Antithrombotic Treatment of Stable Coronary Artery Disease

Abstract

Coronary artery disease (CAD) is one of the leading causes of death in Taiwan. Despite the use of current guideline-recommended therapies for secondary prevention, the residual risk of recurrent cardiovascular events remains high in CAD, warranting the need for new treatment options. Antithrombotic drugs are one of the most important medical therapies for CAD. In this article, we review the unmet needs of the current antithrombotic agents and summarize the results of clinical trials with dual antiplatelet therapy in stable CAD. We also review data from a recent study demonstrating the benefits of a dual pathway inhibition strategy with antiplatelet and anticoagulant therapy, a new option for CAD treatment. Finally, we propose a treatment algorithm for choosing different antithrombotic regimens for CAD based on current scientific evidence and expert opinions.

INTRODUCTION

Cardiovascular (CV) disease is the most common cause of death in the world and was responsible for approximately 17.8 million deaths globally in 2017.^1,2 Coronary artery disease (CAD) accounts for a major portion of CV disease. The original Framingham study reported a lifetime risk of approximately 30 to 50% to develop CAD in middle-aged men and women.³ The mortality rate of CAD has risen sharply in Asia, especially in India and China. From 1984 to 1999, the age-adjusted mortality rates increased by 41% and 39% in middle-aged East Asian men and women, respectively.⁴ In Taiwan, CV disease was the second leading cause of death in 2018, an increase of 4.5% compared to 2017.⁵ In patients with stable CAD or other atherosclerotic cardiovascular disease (ASCVD), the residual risk of recurrent CV events remains high despite the use of aspirin monotherapy and adequate control of risk factors.^6-11 For example, in patients with prior myocardial infarction (MI), stroke, or peripheral artery disease (PAD), the risk of recurrence is 3.1% for MI, 3.8% for stroke, 3.4% for CV death and 5.4% for all-cause death after a median follow-up of 27.6 months.⁸ In Taiwan, patients with prior MI were shown to have an overall recurrent CV event rate of 13.8% in a 3-year follow-up study, including 5.8% for recurrent MI, 5.0% for stroke, and 5.2% for death.¹² New therapeutic options are needed for patients with stable CAD, especially for those with documented prior MI or CAD after revascularization, because high residual risk persists in these patients. Concomitant CAD with atrial fibrillation or other reasons requiring full-dose oral anticoagulation is another complex issue. Therefore, the main purpose of this article was to review the antithrombotic treatments only in patients with stable CAD who did not need oral anticoagulant therapy.

CURRENT MANAGEMENT

The treatment goals for patients with stable CAD are to relieve symptoms and prevent future CV events, such as unstable angina, MI, stroke, and death. The management of CAD comprises lifestyle modification, control of risk factors, pharmacological therapies and/or revascularization.¹³ A variety of medications are recommended to relieve symptoms of angina, including nitrates, beta-blockers, and calcium channel blockers, which may be prescribed as monotherapy or in various combinations. Other therapies that can improve adverse clinical outcomes include antiplatelets, statins, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.¹³

ANTIPLATELET THERAPY

Antiplatelet agents are the cornerstone of treatment for secondary prevention in CAD. In most guidelines, aspirin is still the drug of choice for the prevention of CV events in stable CAD. If aspirin is contraindicated, clopidogrel should be used.^13-16 Dual antiplatelet therapy (DAPT), including aspirin plus a P2Y12 inhibitor, is used for patients with CAD undergoing percutaneous coronary intervention (PCI) to minimize the risk of stent thrombosis and recurrent CV events. For stable CAD, European and American guidelines recommend DAPT for 6 months after PCI with drug-eluting stents and 1 month with bare-metal stents.^17,18 Despite the use of a single antiplatelet agent or DAPT in current practice, the risk of recurrent atherothrombotic events persists in stable CAD.¹⁹ Several studies have investigated the efficacy of DAPT in patients with chronic ASCVD, including CAD, by adding P2Y12 inhibitors (clopidogrel, ticagrelor or prasugrel) to aspirin (Table 1).^8,9,20,21 Although DAPT has been shown to provide greater benefits than aspirin monotherapy, no decrease in mortality has been reported, and the patients still have a significant residual risk. For example, in the CHARISMA trial, the patients had an event rate of approximately 7% at 30 months, and in the PEGASUS-TIMI 54 trial, there was a residual risk of 9% at 36 months, even though most of the patients were also receiving renin-angiotensin system inhibitors and statins.^8,9 Furthermore, the benefits in these trials were counterbalanced by an increased risk of bleeding.

Table 1. Efficacy and safety of dual antiplatelet therapy vs. aspirin monotherapy in patients with ASCVD.

Study (publication year)	Population/sample size	Intervention vs. control	MACE	Major bleeding	All-cause mortality
CHARISMA8 (2007)	ASCVD (Patients with prior MI, ischemic stroke, or symptomatic PAD). N = 9,478	Clopidogrel 75 mg QD plus Aspirin vs. Aspirin. Median follow-up: 27.6 months	HR = 0.83; p = 0.01	GUSTO severe bleeding, HR = 1.114, p = 0.509; GUSTO moderate bleeding, HR = 1.597, p = 0.004	HR = 0.914, p = 0.316
PEGASUS9 (2015)	CAD (Patients with prior MI 1-3 years ago). N = 21,162	Ticagrelor 90 mg/60 mg BID plus Aspirin vs. Aspirin. Median follow-up: 33 months	Ticagrelor 90 mg: HR = 0.85, p = 0.008; Ticagrelor 60 mg: HR = 0.84, p = 0.004	Ticagrelor 90 mg: HR = 2.69, p < 0.001; Ticagrelor 60 mg: HR = 2.32, p < 0.001	Ticagrelor 90 mg: RR = 1.00, p = 0.99; Ticagrelor 60 mg: RR = 0.89, p = 0.14
DAPT20 (2014)	Patients who had PCI with stent 12 months prior to enrollment. N = 9,961	Thienopyridine plus. Aspirin 75-162 mg QD vs. Aspirin. Follow-up: 18 months post-randomization	MACCE: HR = 0.71, p < 0.001	GUSTO severe/moderate bleeding, HR = 1.61, p = 0.001	HR = 1.36, p = 0.052
THEMIS21 (2019)	CAD and DM. N = 19,220	Ticagrelor 60 mg BID plus Aspirin vs. Aspirin. Median follow-up: 39.9 months	HR = 0.9, p = 0.04	HR = 2.32, p < 0.001	HR = 0.98, p = NS

ASCVD, atherosclerotic cardiovascular disease; BID, twice a day; CAD, coronary artery disease; DAPT, dual antiplatelet therapy; DM, diabetes mellitus; GUSTO, Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries; HR, hazard ratio; MACE, major adverse cardiovascular events; MACCE, major adverse cardiovascular and cerebrovascular events; MI, myocardial infarction; NS, not significant; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; QD, once a day; RR, relative risk.

DUAL THERAPY

The limitations of antiplatelet treatment have led to further exploration of the efficacy of dual therapy, consisting of a single antiplatelet and an anticoagulant, on improving atherothrombotic outcomes for CAD. Coagulation is a key component in the formation of arterial clots. Thrombin, an important mediator in the coagulation pathway, amplifies platelet activation which has led to the hypothesis that synergies may exist between platelet inhibition and anticoagulation,²² a treatment combination known as dual pathway inhibition or dual therapy. Rivaroxaban is one of the most extensively studied factor Xa inhibitors for dual pathway inhibition. The phase III Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial randomized 27,395 patients with chronic ASCVD including CAD and/or PAD into three treatment arms over a median duration of 23 months: rivaroxaban 2.5 mg BID plus aspirin, rivaroxaban 5 mg BID, or aspirin alone.²³ CAD patients were included if they had a history of MI in the last 20 years, multi-vessel CAD or a history of multi-vessel revascularization. Rivaroxaban 2.5 mg BID plus aspirin significantly reduced the overall risk of major adverse CV event (MACE), including CV death, MI or stroke, by 24% compared to aspirin alone [4.1% versus 5.4%; hazard ratio (HR) 0.76, p < 0.001]. The number needed to treat was 77. In addition, dual therapy with rivaroxaban 2.5 mg BID plus aspirin significantly reduced the overall risk of stroke by 42% and all-cause mortality by 18% compared with aspirin alone. An increase in major bleeding was reported in the dual therapy treatment group: 3.1% in the rivaroxaban 2.5 mg BID plus aspirin group versus 1.9% in the aspirin alone group. However, the increase was not driven by fatal bleeding or intracranial hemorrhage (ICH). The risks of fatal bleeding (0.2% versus 0.1%) and ICH (0.3% versus 0.3%) were low, and there were no significant differences between the two groups.²³ The COMPASS study is the first clinical trial to demonstrate that intensive antithrombotic treatment can lead to a statistically significant reduction in mortality and clear net clinical benefit. The combination of efficacy and mortality reduction demonstrated in the COMPASS trial makes dual therapy a clinically attractive option for CAD. However, there were study limitations in the COMPASS trial. Early termination in the trial may have resulted in overestimation of the treatment effect. In addition, the use of statins and low-density lipoprotein cholesterol levels were not specifically recorded, so their effects could not be evaluated.²³

GUIDELINE RECOMMENDATIONS

The European Society of Cardiology (ESC) redefined the term "stable CAD" to "chronic coronary syndrome (CCS)" in the 2019 ESC CCS guidelines, implying that CAD patients have a continued risk of recurrent CV events which require long-term intensive antithrombotic treatment to minimize the risk.²⁴ In the 2019 ESC CCS guidelines, among patients with stable CAD and sinus rhythm, in addition to conventional DAPT, rivaroxaban 2.5 mg BID plus aspirin was included as one of the treatment options for dual antithrombotic therapy in patients at a high risk of ischemic events and without a high bleeding risk for long-term secondary prevention (class of recommendation IIa, level of evidence A). Among the different options for the second antithrombotic agent in combination with aspirin, rivaroxaban 2.5 mg BID is the only oral anticoagulant, along with other P2Y12 inhibitors such as ticagrelor, prasugrel and clopidogrel.

RISK STRATIFICATION

In clinical practice, clear risk stratification to identify suitable patients for dual therapy is necessary. In the COMPASS trial, the treatment effect of dual therapy was consistent across the defined subgroups. Among those with a history of CAD, 69% had a history of MI (5% within 1 year, 29% within 1-5 years, and 34% over 5 years) with a mean of 7.1 years after MI onset. In this subgroup, rivaroxaban 2.5 mg BID plus aspirin significantly reduced the primary MACE outcome by 26% and all-cause mortality by 23% with an increase in major bleeding but no significant differences in ICH and fatal bleeding.²⁵ The benefit of dual therapy was found to be consistent in those with and without a prior history of MI and whether the MI was recent or remote. This observation is different from the strategy of DAPT with ticagrelor and aspirin in a similar population.²⁶

Risk stratification has been applied to the COMPASS population to help clinicians identify patients with the highest risk of recurrent CV events and who are more likely to benefit the most from dual therapy. In an independent analysis, two methods of risk stratification were applied to the COMPASS trial population: the REduction of Atherothrombosis for Continued Health (REACH) registry risk score and classification and regression tree (CART) survival analysis.²⁷ The REACH registry score demonstrated that patients with the involvement of two or more vascular beds (for example CAD plus PAD), a history of heart failure, or decline in renal function were likely to obtain the highest net clinical benefit with dual therapy. The CART survival analysis identified that those with polyvascular disease, decline in renal function, and diabetes had a higher risk of recurrent events and benefitted the most from dual therapy.²⁷ For antiplatelet therapy, two major scoring systems, the DAPT score and the PRECISE-DAPT score, were developed to allow physicians to tailor antithrombotic therapy and duration, by comprehensively assessing the bleeding and thrombotic risks in individual patients.^28,29 Developing a standardized scoring system to stratify Taiwanese and other Asian patients as part of the antithrombotic regimen decision-making process will be an important initiative moving forward. Before that, based on the evidence and suggestions of the authors, a simple decision-making algorithm (Figure 1) was proposed to select suitable stable CAD patients for long-term intensive antithrombotic treatment in Taiwan. The definitions of high ischemic and bleeding risk to guide the decision are shown in Table 2.

Figure 1.

An algorithm of choosing antithrombotic therapy for patients with coronary artery disease not requiring full dose oral anticoagulation. The criteria to define high bleeding risk and high ischemic risk are described in Table 2. Patients are considered to have low risk if they do not have high risk features. ACS, acute coronary syndrome; CAD, coronary artery disease; DAPT, dual antiplatelet therapy; DPI, dual pathway inhibition; NSTEMI, non-ST elevation myocardial infarction; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; SAPT, single antiplatelet therapy; STEMI, ST-elevation myocardial infarction; UA, unstable angina.

Table 2. Assessment criteria for ischemic and bleeding risk^16,24.

High ischemic risk	High bleeding risk
• Stent related: long stent (total length > 60 mm) and/or multiple stents	• Low body weight (< 55 Kg for men, < 50 Kg for women)
	• End-stage renal disease requiring dialysis
• Anatomy related: long lesion, smaller vessel; bifurcation lesion, history of complex revascularization (left main, bifurcation stenting, chronic total occlusion, stenting of last patent vessel)	• Moderate to severe anemia (Hemoglobin < 11 g/dL)
	• Thrombocytopenia (Platelet count < 100 × 109/L)
	• Need long term use of anticoagulation
• Patient related: CAD with PAD and/or ischemic stroke, multivessel CAD, heart failure, diabetes, chronic kidney disease (eGFR < 60 mL/min/1.73 m2)	• Liver cirrhosis
	• Active malignancy
	• History of previous major bleeding

CAD, coronary artery disease; eGFR, estimated glomerular filtration rate; PAD, peripheral artery disease.

CONCLUSIONS

Timely and optimal treatments are essential to minimize the risk of recurrent CV events in patients with stable CAD. Adequate medical therapy not only improves patients’ clinical outcomes but also reduces the economic burden on healthcare systems. Various antithrombotic therapies for the management of stable CAD, including single antiplatelet, DAPT and dual therapy, have been clinically validated. In this review, we propose an algorithm to guide the proper use of these treatments among stable CAD patients in Taiwan. For development of stable CAD guidelines in Taiwan in the near future, the recommendation made in this review could be a key-point of reference for antithrombotic treatment for stable CAD.

CONFLICTS OF INTEREST

All the authors declare no conflict of interest.