Dabigatran must be used carefully: literature review and recommendations for management of adverse events

Introduction

Atrial fibrillation increases the risk of stroke and death.¹ The vitamin-K antagonist warfarin is recommended for patients with atrial fibrillation and who are at risk of stroke, which reduces the risk of stroke and death, but increases the risk of bleeding. Vitamin-K antagonists are cumbersome to use due to: interactions with multiple foods and drugs; a narrow therapeutic range; significant changes in anticoagulant response; a slow onset of action; requirement of frequent testing of laboratory parameters. Patients who receive warfarin have poor compliance and a high prevalence of treatment withdrawal due to the factors mentioned above, so many patients do not receive adequate anticoagulant therapy.² Therefore, an effective, safe and convenient new anticoagulant is needed.

Dabigatran acts by inhibiting free and fibrin-bound thrombin directly. It is an oral anticoagulant that was approved by the US Food and Drug Administration in 2010 to prevent embolic events in patients with non-valvular atrial fibrillation.³ Dabigatran has been used increasingly in clinical practice due to its good tolerance, predictable pharmacokinetics, effective anticoagulant effects, and absence of need of coagulation monitoring. Dabigatran is used as an alternative to warfarin, and it appears to be as effective as warfarin in preventing embolic events in patients with non-hemorrhagic stroke and atrial fibrillation rather than in patients with valve problems.⁴

Despite the many advantages of dabigatran, reports of adverse events have emerged in recent years, such as gastrointestinal discomfort and bleeding. Although patients taking dabigatran have fewer life-threatening hemorrhages, the prevalence of gastrointestinal bleeding was significantly higher than in those who used warfarin.³ An increasing prevalence of adverse events has been reported,^5–27 some of them quite serious. Therefore, we searched and reviewed the literature on dabigatran with regard to adverse events (Figure 1).

Figure 1 The adverse events of dabigatran.

We searched PubMed, Google scholar and the Chinese National Knowledge Infrastructure using the key words “dabigatran and adverse events”, “dabigatran and side effects” and “dabigatran and induced” from December 2010 to November 2018. Case reports were selected on the adverse events of dabigatran that they described. Twenty-three case reports were reviewed and analyzed, and the clinical features are listed in Table 1.

Table 1 Clinical features of dabigatran-induced adverse events

Adverse events of dabigatran

Bleeding

As with any anticoagulant drug, various types of hemorrhage are common adverse events. Of the cases we reviewed, seven patients developed severe hemorrhage,^5–11 including three cases of fatal gastrointestinal hemorrhage.^8–10 Major bleeding was reported to occur in a dose-dependent manner, and this was reported in fewer than 3% of patients during a trial comparing dabigatran with other anticoagulants.^28,29 Similarly, Connolly et al reported that the prevalence of major bleeding was 2.71% per year in the group receiving dabigatran (110 mg, b.d.) and 3.11% per year in the group receiving dabigatran (150 mg, b.d.), and that the prevalence of life-threatening bleeding in those receiving 110 and 150 mg of dabigatran twice-daily was 1.22% and 1.45%, respectively.³

The three patients who died of gastrointestinal bleeding caused by dabigatran were old (mean age=81 years). One of them took only 150 mg of dabigatran once-daily,⁸ but this may have been related to the hip arthroplasty that she underwent. These gastrointestinal events may have been due to the dabigatran formulation, which contains granules of tartaric acid to provide an acidic environment. A lower pH is associated with dyspepsia and plays a part in the increased risk of gastrointestinal bleeding.²⁸ Spontaneous hemopericardium,⁵ spontaneous hemothorax⁶ and hemorrhagic cystitis⁷ occurred separately in three patients. Major bleeding in these anatomic areas is uncommon and has rarely been reported, but it should be documented. Other risk factors of dabigatran-induced gastrointestinal bleeding include concurrent use of ulcerogenic drugs, older age, Helicobacter pylori infection, and previous history of gastrointestinal bleeding. Helicobacter pylori infection and use of NSAIDs are independent risk factors for duodenal ulcer and gastric ulcer and related bleeding.^30,31 Therefore, we should prevent the combined hemorrhagic effect of dabigatran and Helicobacter pylori, and the patient should be screened for Helicobacter pylori before anticoagulant therapy. In general, these findings also show that the risk of venous thromboembolism and bleeding should be considered before deciding the anticoagulation given to the patient.

Esophagitis or esophageal injury

Another adverse event that requires attention is esophagitis or esophageal injury (including esophageal ulcers) induced by dabigatran intake.^12–19 In 1983, it was estimated that the esophageal injury caused by drugs was only 3.9 cases per 100,000 people per year.³² In 2016, Toya et al reported that dabigatran use caused ~20% of patients to suffer damage to the esophageal mucosa.³³ However, among the cases we reviewed, 10 of 25 patients developed varying degrees of esophagitis or esophageal injury after dabigatran use. Therefore, dabigatran-induced esophagitis may be overlooked in asymptomatic patients who have not undergone endoscopy. Among the 10 patients (four males and six females) we reviewed, the mean age was 77 years and there was no significant difference between the doses of dabigatran used. It has been speculated that the tartaric-acid core in dabigatran not only plays a part in gastrointestinal bleeding, but is released after digestion and adheres to the esophagus to damage the esophageal mucosa, and then the damaged esophageal mucosa exfoliates after peristalsis.³⁴ In older patients, due to reduced activity (sitting or lying down for long periods) and reduced salivary secretion, if the volume of water consumed is low, the lack of a sufficient liquid bolus will increase the possibility of contact by dabigatran with the esophageal mucosa. The mean age of the patients we reviewed was 77 years, so we speculate that advanced age was an important risk factor for dabigatran-induced esophagitis. Clinicians should not ignore the possibility of esophagitis after giving patients dabigatran, especially if patients develop dysphagia, chest pain, upper abdominal pain, or heartburn.

Impairment of function of the liver and kidney

The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial showed that impairment of liver function (an increase in the levels of aspartate aminotransferase or alanine aminotransferase by more than three times the upper limit of the normal range) caused by dabigatran did not occur more frequently than that with warfarin.³ In the literature that we reviewed, dabigatran-induced acute interstitial nephritis,²⁰ acute hepatitis²¹ and hyperkalemia²² were reported. In a phase-II dose-finding trial of dabigatran, Eriksson et al found only mild increases in transaminase levels in the dose ranges tested, but two patients had severe hepatitis (transaminase levels more than five times the upper limit of normal).³⁵ The cause of liver and kidney dysfunction caused by dabigatran may be because first-pass elimination occurs in the liver and 80% of a given dose is excreted by the kidney.³⁶ One of the patients in a study experienced hyperkalemia. Hyperkalemia is a potentially fatal side-effect that can occur in patients with altered renal function, and understanding that dabigatran can cause hyperkalemia in this patient population is crucial. Dabigatran can induce hyporeninemic hypoaldosteronism in patients with impaired renal function, which leads to hyperkalemia. Careful monitoring of renal function is recommended if physicians prescribe dabigatran for patients with renal insufficiency.

Myocardial infarction or acute coronary syndrome

A small (but significant) increased risk of myocardial infarction or acute coronary syndrome has been noted when combining safety-outcome data from multiple trials.³⁷ The RE-LY trial showed that the prevalence of myocardial infarction per year was 0.53% with warfarin, and that the prevalence per year in patients taking 110 mg of dabigatran and 150 mg of dabigatran was 0.72% and 0.74%, respectively.³ These findings were probably because warfarin provides better protection against coronary ischemic events than dabigatran.³⁸ In the literature that we reviewed, such adverse events were not reported in any patient. Nevertheless, clinicians should continue to consider the possibility of these severe, harmful cardiovascular effects after dabigatran administration.

Allergic reactions

Five patients developed allergic reactions after taking dabigatran.^23–27 In addition, one patient developed drug-induced lupus (DIL).²³ Stöllberger and colleagues suggested that a small lipophilic molecule with a molecular weight of 472 Da may play a part in immune side-effects after dabigatran administration.²³ Furthermore, DIL is characterized by high levels of antinuclear antibodies and antihistone antibodies, with no evidence of complement consumption, and circulating immune complexes within the normal range. The RE-LY trial reported that fewer than 0.1% of patients receiving dabigatran reported drug allergies, allergic edema, allergic reactions, or anaphylactic shock.³ Even though allergic edema and allergic reactions are rare, monitoring and reporting allergic reactions in patients taking dabigatran is important.

Age

Among the patients with adverse events that we reviewed (except for a 20-year-old patient with a dabigatran-induced exanthema), the mean age was 76 (range, 52–90) years.^5–27 Regardless of whether adverse events are associated with age, more clinical trials are needed to ascertain the relationship between age, dose, and adverse effects to better guide management.

Conclusions and recommendations

The oral anticoagulant dabigatran is used widely. Nevertheless, clinicians cannot ignore the adverse events caused by dabigatran. We recommend the management detailed below for the adverse events caused by dabigatran.