European Journal of Cardiovascular Medicine

A change in the heart's electrical rhythm is known as a cardiac arrhythmia. This is mostly a sign of a structural heart disease, although it can also happen when a healthy heart has aberrant conduction, depolarization, or an imbalance in electrolytes [1].

Brady arrhythmia (heart rate < 60/min) and tachy arrhythmia (>100/min) are the two categories into which they fall.

The major source of or dependence on supraventricular tachyarrhythmias is conduction from the atrium or atrioventricular node to the ventricles. They might have a pathological or physiological origin. The most prevalent cardiac arrhythmia among the pathogenic varieties of supraventricular arrhythmias is ATRIAL FIBRILLATION.

Disorganized, fast, irregular atrial electrical activity, aberrant atrial contraction, and a fluctuating ventricular rate resulting from atrioventricular nodal conduction are the hallmarks of atrial fibrillation.[2]. It developed become a significant public health issue that gets worse every day.

Atrial fibrillation affects 1% of those 60–64 years old and 9% of people over 80 years old. The prevalence increases with age, with over 95% of patients being older than 60. For those over 40, the lifetime chance of having atrial fibrillation is about 25%. Black individuals are seldom impacted and men are more affected than women2. There are no particular epidemiological statistics accessible in India, with the exception of a few foreign studies that enlist Indian participants. Females are disproportionately afflicted in India and rheumatic heart disease is the primary cause, according to small research conducted among rural residents of the Himalayan hills [3].

A comparable finding from the entire sample of the Indian cohort of the REALIZE AF research indicates that the primary reason of the average age of 60 years, which is 55 percent male, is valvular heart disease. The average age of the Indian population was found to be 54 years old in the first Indian registry, the INDIAN HEART RHYTHM SOCIETY AF research [4], and data from the RELY AF research confirms the fact that Asians, including Indians, are on average ten years younger than those in other parts of the world.However, there is still a lack of a distinct epidemiological picture in the Indian population.

In addition to age, the primary risk factors for developing atrial fibrillation include hypertension, diabetes mellitus, sleep apnea, coronary artery disease, and valvular heart disease, particularly rheumatic heart disease. In addition to inflammatory pericarditis, it is occasionally linked to acute precipitating causes such as hyperthyroidism, electrolyte imbalance, alcohol intoxication, acute sickness such as chest infection, pulmonary embolism, and post-cardiac surgery.

STUDY SETTINGS-

Department of pharmacology and outpatient department of cardiology of R.G.KAR Medical College and Hospital, Kolkata, west Bengal, India.

STUDY PERIOD-

16 MONTHS, first 4 months is the recruitment period of the patients and next one year will be the follow up period. The study is started after getting approval clearance from the Institutional ethics committee.

STUDY DESIGN-

It is a prospective longitudinal observational open level study designed to compare effectiveness and safety of dabigatran and warfarin.

STUDY POPULATION-

Patients are choosen from the cardiology outpatient department of R.G.KAR Medical College and Hospital treated by attending cardiologists. Data is collected from the outdoor tickets of all the patients newly diagnosed with non-valvular atrial fibrillation by attending cardiologists and treated with one of the anticoagulant drugs.

INCLUSION CRITERIA-

• All the consecutive patients who are diagnosed with non-valvular atrial fibrillation and received anticoagulation therapy with warfarin or dabigatran with CHA2DS2 – VASC SCORE ≥2.
• Patients of hyperthyroidism, who were treated for last one year for thyrotoxicosis, now presented with persistent atrial fibrillation even in euthyroid state.

The other drugs that were prescribed to these patients will not be considered in this study as they were present in both the groups.

EXCLUSION CRITERIA-

• Patients of valvular atrial fibrillation
• Patients with prosthetic heart valve
• Patients receiving other anticoagulant or antithrombotic drugs along with dabigatran or warfarin
• Those undergone any surgical procedure to control atrial fibrillation
• Stroke within last 14 days or severe stroke within 6 months
• Any major surgery within previous month
• Known Haemorrhagic disorder or bleeding diathesis
• Pregnancy
• Active liver disease
• Creatinine clearance ˂30 ml/min
• Patients with active hyperthyroidism
• Patients who are unwilling to participate in this study.

SAMPLE SIZE

Total sample size is 150

STUDY TOOLS

• Informed consent form
• Standardised case record form

STUDY VARIABLES-

• Liver enzyme SGPT
• Liver enzyme SGOT
• Serum Creatinine
• international normalised ratio (INR)
• Number of ischaemic stroke and transient ischaemic attack.
• Number of systemic embolisms
• Number of myocardial infarctions
• Number of bleeding events including major and minor bleeding.

(RELY6 definition of major bleeding includes≥1 of the following criteria- 1) Fatal symptomatic intracranial bleed,

2 ) reduction in haemoglobin level of at least 5gm/dl ,

3)           Transfusion of at least 4 units of blood or packed cells,

4)           associated with hypotension requiring the use of intravenous inotropes,

5)           necessitated surgical intervention)

• Adverse drug reaction.

STATISTICAL ANALYSIS-

Data was entered into MS EXCEL sheet and was analysed by using statistical software SPSS version 17.0. the continuous data was presented by mean ± SD and categorical data was

presented by frequency with their relative percentage. Data was tested for normality by using Kolmogorov smirnov test. The association between the variables was tested by using chi square test or fisher`s extract test as per applicability. The mean was compared by using independent t test and median was compared by using Mann Whitney U test as per applicability of the data.. P-value ≤ 0.05 was considered for statistically significant

Distribution Of Presence of Different Risk Factors in Two Study Population, Types of Non-Valvular Atrial Fibrillation in Two Study Population and Symptoms in Two Study Population

Distribution Of Number of Cardioembolic Stroke After Intervention in Two Study Population and Number of Minor Bleeding Event in Two Study Population

In group-A, 45(60.8%) patients had hypertension, 34 (45.9%) patients had diabetes mellitus, 3(4.05%) patients had hyperthyroidism and 46 (62.2%) patients had old stroke/TIA. In group-B, 29 (38.2%) patients had hypertension, 29(38.2%) patients had diabetes mellitus, 4 (5.26%) patients had hyperthyroidism and 41 (53.94%) patients had old stroke/TIA. In group-A, 36 (48.6%) patients had paroxysmal and 38 (51.4%) patients had persistent atrial fibrillation. In group-B, 24 (31.6%) patients had paroxysmal and 51 (67.1%) patients had persistent atrial fibrillation. In group-A, 38 (51.4%) patients had palpitation, 30 (40.5%) patients had breathlessness and 18(24.3%) patients had fatigue. In group-B, 35 (46.1%) patients had palpitation, 12 (15.8%) patients had breathlessness and 29 (38.2%) patients had fatigue. In group-A, 2 (2.7%) patients had cardioembolic stroke/TIA. In group-B, 8(10.5%) patients had cardioembolic stroke/TIA. P value is 0.098. Relative risk is 0.2568 and 95% confidence interval is 0.056-1.17. In group-A, 2(2.7%) patients had minor bleeding events. In group-B, 4 (5.3%) patients had minor bleeding events. P value was 0.681. Relative risk is 0.5135 and 95% confidence interval is 0.097 to 2.719.

In group-A, 46(62.2%) patients had used atorvastatin, 31(41.9%) patients had used losartan, 48 (64.9%) patients had used metoprolol, 26 (35.1%) patients had used verapamil, 31 (41.9%) patients had used metformin, 2 (2.7%) patients had used glimepiride, 3 (4.05%) patients had used carbimazole, 22 (29.7%) patients had used ranitidine and 4 (5.4%) patients had used insulin. In group-B, 39( 51.3%) patients had used atorvastatin, 43( 56.6%) patients had used losartan, 40 (52.6%) patients had used metoprolol, 36 (47.4%) patients had used verapamil, 21 (27.6%) patients had used metformin, 10 (13.2%), patients had used glimepiride, 4 (5.26%) patients had used carbimazole, 16 (21.1%) patients had used ranitidine and 8 (10.5%) patients had used insulin. In group A there was not much variation in mean Creatinine value though in later part of study after6th month there was mild elevation of mean Creatinine value. Where as in group B the mean Creatinine values are fluctuating up to 8th month and after that there was mild elevation of mean Creatinine value. The values in both group are within normal range.

In the present study, 92 patients (61.3%) were hypertensive, 63 patients (42%) were having diabetes mellitus, 7 patients (4.66%) were having hyperthyroidism and 87 patients (58%) had a history of ischaemic stroke or transient ischaemic attack previously. But no patients had any history of coronary artery disease or prior major bleeding.

Patients of hyperthyroidism were being treated for thyrotoxicosis for last one year and were presented in euthyroid state with persisting atrial fibrillation. And all 7 of them had a CHADS2 score ≥ 2 .So they were included in the study and treated with oral anticoagulant.

A cardiologist in the outpatient department identified two forms of non-valvular atrial fibrillation in the current investigation. Sixty patients (40%) had paroxysmal atrial fibrillation, whereas the remaining ninety patients (60%) had chronic atrial fibrillation. 36 patients (48.6%) had paroxysmal type atrial fibrillation and 38 (51.4%) had persistent type atrial fibrillation in group A, the group that received dabigatran treatment. In contrast, the values in the other group—the one receiving warfarin—were 24 (31.6%) and 52 (68.4%), respectively. The yearly risk of stroke is 4% with a CHA2DS2-VASC score of 4 and rises with increasing score, i.e., 6.7% and 9.8% annually with CHA2DS2-VASC scores of 5 and 6, respectively, according to ACC/AHA 2014 guidelines [5].

In the RELY study, the first ischemic stroke and embolism rate among patients treated with 110 mg dabigatran was only 3%, but the rate for patients treated with warfarin INR adjusted treatment was 3.4%. Additionally, the dabigatran-treated group exhibited numerically fewer incidents than the warfarin-treated group, although there was no statistically significant difference (p value 0.27). This is consistent with the findings of the current investigation.

In 2015, a comparative observational trial that included a database [6] found similar types of results, i.e., the same rate of decrease in ischemic stroke between the groups treated with warfarin and dabigatran (p value 0.06). Another research by Graham et al.[7] using Medicare registered new user cohort between 2010 and 2012 found that the dabigatran-treated group had a lower risk of stroke events (205 in comparison to 270 in the warfarin-treated group; p value 0.02). The discrepancy from the current trial might be the result of a different patient group and dabigatran dosage.

In the present study, there was significant change in INR value at 6th months (p value ˂0.0001) and at 12th months (p value ˂ 0.0001) between these two groups. First, there was no effect of dabigatran over INR value. Whether we had to keep the INR value in warfarin group by regular monitoring between the therapeutic range, that was between 2-3 for non valvular atrial fibrillation. And so there may be a significant difference in mean INR value between two groups.

Second, though the chance of drug interaction from concomitant medications were minimal in warfarin group, we could not rule out the food interactions with warfarin or any over the counter drugs that may interact with warfarin and caused a significant change in mean INR value.

The mean creatinine value differed significantly between the two groups in the current investigation throughout a 12-month period. The following factors might account for this notable shift: dabigatran's proven impact on creatinine levels is unknown. On the other hand, nephropathy is a possibility when using warfarin, as documented in many case studies (132). A new term, anticoagulant linked nephropathy, describes acute kidney damage with an INR of 3 and no prior history. The precise etiology is unclear. The endothelial glomerular barrier is thought to be disrupted by the breakdown of protein C or thrombin, which results in tubular blockage by RBC cast and kidney damage[8].

During the course of a 12-month period, there was a substantial increase in SGPT and SGOT levels in the dabigatran group in the current study. However, the transaminase enzyme levels were only three times higher.

One possible explanation might be that dabigatran has a greater effect on liver enzymes since it is only 35% bound to plasma proteins. On the other hand, 98% plasma protein binding with warfarin may lessen its impact on liver enzymes.

Serum transaminases increased more than three times in the dabigatran 110 mg group, according to a study of the RELY trial [9], although the rate of rise was very similar in the warfarin and dabigatran 110 mg groups. The dissimilarity from the current investigation can stem from a distinct research population or the existence of distinct risk variables.

Serum transaminase levels were elevated more than three times in the dabigatran group but not in the warfarin group in a different trial by Michael et al. [10], despite the fact that no cases of significant liver damage were seen. A different research population might be the cause of the discrepancy from ours.

From an Indian viewpoint, the efficacy and safety profile of dabigatran 110 mg twice day is not inferior to that of warfarin INR adjusted dosage in patients with non-valvular atrial fibrillation. With dabigatran, the prevalence of dyspepsia is noticeably higher.Regarding other adverse medication responses, there is no discernible difference. Additional extensive multicentric investigations are required to validate these results in a comparable population and to offer novel ideas for the treatment of non-valvular atrial fibrillation.

1. Newby De, Grubb Nr. Cardiac arrhythmia. In: Ralston SH, Penman ID, Strachan MW, Hobson R, editors. Davidson's Principles and Practice of Medicine. 23rd edition. Elsevier Health Sciences; 2018.c 16.p.468.
2. Michaud FG, Stevenson GW, Supraventricular Tachy arrhythmias. In : Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J, Fauci AS , editors. Harrison's principles of internal medicine,20th edition. Newyork: Mc Graw Hills education ; c 241 .p. 1476.
3. Narasimhan C, Verma JS, Kishore AGR, Singh B, Dani S, Chawala K, et al. The REALIZE AF study. An International, Observational Cross Sectional Survey Evaluating AF Management and Cardiovascular Risk Profile of AF Patients, Indian Subset Data Presented at the ISE Meeting Jaipur; 2012.
4. IHRS AF Registry Presented in ISE Meeting. Mumbai; 2011
5. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Journal of the American College of Cardiology. 2014 Dec 2;64(21):e1-76.
6. Romanelli RJ, Nolting L, Dolginsky M, Kym E, Orrico KB. Dabigatran versus warfarin for atrial fibrillation in real-world clinical practice: a systematic review and meta-analysis. Circulation: Cardiovascular Quality and Outcomes. 2016 Mar;9(2):126-34.
7. Graham DJ, Reichman ME, Wernecke M, Zhang R, Southworth MR, Levenson M, Sheu TC, Mott K, Goulding MR, Houstoun M, MaCurdy TE. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation. 2015 Jan 13;131(2):157-64.
8. Wheeler DS, Giugliano RP, Rangaswami J. Anticoagulation‐related nephropathy. Journal of Thrombosis and Haemostasis. 2016 Mar;14(3):461-7.
9. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S. Dabigatran versus warfarin in patients with atrial fibrillation. New England Journal of Medicine. 2009 Sep 17;361(12):1139++-5+1
10. Ezekowitz MD, Reilly PA, Nehmiz G, Simmers TA, Nagarakanti R, Parcham- Azad K, Pedersen KE, Lionetti DA, Stangier J, Wallentin L. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). The American journal of cardiology. 2007 Nov 1;100(9):1419-26.