Genotype-guided beta-blocker therapy to prevent atrial fibrillation in HF patients
Phase ii trial of pharmacogenetic guided beta-blocker therapy with bucindolol vs. metoprolol for the prevention of atrial fibrillation/flutter in heart failure: GENETIC-AF
//Presented at ESC Heart Failure 2018 in Vienna, Austria, by William Abraham (Columbus, US) //
Introduction and methods
The β-1 adrenergic receptor exists in different genetic polymorphisms, which affect their function. A common polymorphism is a guanine instead of a cytosine at nucleotide position 1165 of the gene, which results in glycine instead of arginine at amino acid position 389. A change from β1-389Arg to β1-389Gly alters the binding affinity for norepinephrine, the signal transduction capacity, and leads to constitutively active receptors. Bucindolol is a therapy that has two unique properties that are specific for 389Arg- β1-adrenergic receptors, namely the moderately sympatholytic and inverse agonistic effects.
The BEST DNA study had already studied this genotype-specific effect of bucindolol. In patient homozygous for β1-389Arg, bucindolol significantly lowered the risk of atrial fibrillation (HR: 0.26, 95%CI: 0.12-0.57, P=0.0003), while this risk reduction was completely absent in carriers of at least one β1-389Gly allele. Indeed, the interaction of the treatment effect with the genotype was significant.
This GENETIC-AF study aimed to test the hypothesis that bucindolol would reduce the recurrence of symptomatic atrial fibrillation (AF)/atrial flutter (AFl) in patients with HF and the β1-389 Arg/Arg genotype, as compared with metoprolol succinate. Patients were followed-up for 24 weeks, after which patients visited the clinic every 12 weeks in the treatment extension period. The trial was set up as a phase 2b/3 seamless design, meaning that the study would either be stopped, or seamlessly transition to a phase 3 trial, after a phase 2 interim analysis. The primary endpoint was first occurrence of AF, AFl or all-cause mortality (ACM).
The study was completed as a phase 2 study, without transition into phase 3. Note that the study was powered for a full phase 3 population, thus the phase 2b population was underpowered.
- The primary endpoint did not significantly differ between bucindolol- and metoprolol -treated patients (54.5% vs 52.6%, HR: 1.01, 95%CI: 0.71-1.42).
- In the US cohort, a trend for benefit for the primary outcome was seen (60% vs. 55%, HR: 0.70, 95%CI: 0.41-1.19).
- A subanalysis of AF burden (one AF event = AF burden ≥hours/day) showed no significant difference when analyzing the entire cohort (74% vs. 69%, HR: 0.75, 95%CI: 0.43-1.32), and a trend when analyzing the US cohort (78% vs. 63%, HR: 0.49, 95%CI: 0.24-1.04).
- Adverse events were similar in both treatment groups, with a notable exception of less bradycardia in the bucindolol group (3.7% vs. 12.0%).
- A pre-specified regional analysis showed that the four countries that contributed most patients (Netherlands, Poland, Serbia and USA), showed the largest effect. In Canada and Hungary, a potential risk of bucindolol treatment was seen. Analysis suggested that these differences were related to the time of HF diagnosis in relation to randomization.
Pharmacogenetic guided bucindolol treatment did not reduce AF/AFl/ACM recurrence when compared to the active comparator metoprolol in the overall cohort of HF patients homozygous for β1-389 Arg/Arg in the GENETIC -AF study. Trends for a benefit of bucindolol treatment were, however, seen in some large subpopulations. The safety profile of bucindolol was similar to that of metoprolol. At this time, the study did not transition from a phase 2b to a phase 3 trial, but these results merit further investigation in a phase 3 trial with a redefined population, namely patients with HFrEF (LVEF <0.40), HFmrEF (LVEF ≥0.40 and <0.50) if DTRI > -30 days, symptomatic paroxysmal/persistent AF ≤180 days of randomization, and with the β1-389 Arg/Arg genotype.
The discussant called this an extremely important trial, because the intersection of AF and HF is both important and dangerous. It is the first genetically guided trial in HF, and therefore a landmark study. We should follow this adaptive trial design more often, because if we can go seamlessly to phase 3, we should, to save time.
He raised the question why patients with HFrEF and HFmrEF were mixed, as we know that they differ biologically. The answer was that this was to reflect clinical practice. He also wondered what characteristics the US patients had compared with the other nationalities. A clue of the different results in the countries studied may lie in different inclusion, possibly due to the specialty of the participating physicians (electrophysiologists), which may have led to more patients with longstanding AF in some countries. The time between HF diagnosis and AF is of importance, what came first? The pathophysiology differs between the situations in which the one or the other comes first; if AF exists for a long time already, a different type of HF develops and this may respond differently to treatment.
Our reporting is based on the information provided at the ESC Heart Failure 2018 congress