Atrial Fibrillation

Atrial fibrillation (AF) is the irregular and rapid heart rate that causes poor flow of blood in the body. AF incidences have been on the rise. Treatment may be medications or interventions that try to alter the electrical system of the heart. Many questions have been raised on the treatment methods. For the early onset AF, oral anticoagulant is administered. Warfarin and apixaban are the two most known anticoagulants. Warfarin has been used widely but has been raising safety issues. Warfarin administration also requires to be monitored consistently. These concerns with warfarin has made it necessary to research for more anticoagulants. Apixaban is newer and has for a period been used as a substitute for warfarin where safety concerns arise. Most of the elderly adults have a medical history of other conditions that sometimes interfere with the dosing of warfarin which also cause adverse effects. The following analysis compares warfarin and apixaban to determine one which produces better thromboembolic effects with less adverse effects.

Research Question

In adult patients with new onset AF does warfarin therapy produce better thromboembolic effect with less adverse events compared to apixaban?

Literature review

First study. Cakebread, et al (2014), present a case of a man who was 82 years old, with bilateral blanching toes and a rash of type livedoreticularis that developed merely two weeks after he began using warfarin after atrial fibrillation was first detected. A review of vascular surgical and screening of haematology thrombotic could not yield results. After a diagnosis of the purple toe syndrome was carried out, warfarin was stopped, and an oral anticoagulation started with a factor Xa inhibitor, that is, apixaban.

            The man with a history of gout, eczema and hypertension was administered warfarin (10, 10 and 5mg) after being diagnosed with atrial fibrillation. Two weeks later, in addition to the purple toe, the patient complained of bilateral thigh pain and swelling and a rush that was spreading across both shins. On further examination, the big toes were found to be very painful on palpation.

            Further examination were conducted on the patient. Results from blood tests indicated that the man has a normal prothrombin time, normal platelet count and the activation of partial thromboplastin time was normal. ECG was carried out and it confirmed once again that the patient still had atrial fibrillation. A vascular surgical review did not indicate a decreased arterial flow because the posterior tibialis and dorsalis pedis pulses were bilaterally palpable. The prothrombotic screen did not show any abnormalities on the patient.

            A differential diagnosis of the purple toe syndrome was conducted on the history of recent warfarin administration, the clinical signs of the distal localized ischemia and the exclusion of other pathology such as impeded venous or arterial flow.

            After warfarin was stopped and anticoagulation achieved with oral apixaban 5mg BD, the review of the patient indicated that symptoms had settled and anticoagulation maintained in a therapeutic range on apixaban.

            According to discussions presented, the purple toe syndrome was first described in 1961 as a rare effect of warfarin therapy, with one patient out of 5,000 being affected. The risk is higher when a patient is deficient of protein C. Cakebread et al (2014), further advice that if the condition is known early, then warfarin can be substituted with a different anticoagulant. The effect has not been reported with apixaban, making it the best alternative to go for.

Strength. This study used a specific case that covered the adverse effects of warfarin in detail. There was a good comparison on the outcomes of warfarin and apixaban.

Weaknesses. One weakness on this case study is that only one patient is used for the study. Worse still, the patient used had a medical history of other conditions, that is, gout, hypertension and eczema. These conditions may have interfered with the results of warfarin that was administered for atrial fibrillation. A better case study would have used several patients with atrial fibrillation who lack a history of medical conditions.

Results. Purple toe syndrome is an effect that rarely results from warfarin therapy. Studies have shown that one out of 5000 patients is at a risk of getting the purple toe syndrome. Other anticoagulants have also been known to have such adverse effects. However, apixaban anticoagulants do not have any recorded incident of such adverse effects (Cakebread et al, 2014). According to this case study, warfarin are used initially but are later replaced with apixaban after negatively affecting the patient. Good results come out of Apixaban, indicating that Apixaban has less adverse effects compared to warfarin for AF patients.

Second study. In this study, 5599 patients with atrial fibrillation and with a high risk of stroke were used. For all these patients, vitamin k antagonist therapy was unsuitable. The patients would receive apixaban (5 mg daily) or warfarin (81 to 324mg daily) to determine one which was superior.

            Vitamin k antagonists is known to prevent stroke in patients with atrial fibrillation. Many patients do not receive vitamin k because they are either unwilling to take or they may be the unsuitable candidates to receive it. According to Connolly et al (2011), for such patients, apixaban, a factor Xa inhibitor may be the alternative.

            During the study, patients to receive either apixaban or warfarin were randomly selected. Randomization took place using a 24-hour central, computerized voice-response system. To keep up the double-dummy design, the patients that were assigned to be receiving apixaban also received a warfarin placebo and those meant to receive apixaban also received a placebo of warfarin.

            As the study went on, it emerged that 40% of the patients had used vitamin k antagonist before being enrolled into the study. The safety monitoring board recommended an early termination of the study because apixaban would clearly benefit from that favor. From the data that had been received, there were 51 primary outcome events among apixaban patients and 113 among warfarin patients. Rates of death were 3.5 % per year for apixaban group and 4.4% for the warfarin group. 44 cases were recorded for major bleeding in the apixaban group, while warfarin group recorded 39 cases. 11 cases were recorded for the intracranial bleeding in the apixaban group while 13 cases were recorded for warfarin group. The risk of hospitalization for causes of cardiovascular was reduced with apixaban in comparison to that of warfarin.

            The main outcome of the study was that stroke (hemorrhagic or ischemic) or systemic embolism occurred. Brain imaging for the majority of patients was not required but it was recommended so that general diagnosis of stroke may be carried out. The diagnosis using brain imaging was important on differentiating hemorrhagic events from ischemic. This study took a good amount of time and had a good number of patients that acted as the sample for research. Since it was a well-coordinated activity research, the data collected is important for any appropriate conclusions.

Strengths. This study was among the best analyzed. Every part of the report was well explained, and more figures and numbers were used.        

Weakness. The study does not indicate the results of patients in terms of their different ages, making it difficult to making a conclusion in terms of age. The major weakness with this study was that the trial was terminated earlier than it had been planned for. This might have caused theoretical inflation of the estimates.

Results. For the patients who are unsuitable for vitamin k antagonist therapy, compared to warfarin, apixaban reduced systemic embolism or risk of stroke by more than 50% without the risk of bleeding majorly.

            In accordance with this study, Apixaban gave the best results as compared to warfarin. It can therefore be concluded that in patients with new onset AF, warfarin does not produce better thromboembolic effects that have less adverse effects as compared to apixaban.

Third study. Harvorsen et al (2014) conducted this study with an aim to relate warfarin and apixaban on patients with atrial fibrillation disease to stroke, death and bleeding. The study used a total of 18,201 atrial fibrillation patients who were at a risk of stroke or systemic embolism (hypertension, cardiac failure or diabetes). It was conducted in 1034 clinical sites of 39 countries from 2006 to 2010.

Randomly, the patients were administered with warfarin or apixaban.

            Among all the patients used, 30% were less than 65 years, 39% were between 65 to 75 years and the rest 31% were more than 75 years old. The youngest patient was recorded as 19 years old while the oldest was 100 years old. 2436 patients were above 80 years old.

            According to this study, apixaban was more effective than warfarin in reducing systemic embolism or stroke, consistently affecting all the age groups. Apixaban reduced major bleeding rate in comparison to warfarin in all the age groups. The rate of ICH patients was greatly reduced by apixaban than it was reduced by warfarin. Apixaban reduced the fatal bleeding rate or fatal hemorrhagic stroke more than warfarin did across all the age groups. Consistently in the age groups, treatment with apixaban largely reduced the risks due to the net clinical events as compared to warfarin. Even with the adjustment of the baseline differences, there lacked evidence that treatment had been done differently according to age, for safe outcomes. Tests for the interaction between treatment and age gave similar results.

            The dose of apixaban was reduced from 5 mg to 2.5 mg twice per day in the 831 patients that had the following factors: age more than 80 years, body weight that was less than 60 kg. Most of the patients that were receiving this reduced dose were more than 75 years old. This reduced dose was as a result of similar reduced stroke as well as major bleeding. The reduced dose proved to be an appropriate one in the high-risk group of patients.

            This study shows that the risks of major bleeding, stroke or death increase with increased age. It is also clear that apixaban, compared to warfarin reduces these risks regardless of the patient’s age. As the risks were more in the old age group, lack of interaction between treatment and age implies that apixaban was more beneficial to the older population. The development of newer anticoagulants is an attractive idea for the old people because the anticoagulants have proved to be safer and more effective that warfarin requiring less routine coagulation monitoring and less interactions as with warfarin.

Strength. This study used a large sample and it was specific with the different ages when doing the analysis.

Weaknesses. This study gave detailed information that is important for report analysis and therefore lacks weaknesses.

Results. In this study, apixaban proved to be more superior to warfarin with respect to prevention of stroke, complications in bleeding as well as mortality across all the age groups. The superiority of apixaban to warfarin was consistent even in the ages greater than 80 years. Apixaban does not need coagulation monitoring like in warfarin and the interactions with the drug is also less. This makes apixaban to be the best alternative for the elderly patients suffering from AF.

References

Cakebread, H. E., Knight, H. M., Gajendragadkar, P. R., & Cooper, J. P. (2014). Warfarin-induced purple toe syndrome successfully treated with apixaban. BMJ case reports, 2014, bcr2014205320.

Connolly, S. J., Eikelboom, J., Joyner, C., Diener, H. C., Hart, R., Golitsyn, S., … & Yusuf, S. (2011). Apixaban in patients with atrial fibrillation. New England Journal of Medicine, 364(9), 806-817.

Halvorsen, S., Atar, D., Yang, H., De Caterina, R., Erol, C., & Garcia, D. et al. (2014). Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial. European Heart Journal, 35(28), 1864-1872. http://dx.doi.org/10.1093/eurheartj/ehu046