What is the role of revascularization in the management of stable ischemic heart disease (SIHD)?

Stable ischemic heart disease (SIHD) is a condition that results in decreased blood supply to the myocardium, most commonly due to atherosclerotic plaques of epicardial vessels. This can lead to stable angina, ACS, and ischemic cardiomyopathy. Several studies since the 1970s have compared revascularization and optimal medical therapy (OMT) strategies on their ability to decrease the mortality and symptom burden in patients with SIHD. Initial trials comparing these two strategies assessed patients with “high-risk” coronary disease, which was defined as ≥50% atherosclerosis in either the left main coronary artery, the proximal left anterior descending and circumflex artery, or in all three major coronary arteries (3-vessel CAD). The studies demonstrated that revascularization with CABG improved survival, anginal symptoms, and left ventricular dysfunction compared to medical management alone.

The optimal management of patients with SIHD in the absence of high-risk lesions was not clear. Over the past few decades, the use of percutaneous coronary intervention (PCI) has increased dramatically as a method of coronary revascularization without the morbidity surrounding a major surgery such as CABG. OMT of SIHD has also advanced to include beta-blockers, calcium-channel blockers, nitrates, ranolazine, aspirin, and statins. With the advent of more prevalent PCI and a significantly more robust OMT regmien, we present 3 trials comparing early revascularization to OMT in SIHD without high-risk features. By the end of this email, you should have a basic understanding of how you might counsel Anne using your knowledge of the COURAGE, FAME 2, and ISCHEMIA trials.

---

By the end of this post, you should have a basic understanding of a few of these trials and how you might counsel Anne Jina.

---

The Trials

• COURAGE (2007)
• FAME 2 (2012)
• ISCHEMIA (2020)

COURAGE (2007)

PCI did not decrease death or myocardial infarction in SIHD when added to medical therapy.

Population (N = 2287)

• Patients with SIHD and ≥70% stenosis in at least one coronary artery with angina and objective myocardial ischemia
• Excluded left main disease, severe angina, markedly positive stress tests, LVEF ≤30%

Intervention

• PCI plus OMT (N = 1149) 
• OMT alone (N = 1138)

Outcomes

• Primary: No statistically significant difference in primary composite of death from any cause and nonfatal MI (PCI + OMT 19% vs. OMT 18.5%)
• Secondary: rate of revascularization at 4 years was lower in PCI group

Criticism

• Majority of PCI arm received bare metal stents; current standard of care is PCI with drug eluting stents
• Unclear how long patients took clopidogrel or if extended duration of therapy would improve outcomes in the PCI group
• Nearly 1/3 of patients in the OMT group crossed over to revascularization

---

FAME 2 (2012)

Using fractional flow reserve (FFR) during PCI to selectively revascularize hemodynamically significant lesions decreased the composite rate of death, nonfatal MI, and urgent revascularization when compared to medical therapy alone.

Population (N = 888)

• Patients with SIHD with angina and at least 1 stenosis ≥ 50%
• Excluded left main disease, 3v CAD, and LVEF <30%

Intervention

• FFR-guided PCI + OMT (N = 447)
• OMT alone (N = 441)

Outcomes:

• Primary: FFR-guided PCI significantly reduced the primary composite outcome of death, nonfatal MI, and urgent revascularization, compared to OMT alone (PCI 4.3% vs. OMT 12.7%)
• Secondary: Rates of urgent revascularization and any revascularization were significantly less in the PCI group

Criticism

• The primary composite outcome was driven primarily by the softer endpoint of reduction in urgent revascularization

---

ISCHEMIA (2020)

Initial invasive approach to SIHD did not reduce ischemic cardiovascular events or death as compared to medical therapy.

Population (N = 5179)

• Patients with SIHD and moderate-to-severe ischemia based on stress test or cardiac MRI
• Excluded ≥50% left main disease (based on coronary CT), unacceptable angina at baseline, LVEF ≤35%

Intervention

• Initial invasive approach (PCI or CABG) + OMT (N = 2588)
• OMT alone (N = 2591)

Outcomes

• Primary: No statistically significant difference in composite outcome of CV death, MI hospitalizations, heart failure, resuscitated cardiac arrest at mean 3.3 years (invasive 13.3% vs OMT 15.5%)

Criticism

• MI was defined as a combination of procedural-related MIs and spontaneous MIs. Taken together, there was no difference in MIs. However, spontaneous MIs were reduced with an initial invasive strategy, which may be more clinically relevant.

Other points

• Over the entire follow-up period, cardiac catheterization was performed in 96% of the invasive group vs. 28% of the medical therapy group
• There was no association between degree of ischemia and all-cause mortality
• Functional status was studied in the ISCHEMIA patient group and released as a second NEJM article entitled “Health-Status Outcomes with Invasive or Conservative Care in Coronary Disease”. Patients randomly assigned to the invasive strategy had greater improvement in angina-related health status than those assigned to the conservative strategy.

---

The Bottom Line

When deciding between initial revascularization and OMT alone in SIHD, it is important to understand the evidence and indications for both strategies. For patients with high-risk anatomy (left main, left main equivalent, or 3-vessel disease) or ischemic cardiomyopathy, revascularization is generally superior to OMT. The trials discussed above demonstrate that in the absence of these specific indications for revascularization, an initial strategy of OMT vs. OMT/revascularization is no different with respect to hard outcomes (death/MI). However; OMT/revascularization is superior with regards to symptom relief and need for urgent revascularization. PCI with FFR may help identify which lesions are hemodynamically significant and would most benefit from revascularization. As noted by Dr. Parikh below, shared decision making is critical because each patient with SIHD may have different treatment goals. 

---

Experts’ Opinions

Rushi Parikh, MD, FACC, FSCAI

Assistant Clinical Professor 
Co-Assistant Director, Interventional Cardiology Research 
Interventional Cardiology | Advanced Heart Failure
David Geffen School of Medicine | UCLA

Over the past 2 decades, a series of landmark randomized controlled trials—COURAGE (2007), FAME 2 (2012), and most recently, ISCHEMIA (2020)—have investigated the preferred approach to treating patients with stable ischemic heart disease (SIHD). In each of these trials, an initial strategy of optimal medical therapy (OMT) alone was compared with an initial strategy of revascularization (predominantly percutaneous coronary intervention [PCI]) in addition to OMT in selected lower-risk patients (e.g. absence of left main coronary artery disease [LMCA], normal left ventricular systolic function, etc.). Although the data have been consistent in showing that an early revascularization strategy does not improve hard outcomes (death and myocardial infarction [MI]), the management of SIHD remains a controversial and hotly debated topic amongst cardiologists.

From an interventional cardiology perspective, a few salient points should be considered when appraising these data. First, these trials are strategy trials—an initial strategy of OMT is certainly reasonable in select patients with SIHD, but in short-term follow-up, up to one-third of patients “cross over” and undergo revascularization due to medication intolerance, refractory angina, or accelerating symptoms. Second, some patients value “softer” endpoints such as relief of angina and need for urgent revascularization, both of which are significantly improved with revascularization. Third, an initial invasive strategy inevitably leads to more upfront procedural-related MIs with the tradeoff of less downstream spontaneous MIs, which have been shown to be more clinically meaningful. Fourth, just as current OMT has evolved over time to include aspirin, statins, beta blockers, and other anti-anginal therapies, so to has PCI with the advent of drug eluting stents and emergence of coronary physiology (e.g. fractional flow reserve) and intracoronary imaging (e.g. intravascular ultrasound) to guide stenting. Lastly, longer-term outcome data are lacking in the contemporary era, but extended follow-up of ISCHEMIA is expected to fill this evidence gap.

Overall, my take-home message from these trials is that shared decision making is critical because each patient with SIHD may have different treatment goals. ISCHEMIA solidified this tenet and reinforced my practice, as a patient who fits the ISCHEMIA profile—moderate to severe ischemia/absence of LMCA disease/preserved left ventricular systolic function—can be treated with an initial strategy of OMT, but can also reasonably be treated with an invasive strategy at any point in time for symptom relief.

Conflicts of interest to declare:
Grant funding: AHA, Janssen 
Advisor: Stallion Cardio, DocVocate, HeartCloud 

---

Eric H. Yang, MD, FACC, FASE

Associate Clinical Professor of Medicine 
Director, UCLA Cardio-Oncology Program 
Associate Program Director, UCLA/Olive View/West LA VA Cardiovascular Diseases Fellowship 
Division of Cardiology, Department of Medicine 
University of California, Los Angeles

In the field of Cardiology, there remains endless debate on the management of so-called “stable” coronary artery disease—the interpretation of what is deemed “stable” can be muddled by anatomic location, severity of cardiac symptoms, potentially antiquated risk models, and always the underlying concern amongst physicians of one’s risk of cardiac events and/or mortality in the long term if such CAD is found on stress testing and/or imaging.  

Over the past decade, through randomized clinical trials, there has been a gradual push towards the impact of optimal medical therapy. Certainly, much of this has also mirrored more aggressive efforts thanks to ongoing trials demonstrating cardiovascular benefit with blood pressure control, smoking cessation, lipid lowering compared to prior generations of patients with heart disease. This has led many to also question whether the nature of CAD of modern times (ie the 21^st century) has become much more stable compared to the CAD of the 1970s, when the Diamond-Forrester classification model was developed; while this landmark clinical predictive tool was developed decades ago, it still permeates in our conscious and unconscious medical decision making in risk stratification, pretest assessment—and prognosis—of one having ischemic disease.  

One by one however, with sequential trials such as COURAGE, FAME(1 and 2), ISCHEMIA, and other randomized clinical trials looking at the effects of percutaneous coronary intervention (PCI) with optimal medical therapy (OMT) versus OMT alone, have gradually shown the equivalent power of medical therapy in regards to life expectancy—with some caveats in regards to symptom relief.  Although not discussed in this edition in The Evidence, the ORBITA trial also challenged the notion that sham trials involving cardiac procedures could not be done, and demonstrated that PCI did not improve exercise capacity compared to medical therapy, without patients knowing what they received in the cath lab—albeit in a lower risk group with good overall exercise tolerance.  

The 2007 COURAGE trial was one of the first major trials on a wide scale to demonstrate that OMT compared to PCI and OMT did not lower all cause death and nonfatal myocardial infarction (MI), although the trial was limited by overall referral bias with many excluded screening—as the referring physician had to feel comfortable enrolling the patient, thus likely barring many patients with high grade proximal lesions—and a majority of patients receiving bare metal stents, and approximately 1/3 of patients in the OMT arm crossed over to revascularization. However, in the hard outcome of mortality, there was no significant difference in either strategy. While symptom relief was certainly superior in the short term in the PCI arm, endpoints regarding symptoms were ultimately similar in both arms in long term follow-up.  

The FAME trials also used coronary physiology with fractional flow reserve to help predict clinically significant endpoints. However, the FAME-2 trial was also stopped prematurely—at about 50% enrollment–due to a significant difference in the primary outcome—primary composite of death, MI or urgent revascularization–in the PCI versus OMT arm. What many lament about this trial however, was that urgent revascularization was the major driving factor, as opposed to hard endpoints of death, and MI. Patients, nor their cardiologists, were blinded to their disease burden, and a major criticism of the trials were that the threshold to get stented was likely lower if physicians knew their patients had a problem, and symptoms were more likely to drive a patient to the cath lab.  

Finally, the ISCHEMIA trial in 2020 helped reassure many in the cardiovascular field about what to do about moderate to severe ischemia seen on functional testing—which in prior literature implied a benefit in revascularization, although it was never explored in a rigorous, randomized fashion.  Left main coronary artery disease was ruled out in a blinded fashion by cardiac CT, then subsequently randomized to OMT versus OMT and revascularization. It is worth noting however that patients with severe angina, and patients with NYHA Class III-IV heart failure were excluded. No significant difference was found in ischemic event or death at about 3 years in both arms.  

In conclusion, great strides in methodology, and improving the quality of science in evaluating stable CAD have improved our understanding of atherosclerotic disease, and where PCI can play a role in stable disease. It is also worth remembering that PCI strategies were never shown to be worse in these clinical trials. These trials have now afforded cardiologists to have a nuanced, informed discussion about the benefits of how PCI can potentially supplement medical therapy to improve symptoms—which remains paramount and arguably the “gold standard” treatment of CAD—and while there remain other disease states—ie left main coronary artery disease, nonsurgical CAD in symptomatic heart failure—that require further investigation, it is not so much about whether to make one live longer, but it is how a strategy of OMT—and PCI if need be—can help one live a much better quality of life.  

With medical therapy now in the modern era, “stable” symptomatic CAD truly means “stable”without left main involvement, and it is critical to view atherosclerotic disease as a systemic disease.  This evolution is continuing with lipid lowering agents such as anti-PCSK9 inhibitors and other medicines in the pipeline. Physical approaches to reduce disease burden—ie PCI—can help symptoms, but ultimately aggressive medical therapy is needed to reduce the risk of unstable plaque causing future cardiovascular events. 

Conflicts of interest to declare:
Research funding from CSL Behring (AEGIS II) 
Prior research funding from Regeneron/Sanofi (ODYSSEY OUTCOMES) >1 year ago

---