| Citation: |
Please cite this article as: SUN LK, KONG J, YANG XW, WANG J, ZHANG PF. Target versus sub-target dose of renin–angiotensin system inhibitors on survival in elderly patients with heart failure with reduced ejection fraction: a systematic review and meta-analysis. J Geriatr Cardiol 2023; 20(6): 469−478. DOI: 10.26599/1671-5411.2023.06.004.
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Heart failure (HF) with reduced ejection fraction (HFrEF) is a chronic condition and a major cause of mortality and morbidity,[1] predominant in elderly individuals > 65 years of age.[2] The prevalence of HF increases dramatically with age, from 2% in the general population to > 10% among those aged ≥ 75 years.[3] Although renin–angiotensin system inhibitors (RASIs) or angiotensin–receptor neprilysin inhibitors (ARNIs) have been shown to reduce mortality and morbidity rates in patients with HFrEF,[4–8] few studies included patients > 60 years of age, let alone those > 75 years of age. Based on current guidelines, these medications should be commenced at a low dose and up-titrated to the guideline-recommended target dose (GRTD) or maximal tolerable dose.[9,10] However, two aspects have drawn keen consideration. On the one hand, compared to a low dose (< 50% GRTD), a high dose (> 50% GRTD) of RASIs/ARNIs significantly improves the mortality of HFrEF patients.[11–14] However, in the real world, only 1/3 of HFrEF patients can achieve and maintain the GRTD due to adverse effects.[15] On the other hand, the guidelines do not differentiate therapy strategies according to age group.[2] The efficacy of treating patients with HFrEF with the GRTD versus the sub-target dose (50%–99% GRTD) of RASIs/ARNIs remains unclear.[16]
Therefore, we performed this meta-analysis to evaluate the efficiency of the target versus sub-target dose of RASIs/ARNIs on survival in patients > 60 years of age with HFrEF.
We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology reporting guidelines.[17,18] The study protocol was registered in the International Prospective Register of Systematic Reviews under the identification number CRD42020160593.
PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched up to March 2022 to identify eligible clinical trials for inclusion in our analysis. The keywords of interest included “heart failure with reduced ejection fraction”, “HFrEF”, “angiotensin-converting enzyme inhibitors”, “ACEI”, “angiotensin receptor blockers”, “ARB”, “angiotensin–receptor neprilysin inhibitors”, “ARNI”, “target dose”, “sub-target dose”, “optimal dose”, and so on. We reviewed full-text articles designated initially for inclusion and manually checked the references of the retrieved articles and previous reviews to identify additional eligible studies.
Studies satisfying certain PICO (the Population, Intervention, Comparator, and Outcome) criteria were included. With regard to study population, we considered those studies including elderly patients (≥ 60 years) with HFrEF. Appropriate study designs included randomized controlled trials (RCTs) and observational studies (prospective or retrospective cohort studies), and appropriate interventions included the target and sub-target doses of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/ARNIs. For our purposes, the target dose was defined as a dose greater than or equal to the GRTD, while a sub-target dose was defined as that equal to 50%–99% of the GRTD.[9] Outcomes of interest included all-cause mortality, cardiac mortality, HF hospitalization, and the composite endpoint of mortality or HF hospitalization. Finally, studies comparing outcomes of the target and sub-target doses were considered.
A manual search was conducted among all the identified original articles by two independent investigators. For studies comparing > 2 arm doses, we classified those doses greater than or equal to the GRTD as “target doses” and those that were 50%–99% of the GRTD as “sub-target doses”. We extracted crude outcome data from full-text reports into a standardized database. The extracted data included the study first author, setting, publication year, and design as well as the duration of follow-up, the sample size, the drugs being studied and their dosage, baseline patient demographics, and outcomes. The primary outcome was all-cause mortality, and secondary outcomes included cardiac mortality, HF hospitalization, and the composite endpoint of mortality or HF hospitalization. The Cochrane’s risk of bias tool was adopted to assess the risk of bias for each RCT.[19] Observational studies were evaluated using the Newcastle–Ottawa Scale.[20]
We performed all statistical analyses using the Review Manager 5.30 software (Cochrane Collaboration, London, UK) and Stata 16.0 (Stata Corp, College Station, TX, USA) with the target dose set as the experimental intervention and the sub-target dose set as the control intervention, respectively. A meta-analysis of the study results was completed using pooled hazard ratio (HR) and associated 95% CI. The HR with 95% CI was extracted from articles. For those studies in which HR and CI were not available, adjusted relative risk (RR) values were considered equivalent to adjusted HR. Besides, we used the method proposed by Deeks, et al.[21] to derive estimates from survival curves. If results of both univariate and multivariate Cox regression analyses were reported, we chose the multivariate models for a more accurate estimate of the effects. P-value < 0.05 was considered statistically significant. Heterogeneity was evaluated using the Q statistic and quantified with the І2 statistic. A finding of І2 > 50% indicated significant heterogeneity between studies. We performed our analysis using a fixed-effects model initially; however, if heterogeneity was observed, the analysis was repeated using a random-effects model. Subgroup analyses were performed based on variables, including whether patients were aged > 75 years and the study design. Meta-regression was then performed for incidence rates against variables of interest. Publication bias was assessed by funnel plot analysis.
We identified 16 relevant articles after reviewing the titles or abstracts of 484 potentially relevant articles. All 16 articles of 7 studies[16,22–27] satisfying our eligibility criteria were finally included in this meta-analysis. The literature search and screening process are presented in Figure 1.
The main characteristics of the included studies and populations are summarized in Table 1 and Table 2, and the outcomes data of each included study are shown in Table 3. The seven studies of interest included two RCTs[22,23] and five observational studies (three retrospective studies[16,26,27] and two prospective studies[24,25]) containing a total of 16,634 patients (10,052 patients in the target dose group and 6582 patients in the sub-target dose group). The seven studies[16,22–27] were conducted in the United States, Canada or Europe and published from 1998 to 2022. Across the included studies, the reported mean age ranged from 60–83 years, left ventricular ejection fraction values ranged from 25%–40%, and the follow-up period ranged from 0.5–5 years in length, respectively. Four of the five observational studies[16,24–27] conducted a multivariate analysis to adjust for confounding variables.
| Study | Year | Country/Region | Study design | Method for analysis | Simple size | Outcomes | Estimate effect | Follow-up, mean yrs |
| Lam, et al.[22] | 2017 | Multicenter (United States, Canada, Belgium) | RCT | Cox regression analysis | 1224 | All-cause mortality, cardiac mortality, heart failure hospitalization, and combined endpoint of mortality or heart failure hospitalization | Adjusted HR | 2.7 |
| NETWORK investigators[23] | 1998 | Multicenter (United Kingdom) | RCT | Unadjusted analysis | 1026 | All-cause mortality, heart failure hospitalization, and combined endpoint of mortality or heart failure hospitalization | RR | 0.5 |
| Chen, et al.[16] | 2001 | Multicenter (United States) | RC | Adjusted analysis | 454 | All-cause mortality | Adjusted RR | 1 |
| Ouwerkerk, et al.[24] | 2017 | Multicenter (European) | PC | Cox regression analysis | 1109 | All-cause mortality, and combined endpoint of mortality or heart failure hospitalization | Adjusted HR | 1.75 |
| Sargento, et al.[25] | 2016 | Single center (Portugal) | PC | Unadjusted analysis | 73 | All-cause mortality | RR | 3 |
| Barywani, et al.[26] | 2015 | Multicenter (Sweden) | RC | Kaplan-Meier curve | 136 | All-cause mortality, and cardiac mortality | Adjusted HR | 5 |
| D’Amario, et al.[27] | 2022 | Multicenter (Sweden) | RC | Cox regression analysis | 12,612 | All-cause mortality, cardiac mortality, heart failure hospitalization, and combined endpoint of mortality or heart failure hospitalization | Adjusted HR | 2.06 |
| HR: hazard ratio; PC: prospective cohort; RC: retrospective cohort; RCT: randomized controlled trial; RR: relative risk. | ||||||||
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| Study | Medication | Groups | n | Age, mean yrs | Male, % | NYHA III–IV, % | LVEF, mean % | Diabetes, % | eGFR, mean mL/min per 1.73 m2 | MRA use, % | BB use, % |
| Lam, et al.[22] | Enalapril | 20 mg vs. 10 mg | 696 vs. 528 | 60 vs. 60 | 82 vs. 81 | 31 vs. 36 | 25 vs. 25 | 25 vs. 22 | 65 vs. 65 | 10 vs. 9 | 9 vs. 8 |
| NETWORK investigators[23] | Enalapril | 20 mg vs. 10 mg | 516 vs. 510 | 70 vs. 70 | 66 vs. 62 | 34 vs. 37 | NR | 12 vs. 10 | NR | NR | 11 vs. 10 |
| Chen, et al.[16] | ACEIs | Target dose vs. Sub-target dose | 108 vs. 346 | 76 vs. 78 | 55 vs. 49 | NR | < 40 vs. < 40 | 47 vs. 34 | NR | NR | 20 vs. 11 |
| Ouwerkerk, et al.[24] | ACEIs/ARBs | ≥ 100% GMTD vs. 50%–99% GMTD | 470 vs. 639 | 67 vs. 67 | 77 vs. 74 | NR | 30 vs. 30 | 37 vs. 31 | 71 vs. 70 | NR | NR |
| Sargento, et al.[25] | ACEIs/ARBs | Target dose vs. 50%–99% GMTD | 21 vs. 52 | 77 vs. 77 | 64 vs. 64 | NR | 30 vs. 30 | 26 vs. 26 | 56 vs. 56 | 55 vs. 55 | 80 vs. 80 |
| Barywani, et al.[26] | ACEIs/ARBs | Target dose vs. 50%–99% GMTD | 98 vs. 38 | 83 vs. 83 | 62 vs. 66 | 60 vs. 67 | 32 vs. 34 | 13 vs. 13 | 50 vs. 51 | 12 vs. 13 | 100 vs. 100 |
| D’Amario, et al.[27] | ACEIs/ARBs | ≥ 100% GMTD vs. 50%–99% GMTD | 8143 vs. 4469 | 71 vs. 74 | 77 vs. 74 | 34 vs. 48 | < 40 vs. < 40 | 25 vs. 29 | 67 vs. 57 | 55 vs. 47 | 95 vs. 94 |
| ACEIs: angiotensin-converting enzyme inhibitors; ARBs: angiotensin receptor blockers; BB: beta blocker; eGFR: estimated glomerular filtration rate; GMTD: guideline-recommended target dose; LVEF: left ventricular ejection fraction; MRA: mineralocorticoid receptor antagonists; NR: not reported; NYHA: New York Heart Association. | |||||||||||
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| Study | All-cause mortality | Cardiac mortality | Heart failure hospitalization | Composite endpoint |
| Lam, et al.[22] | Adjusted HR 1.01 (0.82–1.24) | Adjusted HR 1.02 (0.83–1.27) | Adjusted HR 0.99 (0.78–1.25) | Adjusted HR 1.04 (0.87–1.23) |
| NETWORK investigators[23] | RR 0.87 (0.44–1.73) | NR | RR 1.27 (0.79–2.05) | RR 1.12 (0.76–1.64) |
| Chen, et al.[16] | Adjusted RR 0.82 (0.50–1.34) | NR | NR | NR |
| Ouwerkerk, et al.[24] | Adjusted HR 1.20 (0.98–1.61) | NR | NR | Adjusted HR 1.16 (1.00–1.41) |
| Sargento, et al.[25] | RR 1.49 (0.62–3.57) | NR | NR | NR |
| Barywani, et al.[26] | Adjusted HR 0.78 (0.53–1.17) | Adjusted HR 0.67 (0.40–1.11) | NR | NR |
| D’Amario, et al.[27] | Adjusted HR 0.90 (0.84–0.96) | Adjusted HR 0.92 (0.85–1.00) | Adjusted HR 0.93 (0.87–1.00) | Adjusted HR 0.94 (0.88–1.00) |
| HR: hazard ratio; NR: not reported; RR: relative risk. | ||||
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A risk-of-bias assessment on the included studies is presented in Figure 2 and Table 4. One RCT[22] showed a medium risk of bias, the other one was rated as low risk of bias.[23] Meanwhile, the five observational studies[16,24–27] showed a low risk of bias with a total score of > 5 points based on the Newcastle–Ottawa Scale.
| Study | Selection | Comparability | Outcome | Total score | |||||
| Exposed cohort | Nonexposed cohort | Ascertainment of exposure | Outcome of interest | Assessment of outcome | Length of follow-up | Adequacy of follow-up | |||
| Chen, et al.[16] | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | 6 | ||
| Ouwerkerk, et al.[24] | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | 8 |
| Sargento, et al.[25] | ☆ | ☆ | ☆ | ☆ | ☆☆ | ☆ | ☆ | ☆ | 9 |
| Barywani, et al.[26] | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | 6 | ||
| D’Amario, et al.[27] | ☆ | ☆ | ☆ | ☆ | ☆☆ | ☆ | ☆ | ☆ | 9 |
| ☆Refers to one point. Risk of bias was assessed using the Newcastle-Ottawa Scale. A higher overall score corresponds to a lower risk of bias, a score of ≤ 5 (out of 9) indicates a high risk of bias. | |||||||||
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Seven studies[16,22–27] were included in the analysis of the effect of RASIs dose on all-cause mortality (Figure 3). The target dose led to a better survival benefit in patients aged ≥ 60 years with HFrEF compared to the sub-target dose (HR = 0.92, 95% CI: 0.87–0.98, I2 = 21%). No significant heterogeneity was found across the studies (I2 = 21%, P = 0.27). Note that the observed survival benefit may largely rely on data from the subgroup of observational studies (HR = 0.91, 95% CI: 0.86–0.97, I2 = 41%) (Figure 4). Meta-regression of HR across studies revealed no significant association between RASIs doses and the study design, age, diabetes, or sample size (Figure 5).
A pooled analysis suggested that the target dose of RASIs led to a lower rate of cardiac mortality (HR = 0.93, 95% CI: 0.85–1.00, I2 = 15%) (Figure 6) but not of HF hospitalization (HR = 0.94, 95% CI: 0.88–1.01, I2 = 0) (Figure 7) or the composite endpoint (HR = 1.03, 95% CI: 0.91–1.15, I2 = 51%) (Figure 8).
We further conducted a subgroup analysis to interrogate the dose-related effect of RASIs in patients > 75 years of age. The target dose of RASIs was associated with a similar outcome of all-cause mortality (HR = 0.85, 95% CI: 0.64–1.14, I2 = 0) in this very elderly population (Figure 9).
Publication bias was assessed using funnel plots. We found that the funnel plots for all-cause mortality were symmetric, indicating no evidence of publication bias (Figure 10).
The main finding of the present systematic review and meta-analysis was that in elderly patients with HFrEF, the target (versus sub-target) dose of RASIs led to lower rates of all-cause mortality and cardiac mortality, which may reinforce the recommendations of the guideline’s recommendation to up-titrate the RASI dose in elderly patients.[9] However, for HFrEF patients older than 75 years, our results did not support the superiority of the target dose of RASIs.
Target dose of RASIs is usually hard to achieve in elderly patients with HFrEF, due to frailty and complicated comorbidity. Evidences on this special population are debatable. Ouwerkerk, et al.[28] found that the sub-target dose of RASIs was not inferior to the target dose on all-cause mortality rate in patients with HFrEF; however, their study’s relatively small sample size (n = 369) might hamper the statistical power.
Khan, et al.[13] considered 9171 patients from six RCTs and concluded that high-dose (versus low-dose) RASIs decreased the all-cause mortality rate modestly (RR = 0.94, 95% CI: 0.89–1.00, P = 0.05, I2 = 0). It is worth noting that the definition of the low dose in most of the six RCTs was much lower than half dose of the GRTD mentioned in our study. Turgeon, et al.[29] included ten RCTs and reached the opposite conclusion. However, in this study, the results were quantitatively nearly identical (95% CI: 0.89–1.02 vs. 95% CI: 0.89–1.00), so the findings might be overrated.[30] In these two meta-analyses, the dose definition of “high” and “low” was vague and arbitrary to some extent. In our study, we selected the target dose and sub-target dose with clear dose ranges. In addition, the RR was calculated in the meta-analyses. It emphasizes the event counts and the number of patients in each group, but might neglect the fact that the events accumulate over time.[31] We performed HR analysis instead, which is more appropriate when analyzing time-to-event outcomes. Nevertheless, the beneficial tendency of higher dose of RASI on mortality was consistent across studies.
The dosage of RASIs is particularly important in HFrEF patients > 75 years of age, who are not a negligible population in clinical practice despite their under-representation in large RCTs.[32] Some RCTs without a specific age-exclusion criterion failed to recruit sufficient numbers of these very elderly patients.[2,33] Only three observational studies[16,25,26] enrolled in our study met the age criteria, and the results showed the sub-target dose was associated with a similar risk of all-cause mortality in this very elderly population. Since the benefit of RASI was evidenced in the Euro Heart Failure Survey II, the Swedish Heart Failure Registry trial, and other studies, it can be inferred that the optimal dose should be individualized in octogenarian patients with HFrEF.[3,34,35]
Several potential limitations should be taken into consideration. Firstly, only two RCTs and five observational studies were included in this analysis. Observational studies are inclined to have selection bias and confounding by indication. However, four of the five enrolled observational studies were designed using adjusted analysis to reduce the effects of confounders. Secondly, for patients aged > 75 years, we only performed a subgroup analysis due to the paucity of data from relative RCTs concerning these patients. Last but not least, although ARNIs have a similar pharmaceutical effect as RASIs, only a single study compared the outcome differences between target and sub-target doses of ARNIs in the elderly population.[36] Thus, we did not consider ARNIs in our meta-analysis. It should point out the study comparing the efficiency of target and sub-target doses of RASIs and ARNI by D’Amario, et al.[27] was included, because most patients (92.1%) in this study took RASIs.
Our analysis suggests that the target dose of RASIs leads to a better survival benefit in elderly patients with HFrEF compared to the sub-target dose of RASIs. However, the sub-target dose of RASIs is associated with a similar mortality rate in very elderly patients > 75 years of age. Future high-quality and adequately powered RCTs are warranted.
This study was supported by the Key R&D Program of Shandong Province (No.2020ZLYS05). All authors had no conflicts of interest to disclose.
| [1] |
Koudstaal S, Pujades-Rodriguez M, Denaxas S, et al. Prognostic burden of heart failure recorded in primary care, acute hospital admissions, or both: a population-based linked electronic health record cohort study in 2.1 million people. Eur J Heart Fail 2017; 19: 1119−1127. doi: 10.1002/ejhf.709
|
| [2] |
Zachariah D, Taylor J, Rowell N, et al. Drug therapy for heart failure in older patients-what do they want? J Geriatr Cardiol 2015; 12: 165−173. doi: 10.11909/j.issn.1671-5411.2015.02.011
|
| [3] |
Komajda M, Hanon O, Hochadel M, et al. Contemporary management of octogenarians hospitalized for heart failure in Europe: Euro Heart Failure Survey II. Eur Heart J 2009; 30: 478−486. doi: 10.1093/eurheartj/ehn539
|
| [4] |
CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 316: 1429−1435. doi: 10.1056/NEJM198706043162301
|
| [5] |
Yusuf S, Pitt B, Davis CE, et al. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325: 293−302. doi: 10.1056/NEJM199108013250501
|
| [6] |
Maggioni AP, Anand I, Gottlieb SO, et al. Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors. J Am Coll Cardiol 2002; 40: 1414−1421. doi: 10.1016/S0735-1097(02)02304-5
|
| [7] |
Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003; 362: 772−776. doi: 10.1016/S0140-6736(03)14284-5
|
| [8] |
McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371: 993−1004. doi: 10.1056/NEJMoa1409077
|
| [9] |
McDonagh TA, Metra M, Adamo M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021; 42: 3599−3726. doi: 10.1093/eurheartj/ehab368
|
| [10] |
Correction to: 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation 2016; 134: e298.
|
| [11] |
Konstam MA, Neaton JD, Dickstein K, et al. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet 2009; 374: 1840−1848. doi: 10.1016/S0140-6736(09)61913-9
|
| [12] |
Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation 1999; 100: 2312−2318. doi: 10.1161/01.cir.100.23.2312
|
| [13] |
Khan MS, Fonarow GC, Ahmed A, et al. Dose of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers and outcomes in heart failure: a meta-analysis. Circ Heart Fail 2017; 10: e003956. doi: 10.1161/CIRCHEARTFAILURE.117.003956
|
| [14] |
Corrado E, Dattilo G, Coppola G, et al. Low- vs high-dose ARNI effects on clinical status, exercise performance and cardiac function in real-life HFrEF patients. Eur J Clin Pharmacol 2022; 78: 19−25. doi: 10.1007/s00228-021-03210-0
|
| [15] |
Gheorghiade M, Albert NM, Curtis AB, et al. Medication dosing in outpatients with heart failure after implementation of a practice-based performance improvement intervention: findings from IMPROVE HF. Congest Heart Fail 2012; 18: 9−17. doi: 10.1111/j.1751-7133.2011.00250.x
|
| [16] |
Chen YT, Wang Y, Radford MJ, et al. Angiotensin-converting enzyme inhibitor dosages in elderly patients with heart failure. Am Heart J 2001; 141: 410−417. doi: 10.1067/mhj.2001.113227
|
| [17] |
Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6: e1000097. doi: 10.1371/journal.pmed.1000097
|
| [18] |
Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283: 2008−2012. doi: 10.1001/jama.283.15.2008
|
| [19] |
Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011; 343: d5928. doi: 10.1136/bmj.d5928
|
| [20] |
Deeks JJ, Dinnes J, D’Amico R, et al. Evaluating non-randomised intervention studies. Health Technol Assess 2003; 7: iii–x, 1−173. doi: 10.3310/hta7270
|
| [21] |
Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 1998; 17: 2815−2834. doi: 10.1002/(SICI)1097-0258(19981230)17:24<2815::AID-SIM110>3.0.CO;2-8
|
| [22] |
Lam PH, Dooley DJ, Fonarow GC, et al. Similar clinical benefits from below-target and target dose enalapril in patients with heart failure in the SOLVD Treatment trial. Eur J Heart Fail 2018; 20: 359−369. doi: 10.1002/ejhf.937
|
| [23] |
Clinical outcome with enalapril in symptomatic chronic heart failure; a dose comparison. The NETWORK Investigators. Eur Heart J 1998; 19: 481−489. doi: 10.1053/euhj.1997.0839
|
| [24] |
Ouwerkerk W, Voors AA, Anker SD, et al. Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study. Eur Heart J 2017; 38: 1883−1890. doi: 10.1093/eurheartj/ehx026
|
| [25] |
Sargento L, Simões AV, Longo S, et al. Treatment with optimal dose angiotensin-converting enzyme inhibitors/angiotensin receptor blockers has a positive effect on long-term survival in older individuals (aged > 70 years) and octogenarians with systolic heart failure. Drugs Aging 2016; 33: 675−683. doi: 10.1007/s40266-016-0393-y
|
| [26] |
Barywani SB, Ergatoudes C, Schaufelberger M, et al. Does the target dose of neurohormonal blockade matter for outcome in systolic heart failure in octogenarians? Int J Cardiol 2015; 187: 666−672. doi: 10.1016/j.ijcard.2015.03.428
|
| [27] |
D’Amario D, Rodolico D, Rosano GMC, et al. Association between dosing and combination use of medications and outcomes in heart failure with reduced ejection fraction: data from the Swedish Heart Failure Registry. Eur J Heart Fail 2022; 24: 871−884. doi: 10.1002/ejhf.2477
|
| [28] |
Ouwerkerk W, Teng TK, Tromp J, et al. Effects of combined renin-angiotensin-aldosterone system inhibitor and beta-blocker treatment on outcomes in heart failure with reduced ejection fraction: insights from BIOSTAT-CHF and ASIAN-HF registries. Eur J Heart Fail 2020; 22: 1472−1482. doi: 10.1002/ejhf.1869
|
| [29] |
Turgeon RD, Kolber MR, Loewen P, et al. Higher versus lower doses of ACE inhibitors, angiotensin-2 receptor blockers and beta-blockers in heart failure with reduced ejection fraction: systematic review and meta-analysis. PLoS One 2019; 14: e0212907. doi: 10.1371/journal.pone.0212907
|
| [30] |
McCormack J, Vandermeer B, Allan GM. How confidence intervals become confusion intervals. BMC Med Res Methodol 2013; 13: 134. doi: 10.1186/1471-2288-13-134
|
| [31] |
Tierney JF, Stewart LA, Ghersi D, et al. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 2007; 8: 16. doi: 10.1186/1745-6215-8-16
|
| [32] |
Stolfo D, Savarese G. Use of renin-angiotensin-aldosterone system inhibitors in older patients with heart failure and reduced ejection fraction. Card Fail Rev 2019; 5: 70−73. doi: 10.15420/cfr.2019.6.2
|
| [33] |
Masoudi FA, Havranek EP, Wolfe P, et al. Most hospitalized older persons do not meet the enrollment criteria for clinical trials in heart failure. Am Heart J 2003; 146: 250−257. doi: 10.1016/S0002-8703(03)00189-3
|
| [34] |
Flather MD, Yusuf S, Køber L, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet 2000; 355: 1575−1581. doi: 10.1016/s0140-6736(00)02212-1
|
| [35] |
Savarese G, Dahlström U, Vasko P, et al. Association between renin-angiotensin system inhibitor use and mortality/morbidity in elderly patients with heart failure with reduced ejection fraction: a prospective propensity score-matched cohort study. Eur Heart J 2018; 39: 4257−4265. doi: 10.1093/eurheartj/ehy621
|
| [36] |
Kido K, Bianco C, Caccamo M, et al. Evaluating sacubitril/valsartan dose dependence on clinical outcomes in patients with heart failure with reduced ejection fraction. Ann Pharmacother 2021; 55: 1069−1075. doi: 10.1177/1060028020983522
|
Figures(10) / Tables(4)
Supported by: Beijing Renhe Information Technology Co., Ltd. 
| Study | Year | Country/Region | Study design | Method for analysis | Simple size | Outcomes | Estimate effect | Follow-up, mean yrs |
| Lam, et al.[22] | 2017 | Multicenter (United States, Canada, Belgium) | RCT | Cox regression analysis | 1224 | All-cause mortality, cardiac mortality, heart failure hospitalization, and combined endpoint of mortality or heart failure hospitalization | Adjusted HR | 2.7 |
| NETWORK investigators[23] | 1998 | Multicenter (United Kingdom) | RCT | Unadjusted analysis | 1026 | All-cause mortality, heart failure hospitalization, and combined endpoint of mortality or heart failure hospitalization | RR | 0.5 |
| Chen, et al.[16] | 2001 | Multicenter (United States) | RC | Adjusted analysis | 454 | All-cause mortality | Adjusted RR | 1 |
| Ouwerkerk, et al.[24] | 2017 | Multicenter (European) | PC | Cox regression analysis | 1109 | All-cause mortality, and combined endpoint of mortality or heart failure hospitalization | Adjusted HR | 1.75 |
| Sargento, et al.[25] | 2016 | Single center (Portugal) | PC | Unadjusted analysis | 73 | All-cause mortality | RR | 3 |
| Barywani, et al.[26] | 2015 | Multicenter (Sweden) | RC | Kaplan-Meier curve | 136 | All-cause mortality, and cardiac mortality | Adjusted HR | 5 |
| D’Amario, et al.[27] | 2022 | Multicenter (Sweden) | RC | Cox regression analysis | 12,612 | All-cause mortality, cardiac mortality, heart failure hospitalization, and combined endpoint of mortality or heart failure hospitalization | Adjusted HR | 2.06 |
| HR: hazard ratio; PC: prospective cohort; RC: retrospective cohort; RCT: randomized controlled trial; RR: relative risk. | ||||||||
DownLoad:
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| Study | Medication | Groups | n | Age, mean yrs | Male, % | NYHA III–IV, % | LVEF, mean % | Diabetes, % | eGFR, mean mL/min per 1.73 m2 | MRA use, % | BB use, % |
| Lam, et al.[22] | Enalapril | 20 mg vs. 10 mg | 696 vs. 528 | 60 vs. 60 | 82 vs. 81 | 31 vs. 36 | 25 vs. 25 | 25 vs. 22 | 65 vs. 65 | 10 vs. 9 | 9 vs. 8 |
| NETWORK investigators[23] | Enalapril | 20 mg vs. 10 mg | 516 vs. 510 | 70 vs. 70 | 66 vs. 62 | 34 vs. 37 | NR | 12 vs. 10 | NR | NR | 11 vs. 10 |
| Chen, et al.[16] | ACEIs | Target dose vs. Sub-target dose | 108 vs. 346 | 76 vs. 78 | 55 vs. 49 | NR | < 40 vs. < 40 | 47 vs. 34 | NR | NR | 20 vs. 11 |
| Ouwerkerk, et al.[24] | ACEIs/ARBs | ≥ 100% GMTD vs. 50%–99% GMTD | 470 vs. 639 | 67 vs. 67 | 77 vs. 74 | NR | 30 vs. 30 | 37 vs. 31 | 71 vs. 70 | NR | NR |
| Sargento, et al.[25] | ACEIs/ARBs | Target dose vs. 50%–99% GMTD | 21 vs. 52 | 77 vs. 77 | 64 vs. 64 | NR | 30 vs. 30 | 26 vs. 26 | 56 vs. 56 | 55 vs. 55 | 80 vs. 80 |
| Barywani, et al.[26] | ACEIs/ARBs | Target dose vs. 50%–99% GMTD | 98 vs. 38 | 83 vs. 83 | 62 vs. 66 | 60 vs. 67 | 32 vs. 34 | 13 vs. 13 | 50 vs. 51 | 12 vs. 13 | 100 vs. 100 |
| D’Amario, et al.[27] | ACEIs/ARBs | ≥ 100% GMTD vs. 50%–99% GMTD | 8143 vs. 4469 | 71 vs. 74 | 77 vs. 74 | 34 vs. 48 | < 40 vs. < 40 | 25 vs. 29 | 67 vs. 57 | 55 vs. 47 | 95 vs. 94 |
| ACEIs: angiotensin-converting enzyme inhibitors; ARBs: angiotensin receptor blockers; BB: beta blocker; eGFR: estimated glomerular filtration rate; GMTD: guideline-recommended target dose; LVEF: left ventricular ejection fraction; MRA: mineralocorticoid receptor antagonists; NR: not reported; NYHA: New York Heart Association. | |||||||||||
DownLoad:
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| Study | All-cause mortality | Cardiac mortality | Heart failure hospitalization | Composite endpoint |
| Lam, et al.[22] | Adjusted HR 1.01 (0.82–1.24) | Adjusted HR 1.02 (0.83–1.27) | Adjusted HR 0.99 (0.78–1.25) | Adjusted HR 1.04 (0.87–1.23) |
| NETWORK investigators[23] | RR 0.87 (0.44–1.73) | NR | RR 1.27 (0.79–2.05) | RR 1.12 (0.76–1.64) |
| Chen, et al.[16] | Adjusted RR 0.82 (0.50–1.34) | NR | NR | NR |
| Ouwerkerk, et al.[24] | Adjusted HR 1.20 (0.98–1.61) | NR | NR | Adjusted HR 1.16 (1.00–1.41) |
| Sargento, et al.[25] | RR 1.49 (0.62–3.57) | NR | NR | NR |
| Barywani, et al.[26] | Adjusted HR 0.78 (0.53–1.17) | Adjusted HR 0.67 (0.40–1.11) | NR | NR |
| D’Amario, et al.[27] | Adjusted HR 0.90 (0.84–0.96) | Adjusted HR 0.92 (0.85–1.00) | Adjusted HR 0.93 (0.87–1.00) | Adjusted HR 0.94 (0.88–1.00) |
| HR: hazard ratio; NR: not reported; RR: relative risk. | ||||
DownLoad:
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| Study | Selection | Comparability | Outcome | Total score | |||||
| Exposed cohort | Nonexposed cohort | Ascertainment of exposure | Outcome of interest | Assessment of outcome | Length of follow-up | Adequacy of follow-up | |||
| Chen, et al.[16] | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | 6 | ||
| Ouwerkerk, et al.[24] | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | 8 |
| Sargento, et al.[25] | ☆ | ☆ | ☆ | ☆ | ☆☆ | ☆ | ☆ | ☆ | 9 |
| Barywani, et al.[26] | ☆ | ☆ | ☆ | ☆ | ☆ | ☆ | 6 | ||
| D’Amario, et al.[27] | ☆ | ☆ | ☆ | ☆ | ☆☆ | ☆ | ☆ | ☆ | 9 |
| ☆Refers to one point. Risk of bias was assessed using the Newcastle-Ottawa Scale. A higher overall score corresponds to a lower risk of bias, a score of ≤ 5 (out of 9) indicates a high risk of bias. | |||||||||
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