What are the most important clinical trials in cardiology related to Coronary Artery Disease (CAD)?

Most Important Clinical Trials in Coronary Artery Disease

The most significant clinical trials in coronary artery disease management include COURAGE, ISCHEMIA, SYNTAX, FREEDOM, BARI 2D, HOPE, EUROPA, and HPS, which have collectively shaped our current approach to CAD management through evidence on medical therapy, revascularization strategies, and preventive pharmacotherapy.

Landmark Medical Therapy Trials

Antiplatelet and Antithrombotic Therapy

• CURE (2001): Demonstrated dual antiplatelet therapy (aspirin plus clopidogrel) significantly reduced cardiovascular events in ACS patients 1
• PLATO (2009): Showed ticagrelor's superiority over clopidogrel in reducing death from vascular causes, MI, or stroke in ACS patients 1
• TRITON-TIMI 38 (2007): Established prasugrel's efficacy in reducing cardiovascular events compared to clopidogrel in ACS patients undergoing PCI, though with increased bleeding risk 1

Lipid-Lowering Therapy

• Heart Protection Study (HPS) (2002): Landmark trial showing statin therapy (simvastatin) reduced mortality and cardiovascular events regardless of baseline cholesterol levels 2
• PROVE IT-TIMI 22 (2004): Demonstrated intensive statin therapy (atorvastatin 80mg) was superior to moderate therapy (pravastatin 40mg) in reducing cardiovascular events after ACS 1
• IMPROVE-IT (2015): Showed adding ezetimibe to statin therapy provided incremental benefit in reducing cardiovascular events 1
• FOURIER (2017): Established PCSK9 inhibitor evolocumab significantly reduced cardiovascular events in patients with atherosclerotic disease 1

ACE Inhibitors and ARBs

• HOPE (2000): Demonstrated ramipril reduced cardiovascular death, MI, and stroke in high-risk patients with vascular disease without heart failure 2
• EUROPA (2003): Showed perindopril reduced cardiovascular events in stable CAD patients with lower risk profiles than those in HOPE 2

Revascularization vs. Medical Therapy Trials

Stable CAD

• COURAGE (2007): Pivotal trial showing PCI did not reduce death or MI compared to optimal medical therapy alone in stable CAD patients 2
• BARI 2D (2009): Demonstrated that prompt revascularization versus intensive medical therapy alone did not reduce mortality in diabetic patients with stable CAD, though the CABG stratum showed reduced major adverse cardiac events 2
• ISCHEMIA (2020): Largest and most recent trial showing routine invasive strategy did not reduce major adverse cardiovascular events compared to optimal medical therapy in patients with moderate-to-severe ischemia 1

Multivessel and Complex CAD

• SYNTAX (2009): Established the role of SYNTAX score in guiding decision-making between CABG and PCI in patients with complex CAD, showing CABG superiority for high SYNTAX scores 1
• FREEDOM (2012): Demonstrated CABG's superiority over PCI in diabetic patients with multivessel disease 1
• EXCEL (2019): Compared PCI versus CABG in left main coronary artery disease, showing non-inferiority of PCI for the primary composite endpoint 1

Imaging and Diagnostic Trials

• PROMISE (2015): Compared coronary CTA versus functional testing as initial diagnostic strategy, showing similar outcomes but different downstream testing patterns 2
• SCOT-HEART (2018): Demonstrated coronary CTA-guided strategy reduced myocardial infarction compared to standard care 2
• FAME (2009): Established the value of fractional flow reserve (FFR) in guiding PCI decisions, showing improved outcomes with FFR-guided PCI versus angiography alone 1

Acute Coronary Syndrome Trials

• HORIZONS-AMI (2008): Demonstrated benefits of bivalirudin versus heparin plus GP IIb/IIIa inhibitors in primary PCI for STEMI 2
• ACUITY (2006): Showed bivalirudin alone was non-inferior to heparin plus GP IIb/IIIa inhibitors in moderate to high-risk ACS patients 2
• EARLY-ACS (2009): Evaluated early versus delayed GP IIb/IIIa inhibition in ACS patients 2

Secondary Prevention Trials

• BEAUTIFUL (2008): Evaluated ivabradine in patients with CAD and left ventricular dysfunction, showing no significant effect on the primary composite endpoint 3
• SIGNIFY (2014): Assessed ivabradine in patients with stable CAD without heart failure, showing no benefit on cardiovascular outcomes 3
• COMPASS (2017): Demonstrated that low-dose rivaroxaban plus aspirin reduced major adverse cardiovascular events compared to aspirin alone in stable atherosclerotic disease 1

Polypill Concept Trials

• ACOS Registry (2011): Showed combination therapy with aspirin, ACE inhibitor, and statin reduced 1-year mortality in post-MI patients 4
• SECURE (2022): Demonstrated polypill strategy improved medication adherence and cardiovascular outcomes in secondary prevention 1

Key Insights for Clinical Practice

• Medical therapy remains the cornerstone of CAD management, with aspirin, statins, beta-blockers, and ACE inhibitors forming the foundation of treatment 2, 1
• Revascularization decisions should be guided by anatomical complexity (SYNTAX score), functional significance (FFR), and patient characteristics (diabetes, renal function) 2, 1
• Newer agents including SGLT2 inhibitors and GLP-1 receptor agonists have shown cardiovascular benefits in diabetic patients with CAD 1
• Coronary CTA with CT-FFR and high-risk plaque assessment is emerging as a valuable tool for CAD diagnosis and risk stratification 2

These landmark trials have progressively refined our understanding of CAD pathophysiology and management, leading to improved outcomes through evidence-based approaches to both medical and interventional therapies.