Beta-blockers Safe, Effective for HFrEF Patients With Renal Dysfunction: Meta-analysis

PARIS, France—Even when facing moderately-severe renal impairment, patients who have heart failure with reduced ejection fraction (HFrEF) and are in sinus rhythm can derive a survival benefit from beta-blockers, according to new meta-analysis.

Up until now, limited data have existed regarding the safety of HFrEF treatment in patients with either moderate (estimated glomerular filtration rate [eGFR] 45 to 59 mL/min/1.73 m² ) or moderately-severe (eGFR 30 to 44 mL/min/1.73 m² ) kidney dysfunction, with most studies either being small or excluding this subgroup.

“All of us appreciate in our clinical practice that renal dysfunction is a big problem in heart failure, and it’s a big problem because it changes our thoughts about commencing, uptitrating, and maintaining therapy for heart failure,” said Dipak Kotecha, MBChB, PhD (University of Birmingham, England), while presenting results of the BB-meta-HF study in a Hot Line session at the European Society of Cardiology Congress 2019. “We’ve shown conclusively with sufficient power that even patients who have moderately-severe renal function . . . can benefit from beta-blockers.”

While beta-blockers did not cause any further deterioration of preexisting kidney dysfunction, “those patients who did have worsening need extra support and . . . perhaps more careful observation to prevent what we know are very poor outcomes in these patients with heart failure and reduced ejection fraction,” he continued. “In summary, renal impairment should not obstruct our prescription—it should not obstruct the doses we use for our patients for beta-blockers in heart failure and reduced ejection fraction.”

Discussing the study during the main session, Theresa McDonagh, MD (King’s College Hospital, London, England), echoed those sentiments. “The take-home message for me would be: do prescribe and uptitrate beta-blockers in HFrEF, don’t worry about the renal function, [and] do not find any excuses to deny patients beta-blockers,” she said.

More Than 17,000 Patients

For the study, Kotecha and colleagues included individual data from 17,433 heart failure patients enrolled in 10 randomized trials comparing beta-blockers and placebo as part of the Beta-blockers in Heart Failure Collaborative Group. Over a median follow-up period of 1.3 years, renal dysfunction was associated with increased mortality—there was a 12% increase in the hazard of death for every 10-mL/min/1.73 m² lower eGFR (P < 0.001).

Among the 79.5% patients who were in sinus rhythm (median eGFR 64 mL/min/1.73 m² ), beta-blockers reduced the risk of mortality compared with placebo regardless of baseline eGFR (P for interaction = 0.021). Patients with both moderately-severe and moderate renal impairment saw “very substantial benefits” despite extra comorbidities, Kotecha said, noting that the number needed to treat to prevent one death was “the same” at 21.4 in the moderately-severe group and 21.5 in those with eGFR > 90 mL/min/1.73 m² .

Beta-blockers did not seem to worsen renal function over time even in those who presented with it at baseline. However, it should be noted that patients who did see a worsening in their kidney impairment were more likely to die through 2 years.

Renal impairment should not obstruct our prescription—it should not obstruct the doses we use for our patients for beta-blockers in heart failure and reduced ejection fraction. Dipak Kotecha

Among those with baseline A-fib (n = 2,879), the baseline median eGFR was lower at 60 mL/min/1.73 m² and mortality was 5% higher after follow-up compared with patients in sinus rhythm. There was no impact of beta-blockers seen in this group across the range of eGFRs (P for interaction = 0.18).

The overall rates of adverse events leading to discontinuation of the study drug were similar with the placebo and beta-blocker in those with moderate (20.9% vs 19.4%) and moderately-severe (14.9% vs 14.8%) renal dysfunction, as well as preserved renal function (15.1% vs 11.0%).

Also, similar proportions of patients with moderate (76.3%) and moderately-severe (77.9%) renal dysfunction and preserved renal function (83.8%) received greater than 50% of the maximum target beta-blocker dose. “This just highlights that you can get patients up to quite useful doses that can then help to prevent death and other adverse events,” Kotecha said.

Extended Knowledge

The study “extends our knowledge from subgroup analyses of the individual trials; particularly CIBIS and COPERNICUS did show that beta-blockers had the same risk reduction for people with low eGFRs of less than 60,” McDonagh said, adding that it “confirms that beta-blockers reduce mortality for people with HFrEF who are in sinus rhythm, even in moderately-severe renal dysfunction.”

However, the meta-analysis “does lack power for those with eGFRs of less than 30,” she noted.

What’s interesting is that already most clinicians do not use renal dysfunction as a reason to not uptitrate beta-blockers, according to McDonagh. “We have many other good biomarkers of safety here—heart rate and blood pressure. We use many other excuses—COPD, asthma, erectile dysfunction, and most recently atrial fibrillation—and it’s quite surprising because the nephrologists believe in beta-blockers in reduced ejection fraction heart failure . . . . [This is] good news for heart failure patients with chronic kidney disease that we’re not going to deny them arguably the most effective treatment for reducing all-cause mortality in HFrEF.”

Lastly, she stressed that the A-fib data in the study are “only hypothesis-generating,” although on the flip side there’s no evidence that beta-blockers harm these patients. Also, “there are no trials of stopping beta-blockers in patients with A-fib and HFrEF, and there’s no randomized control trial of using beta-blockers in patients with A-fib and HFrEF. So use them and uptitrate them, and if you’re not convinced by this data, you may have to give beta-blockers anyway to patients with heart failure and A-fib because of needs for rate control, MI, and coronary artery disease.”

Commenting on the study for TCTMD, Shaline Rao, MD (NYU Langone Health, New York), said she was surprised to see no benefit of beta-blockers in patients with A-fib. “A-fib is very common in heart failure, as well as with chronic kidney disease, so it's definitely interesting that that group didn't map to the same benefit,” she said. “CASTLE-AF and some other studies have shown that the contribution of A-fib in heart failure is quite meaningful,” she noted, and it could be “that's why the beta-blocker effect is not enough to really change outcomes.”

This cohort deserves more study and perhaps a rethink in management, according to Rao. “Maybe it should be more invasive ablation strategies, maybe that's actually valuable for that group of people and it can be safely done,” she said. “Or are there alternate versions of drug therapy combinations that do work better in this group?”

Ultimately, Rao said, “it's nice to see” the study confirm that maximizing beta-blockers in HFrEF patients with chronic kidney disease is an appropriate strategy. “People with chronic kidney disease are often excluded from trials, so we extrapolate from what we know,” she explained. “But sometimes you do wonder [if] we’re getting it wrong, or [ask] is it less effective and do we need another strategy? I think in this case they've shown through their analysis that beta-blockers are an effective tool.”