the S-C therapy group. The combination of baseline HBeAg of <200 S/CO and HBsAg of <1,000 IU/ml and an HBsAg decline at week 12 of ≥0.5 log10IU/ml provided the highest rate of HBeAg seroconversion (92.31%) and HBsAg loss (83.3%) at week 48. Patients receiving sequential combination therapy have a higher rate of HBeAg seroconversion and are more likely to experience HBsAg clearance than do those continuing entecavir monotherapy. Sequential combination therapy can be guided by baseline HBsAg/HBeAg levels and on-treatment HBsAg dynamics.

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