Polygenic Score For Beta-blocker Survival Benefit In Heart Failure With Preserved Ejection Fraction Patients

Abstract

Background Beta-blockers (BB) are mainstay therapy for heart failure with reduced ejection fraction (HFrEF), but are not proven helpful for HF with preserved EF (HFpEF). We recently defined a genomic profile for enhanced BB survival benefit in HFrEF (Polygenic Response Predictor; PRP) and sought to test whether this could define a favorable responder group among HFpEF patients. Methods Patients with HF and EF ≥50% of European descent (n=450, deaths=132) from two studies (the Henry Ford Pharmacogenomic Registry (HFPGR); n=338 and TIME-CHF; n=112) were included. The PRP was used to categorize patients into predicted responders vs. predicted non-responders as previously described. This was tested in Cox models predicting time to all-cause mortality, adjusted for clinical risk score (MAGGIC), level of BB-exposure, PRP category and BB-exposure*PRP-category interaction, with meta-analysis then used to pool overall study results. Results Greater BB exposure trended toward reduced all-cause mortality in HFpEF patients in PRP predicted responder group (n=103; HR=0.39 [95% CI=0.097-1.56], p=0.18), and toward hazard among PRP predicted non-responders (n=347; HR=1.38 [95% CI=0.67-2.8], p=0.38), an interaction that was near significant (p interaction =0.11). The figure shows forest plot of BB HR in each PRP category for each study cohort and overall. Conclusions Among patients of European ancestry with HFpEF, the BB PRP may be able to differentiate BB responders from those that derive hazard from BB exposure. Additional testing is needed in larger HFpEF cohorts. Beta-blockers (BB) are mainstay therapy for heart failure with reduced ejection fraction (HFrEF), but are not proven helpful for HF with preserved EF (HFpEF). We recently defined a genomic profile for enhanced BB survival benefit in HFrEF (Polygenic Response Predictor; PRP) and sought to test whether this could define a favorable responder group among HFpEF patients. Patients with HF and EF ≥50% of European descent (n=450, deaths=132) from two studies (the Henry Ford Pharmacogenomic Registry (HFPGR); n=338 and TIME-CHF; n=112) were included. The PRP was used to categorize patients into predicted responders vs. predicted non-responders as previously described. This was tested in Cox models predicting time to all-cause mortality, adjusted for clinical risk score (MAGGIC), level of BB-exposure, PRP category and BB-exposure*PRP-category interaction, with meta-analysis then used to pool overall study results. Greater BB exposure trended toward reduced all-cause mortality in HFpEF patients in PRP predicted responder group (n=103; HR=0.39 [95% CI=0.097-1.56], p=0.18), and toward hazard among PRP predicted non-responders (n=347; HR=1.38 [95% CI=0.67-2.8], p=0.38), an interaction that was near significant (p interaction =0.11). The figure shows forest plot of BB HR in each PRP category for each study cohort and overall. Among patients of European ancestry with HFpEF, the BB PRP may be able to differentiate BB responders from those that derive hazard from BB exposure. Additional testing is needed in larger HFpEF cohorts.