CardioExchange Archive

Following is an exchange between Bill Boden and Gregg Stone, facilitated by Interventional Cardiology moderators Richard Lange and David Hillis. An audio file of the complete conversation from which this text was adapted is available here.

Rick Lange: Given all the debate and controversy surrounding the COURAGE trial, what are the issues on which you find agreement?

Gregg Stone: Bill and I agree with many of the central issues now, much more than we did two years ago. We’ve learned from this study that there are two groups with stable ischemic heart disease that tend to benefit from a routine interventional strategy: patients who have significant symptoms, whose quality of life tends to improve after the procedure; and those with a significant amount of ischemia. While COURAGE was not large enough to definitively prove that death and myocardial infarction are reduced in patients with a large amount of ischemia who are revascularized, data from the COURAGE nuclear substudy suggest that this is a very reasonable hypothesis.

Bill Boden: We agree that optimal medical therapy forms the cornerstone or the foundation upon which all other therapy is layered. Regardless of whether a decision is made to proceed to PCI, bypass surgery, or to just continue medical therapy, robust medical therapy is a critical determinant of how patients will do, and one can achieve very good clinical outcomes with the disease-modifying therapy that is now available to us. It’s clear that the patients who had the most frequency and severity of angina and the most impaired quality of life were the patients who derived the most benefit from revascularization. In addition, the patients who had severe myocardial ischemia at baseline were the ones who had better resolution of their ischemia with the performance of PCI as compared with optimal medical therapy. What we weren’t able to demonstrate in COURAGE was the link between ischemia reduction and event reduction. The study simply was too small and underpowered to examine that critically.

Gregg: I believe the COURAGE nuclear substudy did establish the link between ischemia reduction and event reduction. Those patients who had the largest reductions in ischemia and the lowest amount of residual ischemia had the lowest subsequent event rates. What it did not establish was whether a therapy applied to reduce ischemia in a randomized fashion would then lead to lower event rates.

Bill: Right. The ischemia reduction in the 20% of patients who fell into that category was associated with better outcomes — so, a signal of benefit. But that was a pretty small subset of patients, and one has to be concerned about the validity of a small substudy. It was totally underpowered for clinical outcomes.

Rick: How should we design the next study to resolve some of these uncertainties and these unresolved issues?

Gregg: There were several important aspects of COURAGE that might inform that next study. COURAGE required up-front angiography; this may bias enrollment, and also may result in a high rate of crossovers once the coronary anatomy is known. COURAGE primarily employed bare-metal stents and didn’t use optimal adjunct pharmacotherapy in the invasive arm. Drug-eluting stents are significantly more effective than bare-metal stents at reducing ischemia. Moreover, an artificial situation exists favoring medical therapy in randomized trials in which the medications are provided at no cost, in addition to frequent free office visits with easier access to care than would occur in the real world. The compliance with medical therapy in COURAGE was much greater than has been achieved in any real-world situation. So, I don’t know if studies such as this, while laudable, apply to the real-world.

Bill: These caveats aside, however, COURAGE does demonstrate what can be achieved when intensive pharmacotherapy and lifestyle intervention are implemented to achieve control of multiple treatment targets, such as smoking cessation, blood pressure, hemoglobin A1c, and especially lipids.

Rick: So, let’s come out with the optimal study. What does it look like?

Bill: We, along with other key opinion leaders and experts, have configured what we hope will be the logical trial that would be a worthy sequel to COURAGE and address several of the areas that Gregg listed, which is to say, a randomized trial that will enroll patients on the basis of having moderate to severe ischemia. Randomization occurs before the anatomy is defined, in order to eliminate the whole issue of selection bias. We’ll use drug-eluting stents with a strategy to achieve complete revascularization of all proximal stenoses that are subtending moderate to severe ischemic segments. Optimal medical therapy as applied in COURAGE can be generalized and facilitated. I think that we can, in fact, design the optimal trial where the treatment that we used in COURAGE targets a population of high-risk patients with ischemia, hopefully with a more representative spectrum of left ventricular dysfunction.

Gregg: We’ve learned from COURAGE that patients with stable ischemic heart disease who have minimal symptoms and small amounts of — or absent –- ischemia, identified via screening angiography, certainly don’t need revascularization and can and should be managed medically. The real question is whether patients with moderate or significant ischemia would benefit from revascularization, with a reduction in the hard events of death, myocardial infarction, and repeat hospitalization for acute cardiac disease. So we have designed a trial called ISCHEMIA, which will randomize approximately 8000 to 10,000 patients with stable ischemic heart disease and a moderate to significant amount of ischemia to optimal medical therapy without screening angiography versus optimal medical therapy followed by angiography with subsequent revascularization with either coronary intervention or bypass surgery, as appropriate based on the coronary anatomy. So, this is different than COURAGE in multiple respects: there has to be moderate to severe ischemia; randomization occurs before angiography; the control arm does not undergo routine angiography; and the revascularization modalities allowed are either PCI or CABG (with drug-eluting stents and optimal pharmacotherapy strongly recommended for PCI).

Rick: Will this actually resolve the issue, or is this something that we’re going to need to re-address on a regular basis?

Gregg: Every randomized trial represents a snapshot in time, testing the devices, drugs, and strategies that are available at that point. Nonetheless, I’m optimistic that these results will apply to the foreseeable future.

Bill: The whole approach to managing patients with ischemic heart disease represents a rapidly moving target. So, all we can do is to try to design this next trial as carefully and as deliberately as we possibly can to incorporate the best available treatments to achieve the best outcomes that we seek for our patients. Some of the issues that hopefully will become clarified with this new study will be in patients with diabetes. The BARI-2D study didn’t indicate that there was any significant difference in clinical outcomes among diabetics with stable coronary disease who received revascularization versus optimal medical therapy. Other populations of patients worthy of study in this particular trial will be women, the elderly, and patients with silent myocardial ischemia. I’m hopeful that the study — with some 8000 to 10,000 patients — can be as informative as it possibly can be in the context of what is viewed to be really optimal treatment, both catheter-based and pharmacologic.

Rick: On behalf of CardioExchange, David Hillis and I would like to thank both of you for your insights.