Tadalafil in Idiopathic or Heritable Pulmonary Arterial ...

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Tadalafil in Idiopathic or Heritable Pulmonary Arterial Hypertension (PAH) Compared to PAH Associated with Connective Tissue Disease

Nazzareno Galie`, Christopher P. Denton, Fabio Dardi, Alessandra Manes, Gaia Mazzanti, Baohui Li, Lucio Varanese, Anne Esler, Cathi Harmon, Massimiliano Palazzini

PII: DOI: Reference:

S0167-5273(17)31124-5 doi:10.1016/j.ijcard.2017.02.094 IJCA 24620

To appear in:

International Journal of Cardiology

Received date: Revised date: Accepted date:

18 August 2016 13 January 2017 20 February 2017

Please cite this article as: Gali`e Nazzareno, Denton Christopher P., Dardi Fabio, Manes Alessandra, Mazzanti Gaia, Li Baohui, Varanese Lucio, Esler Anne, Harmon Cathi, Palazzini Massimiliano, Tadalafil in Idiopathic or Heritable Pulmonary Arterial Hypertension (PAH) Compared to PAH Associated with Connective Tissue Disease, International Journal of Cardiology (2017), doi:10.1016/j.ijcard.2017.02.094

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Title: Tadalafil in Idiopathic or Heritable Pulmonary Arterial Hypertension (PAH) Compared to PAH Associated with Connective Tissue Disease Authors: Nazzareno Gali?1, Christopher P. Denton2, Fabio Dardi3, Alessandra Manes4, Gaia Mazzanti5, Baohui Li6, Lucio Varanese7, Anne Esler8, Cathi Harmon9, Massimiliano Palazzini10 Corresponding Author: Professor Nazzareno Gali?, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, via Massarenti 9, 40138-Bologna, Italy Tel: +39 051 349 858 Fax: +39 051 344 859 Email: nazzareno.galie@unibo.it Affiliations and Authorship 1Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. During the conduct of the study, Dr. Gali? reports grants and personal fees from Eli Lilly and Company, grants and personal fees from Actelion, grants and personal fees from GSK, grants and personal fees from Bayer, grants and personal fees from Pfizer.

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2Centre for Rheumatology at the Royal Free and University College Medical School, Hampstead, London. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. Outside the submitted work, Dr. Denton reports personal fees from Actelion Pharmaceuticals, personal fees from GSK, grants from Actelion Pharmaceuticals, personal fees from Bayer. 3Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. Dr. Dardi has nothing to disclose. 4Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. Dr. Manes has nothing to disclose. 5Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. Dr. Mazzanti has nothing to disclose. 6Eli Lilly and Company, Indianapolis, IN, USA. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. Dr. Li has nothing to disclose.

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7Eli Lilly and Company, Indianapolis, IN, USA. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. Dr. Varanese has nothing to disclose. 8inVentiv Clinical Solutions, LLC, Indianapolis, IN, USA. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. Dr. Esler has nothing to disclose. 9Eli Lilly and Company, Indianapolis, IN, USA. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. Mrs. Harmon has nothing to disclose. 10Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. Dr. Palazzini has nothing to disclose.

Keywords: Associated PAH, PHIRST, PHIRST-2, idiopathic, heritable

Abstract

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Background The primary objective of this post hoc analysis was to evaluate clinical outcomes of tadalafil in patients with pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD-PAH) compared with patients with idiopathic/heritable PAH (I/H-PAH) for primary and key secondary efficacy endpoints, and safety. This analysis included adult patients with CTD-PAH or I/H-PAH who participated in the PHIRST and PHIRST-2 studies. Methods Patients were randomized 1:1:1:1:1 to tadalafil (2.5, 10, 20, or 40 mg) or placebo in the PHIRST study and the majority of these patients were subsequently assigned 40 mg in PHIRST-2. Patients taking 20 mg in PHIRST without demonstrating clinical worsening continued on 20 mg in PHIRST-2. Outcomes analyzed included 6MWD, WHO-FC, and incidence and time to first occurrence of clinical worsening. Safety was assessed through evaluation of adverse events (AEs), clinical laboratory data, electrocardiograms, and physical examinations. Results Increased 6MWD in PHIRST was maintained in both CTD-PAH and I/H-PAH subgroups for 52 weeks. Patients with CTD-PAH tended to be older, were more likely female, had lower exercise capacity, were more likely to have clinical worsening, and experienced AEs more frequently than patients with I/H-PAH.

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Conclusion The effect of tadalafil treatment in patients enrolled in both PHIRST studies was detectable for both I/H-PAH and CTD-PAH subgroups. In general, subgroup differences were modest. Patients with CTD-PAH may perform less well than patients with I/H-PAH in safety and efficacy measures in all treatment groups, which is similar to other studies demonstrating a worse prognosis for patients with CTD-PAH.

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1. Introduction Pulmonary arterial hypertension (PAH) is a severe and chronic disease

characterized by a progressive obstructive remodeling of the distal pulmonary arteries which results in increased pulmonary vascular resistance and pressure. PAH includes a heterogeneous group of clinical entities: idiopathic PAH (IPAH), heritable PAH (HPAH), drug and toxin induced PAH, and PAH associated with other conditions such as, connective tissue disease (CTD-PAH) [1].

When considering the entire adult PAH population, it has been estimated that up to 30% suffer from CTD-PAH [2], the second largest patient subgroup after IPAH. Patients with CTD-PAH have been included in many of the randomized controlled trials and adequately represent the subgroup as it occurs in the general PAH population. Previous studies suggest that CTD-PAH patients have a worse prognosis than other PAH subgroups and that patients with PAH associated with the scleroderma spectrum of diseases have a particularly poor outcome [3].

The Pulmonary Arterial HypertensIon and ReSponse to Tadalafil (PHIRST) study was a 16-week, double-blind, placebo-controlled study evaluating 4 doses of tadalafil (an oral, once-daily phosphodiesterase [PDE]-5 inhibitor) [4]. Significant improvement as compared with placebo (PBO) was seen in the highest dose studied (40 mg), for six-minute walk distance (6MWD), time to clinical worsening (TTCW) and quality of life [4]. The approved dose of tadalafil for PAH treatment in adults is 40 mg [4]. After participating in the PHIRST trial,

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eligible patients were enrolled in a 52-week, double-blind, multicenter, long-term prospective extension study (PHIRST-2) and received either tadalafil 20 mg (T20) or 40 mg (T40) [5]. The increased 6MWD observed in both T20 and T40 groups in PHIRST was also maintained during PHIRST-2 [5].

This study reports the result of a post hoc analysis of PHIRST and PHIRST-2 data in order to evaluate the effect of tadalafil treatment in the subset of patients with CTD-PAH as compared to the subset of patients with idiopathic/heritable PAH (I/H PAH).

2. Methods 2.1 Patients

Patient eligibility for the PHIRST and PHIRST-2 studies has been previously reported [4,5]. This post hoc analysis includes the subset of patients with CTD-PAH or I/H PAH who were randomized in the PHIRST study and transitioned to the PHIRST-2 extension study [5].

Both PHIRST study protocols were approved by local institutional review boards or independent ethics committees, and written informed consent (or assent when appropriate) was obtained from all patients. The PHIRST and PHIRST-2 studies were conducted in full compliance with the principles of the Declaration of Helsinki, the International Conference on Harmonisation guidelines, or with the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the study subject.

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