Improvement in left ventricular ejection fraction after pharmacological up-titration in new-onset heart failure with reduced ejection fraction

Objective Recent studies have reported suboptimal up-titration of heart failure (HF) therapies in patients with heart failure and a reduced ejection fraction (HFrEF). Here, we report on the achieved doses after nurse-led up-titration, reasons for not achieving the target dose, subsequent changes in left ventricular ejection fraction (LVEF), and mortality. Methods From 2012 to 2018, 378 HFrEF patients with a recent (< 3 months) diagnosis of HF were referred to a specialised HF-nurse led clinic for protocolised up-titration of guideline-directed medical therapy (GDMT). The achieved doses of GDMT at 9 months were recorded, as well as reasons for not achieving the optimal dose in all patients. Echocardiography was performed at baseline and after up-titration in 278 patients. Results Of 345 HFrEF patients with a follow-up visit after 9 months, 69% reached ≥ 50% of the recommended dose of renin-angiotensin-system (RAS) inhibitors, 73% reached ≥ 50% of the recommended dose of beta-blockers and 77% reached ≥ 50% of the recommended dose of mineralocorticoid receptor antagonists. The main reasons for not reaching the target dose were hypotension (RAS inhibitors and beta-blockers), bradycardia (beta-blockers) and renal dysfunction (RAS inhibitors). During a median follow-up of 9 months, mean LVEF increased from 27.6% at baseline to 38.8% at follow-up. Each 5% increase in LVEF was associated with an adjusted hazard ratio of 0.84 (0.75–0.94, p = 0.002) for mortality and 0.85 (0.78–0.94, p = 0.001) for the combined endpoint of mortality and/or HF hospitalisation after a mean follow-up of 3.3 years. Conclusions This study shows that protocolised up-titration in a nurse-led HF clinic leads to high doses of GDMT and improvement of LVEF in patients with new-onset HFrEF. Supplementary Information The online version of this article (10.1007/s12471-021-01591-6) contains supplementary material, which is available to authorized users.


Introduction
Heart failure (HF) is considered a chronic and often progressive disease. In the years following the diagnosis of HF a substantial proportion of patients develop left ventricular remodelling, which over time becomes maladaptive, and is characterised by increased dimensions of the left ventricle, thinner walls and decreased left ventricular ejection fraction (LVEF) [1]. However, reverse remodelling (marked by a reduction of LV dimensions and improvement in LVEF) can be achieved in selected patients [2]. In a recent study of 1160 patients with heart failure with reduced ejection fraction (HFrEF), LVEF showed a marked rise during the first year, followed by a relatively long plateau phase of up to a decade and then a subsequent slow decline [3]. One of the factors that is positively associated with reverse remodelling is up-titration of guideline-directed medical therapy (GDMT) [4].
In clinical trials and registries, a large majority of patients with HFrEF (80-90%) receive beta-blockers and/or angiotensin-converting-enzyme inhibitors/ angiotensin receptor blockers (ACEIs/ARBs) (at any dose). However, up-titration of GDMT is notoriously difficult and many patients never receive adequate doses. In the CHAMP-HF registry of 2588 outpatients with HFrEF from the United States, the percentage of those receiving target doses of mineralocorticoid receptor antagonists (MRAs), beta-blockers, ACEIs/ARBs or angiotensin receptor-neprilysin inhibitor (ARNIs) after 12 months of follow-up was 27%, 22%, 10% and 3% respectively [5]. In the cross-sectional CHECK-HF registry of 34 HF outpatient clinics in the Netherlands, median achieved drug doses were 50% of the target dose for renin-angiotensin-system (RAS) inhibitors, 25% of the target dose for betablockers, and 25% of the target dose for MRAs [6].
Reasons for poor up-titration might be related to the healthcare system, patient preference, or medication side effects [7]. Common side effects such as fatigue, hypotension, renal dysfunction and hyperkalaemia can overlap with the syndrome of HF itself, further complicating treatment decisions.
The 2016 European Society of Cardiology (ESC) HF guidelines recommend multidisciplinary care management programmes for HF patients to improve survival and reduce the number of HF hospitalisations. One way to provide structured care to HF patients is the implementation of HF outpatient clinics led by specialised HF nurses. In a nurse-led disease management programme, nurses provide structured education on self-care and psychosocial care for patients and their family. Nurse-led care also improves the adoption of GDMT, and led to more favourable improvement in patient-reported outcomes and LVEF in a randomised controlled study [8]. Moreover, referral to a nurse-led HF clinic was associated with a lower risk of death in a Swedish national registry [9].
In the present study in a population of patients with newly diagnosed HFrEF, the doses achieved after uptitration in a nurse-led HF clinic were analysed, including the reasons for not achieving the guidelinerecommended target dose. Furthermore, we assessed changes in LVEF after 9 months of follow-up, and studied HF hospitalisations and all-cause mortality.

Study population
We performed a retrospective longitudinal cohort study of consecutive patients with new-onset HF who presented to our tertiary care hospital between 2012 and 2018. Patients were included when they were referred to a specialised HF outpatient clinic, either after a first appointment with a cardiologist or 10 days after discharge following a first hospitalisation for HF. Patients had to be diagnosed with HF by a cardiologist no longer than 3 months before inclusion. In the outpatient clinic, GDMT was initiated and/or up-titrated by specialised HF nurses. Up-titration was done using pre-specified protocols based on the ESC guidelines for the diagnosis and treatment of HF (Electronic Supplementary Material, Table S1) [10,11]. Furthermore, patients received education on self-care and had easy access to the HF clinic in the case of worsening HF. Clinical characteristics and doses of HF medication were recorded at the baseline and follow-up visits. We selected the visit that was performed 9 months after the baseline visit, or the visit that was closest to 9 months after baseline, to establish the success of up-titration and to assess changes in LVEF. We chose 9 months because patients were expected to be fully up-titrated by this time [12]. If patients had not achieved 100% of the guideline recommended target dose for either beta-blockers, ACEIs/ARBs/ARNIs or MRAs at this visit, the reason for incomplete up-titration was recorded. At the censor date of 1 September 2018, survival status and number of HF hospitalisations were recorded for every patient. This study complied with the Declaration of Helsinki and all national and local regulations as confirmed by the medical ethical evaluation committee. Patients were involved in the design and conduct of this research.

Echocardiography
Echocardiography was performed as part of routine clinical care. A baseline echocardiogram was selected that was closest to the actual date of the baseline visit to the clinic. Patients were excluded if LVEF could not be reliably determined at baseline. A follow-up echocardiogram was selected closest to the 9-months follow-up visit, and at least 6 months after the initial visit.

Statistical analysis
Normally distributed data are presented as mean (standard deviation). Data that were not normally distributed are presented as median (25th percentile, 75th percentile). Intergroup differences were tested using one-way ANOVA for normally distributed data. The chi-square or Kruskal-Wallis test was used for not normally distributed data. We performed linear regression to analyse determinants of change in ejection fraction. We considered any baseline demographic, clinical, laboratory and medication characteristic that was deemed important based on clinical reasoning for our multivariable analysis. Subsequently, stepwise backward selection was performed to derive the final model. Crude and multivariable adjusted Cox proportional hazard models were performed to evaluate the effect of changes in LVEF on mortality. All analysis were performed in R version 3.6.0.

Baseline characteristics
In our cohort of new-onset HFrEF patients, the mean age of the 378 patients was 65.5 (±14.1) years and 34.1% were women. Baseline characteristics are presented in Tab. 1. A total of 345 patients had a followup visit, and 278 patients had echocardiography performed both at baseline and follow-up. Use of beta-blockers and RAS inhibitors at any dose was already high at the baseline visit, with 90% of patients with HFrEF using any dose of beta-blockers. For RAS inhibitors, 87% used any dose at baseline. Use of MRAs was lower, with 41% of patients with HFrEF using an MRA at baseline (Tab. 1).

Improvement in ejection fraction
During a median follow-up of 9 months, improvement from HFrEF to HF with mid-range EF/HF with preserved EF was seen in 131 of 344 of patients (35%). Fig. 1 shows a flow diagram of changes in LVEF categories. LVEF improved from a mean of 27.6% at baseline to 38.8% at follow up (+11.2%). Multivariable predictors of improvement of LVEF are presented Adjusted for age, sex, history of ischaemic heart disease, history of hypertension, history of dilated cardiomyopathy, history of diabetes mellitus, history of chronic obstructive pulmonary disease, history of atrial fibrillation, presence of device, systolic blood pressure, weight, sodium, potassium, creatinine (log), N-terminal pro-B-type natriuretic peptide (log), heart rate, achieved target dose of beta-blockers, achieved target dose of angiotensinconverting-enzyme inhibitor or angiotensin receptor blocker or angiotensinreceptor-neprilysin inhibitor, achieved target dose of mineralocorticoid antagonist LVEF left ventricular ejection fraction, HF heart failure in Tab. 4. Baseline LVEF was the strongest predictor of subsequent improvement. In addition, older age, non-ischaemic aetiology and higher plasma levels of N-terminal pro-B-type natriuretic peptide were all significantly associated with an increase in LVEF in a multivariable linear model. A history of hypertension was associated with a decrease in LVEF.

Clinical outcomes
For patients with HFrEF, 1-year mortality was 10%, and mortality after 3.3 years was 22%. In patients with HFrEF, each 5% increase in LVEF was associated with a hazard ratio of 0.83 (0.72-0.96, p = 0.011) for mortality in a Cox proportional hazards model adjusted for age and sex, and a hazard ratio of 0.82 (0.73-0.93, p = 0.001) for the combined endpoint of mortality and/or HF hospitalisation (Tab. 5).

Discussion
Employing a protocolised scheme of up-titration in a nurse-led HF clinic in patients with new-onset HF leads to appropriate use of GDMT, which is similar compared to that reported in recent studies [5,6]. Moreover, reasons for not achieving target doses were recorded in all patients, which was often lacking from previous registries. This approach was accompanied by substantial increases in LVEF in more than one third of patients. Finally, all-cause mortality was in line with the number reported in literature [13].

Nurse-led HF clinics
Several studies have investigated the effects of nurseled disease management programmes in HF. Nurseled care was associated with better patient-reported Improvement in left ventricular ejection fraction after pharmacological up-titration 391 outcomes in a randomised study from Germany [8].
Planned referral to a nurse-led HF clinic was associated with lower risk of death (but not HF hospitalisation) in the Swedish Heart Failure Registry [9]. Similar results were found in the Dutch Deventer-Alkmaar study [14]. In contrast, in a multi-centre randomised trial (the Which Heart failure Intervention is most Cost-effective in reducing Hospital stay (WHICH? II) Trial) a structured, nurse-led, multidisciplinary management programme did not lead to a reduction in hospitalisation rate or all-cause mortality in Australia. There was, however, a better cardiac recovery on echocardiography (defined as improvement in either LVEF, left ventricular hypertrophy or E/e') after 3 years of follow-up [15]. In the Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH) study with 1023 participants, investigating the effect of education and counselling in HF, there was no difference in all-cause mortality or HF hospitalisation after 18 months of follow-up [16].
In this latter study however, up-titration of HF medication was not part of the study protocol. The additive value of a nurse-led HF clinic might therefore depend on the healthcare system where it is initiated. Reasons why nurse-led HF clinics might be superior to standard care are the ability to closely monitor symptoms, optimise treatment by frequent dose adjustments, and the possibility of providing elaborate education on self-care and psychosocial support to patients with HF, including easy access to a healthcare provider in the case of deterioration.

Factors limiting up-titration
In the present study, we carefully documented reasons for not reaching the recommended target doses in all patients. For beta-blockers, the most common reasons preventing further up-titration were hypotension, or associated complaints such as dizziness or light-headedness, and bradycardia. Hypotension is common in HF, and it can be difficult to distinguish disease-related hypotension from the effect of drugs. A recent meta-analysis found that individual betablockers did not exhibit a graded dose-response effect on systolic or diastolic blood pressure over the recommended dose range, suggesting that patients on lower doses might be able to tolerate higher doses as well [17]. In addition, there is evidence from a post hoc analysis of the COPERNICUS trial that patients with the lowest initial blood pressure had the highest improvement in quality of life if treated with carvedilol. In this group of HF patients, blood pressure increased instead of decreasing after treatment with a beta-blocker [18]. For ACEIs/ARBs/ARNIs, other frequent reasons hampering up-titration were renal dysfunction and hyperkalaemia. However, patients with incident hyperkalaemia who are maintained on ACEIs/ARBs/ARNIs might have better survival than those in whom ACEIs/ARBs/ARNIs were down-titrated or stopped because of hyperkalaemia [19]. The ESC HF guidelines provide a class IA recommendation to start with a beta-blocker and RAS inhibitor for all patients with HFrEF. An MRA is indicated in those patients who remain symptomatic despite treatment (NYHA class II or higher) and have a LVEF < 35%. In our cohort of patients with HFrEF, after 9 months of protocolised up-titration, a frequent reason for not receiving the target dose of MRAs was that patients had become asymptomatic (NYHA class I) or that their LVEF had improved. This raises the question whether introducing an MRA earlier, before target doses of beta-blockers and RAS inhibitors are achieved, might lead to improved outcomes. At present, there are few data available to answer this question.

Improvement in ejection fraction
We found a high percentage of improvement of LVEF in patients with new-onset HFrEF. This percentage is similar to that in a recent retrospective cohort study that found that in 38% of 3124 patients with HFrEF had an increase in LVEF of ≥ 10% after ≥ 6 months of follow-up [3]. In our cohort, patients with ischaemic heart disease were less likely to improve, whereas improvement was more likely in those with a dilated cardiomyopathy. Of note is that LVEF is subject to measurement variation. A study from 2012 concluded that around 20% of patients would be reclassified to a different category if two observers assessed the same echocardiogram and a single cut-off was used [20].

Strengths and limitations
This study has some limitations. First, this is a single-centre study, which limits the generalisability of the results. The population we studied is on average slightly younger than that of other (larger) HF registries. In addition, by including only patients who were referred to the nurse-led outpatient clinic, HF patients that were being treated by a cardiologist only are not included in the study, which might introduce selection bias. However, other baseline characteristics are very similar to those seen in the literature. Second, because we assessed up-titration and LVEF at 9 months, survivorship bias is introduced since patients that died (n = 35) before the follow-up visit were not included.

Conclusion
Protocolised up-titration of GDMT by a specialised HF nurse as part of a HF management programme leads to doses that are higher than those thus far reported in the literature. This approach was accompanied by an improvement in LVEF in more than one third of patients with new-onset HFrEF. Improvement of LVEF was independently associated with a lower risk of allcause mortality and HF hospitalisation. This study supports the recommendation to use a specialised HF clinic setting in patients who have been recently diagnosed with HF.