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The Relationship Between a PAI-1 Polymorphism and Clinical Response to Endothelin Antagonists

Raymond Benza

Diane Vido

Adaani Frost

Erika Berman Rosenzweig

Kelly Chin

Srinivas Murali

Priscilla Correa-Jaque

H. Tiwari


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Conference: 2010 International PHA Conference and Scientific Sessions

Release Date: 06.24.2010

Presentation Type: Abstracts

Benza R1, Vido D1, Frost A2, Rosenzweig E3, Chin K4, Murali S1, Correa P1, Nowicki A1, Tiwari H5.
1. Allegheny General Hospital, Pittsburgh, PA, USA
2. Baylor College of Medicine, Houston, TX, USA
3. Columbia University Medical Center, New York, NY, USA 
4. University of Texas Southwestern Medical Center, Dallas, TX, USA 
5. University of Alabama at Birmingham, Birmingham, AL, USA

BACKGROUNDResponse to therapy for PAH is heterogeneous and predicting responses based on polymorphisms (PM) could enhance patient specific care. We sought to examine differences between homozygous and heterozygous HindIII on 6 minute walk distance (6MWD) in patients treated with endothelin antagonists (ERAs).

METHODSGenomic and clinical data were collected from participants in the Sitaxsentan To Relieve ImpaireD Exercise (STRIDE) trials and PAH patients treated with ERAs prospectively enrolled from 30 centers. Associations between genotype and change in 6MWD from baseline were assessed at 4 and 12 months using general linear modeling, controlling for the effect of the baseline 6MWD.

RESULTSHindIII frequencies for CC, GC, GG genotypes were 32.3%, 50.3%, and 17.4%, respectively, with an allele frequency of 57.45% and 42.55% for the C and G alleles. Of 570 PAH patients genotyped for the HindIII PM, 474 had a baseline 6MWD and at least one post-baseline 6MWD and were included in analysis. Of these, 80.2% were STRIDE participants and 19.8% were prospectively enrolled; 80.2% were on Sitaxsentan, 18.4% Bosentan, and 1.5% Ambrisentan. Median age at start of drug was 50.0 years. 78.7% were female and 74.3% were Caucasian. Mean baseline 6MWD was 368.9 + 110.9 m (median=366); mean Borg dyspnea index 3.6 + 2.2; 43.7% were WHO functional class II, 49.6% were class III. Baseline 6MWD was similar among the homozygous CC and GG and heterozygous GC groups (p=0.32). There was a marginally significant effect of the CC and GG homozygous or GC heterozygous HindIII on mean change from baseline in 6MWD at month 4 (p=0.07) and also on change in 6MWD from baseline to year 1 (p=0.13), after controlling for the effect of the baseline 6MWD. At 4 months, the 6MWD improved for all genotype groups with a mean increase from baseline in the heterozygous CG genotype group of +23.9 m (p<0.001) and a mean increase from baseline in homozygous CC and GG groups of +11.7 m (p=.02). There were similar improvements at one year. There was also a significant relation between genotypes and a decline of >15% from baseline at 4 months (X2 (1df)=4.0; P=0.045) but not at 1 year. Sixty-nine percent of those patients declining >15% from baseline at 4 months were in the homozygous CC and GG group as compared with 31% of patients in the heterozygous CG genotype group.

CONCLUSIONSUnderstanding the variability associated with predicting clinical responses based on polymorphisms represents a significant clinical advance in the treatment of PAH.