Coronary artery disease (CAD) is the most common type of cardiovascular (CV) disease in the United States, affecting an estimated 6.7% of adults aged 20 years and older.1 Individuals with CAD who have not experienced a recent CV event are generally considered to have stable CAD. However, the authors of an article published in Nature Reviews Cardiology argue that the term “stable CAD” is a misnomer that should be replaced with the term “chronic CAD.”2 Noting that a wide range of significant risk factors underlie the persistent long-term risk of major adverse cardiovascular events (MACE) in CAD, they propose that “chronic CAD” would be a more accurate term to describe this condition.

“I agree with the suggested terminology change because, as the authors point out, the word ‘stable’ implies that the process is quiescent but in fact it is ongoing and could eventually lead to a CV event, thus underscoring the continuum of this condition,” said Ragavendra Baliga, MBBS, MBA, FACC, cardiologist and professor of internal medicine at The Ohio State University Wexner Medical Center in Columbus. “I think the terminology of ‘chronic’ is apt because it signals both to the patient and the treating clinician that continued concern is warranted.”

The elevated risk for MACE often persists in patients with CAD despite guideline-based secondary prevention measures such as lifestyle changes and optimal medical therapy, highlighting the need for improved interventions for this population. The novel secondary prevention strategies described below have shown promise in further reducing the risk for adverse events in patients with CAD.

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Antithrombotic therapy. “Attempts to optimize antithrombotic strategies for chronic­phase cardiovascular disease are increasingly focused on dual targeting of platelet activation and the coagulation pathway,” noted the review authors.2 Although studies investigating the use of vitamin K antagonists (VKAs) indicate a reduced risk of CV events (including a 44% reduction in the annual risk of recurrent myocardial infarction) compared with aspirin, the incidence of associated major bleeding events increased by more than 2-fold among patients taking VKAs.2

Other studies examined the efficacy of non-VKA oral anticoagulants in patients with acute coronary syndrome (ACS), including the phase III, double­blind ATLAS ACS 2-TIMI 51 trial evaluating rivaroxaban 2.5 mg and 5.0 mg twice daily in patients taking aspirin or aspirin plus clopidogrel or ticlopidine. While both doses led to significant reductions in the risk for MACE compared with placebo, the risk for bleeding events was higher in the treatment groups.3 Rivaroxaban 2.5 mg dosage had better safety outcomes compared with the 5.0 mg dosage and was subsequently approved in Europe for secondary prevention in patients with elevated biomarkers following ACS.

Findings from the phase III COMPASS trial added support for the use of the factor Xa inhibitor rivaroxaban combined with antiplatelet therapy in patients with chronic CAD or peripheral artery disease (PAD). Participants who received (along with standard secondary preventive therapies) rivaroxaban 2.5 mg twice daily plus acetylsalicylic acid (ASA) 100 mg once daily had a 24% reduction in the risk for MACE compared with patients receiving only ASA 100 mg once daily and  a 70% increase in the risk for major bleeding.

A sub-analysis of the COMPASS data indicated that rivaroxaban 2.5 mg twice daily plus aspirin reduced the risk for MACE and major adverse limb events compared with aspirin alone in patients with PAD or carotid artery disease and/or CAD.

Lipid-lowering agents. While the use of statins is recommended in patients with established CAD, alternate or adjunctive lipid-lowering therapies may be warranted for patients who do not reach the treatment goal of a low-density lipoprotein (LDL)­ cholesterol level <1.8 mmol/l (<70 mg/dl) or >50% reduction in LDL­ cholesterol level. Results from the IMPROVE-IT trial indicated reductions in average LDL-cholesterol levels and in the composite risk for MACE and unstable angina requiring hospitalization and revascularization in patients with ACS taking ezetimibe with simvastatin vs simvastatin alone.4

The PCSK9 monoclonal antibodies represent another therapeutic option for patients who do not tolerate or adequately respond to statins. In a  meta-analysis, these agents were linked to significant reductions in LDL­cholesterol levels, and in rates of myocardial infarction, coronary revascularization, and stroke, with no significant increase in the risk for treatment­emergent adverse events.5

Anti-inflammatory agents. “Research has suggested that inflammatory activity contributes to the vulnerability of plaques and that systemic inflammation might increase the risk [for] thrombosis at sites of plaque rupture or erosion,” noted the review authors.2 “Furthermore, biomarkers of inflammation, such as high-​sensitivity C-​reactive protein (hsCRP) and interleukin (IL)­6, are associated with an increased risk [for] cardiovascular events independently of the cholesterol level.” Findings indicate that the anti-inflammatory effects of statins may underlie the reduction in CRP levels and in the risk for MACE.

In addition, investigators in the phase III CANTOS trial reported that the IL­1β inhibitor canakinumab significantly reduced hsCRP levels vs placebo in patients with a history of myocardial infarction and persistent inflammation, without reducing lipid levels.6 The incidence of recurrent CV events was lower in patients taking canakinumab 150 mg vs placebo.

Along with the antithrombotic, lipid-lowering, and anti-inflammatory agents described above, recent randomized controlled trials also suggest that several newer antidiabetic agents may reduce the risk for MACE, including the sodium–glucose cotransporter 2 antagonist empagliflozin, the glucagon­ like peptide 1 receptor agonist liraglutide, and the long­acting glucagon­ like peptide 1 receptor agonist semaglutide.

“The latest advances demonstrate that chronic vascular risk is modifiable and that novel approaches in managing these risk factors have the potential to produce clinically worthwhile gains in the patients who are most susceptible to cardiovascular events,” the review authors concluded.2 With ongoing developments in the field, the use of novel imaging techniques and systemic biomarkers may ultimately enable identification of patients at highest risk for CAD. 

“The emphasis has been on disease management hitherto, but future research should focus on prevention, particularly public health approaches,” noted Dr Baliga. In a 2014 editorial, he and colleagues aimed to “create awareness that a billion hearts can be protected from death or disability in the next decade” with the implementation of a system-wide strategy (including efforts by government, health systems, and insurers) to prevent ischemic heart disease and stroke.7


  1. Centers for Disease Control and Prevention. Heart disease facts. Accessed online May 8, 2020.
  2. Fox KAA, Metra M, Morais J, Atar D. The myth of ‘stable’ coronary artery disease. Nat Rev Cardiol. 2020;17(1):9-21.
  3. Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366(1):9‐19.
  4. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387‐2397.
  5. Bai J, Gong LL, Li QF, Wang ZH. Long-term efficacy and safety of proprotein convertase subtilisin/kexin 9 monoclonal antibodies: A meta-analysis of 11 randomized controlled trials. J Clin Lipidol. 2018;12(2):277‐291.e3.
  6. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119‐1131.
  7. Baliga RR, Smith SC Jr, Narula J. Protecting a billion hearts. Glob Heart. 2014;9(4):361‐362.