Digoxin use remains a common therapeutic option in the pharmacological control of heart rate in patients with atrial fibrillation, endorsed in current guidelines with the same level of evidence than beta-blockers in patients with and without heart failure. Digoxin has a narrow therapeutic range and is influenced by drug‐to‐drug interactions, serum electrolyte concentrations, and renal function. Conflicting data exist regarding adverse outcomes that are associated with digoxin use in patients with atrial fibrillation. It remains unclear whether the association between digoxin use and worse clinical outcome is causal or may be the result of confounding by differences in the characteristics of patents including age, comorbidities and treatment. Particularly in older patients with atrial fibrillation, who are frequently prescribed a multitude of agents for stroke prevention, treatment of cardiovascular disease and other comorbidities, use of digoxin should be cautious and instituted with assessment of drug concentrations

Egidio Traversi

Maria Teresa La Rovere

Monaldi Archives for Chest Disease

Directory of Open Access Journals

[Monaldi Archives for Chest Disease 2018; 88:954] [page 19]pimeEDITRICE Monaldi Archives for Chest Disease 2018; volume 88:954Prognostic impact of digoxin use for rate control of atrial fibrillation in patients ≥75 years of ageMaria Teresa La Rovere, Egidio TraversiDepartment of Cardiology, Istituti Clinici Scientifici Maugeri, IRCCS Montescano, ItalyAbstractDigoxin use remains a common therapeutic option in the pharma-cological control of heart rate in patients with atrial fibrillation, en-dorsed in current guidelines with the same level of evidence than beta-blockers in patients with and without heart failure. Digoxin has anarrow therapeutic range and is influenced by drug-to-drug interac-tions, serum electrolyte concentrations, and renal function.Conflicting data exist regarding adverse outcomes that are associatedwith digoxin use in patients with atrial fibrillation. It remains unclearwhether the association between digoxin use and worse clinical out-come is causal or may be the result of confounding by differences in thecharacteristics of patents including age, comorbidities and treatment.Particularly in older patients with atrial fibrillation, who are frequentlyprescribed a multitude of agents for stroke prevention, treatment of car-diovascular disease and other comorbidities, use of digoxin should becautious and instituted with assessment of drug concentrations.IntroductionLong-term pharmacological rate control is the preferred managementstrategy for atrial fibrillation (AF), among elderly and comorbid patients.Data from the EORP-AF Pilot (EURObservational Research ProgrammeAtrial Fibrillation), a contemporary ESC Registry including 3119 sub-jects from 9 members ESC Countries, indicate that, at 1-year follow-up,76% of those patients planned for rate control at baseline were con-tinued in a rate control strategy. Besides, a rate control approach wasconsidered in 15.6% of those patients who had been candidates for arhythm control management strategy at baseline [1]. Patients aged ≥75years of age accounted for 45% and 21% of patients assigned to a rate orrhythm control strategy, respectively [2]. Beta-blockers were the mostcommonly used rate agents, followed by digoxin [2].The frequent use of digoxin in patients with AF, particularly in eld-erly patients, is confirmed in the ROCKET AF trial that included over14,000 patients with a mean age of 73 years [3]. Digoxin was pre-scribed in 37% of patients at baseline and 41% of patients were exposedto digoxin during the trial.Indeed, the more recent European Guidelines [4] endorse the use ofdigoxin in AF, giving digoxin the same Class I, Level B indication thanbeta-blockers both in patients with and without heart failure. However,some controversies do exist on its safety. Digoxin has a narrow thera-peutic range and digoxin toxicity is responsible for the third higherhospitalization rate for adverse drug events in elderly patients [5].Whether the safety issue relate to the drug or to the type of patient (i.e.,presence of comorbidities) treated with digoxin is unclear. At variancewith heart failure, in AF there are no RCTs, and the conflicting evi-dence relating digoxin use and mortality is mainly deriving from post-hoc analyses and administrative data.Conflicting evidence on the association of digoxin use and mortalityPost-hoc analysesTwo different post-hoc analysis of the AFFIRM trial yielding oppositeconclusions, provide the emblematic representation of the conflictingevidence regarding digoxin use and mortality in AF [6,7]. In one study,Whitbeck et al. [6] found an association with digoxin use and an in-crease in all-cause mortality [HR 1.41, 95% CI 1.19–1.67, p=0.001]after controlling for clinical and demographic variables, as well aspropensity score. By contrast, Gheorghiade et al. [7] revealed no asso-ciation with digoxin and no increase in all-cause mortality [HR 1.06,95% CI 0.83–1.37, p=0.67] in a propensity-matched analysis. Differ-ences in the statistical methods that have been adopted to analyzedigoxin use can explain the divergent results [8]. In the Whitbeck’s et al. [6] study, digoxin use was assessed at baseline and during follow-up, while in the Gheorghiade’s et al. study [7], digoxin use was as-sessed at a fixed time point only, at the time of the baseline AFFIRMevaluation. With the first method, an indication bias is likely to be in-curred in, as the analysis accounts for changes in digoxin use over timethat might be related to changes in clinical status (i.e. heart failure)that could lead per se to the event (physicians tend to use digoxin insicker patients). Vice versa, the second method can introduce a selec-tion bias as a significant number of patients are excluded if data aremissing at the fixed time point.Finally, a third post-hoc analysis from the same AFFIRM trial evenfound that digoxin use was associated with improved survival in thosepatients with a markedly depressed left ventricular function (<30%) [9].Corresponding author: Maria Teresa La Rovere, Department of Cardiology,Istituti Clinici Scientifici Maugeri, IRCCS Montescano, 27040 Montescano(PV), Italy. Tel. +39.0385.247290 - Fax +39.0385.61386.E-mail: mariateresa.larovere@icsmaugeri.itKey words: Digoxin; atrial fibrillation; rate control; prognosis; age.Received for publication: 24 April 2018Accepted for publication: 11 May 2018©Copyright M.T. La Rovere and E. Traversi, 2018Tipografia PI-ME Editrice, ItalyMonaldi Archives for Chest Disease 2018; 88:954doi: 10.4081/monaldi.2018.954This article is distributed under the terms of the Creative CommonsAttribution Noncommercial License (by-nc 4.0) which permits anynoncommercial use, distribution, and reproduction in any medium,provided the original author(s) and source are credited.Non ommercial use only[page 20] [Monaldi Archives for Chest Disease 2018; 88:954]Original Article pimeEDITRICEIt is critical to note that, in the AFFIRM trial, high serum concentra-tion of digoxin (>1.0 ng/mL) were encouraged to achieve the targetheart rate for rate control. With the lower dosages prescribed in theRACE II (Rate Control Efficacy in Permanent AF: A Comparison be-tween Lenient versus Strict rate Control II) trial, digoxin use was notassociated with an impaired outcome [10]. By contrast, the largestpost-hoc analysis from the ROCKET AF trial [3] showed an increasedrisk of all-cause mortality for digoxin treatment after adjustment forbaseline variables.Registry dataObservational studies and nationwide registries may be of utility forevaluating the association between digoxin and mortality in AF. How-ever, similarly to post-hoc analyses, observational data are also con-flicting in their results. It is worth noting that observational analysesare particularly prone to be confounded by the fact that sicker patientstend to receive digoxin more often and statistical adjustments cannotmitigate completely profound differences in baseline characteristics.The TREAT-AF (The Retrospective Evaluation and Assessment ofTherapies in AF) study [11] evaluated 122,465 patients with newly di-agnosed, non valvular AF and seen within 90 days in the outpatient caresetting of the U.S. Department of Veterans Affairs healthcare system.The mean age was 72.1±10.3 years. Compared with nonrecipients,digoxin recipients were of similar age but had a higher prevalence ofheart failure and receipt of other treatment drugs. Digoxin use was in-dependently associated with mortality after multivariate adjustment[HR: 1.26, 95% CI: 1.23-1.29, p<0.001]. The risk of death was not mod-ified by age, sex, heart failure, kidney function, or concomitant use ofbeta-blockers, amiodarone, or warfarin.The ORBIT-AF (Outcome Registry for Better Informed Treatment ofAtrial Fibrillation), a US prospective outpatient registry specificallyaimed to assess the use of digoxin and its association with outcome,provides a clinically detailed look at the patterns of digoxin use in pa-tients with existing AF [12]. Medication use was collected prospec-tively at each study visit, including a field specific for digoxin. Among9619 patients with AF and serial follow-up every 6 months for up to 3years, 2267 (23.6%) received digoxin at study enrollment, 681 (7.1%)were initiated on digoxin during follow-up, and 6671 (69.4%) werenever prescribed digoxin. Overall 15% of ORBIT-AF patients either ini-tiated or discontinued the drug, suggesting that use was dynamic.Prevalent digoxin use at registry enrollment was not associated withsubsequent onset of symptoms, hospitalization, or mortality (in pa-tients with HF, adjusted HR for death: 1.04; without HF, HR: 1.22). Inci-dent digoxin use during follow-up was not associated with subsequentdeath in patients with HF (propensity adjusted HR: 1.05), but was as-sociated with subsequent death in those without HF (propensity ad-justed HR: 1.99).The ATRIA-CVRN (AnTicoagulation and Risk factors In Atrial fibrilla-tion-Cardiovascular Research Network) Study evaluated the inde-pendent association between newly initiated digoxin and the risk ofdeath and hospitalization in a large, community-based cohort of adultswith newly diagnosed AF and no documented heart failure [13]. In thisanalysis, involving 14,787 age, sex and high-dimensional propensityscore-matched adults (mean age of the whole population 71.7±11.3years) digoxin use was independently associated with a 71% higherrisk of death and a 63% higher risk of hospitalization. Among digoxinuser who did have serum digoxin concentration measured, levels weresignificantly higher among those who died compared with those whodid not die. However, it is worth to underscore that approximately 30%of the digoxin users never had a serum digoxin concentration meas-ured and an additional 27% only had it measured once.Meta-analysesIn an attempt to settle the uncertainty over the association ofdigoxin with adverse outcome, two systematic reviews including allstudies published from 1993 to 2014 [14] and from 1960 to 2014 [15]have been undertaken. Remarkably, also the two meta-analyses weredivergent in their findings. In one [14], based on 19 studies com-prising more than 300,000 patients, digoxin therapy was associatedwith an increased mortality, particularly in those treated for AF andwithout proper serum level control. The second meta-analysis [15], in-cluded 52 observational studies and controlled trials comprising621,845 patients, and showed that digoxin use has a neutral effect onmortality and reduces hospitalizations. These results lend the Authorsto suggest that digoxin should continue to be considered as a treatmentoption to achieve control of heart rate in those with AF and to avoidhospital admissions in patients with heart failure.A very large nationwide population-based study – not included inthe above systematic reviews – investigated the risk of mortality inpatients without rate-control treatments compared with those who re-ceived different rate-control drugs [16]. Patients with combinationsof rate control drugs were excluded. After adjustment for baseline dif-ferences, the risk of mortality was lower in patients receiving β-blockers (adjusted HR=0.76; 95% confidence interval=0.74-0.78)and calcium channel blockers (adjusted HR=0.93; 95% confidence in-terval=0.90-0.96) compared with those who did not receive rate-con-trol medications. On the contrary, the digoxin group had a higher riskof mortality with an adjusted HR of 1.12 (95% confidence in-terval=1.10-1.14).Digoxin and the elderly patient with AFPolypharmacy (defined as the use of 5 or more regular medications)in common in older adults. Older AF patients are frequently prescribeda multitude of agents for stroke prevention, management of the ar-rhythmia, treatment of cardiovascular disease and other comorbidities.In these patients, the prevalence of polypharmacy has been reported upto 94.8% [17]. Although prescribed and over-the-counter medicationsmay improve a wide range of health problems, they also may cause orcontribute to harm, especially in older adults. Digoxin has a complexpharmacokinetic profile, a narrow therapeutic range and multiple druginteractions that may increase the risk of digoxin toxicity. Thus, the as-sessment of patient-specific factors that can influence the dose-effectrelationship such age, liver and renal function, body habitus, comorbidconditions and medications is of utmost importance when prescribingdigoxin in the elderly.Conclusions and clinical implicationsAlthough beta-blockers are the most commonly used rate controlagents in AF, digoxin use remains high in the contemporary treatmentof AF. Guidelines do not assist clinicians in choosing first-line and sub-sequent therapy other than suggesting that the choice of medicationshould be individualized, depending on the presence of ongoing symp-toms. In the ongoing RATE-AF (Rate control Therapy Evaluation in per-manent Atrial Fibrillation) study [18], digoxin and bisoprolol will becompared head-to head as the initial rate control agent in patients withpermanent AF with NYHA class II and above to assess the effect oftherapy on patient-reported quality of life. While the trial will also eval-uate the long-term impact on cardiac function, it will not have thepower to identify differences in clinical events.Non comercial use only[Monaldi Archives for Chest Disease 2018; 88:954] [page 21]Original ArticlepimeEDITRICE6. Whitbeck MG, Charnigo RJ, Khairy P, et al. Increased mortalityamong patients taking digoxin–analysis from the AFFIRM study.Eur Heart J 2013;34:1481-8.7. Gheorghiade M, Fonarow GC, van Veldhuisen DJ, et al. Lack ofevidence of increased mortality among patients with atrialfibrillation taking digoxin: findings from post hoc propensity-matched analysis of the AFFIRM trial. Eur Heart J 2013;34:1489-97.8. Murphy SA. When “digoxin use” is not the same as “digoxin use”:lessons from the AFFIRM trial. Eur Heart J 2013;34:1465-7.9. Patel NJ, Hoosien M, Deshmukh A, et al. Digoxin significantlyimproves all-cause mortality in atrial fibrillation patients withseverely reduced left ventricular systolic function. Int J Cardiol2013;169:e84-6.10. Mulder BA, Van Veldhuisen DJ, Crijns HJ, et al. Digoxin in patientswith permanent atrial fibrillation: data from the RACE II study.Heart Rhythm 2014;11:1543-50.11. Turakhia MP, Santangeli P, Winkelmayer WC, et al. Increasedmortality associated with digoxin in contemporary patients withatrial fibrillation: findings from the TREAT-AF study. J Am CollCardiol 2014;64:660-8.12. Allen LA, Fonarow GC, Simon DN, et al. Digoxin use andsubsequent outcomes among patients in a contemporary atrialfibrillation cohort. J Am Coll Cardiol 2015;65:2691-8.13. Freeman JV, Reynolds K, Fang M, et al. Digoxin and risk of death inadults with atrial fibrillation: the ATRIA-CVRN study. Circ ArrhythmElectrophysiol 2015;8:49-58.14. Vamos M, Erath JW, Hohnloser SH. Digoxin-associated mortality: asystematic review and meta-analysis of the literature. Eur Heart J2015;36:1831-8.15. Ziff OJ, Lane DA, Samra M, et al. Safety and efficacy of digoxin:systematic review and meta-analysis of observational andcontrolled trial data. BMJ 2015;51:h4451.16. Chao TF, Liu CJ, Tuan TC, et al. Rate-control treatment andmortality in atrial fibrillation. Circulation 2015;132:1604-12.17. Wang Y, Singh S, Bajorek B. Old age, high risk medication,polypharmacy: a ‘trilogy’ of risks in older patients with atrialfibrillation. Pharm Pract 2016;14:706.18. Kotecha D, Calvert M, Deeks JJ, et al. A review of rate control inatrial fibrillation, and the rationale and protocol for the RATE-AFtrial. BMJ Open 2017;7:e015099.Whether digoxin is associated with an increased mortality risk re-mains unclear. An argument is made that patients prescribed digoxinare sicker and that is why they have a higher mortality in observationalstudies. Because AF is one of the evolving epidemics in cardiovascularmedicine, assessing the association between digoxin use adverse out-comes is of utmost importance. As an RCT is unlikely to be performed,a pragmatic trial of real-world contemporary digoxin use should be akey priority.Particularly in older patients, the effect of digoxin on outcome may de-pend on the type of patients and the dosage used. Cautious use of low-dose digoxin is suggested in older patients, in patients with renal insuf-ficiency and in patients with concomitant use of other drugs that couldraise digoxin concentrations. Although not commonly performed in com-munity practice, assessment of the digoxin plasma concentration canhelp in dose finding and modulation during the course of the disease.References1. Lip GY, Laroche C, Ioachim PM, et al. Prognosis and treatment ofatrial fibrillation patients by European cardiologists: one yearfollow-up of the EURObservational Research Programme-AtrialFibrillation General Registry Pilot Phase (EORP-AF Pilot registry).Eur Heart J 2014;35:3365-76.2. Purmah Y, Proietti M, Laroche C, et al. Rate vs. rhythm control andadverse outcomes among European patients with atrial fibrillation.Europace 2017 Feb 4. doi: 10.1093/europace/euw421. [Epub aheadof print].3. Washam JB, Stevens SR, Lokhnygina Y, et al. Digoxin use inpatients with atrial fibrillation and adverse cardiovascularoutcomes: a retrospective analysis of the rivaroxaban once dailyoral direct factor Xa inhibition compared with vitamin Kantagonism for prevention of stroke and embolism trial in atrialfibrillation (ROCKET AF). Lancet 2015;385:2363-70.4. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines forthe management of atrial fibrillation developed in collaborationwith EACTS. Europace 2016;18:1609-78.5. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergencyhospitalizations for adverse drug events in older Americans. N EnglJ Med 2011;365:2002-12.Non commercial use only

Prognostic impact of digoxin use for rate control of atrial fibrillation in patients ≥75 years of age

https://www.monaldi-archives.org/index.php/macd/article/download/954/832

Prognostic impact of digoxin use for rate control of atrial fibrillation in patients ≥75 years of age

Abstract

Similar works

Full text

Available Versions

Directory of Open Access Journals