Renal impairment and fluctuations in renal function are common in patients with recent acute decompensated heart failure (ADHF) hospitalization,1,2 and in those with atrial fibrillation (AF).3 However, there have been no studies of the effect of these fluctuations occurring at different time points after hospital discharge on the need for dosage adjustment of nonvitamin K oral anticoagulants (NOACs). The aim of the present study was to evaluate the hypothetical need for dosage adjustment (based exclusively on fluctuations in kidney function) of dabigatran, rivaroxaban and apixaban during the first 6 months after hospital discharge in patients with concomitant AF and ADHF.

The demographic and clinical characteristics of the study population are listed in Table 1. The median CHA2DS2-VASc score was 5 [4-6] and 158 (98%) patients had a CHA2DS2-VASc score ≥ 2. The mean estimated CrCl was 60mL/min ± 27mL/min, and 93 (57%) patients had a CrCl < 60mL/min.

Over the study period, 3 [2-6] serum creatinine measurements per patient were analyzed. The maximum absolute and relative variations of CrCl from the baseline values were 15 [9-25] mL/min and 28% [17%-46%], respectively. A total of 107 patients (66%) had ≥ 20% of variation in estimated CrCl from the baseline values; patients with ≥ 20% CrCl variations had more prevalent hypertension and poorer baseline kidney function (Table 2).

At hospital discharge, the recommended dosages of each NOAC according to baseline estimated CrCl would have been widely variable. As shown in Figure 1, most patients (85.8%) would have continued with a nonadjusted dose for apixaban (5mg twice daily). The proportion of patients who would have required reduced dosages for dabigatran (110mg twice daily) and rivaroxaban (15mg once daily) was significantly higher than for apixaban (2.5mg twice daily): 33%, 43%, and 14%, respectively. The proportion of patients with a contraindication for dabigatran would have been higher than for rivaroxaban and apixaban: 11.0%, 0.6%, and 0.6%, respectively.

Figure 1.

Nonvitamin K oral anticoagulants dosage hypothetically recommended at hospital discharge based exclusively on kidney function estimate. bid, twice daily; qd, once daily.

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During the 6 months following hospital discharge, 72 (44%), 57 (35%), and 47 (29%) would have required at least 1 dosage adjustment for dabigatran, rivaroxaban and apixaban, respectively (Figure 2). As expected, the variations in CrCl from the baseline values were significantly higher among patients who would have required dosage adjustment regardless of NOACs (Table 1 of the supplementary material). Moreover, the proportion of patients who would have required hypothetical NOACs dosage adjustment was higher among older patients (≥ 75 years) and those with CrCl<60mL/min for all 3 NOACs (Table 3). Specifically, among elderly patients, dabigatran showed the highest hypothetical need for dosage adjustment (P=.013 for dabigatran vs rivaroxaban; P=.039 for dabigatran vs apixaban and P=.855 for rivaroxaban vs apixaban), while in younger patients, apixaban showed the lowest (P=.017 for apixaban vs rivaroxaban; P<.001 for apixaban vs dabigatran and P=.219 for dabigatran vs rivaroxaban). In patients with CrCl<60mL/min, dabigatran also showed the highest hypothetical need for dosage adjustment (P=.003 for dabigatran vs rivaroxaban; P=.026 for dabigatran vs apixaban and P=.874 for rivaroxaban vs apixaban), while among patients with normal or mildly depressed renal function (CrCl ≥ 60mL/min), apixaban showed an even lower need for adjustment (3 [4%] for apixaban vs 15 [22%] for dabigatran and rivaroxaban, both P values <.001). Additionally, the percentage of patients that would have needed at least 1 hypothetical dosage adjustment of each NOAC according to CrCl intervals are detailed in Table 2 of the supplementary material.

Figure 2.

Percentage of patients that would have needed at least 1 hypothetical dosage adjustment of each nonvitamin K oral anticoagulant.

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Lastly, among patients with available follow-up INR values (n=108), the average estimated TTR was 48% and two-thirds of them (n=71) had poor TTR control (TTR<60%).

The major findings of this study are as follows. Firstly, fluctuations in renal function are common in the mid.-term after hospitalization for ADHF. Secondly, these changes in renal function should be taken into account for dosage adjustment of NOACs. Thirdly, the need for dosage adjustment was more likely in the elderly and in patients with renal dysfunction at baseline. Fourthly, in younger patients and in those with normal or only mildly depressed renal function, the need for dosage adjustment can vary widely across NOACs, tending to be the lower with apixaban.

The early post-discharge period is sometimes referred to as the “vulnerable phase” when morbidity and mortality is highest and is therefore a critical time-period to closely monitor patients.5,6 Indeed, a strategy of early visits led to better outcomes in a recent analysis of the OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized) and GWTG-HF (Get With The Guidelines-Heart Failure) registries.7 Although few data exist on fluctuations in renal function after hospitalization for ADHF, a subanalysis of the COACH study2 showed that the magnitude of these changes are predominant in the short- and mid-term. In our study, up to two-thirds of patients experienced ≥ 20% variation in CrCl over 6 months, confirming the absence of stable renal function in a significant proportion of patients. This period is influenced by changes in renal perfusion and venous congestion, neurohormonal activation, and inflammation.

Moreover, initiation of adequate therapy may affect renal function in opposite ways. While in some patients it can prevent further worsening of renal function and may eventually improve renal function, in others—and especially in patients with comorbidities and with high diuretic requirements—it can impair renal function. This complex scenario is the “real world” clinical practice scenario as reflected in our baseline clinical demographics.

Heart failure and AF frequently coexist8,9 as they share common risk factors.10,11 The presence of AF in heart failure is associated with increased morbidity, hospitalizations, and poorer functional status.12,13 Moreover, AF in heart failure patients is an independent risk factor for ischemic stroke and thromboembolism14 and has been incorporated in validated risk stratification scores.15,16 Classically, adjusted-dose vitamin K antagonists have been the oral anticoagulants most frequently used in the prevention of thromboembolic events in these patients,17,18 but the effectiveness and safety of these drugs are strongly associated with its stability, reflected by the TTR of the INR.19

Recently studies have shown that AF patients with heart failure tended to present significantly poorer TTR control than those without heart failure.20–22 Given that these patients are less likely to keep within the target INR range with vitamin K antagonists, some authors suggest that NOACs could be an attractive alternative.23 In fact, in large phase III randomized trials of NOACs, heart failure patients were highly represented (ranging from 32.0% to 62.5%), and in subgroup analyses, no statistically significant heterogeneity of treatment efficacy or safety was observed in these patients.24–26 However, all NOACs are partially eliminated by renal clearance and hence require dose adjustment depending on renal function. This is a critical point, as evidence shows that the risk of major bleeding and ischemic stroke may be highly correlated to plasma concentrations of these drugs.27

The 3 currently available NOACs differ in terms of renal elimination. Apixaban is less dependent on renal clearance than the other 2 NOACs, with about 27% of renal excretion compared with 80% for dabigatran and 35% for rivaroxaban.28–30 The different recommendations about dosage adjustment of these drugs based in these features explain our study finding that 44%, 35%, and 29% of patients required at least 1 hypothetical dosage adjustment for dabigatran, rivaroxaban, and apixaban respectively in a real world population of ADHF patients with AF soon after discharge. We found that this is especially true for older patients (age ≥ 75 years) and/or in those with poor renal function (CrCl<60mL/min) who are otherwise at high risk of bleeding and thromboembolic complications, as demonstrated previously.31–35 Therefore, they would need a careful risk-benefit balance, avoiding either over- or underexposure to these drugs. Of the different NOACs, apixaban was theoretically associated with less need for dose adjustments in our population, especially in younger patients (< 75 years) and in those with normal or mildly depressed renal function (CrCl ≥ 60mL/min) at hospital discharge. Nevertheless, it is important to note that renal function is not the only clinical parameter in NOACs dosing adjustment in all patients. Moreover, we recently showed that differences between equations for estimating kidney function and drug dosing are frequent in AF patients.36 Therefore, regardless of renal function, clinicians must always choose the NOACs regimen that optimizes the risk-benefit ratio, given the patient-specific clinical scenario.

Frequent monitoring of renal function is advised in AF patients starting treatment with NOACs. Current European Society of Cardiology guidelines recommend annual assessment of renal function in patients with CrCl ≥ 50mL/min, and 2 to 3 times per year in patients with CrCl from 30mL/min to 50mL/min.37 However, there are no specific recommendations in patients with heart failure or other clinical conditions that coexist in our population. Our results suggest that the recommendation for annual assessment of renal function in these patients could be inadequate. Indeed, renal function testing 2-3 times per year could be safer in patients in this context, or even more frequently in those with renal impairment or in older patients (≥ 75 years).

Fluctuations in renal function and consequently the need for dosage adjustment of NOACs are frequent in the mid-term after ADHF, especially among the elderly or in patients with poor renal function. Further studies are needed to clarify the clinical importance of these needs for dose/drug adjustment and the ideal renal function monitoring regime in heart failure and other subgroups of patients with AF.

V. Roldán has received funding for consultancy and lecturing from Bristol-Myers Squibb, Bayer, and Boehringer Ingelheim. G.Y.H. Lip has received funding for research, consultancy, and lecturing from different manufacturers of drugs used for the treatment of atrial fibrillation, including AstraZeneca, Bayer, Boehringer Ingelheim, Astellas, Sanofi-Aventis, and Daiichi Sankyo.