Management Overview of ACS in LC
Despite a demonstrated better survival in LC patients with ACS treated with optimal medical therapy and invasive revascularization techniques, both remain underutilized in this population. Many well validated pharmacotherapies, such as antiplatelet drugs, high-potency statins, and renin-angiotensin-aldosterone system (RAAS) inhibitors (including angiotensin-converting enzyme [ACE] inhibitors, angiotensin-receptor blockers [ARBs], and direct renin inhibitors) are frequently withheld due to concerns about bleeding, liver toxicity, and profound vasodilation, respectively. Similarly, these patients are often not taken to the cardiac catheterization laboratory because of concerns related to bleeding, frailty, and even life expectancy.
LC patients tend to have a high prevalence of comorbidities such as chronic kidney disease (CKD), anemia, thrombocytopenia, deranged coagulation parameters, and diabetes mellitus. Thus, they are less likely to receive guideline-directed management in the form of PCI and dual antiplate-let therapy (DAPT). The higher comorbidity burden along with states of active bleeding/coagulopathy might preclude clinicians from adapting an invasive strategy. This "risk aversion" strategy adopted by healthcare providers in high bleeding risk patients puts LC patients with ACS at risk of unfavorable short-term outcomes.
The differences in management strategies and outcomes of LC patients with ACS have been shown to depend on both the severity (compensated vs decompensated) and the etiology of LC. Patients with decompensated/severe/Child–Pugh class C LC have lesser odds of undergoing angiography and PCI. Alcoholic etiology in decompensated LC is associated with the worst utilization of coronary angiography and PCI.[15,16] NASH cirrhosis is associated with a higher incidence of cardiovascular events, mortality, and major bleeding.[16,17]
Recommendation: Despite the underutilization of an invasive approach for ACS in LC patients, the odds of major bleeding remain high. Hence, we recommend carefully weighing individualized risks versus benefits of both medical and invasive strategies in high-risk LC patients with ACS.
Pharmacologic Management of ACS in LC
Antithrombotic and antiplatelet therapies, beta-blockers, statins, RAAS inhibitors, as well as coronary angiography and revascularization when indicated, are the cornerstones of management of ACS. Although patients with LC have been excluded from major clinical trials involving antithrombotic and antiplatelet therapies, there is significant circumstantial evidence that similar benefit generally exists for these therapies in this population as well.
Aspirin for ACS in LC. Aspirin administration was once considered an absolute contraindication for patients with LC due to a perceived prohibitive bleeding risk. Added concerns were that aspirin might also potentiate acute renal failure, hyponatremia, and/or diuretic resistance in LC patients with ascites. On the other hand, there exists a growing amount of data suggesting that aspirin may prevent progression of liver disease and hepatocarcinogenesis, and may even have a survival benefit.[18,19] Aspirin appears to confer antifibrotic effects, although in fairness it has only been shown in small prospective studies and no randomized trials have been performed. In murine models, aspirin limits hepatic stellate cell activation by inhibiting the cyclooxygenase 2 (COX-2) enzyme, and antagonism of COX-2 seems to improve NASH-related fibrosis.
Russo et al. demonstrated the relative safety of aspirin in terms of bleeding risk in patients with cirrhosis, but without significant varices, after coronary revascularization.
Recommendation: For LC patients without active bleeding presenting with ACS, we recommend urgent and daily administration of 81 mg of aspirin only.
Statins for ACS in LC. Early start of statin treatment has become a guideline-directed standard of care after ACS, since they target pathways that link inflammation and thrombosis. Statins, like aspirin, are significantly underutilized for the management of CAD in LC patients. Importantly, in this sub-population, lipid profile alone is not able to risk stratify patients with CAD. Patients with chronic liver disease, especially LC, have impaired hepatic clearance; so, there exists the presumption that this patient population may be at a higher risk for complications from statin therapy. However, several retrospective studies showed that statin use in chronic liver disease and LC is safe and effective.[23,24] A recent meta-analysis suggested that statins may retard progression of hepatic fibrosis and may prevent hepatic decompensation and reduce mortality in LC patients.
Recommendation We recommend urgent and daily use of moderate-high intensity statins in LC patients presenting with ACS.
P2Y12 Inhibitors for ACS in LC. These agents inhibit the P2Y12 receptor, blocking the adenosine diphosphate-induced platelet aggregation. This class of medications is an integral component of treatment and prevention of arterial thrombosis. Clopidogrel, an irreversible inhibitor of P2Y12, requires metabolic activation by the liver. Its pharmacokinetics and pharmacodynamics are relatively unaltered in Child–Pugh class A/mild cirrhosis. Hence, no dosage adjustment is required in mild hepatic impairment; however, caution is recommended for more severe cirrhosis. A recent single-center study in patients with decompensated/Child–Pugh class C LC referred to PCI noted appropriately inhibited platelet function following clopidogrel therapy.
Prasugrel, another irreversible inhibitor of P2Y12, does not require hepatic activation and hence is not contraindicated in cirrhosis, although caution is advised. Ticagrelor, a reversible P2Y12 inhibitor, is converted to an active metabolite (AM) by hepatic cytochrome (CYP) 3A4 enzyme. Therefore, LC can potentially alter the pharmacokinetics and pharmacodynamics of ticagrelor and AM. Both ticagrelor and AM are cleared by the liver and excreted in feces. As per the package insert, no dosage adjustment is required in moderate hepatic impairment/Child–Pugh class B LC (caution advised), but it is not recommended for use in severe/Child–Pugh class C cirrhosis. Zhang et al. evaluated the pharmacokinetics and pharmacodynamics of ticagrelor and its AM using physiologic models and found prolonged inhibition of platelet aggregation with increasing severity of LC.
Recommendation: We generally use clopidogrel monotherapy for very high-risk LC patients with ACS who do not undergo PCI, in the absence of bleeding or significant thrombocytopenia (platelet counts less than 50 × 109/L). In LC patients presenting with STEMI undergoing invasive management of ACS, we consider using prasugrel. Prasugrel has been shown to be beneficial over ticagrelor in achieving lower incidence of MI, death, or stroke without increasing the incidence of major bleeding events. For all other patients, we favor clopidogrel.
GPIIb/IIIa Inhibitors for ACS in LC. Data on use of glycoprotein (GP) IIb/IIIa inhibitors in patients with LC are limited to case reports demonstrating profound thrombocytopenia with eptifibatide use. However, these agents place patients at particularly high bleeding risk.
Recommendation: We generally avoid the use of GP IIb/IIIa inhibitors, especially if patients have been preloaded with P2Y12 inhibitors.
DAPT in LC. DAPT is generally recommended for a minimum of 12 months after placement of drug-eluting stent (DES) and for at least 1 month after placement of bare metal stent (BMS). For all patients presenting with ACS, however, current recommendations are still for 12 months of DAPT thereafter.
The main reason for maintaining DAPT is to prevent stent thrombosis. The primary limitation, however, of DAPT in LC patients is major bleeding. In addition, for those patients being considered for liver transplantation, DAPT recommendations will logically postpone the procedure. As such, a 12-month regimen of antiplatelet therapy may be challenging.
Limited data exist on survival in LC patients who are on DAPT, but the presence of varices may be an important deterrent. Russo et al. retrospectively evaluated 423 LC patients referred for liver transplant and found 16 (3.8%) had received a coronary stent and required DAPT (aspirin and clopidogrel). The investigators compared this group's data with that of an age- and sex-matched control group of patients with LC without stents and not on any antiplatelet therapy. During follow-up there was no statistically significant difference in fatal variceal bleed between the groups (12.5% vs 6.3%, p = 0.86). Even so, a fatal bleeding prevalence of 12.5% was prohibitively high; so, perhaps antiplatelets need to be restricted to patients without esophageal varices. Azarbal et al. demonstrated no significant difference in deaths, recurrent MI, or clinically significant bleeding at 30 days following PCI on DAPT. However, a high incidence of gastrointestinal bleeding in LC cases was noted.
Bleeding rates at 1 year follow-up were found to be 46% compared to a 7% in-hospital bleeding rate in LC patients, suggesting that DAPT use after PCI might increase major bleeding in this cohort. Wu et al. looked at the national database in Taiwan and found that LC patients having MI and on DAPT had decreased recurrent MI at the expense of increased gastrointestinal bleeding. Using institutional databases, Krill et al. found that patients with CAD and LC receiving DAPT had a significantly higher incidence of gastrointestinal bleeding as compared to medical therapy and use of a proton pump inhibitor (PPI) was highly protective. Chen et al. from Taiwan looked at patients with ischemic stroke on long-term aspirin therapy. Looking into a national database and including LC patients admitted to hospital for first-time ischemic stroke, they estimated efficacy of DAPT as a risk of recurrent ischemic stroke. The investigators found DAPT to be safe and effective for secondary prevention of stroke in patients with LC.
Due to challenges with deciding DAPT duration in scenarios like these, the European Society of Cardiology introduced a DAPT score and the PRECISE-DAPT scores.[37,38] These tools guide determination of optimal DAPT duration by ischemic and bleeding risk stratification. Although the DAPT and PRECISE-DAPT risk scoring can potentially help individualize DAPT strategy for the general population, these assessments have not been validated in patients with LC, where DAPT duration continues to be decided based on clinical judgment
Overall, the field has been moving towards shorter DAPT duration, particularly for patients with high bleeding risk. The advancement in stent design with thinner struts and increasing use of intravascular imaging for optimal stent deployment makes us more comfortable with shorter DAPT duration.
There has been a preferential strategy for discontinuing aspirin in favor of P2Y12 inhibitor monotherapy. Once thought of as a cornerstone of DAPT and despite demonstrated cardiovascular efficacy in secondary prevention, aspirin is known to increase the risk of bleeding. A meta-analysis of randomized controlled trials involving > 30,000 patients showed that discontinuation of aspirin 1–3 months after PCI in favor of P2Y12 inhibitor monotherapy reduces the risk of bleeding without increasing the risk of major acute cardiovascular events.
Although the current guidelines recommend 12 months of DAPT, this recommendation is based on trials performed almost 2 decades back and mostly do not include high bleeding risk patients such as those with LC. While removing the P2Y12 inhibitor after a short DAPT appears to be safe in the low bleeding and ischemic risk population, removing aspirin and continuing P2Y12 inhibitor monotherapy would be the preferred strategy in intermediate- to high-risk patients, to mitigate the bleeding risk.
Recommendation: We advise the use of intravascular imaging (such as optical coherence tomography and intravascular ultrasonography) for optimal stent deployment and assessment of adequate stent expansion in LC patients undergoing PCI.
We recommend an individualized approach for DAPT (based upon ischemic and bleeding risk assessment) along with a PPI for LC patients undergoing PCI with DES implantation.
Anticoagulation and Triple Therapy in LC
Patients with LC are at increased risk of venous thromboembolism, in particular portal or deep venous thrombosis. In events like these or with the concurrent presence of atrial fibrillation in LC patients, the occurrence of ACS with stenting raises questions for triple therapy (anticoagulant + DAPT) or dual therapy (anticoagulant + antiplatelet agent). LC patients have been excluded from the major trials comparing dual versus triple therapy for patients with atrial fibrillation undergoing PCI. In a nationwide registry analysis from Taiwan, LC patients with atrial fibrillation had a higher risk of ischemic stroke and intracranial hemorrhage (ICH) compared to those without. Given the high propensity of both ischemic stroke and ICH in LC, the optimal stroke prevention strategy is a clinical dilemma. Kuo et al. showed that patients taking antiplatelet therapy had a similar risk of ischemic stroke as those not treated, and therefore, antiplatelet agents should not be used for stroke prevention among LC patients with atrial fibrillation. However, the risk of ischemic stroke was significantly lowered among warfarin users. For ICH, there were no significant differences between those untreated and those taking antiplatelet or warfarin therapy, further supporting the use of AC in patients with LC. Major antithrombotic agents as well as their reversal agents in case of minor or major bleeding are tabulated (Table 2).[12,13,44,45]
Recommendation We recommend avoiding triple therapy and employing dual therapy with clopidogrel and oral anticoagulant in LC patients with ACS and concomitant atrial fibrillation/venous thrombosis.
Thrombolytics for ACS in LC. As mentioned, LC is accompanied by a state of hyperfibrinolysis, which could potentially delay hemostasis and theoretically aggravate bleeding complications after administration of thrombolytics for ACS/acute stroke in patients with decompensated/Child–Pugh class C LC. The use of thrombolytic therapy in high-risk patients has mostly been studied in ischemic stroke patients. According to the current Food and Drug Administration (FDA) labeling and the 2013 American Heart Association guidelines, the presence of a preexisting known or acute bleeding diathesis or coagulopathy is a contradiction to administration of intravenous alteplase for the treatment of acute ischemic stroke. However, experts also suggest that in the presence of Child–Pugh class A/mild LC with normal bleeding indices, there is no existing evidence for withholding intravenous alteplase for conditions like acute ischemic stroke.
Thrombolytic therapy has been studied in the management of portal vein thrombosis in LC patients, but the evidence is limited to case series.
Peri-procedural Anticoagulation During PCI in LC. Unfractionated heparin (UFH) and enoxaparin are relatively safe to use for patients with cirrhosis with venous thromboembolism, which makes them potentially usable for anticoagulation during PCI. Bivalirudin and other direct thrombin inhibitors have been promoted as being associated with a decreased bleeding risk. Bivalirudin undergoes renal excretion and could pose issues in patients with concomitant renal insufficiency; additional studies regarding its utility are required. Argatroban undergoes hepatic metabolism, and is postulated to be relatively contraindicated in liver disease.
Use of micropuncture techniques might reduce arterial puncture site bleeding in LC patients. Arterial closure devices are safe to use in LC patients with fewer vascular complications and decreased time to ambulation.
Recommendation: We recommend the use of UFH or enoxaparin in LC patients undergoing PCI for peri-procedural anticoagulation and suggest the use of micropuncture technique and arterial closure devices.
Invasive Approach to ACS in LC
LC with evidence of portal hypertension has been classified as a major criterion for high bleeding risk at the time of PCI. Mortality with ACS in LC patients is shown to be high. Abougergi et al. showed that with the trends of better control of risk factors and better practices in the clinical management of ACS including prompt revascularization with stenting and cardiovascular drugs, the survival of LC patients presenting with ACS has improved; however, the mortality rates are still higher than those for individuals without LC.
Coronary angiography and PCI is a less invasive approach to manage obstructive coronary artery lesions compared to bypass surgery; however, the inherent procedural risks and the requisite antiplatelet therapy cannot be undermined. The choice of vascular access for PCI is crucial in LC patients with increased bleeding tendency. The transradial approach is associated with lower rates of vascular access site complications in LC, including the risk of major bleeding, as compared to the transfemoral approach, consistent with the general population.[51,52]
PCI in LC can be associated with procedural risks due to thrombocytopenia, possible coagulopathies, bleeding, and renal failure. Data from national samples show fourfold higher in-hospital and 90-day mortality, as well as a higher 90-day readmission rate in LC patients undergoing PCI. Moreover, LC patients tend to present with higher odds of cardiogenic shock and cardiac arrest requiring percutaneous mechanical support. There is a threefold increase in gastrointestinal bleeding and fivefold increase in acute kidney injury (AKI) requiring dialysis in LC patients undergoing PCI. This results in a longer hospital stay, associated with greater cost and more readmissions. DESs were employed more than BMSs and were associated with favorable outcomes.
One study looked at 1-year outcomes from a single center for patients with significant CAD and cirrhosis undergoing PCI. With a sample size of 42 patients with cirrhosis, they found no difference in mortality, subsequent revascularization, and MI in patients undergoing PCI compared to medical management, with significantly increased incidence of AKI, severe bleeding and peri-procedural stroke in the PCI group. Interestingly, coronary intervention used BMSs in 55%, DESs in 39%, and balloon angioplasty in 8% of patients.
LC patients tend to have lower hemoglobin and higher international normalized ratios and creatinine values compared with general population/matched cohorts. This portends a higher risk of peri-procedural bleeding, pseudoaneurysm formation, and the need for blood products. Analysis from the National Inpatient Sample showed PCI to be a plausible option for patients with cirrhosis, but with an increased risk compared with the general population. A Japanese study showed BMSs to be used in 184 out of 233 LC patients undergoing PCI.
PCI can be safely performed in LC patients despite the abovementioned risks. A reduction in MI incidence and cardiac mortality is demonstrated with increased frequency of cardiac catheterization in liver transplant candidates compared to non-invasive coronary assessment strategies.
National trends of annual PCI rates show these are on the rise in patients with cirrhosis.[16,57] Data from the National Inpatient Samples show that PCI in LC patients is associated with higher in-hospital mortality, as well as complications including AKI, longer hospital stay, and higher healthcare cost. However, patients with LC had a higher prevalence of diabetes, CKD, atrial fibrillation, coagulopathy, alcohol use disorder, and anemia along with high-risk characteristics and poor socioeconomic status.[16,57] PCI itself is shown to be independently associated with a lower mortality rate in LC patients.]
There had been a preferential approach of opting for BMSs in patients with cirrhosis because of earlier endothelialization and shorter DAPT duration times. However, several prospective, large, contemporary clinical trials have demonstrated the superior outcomes of second-generation DESs compared to BMSs.[58,59]
Coronary artery stenting and DAPT is associated with an independent risk of upper gastrointestinal bleeding not related to LC and the consequent portal hypertension. A history of variceal bleeding or presence of varies confers an increased risk; hence, up-to-date screening/management for varices is recommended prior to cardiac catheterization.
Recommendation: We recommend patients with small or no varices can safely proceed with PCI and DES implantation with DAPT (duration individualized for bleeding and ischemic risk as per the algorithm mentioned in Figure 3) with PPI followed by P2Y12 monotherapy.
Proposed management algorithm for ACS in LC. High ischemic risk is defined as having at least one of the following features: unprotected left main lesion; > 3 stents implanted; lesion length > 30 mm; bifurcation stenting; bypass graft stenting; chronic total occlusion. High bleeding risk is defined as per the Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria: LC with portal hypertension; severe or end-stage CKD; spontaneous bleeding requiring hospitalization or transfusion in the past 6 months or any time, if recurrent; chronic bleeding diathesis; active malignancy; previous spontaneous intracranial bleeding; no deferrable major surgery on DAPT; recent major surgery or major trauma within 30 days before PCII. ACS acute coronary syndromes, Anticoag anticoagulant, ASA acetylsalicylic acid/aspirin, CABG coronary artery bypass grafting, CKD chronic kidney disease, Clopi clopidogrel, DAPT dual antiplatelet therapy, DES drug-eluting stent, Enox enoxaparin, Inhib. inhibitor, LC liver cirrhosis, NSTEMI non-ST elevation myocardial infarction, PCI percutaneous coronary intervention, PPI proton pump inhibitor, STEMI ST-elevation myocardial infarction, TIMI thrombolysis in myocardial infarction, UFH unfractionated heparin
CABG for ACS in LC
Cirrhosis has been shown to be a major risk factor for cardiac surgery, particularly when using cardiopulmonary bypass. Marui et al. studied the coronary revascularization strategies in LC patients in Japan. The investigators found increased in-hospital mortality with coronary artery bypass grafting (CABG) compared to PCI. Off-pump CABG was associated with a lower in-hospital mortality compared to conventional CABG. None of the differences, however, achieved statistical significance, and the author concluded that complete revascularization may not be associated with improved survival in cirrhosis because of high overall non-cardiovascular mortality in this cohort. A Child Pugh score of less than or 7 is considered safe for cardiac surgery, whereas a score of 8 or higher is associated with significant risk of mortality. A sequential/combined approach for CABG/valvular heart surgery and liver transplant was studied recently by Wood et al.. Based upon a sample size of 15 patients (nine of whom got CABG) with a mean model for end-stage liver disease (MELD) score of 24, the authors found a 1-year survival rate of 73% and suggested a combined liver transplant and cardiac surgery approach is feasible.
Recommendation: We recommend cardiac surgery for LC patients with CAD not amenable to percutaneous intervention, preferably with valvular heart surgery or combined liver transplant only at high volume centers with a cohesive multidisciplinary team.
Management Algorithm for ACS in LC
Based upon the recommendations provided above, we propose the algorithm shown in Figure 3 for the management of ACS in LC patients.
Am J Cardiovasc Drugs. 2022;22(1):55-67. © 2022 Adis Springer International Publishing AG