Dabigatran for intracardiac thrombus: Evidence and experience
The vitamin K antagonist (VKA) warfarin has conventionally been used for managing patients with intracardiac thrombus. However, its limitations, including slow onset of action and requirement for bridging with parenteral low-molecular weight heparin (LMWH), highlight a need for alternative treatment options. Non–vitamin K antagonist oral anticoagulants (NOACs) have demonstrated efficacy and safety vs warfarin in management of intracardiac thrombus. At an interview with MIMS Doctor, Professor Alex Lee and Dr Kevin Kam from the Division of Cardiology, Chinese University of Hong Kong, discussed these study findings and shared their experience in the use of dabigatran in patients with intracardiac thrombus.
Intracardiac thrombus increases stroke/embolic risk
"Intracardiac thrombus is commonly seen in patients with atria fibrillation [AF]. A majority of intracardiac thrombi are found in the left atrial appendage [LAA; 70 percent], followed by the left ventricle [LV; 20 percent] and left atrium [LA; 10 percent], upon transoesophageal echocardiography [TEE] assessment," said Lee. [J Neurol Neurosurg Psychiatry 2004;75:1421-1425]
"A recent systematic review showed that the presence of LA thrombus is associated with a 3.5- fold increase in the risk of stroke and systemic embolism [SE] in patients with comorbid AF [odds ratio (OR), 3.53; 95 percent confidence interval (CI), 2.24 to 5.56]. In patients with acute anterior ST elevation myocardial infarction [STEMI], the risk of embolic stroke or SE could be increased by 15 percent [13 percent vs 2 percent; p<0.01] with the presence of LV thrombus,” said Kam. [Thromb Haemost 2016;115:663-677; Circulation 1987;75:1004-1011]
Limitations of warfarin in intracardiac thrombus management
"Currently, there is no specific international guideline recommendation on management of intracardiac thrombus. The anticoagulation strategy is the same as that in patients with AF, where NOACs, including dabigatran, are recommended as first-line treatment in patients with AF and intracardiac thrombus," pointed out Lee. [Eur Heart J 2021;42:373-498]
While VKAs such as warfarin have traditionally been used as anticoagulation therapy for managing patients with AF, a prospective study in 43 patients with AF and LA thrombus showed that despite anticoagulation with warfarin (average international normalized ratio [INR], 2.2), cerebral embolism occurred in 16 percent of patients during the 12-month observation period. [Am J Cardiol 2004;94:801-804]
“In addition, early doses of warfarin are known to have a paradoxical procoagulant effect due to inhibition of vitamin K–dependent synthesis of protein C and protein S, two endogenous anticoagulants with a role in preventing thrombus formation. Bridging therapy with parenteral LMWH, which blocks factor Xa without deactivation of protein C and protein S, is thus needed when initiating warfarin therapy,” said Lee. [J Stroke 2015;17:216-218] “However, the use of warfarin in combination with LMWH in the first few days of treatment requires hospitalization for parenteral LMWH administration as well as close monitoring and dose titration for warfarin initiation, which can be cumbersome to patients and imposes a burden on the healthcare system.”
Thrombus inhibition and resolution with dabigatran
“The NOAC dabigatran is the only direct thrombin inhibitor currently available. It acts by preventing the conversion of fibrinogen into fibrin [ie, thrombus] in the coagulation cascade,” said Lee. (Figure 1) Dabigatran also inhibits free thrombin, fibrin-bound thrombin and thrombin induced platelet aggregation in serum, and may therefore have a unique advantage of additional thrombolytic effect leading to thrombus resolution. [Med J Aust 2010;192:407-412]
“In addition, dabigatran has a stable and predictable pharmacokinetic profile, and can be administered without laboratory monitoring or dose titration, offering convenience compared with warfarin and heparin,” explained Lee.
In a recent retrospective study in 15 patients with LV thrombus (mean LV ejection fraction [LVEF], 32 percent; mean clot size, 157 cm2) treated with dabigatran 110 mg or 150 mg BID, complete resolution of thrombus of both acute (eg, STEMI) and chronic (eg, nonischaemic cardiomyopathy) aetiology was observed in 33 percent, 80 percent, 93 percent and 100 percent of patients, respectively, at 2-week, 1-month, 3-month and 6-month follow-up. [J Family Med Prim Care 2019;8:2656-2660]
“The study results suggest that dabigatran may be a suitable alternative to warfarin in treatment of LV thrombus. The findings also support the thrombolytic action of dabigatran due to its specific binding to free thrombin and fibrin-bound thrombin,” said Kam.
“We conducted a study on the efficacy and safety of NOACs vs warfarin for management of LV thrombus at the Prince of Wales Hospital between January 2011 and January 2020,” said Kam.
The study included 43 patients (mean age, 61 years) with mean LVEF of 30 percent and mean LV thrombus size of 18.1 mm. Baseline characteristics were comparable in both treatment groups, except for a significantly higher proportion of patients with diabetes mellitus in the NOAC group. [Chan J, et al, ESC 2021]
“At a mean follow-up period of 21 months, patients in the NOACs group had a significantly lower rate of net adverse clinical events [NACE; ie, cerebrovascular accident, systemic thromboembolism, intracranial haemorrhage, fatal bleeding, and overt bleeding] [6.67 percent vs 50.0 percent; hazard ratio (HR), 0.109; 95 percent Cl, 0.012 to 0.962; p=0.046] and a numerically lower rate of cumulative mortality [13.3 percent vs 42.9 percent; HR, 0.184; 95 percent CI, 0.032 to 1.059; p=0.058] compared with the warfarin group,” said Kam. (Figure 2)
“Higher, although statistically nonsignificant, rates of LV thrombus resolution and reduction in LV thrombus size at 3-month follow-up were also observed in patients treated with NOACs vs warfarin [resolution of LV thrombus: 86.7 percent vs 71.4 percent; p=0.451] [reduction of LV thrombus size: 93 percent vs 88.1 percent; p=0.390],” Kam added.
In a meta-analysis of data from 1,955 patients treated with either warfarin or NOACs (including dabigatran, apixaban, rivaroxaban and edoxaban), no statistically significant differences were found in the rate of thrombus resolution (OR, 1.11; 95 percent CI, 0.51 to 2.39; p=0.76), risk of stroke or SE (OR, 1.04; 95 percent CI, 0.64 to 1.68; p=0.85), and bleeding complications (OR, 1.15; 95 percent CI, 0.62 to 2.13; p=0.57) in patients treated with NOACs vs warfarin. The overall relative risk of mortality was 1.09 (95 percent CI, 0.70 to 1.70; p=0.48). [Thromb J 2021;doi:10.1186/s12959-021-00259-w]
In another meta-analysis involving 1,615 patients treated with NOACs or VKA, similar rates of unresolved thrombus (OR, 0.61; 95 percent CI, 0.26 to 1.41), embolic events (OR, 1.24; 95 percent CI, 0.90 to 1.69), embolic events and death (OR, 1.10; 95 percent CI, 0.84 to 1.45), and bleeding events (OR, 1.13; 95 percent CI, 0.74 to 1.72) were observed in patients in the NOACs group and the VKA group. [J Cardiovasc Pharmacol Ther 2021;26:173-178]
"Results of these meta-analyses suggest that NOACs are noninferior to warfarin in treatment of LV thrombus, and may serve as an alternative option to warfarin, especially in patients who require close INR monitoring in Hong Kong," commented Kam.
Use of dabigatran in the clinic
"Intracardiac thrombus management requires an individualized approach. In our cardiology centre, NOACs are the preferred treatment option in patients with intracardiac thrombus and comorbid AF. The decision to use NOACs in patients with intracardiac thrombus who are in sinus rhythm is, however, at physician’s discretion following a discussion of the risk and benefit of dabigatran or other NOACs with the patients," said Lee.
"Dabigatran is predominately excreted via the renal route in an unchanged form. Therefore, the dosage of dabigatran should be reduced in patients aged 75–80 years, patients with moderate renal impairment, or those with an increased risk of bleeding. In patients with severe renal impairment [ie, creatinine clearance <30 mL/min], the use of dabigatran is contraindicated," noted Lee. [Clin Pharmacokinet 2008;47:285-295; Dabigatran Etexilate Hong Kong Prescribing Information]