Contemporary guideline-directed medical therapy in de novo, chronic, and worsening heart failure patients: First data from the TITRATE-HF study.

AIMS: Despite clear guideline recommendations for initiating four drug classes in all patients with heart failure (HF) with reduced ejection fraction (HFrEF) and the availability of rapid titration schemes, information on real-world implementation lags behind. Closely following the 2021 ESC HF guidelines and 2023 focused update, the TITRATE-HF study started to prospectively investigate the use, sequencing, and titration of guideline-directed medical therapy (GDMT) in HF patients, including the identification of implementation barriers. METHODS AND RESULTS: TITRATE-HF is an ongoing long-term HF registry conducted in the Netherlands. Overall, 4288 patients from 48 hospitals were included. Among these patients, 1732 presented with de novo, 2240 with chronic, and 316 with worsening HF. The median age was 71 years (interquartile range [IQR] 63-78), 29% were female, and median ejection fraction was 35% (IQR 25-40). In total, 44% of chronic and worsening HFrEF patients were prescribed quadruple therapy. However, only 1% of HFrEF patients achieved target dose for all drug classes. In addition, quadruple therapy was more often prescribed to patients treated in a dedicated HF outpatient clinic as compared to a general cardiology outpatient clinic. In each GDMT drug class, 19% to 36% of non-use in HFrEF patients was related to side-effects, intolerances, or contraindications. In the de novo HF cohort, 49% of patients already used one or more GDMT drug classes for other indications than HF. CONCLUSION: This first analysis of the TITRATE-HF study reports relatively high use of GDMT in a contemporary HF cohort, while still showing room for improvement regarding quadruple therapy. Importantly, the use and dose of GDMT were suboptimal, with the reasons often remaining unclear. This underscores the urgency for further optimization of GDMT and implementation strategies within HF management.

Guideline implementation, drug sequencing, and quality of care in heart failure: design and rationale of TITRATE-HF.

AIMS: Current heart failure (HF) guidelines recommend to prescribe four drug classes in patients with HF with reduced ejection fraction (HFrEF). A clear challenge exists to adequately implement guideline-directed medical therapy (GDMT) regarding the sequencing of drugs and timely reaching target dose. It is largely unknown how the paradigm shift from a serial and sequential approach for drug therapy to early parallel application of the four drug classes will be executed in daily clinical practice, as well as the reason clinicians may not adhere to new guidelines. We present the design and rationale for the real-world TITRATE-HF study, which aims to assess sequencing strategies for GDMT initiation, dose titration patterns (order and speed), intolerance for GDMT, barriers for implementation, and long-term outcomes in patients with de novo, chronic, and worsening HF. METHODS AND RESULTS: A total of 4000 patients with HFrEF, HF with mildly reduced ejection fraction, and HF with improved ejection fraction will be enrolled in >40 Dutch centres with a follow-up of at least 3 years. Data collection will include demographics, physical examination and vital parameters, electrocardiogram, laboratory measurements, echocardiogram, medication, and quality of life. Detailed information on titration steps will be collected for the four GDMT drug classes. Information will include date, primary reason for change, and potential intolerances. The primary clinical endpoints are HF-related hospitalizations, HF-related urgent visits with a need for intravenous diuretics, all-cause mortality, and cardiovascular mortality. CONCLUSIONS: TITRATE-HF is a real-world multicentre longitudinal registry that will provide unique information on contemporary GDMT implementation, sequencing strategies (order and speed), and prognosis in de novo, worsening, and chronic HF patients.

The different risk of new-onset, chronic, worsening, and advanced heart failure: A systematic review and meta-regression analysis.

AIMS: Heart failure (HF) is a chronic and progressive syndrome associated with a poor prognosis. While it may seem intuitive that the risk of adverse outcomes varies across the different stages of HF, an overview of these risks is lacking. This study aims to determine the risk of all-cause mortality and HF hospitalizations associated with new-onset HF, chronic HF (CHF), worsening HF (WHF), and advanced HF. METHODS AND RESULTS: We performed a systematic review of observational studies from 2012 to 2022 using five different databases. The primary outcomes were 30-day and 1-year all-cause mortality, as well as 1-year HF hospitalization. Studies were pooled using random effects meta-analysis, and mixed-effects meta-regression was used to compare the different HF groups. Among the 15 759 studies screened, 66 were included representing 862 046 HF patients. Pooled 30-day mortality rates did not reveal a significant distinction between hospital-admitted patients, with rates of 10.13% for new-onset HF and 8.11% for WHF (p = 0.10). However, the 1-year mortality risk differed and increased stepwise from CHF to advanced HF, with a rate of 8.47% (95% confidence interval [CI] 7.24-9.89) for CHF, 21.15% (95% CI 17.78-24.95) for new-onset HF, 26.84% (95% CI 23.74-30.19) for WHF, and 29.74% (95% CI 24.15-36.10) for advanced HF. Readmission rates for HF at 1 year followed a similar trend. CONCLUSIONS: Our meta-analysis of observational studies confirms the different risk for adverse outcomes across the distinct HF stages. Moreover, it emphasizes the negative prognostic value of WHF as the first progressive stage from CHF towards advanced HF.

Guideline-directed medical therapy for HFrEF: sequencing strategies and barriers for life-saving drug therapy.

Multiple landmark trials have helped to advance the treatment of heart failure with reduced ejection fraction (HFrEF) significantly over the past decade. These trials have led to the introduction of four main drug classes into the 2021 ESC guideline, namely angiotensin-receptor neprilysin inhibitors/angiotensin-converting-enzyme inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors. The life-saving effect of these therapies has been shown to be additive and becomes apparent within weeks, which is why maximally tolerated or target doses of all drug classes should be strived for as quickly as possible. Recent evidence, such as the STRONG-HF trial, demonstrated that rapid drug implementation and up-titration is superior to the traditional and more gradual step-by-step approach where valuable time is lost to up-titration. Accordingly, multiple rapid drug implementation and sequencing strategies have been proposed to significantly reduce the time needed for the titration process. Such strategies are urgently needed since previous large-scale registries have shown that guideline-directed medical therapy (GDMT) implementation is a challenge. This challenge is reflected by generally low adherence rates, which can be attributed to factors considering the patient, health care system, and local hospital/health care provider. This review of the four medication classes used to treat HFrEF seeks to present a thorough overview of the data supporting current GDMT, discuss the obstacles to GDMT implementation and up-titration, and identify multiple sequencing strategies that could improve GDMT adherence. Sequencing strategies for GDMT implementation. GDMT: guideline-directed medical therapy; ACEi: angiotensin-converting enzyme inhibitor; ARB: Angiotensin II receptor blocker; ARNi: angiotensin receptor-neprilysin inhibitor; BB: beta-blocker; MRA: mineralocorticoid receptor antagonist; SGLT2i: sodium-glucose co-transporter 2 inhibitor.

Decreased mortality and increased side effects in COVID-19 patients treated with IL-6 receptor antagonists: systematic review and meta-analysis.

There is controversy whether IL-6 (receptor) antagonists are beneficial in treating COVID-19 patients. We therefore update our systematic review to answer the following research questions: (1) Do patients hospitalized for COVID-19 treated with IL-6 (receptor) antagonists have lower mortality compared to standard of care? (2) Do patients hospitalized for COVID-19 treated with IL-6 (receptor) antagonists have more side effects compared to standard of care? The following databases were search up to December 1st 2020: PubMed, PMC PubMed Central, MEDLINE, WHO COVID-19 Database, Embase, Web-of-Science, COCHRANE LIBRARY, Emcare and Academic Search Premier. In order to pool the risk ratio (RR) and risk difference of individual studies we used random effects meta-analysis. The search strategy retrieved 2975 unique titles of which 71 studies (9 RCTs and 62 observational) studies comprising 29,495 patients were included. Mortality (RR 0.75) and mechanical ventilation (RR 0.78) were lower and the risk of neutropenia (RR 7.3), impaired liver function (RR 1.67) and secondary infections (RR 1.26) were higher for patients treated with IL-6 (receptor) antagonists compared to patients not treated with treated with IL-6 (receptor) antagonists. Our results showed that IL-6 (receptor) antagonists are effective in reducing mortality in COVID-19 patients, while the risk of side effects was higher. The baseline risk of mortality was an important effect modifier: IL-6 (receptor) antagonists were effective when the baseline mortality risk was high (e.g. ICU setting), while they could be harmful when the baseline mortality risk was low.

Decreased Mortality in Coronavirus Disease 2019 Patients Treated With Tocilizumab: A Rapid Systematic Review and Meta-analysis of Observational Studies.

BACKGROUND: We systematically reviewed the literature to answer the following research questions: (1) Does interleukin 6 (IL-6) (receptor) antagonist therapy reduce mortality in coronavirus disease 2019 (COVID-19) patients compared to patients not treated with IL-6 (receptor) antagonists; and (2) is there an increased risk of side effects in COVID-19 patients treated with IL-6 (receptor) antagonists compared to patients not treated with IL-6 (receptor) antagonists? METHODS: We systematically searched PubMed, PMC PubMed Central, Medline, World Health Organization COVID-19 Database, Embase, Web of Science, Cochrane Library, Emcare, and Academic Search Premier (through 30 June 2020). Random effects meta-analysis was used to pool the risk ratios and risk differences of individual studies. Risk of bias was appraised using the Methodological Index for Non-randomized Studies (MINORS) checklist. RESULTS: The search strategy retrieved 743 unique titles, of which 10 studies (all on tocilizumab [TCZ]) comprising 1358 patients were included. Nine of 10 studies were considered to be of high quality. Meta-analysis showed that the TCZ group had lower mortality than the control group. The risk ratio was 0.27 (95% confidence interval [CI], .12-.59) and the risk difference was 12% (95% CI, 4.6%-20%) in favor of the TCZ group. With only a few studies available, there were no differences observed regarding side effects. CONCLUSIONS: Our results showed that mortality was 12% lower for COVID-19 patients treated with TCZ compared with those not treated with TCZ. The number needed to treat was 11, suggesting that for every 11 (severe) COVID-19 patients treated with TCZ, 1 death is prevented. These results require confirmation by randomized controlled trials.