Discussion
Our study shows consistency of the results of the RELAX-AHF trial across different patient subgroups based on baseline clinical characteristics. These subgroups included all the pre-specified subgroups as well as additional ones generally considered as clinically important in AHF studies.
Patients hospitalized for HF are known to be a heterogeneous group of patients. The main pathophysiological mechanisms leading to HF decompensation may range from severe LV systolic dysfunction with low cardiac output, low blood pressure, peripheral hypoperfusion, fluid retention and oedema, to increased vascular stiffness, increased pre- and afterload, impairment of LV diastolic function, pulmonary congestion, and oedema. RELAX-AHF was among the first trials to take these differences into account and specifically target those patients most likely to benefit from the study drug.
Our present analysis shows that the effects of serelaxin on study outcomes were generally consistent across subgroups. Specifically, there was no interaction between the effects of serelaxin and critical variables (such as SBP, time from presentation to randomization, and baseline NT-proBNP values). However, since the study was designed to include patients with SBP >125 mmHg, within 16 h from presentation and with relatively high baseline NT-proBNP or BNP levels, it cannot be excluded that the patients selected were sufficiently homogenous so that subgroup analysis could not yield any further selection of the patients with a better response. Thus, while generally representative of most of the AHF patients, inclusion/exclusion criteria of RELAX-AHF may have resulted in the selection of a relatively homogeneous population, more likely to benefit from a treatment with a predominant vascular mode of action, and with no evident subgroup differences. Secondly, the drug may act on some mechanisms which contribute to the symptoms and the poor survival of the patients having characteristics similar to those of the patients enrolled in RELAX-AHF.
Systolic blood pressure is a major prognostic factor in patients hospitalized for AHF. It is also a major determinant of the effects of therapy, with the untoward effects of new therapies associated with an excessive blood pressure drop. Based on these data, a SBP >125 mmHg was selected as entry criterion for the RELAX-AHF trial. This criterion still allows the inclusion of > 70% of the patients admitted for AHF. Despite its vasodilatatory effects, also shown by the larger proportion of patients who had had a protocol-defined blood-pressure-related study drug dose adjustment or study drug discontinuation, no interaction was found between the effects of serelaxin, compared with placebo, and the baseline SBP.
Early treatment is considered essential to obtain better effects in patients admitted for AHF. In analyses of patients included in the Acute Decompensated Heart Failure (ADHERE) Registry, Peacock et al. showed that early administration of vasodilators was associated with a better outcome, compared with late treatment. In the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial, patients could be enrolled 24 h from the start of furosemide treatment and the median time from the start of treatment to randomization was 16 h. However, these considerations were already taken into account in the design of RELAX-AHF, where patients were enrolled within 16 h from presentation with the median time from presentation to randomization being 7.9 ± 4.7 and 7.8 ± 4.6 h, in the placebo and the serelaxin groups, respectively. It is possible that the relatively short time from presentation may have reduced the interpatient variability and, therefore, the interaction between time from presentation to randomization and serelaxin's effect.
N-terminal prohormone of BNP is a major prognostic variable in most studies of patients hospitalized for HF. Increased NT-proBNP or BNP levels at baseline were required as inclusion criteria in RELAX-AHF, with the aim to avoid the enrolment of patients without congestion. This criterion has allowed the enrolment of patients at relatively high risk of events. However, also in this case, baseline NT-proBNP levels did not influence the effects of serelaxin vs. placebo and this may be related to the pre-selection of patients with high BNP or NT-proBNP levels at baseline, since this was an inclusion criterion.
Patients with a preserved LVEF represent approximately half of the patients admitted for AHF and this proportion is growing due to ageing of the general population. No treatment has been shown as effective in the patients with HF and preserved LVEF, to date. These patients have unique clinical characteristics and were excluded or under-represented in previous large AHF trials. Less than 20% of all the patients included in ASCEND-HF had a LVEF <40%, and LVEF was available in only approximately half of all the patients in two other AHF trials.
In RELAX-AHF, LVEF was available in most of the patients (Table 1) and 45% of the patients had a LVEF above the pre-specified cut-off for subgroup analysis of 40%. No differences in the response to serelaxin administration were found in the patients with a LVEF < or ≥40% with respect to any endpoint. These results are consistent with the presence of common pathogenetic mechanisms in AHF, such as increased LV afterload, pulmonary congestion, and end-organ damage, which are independent of LVEF, and on which serelaxin may exert beneficial effects. These results are also consistent with serelaxin's mechanism of action, which is active more on the peripheral vasculature and arterial elastance, rather than on the myocardium.
Another subgroup of potential interest is that of patients on i.v. nitrates at the time of randomization. Nitrates are a treatment option for patients with AHF and high blood pressure and were allowed in RELAX-AHF for the patients with a SBP >150 mmHg at screening. Although, theoretically, their concomitant administration might have blunted some of the favourable effects of serelaxin, estimated treatment effects on mortality and dyspnoea were in the same direction as for the patients not on nitrates. However, the proportion of patients on i.v. nitrates at randomization was small and the confidence intervals for the estimated treatment effects were wide.
Some interactions were nominally statistically significant when the 180-day CV mortality and all-cause mortality data were considered (Figure 3). However, these data have to be interpreted with caution as these subgroup analyses were not pre-specified, the number of subgroups examined was large and the number of events was small. The interaction between some variables and the effects of serelaxin on mortality, compared with placebo, may be explained by the low incidence of deaths in the subgroups at lower risk, such as that of the patients ≤75 years old or with an eGFR ≥50 mL/min/m. Some data seem, however, to suggest that serelaxin was more effective in patients with no history of HF, as shown by the subgroups with no HF hospitalization in the previous year and no concomitant treatment with neurohormonal antagonists, such as angiotensin-converting enzyme inhibitors, mineralocorticoid receptor antagonists and beta-blockers (Figures 1–3). One potential explanation is that patients not treated with neurohormonal antagonists are more likely to be more sensitive to the untoward effects of diuretic therapy, and serelaxin administration was associated with lower diuretic doses in the RELAX-AHF trial. The same might also apply to the subgroup with reduced eGFR as kidney dysfunction is also associated with the need to use higher doses of loop diuretics. In addition, serelaxin may be effective on neurohormonal and inflammatory mechanisms which are favourably affected also by neurohormonal antagonists.
The limitations of subgroup analyses are well known. Although the results suggest a homogeneous response to serelaxin among the subgroups examined, the study was not powered to detect differential treatment effects. On the other hand, any nominally statistically significant interactions should be interpreted cautiously given the number of both pre-specified and post hoc analyses performed. The results of the present study must be limited to the patients with characteristics similar to those of the patients enrolled in RELAX-AHF with, namely, a SBP >125 mmHg and <16 h from presentation to hospital. Any extension of the present findings to patients with different characteristics from those of the patients in RELAX-AHF is not possible.
In conclusion, subgroup analyses of the RELAX-AHF trial has shown similar effects of serelaxin, when compared with placebo, across various subgroups, suggesting a consistency of the effect of serelaxin in the patients with AHF with the characteristics used in this study.