Intern Emerg Med DOI 10.1007/s11739-015-1236-2

IM - ORIGINAL

To treat or not to treat very elderly naı¨ve patients with atrial fibrillation with vitamin K antagonists (VKA): results from the VENPAF cohort Serena Granziera1 • Giulia Bertozzo1 • Vittorio Pengo2 • Lucia Marigo1 • Gentian Denas2 • Florinda Petruzzellis1 • Katia Rossi1 • Tiziana Infante1 • Seena Jose Padayattil2 • Egle Perissinotto3 • Enzo Manzato1 • Giovanni Nante1

Received: 16 January 2015 / Accepted: 27 March 2015 Ó SIMI 2015

Abstract Despite the recommendations in the guidelines, physicians still underuse warfarin in very elderly patients with non-valvular atrial fibrillation (NVAF). The risks of stroke and major bleeding both increase with age, but it is still not clear whether the beneficial effects of vitamin K antagonists (VKA) in preventing stroke outweigh the related bleeding risks in fragile, very elderly patients. The bleeding rates reported in real-world observational studies differ considerably. The aim of this study was to retrospectively assess the incidence of major bleeding in VKAnaı¨ve patients over 80 years old with NVAF at a large anticoagulation clinic. Significant predictors of major bleeding were also investigated. Sixty-five major bleeding events (3.4 per 100 patient-years) and 25 thromboembolic events (1.3 per 100 patient-years) were recorded in a sample of 798 patients with a median follow-up of 2.2 years. Patients over 85 years old had significantly more major bleeding events than the 80- to 84-year olds (4.7 vs. 2.6 per 100 patient-years, p 0.014). Spontaneous bleeding was also significantly more common (3.0 vs. 1.3 per 100 patient-years, p 0.008) in the very elderly group. Age and diabetes were the only independent risk factor for bleeding on multivariate Cox analysis (Age HR 1.80, 95 % CI 1.10–2.93; diabetes HR 1.76, 95 % CI 1.00–3.09). These

& Serena Granziera [email protected] 1

Department of Medicine-DIMED, University of Padua, Padua, Italy

2

Clinical Cardiology, Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy

3

Biostatistics, Epidemiology and Public Health Unit, Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy

data show a sharp increase in major bleeding episodes among the very elderly with atrial fibrillation. Further studies are warranted with a view to identifying patients at risk. Keywords Atrial fibrillation
Elderly
Oral anticoagulant treatment
Major bleeding
Net clinical benefit

Introduction Atrial fibrillation (AF) is the most common serious dysrhythmia, with a high incidence and prevalence in the elderly that reaches 18 % in those aged 85 or more [1, 2]. This condition is associated with a fivefold increase in the risk of stroke, especially when associated with other risk factors such as hypertension, diabetes, and cardiovascular disease [1]. ‘‘Upstream therapies’’ have not been very successful in slowing the progression of this condition, so attention has turned towards stroke prevention. Oral anticoagulant therapy (OAT) remains the mainstay of stroke prevention in AF. Vitamin K antagonists (VKA) dominated the anticoagulation scenario until recently, when a new class of drugs emerged. Despite the proven efficacy of anticoagulants in thromboembolic prevention, and the perceived advances achievable with the latest drugs, bleeding risk remains the Achilles tendon of anticoagulation therapy. In addition, the risk of bleeding is known to increase with age, and elderly VKA users tend to bleed more than younger patients [3–5]. This has led to controversies over the use of oral anticoagulants in the elderly [6, 7]. Current guidelines include age as a risk factor for both stroke and bleeding, and do not provide definitive recommendations on oral anticoagulant management in the

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elderly [8, 9]. These patients are also underrepresented in clinical trials, so the net clinical benefit in this subgroup is difficult to ascertain. Under these circumstances, VKA are reportedly still being underused in the elderly [10–12]. There is ongoing debate and contradictory evidence concerning whether older age exposes patients to a higher bleeding risk even with high-quality anticoagulation [3, 13–15]. The incidence of bleeding is influenced by the quality of anticoagulant management, in terms of the time in the therapeutic range (TTR), but data on the elderly population are inconsistent. To contribute to the debate on whether age is an independent risk factor for bleeding in elderly patients with non-valvular atrial fibrillation (NVAF) treated with VKA (warfarin), we performed a single-centre, inception cohort retrospective follow-up study. [13] All patients were naı¨ve to VKA therapy, and were followed up at a high-quality anticoagulation centre.

Materials and methods Study population and risk definition For this retrospective study, we screened 4563 patients referred to the Anticoagulation Centre at Padua University Hospital from January 2007 to January 2012. All patients C80 years old with NVAF (INR range 2–3) were considered for inclusion in the study. They were excluded if they were already on VKA therapy at the baseline, or had been in the previous 2 years, or if they suspended VKA within a month of starting the treatment, unless a bleeding event occurred earlier. Of the 2757 patients with NVAF being followed up at our centre during the 5-year period considered, 891 were at least 80 years old; 93 of these patients did not meet our inclusion criteria (40 were not anticoagulant-naı¨ve, 52 had been followed up for \1 month, and data were lacking for 1), so the final VENPAF cohort consisted of 798 patients. Patients’ demographics and clinical baseline information were collected for analysis from the electronic records held at the Padua University Hospital and the Anticoagulation Clinic, or by means of telephone calls to family physicians. Comorbidities like hypertension, diabetes mellitus, and heart disease were defined according to the corresponding guidelines [16–19]. The thromboembolic risk profile was calculated using the CHADS2 score [20]. The quality of anticoagulation was calculated as the time in the therapeutic range (TTR) from starting the treatment to the end of the follow-up, using the linear interpolation method devised by Rosendaal et al. [21]. The resulting TTR included all INR data available during the observation period, including when the therapy

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was started, and any temporary suspensions for invasive procedures requiring heparin bridging. Outcomes and follow-up The primary outcome of the study was the incidence of bleeding according to the ISCOAT study and the ISTH criteria [3, 22] Secondary outcomes were the incidence of thromboembolic events and deaths. Major bleeding was defined as fatal bleeding, bleeding at critical sites (intracranial, retroperitoneal, intra-ocular, joint haemorrhage, pericardial, intraspinal, intramuscular with compartment syndrome), a drop in haemoglobin level of 20 g/L or requiring the transfusion of 2 or more units of packed red blood cells/whole blood, or surgery or angiographic procedures to stop bleeding. All bleeding episodes not fulfilling the criteria for major bleeding were defined as minor bleeding. Any causes related to the event such as accidental falls or invasive interventions were also investigated. Thromboembolic events were defined as ischemic stroke characterised by sudden neurological deficit in the absence of cerebral haemorrhage on neuroimaging, peripheral or visceral embolism characterised by the occurrence of acute ischemia documented by angiography or surgery in the absence of atherosclerotic occlusive disease. The event-related INR for both bleeding and thromboembolic events was defined as the INR at the time of the event, or the latest known INR within 2 days. The causes of death recorded in the medical reports were analysed and classified as being secondary to a haemorrhagic event, an ischemic event, or other causes. To reduce biases due to the retrospective nature of the study, all data were collected and processed by the same team of investigators, who crosschecked the Padua University Hospital and Anticoagulation Clinic electronic databases. Any doubts were clarified by contacting the family physician by telephone. Patients fulfilling the inclusion criteria were followed up from when they started taking VKA until a primary outcome event occurred, their anticoagulant therapy was suspended, the patient died, or the study period came to an end, whichever came first. Nested case–control sub-analysis We further refined our patients’ assessment by conducting a nested case–control study analysis on their bleeding risk using the HAS-BLED score. This analysis included the sample of 65 cohort members with incident major haemorrhage during the follow-up and 65 control patients matched by age and gender. To ensure consistency, hepatic and renal functions were defined according to the original work form Pisters et al. [23] Abnormal kidney function was

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defined in the presence of chronic dialysis, renal transplantation, or serum creatinine C 200 lmol/L. Abnormal liver function was defined as chronic hepatic disease (e.g., cirrhosis) or biochemical evidence of significant hepatic derangement (e.g., bilirubin [ 2 9 upper limit of normal, in association with aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase [ 3 9 upper limit normal, etc). Statistical analysis The dataset was analysed for the sample as a whole and for patients stratified by age group (80–84 vs. C85 years). Qualitative data were reported as counts and percentages. For quantitative variables, we recorded the median, range and mean ± standard deviation. Proportions were compared with the Chi-square test or Fisher’s test, as appropriate. The statistical significance of differences between median values in younger and older patients was tested using Wilcoxon’s rank sum test. To establish the incidence rate of major/fatal/site-specific bleeding episodes, the number of cases was computed, and the length of the follow-up was calculated as the difference between date of the event and the date of starting VKA therapy. For patients lost to follow-up or censored, the length of the follow-up was calculated as the difference between the date of their last visit or data collection and the date of starting VKA therapy. The probability of major bleeding events over time was modelled using the Kaplan– Meier survival method, while the statistical significance of the association between covariates was tested with Cox’s simple and multivariate stepwise regression. The results are expressed as hazard ratios and 95 % confidence intervals (CI). In the regression models, age and TTR were entered as a dichotomous variable (80–84 vs. C85 years; TTR C 60 % vs. TTR \ 60 %), while CHADS2 scores were treated as categorical data. For each test, the threshold for statistical significance level was set at 0.05.

Major bleeding The 798 patients considered were followed up for a median 2.2 years (IQR 1.2–3.5 years) for a total observation time of 1912 years. Among those, 15 % (120) died, 18.5 % (148) suspended VKA before the end of the follow-up and 6.6 % (53) were monitored elsewhere (e.g. by their general practitioners or at other anticoagulation centres). There were 65 major bleeding events (3.4 per 100 patient-years) during the follow-up (Table 2). Sixteen (24.6 %) were fatal, 38 (58.5 %) needed hospitalisation or blood transfusions, 6 (9.2 %) needed surgery or invasive intervention to stop the bleeding, and 5 (7.7 %) were treated in an outpatient setting. It is noteworthy that 29 major bleeding episodes were intracranial (1.5 per 100 patient-years), and 18 (0.9 per 100 patient-years) involved the gastrointestinal tract. Most of the major bleeding events recorded were spontaneous (58.5 %), while 29.2 % were post-traumatic, and this information was not available for 12.3 %. Patients experiencing major bleeding episodes were a mean 84.8 (±2.7) years old. As shown in Table 2, patients over 85 years old had significantly more events than the 80- to 84-year olds (4.7 vs. 2.6 per 100 patient-years, p 0.01). The older patients also had a higher rate of gastrointestinal bleeding, and significantly more spontaneous bleeding episodes (3.0 vs. 1.3 per 100 patient-years, p 0.008). The Kaplan–Meier survival curves very soon diverge significantly, as shown in Fig. 1 (HR 1.8, 95 % CI 1.1–3.0, p = 0.014). At 3 months, the overall major bleeding rate was 3.1 per 100 patient-years, 1.76 per 100 patient-years for patients \85 years old and 5 per 100 patient-years for older patients. Conversely, the intracranial bleeding rate did not differ statistically between the two age groups. Cox’s multivariate regression analysis (Table 3) identified older age (HR 1.80 95 % CI 1.10–2.93, p = 0.02) and diabetes mellitus (HR 1.76 95 % CI 1.00–3.09, p = 0.05) as the only independent risk factors for bleeding in our cohort, after adjusting for other covariates, including the quality of anticoagulation (TTR).

Results Nested case–control analysis of the bleeding risk Patients’ clinical characteristics Baseline patient demographics are shown in Table 1, for the whole sample and by age group. The VENPAF sample included 485 females (60.8 %) and the mean age was 84.4 (±3.3) years. Among the oldest patients, the prevalence of female gender and the heart failure rate were significantly higher (p = 0.007 and p = 0.002, respectively) and so was the CHADS2 score (2.72 vs. 2.51, p = 0.003).

From the nested case–control analysis of the bleeding risk, we found a higher HAS-BLED score among patients who experienced a major bleeding event, with higher prevalence of hypertension and previous bleeding, although the prevalence of labile INR, aspirin or non-steroidal anti inflammatory drugs (NSAID) use and alcohol abuse was higher in the control group (Table 4). The mean HASBLED score for the 65 patients who bled was 2.86 (±1.0).

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Intern Emerg Med Table 1 Baseline characteristics of patients with non-valvular atrial fibrillation, stratified by age group Characteristics

All patients (n = 798)

80- to 84-year olds (n = 463)

C85-year olds (n = 335)

84 (80–99)

82 (80–84)

87 (85–99)

60.8 (485)

56.8 (263)

66.3 (222)

p value

Age Median (range), years Female % (n)

0.007

Follow-up Median (range), years

2.2 (0.01–6.00)

2.5 (0.01–6.00)

1.8 (0.01–5.94)

Mean ± SD (years)

2.4 ± 1.6

2.6 ± 1.5

2.2 ± 1.6

63 (7–100)

64 (8–97)

62 (7–100)

61.9 ± 15.1

62.5 ± 14.7

61.1 ± 15.6

\0.001

Time in the therapeutic range % Median (range) Mean ± SD

a

CHADS2 score Median (range) Mean ± SD

0.19

2 (1–6)

2 (1–6)

2 (1–6)

2.60 ± 1.04

2.51 ± 1.05

2.72 ± 1.02

0.003

29.1 (231)

24.8 (114)

35.1 (117)

0.002

82.6 (657)

80.7 (372)

85.3 (285)

0.11

17.9 (142)

16.5 (76)

19.8 (66)

0.26

15.5 (123)

15.2 (70)

15.9 (53)

0.84

Heart failure % (n) Hypertension % (n) Diabetes mellitus % (n) Prior stroke % (n) a

The TTR includes all INR data available during the observation period, including when therapy was started and any temporary suspensions for invasive procedures requiring heparin bridging

Thromboembolic events There were 25 thromboembolic events during the followup (1.3 per 100 patient-years) (Table 2), in patients with a mean age of 84.5 (±2.7) years; 24 of them were strokes (1.2 per 100 patient-years), and 3 were fatal. The mean INR at the time of the bleeding was 2.64 ± 0.9, and approximately 70 % of the thromboembolisms (18) took place with an INR C 2. The mean time from VKAs initiation and the ischemic event was 1.71 ± 1.46 years. The CHADS2 score was higher among patients who had a thromboembolic event (data not shown). As shown in Table 2, observed thromboembolic events were similar in the two age groups. Net clinical benefit To weigh the risks and benefits of administering anticoagulants in our observational cohort, we compared the rates of major bleeding events actually observed with the thromboembolic event rates that patients might have been expected to experience without taking oral anticoagulants, given that oral anticoagulants are known to lower the rate of thromboembolic events by 64 %, thus preventing

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approximately two in three of such events [24]. Figure 2 shows the comparison between observed major bleeding and calculated thromboembolic events in the upper graph, and the comparison between fatal major bleeding and calculated fatal Thromboembolic events in the lower graph.

Discussion One of the clinical issues regarding anticoagulation is whether or not the elderly with AF should be given OAT for the purpose of stroke prevention [25]. The incidence of bleeding among elderly patients on VKA has been investigated, but studies conducted so far have failed to settle the debate on whether the elderly’s higher bleeding risk justifies greater caution in prescribing OAT for very elderly patients. One of the reasons for this still cloudy picture is because patients over 80 years of age are poorly represented in most randomised controlled studies. In this inception cohort study, we followed up 798 anticoagulant-naı¨ve patients over 80 years of age for a total of 1912 patient-years. The incidence of major bleeding episodes in the VENPAF cohort was 3.4 per 100 patient-

Intern Emerg Med Table 2 Rates of major bleeding and thromboembolic events during follow-up by age group

Cumulative follow-up (years)

All patients (n = 798)

80- to 84-year olds (n = 463)

C85-year olds (n = 335)

1912

1189

723

p value

HR (95 % CI)a

0.01

1.82 (1.12–2.97)

Bleeding events Major % (n)

8.1 (65)

6.7 (31)

10.1 (34)

%/pt/y

3.4

2.6

4.7

Fatal % (n)

2 (16)

1.5 (7)

2.7 (9)

%/pt/y

0.8

0.6

1.2

0.14

2.08 (0.77–5.60)

3.6 (29) 1.5

3 (14) 1.2

4.5 (15) 2.1

0.12

1.76 (0.85–3.65)

% (n)

2.3 (18)

1.5 (7)

3.3 (11)

%/pt/y

0.9

0.6

1.5

0.04

2.64 (1.02–6.84)

0.53

1.34 (0.53–3.41)

0.008

2.32 (1.22–4.42)

0.40

1.47 (0.60–3.63)

0.33

1.48 (0.67–3.28)

By anatomic site Intracranial % (n) %/pt/y Gastrointestinal

Other sites % (n)

2.3 (18)

2.2 (10)

2.4 (8)

%/pt/y

0.9

0.8

1.1

By natural history Spontaneous % (n)

4.8 (38)

3.5 (16)

6.6 (22)

%/pt/y

1.9

1.3

3

Post-traumatic % (n)

2.4 (19)

2.2 (10)

2.7 (9)

%/pt/y

0.99

0.8

1.2

Thromboembolic events Thromboembolic % (n) %/pt/y a

3.1 (25)

2.8 (13)

3.6 (12)

1.3

1.1

1.7

HR: hazard ratio for age C85 vs. 80–84

Fig. 1 Cumulative frequency (Kaplan–Meier curve) of major bleeding events during the follow-up by age group (80–84 vs. C85); p = 0.014

years, and was higher for the C85-year olds. Age emerged as an independent risk factor for bleeding on multivariate survival analysis, together with diabetes mellitus.

Overall, there is plenty of evidence of the risk of bleeding increasing with age, but the incidence of bleeding recorded in our study is higher than in previous reports [15, 26–28], which described bleeding rates in the range of 1.1–2.9 per 100 patient-years. This difference may be partly explained by the lower mean age of patients enrolled in other studies [27], selection and survivorship biases in non-inception cohort studies [27, 28], lower INR targets [28], and lower comorbidity rates [15, 26]. On the other hand, one Italian study [29] and one North American study [4] find very high bleeding rates in the elderly (9.9 and 13.6 per 100 patient-years, respectively), although the former included patients with heart valves (and consequently higher INR ranges), and the latter investigated a non-inception cohort with a shorter follow-up (1 year). Diabetes is also a known risk factor for haemorrhage, although it is not considered in the main bleeding risk assessment scores [30, 31]. Of interest, gastrointestinal bleeding is higher in

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Intern Emerg Med Table 3 Risk factors associated with major bleeding events

MODEL 1a

Covariates

MODEL 2b

Unadjusted HR

95 % CI

p value

Adjusted HR

95 % CI

p value

1.10–2.93

0.02

1.00–3.09

0.05

Age C85 years

1.84

1.13–3.00

0.01

1.80

Sex (M vs. F)

1.12

0.68–1.84

0.67

–

TTR C 60 %

0.99

0.98–1.01

0.51

–

CHADS2 1–2 vs. 3–6

0.82

0.49–1.33

0.41

–

Heart failure

0.87

0.49–1.53

0.62

–

Hypertension

1.32

0.67–2.59

0.42

–

Diabetes mellitus

1.80

1.02–3.18

0.04

1.76

Prior stroke

0.73

0.33–1.59

0.42

–

Results of Cox’s simple and multivariate stepwise regression models a

Cox’s simple regression analysis

b

Cox’s multivariate stepwise regression analysis including all covariates

Table 4 Nested case–control sub-analysis, matched for age and sex, of the bleeding risk (HAS-BLED score): patients who experienced a major haemorrhage vs. patients who did not experience a major haemorrhage during the follow-up All patients (n = 130)

With major haemorrhage (n = 65)

Without major haemorrhage (n = 65)

p value

HAS-BLED score Median (range)

3 (1–6)

3 (1–6)

2 (1–5)

Mean ± SD Hypertension % (n)

2.69 ± 0.979 72.3 (94)

2.86 ± 0.966 84.6 (55)

2.52 ± 0.97 60 (39)

0.046 0.002

Abnormal renal or liver function % (n)

7.7 (10)

9.2 (6)

6.2 (4)

0.510

Stroke % (n)

9.2 (12)

12.3 (8)

6.2 (4)

Bleeding % (n)

33.1 (43)

55.4 (36)

10.8 (7)

\0.001 \0.001

0.226

Labile INR % (n)

16.9 (22)

3.1 (2)

30.8 (20)

Elderly % (n)

100 (130)

100 (65)

100 (65)

–

Drugs % (n)

26.9 (35)

15.4 (10)

38.4 (25)

0.003

The threshold for statistical significance level was set at 0.05

the C85-year olds. Pathological changes related to ageing increase the incidence of upper and lower gastrointestinal bleeding. Risk of perforated peptic ulcer increases exponentially with age in patients in antiplatelet therapy, while various pathologies, including angiodysplasia, malignancy and diverticulosis, may increase the risk of lower intestinal bleeding [32]. Such risk is 200-fold higher in patients 90 years old compared to patients 30 years old [33]. Intracranial bleeding should also increase with ageing, due to pathological changes in the vascular vessels. Nevertheless, in the VENPAF cohort the 2 age groups have a similar rate of intracranial bleeding. This may be due to the higher number of spontaneous bleeding in the C85-year olds, intracranial bleeding more often being related to traumas in the elderly compared to gastrointestinal bleeding [34]. Previous meta-analyses on the net clinical benefit of VKA in elderly patients with NVAF concludes in favour of

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administering anticoagulants, because their beneficial effect in preventing ischemic stroke outweighs the related bleeding risk [35, 36]. Nevertheless, our general understanding of the risk factors for bleeding in the elderly might be faulty, since they are underrepresented in trials. As shown in Fig. 2, the latter theoretical ischemic event rate is higher than the actual rate of bleeding episodes in both age groups. When the fatal event rates are compared, major bleeding events are more often killers than ischemic events, especially among the older age group. The net clinical benefit of OAT in the VENPAF cohort is therefore unclear. In patients C85 years old, the risks and benefits, and the chances of achieving a good-quality anticoagulation, should be carefully weighed before starting OAT. A clear understanding of the risk of both stroke and bleeding can help clinicians to provide for elderly patients at high risk by

Intern Emerg Med Fig. 2 Thromboembolic events and fatal thromboembolic events were calculated by multiplying the rate of events observed during the follow-up 93: anticoagulant therapy is known to prevent two in three ischemic events, on average [24]. a Observed major bleeding events vs. calculated thromboembolic events by age group; b observed fatal major bleeding events vs. calculated fatal thromboembolic events, by age group

performing frequent checkups, correcting reversible risk factors where possible, and using great caution in the choice of anticoagulant medication. In our cohort, the HAS-BLED score is higher in patients who bleed from a nested case analysis. Nevertheless, it does not appear to accurately predict major bleeding events: patients who bleed have a mean score below the high-risk cutoff of 3. New bleeding risk assessment tools need to be developed, focusing especially on the elderly. Among other options, a lower INR target [37] might be considered. Unfortunately, a significant interaction between age and safety outcomes is also found for direct oral anticoagulants (DOACs) [38– 41]. Although the overall incidence of major bleeding events is lower in all phase III trials compared to warfarin [42], with the exception of apixaban and low dose edoxaban, an association between age and haemorrhagic events is noted [43]. Comorbidities such as renal and liver failure (which tend to be frequent in the elderly) are a limitation for the use of DOACs in the elderly. Nevertheless, in

patients with moderate renal failure, the trials demonstrate a reduction in the risk of bleeding with apixaban compared with VKAs, and no difference in the risk of bleeding with dabigatran and rivaroxaban [44]. Strengths and limitations This study has a number of strengths: by analysing an inception cohort, we were able to avoid biases inherent in survival populations; in contrast with other studies, our cohort includes all patients fulfilling the inclusion criteria from among the total population attending our anticoagulation clinic, with no need for selection or randomisation; a careful data collection from different databases, completed with telephone contacts with general practitioner, enabled us to avoid missing any events occurring during the follow-up. The study also has some limitations, however, mainly concerning the fact that it is retrospective, and data were

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not always available on the INR at the time of any bleeding or thromboembolic events. Another limitation concerns the lack of data on renal failure for the whole cohort. This was also a single-centre cohort study, and the clinical characteristics of our patients may not represent those of NVAF patients in general, in Italy or elsewhere.

8.

Conclusion In conclusion, major bleeding is a frequent complication in elderly users of VKA. Clinicians should carefully assess the indications for, and safety of oral anticoagulants in such patients, balancing each individual’s risk/benefit ratio. Conflict of interest

None.

Statement of human and animal rights All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent required.

For this type of study formal consent is not

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