Titration of medications and outcomes in multi‐ethnic heart failure cohorts (with reduced ejection fraction) from Singapore and New Zealand

Abstract

Aims We investigated titration patterns of angiotensin‐converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs) and beta‐blockers, quality of life (QoL) over 6 months, and associated 1 year outcome [all‐cause mortality/heart failure (HF) hospitalization] in a real‐world population with HF with reduced ejection fraction (HFrEF). Methods and results Participants with HFrEF (left ventricular ejection fraction <40%) from a prospective multi‐centre study were examined for use and dose [relative to guideline‐recommended maintenance dose (GRD)] of ACEis/ARBs and beta‐blockers at baseline and 6 months. ‘Stay low’ was defined as <50% GRD at both time points, ‘stay high’ as ≥50% GRD, and ‘up‐titrate’ and ‘down‐titrate’ as dose trajectories. Among 1110 patients (mean age 63 ± 13 years, 16% women, 26% New York Heart Association Class III/IV), 714 (64%) were multi‐ethnic Asians from Singapore and 396 were from New Zealand (mainly European ethnicity). Baseline use of either ACEis/ARBs or beta‐blockers was high (87%). Loop diuretic was prescribed in >80% of patients, mineralocorticoid receptor antagonist in about half of patients, and statins in >90% of patients. At baseline, only 11% and 9% received 100% GRD for each drug class, respectively, with about half (47%) achieving ≥50% GRD for ACEis/ARBs or beta‐blockers. At 6 months, a large majority remained in the ‘stay low’ category, one third remained in ‘stay high’, whereas 10–16% up‐titrated and 4–6% down‐titrated. Patients with lower (vs. higher) N‐terminal pro‐beta‐type natriuretic peptide levels were more likely to be up‐titrated or be in ‘stay high’ for ACEis/ARBs and beta‐blockers ( P = 0.002). Ischaemic aetiology, prior HF hospitalization, and enrolment in Singapore (vs. New Zealand) were independently associated with higher odds of ‘staying low’ (all P < 0.005) for prescribed doses of ACEis/ARBs and beta‐blockers. Adjusted for inverse probability weighting, ≥100% GRD for ACEis/ARBs [hazard ratio (HR) = 0.42; 95% confidence interval (CI) 0.24–0.73] and ≥50% GRD for beta‐blockers (HR = 0.58; 95% CI 0.37–0.90) (vs. Nil) were associated with lower hazards for 1 year composite outcome. Country of enrolment did not modify the associations of dose categories with 1 year composite outcome. Higher medication doses were associated with greater improvements in QoL. Conclusions Although HF medication use at baseline was high, most patients did not have these medications up‐titrated over 6 months. Multiple clinical factors were associated with changes in medication dosages. Further research is urgently needed to investigate the causes of lack of up‐titration of HF therapy (and its frequency), which could inform strategies for timely up‐titration of HF therapy based on clinical and biochemical parameters.

Vericiguat Use in Patients with Heart Failure in Real-World Settings during the First Year after the Drug Authorization in Japan

“…A multivariable Cox proportional hazards model was computed to assess the factors associated with reaching the vericiguat maximal daily dose at any given time over the 90 days of follow-up. The model included the time to reach the maximal daily dose during the 90 days of follow-up as the outcome and was adjusted for known predictors of HF medication uptitration [ 26 , 27 ], such as age, sex, comorbidities, and the use of HF medications and non-pharmacological therapies. The model computed hazard ratios (HRs) with 95% confidence intervals (CIs) for each variable included.…”

Optimization of GDMT for patients with heart failure and reduced ejection fraction: can physiological and biological barriers explain the gaps in adherence to heart failure guidelines?

“…12,17,18 Prescription rates of evidence-based therapies in clinical practice: status quo Great variability exists in the prescription rates of each class of agent comprising GDMT for ambulatory patients with HFrEF (Table 1). [10][11][12][13][18][19][20][21][22][23][24][25][26] In 2008, the Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting (IMPROVE HF) evaluated 167 outpatient cardiology clinics and showed high prescription rates of beta-blockers (86%) and RAS inhibitors (ACEI or ARB; 80%) in eligible patients but much lower use of MRAs (36%); this was believed to be due to a perceived risk of increased mortality or hospitalization associated with hyperkalaemia as shown after the publication of the RALES and the subsequently wide use of MRAs. 19,27 Moreover, an analysis from the Swedish Heart Failure Registry showed that use of beta-blockers improved from 85% to 93% (p=0.008) between 2003 and 2012, whereas use of RAS inhibitors remained unchanged (88% versus 86%; p=0.091) and the use of MRAs decreased (53% versus 42%; p<0.001) after adjusting for 38 clinically significant baseline variables.…”

“…Previous studies have shown that a significant proportion of patients remain on suboptimal doses of GDMT despite no obvious intolerance or contraindication (Table 1). [10][11][12][13]18,21,22,[24][25][26]46 An analysis from CHAMP-HF showed that very little up-titration occurs in clinical practice, with less than 1% of eligible patients being treated with the triple combination at target doses of a beta-blocker, RAS inhibitor and MRA combination over 12 months. Noteworthy, there were minimal or no changes in dosage at each 3-month visit during follow-up, with most patients The QUALIFY study group proposed an adherence score that was calculated for each patient: 0 points were attributed if medication was not prescribed in the absence of contraindications, 0.5 points if <50% of target doses were prescribed or 1 point for the prescription of ≥50% of target dose of GDMT.…”

“…Lower levels of NT-proBNP were actually associated with a higher likelihood of up-titration for ACEI/ARBs and beta-blockers, reflecting either difficulty to treat the sicker patients or the risk-treatment paradox. 26 These gaps in adherence have a significant impact on patient outcomes. First, in CHAMP-HF, patients receiving subtarget doses had an increased risk of all-cause mortality proportional to the level of target dose of RAS inhibitors (0%: HR 1.75, 95% CI 1.32-2.34; 1-49%: 1.37, 1.05-1.79; 50-99%: 1.16, 0.87-1.55) and beta-blockers achieved (0%: 1.24, 0.92-1.67; 1-49%: 1.41, 1.11-1.79; 50-99%: Jarjour M, Ducharme A.…”

“…), female sex, lower body habitus/body mass index (BMI), HR, SBP and serum potassium level. 18,26,47,[62][63][64][65][66] These parameters may be perceived as an individual's fragility, leading to either careful up-titration of GDMT or no intent at all. 25 Indeed, there was an independent association between obesity (BMI ≥30 kg/m 2 ) and likelihood of prescription/ up-titration to target doses of GDMT in the Swedish Heart Failure Registry.…”