The Nuclear Option: COURAGE Substudy Supports PCI for Ischemia Relief in Stable CAD

November 05, 2007

November 5, 2007 (Orlando, FL) - If the primary results [ 1] were contentious in some quarters, insights from its much smaller nuclear-imaging substudy [ 2] may be less so.

Adding PCI to optimal medical therapy didn't improve clinical end points among the patients with stable CAD randomized in the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial. In the substudy, however, the PCI-based approach was more effective at reducing the total burden of ischemia, as measured by stress- single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI), investigators reported here at the American Heart Association 2007 Scientific Sessions.

The reduction in ischemia by PCI in the 313-patient COURAGE substudy, according to MPI performed at baseline and six to 18 months later (mean 374 days), was greatest among patients initially with moderate to severe ischemia, according to Dr Leslee J Shaw (Emory University, Atlanta, GA), speaking with heart wire . The analysis defined "moderate to severe" as a perfusion defect at MPI encompassing >10% of myocardium.

Proportion of patients in each group with ischemia reduction >5% of myocardium in the COURAGE nuclear substudy

End points PCI + OMT, % (n) OMT alone, % (n) p
Primary end point: % of patients with ischemia reduction amounting to >5% of myocardium at follow-up MPI 33.3 (159) 19.8 (154) 0.004
% of patients with ischemia reduction amounting to >5% of myocardium at follow-up MPI, limited to patients with moderate to severe ischemia at baseline 78 (54) 52 (51) 0.007

OMT=optimal medical therapy; MPI=myocardial perfusion imaging

The findings support a classic strategy of selective, ischemia-driven PCI in most patients with stable CAD, Shaw observed, but they don't imply that such an approach will necessarily improve clinical outcomes.

That PCI was associated with significantly greater resolution of ischemia "is consistent with the COURAGE finding that there's greater resolution of angina with PCI than with optimal medical therapy," observed study co-principal investigator Dr William S Weintraub (Emory University).

"We know that nuclear stress tests predict events," he told heartwire. "What we don't know is whether we should stratify patients based on how much ischemia they have, on the idea that if we relieve a lot of the ischemia, it will prevent events. That's a jump we can't make at the present time."

Observed Dr Raymond J Gibbons (Mayo Clinic, Rochester, MN), as a member of a panel charged with discussing Shaw's COURAGE presentation, "I think we all hold the concept that reducing ischemia is good and should improve outcomes, but the actual data in the literature to support that contention with respect to noninvasive imaging are very scant."

But the COURAGE-substudy investigators conducted an admittedly underpowered, "exploratory" outcomes analysis, intended to guide further research, that suggested that very thing: the less residual ischemia detected at follow-up MPI, the lower the associated risk of death or MI.

Going back a few steps . . .

In COURAGE, 2287 patients with a history of angina or documented myocardial ischemia and at least one significant coronary lesion who were stable on medical therapy were randomized to continue on optimal meds with or without the addition of PCI. Allpatients, Shaw observed during her presentation, were maintained on "intensive, guideline-driven" drug therapy and lifestyle risk-factor modification.

As published and as covered by heart wire last March, the composite rates of death from any cause or nonfatal MI in the larger trial were statistically similar, at 19.0% and 18.5%, respectively, over about four and a half years. Nor did the two groups differ with respect to secondary end points of death, MI, or stroke, and hospitalization for acute coronary syndromes.

Reactions to the trial, as heart wire has described, have been wide-ranging, with some clinicians pleasantly surprised at the demonstrated prowess of medical therapy alone, others contending that no other results should have been expected, and still others questioning their relevance to "real-world" clinical practice.

Ischemia reduction as a therapeutic target? The 5% solution

The nuclear substudy has a presumably less controversial message, that in COURAGE, even on a background of exceptionally rigorous guidelines-based medical therapy, the addition of PCI relieved ischemia better than medical therapy alone.

Change in extent of ischemic myocardium at MPI and change in angina class

End points PCI + OMT, n=159 (%) OMT alone, n=154 (%) p
Myocardium with ischemia at baseline 8.2 8.6 --
Myocardium with ischemia at follow-up 5.5 8.1 --
Mean change (% of myocardium with ischemia) -2.7 -0.5 <0.0001
Patients with >1 CCS-angina class improvement by follow-up MPI 82 70 0.0077

OMT=optimal medical therapy. MPI=myocardial perfusion imaging. CCS=Canadian Cardiovascular Society

"These findings, we believe, confirm the value of myocardial perfusion SPECT to identify at-risk patients," Shaw said, and suggest that a 5% reduction in ischemia, defined by MPI or some other form of quantitative imaging, could serve as a useful therapeutic target.

Exploratory analysis

The substudy's exploratory outcomes analysis suggested that the risk of death or MI rises and falls in tandem with the extent of residual ischemic myocardium at follow-up imaging. Compared with the 231 patients with a smaller reduction in ischemia, the 82 with an ischemia reduction >5% of myocardium had a 0.47 relative risk of death or MI (95% CI 0.23-0.95, p=0.037).

Exploratory analysis, outcomes by extent of residual ischemia (% of myocardium with ischemia at follow-up MPI)

Parameter 0%, n=23 1%-4.9%, n=141 5%-9.9%, n=88 >10%, n=62
Rate of death or MI (%) 0 15.6 22.3 39.3
p vs 0% residual ischemia -- 0.063 0.023 0.002

MPI=myocardial perfusion imaging

Speaking after Shaw's presentation, discussant Dr John D Rutherford (University of Texas Southwestern Medical Center, Dallas) observed that the COURAGE substudy didn't account for two variables important to the consideration of PCI in patients with stable CAD. "We have known for over 20 years that both the number of coronary arteries with severe obstruction and the degree of left ventricular dysfunction are independent risk factors for adverse outcomes," he said.

When presenting the substudy, Shaw commented that the population was too small to conduct meaningful subgroup analyses by LVEF or coronary-artery involvement.

Rutherford, however, offered a scenario for evaluating and treating patients with mild to moderate chronic stable coronary disease that considers those two factors. "In my opinion, the initial evaluation of a patient with chronic stable angina requires an evaluation of ventricular function, typically using 2D echo and some sort of stress testing," he said.

"Patients with significant ventricular dysfunction require coronary angiography to identify patients we know have improved survival with revascularization, namely [those with] left main disease, three-vessel disease, and two-vessel disease with significant proximal [left anterior descending coronary artery] stenoses."

An "early positive stress test at a low workload, with evidence of significant ischemia, or the presence of other criteria that define high risk" should also indicate angiography, according to Rutherford.

Consistent with COURAGE, "in intermediate- and low-risk patients, an approach of continued optimal therapy with later retesting seems reasonable," he said.

If significant ischemia is observed at retesting, "then consideration of revascularization may be warranted. Some patients, despite optimal medical therapy, will develop angina that is unresponsive or objective evidence of worsening ischemia and require revascularization on a case-by-case basis."

The COURAGE nuclear substudy was supported by Bristol-Myers Squibb Medical Imaging and Astellas Healthcare. The primary COURAGE investigation was supported by "unrestricted research grants" from Merck, Pfizer, Bristol-Myers Squibb, Fujisawa, Kos Pharmaceuticals, Datascope, AstraZeneca, Key Pharmaceutical, Sanofi-Aventis, First Horizon, and GE Healthcare. "All industrial funding in support of the trial was directed through the US Department of Veterans Affairs."

  1. Boden WE, O'Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007; 356:1503-1516. Abstract

  2. Shaw, LJ. Differential improvement in stress myocardial perfusion ischemia following percutaneous coronary intervention as compared with optimal medical therapy alone: Nuclear substudy results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial. American Heart Association 2007 Scientific Sessions; November 4, 2007; Orlando, FL. Late-breaking clinical trials 1.

The complete contents of Heart wire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

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