Tracy E. Macaulay, PharmD, AACC, BCPS-AQ Cardiology

and Tracy E. Macaulay, PharmD, AACC, BCPS-AQ Cardiology

Turakhia MP, Santangeli P, Winkelmayer WC, et al. Increased mortality associated with digoxin in contemporary patients with atrial fibrillation. Findings from the TREAT-AF Study. 

Although digoxin has a very long clinical history, no randomized controlled trial (RCT) has evaluated the use of digoxin for atrial fibrillation (AF). Therefore, the evidence for its use in AF is based on post hoc analyses of RCTs or on findings from observational studies. Several studies have shown the association of digoxin use with increased mortality rates.

 However, other studies have reported the opposite conclusions,

 and it remains controversial whether digoxin use is associated with increased mortality in patients with AF.

Turakhia and colleagues recently published a report in the 

Journal of the American College of Cardiology

 of their evaluation of digoxin use in patients with newly diagnosed, nonvalvular AF and its association with mortality.

 The Retrospective Evaluation and Assessment of Therapies in AF (TREAT-AF), was a retrospective cohort study from the Veterans Affairs (VA) health care system outpatient database between VA fiscal years 2004 and 2008. Key inclusion criteria were a primary or secondary diagnosis of AF by ICD-9 codes 427.31 or 427.32 in a VA inpatient or outpatient encounter, a second confirmatory diagnosis 30 to 365 days after the initial diagnosis, and an outpatient follow-up visit in the clinic 90 days after the initial diagnosis.

Main exclusion criteria included prior AF diagnosis, history of valve diseases, thyroid disease, kidney transplant, or cardiac surgery within the previous 30 days. The primary outcome was time to death, beginning from 90 days after index AF diagnosis. Cox multivariate regression analysis was performed to adjust for the effect of variables in both the full study population and in a propensity-matched cohort.

The full study cohort included 122,465 patients from the VA health care system centralized data sets. The mean age of the patients was 72.1 years, 1.6% were women, and 36.8% had impaired renal function (estimated glomerular filtration rate <60 mL/min/1.73 m

 or on dialysis). Baseline characteristics between digoxin recipients and non-recipients were similar in age and race, but the percentage of patients with heart failure (HF) or who used beta-blockers, angiotensin receptor blockers, antiplatelet therapy, diuretics, and warfarin was significantly higher in the digoxin recipient group. Of note, ejection fraction was not included in the evaluation. The propensity-matched cohort demonstrated comparable baseline characteristics between digoxin recipients and nonrecipient groups (n = 26,703 in each group), with no statistically significant differences in characteristics.

Digoxin use was associated with an increased mortality rate in the unadjusted full cohort ( HR, 1.37; 95% CI, 1.33-1.40; 

<.001). The association persisted but the degree of this association was attenuated in multivariate Cox regression analysis (HR, 1.26; 95% CI, 1.23-1.29; 

<.001) and after propensity matching (HR, 1.21; 95% CI, 1.17-1.25; 

<.001). The association was consistent across subgroups based on drug adherence, clinical comorbidities, concomitant therapy, and kidney function. The risk may be increased in patients with prior myocardial infarction (MI) based on subgroup analysis in both the full cohort (HR, 1.49; 95% CI, 1.34-1.67; 

 value for interaction, .002) and the propensity-matched cohort (HR, 1.45; 95% CI, 1.26-1.66; 

Currently, few other studies have evaluated the effect of digoxin use on mortality rate in AF. One of the published prospective studies is the Stockholm cohort study, with 2824 patients followed for approximately 4.6 years prospectively.

 Propensity score matching and Cox multivariate regression analysis were utilized. Investigators found that digoxin use was associated with increased mortality (HR, 1.94; 95% CI, 1.71-2.20; 

<.001), but the association was no longer observed after adjusting for baseline differences (HR, 1.05; 95% CI, 0.92-1.20).

Two post-hoc analyzes of the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial have evaluated the relationship between digoxin therapy and mortality in patients with AF, with different outcomes.

 The first group assessed the association between digoxin and mortality using multivariate Cox proportional hazards models.

 They found that digoxin was associated with the increased all-cause mortality rate (HR, 1.35; 95% CI, 1.06-1.71; 

= .016). Remarkably, it also showed that there was no significant digoxin-gender interaction for all-cause mortality, and interactions existed regardless of HF status. The second group employed a different trial design to the same AFFIRM cohort, using propensity score matching, and found no negative association between digoxin use and mortality (HR, 1.06; 95% CI, 0.83-1.37; 

 Conflicting findings in these evaluations still offer little resolution to the safety of digoxin use in patients with AF.

This large retrospective cohort study has remarkable strengths. First, the database-based cohort study included the largest AF cohort, which allows this study to conduct more robust subgroup analysis based on age, drug adherence, kidney function, past medical histories of MI or HF, or concomitant therapy with warfarin, beta-blockers, and amiodarone, without any concern for type 2 error. Also, multivariate logistic analysis was conducted in the propensity-matched cohort because of the large sample size. Second, the VA database in the TREAT-AF trial may be more representative of current US practice than the other data sources were, and may be more applicable to current medicine practice. For example, the AFFIRM trial

 was published in 2002 and the TREAT-AF trial collected data from 2003 to 2008. The outcomes of earlier studies could have been affected by not being able to use more contemporary treatments for HF, CAD, and stroke prevention, thus resulting in lower external validity.

Several limitations do exist. The most notable is that the TREAT-AF study is not randomized, merely observational. Therefore, findings from this study need to be applied with caution. Also, some other features of this study design limit generalizability. First, this cohort mainly included male veterans, which makes it difficult to apply findings to women. The Digitalis Investigation Group trial showed the effect of sex on mortality in patients with HF, but the relationship between digoxin use and outcomes was more significant in the subgroup of women.

 In addition, the cohort only included newly diagnosed AF patients; the AFFIRM trial population was more elderly, asymptomatic, or marginally symptomatic. More important, this cohort study was not able to include assessments of New York Heart Association functional class or measures of left ventricular ejection fraction, whereas differences in these variables could have affected the results. However, the AFFIRM trial post-hoc study by Whitbeck et al

 showed that digoxin use was associated with a significantly increased mortality in AF patients regardless of the presence or absence of HF.

It remains a matter of controversy whether patients maintained on digoxin should be stopped completely based only on study results from this observational study. However, at the least, the use of digoxin should be strictly evaluated and its initiation selected with care in AF patients. Until further evaluation, digoxin should be reserved for patients who have symptomatic hypotension and/or HF with reduced ejection fraction when other rate-control agents cannot be safely initiated.

1. Hallberg P, Lindback J, Lindahl B, et al. Digoxin and mortality in atrial fibrillation: a prospective cohort study. 

2. Friberg L, Hammar N, Rosenqvist M. Digoxin in atrial fibrillation: report from the Stockholm cohort study of atrial fibrillation (SCAF). 

3. Whitbeck MG, Charnigo RJ, Khairy P. et al. Increased mortality among patients taking digoxin—analysis from AFFIRM study. 

4. Gheorghiade M, Fonarow GC, van Veldhuisen DJ, et al. Lack of evidence of increased mortality among patients with atrial fibrillation taking digoxin: findings from post-hoc propensity-matched analysis of the AFFIRM trial. 

5. Turakhia MP, Santangeli P, Winkelmayer WC, et al. Increased mortality associated with digoxin in contemporary patients with atrial fibrillation. 

6. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation

7. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. 

Kazuhiko Kido, PharmD, is a PGY2 cardiology pharmacy resident at the University of Kentucky HealthCare, Lexington, Kentucky. He was assisted in the writing of this article by Tracy E. Macaulay, PharmD, AACC, BCPS-AQ Cardiology, clinical pharmacy specialist-cardiology, PGY2 residency program director-cardiology, and adjunct assistant professor at University of Kentucky HealthCare in the Department of Pharmacy Services and Division of Cardiovascular Medicine, Lexington, Kentucky.

Articles

Although digoxin has a very long clinical history, no randomized controlled trial has evaluated the use of digoxin for atrial fibrillation (AF). Therefore, the evidence for its use in AF is based on post hoc analyses of RCTs or on findings from observational studies. Several studies have shown the association of digoxin use with increased mortality rates. However, other studies have reported the opposite conclusions, and it remains controversial whether digoxin use is associated with increased mortality in patients with AF. 

Increased Mortality Associated with Digoxin in AF Patients

Tracy E. Macaulay, PharmD, AACC , BCPS (AQ Cardiology)

Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. 

Pulmonary arterial hypertension (PAH) is characterized by chronically increased pulmonary arterial pressure and is associated with a 3- to 5-year survival rate ranging from 50% to 80%, depending on underlying etiology. The mean age of diagnosed patients is 50 years, and women are affected more commonly than men.

 Pharmacologic options are limited and treatments for severely symptomatic disease are very complex. Additional pharmacologic alternatives that decrease progression of disease and delay requirement of IV or subcutaneous treatment modalities are needed.

The pathophysiology of idiopathic PAH involves a defect in the ability of the pulmonary vasculature to appropriately dilate in response to increased pressure and vascular shear forces secondary to the flow of blood. Current FDA-approved drug therapies promote vasodilation. In properly functioning vessels, increased blood flow forces open calcium channels in the endothelium, thus leading to a calcium- dependent activation of endothelial nitric oxide (NO) synthase (eNOS), which causes a release of NO. NO diffuses in the vascular smooth muscle and activates soluble guanylate cyclase (sGC), which increases the production of cGMP, subsequently leading to smooth muscle relaxation.

Current therapy options include calcium channel blockers, phosphodiesterase-5 inhibitors, endothelin antagonists, and prostacyclin analogues. Prostacyclin treatments are administered as continuous parenteral infusions or may be inhaled or delivered subcutaneously. Stability issues and pharmacokinetic properties of these medications make for complicated, error-prone dosing schemes; health literacy and patient accountability are also issues when prescribing prostacyclin analogues. Therefore, development of safe and efficacious oral agents that can postpone the need for parenteral/inhaled therapy is of great value to the PAH community.

The Pulmonary Arterial Hypertension Soluble Guanylate Cyclase- Stimulator trial-1 (PATENT-1) was a randomized, double blind, placebo- controlled trial comparing riociguat, a novel guanylate cyclase stimulator agent, with placebo in patients with symptomatic PAH.

 PATENT-1 was supported by Bayer Healthcare.

Patients were included in the study if they had a pulmonary vascular resistance >300 dynâˆ™secâˆ™cm

, a mean pulmonary-artery pressure of at least 25 mm Hg, and a 6-minute walk distance of at least 150 m to 450 m. Patients were either treatment naïve or receiving concomitant therapy with endothelin-receptor antagonists or prostanoids (excluding IV) at stable doses for at least 90 days. Diuretics and anticoagulants were permitted, although patients receiving phosophodiesterase-5 inhibitors were excluded. A total of 443 patients were enrolled from December 2008 to February 2012. The primary end point was change from baseline in 6-minute walk distance after 12 weeks of therapy.

Patients were randomized in a 2:4:1 ratio to receive placebo, highdose riociguat (up to 2.5 mg 3 times/d), or low-dose riociguat (up to 1.5 mg 3 times/d), with a starting dose of riociguat in both groups of 1 mg 3 times/d, titrated as systolic blood pressure would allow. End points of the low-dose group were considered exploratory, and results were not included in the analysis. In the higher-dose riociguat group, 75% achieved the maximum total daily dose of 7.5 mg, while 3% received dose reductions and were taking only 0.5 mg 3 times/d.

The groups were well matched at baseline. The majority of patients were WHO functional class II and III, and most had idiopathic PAH. At baseline, both the placebo and treatment groups had pulmonary capillary wedge pressure of ~9 mm Hg, evidence that neither group had hemodynamically significant left ventricular systolic dysfunction. Roughly 44% of patients were also receiving an endothelin-receptor antagonist, while only 6% were on a prostacyclin analogue. The average 6-minute walk distance was 363 (± 69) m.

In the modified intention-to-treat population, the high-dose riociguat group was found to be statistically superior to placebo for the primary efficacy outcome of 6-minute walk distance. In the riociguat group, the distance was increased by 30 m; in the placebo group, the distance had decreased by 6 m (

 <0.001). The secondary end points of pulmonary-artery pressure, cardiac output, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, WHO functional class, and Borg dyspnea scale scores were also improved with riociguat therapy as compared with placebo (all 

 values <0.003). Patients in the riociguat group also showed significantly lower incidence of events indicating clinical worsening. Exploratory end points including EuroQol Group 5-Dimension Self-Report Questionnaire (EQ-5D) score and Living with Pulmonary Hypertension Questionnaires (LPH) were nominally different between treatment and control.

Safety outcomes were reported descriptively and did not include P values. In the high-dose riociguat group 3% of patients discontinued riociguat because of adverse events, while 7% in the placebo group discontinued. The most common adverse effect was headache (27% in the riociguat group vs 20% in placebo), and the most frequently occurring serious adverse effect was hypotension (1% in the riociguat group vs 4% in placebo).

Riociguat is a new agent with a unique mechanism of action. A member of the soluble guanylate stimulator class, riociguat increases sensitivity to low levels of NO to stimulate guanylate cyclase. Additionally, riociguat directly stimulates sGC in order to promote vasodilation in the pulmonary artery.

 The drug’s mechanism of action offers a new approach to modifying the pathophysiology of PAH, and if FDA approved will expand the armamentarium of therapies for the treatment of this disease.

Phosphodiesterase-5 inhibitors are another class of PAH medications with mechanisms acting on the NO signaling pathway.

 Sildenafil and tadalafil are FDA approved for treatment of PAH; both agents inhibit the breakdown of cGMP through the inhibition of phosphodiesterase-5, implying a dependence on the presence of NO to stimulate the pathway. This reliance on the intact NO-sGCcGMP axis may explain why some patients are not responsive to treatment with agents such as sildenafil. Riociguat bypasses NO by increasing sensitivity to low levels and directly stimulating sGC, suggesting it may have a role for patients not responsive to PDE-5 agents.

The Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) trial compared multiple doses of sildenafil with placebo (n = 256). The patient population and end points studied in this trial were similar to PATENT-1, including exercise capacity (6-minute walk distance), pulmonary pressure, Borg dyspnea score, and time to progression of disease. However, no concomitant medications intended for the treatment of PAH were permitted in the study. SUPER patients in the sildenafil group had a statistically significant improvement in 6-minute walk distance and in hemodynamics.

 However, unlike the results in PATENT-1, sildenafil did not show improvement in the Borg dyspnea score, nor did it prove to have a statistically significant impact on time to clinical worsening or incidence of clinical worsening. Comparison may be made with the ~50% of patients (n = 66) in PATENT-1 who were on riociguat monotherapy, in whom riociguat was able to demonstrate added benefit to the primary end point of 6-minute walk distance with a least squares mean improvement of 38 m (95% confidence interval [CI]; 16-60).

Combination tadalafil and stable-dose bosentan was allowed in the Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) trial, and this combination was present in 53% of patients. In PHIRST, patients with baseline bosentan therapy did not have a statistically significant improvement in the primary end point of 6-minute walk distance (change of 24 m; 

 In PATENT-1, improvement was shown in both treatment-naïve and pretreated groups with a least squares mean improvement in the concomitant endothelin receptor antagonist group of 24 m (95% CI; 1-48) and in the concomitant prostanoid group of 106 m (95% CI; 38-173). Most of the statistical improvement in the pretreated group was driven by improvements in the prostanoid group; nevertheless, this suggests that riociguat may have a greater role as additive therapy compared with PDE-5 inhibitors.

 Progression of PAH ultimately requires utilization of prostacyclin therapy; thus, increasing the time and/or trajectory of decline is likely an important end point and may highlight an advantage of riociguat over PDE-5 inhibitors, although direct comparison with sildenafil and randomized trials to evaluate combination therapy is warranted.

Regarding safety, riociguat had an extremely low incidence of severe adverse reactions, with hypotension being the most common. In PATENT-1, however, there were few cases of serious hypotension (none were symptomatic) and these were not significant relative to placebo. Another potential disadvantage of riociguat is the requirement of frequent dosing; therefore, barriers to adherence are to be expected.

 This regimen is still far simpler than those of prostacyclin analogues and similar to sildenafil. The other oral agent alternative, endothelin antagonists, may be dosed once daily; however, the toxicity profile (including teratogenicity) of these agents supports the first-line use of sildenafil or potentially riociguat.

The primary end point of 6-minute walk distance has proposed prognostic significance in patients with PAH, and has been used as the primary end point for studies in the approval of at least 7 drugs for PAH. However, the use of 6-minute walk distance has been challenged by some as a surrogate end point in PAH drug studies. Gabler et al

 conducted a validation study of the 6-minute walk distance for PAH and concluded that this end point explains only a small portion of treatment effect, and may not be sufficient as a lone primary end point. Therefore, there is no conclusive information regarding the clinical relevance or mortality benefit associated with these oral medications, and further analysis that provides more information regarding end points such as mortality is warranted.

In conclusion, riociguat serves as a reasonable first-line alternative to PDE-5 inhibitors for PAH WHO functional class II or III, or in combination therapy with an endothelin antagonist or inhaled prostacyclin analogues. There are several advantages of this medication over sildenafil, including utility in PDE-5 refractory patients because of the NO bypassing mechanisms. PATENT-1 was also able to show statistically significant improvement in secondary end points such as clinical worsening and Borg dyspnea score, end points in which sildenafil failed to demonstrate a difference when compared with placebo. PATENT-1 was not designed to show the impact of riociguat on mortality outcomes, so conclusions about long-term outcomes associated with this medication cannot be made at this time. However, PATENT-2, an extension study of PATENT-1, seeks to provide information regarding longer-term outcomes of patients on riociguat therapy.

1. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry.

2. Giles TD, Sander GE, Nossaman BD, Kadowitz PJ. Impaired vasodilation in the pathogenesis of hypertension: focus on nitric oxide, endothelial- derived hyperpolarizing factors, and prostaglandins. 

3. Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. 

4. Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. 

5. Galie N, Brundage BH, Gofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. 

6. Pullar T, Birtwell AJ, Wiles PG, Hay A, Feely MP. Use of a pharmacologic indicator to compare compliance with tablets prescribed to be taken once, twice, or three times daily. 

7. Grimminger F, Weimann G, Frey R, et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. 

8. Gabler NB, French B, Strom BL, et al. Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. 

Mary Blanton Wheeler, PharmD, MPH, is a Cardiology Pharmacy Specialty Resident at University of Kentucky HealthCare Pharmacy Services and Jack and Linda Gill Heart Institute in Lexington, KY. She was assisted in the writing of this article by Tracy E. Macaulay, PharmD, AA CC, BCPS-AQ Cardiology, Clinical Pharmacy Specialist- Cardiology, PGY2 Residency Program Director-Cardiology, and Adjunct Assistant Professor at University of Kentucky HealthCare in the Department of Pharmacy Services and Division of Cardiovascular Medicine, Lexington, KY.

In pulmonary arterial hypertension patients, riociguat serves as a reasonable first-line alternative to PDE-5 inhibitors or in combination therapy with an endothelin antagonist or inhaled prostacyclin analogues. 

Tracy E. Macaulay, PharmD, AACC, BCPS-AQ Cardiology

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