Patients who are at risk of thromboembolic disorders may also be at risk of myocardial infarction (MI). This is because shared risk factors such as hypertension, diabetes, and advancing age may predispose them to both conditions, and the pathogenesis of MI results from thrombus formation following the rupture of an atherosclerotic plaque in a coronary artery.¹

Appropriate antithrombotic and anticoagulant treatment can prevent the development of thrombosis and thus potentially reduce the likelihood of MI. Data suggest that treatment with the vitamin K antagonist (VKA) warfarin might actually

be protective against the development of cardiovascular events in patients who have already had a heart attack.^2-4 The mechanism responsible for this cardioprotective effect is explained by the fact that the pathophysiology of MI involves both platelets and the coagulation system, the latter being the target of warfarin.³

Recently, novel oral anticoagulants have been introduced to the market, which have the potential to overcome many of the barriers that currently limit VKA anticoagulation therapy. Oral thrombin (Factor II) inhibitors, however, have been linked to an increased number of cases of MI ►

when compared to treatment with warfarin.^5,6 At the same time, patients being treated with other novel oral anticoagulants such as factor Xa inhibitors have shown low rates of MI similar to treatment with a VKA.^7,8 This has led to debate over whether or not there could be an intrinsic difference between various novel oral anticoagulation agents in terms of MI.

This article examines recent evidence and discusses if the mechanism by which the coagulation cascade is blocked could be a contributing factor in the development of, or protection against MI.

Novel Anticoagulants: Different
Targets in the Coagulation Cascade

Thrombin is a central step to the blood clotting process and the primary target of oral direct thrombin inhibitors (DTIs) such as dabigatran (Figure 1). DTIs prevent thrombin from converting soluble fibrinogen to fibrin, as well as preventing the activation of clotting factors that result in more thrombin generation and the stabilisation of a blood clot.⁹

Another central point in the coagulation cascade is the conversion of prothrombin to thrombin by activated Factor X. This is now acknowledged as an appealing target for ►

anticoagulation due to its ‘upstream’ position in the coagulation cascade, at the convergence of the intrinsic and extrinsic pathways.^10,11 Inhibition of Factor Xa has potent anticoagulant effects as this is the primary site of amplification – one molecule of Factor Xa catalyzes the formation of around 1,000 thrombin molecules.^12,13 Targeting this higher point in the cascade has a powerful effect on clot formation, as thrombin production is very effectively inhibited.¹⁴

MI and Direct Thrombin Inhibition

The suggestion that direct thrombin inhibition may be associated with higher rates of

MI came after the publication of phase II and III studies investigating efficacy and safety of the oral thrombin inhibitor dabigatran comparing it to VKA treatment, the current standard of care. A number of these trials showed numerically higher rates of acute coronary events in patients treated with dabigatran.^15,16

One of these trials is the RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) study which included more than 18,000 patients with atrial fibrillation.^5,17

RE-LY was not designed to detect a difference in MI rates between dabigatran and warfarin. ►

However, the annual rate of MI (a secondary endpoint of the trial) in patients taking dabigatran was higher than in those taking dose-adjusted warfarin. The annual rate of MI was 0.53% for warfarin but 0.72% for the 110 mg twice-daily dose of dabigatran (p=0.07) and 0.74% for the 150 mg twice-daily dose (p=0.048).⁵

The RE-LY investigators later performed a post-hoc analysis that included more cardiovascular events.^15,16 While there were numerically more cases of MI in patients treated with dabigatran versus the VKA, the results were no longer statistically significant.^15,16 However, the discussion is still ongoing and

other analyses suggest that there are valid signs of increased MI rates.⁶

Meta-analysis Performed

The conflicting RE-LY data led to the recent publication of a meta-analysis comparing the rates of MI in dabigatran versus warfarin treated patients. (Figure 2).⁶ Considering data from seven randomised controlled trials – representing data on more than 30,000 patients – dabigatran was again associated with an increased risk of MI or acute coronary syndrome when compared to control treatments. The annual risk of MI was 1.19% for dabigatran versus 0.79% for control treatments that included ►

warfarin, enoxaparin and placebo (p=0.03). The risk remained even after the revised results from the RE-LY trial¹⁴ were used and when data from short-term trials were excluded.⁶

Acute Coronary Events in Patients
Receiving Rivaroxaban

Reassuringly, Factor Xa inhibition has not been associated with an increased incidence of MI when compared to a VKA. In clinical trials of a broad range of patients, including those with atrial fibrillation (Figure 3) and those at high risk of venous thromboembolism, Xarelto^® (rivaroxaban) has demonstrated that it is not associated with higher rates of MI than a VKA.⁸ Hence, it can

be assumed that Xarelto^® has a similar cardioprotective effect to warfarin.

What Could be the Cause?

It is not known why Factor II inhibition has been associated with a relative increase in MI rates compared to warfarin.^5,6 It could be the result of inhibiting thrombin production directly – as the effect is not seen with the Factor Xa inhibitors.⁸ In their original report,⁵ the RE-LY investigators postulated that dabigatran might lack protective effects against coronary ischaemic events that had previously been seen with warfarin.³ The authors of the meta-analysis, however, suggested that perhaps it was ►

a feature of direct thrombin inhibition itself as no such signal has been seen to date with any of the Factor Xa inhibitors.^6,8 Perhaps, they hypothesised, DTIs have unfavourable effects that influence the development of atherosclerosis or atherosclerotic events.⁶

What Next?

In the recently published Focused 2012 Update of the Canadian Cardiovascular Society Atrial Fibrillation Guidelines, the committee clearly acknowledges the possible link between dabigatran and MI based on recent data. However the statement present in the 2010

CCS guidelines that warfarin is preferred over dabigatran for patients at increased risk of coronary events has been removed in these latest guidelines, since recent data does not “suggest an excess of coronary events among those receiving any of the new OAC’s”.¹⁸ Nevertheless, further trials are warranted to investigate the underlying mechanisms explaining the link between direct thrombin inhibition and cardiovascular adverse events.¹⁶

Specifically, studies need to look at the risk of MI in patients with AF who may already have a higher than average risk of having a heart attack or developing an acute coronary syndrome.^16,18

Currently, awareness of the problem and appropriate assessment of patients who may be at higher risk than others could be the most responsible clinical path to follow when using a novel anticoagulant, especially when using a direct thrombin inhibitor.