Recommended
Recommended
More Related Content
What's hot
What's hot (20)
Similar to A systematic review and network meta analysis of pharmacological treatment of heart failure with reduced ejection fractioon
Similar to A systematic review and network meta analysis of pharmacological treatment of heart failure with reduced ejection fractioon (20)
Recently uploaded
Recently uploaded (20)
A systematic review and network meta analysis of pharmacological treatment of heart failure with reduced ejection fractioon
- 1. A Systematic Review and Network Meta-Analysis of Pharmacological Treatment of Heart Failure With Reduced Ejection Fraction February 21th, 2022
- 2. Tromp, J., Ouwerkerk, W., van Veldhuisen, D. J., Hillege, H. L., Richards, A. M., van der Meer, P., Anand, I. S., Lam, C. S. P., & Voors, A. A. (2022). A Systematic Review and Network Meta-Analysis of Pharmacological Treatment of Heart Failure With Reduced Ejection Fraction. JACC: Heart Failure, 10(2), 73–84. https://doi.org/10.1016/J.JCHF.2021.09.004 JOURNAL CLUB
- 3. • Mortality and hospitalizations • ACEi, ARBs, BBs, MRAs • ARNi, ivabradine • SGLT2i, sGC, INN (CK-1827452) • Sequentially vs parallel • NMA = best combination pharmacological agents INTRODUCTION
- 4. • Systematic review and network metanalysis with frequentist statistical approach • Search strategy MEDLINE, EMBASE, and Cochrane • Studies between 1987 and 2021 • Inclusion criteria • > 18 yo • Digoxin, isosorbide dinitrate and hydralazine (H-ISDN), ACEi, ARB, BB, MRA, ivabradine, ARNi, SGLT2i, vericiguat, and omecamtiv-mecarbil • Exclusion criteria • Comorbiditis • Acute heart failure • Same drug group METHODOLOGY
- 5. all-cause death CV death HF hospitalization CV death alone likelihood of drug discontinuation OUTCOMES
- 6. • Effect of treatment combinations = ∑ components • SUCRA • CINeMA 1. within-study bias 2. reporting bias 3. Indirectness 4. Imprecision 5. Heterogeneity 6. Incoherence NETWORK META-ANALYSIS
- 9. • Risk of bias was low • No evidence of systematic reporting bias • Indirectness and imprecision were low among the studies • Heterogeneity • 9,1% for all cause death • 29.6% for the composite endpoint of CV or HHF • 11% for CV death • No incoherence (P >0,1 for all) RISK OF BIAS
- 10. RESULTS
- 14. DRUG DISCONTINUATION • Heterogeneity of 60.7% • No publication bias • Higher risk of discontinuation with ARBs than ARNis and ACEis
- 15. SENSITIVITY ANALYSES • 50% of the studies did not use ARNIs • SGLT2i, vericiguat, and omecamtivmecarbil against a background of ACEi /ARNi • ACEi, BB, MRA, and SGLT2i more effective in reducing all-cause death
- 16. ESTIMATED LIFE-YEARS GAINED • 7,376 patients with HFrEF in the BIOSTATCHF and ASIAN-HF treated with ACEi • With treatment, estimated life-years gained with ARNi, BB, MRA, and SGLT2i • 50 years old = 4.9 years • 70 years old = 3,3 years • With placebo, estimated life-years gained with ARNi, BB, MRA, and SGLT2i • 50 years old = 7,9 years • 70 years old = 5 years
- 18. DISCUSSION • ARNi, BB, MRA, and SGLT2i MOST EFFECTIVE • ACEi, BB, MRA, and SGLT2i extend L-Y • ARNi showed < HR for all-cause mortality and lower risk for discontinuation than ACEi/ARB • ARNi + BB + MRA + SGLT2i >>>> vericiguat or omecamtiv-mecarbil • H-ISDN in symptomatic patients after treatment
- 19. DISCUSSION • Extend life-expectancy in HFrEF by 7.9 years in a 50-year-old and by 5.0 years in a 70-year-old • reduce the mortality risk by 73% • two main advantages over the other NMA: 1. HISDN, digoxin, SGLT2i, vericiguat, and omecamtivmecarbil 2. Estimating the aggregate treatment effect in 2 large and well-phenotyped HF cohorts • Cost/effectiveness
- 20. STRENGTHS AND LIMITATIONS • Did not explore vericiguat + SGLT2i or omecamtiv-mecarbil + SGLT2i • ARNi used in fewer than 50% of the studies • Differences in drug dosages • Resultsfor discontinuation showed considerable heterogeneity
- 21. CONCLUSION ARNi + BB +MRA + SGLT2i increase in number of life-years
Editor's Notes
- Good afternoon everyone And I Will be presenting today´s journal club article Which is title “a systemati Review and Network meta-análisis of pharmacological treatment of heart failye with reduced ejection fraction” It was written by a group o researchers from netherlands, singapore and New zealand It was published in the Journal of the America College of Cardiology: Heart Failure edition on Septembre 14th, 2021. Initially I mention aquick overview of the topics to cover and then we go over the objectives, bacgkgorund, methodology, results and conclusions.
- Heart failure is still one of the main causes of mortality and hospitalization around the world up to this date. There have been many advances in terms of pharmacological treatment options but unfortunately these have only slightly impacted these outcomes. Pharmacological agents such as angiotensin-converting enzyme inhibitors (ACEi,) angiotensin receptor blockers (ARBs), betablockers (BBs), and mineralocorticoid receptor antagonists (MRAs) were established very early on through clinical trials as the cornerstone of the treatment of heart failure with reduced ejection fraction. And in the last few years more treatment options that may directly impact mortality and hospitalization rates have been included to the arsenal such as sacubitril/valsartan, ivabradine, sodium-glucose cotransporter2 inhibitors (SGLT2i) such empagliflozin and dapagliflozin, soluble guanylase cyclase stimulator vericiguat, and cardiac-specific myosin activator omecamtiv-mecarbil In past, clinical trials were conducted sequentially meaning that the results would show the precise effects of the pharmacological agent in question when added to already existing treatment options. However newly developed clinical trials have been performed in parallel so they do not provide reliable results in terms of the most beneficial and impactful combination of pharmacological agents. As a result, Network-meta-analyses such as the one we are currently analyzing, serves this purpose, to allow us to identify what´s the best combination in terms of pharmacotherapy.
- Now… in terms of the method used in this article, the study design was a systematic review and network metanalysis with frequentist statistical approach which in simple terms, this inference treats probability and frequency equally in order draw conclusions from the data at hand. In a few more slides we will go a bit more into detail regarding this approach. Also, this article followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses framework. With regards to the SEARCH STRATEGY a systematic search was conducted using MEDLINE, EMBASE, and the Cochrane specifically looking for randomized controlled trials that were published between 1987 and January 1, 2021. The selection criteria was based on studies that included participants over the age of 18 and articles that used or compared pharmacological agents that have shown benefits on previous clinical trials with regards to the treatment of heart failure with reduced ejection fraction (such as digoxin, isosorbide dinitrate and hydralazine (H-ISDN), ACEi, ARB, BB, MRA, ivabradine, ARNi, SGLT2i, vericiguat, and omecamtiv-mecarbil.) On the other hand, studies including participants with comorbidities that may have indirectly affected the results of heart failure treatment were excluded, as well as studies with patients suffering from acute heart failure or when comparing pharmacological agents from the same drug group. After a promising list of studies was built, Two investigators screened these articles, developed a final list of citations and extracted the relevant data.
- With regards to the outcomes analyzed in this article The primary outcome was all-cause death. The reason for choosing this as the main outcome, was because most of the selected studies had include it in their analysis. Also, a second outcome, specifically composite endpoint, was included in this study, it involved cardiovascular (CV) death and hospitalization for heart failure (HHF), CV death alone, and the likelihood of drug discontinuation because of any reason.
- NETWORK META-ANALYSIS. As it was previously mentioned, this article used a network meta-analysis model using a frequentist framework with fixed and random effect models. The network meta-analysis model assumes that the effect of treatment combinations is the sum of the effects of its components, which allows to evaluate the influence of individual components and compare the different combinations of the treatments All the treatments from the selected studies were ranked using the surface under the cumulative ranking curve (SUCRA) score, also known as the P-Score. And to evaluate the confidence in the results, the Confidence in Newtwork Metanalysis framework (CINeMA) was used. This framework consists of 6 domains which included: 1) within-study bias; 2) reporting bias; 3) indirectness; 4) imprecision; 5) heterogeneity; and 6) Incoherence To assess within-study bias, the Cochrane tool classifying as “low,” “medium,” and “high” across 6 domains. If more than 3 domains out of the 6 of a particular study were “high” then the study would be considered high risk for within-study bias , if less than 3 then low risk Reporting bias the Egger test was used and if the result of this test was nonsignificant, then the study was low risk for reporting bias Indirectness was assessed as low for all the studies Imprecision was used to compare the treatment effects included in the 95% coefficient intervals with the range of equivalence using clinically important effects as OR of 2.0. To assess heterogeneity, I2 values where calculated using chi square test and if I2 was greater than 30% then the effects of treatments were attributed to randomness Incoherence was assessed using a global test based on a random effects design-by-treatment interaction model.
- ESTIMATION OF LIFE-YEARS GAINED. A secondary analysis was conducted, where the absolute risk reduction and life-years gained in two studies was determined: 1. BIOSTAT-CHF (The BIOlogy Study to TAilored Treatment in Chronic Heart Failure) study 2. the ASIANHF (Asian Sudden Cardiac Death in Heart Failure) registry. BIOSTAT-CHF (The BIOlogy Study to TAilored Treatment in Chronic Heart Failure) study conducted in Europe that included 2,516 adult patients with HF, of whom 2,100 had HFrEF On the other hand, ASIANHF registry as its name suggests it was conduct in Asia and included 5,276 adult patients with HFrEF The inclusion criteria for both studies were similar and consisted of: 1 patients with signs and symptoms of heart failure 2. Quantifiable evidence of reduced LVEF, and 3. followed up for clinical outcomes of death and hospitalization. To estimate the number of life-years free of death, a model based on the age of the participants was implemented using Kaplan Meier plots. Also, the difference in background treatment was taken into account by estimating the benefit of each treatment combination, to this the treatment that the patient was receiving was compared in terms of life-years to all the treatment options and also the treatment combination was compared with placebo.
- RESULTS STUDY SELECTION. Now we will talk about the results, as it can be seen on the graph through their systematic search they were able to identify 9,328 studies and after applying the inclusion and exclusion criteria they were left with only 75 studies. These had a total of 95,444 patients, of which most of them were classified as NYHA class II . Patients were followed in average for 11 months .
- RISK OF BIAS AND PUBLICATION BIAS. Of the 75 studies included, overall risk of bias was low. The majority of studies were multicenter, double-blind, placebo-controlled trials. There was no evidence of systematic reporting bias for any of the outcomes ie, mortality (Egger test P ¼ 0.122), the composite of CV mortality and HF hospitalization (Egger test P ¼ 0.267), and CV death alone (Egger test P ¼ 0.283). Indirectness was judged as low. The majority of comparisons did not show concerns of imprecision. Except in the SOCRATES and COSMIC-HF which studied the use of Guanylate Cyclase Stimulator and omecamtivmecarbil respectively The overall heterogeneity was estimated to be 9,1% for all cause death, 29.6% for the composite endpoint of CV or HHF and 11% for CV death There was no evidence for incoherence found for any of the outcomes (P > 0.1 for all).
- OUTCOMES. All-cause mortality was reported in a total of 17,684 events As it can be seen on the figure on the left (Figure 2A) the ARNi (HR: 0.75; 95% CI: 0.66-85) and MRA (HR: 0.76; 95% CI: 0.67-0.85) was associated with the largest reduction in all-cause death, followed by BB (HR: 0.78; 95% CI: 0.72-0.84), ACEi (HR: 0.89; 95% CI: 0.82-0.96), SGLT2i (HR: 0.88; 95% CI: 0.78-0.99), and ARB (HR:0.95; 95% CI: 0.88-1.02). Vericiguat (HR: 0.94; 95% CI: 0.79-1.11) and omecamtiv-mecarbil (HR: 1.0; 95% CI: 0.92-1.09) did reduce the risk of all-cause death. On the on the right (Figure 2B) shows that MRA (HR: 0.62; 95% CI: 0.54- 0.72) was associated with the largest reduction in the composite outcome, followed by SGLT2i (HR: 0.70; 95% CI: 0.63-0.77).
- Here we can see the combination of pharmacological agents that are the most effective in reducing all-cause death. In this case by looking at the top of the figure we can see that the combination of ARNi, BB, MRA, and SGLT2i (HR: 0.39; 95% CI: 0.31- 0.49) was most effective in reducing all-cause death when compared to placebo. However there is no significant difference in the reduction of all-cause death among a combination of: ARNi, BB, MRA, and SGLT2i; ARNi, BB, MRA, and vericiguat (P ¼ 0.562); ARNi, BB, MRA, and omecamtiv-mecarbil (P ¼ 0.088). But this does not apply to other scenarios in which ARNi, BB, MRA, and SGLT2i did in fact showed to be significantly more effective in reducing all-cause death than ARNi, BB, and MRA (HR: 0.88; 95% CI: 0.78-0.99; P ¼ 0.037).
- With regards to the composite outcome of CV mortality or HH hospitalization, A combination of ARNi, BB, MRA, and SGLT2i was shown to be most effective compared with ACEi alone (HR: 0.36; 95% CI: 0.29-0.46) and compared with the second-best combination of ARNi, BB, MRA, and vericiguat (HR: 0.82; 95% CI: 0.66-0.1.01; P ¼ 0.061), and ARNi, BB, MRA and omecamtivmecarbil (HR: 0.81; 95% CI: 0.66-0.1.00; P ¼ 0.049). There was no significant difference between the combination of ARNi, BB, MRA, and vericiguat and ARNi, BB, MRA, and omecamtiv-mecarbil in reducing the composite outcome.
- In terms of cardiovascular mortality it was shown that the combination of ARNi, BB, MRA, and SGLT2i was most effective in reducing CV death (HR: 0.33; 95% CI: 0.26-0.43), followed by ARNi, BB, MRA, and vericiguat (HR: 0.35; 95% CI: 0.26-0.47) and ARNi, BB, MRA, and omecamtiv-mecarbil (HR: 0.36; 95% CI: 0.27-0.46), But without a significant difference between the 3 combinations (P > 0.1 )
- DRUG DISCONTINUATION. Drug discontinuation was reported in 58 studies There was considerable heterogeneity in the network (60.7%; range 47.0% to 70.9%; P < 0.001); therefore, a random effects model was used. There was no evidence for publication bias (Eggers test P ¼ 0.726). In total, 9,451 patients discontinued pharmacotherapy. Compared with placebo, the risk of discontinuation was lower for ACEi (OR: 0.89; 95% CI: 0.82-0.96) and ARNi (OR: 0.77; 95% CI: 0.67-0.93), but higher for ARB (OR: 1.2; 95% CI: 1.07-1.36). There were no differences between the remaining drug classes compared with placebo (P > 0.05 for all)
- SENSITIVITY ANALYSES. Sensitive analysis had to be conducted as 50% of the studies did not use ARNis. ACEi, BB, MRA, and SGLT2i was numerically more effective in reducing all-cause death (HR: 0.44; 95% CI: 0.37-0.54), than ACEi, BB, MRA, and vericiguat (HR: 0.49; 95% CI: 0.39-0.62) and ACEi, BB, MRA, and omecamtivmecarbil (HR: 0.52; 95% CI: 0.43-0.63) However, In sensitivity analyses considering SGLT2i, vericiguat, and omecamtivmecarbil against a background of ACEi instead of ARNi, results were comparable.
- ESTIMATED LIFE-YEARS GAINED. We estimated survival in 7,376 patients with HFrEF in the BIOSTATCHF and ASIAN-HF study who were treated with ACEi and BB. At baseline, 5,691 (77%) patients were on ACEi/ARB, 6,018 (82%) on BB, and 4,093 (55%) on MRA. Compared with actual care, the estimated life-years gained at age 50 years when all patients were treated with ARNi, BB, MRA, and SGLT2i was 4.9 years (95% CI: 1.4-8.4 years), and 3.3 years (95% CI: 0.7-5.8 years) in a 70-year-old patient Compared with estimated placebo (no treatment), the aggregate treatment effect of ARNi, BB, MRA, and SGLT2i was 7.9 life-years (95% CI: 4.7-11.2 life-years) gained for a 50-year-old and 5.0 life-years (95% CI: 2.5-7.5 life-years) gained for a 70-year-old
- Here can see two Kaplan Meier plots of Life-years gained by using different drug combinations Estimated average lifetime benefit for selected treatment combinations in BIOSTAT-CHF and ASIAN-HF at age 50 years (A) and age 70 years (B) The difference between no treatment and comprehensive treatment for all ages was similar between ASIAN-HF and BIOSTAT-CHF.
- DISCUSSION Results of this study support the concept of treating patients with a combination of ARNi, BB, MRA, and SGLT2i as firstchoice therapy, and highlight its significant benefit. Although current guidelines for HF recommend starting with ACEi/ARB as first-line treatment. It was shown through this analysis that ARNi showed a smaller HR for all-cause mortality than ACEi/ARB and a lower risk for discontinuation compared with placebo. Therefore, our results support starting with ARNi as first-line therapy rather than ACEi or ARB A combination of ARNi, BB, MRA, and SGLT2i demonstrated the greatest reduction in risk for all-cause death and composite of CV death or HHF compared with the same combination replacing SGLT2i by vericiguat or omecamtiv-mecarbil. There were no differences between the combination of ARNi, BB, MRA, and vericiguat or of ARNi, BB, MRA, and omecamtiv-mecarbil in reducing any of the outcomes. Notably, a combination of H-ISDN on top of ACEi and BB significantly reduced the risk of CV death and HHF in our analyses. H-ISDN can therefore be considered in symptomatic patients after treatment with ARNi, BB, MRA, and SGLT2i, but these findings were only reported in African American participants
- As it was previously mentioned The analysisis in this study was able to determine that (ARNi, BB, MRA, and SGLT2i) can collectively extend life-expectancy in HFrEF by 7.9 years in a 50-year-old and by 5.0 years in a 70-year-old patient compared with no treatment. Which are findings similar to clinica trials such as from EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure), PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortalilty and morbidity in Heart Failure) trial, and DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), The estimated treatment benefit of quadruple therapy can reduce the mortality risk by 73% In the past, 3 network metaanalysis have evaluatedpharmacotherapy in heart failure with reduced eyecion fraction but they are fairly old and don’t include many of the new drugs that are currently available As a result this network metanlysis has two main advantages over the others: 1) including more comprehensive data on pharmacological treatment for HFrEF including HISDN, digoxin, SGLT2i, vericiguat, and omecamtivmecarbil; 2) estimating the aggregate treatment effect in 2 large and well-phenotyped HF cohorts with global representation. Estimating the aggregate treatment benefit is important to guide shared decision-making for patients and doctors, especially in the presence of polypharmacy The increase in life-expectancy after comprehensive pharmacological treatment for HFrEF is substantial, especially compared with more expensive therapies for other diseases, there are more expensive medications such as PCSK9 which only extends life expectancy 1,1 years and is 10 more expensive than other pharmacologic agents
- STUDY STRENGTHS AND LIMITATIONS. Although the results of this study support treatment with a combination of ARNi, BB, MRA and SGLT2i, we were not able to assess the aggregate treatment effect of vericiguat or omecamtiv-mecarbil on top of SGLT2i. ARNi was used by fewer than 50% of the populations in the recent trials. So sensitivity analyses had to be done substituting ARNi by ACEi in the different treatment Combinations Studies had very variable drug dosages. Our estimated risk reduction with ARNI, BB, MRA, and SGLT2i compared with ACEi/BB and projected life years gained is similar to a previous report using patient level estimates The analyses used to estimate the lifetime treatment benefit assume that adherence to treatment persists over time. The results for discontinuation showed considerable heterogeneity, despite the use of a random effects model. This might be caused by differences in definition of discontinuation. Therefore, these results should be interpreted with caution. Last, we did not take nonpharmacological device use into account, which can affect estimation of treatment benefit.
- Finally, the main message or conclusion that we can draw from this is article is that the combination of ARNi, BB, MRA, and SGLT2i for the treatment of heart failure with reduced ejection fraction has beneficial effects which can be perceived by the increased in number of years-life of these patients