Clinical Implications of Recommendations in Current Guidelines on Anticoagulation in Patients with Atrial Fibrillation

  

    
Within indication but do not receive warfarin
    
n
    
%
  
  

    
Known reasons
    
 
    
 
  
  

    
rejected by the patient
    
14
    
6,9
  
  

    
bleeding history of the patient
    
4
    
5.4
  
  

    
High HAS-BLED score (=3)
    
2
    
2,7
  
  

    
Unknown reasons and possible situations
    
 
    
 
  
  

    
high blood pressure
    
64
    
87,7
  
  

    
75 years over
    
32
    
43,8
  
  

    
History of cerebrovascular disease
    
12
    
16,4
  
  

    
History of Chronic Renal Failure
    
11
    
15,1
  
  

    
The presence of major bleeding history
    
4
    
5,4
  

Table 5:  Distribution of reasons for not using warfarin in patients with warfarin
indication but not using warfarin.

Discussion

Atrial Fibrillation (AF) is the most common arrhythmia in general population. Its prevalence increases markedly by ageing and reaches to 8%-10% at the age of >80 years [6]. Currently, several risk calculation methods are used to determine stroke risk in AF patients. After initiation of OAC therapy in patients with high risk for stroke, risk of stroke decreases markedly [9]. When transient ischemic attacks and clinically silent ischemia that can be detected by cerebral imaging methods are also taken into account, cerebral ischemia associated with non-valvular AF is over 7% annually [10].

In the first large study presenting the national data regarding OAC therapy in AF patients, the rate of OAC use in AF patients was 7% in 1980-1981 but increased to 32% in 1992-1993. The rate of never treated patients was reported as down to 48% from 90% [10]. In other OAC studies, OAC use was found as between 32-57% and rate of never treated patients was reported as between 22-59% [11,12]. AFFIRM trial was conducted in 4.060 AF patients with a mean age >70 years and in 70.8% of the patients’ hypertension, 38.2% CAD, 13% stroke, 32.1% CF was reported. In the end of the trial, in terms of stroke rate no difference was found between patients with sustained AF and patients returning to normal sinusal rhythm. Trial has revealed that most of the patients who have experienced stroke were either not using warfarin treatment or their INR values were below therapeutic levels [13]. In our study presence of CVD (n=27, 13, 2%), CF (n=54, 26, 3%), hypertension (n=162, 79%) is similar to AFFIRM trial.

In our study, retrospective evaluation of patients with OAC indication who were using warfarin has revealed that number of patients with INR control was 83 and in 58 of these patients (69.9%) INR was effective. These figures that are obtained from patients followed up in a tertiary center are consistent with the INR effectiveness rate target outlined in the guidelines. Conduction of this study in a large tertiary center of our country may have contributed to the fact that the findings are within the range of worldwide standards. In our study, it was observed that 12.3% of patients with an indication for warfarin use but haven’t used the drug (n=73, 35, 4%) have used clopidogrel + acetyl salicylic acid and 23.1% have used only acetyl salicylic acid. The fact that the study was conducted in a tertiary center which is serving to a very large geographic area and a heterogeneous patient population makes the findings more significant. 69.9% of the patients with warfarin indication who have showed up in follow up have achieved effective INR values and this rate is within the targeted range; however, the fact that 35.4% (n=73) of patients with warfarin indication haven’t used warfarin for various reasons is an indicator for us that we’re still in 1990’s in terms of indicated warfarin use [12].

The results of warfarin use were analyzed along with analysis of various trials studying a very large number of stroke incidents. Prognosis of stroke patients with AF were found to be worse than stroke patients with sinusal rhythms and mortality rate was 2 times more [14,15]. At the follow up after 6 months and 12 months recurrent stroke was found to be 2 times higher than patients without AF [16-18]. The fact that 5-year mortality rate is higher in patients with AF (52% vs 78%) have shown us that we’re far from the desired values [19].

In our study, when non-valvular AF patients were evaluated by CHA₂DS₂-VASc score the number of patients with their respective scores were as follows: 0=7 patients (4.4%); 1=16 patients (9.8%); = 2=139 (85, 8%). Distribution of patients with indication for warfarin according to CHA₂DS₂-VASc score and have used the drug was as follows: 0=0 patient (0%), 1=6 patients (7.2%), = 2=77 (92, 8%); distribution of patients with indication for warfarin according to CHA₂DS₂-VASc score but haven’t used the drug was as follows: 0=0 patient (0%), 1=6 patients (9, 4%), = 2=58 patients (90, 6%). Analysis of the findings have revealed that warfarin use increases as the risk score increases; but in higher scores the number of patients with indication for warfarin but haven’t used the drug has also increased. The notion that adverse event risk such as risk of embolism and risk of bleeding increases in these patients may have led to non-prescription of warfarin even by clinicians in tertiary health institutions in indicated cases.

In daily practice, it’s known that OAC is not prescribed to AF patients with high risk of stroke and in most of the patients using warfarin INR control is ineffective and a portion of patients stop taking warfarin after starting therapy. There are various factors effecting patients’ compliance. These are mainly patient-related, clinician-related, drug-related and environmental factors and interaction between them. OAC treatment is not prescribed to patients in daily practice because of following reasons: the patients can’t properly conduct INR control, don’t want to use the drug, there is uncertainty in risk-benefit status of patients with poor condition and clinicians beware of prescribing the drug since they are wary of the major bleeding complications. In a trial 313 AF patients were followed up for 6 months. In that study, it was reported that 75 (50%) of 168 patients with OAC indication have used OAC therapy, 54 (30%) have used antiplatelet therapy and 39 (20%) haven’t used any prophylactic treatment. 80% of patients included into study were over 70 years old and/or have high risk for stroke [20]. In our patient population, the patients who have indication for warfarin but haven’t used the drug because of unknown reasons were the largest group by 17.1%. These were followed by 17 patients (8.4%) in whom reason of the non-prescription of the drug is not known, 4 patients with history of major bleeding (2%), 2 patients with high HAS-BLED score (1%). The number of patients rejecting warfarin prescription was 14 (6.9%) and regarding warfarin use this leads to the notion that since clinicians and patients are wary of the adverse effects, the treatment of the patients is often interrupted.

In SPORTIVE II study a total of 254 AF patients were distributed into two treatment arms: “ximelagatran” and “warfarin”, and dose safety and tolerability of ximelagatran were researched. This study has showed that 12 months after the start of the therapy, rate of patients with INR values of 2-3 was 57% and 43% in warfarin treatment arm could not reach targeted INR values [21]. In our study, the number of patients using warfarin during the follow-up with an indication for it, and having INR control with effective INR value was 58; constituting 28.6% of all patients and % 69.9 of followed-up patients with warfarin indication have used warfarin.

At the same time, in our study anticoagulant therapy wasn’t started in 73 (35, 4%) patients with anticoagulant indication. When these 73 (35, 4%) patients were evaluated, it was observed that 12, 3% used clopidogrel + acetylsalicylic acid, and 23, 1% used only acetyl salicylic acid. In our study it was found out that the rate of patients having oral anticoagulant therapy indication, however using antiplatelet therapy (n=73, 35, 4%) was similar to literature data [22].

A study comparing 2004 guidelines with anticoagulation guidelines of 2000 has showed that indications for starting the therapy is slightly expanded and became clearer. During the transition from 2000 to 2004 guidelines, oral anticoagulant therapy rate has increased, and has approximately been doubled. Increase was observed in patients with high and very high risk (17%). In the study by Simona Bo et al. a total of 313 AF patients were included, and 106 patients with oral anticoagulant therapy indication were followed-up between April 2000 and April 2004. Since the therapy was highly recommended and the necessary explanations were made clearly, rate of oral anticoagulant therapy use have increased to 81, 9% (n=87) from 56, 6% (n=60) (23-199) [21]. In our study, due to being inadequately informed of oral anticoagulant therapy, 19.2% (n=14) of 73 patients not using warfarin themselves have rejected the therapy, and therefore their therapies could not be started. It is obvious that oral anticoagulant therapy use will increase if the importance of oral anticoagulant therapy in AF patients is clearly communicated to the patient. In a study by Mc Alister FA et al., out of 307 AF patients, 185 patients having indication for oral anticoagulant therapy were followed-up for 6 months. As a result of an increase in patients’ training program, the number of patients using oral anticoagulant therapy increased to 135 (73%) from 89 (48%) at the end of 6 months. This increase in the number has reached to a statistically significant level (p< 0.0001) [23].

In the cohort study of 601 patients with AF using warfarin, records of approximately 6-year were screened. During 5-year follow up, 263 patients (44%) used oral anticoagulant, 309 (51%) patients used oral anticoagulant therapy in a certain interval during the study, INR was between 2-3 at 68% of the time during the study, and annual bleeding risk was found to be higher in patients using warfarin (9%) relative to the patients using aspirin (4, 7%) and patients not having any treatment (4, 6%). Bleeding was the most common complication of the therapy. While bleeding risk increases along with INR increase, 50% of the bleeding episodes occurred while INR was below 4. Bleeding risk was highest within 3 months after the start of the therapy. In earlier months of the therapy, bleeding is usually gastrointestinal, and originates from urinary system, and underlying lesion usually needs to be investigated [24]. In our study, reason for non-prescription of warfarin in terms of bleeding was history of major bleeding by 5.4% (n=4) and the most common major bleeding was upper gastrointestinal system bleeding (2.3%). As it can be concluded from the above mentioned study; even though oral anticoagulant therapy markedly decreases mortality, morbidity and stroke risk in AF patients, use of anticoagulant therapy is still inadequate due to certain reasons. The therapeutic level can’t be achieved in most of the patients in whom oral anticoagulant therapy was started or most of the patients can’t take the drugs regularly once the therapy is started.

None of the studies about the oral anticoagulant therapy use predictors of (until the study by Albert et al.) hasn’t looked for the possibility that AF classification could be a predictor for anticoagulant therapy use. For the first time, Albert et al. suggested that persistent/ permanent AF was an independent predictor for anticoagulant therapy use [25]. In our research, when classified as paroxysmalpersistent- permanent, AF classification/typology, with p=0.32, did not reach a statistically significant level. However, when AF ethiology was classified as valvular-mitral disease/valvular-prostethic valve/ non-valvular, it was determined that warfarin use, with p=0.004, was significantly higher at valvular AF with prosthetic valve.

A study conducted by McCormick et al. on long-term care patients indicated that as the number of risk factors for stroke increased, so did the use of anticoagulant therapy [26]. However, these values could not reach statistical significance. Similarly, on the basis of the idea that having high risk score for stroke could be an independent predictor for indicated oral anticoagulant therapy, a tendency for increase was observed in our study but it wasn’t statistically significant, either. These findings suggest that what constitutes a high stroke risk is not clear on clinicians’ minds.

Atrial Fibrillation (AF) is the most common arrhythmia in the clinics. The prevalence has been gradually increasing in last several decades due to the aging population and prolongation of survival. Stroke and systemic embolism risk are significantly higher for AF patients compared to patients without AF. Oral Anticoagulant Therapy (OAC) therapy is recommended for patients with high stroke risk. OAC therapy significantly decreases the risk of mortality, morbidity and stroke, and that is why this therapy is especially important for OAC patients. However, OAC therapy of patients with OAC indication is usually not initiated, initiated warfarin therapy does not reach at the targeted INR level, or drug cannot be used regularly and is stopped for various reasons. Consequently, inadequate and incomplete use of anticoagulation therapy significantly increases the stroke, stroke-based mortality, hospitalization rate and the economic costs. Recent studies and recently available agents, as well as up to date guidelines encourage clinicians for the initiation of OAC therapy.

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