Should Be the INR Target?
G. DIPASQUALE, M.DI NIRO, G. CASELLA, P.C. PAVESI, A. RUBBOLI, C. GRECO, V. CARINCI
Epidemiology
Atrial fibrillation (AF) is the most common arrhythmia in clinical practice, and its prevalence increases substantially with age. In the ATRIA study, AF occurred in 4% of people aged 60 years and older and in 9% of people aged 80 years and older [1]. The authors estimated that approximately 2.3 million US adults currently have AF, projecting that this figure will increase to more than 5.6 million by the year 2050, with more than 50% of affected individu- als aged 80 years or older. The estimate of AF in Italy is about 500 000 sub- jects with an incidence of 60 000 new cases per year.
Thromboembolic Risk
In the absence of any antithrombotic therapy, the annual risk of stroke and systemic thromboembolism is 4.5% and rises to 8% in subjects older than 75 years of age. Taking into account also the risk of transient ischaemic attack (TIA) and silent cerebral infarction, the risk of cerebral embolism exceeds 7% per year [2, 3]. Clinical features independently associated with a high risk of stroke in AF patients have been defined and integrated into several risk stratification schemes. High-risk factors include age > 75 years, prior stroke/TIA or systemic embolism, history of hypertension, congestive heart failure or poor left ventricular systolic function, diabetes mellitus, rheumatic mitral valve disease, and prosthetic heart valves.
Moderate risk factors include age 65–75 years, and coronary artery dis-
Unità Operativa di Cardiologia, Ospedale Maggiore, Bologna, Italy
ease with preserved left ventricular function.
It is evident from thromboembolic risk stratification that older age (> 75 years) per se is a high-risk factor for thromboembolism and all patients older than 75 years should receive oral anticoagulant treatment (OAT) for effective prophylaxis. This represents a therapeutic dilemma because of the higher risk of life-threatening haemorrhages, in particular cerebral haemor- rhage, in these patients during OAT.
Indications for Oral Anticoagulant Therapy
The effectiveness of OAT for the prevention of thromboembolism and stroke has been assessed by a number of randomised clinical trials [4, 5]. Six trials (AFASAK, SPAF, BAATAF, CAFA, SPINAF, and EAFT) compared the therapeu- tic effects of adjusted-dose warfarin with placebo. Overall adjusted-dose warfarin reduced stroke by 62% (95% CI, 48–72%); absolute risk reductions were 2.7% per year for primary prevention [number needed to treat (NNT) for 1 year to prevent one stroke = 37] and 8.4% per year (NNT = 12) for secondary prevention.
The efficacy of aspirin for stroke prevention in AF patients is unclear and more controversial [4, 5]. Six trials (AFASAK, SPAF I, EAFT, ESPS II, LASAF, and UK TIA) compared the therapeutic effects of antiplatelet therapy with placebo. Meta-analysis of all six trials showed that aspirin reduced the inci- dence of stroke by 22% (CI, 2–38%). On the basis of these six trials, the absolute risk reduction was 1.5% per year (NNT = 67) for primary preven- tion and 2.5% per year (NNT = 40) for secondary prevention. Although all six trials showed trends toward reduced stroke with aspirin, this result was statistically significant only in the SPAF I study.
Recommendations for treatment, based on the evidence from clinical tri- als and thromboembolic risk stratification, were reconfirmed in the 2001 ACC/AHA/ESC guidelines for the management of patients with AF [5] and in the Seventh 2004 Consensus Conference on antithrombotic therapy of the American College of Chest Physicians [6]. OAT is mandatory in AF high-risk patients (those with any high-risk factor or with more than one moderate- risk factor), provided that high-quality monitoring of OAT is possible and no risk factors for bleeding are present. These two last requirements are partic- ularly important when deciding on OAT in patients older than 75 years.
Aspirin is a possible and acceptable alternative to OAT in moderate-risk patients (those without high-risk factors and with only one moderate-risk factor). In this group of patients, the choice between aspirin and OAT is based on the assessment of the risk/benefit ratio of OAT and also on the patient’s preference [7].
Finally, aspirin is the treatment of choice in low-risk patients (those with- out high-risk or moderate-risk factors). This group is represented by patients with no clinical or echocardiographic evidence of cardiovascular disease.
Despite the strong evidence for the efficacy of OAT, the use of warfarin for stroke prevention in patients with AF is still low in general clinical prac- tice [8–10]. Underutilisation of OAT is especially evident among elderly peo- ple with AF, in whom, paradoxically, the thromboembolic risk is higher. In fact, anticoagulation treatment decreases with age (44% of eligible patients age 65–75 years are treated with anticoagulants as opposed to less than 20%
after 80 years) and it is estimated that less than 40% of eligible patients receive OAT.
A recent study has shown that, despite the known increased risk for stroke with advancing age in AF patients, there is a 14% reduction in war- farin use with each advancing decade of life [11].
Major reasons for the underuse of OAT are the difficulty of high-quality monitoring of OAT, especially in older patients, and the fear of bleeding.
Therefore new, safer and effective thromboprophylactic strategies for AF are warranted, particularly for older patients, who represent a substantial pro- portion of the AF population.
Bleeding Risk of Oral Anticoagulant Therapy
Bleeding is the most important complication of OAT, even if the risk of bleeding in patients receiving OAT in randomised clinical studies was quite low. The annual frequency of major bleeding events was 1.3% in warfarin- treated patients (vs 1.0% in patients receiving placebo or controls, and 1.0%
in aspirin-treated patients). However the bleeding risk is likely higher in patients treated in general clinical practice. Patients included in the clinical trials were carefully selected (representing only 7–39% of the screened patients) and followed up carefully according to strict protocols. This can explain the low bleeding risk during warfarin therapy. Moreover, the safety and tolerability of long-term anticoagulation at conventional levels has not been completely defined among patients older than 75 years. In the AFASAK study [12], which involved AF patients older than those enrolled in every other trial (mean age of 75 years), the withdrawal rate from warfarin was 38% after 1 year. In the SPAF II study [13] (INR 2.0–4.5, mean 2.7), the risk of major haemorrhage, mainly cerebral, was substantially higher among AF patients older than 75 years.
In the the real world, bleeding is often a major concern regarding antico- agulation of elderly patients for stroke prevention. In particular, convention- al intensities of anticoagulation increase the risk of intracranial haemor-
rhage 7- to 10-fold, and the risk of cerebral bleeding is significantly higher in the elderly. The key issue in using warfarin to prevent stroke and systemic embolism in AF patients is whether the benefit of therapy outweighs the risk of bleeding in an individual patient.
Risk factors for bleeding during OAT include advanced age, intensity of anticoagulation, recent initiation of warfarin therapy, and comorbid condi- tions.
Patients with advanced age are more prone to complications of OAT than younger patients [14, 15]. Only a few studies have shown that advanced age by itself does not increase the complication rate of OAT. In a large prospec- tive Italian collaborative study (ISCOAT), the frequency of bleeding compli- cations was studied in outpatients treated routinely in anticoagulation clin- ics [16]. The rate of fatal, major and minor bleeding events was quite low, 1.1 and 6.2 per patient-years of follow-up, respectively. The rate was higher in older patients and during the first 90 days of treatment. The risk of bleeding was related to the intensity of anticoagulation, even if a fifth of the bleeding events occurs at INR < 2.0.
A subsequent analysis of patients age > 75 years who were included in ISCOAT showed a nonsignificant trend toward a higher rate of both bleeding and thrombotic complications in elderly versus matched younger patients [17]. In addition, intracranial bleedings and fatal thrombotic events were more frequent in the elderly. The results of this analysis also indicated that INRs < 2.0 do not preclude bleeding in the elderly nor offer adequate pro- tection from thrombotic events. In the subset of patients with AF, major bleeding occurred more frequently in patients over 75 years of age (5.1%
per year) than in younger patients (1.0% per year) [18]. Univariate analysis revealed a higher frequency of major bleeding in females, in diabetics, and in those who had suffered a previous thromboembolic event.
A clear correlation was reported between intensity of anticoagulation and risk of bleeding. In ISCOAT, the risk of bleeding in patients aged > 75 years markedly increased with INR values of 3.0–4.4, and became dispropor- tionately high for INR values > 4.5 [17]. However, a substantial number of events (10%) occurred in association with very low INR values (< 2.0), con- firming previous reports that bleeding during OAT is not always related to the intensity of OAT but that OAT can unmask a local bleeding source.
A higher frequency of bleeding early in the course of OAT was reported in a number of studies [16, 17, 19]. Several factors may contribute to the increased risk of bleeding within the first months of each course of OAT.
First, OAT can unmask a cryptic, often neoplastic, lesion. Second, dose adjustment may be less well-controlled at the start of treatment.
Furthermore, multiple drug therapies are quite common in elderly patients and this increases the risk of adverse drug interaction with OAT. In a
recent large study [20] in patients treated with OAT, subjects receiving more than three drugs had a six-fold higher risk of bleeding or embolic complica- tions than patients receiving less than three drugs (24.4%/100 patient-years versus 4.3%; P = 0.01). Since the complication rate did not differ between patients taking drugs known to interact with OAT and those who did not take interacting drugs, it may be inferred that the increased complication rate of patients with multiple medications was a consequence of comorbidity rather than of drug interaction.
The quality of anticoagulation laboratory control is also affected by the mental status of the patient. Palareti et al. [21] found a previously unsuspect- ed reduction of mental status or attention level in a number of elderly patients receiving OAT; these patients had been exposed to longer periods of either under- or over-anticoagulation and therefore to a higher risk of thrombotic or bleeding complications.
A recent combined retrospective and prospective study [22] comprising a large group of older patients evaluated the importance of OAT education.
This study showed that the rate of bleeding complications, especially major bleeding, is low in well-informed elderly patients.
Recommendations
The management of OAT in older subjects needs regular monitoring of INR, which should be kept in the narrow therapeutic range of 2.0–3.0 most of the time, with adjustments of the dose as required [23]. Moreover, elderly patients should be administered a low dose of warfarin during the induction phase, because of their increased sensitivity to the drug [24].
In older patients, a risk/benefit assessment is warranted before initiating OAT. Major considerations should include:
1. Decision for AF electrical cardioversion which, at least in some cases, could obviate the need of long-term OAT
2. Thromboembolic risk stratification in the individual patient; the preva- lence of additional risk factors for thromboembolism beside advanced age (i.e. hypertension, prior stroke or TIA, heart failure or left ventricular dysfunction, or diabetes mellitus, should reinforce the decision for OAT 3. Ability to provide high-quality monitoring of OAT through coordinated
medical care (e.g. anticoagulation clinics) 4. Patient’s inherent risk of bleeding with OAT
5. Evaluation of risk factors for OAT-related bleeding complications.
When deciding whether to initiate OAT in older patients, patient educa- tion and optimal OAT monitoring are key issues for minimising the risk of bleeding. An Italian study has shown that, in a group of elderly patients fol-
lowed by their general practitioner with the support of a specialised cardio- logic unit, OAT was well-tolerated and associated with a significant decrease in mortality and hospitalisation, in the absence of an increase of major bleeding [25].
High-quality monitoring of OAT is of utmost importance. A systematic approach to anticoagulation management, as offered by anticoagulation clin- ics, can improve the safety and effectiveness of warfarin therapy by reducing related and unrelated complications. This coordinated care can be contrasted with that provided by a patient’s own physician, without systematic coordi- nation (routine medical care). Available data indicate that coordinated care, compared with routine medical care, reduces the incidence of adverse out- comes and also the cost of OAT [26–28].
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