Warfarin or Aspirin Which Is a Better Drug in Myocardial Infarction Prevention?

Introduction:

Non communicable diseases, especially Cardio-Vascular Diseases (CVD) are emerging as a global health concern especially among low and middle income countries. Around 71% of deaths globally are due to non-communicable diseases and 78% of global NCD deaths occurred in low and middle income countries. 44% of NCD fatalities at global level are attributed to cardiovascular diseases (CVD). Ischemic heart disease and stroke have been identified as leading causes of CVD related deaths for more than a decade. To add to it, these two CVD related fatalities accounted for 15.2 million deaths in 2016 in low and middle income countries. (WHO, 2018). While the above-mentioned figures do present a very grim picture, they also present a substantial opportunity of reducing NCD related morbidity if the ischemic heart disease and stroke are taken on priority and are treated with prompt response and utmost efficiency.

As identified earlier, Ischemic heart diseases and strokes are two major causes of CVD related deaths and can be categorized as Coronary Artery Disease (CAD). CAD are the most common type of CVD which narrows the circumference of circulatory vessels supplying oxygenated blood to the heart due to deposition of plaque. When the plaque ruptures, it is replaced by blood clots in arteries causing blockage of blood supply to the heart muscles. This adversity increases likeliness of damage to the myocardial cells, which in turn, increases risk of myocardial infarction commonly known as heart attack. Cardiovascular disease (CVD) patients with an earlier event of myocardial infarction (MI) or ischemic stroke are very likely to experience a subsequent MI. Atrial fibrillation (AF) is a known complication of acute myocardial infarction (AMI). Atrial fibrillation also known as arrhythmia or irregular heart beat is common in 6-21% of MI patients which could increase the risk of MI in CVD patients. The rapid, irregular heart rate causes poor blood flow leading to blood clot, stroke, heart failure and other heart related diseases.

Anticoagulant agents and platelet inhibiting are the choice of drugs for long term management of thrombosis (blood clotting) and MI. Aspirin is a popular choice administered for platelet inhibition in order to reduce chances of CVD mortality and subsequent cases of MI as well, despite of its use for CVD prevention being subject to controversy. 15-20% of patients are at risk of dying due to re-infarction within 2-5 years of prior MI. The most common oral anticoagulant prescribed to patients worldwide with AF is Warfarin. Warfarin are blood thinners which inhibits the vitamin K dependent coagulating factors (prothrombin). Prothrombin decreases the production of thrombin which is mainly modulates formation of blood clots. Reduction in thrombin levels, reduces thrombogenicity in addition to anticoagulation.

Aspirin also known as Acetylsalicylic acid acts as an acetylating agent, which irreversibly inactivates platelet dependent enzyme cyclooxygenase (COX)- 1 and suppresses the generation of thromboxane A2 creating anti-platelet effect. It further, reduces inflammatory responses in CAD and inhibits progression of atherosclerosis. Aspirin blocks the formation of COX dependent vasoconstrictors by improving endothelial dysfunction in atherosclerosis, increasing vasodilation and reduces thrombosis. As Aspirin has an immediate and long term effect on platelets, Aspirin is prescribed as a secondary preventive measure in CVD patients.

An American comparative study of MI and AF showed higher risk of mortality in patient with both MI and AF and as opposed to AF alone, through the results were not statistically significant. Use of Warfarin showed significant reduction in MI when compared to non- Warfarin.

Hypothesis:

Although, there have been controversies on the short term as well as long term merits and demerits of combination therapy of anticoagulant and antiplatelet, their intrinsic and extrinsic effect may clinically benefit in treatment of acute ischemic heart diseases. Generally Aspirin is preferred over Warfarin because of ease of administration, low cost, comparable and efficacy. Earlier studies have established beneficial effects of Warfarin in comparison to placebo is known to prevent new events of MI. Further, Warfarin is known to have superior benefits over Aspirin, whereas Aspirin is the most widely used drug currently.

Method:

Three randomized studies of Aspirin and Warfarin in different dose and combination aided in the knowledge of use of two drugs in case of patients with MI.

The first study of 1997, is a randomized, double blind comparative study in USA on fixed low dose Warfarin and Aspirin with Aspirin alone after MI. 8803 MI patients, of the age group of 21-85 years, post an event of MI, with elevated myocardial enzyme concentration, along with chest pain or changes in electrocardiograph were either treated with daily dose of 160 mg Aspirin or 1mg Warfarin + 80mg Aspirin or 3 mg Warfarin + 80 mg Aspirin based on random allocation. All the drugs were identical in appearance including the placebo. There was an interim analysis conducted by an independent data and safety monitoring board to ensure safety, efficacy and futility.

Second, is a comparative study of 2002, hypothesis the combination of Aspirin and Warfarin was more effective than Aspirin alone. A randomized open label controlled study with 2.7 year follow-up across 78 Department of Veterans Affairs medical centres in the United States. 5059 patients (median age 62 y, 98% men) who had an acute MI were administered daily with Warfarin (target international normalized ratio [INR] 1.5 to 2.5 IU) + Aspirin (81 mg/dl) or Aspirin (162 mg/dl) alone.

A comparative efficacy study of Aspirin (160 mg daily), Warfarin with a combination of dose of Aspirin (75 mg daily) and Warfarin as an open label, multi-centric, randomized controlled trial post a MI. Patients of both genders, less than 75 years of age, with acute myocardial infarction as per the World Health Organisation recommendations: chest pain, change in electrocardiograph, creatine kinase <250 U/litre, aspartate aminotransferase <50 U/litre were included in the study. Treatment continued until a predetermined number of events occurred and no interim analyses was conducted.

Results:

The daily dose of 160 mg Aspirin or 1mg Warfarin + 80mg Aspirin (1mg W+ 80mg A) or 3 mg Warfarin + 80 mg Aspirin (3mg W+ 80mg A) showed similar efficacy with less than 1% change of difference between the three treatments. The relative risk of primary event across the three groups was:

Treatment Group

160 mg A compared with (3mg W+ 80mg A)

160 mg A compared with (1mg W+ 80mg A)

(1 mg W with 80 mg A) compared with (3 mg W + 80 mg A)

Relative Risk of primary event

0·95 (95% CI 0·81-1·12, p=0·57)

1·03 (0·87-1·22, p=0·74)

0·93 (0·78-1·11, p=0·41)

In the study of Warfarin+ Aspirin against Aspirin study, a 15% reduction in annual mortality was observed in combination dose of Warfarin + Aspirin as opposed to Aspirin alone, along with major bleeding (1.28 vs 0.72 events per 100 person-years of follow-up, P < 0.001). However, intracranial hemorrhage rates were same in both groups (14 patients each).

In the efficacy study of Warfarin, Aspirin or both, statistically, there was no difference in overall mortality rate among the three groups (Aspirin (160 mg daily) and Warfarin in combination dose with Aspirin (75 mg daily) and Warfarin). However, Warfarin in combination with aspirin and alone showed better effect on reinfarction when compared with Aspirin. Total number or events including repeated events was highest in Aspirin group (24.5%) as compared to Warfarin (19.4%) and Aspirin + Warfarin group (17.4%). Out of the 14 hemorrhagic deaths, 11 occurred while active on medication of which 5 were in Warfarin drug and 6 on combination dose of Warfarin and Aspirin.

Of the total adverse events of non-fatal major bleeding episodes in the patients under treatment, 0.17% received Aspirin, 0.68% received Warfarin and 0.75% received combination of Aspirin and Warfarin per year. Minor bleeding episodes observed in the three arms- Aspirin, Warfarin and combination was 0.84%, 2.14% and 2.70% per year in respectively.

Discussion:

In patients with an episode of Myocardial Infarction, no additional clinical benefits were observed in low, fixed-dose warfarin (1 mg or 3 mg) combination with low-dose aspirin (80 mg) 160 mg aspirin alone. Neither did the combination dose of Warfarin (at a mean international normalized ratio of 1.8) with low dose Aspirin have any added clinical benefits.

Whereas, Warfarin, was an effective drug when administered alone or in combination with aspirin, as compared to aspirin alone. There was reduction the incidence of several events after an acute myocardial infarction but was associated with a higher risk of bleeding. Large number of patient withdrawal was observed in patients on Warfarin due to bleeding, percutaneous coronary intervention or coronary- artery bypass grafting, which may have impacted the effect of Warfarin.

Conclusion

Thus, Combination dose of Warfarin and Aspirin was the most effective drug for prevention of event after myocardial infarction when compared with Aspirin or Warfarin alone. However, major bleeding occurred more frequently with combination dose.

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