The Debate on Anticoagulation in Cirrhotic Patients
Cirrhosis is a form of end-stage liver disease characterised by cell degeneration, inflammation, and fibrosis, most often caused by alcoholic and viral hepatitis. In particular, the condition is associated with thrombocytopenia and decreased synthesis of several pro- and anticoagulant factors, which affects the haemostasis of several organs. The abnormal haemostasis related to liver cirrhosis would increase the risk of either bleeding or thrombosis1. Cirrhotic patients with atrial fibrillation (AF) may have a higher risk of ischaemic stroke or cerebral haemorrhage. Former randomised control trials demonstrate the efficacies of non-vitamin K antagonist oral anticoagulants (NOACs) in management of AF. However, existing evidence on the effectiveness and safety profiles of NOACs among cirrhotic AF patients in clinical practice are limited and inconsistent2. Thus, optimisation of health outcomes in AF patients with cirrhosis with NOACs remains challenging.
The Pathologic Crosstalk between Heart and Liver
The interactions between the functioning of the heart and the liver have been extensively reported. For instance, arrhythmias and electrocardiographic changes, including AF and flutter, premature atrial and ventricular contractions, and ventricular arrhythmias, can occur with liver cirrhosis3. A recent meta-analysis of 7 cohort studies including 385,866 patients with cirrhosis suggested that the prevalence of AF in this group of patients was approximately 5.0%, whereas a significant association between AF and increased mortality risk in cirrhotic patients was observed with a pooled odds ratio of 1.44 (95% confidence interval [CI]: 1.36-1.53)4. The findings highlight the potential health burden of comorbid liver cirrhosis in patients with AF.
Cirrhosis induces AF through various proposed mechanisms. For instance, it has been reported that β-adrenergic receptor density in cirrhotic patients and animal models were reduced, leading to alteration of heart cell contractility5. Besides, the function of muscarinic receptors is reduced in cirrhosis, while muscarinic receptor stimulation exerts a negative inotropic effect on cardiac muscle counterbalancing the stimulatory β-adrenergic system. Thus, an enhanced muscarinic tone could contribute to the pathogenesis of negative inotropic effects on the myocardium6.
On the other hand, the fluidity of the plasma membranes from heart cells and other tissues is decreased in cirrhotic patients, whereas the increased rigidity of cardiomyocyte plasma membranes seen with cirrhosis is associated with decreased β-adrenoceptor function7. Moreover, changes in the function of calcium and potassium channels and alterations in other factors such as nitric oxide, carbon monoxide, and endocannabinoids appear to affect cardiac contractility and conductivity as well8. While QT interval measures the length of ventricular systole, QT prolongation has been reported in patients with cirrhosis. This suggests an increased risk of ventricular arrhythmias and sudden death in patients with cirrhosis9. Yet, the exact mechanism of QT prolongation in cirrhosis is still unclear.
Clinical Benefits of NOACs in AF with Cirrhosis
As described, the coagulopathy of cirrhosis is highly complicated, which would increase the risk of AF and hence places the patients at risk for both bleeding and thrombosis. NOACs have equivalent or superior efficacy and safety as compared to vitamin K antagonists (VKAs). In order to evaluate the therapeutic impact of NOACs in liver cirrhosis, Hum et al (2017) conducted a retrospective cohort study of patients with cirrhosis prescribed therapeutic anticoagulation over a 3-year period. During the study period, 27 patients with cirrhosis were prescribed a NOAC and 18 were prescribed VKA or low molecular weight heparin (LMWH). The results reflected no difference in total bleeding events between NOACs (8 cases) and VKA/LMWH (10 cases), whereas the occurrence of major bleeding episodes in NOACs group (1 patient [4%]) was significantly less than that in VKA/LMWH (5 patients [28%], p=0.03)10. The results showed that NOACs would be as safe as traditional anticoagulants in patients with cirrhosis while maintaining efficacy in preventing stroke or thrombosis.
The efficacy and safety of NOACs in patients with cirrhosis were further examined in a nationwide retrospective cohort study involving data of 2,428 liver cirrhotic patients with nonvalvular AF taking apixaban (n=171), dabigatran (n=535), rivaroxaban (n=732), or warfarin (n=990). The results demonstrated that NOAC group (n=1438) showed the risk of ischaemic stroke/systemic embolism and intracranial haemorrhage was comparable to that of the warfarin group (n=990) after adjustment. Essentially, NOAC treatment yielded significantly lower risk of gastrointestinal bleeding (hazard ratio [HR]: 0.51, 95% CI, 0.32-0.79, p=0.003) and all major bleeding (HR: 0.51, 95% CI: 0.32-0.74, p=0.0003) compared with warfarin group (Figure 1). Further, the subgroup analysis indicated that both dabigatran and rivaroxaban showed lower risk of all major bleeding than warfarin. Notably, 90% of the patients were taking a low-dose NOACs1. The findings of the study thus have suggested that NOACs have a comparable risk of thromboembolism to that of warfarin and a lower risk of major bleeding among liver cirrhotic patients with nonvalvular AF.
Figure 1. Cumulative incidence curves of (A) major bleeding and (B) major gastrointestinal bleeding1, GIB: gastrointestinal bleeding
Besides, the findings of a recent meta-analysis of 7 retrospective cohort studies, involving 19,798 patients with AF and cirrhosis, demonstrated that anticoagulation use for AF in patients with cirrhosis was significantly associated with a reduced risk of stroke (pooled HR: 0.58, 95% CI: 0.35-0.96), whereas no significant difference in the risk of bleeding was observed between anticoagulation use for AF in patients with cirrhosis and those without anticoagulation. Moreover, compared to warfarin, the use of NOACs was associated with a lower risk of bleeding among AF patients with cirrhosis (p=0.05, Figure 2)11.
Figure 2. Forest plot of the risk of bleeding among AF patients with cirrhosis on warfarin versus direct oral anticoagulants (DOACs)11
Evidence from Randomised Trials Is Needed
NOACs are a breakthrough therapy for patients requiring anticoagulation. Among potential therapeutic advantages in cirrhotic patients, the benefits of NOACs include their quick onset of action, their simple dosage, and international normalisation ratio monitoring is not required. Clinical data on the efficacy and safety of NOACs in AF patients with cirrhosis are emerging. However, it is important to realise that most of the data currently available are generated in retrospective observational studies while high-quality evidence from prospective trials is still limited. Notably, most clinical trials determining the efficacy and safety profiles of anticoagulants in the management of AF exclude patients with hepatic insufficiency making it difficult to extrapolate the results to cirrhotic patients2. Moreover, all currently approved NOACs undergo metabolism in the liver, hepatic dysfunction may cause increased bleeding12. Therefore, randomised controlled trials (RCTs) are needed to examine the efficacy, pharmacodynamics, and safety of NOACs especially in moderate to severe cirrhosis. Practically, the usage of NOACs in patients with cirrhosis must be evaluated on a case-by-case basis.
References
1. Lee et al. J Am Heart Assoc 2019; 8. DOI:10.1161/JAHA.118.011112. 2. Sasso et al. Curr. Opin. Gastroenterol. 2019; 35: 161-7. 3. Mozos. World J. Hepatol. 2015; 7: 662-72. 4. Chokesuwattanaskul et al. Eur J Gastroenterol Hepatol 2019; 31: 514-9. 5. Lee et al. Hepatology 1990; 12: 481-5. 6. Jaue et al. Hepatology 1997; 25: 1361-5. 7. Ma et al. Am J Physiol - Gastrointest Liver Physiol 1994; 267. DOI:10.1152/ajpgi.1994.267.1.g87. 8. Al-Hamoudi. Saudi J. Gastroenterol. 2010; 16: 145-53. 9. Bernardi et al. Expert Rev. Gastroenterol. Hepatol. 2012; 6: 57-66. 10. Hum et al. Eur J Haematol 2017; 98: 393-7. 11. Chokesuwattanaskul et al. Dig. Liver Dis. 2019; 51: 489-95. 12. Qamar et al. J. Am. Coll. Cardiol. 2018; 71: 2162-75.
