Latent Pulmonary Vascular Disease May Alter the Response to Therapeutic Atrial Shunt Device in Heart Failure

Abstract

Background: In the REDUCE LAP-HF II trial, implantation of an atrial shunt device did not provide, overall, clinical benefit for patients with heart failure and preserved or mildly reduced ejection fraction (HFpEF/HFmrEF). However, pre-specified analyses identified differences in response in subgroups defined by pulmonary artery systolic pressure during submaximal exercise, right atrial (RA) volume, and sex. Shunt implantation reduces left atrial (LA) pressures but increases pulmonary blood flow, which may be poorly tolerated in patients with pulmonary vascular disease (PVD). Based upon these results, we hypothesized that patients with latent PVD, defined as elevated pulmonary vascular resistance (PVR) during exercise, might be harmed by shunt implantation, and conversely that patients without PVD might benefit. Methods: REDUCE LAP-HF II enrolled 626 patients with HF, EF ≥40%, exercise pulmonary capillary wedge pressure ≥25 mmHg, and resting PVR <3.5 WU who were randomized 1:1 to atrial shunt device or sham control. The primary outcome, a hierarchical composite of cardiovascular death, nonfatal ischemic stroke, recurrent HF events, and change in health status, was analyzed using the win ratio. Latent PVD was defined as PVR ≥1.74 WU (highest tertile) at peak exercise, measured prior to randomization. Results: Compared to patients without PVD (n=382), those with latent PVD (n=188) were older, had more atrial fibrillation and right heart dysfunction, and were more likely to have elevated LA pressure at rest. Shunt treatment was associated with worse outcomes in patients with PVD (win ratio 0.60, [95% CI 0.42, 0.86]; p=0.005) and signal of clinical benefit in patients without PVD (win ratio 1.31 [95% CI 1.02, 1.68]; p=0.038). Patients with larger RA volumes and men had worse outcomes with the device, and both groups were more likely to have pacemakers, HFmrEF, and increased LA volume. For patients without latent PVD or pacemaker (n=313, 50% of randomized patients), shunt treatment resulted in more robust signal of clinical benefit (win ratio 1.51 [95% CI 1.14, 2.00]; p=0.004). Conclusions: In patients with HFpEF/HFmrEF, the presence of latent PVD uncovered by invasive hemodynamic exercise testing identifies patients who may worsen with atrial shunt therapy, whereas those without latent PVD may benefit.

2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension

“…The recent REDUCE LAP-HF II trial failed to show a reduction in HF events after placement of an atrial shunt device in a population of HF patients with LVEF ⩾40% [689], with worse outcomes in the presence of PVD [690]. In addition, a sustained increase in PA blood flow may be a matter of concern, as this may trigger vascular remodelling in patients with pre-existing PH.…”

Atrial Shunt Devices in Patients With Heart Failure and Preserved or Mildly Reduced Ejection Fraction and the Pulmonary Circulation: Promises and Concerns

“…The authors argue that they can be explained simply by the fact that the decongestion of the left atrium led to more blood filling the right chambers. But when one looks at the aSD group at 12 months, left atrial size and E/e’ ratio had not changed 4 , suggesting that the left atrial function may have not improved. The authors also argue that this increase in volumes was not associated with a decrease in right ventricular function (judged via the echo surrogate marker of tricuspid annular plane systolic excursion); but it may be too early before a potential recent-onset PH may start affecting the right ventricular function.…”

“…Thankfully, the authors had the insight to include, as a prespecified factor, exercise-induced increase in systolic pulmonary artery pressure at the baseline catheterization, which revealed a possible association of exercise-induced (but not resting) pulmonary pressures with the trial outcomes. In this issue of Circulation , Borlaug et al 4 present a post hoc analysis of the trial data. They show that patients with latent PH (defined by the authors as exercise-induced increase in pulmonary vascular resistance of ≥1.74 Wood Units, n=188) not only did not show benefit, but worsened clinically, including increased risk for heart failure events and decrease in the KCCQ score.…”

The future of heart failure with preserved ejection fraction

“…However, further post hoc analyses demonstrated that patients with peak exercise pulmonary vascular resistance < 1.74 WU appeared to benefit from the device (Fig. 6 ; [ 83 ]). Thus, future precision medicine trials of atrial shunt devices and procedures in HFpEF may benefit from only including those patients with the ability to vasodilate the pulmonary vasculature during exertion.…”