Early and rapid initiation of quadruple therapy for heart failure with reduced ejection fraction: A real-world experience

Highlights

• •Individualised rapid initiation of quadruple therapy in heart failure patients.
• •Four drugs in 4 weeks (4×4 approach) facilitated by heart failure specialists.
• •The approach is feasible, safe and effective at reducing hospital admissions.
• •Main barriers are low blood pressure, kidney and potassium abnormalities.
• •Patient selection is key to the success of this approach.

Abstract

Objectives

To evaluate the feasibility, safety and efficacy of early and rapid initiation of quadruple therapy (four drugs in 4 weeks – '4×4 approach') for heart failure with reduced ejection fraction (HFrEF) patients in a real-world clinical setting.

Design

Prospective service evaluation study.

Setting

Secondary care.

Participants

Consecutive patients with de novo HFrEF between March and August 2021.

Intervention

'4×4 approach' – individualised initiation and up-titration of four pillars of HFrEF therapy by heart failure specialist.

Main outcome

Proportion of patients initiated on four pillars of HFrEF therapy within 4 weeks.

Results

Of 100 patients approached, 19 patients were not suitable for the rapid initiation and up-titration pathway due to severe frailty and significant comorbidities. 81 patients were enrolled (61% male, median age = 73 years, median N-terminal pro-brain natriuretic peptide [NT-proBNP] = 3,764 ng/L).

39 patients (48%) achieved 4×4. Of the 42 patients who did not, 26 (62%), nine (21%) and seven (17%) patients were on three drugs, two drugs and one drug, respectively. 33 patients had one or more contraindication at the outset; most commonly renal impairment (28%), bradycardia (18%) and hyperkalaemia (15%). Five patients experienced significant side effects during medication up-titration, most commonly symptomatic hypotension.

During median follow-up of 554 days, 32 (40%) patients experienced the combined outcome (all-cause hospitalisation/death). Patients who did not achieve 4×4 had an increased risk of the combined outcome (HR 2.25 [1.09–4.68], p=0.029) compared to those who achieved 4×4.

Conclusion

Early and rapid initiation of four pillars HFrEF therapy is clinically feasible and safe when implemented in selected patients and is associated with improved clinical outcomes.

Graphical abstract

Introduction

Pharmacotherapy is the cornerstone of treatment for patients with heart failure with reduced ejection fraction (HFrEF).1, 2, 3, 4 The European Society of Cardiology (ESC) recommends that all patients with HFrEF should receive the four pillars of HFrEF therapy (renin-angiotensin-aldosterone system inhibitor [RAASi]/ beta-blockers [BB]/ mineralocorticoid receptor antagonist [MRA]/ sodium-glucose co-transporter two inhibitors [SGLT2i]).⁵ A recent meta-analysis showed that treatment with the four drug classes compared to no treatment resulted in 5 additional life years for a 70-year-old patient.⁶ Furthermore, randomised controlled trials (RCTs) of HFrEF therapy demonstrated a rapid and significant treatment effect, as early as 2–4 weeks after initiation of therapy.^1,3,4,7 The totality of evidence advocates early initiation of comprehensive HFrEF therapy.

The Safety, Tolerability and Efficacy of Rapid Optimisation, Helped by N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) Testing of Heart Failure Therapies (STRONG-HF) study is the first prospective, multinational RCT which showed that rapid up-titration of guideline-directed medical therapy (GDMT), including RAASi, BB and MRA, combined with close follow-up after an acute HF hospitalisation was safe, reduced the risk of all-cause death or HF readmission and improved quality of life compared with usual care.⁸ However, STRONG-HF included patients with HF with preserved ejection fraction (HFpEF), for whom routine prescription of RAASi/BB/ MRA is not appropriate. Importantly, no UK patients were enrolled in STRONG-HF; the applicability of these results in a UK setting is unclear. STRONG HF also did not include the use of SGLT2 inhibitors, which only subsequently become part of standard GDMT.

Nonetheless, in real-world clinical practice, timely initiation and up-titration of life-saving medications to target doses in HFrEF patients remain challenging.⁹ According to the Change the Management of Patients with HF (CHAMP-HF) registry, amongst 2,588 patients with HFrEF and no contraindications to medical therapy, over a period of 12 months, <1% of patients were simultaneously treated with target doses of RAASi, BB and MRA.¹⁰

In order to reduce inertia in drug initiation and titration in HFrEF, several rapid sequencing and implementation strategies have been proposed.^11,12 Given the heterogeneity in clinical characteristics of HFrEF patients, the HF Association of the ESC highlights the need for an individualised approach when initiating and titrating GDMT.¹³ We conducted this service evaluation project to evaluate, in a real-world setting, the feasibility and safety of early and rapid initiation of quadruple therapy within 4 weeks via an individualised approach in patients with de novo HFrEF.

Methods

Study design and objectives

This was a prospective service evaluation study conducted in patients with de novo HFrEF. We assessed the feasibility of implementing the 4×4 approach (individualised initiation of four pillars of HFrEF therapy in 4 weeks) in patients with HFrEF within a real-world clinical setting. Furthermore, the safety and efficacy of such an approach was also explored.

Study population

Between 29 March 2021 and 6 August 2021, we prospectively assessed and identified consecutive patients ≥ 18 years of age who presented to our tertiary cardiology centre with a new diagnosis of HFrEF. All patients had signs and symptoms of HF with evidence of left ventricular systolic dysfunction [left ventricular ejection fraction (LVEF) <40%) on echocardiogram.⁵ We focused on patients with HFrEF as quadruple therapy with RAASi, BB, MRA and SGLT2i has been shown to result in symptomatic and prognostic benefit in these patients.⁵ Patients were identified either from our urgent HF clinic or following stabilisation during a hospital admission with HF. Patients with significant comorbidities or severe frailty for palliative management, those who were unable to commit to frequent follow-ups for medication titration or those who declined to participate were excluded. Patients who required significant care input at home, were immobile or unable to access the hospital due to these reasons were considered to have severe frailty. All patients provided verbal consent prior to participating in this service evaluation project, which was approved by and registered on the trust's audit register.

Medication titration

Following identification, patients were reviewed regularly at our hospital-based HF clinic by an HF specialist (in this project, we had three HF consultants and one senior HF specialist nurse) for initiation and up-titration of GDMT for HFrEF including ACEi, ARB or ARNI, BB, MRA and SGLT2i. All appointments took place at the hospital. The first appointment for all patients was a face-to-face consultation, typically within 1 week after hospitalisation for HF or after a new diagnosis of HFrEF in the community. The frequency and the format of subsequent reviews (face to face or telephone consultation) was determined by the HF specialist according to the clinical need and treatment response of the individual patient. We planned a weekly review strategy for all patients. Follow-ups were primarily conducted via telephone unless a clinical need necessitated an in-person visit. This hybrid model ensured both frequent follow-up and patient convenience.

Blood tests including renal function, were typically conducted at initiation or titration of a relevant HF therapy (ie RAASi/ MRA/ SGLT2i). Baseline blood test were conducted for all patients during the first face-to-face clinic visit at the HF clinic. For follow-up visits, blood tests were arranged at locations convenient to the patient (HF clinic or GP practice), ensuring accessibility and continuity of care.

For patients identified from HF admission, the priority of treatment is decongestion. While some of the four pillars of HFrEF therapy would have been initiated during hospitalisation, the majority of drug optimisation happens during follow-up at the HF clinic. For patients identified from urgent HF clinic, diuretics are commonly prescribed by the GP at the point of referral to relieve symptoms of congestion. The initiation and titration of GDMT mainly occurs during subsequent follow-up visits at the HF clinic.

Early and rapid up-titration of GDMT was delivered via the 4×4 approach. The aim was to initiate the four pillars of HFrEF therapy within 4 weeks and up-titrate to maximally tolerated doses. We adopted an individualised approach, in accordance with recommendations from the ESC consensus document on tailoring medical therapy for patients with HF.¹³ Instead of a fixed titration protocol, each HF specialist determined the sequence of drug initiation and the speed of titration on a case-by-case basis, according to the individual patient's vitals, symptoms and signs of congestion, comorbidities, renal function and potential associated side effects.

Follow-up

After 4 weeks of medication review and up-titration, patients were invited to return for a clinical assessment, which comprised a physical examination, including measurement of vitals (eg heart rate and blood pressure) and assessment of HF symptoms, followed by a blood test including renal function and NT-proBNP. The final dosage of each class of HFrEF medications was also recorded. At 6 months, a repeat echocardiogram was performed to evaluate any change in LVEF. We assessed clinical outcomes over a minimum follow-up period of 1 year until 17 January 2023.

Outcomes

The primary outcome was the feasibility of implementing the 4×4 approach, defined as the proportion of patients initiated on all 4 pillars of HFrEF therapy within 4 weeks. We also assessed the proportion of patients who reached target doses of each drug class of GDMT by week 4. For patients who did not achieve 4×4, we explored factors associated with unsuccessful delivery. Furthermore, we evaluated the healthcare resources required to deliver the 4×4 strategy, specifically reporting on the number of clinic appointments attended by patients within the study period.

The secondary outcomes included a variety of exploratory endpoints to further understand the safety and efficacy of the 4×4 approach. Safety endpoints included fatal and non-fatal adverse events and changes in blood pressure, heart rate, estimated glomerular filtration rate (eGFR), sodium (Na) and potassium (K) levels between baseline and 4 weeks. Efficacy endpoints included changes in New York Heart Association (NYHA) class and NT-proBNP between baseline and 4 weeks, change in LVEF between baseline and 6 months; death and hospitalisation during follow-up.

Statistical analysis

Continuous data are expressed as a median (25th–75th percentiles) and categorical data as n (%). Independent t test and Mann–Whitney U test were used to compare two continuous variables for normally and non-normally distributed data, respectively. The chi-squared test and Fisher's exact test were used to compare proportions between groups.

Comparisons were carried out between two groups: 1) patients who achieved 4×4 and 2) patients who did not achieve 4×4. We compared their baseline characteristics, proportion of patients on target doses HFrEF therapy at 4 weeks, changes in clinical parameters between baseline and 4 weeks/6 months and clinical outcomes. A detailed description of target doses of medications for patients with HFrEF (based on the ESC guideline⁵) is shown in Appendix 1. Time-to-event data are presented graphically using Kaplan–Meier curves. Log-rank tests were used to compare survival between groups. The relation between a variable and outcome was explored using Cox regression analysis.

All statistical analyses were performed using SPSS 28 (SPSS INc., Chicago, IL, USA) and The Stata (14th Version, StataCorp, TX, USA) statistical computer package. A two-tailed P-value of <0.05 was considered significant in all analyses.

Results

Participant flow and baseline characteristics

Between 29 March 2021 to 6 August 2021, 100 patients were screened for eligibility. 19 patients were considered by the medical team to be unsuitable for rapid drug initiation and up-titration and were excluded. The most common reason for exclusion was the presence of severe frailty (N=10, 53%) and significant comorbidities such as end stage renal disease (N= 5, 26%). The remaining 81 patients were enrolled. Appendix 2 is a flow diagram of study participants.

Table 1 shows the baseline characteristics of the study cohort. The median age of participants was 73 years (range: 39–89); the majority (N=49, 61%) were male, half were identified from the inpatient setting. Over half of the patients had NYHA class III symptoms (N=47, 57%); median NT-proBNP was 3764 ng/L (interquartile range [IQR]: 1,597–7,487). The aetiology of HF was mostly non-ischaemic cardiomyopathy (N=57, 70%); median LVEF was 32% (IQR: 28–35).

Table 1.

Baseline characteristics of the study cohort, comparing patients who achieved versus those who did not achieve the 4×4 strategy.

	Entire cohort	Achieved 4×4	Did not achieve 4×4	p
	N=81	N=39	N=42	(Achieved vs did not achieve 4×4)
Demographics
Age, years	73 (67–82)	70 (64–77)	78 (70–82)	0.002
Male sex, n (%)	49 (61%)	26 (67%)	24 (55%)	0.27
Ethnicity, n (%)				0.57
White	72 (89%)	34 (87%)	38 (90%)
Asian	8 (10%)	4 (10%)	4 (10%)
Black	1 (1%)	1 (3%)	0 (0%)
Systolic BP, mmHg	130 (108–145)	119 (105–144)	132 (112–147)	0.30
Diastolic BP, mmHg	73 (66–80)	72 (66–86)	74 (66–80)	0.78
Heart rate, bpm	76 (66–90)	74 (69–88)	77 (65–92)	0.79
NYHA class, n (%)				0.02
I	2 (3%)	2 (5%)	0
II	32 (40%)	20 (51%)	12 (29%)
III	47 (57%)	17 (44%)	30 (71%)
LVEF, %	32 (28–35)	31 (25–35)	33 (30–35)	0.38
Aetiology, n (%)				0.37
Ischaemic	23 (29%)	9 (23%)	14 (33%)
Non-ischaemic	57 (70%)	29 (74%)	28 (67%)
Specific CM	1 (1%)	1 (3%)	0
Devices, n (%)				0.08
PPM	5 (6%)	0	5 (12%)
ICD	5 (6%)	3 (8%)	2 (5%)
Recruitment, n (%)				0.90
Inpatient	43 (52%)	21 (54%)	22 (52%)
Outpatient	39 (48%)	18 (46%)	20 (48%)

Comorbidities
HTN, n (%)	44 (54%)	18 (46%)	26 (62%)	0.16
AF, n (%)	37 (46%)	22 (56%)	15 (36%)	0.06
MI, n (%)	14 (17%)	9 (23%)	5 (12%)	0.18
PVD, n (%)	2 (3%)	0	2 (5%)	0.17
CVA/ TIA, n (%)	6 (7%)	4 (10%)	2 (5%)	0.35
Diabetes, n (%)	15 (19%)	5 (13%)	10 (24%)	0.20
CKD, n (%)	34 (42%)	8 (21%)	26 (62%)	<0.001
COPD, n (%)	12 (15%)	5 (13%)	7 (17%)	0.63

Medications
ACEi, n (%)	32 (40%)	16 (41%)	16 (38%)	0.79
ARB, n (%)	11 (14%)	4 (10%)	7 (17%)	0.40
ARNI, n (%)	19 (24%)	14 (36%)	5 (12%)	0.01
BB, n (%)	60 (74%)	32 (82%)	28 (67%)	0.11
MRA, n (%)	29 (36%)	16 (41%)	13 (31%)	0.35
SGLT2i, n (%)	0	0	0	NA
Digoxin, n (%)	5 (6%)	3 (8%)	2 (5%)	0.58
Loop diuretic, n (%)	60 (74%)	28 (72%)	32 (76%)	0.65
Thiazide diuretic, n (%)	2 (3%)	1 (3%)	1 (2%)	0.96
No of GMDT				0.17
0	12 (15%)	3 (8%)	9 (21%)
1	14 (17%)	5 (13%)	9 (21%)
2	29 (36%)	17 (44%)	12 (29%)
3	26 (32%)	14 (35%)	12 (29%)
4	0	0	0

Laboratory markers
Hb, g/L	133 (123–145)	143 (132–151)	126 (121–136)	<0.001
eGFR, mL/min/1.73m2	62 (49–79)	68 (62–89)	56 (37–73)	<0.001
NT-proBNP, ng/L	3,764 (1,597–7,487)	2,919 (1,340–6,425)	5,223 (1,682–8,491)	0.08
Na, mmol/L	140 (138–141)	140 (139–142)	139 (136–141)	0.02
K, mmol/L	4.4 (4.0–4.8)	4.2 (3.8–4.7)	4.6 (4.2–5.0)	0.008

BP, blood pressure; NYHA, New York heart association; LVEF, left ventricular ejection fraction; CM, cardiomyopathy; PPM, pacemaker; ICD, implantable cardiac defibrillator; HTN, hypertension; AF, atrial fibrillation; MI, myocardial infarction; PCI/ CABG, percutaneous coronary intervention / coronary artery bypass graft; mod-sev, moderate to severe; PVD, peripheral vascular disease; CVA/TIA, cerebrovascular accident/ transient ischaemic attack; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; OSA, obstructive sleep apnoea; ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor blocker neprilysin inhibitor; BB, beta-blocker; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium glucose cotransporter 2 inhibitor; GDMT, guideline-directed medical therapy; Hb, haemoglobin; eGFR, estimated glomerular filtration rate; NT-proBNP, N-terminal pro-B-type natriuretic peptide; Na, sodium; K, potassium.

Feasibility of the 4×4 approach

Almost half of the enrolled patients achieved 4×4 (N=39, 48%). Of the 42 patients who did not, 26 (62%) patients were on three drugs, nine (21%) on two drugs and seven (17%) on one drug. The most common reason for not achieving 4×4 was contraindication at the outset (N=33, 79%), specifically renal impairment (eGFR <30 mL/min/1.73m²) (N=9, 28%), bradycardia (heart rate <60 beats per minute) (N= 6, 18%) and electrolyte imbalance (K >5.5 mmol/L) (N= 5, 15%) (Appendix 3).

Compared to those who achieved 4×4, patients who did not were older, had higher symptom burden and more advanced HF (higher-NTproBNP); they also had worse renal function, higher baseline potassium and lower haemoglobin level (Table 1). Identification context, LVEF and medical therapy at baseline were similar in each group.

By week 4, a higher proportion of patients who achieved 4×4 had been up-titrated to target doses of SGLT2i compared to those who did not achieve 4×4 (SGLT2i 100% [N=39] vs 43% [N=18], p<0.001) (Fig. 1). Similarly, patients who achieved 4×4 were more likely to reach at least 50% target doses of BB and MRA at 4 weeks compared to those who did not achieve 4×4 (BB: 41% [N=16] vs 36% [N=15], p=0.009; MRA 72% [N=28] vs 38% [N=16], p<0.001) (Fig. 1). There was a trend towards those achieving 4×4 being more likely to reach at least 50% target doses of RAASi at 4 weeks compared to those who did not achieve 4×4, although it did not reach statistical significance (ACEi/ARB/ARNI: 59% [N=23] vs 40% [N=17], p=0.19).

Fig. 1.

Guideline-directed medical therapy for HFrEF, comparing patients who achieved versus those who did not achieve the 4×4 strategy.

In total, 252 appointments were needed to implement the 4×4 strategy in the entire cohort (achieved 4×4: N=130; did not achieve 4×4: N=122). The median (IQR) number of appointments was three (3–4) for both groups.

Safety of the 4×4 approach

Of the entire cohort, five (6%) patients experienced significant side effects during medication up-titration (four patients had symptomatic hypotension, one patient had hyperkalaemia), all of whom did not achieve 4×4 (Appendix 2). None of the side effects resulted in hospitalisation. There were no deaths related to the 4×4 approach in either group.

There were no significant differences between the groups in terms of changes in heart rate, systolic or diastolic blood pressure, Na, K or eGFR from baseline to 4 weeks (Table 2).

Table 2.

Change in clinical parameters (baseline vs 4 weeks), comparing patients who achieved versus those who did not achieve the 4×4 strategy.

	Entire cohort	Achieved 4×4	Did not achieve 4×4	p
	N=81	N=39	N=42	(Achieved vs did not achieve 4×4)
HR (bpm)
Baseline	76 (66–90)	74 (69–88)	77 (65–92)	0.79
4 weeks	76 (68–84)	76 (68–84)	79 (67–84)	0.87
Change	−1.5 (11.8–8)	1 (−8 to 6)	3 (−17 to 12)	0.84
Systolic BP (mmHg)
Baseline	130 (108–145)	119 (105–144)	132 (112–147)	0.30
4 weeks	117 (104–137)	115 (100–131)	118 (105–138)	0.47
Change	−6 (−20 to 1)	−8 (−16 to 1)	−5 (−20 to 0.5)	0.96
Diastolic BP (mmHg)
Baseline	73 (66–80)	72 (66–86)	74 (66–80)	0.78
4 weeks	71 (63–82)	75 (63–82)	70 (63–82)	0.50
Change	−2.5 (−9.8 to 5.8)	−3 (−11 to 7)	−2 (−9 to 5)	0.98
NYHA (III/IV)
Baseline	47 (58%)	17 (44%)	30 (71%)	0.02
4 weeks	7 (9%)	3 (8%)	4 (10%)	0.02
LVEF (%)
Baseline	32 (28–35)	31 (25–35)	33 (30–35)	0.38
6 months	37 (30–45)	39 (32–46)	35 (30–43)	0.16
Change	4 (0–15)	8 (0–20)	2.2 (0–14)	0.19
NT-proBNP (ng/L)
Baseline	1,597 (3,764–7,487)	2,919 (1,340–6,425)	5,223 (1,682–8,491)	0.08
4 weeks	1,133 (335–2,438)	772 (287–1,827)	1,318 (432–2,617)	0.10
Change	−1,432 (−5,960 to −137)	−1,289 (−44,78 to −210)	−2,573 (−7,310 to −44)	0.42
Na (mmol/L)
Baseline	140 (138–141)	140 (139–142)	139 (136–141)	0.02
4 weeks	139 (138–142)	140 (138–141)	139 (137–142)	0.33
Change	0 (−2 to 2)	−1 (−2 to 1)	1 (−2 to 3)	0.07
K (mmol/L)
Baseline	4.4 (4.0–4.8)	4.2 (3.8–4.7)	4.6 (4.2–5.0)	0.008
4 weeks	4.5 (4.2–4.8)	4.5 (4.1–4.8)	4.6 (4.3–4.8)	0.26
Change	1.0 (−3.5 to 0.5)	0.2 (−0.2 to 0.6)	0 (−0.4 to 0.4)	0.10
eGFR (mL/min/1.73m2)
Baseline	62 (49–79)	68 (62–89)	56 (37–73)	<0.001
4 weeks	58 (47–71)	65 (54–79)	55 (43–64)	0.002
Change	−3 (−10 to 5)	−4 (−12 to 0)	−1 (−8 to 7)	0.10
Device therapy
Baseline	10 (12%)	3 (8%)	7 (17%)	0.22
6 months	22 (27%)	10 (26%)	12 (29%)	0.77
New/device upgrade at 6 months	12 (15%)	7 (18%)	5 (12%)	0.44

HR, heart rate; BP, blood pressure; NYHA, New York Heart Association; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-B-type natriuretic peptide; Na, sodium; K, potassium; eGFR, estimated glomerular filtration rate.

Efficacy of the 4×4 approach

There was a marked improvement in symptom burden (NYHA class) and NT-proBNP at 4 weeks in both groups. In patients who achieved 4×4, there was a trend towards greater improvement in LVEF at 6 months compared to those who did not, although this did not reach statistical significance (8% [0–20] vs 2.2% [0–14], p=0.19) (Table 2).

During a median follow-up of 554 days, 32 (40%) patients had an all-cause hospitalisation/death; 30 (37%) patients had ≥1 hospitalisation and six (7%) patients died. Patients who did not achieve 4×4 had an increased risk of all-cause death/hospitalisation (HR 2.25 [1.09–4.68], p=0.029) compared to those who achieved 4×4 (Fig. 2). The 6-month and 12-month combined outcome rates were significantly higher in patients who did not achieve 4×4 compared to those who achieved 4×4 (6 month: 29% vs 10%, p=0.04; 12 month: 43% vs 15%, p=0.01) (Appendix 4). Similar results were seen for hospitalisation alone (Appendix 5). Specifically, within a 12-month period, patients who achieved 4×4 had 10 fewer hospitalisations (12 vs 22) than those who did not, resulting in shorter total length of stay (102 vs 169 days) (Appendix 4). There was no significant difference in risk of all-cause death between the groups (Appendix 4).

Fig. 2.

Kaplan−Meier curves illustrating the relation between successful or unsuccessful 4×4 strategy and the combined outcome. (χ² = 5.0, p=0.025 by the log-rank test).

Discussion

Our study examined the feasibility of implementing an individualised rapid titration strategy for patients with de novo HFrEF in a real-world setting. We found the 4×4 approach to be feasible, safe and efficacious when implemented in selected patients. Our study evaluated a relatively high-risk cohort including older patients with significant comorbidities, high symptom burden and markedly elevated natriuretic peptide levels. Despite these factors, within 4 weeks, we were able to initiate all four pillars of GDMT in almost half of our cohort (48%), three drugs in a further 32% of patients, two drugs in 11% of patients and one drug in 9% of patients. Our results are similar to those reported in a recent study by Coons et al, which evaluated the impact of a medication optimisation clinic on GDMT in patients with HFrEF.¹⁴ Similar to our approach, they aimed to initiate patients on four key classes of medications within 4 weeks, with titration to target doses by 12 weeks, and achieved quadruple therapy by the last study visit in 49% of patients.

In our cohort, the presence of comorbidities such as chronic kidney disease (CKD), lower blood pressure and unfavorable prognostic factors such as older age, worse NYHA class and higher NT-proBNP were associated with lower likelihood of achieving 4×4. These factors have also been previously reported to be associated with lower use and titration of GDMT.¹⁵ Our findings are compatible with the well-recognised 'risk−treatment paradox',¹⁶ where HF patients with the greatest need are less likely to achieve disease-modifying therapy. As the population ages and multimorbidity becomes more common, initiation and titration of GDMT is likely to become more challenging. Other associated factors such as high pill burden and poor adherence to medications could also add to the complexity of drug initiation and titration and should be routinely evaluated in clinical practice.¹⁷ Identifying the most suitable population to implement rapid titration is key to its successful delivery. In this context, we excluded patients for whom aggressive up-titration of therapy was felt, in the opinion of the responsible clinician, to be inappropriate. The main reasons for exclusion include end-stage renal failure, severe frailty, palliative care and inability to attend regular follow-ups for medication titration. These are important to consider if the 4×4 approach is to be implemented broadly across the UK.

Safety is one of the biggest concerns when implementing rapid titration, especially in a high-risk population. In our cohort, a significant proportion (41%) of patients were considered by the medical team to have a 'contraindication' that limited the initiation and titration of GDMT. The main contraindications were CKD stage 4 (eGFR<30 mL/min/1.73m²), bradycardia (heart rate <60 bpm) and hyperkalaemia (K >5.5 mmol/L). Strategies to optimise these factors may increase the potential for widespread application of the 4×4 approach. Of patients without a contraindication, the 4×4 approach is safe with a low adverse event rate of 6%; the main adverse effects encountered were symptomatic hypotension and hyperkalaemia. These have also been frequently reported in other studies as reasons for inability to attain GDMT.^14,18 From the safety perspective, those with good renal function or only mild impairment (eGFR>60), low normal potassium levels (3–4.5 mmol/L), adequate/high blood pressure (>120/80 mmHg) and heart rate (>80 bpm) could be ideal candidates for the 4×4 approach.

Successful initiation /titration of quadruple therapy within 4 weeks was associated with reduction in risk of all-cause hospitalisations. We observed a 29% lower rate of all-cause hospitalisation and a mean reduction of 1.3 bed days per patient in hospital within 12 months in patients who achieved 4×4 compared to those who did not. Our results are in line with those reported by other studies of rapid drug initiation and titration.^8,14

Despite the clinical benefit associated with early and rapid initiation and titration of GDMT, this is not yet widely adopted in clinical practice, likely due to a complex interplay of factors contributing to clinical inertia. GDMT underuse may be more prevalent in higher risk patients due to clinicians’ disproportionate emphasis on the potential side effects and patient harm, intolerance rather than clinical benefits of the therapy. Relative contraindications should not immediately rule out the possibility of GDMT; an absolute contraindication at one point does not mean patients will never be eligible for GDMT. Haemodynamics and renal function of patients often change over time; regular monitoring could potentially identify a window for initiating life-saving GDMT.

The pathway of rapid initiation and titration could also contribute to clinical inertia. The traditional method requires sequential initiation and titration of different classes of GDMT, which is often time-consuming and may contribute to underutilisation of GDMT in HF patients.¹⁹ Unlike other studies,^14,20 we did not restrict HF specialists to follow a specific sequential, stepped titration algorithm. Instead, the order and speed of drug titration was determined by the treating team considering the patient's clinical status and tolerability to different medications. In our cohort, medication titration was mostly done via remote monitoring. We felt that this approach was reflective of real-world clinical practice; it was also flexible and individualised, thereby likely to increase tolerability and adherence.

Implementation of the 4×4 strategy has potential resource implications. In our cohort of 81 patients, 252 clinical appointments were required to deliver this strategy, equating to around 13 appointments per week. With the more traditional approach, we suggest that a similar, or higher, number of visits would be needed, over a longer period of time. Our approach compresses the period of drug initiation (and optimisation) to 4 weeks, which could potentially result in long-term gain from reduced hospitalisations and mortality as a consequence of more optimal and timely use of GDMT.^8,14

Limitations

This study has limitations. First, we conducted a single-centre service evaluation study involving a relatively small sample size. Our study was also not powered for evaluation of clinical outcomes, which are reported on an exploratory basis. Our findings showed that patients who achieved 4×4 had better clinical outcomes compared to those who did not; however, it is not possible to attribute improvement in clinical outcomes to more aggressive drug therapy. This observation may be confounded by a population that is younger and less sick to begin with. Second, our study focused on evaluating the feasibility and safety of an early and rapid initiation approach; we did not study the titration process in detail, including the medication prescription pattern of patients after 4 weeks and how this may have contributed to clinical outcomes.

Conclusions

Early and rapid initiation of quadruple therapy in patients with HFrEF is clinically feasible and safe when implemented in selected patients and may prevent recurrent hospitalisations. Our study highlighted that selection of patients is key to the success of the 4×4 strategy. Effort focusing on optimising the uptake of the 4×4 strategy in those with good renal function, heart rate and blood pressure profile and those with normal potassium level might enhance the effectiveness of this approach. Future study should investigate how the 4×4 strategy could be implemented effectively at larger scale across a variety of healthcare settings.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Ethics approval and consent to participate

No ethics approval is required for this project as this is a service evaluation project and not research. All patients provided verbal consent prior to participating in this service evaluation project, which was approved by and registered on the Trust’s audit register.

CRediT authorship contribution statement

Shirley Sze: Writing – original draft, Methodology, Formal analysis, Conceptualization. Chokanan Thaitirarot: Writing – review & editing, Data curation, Conceptualization. Sunanthiny Krishnan: Writing – review & editing. Daniel Chan: Writing – review & editing, Data curation. Will Nicolson: Writing – review & editing, Data curation. Iain Squire: Writing – review & editing, Supervision, Data curation. Louise Clayton: Writing – review & editing, Data curation, Conceptualization. Ian Loke: Writing – review & editing, Supervision, Data curation, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.