Medical therapy takes COURAGE: No benefit of PCI over optimal drugs for preventing events in stable CAD

Shelley Wood

March 26, 2007

Click here to see The Cardiology Show: The COURAGE trial, moderated by Dr Valentin Fuster (Mount Sinai Medical Center, NY).

New Orleans, LA - PCI plus stenting and optimal medical therapy is no better at preventing future events than optimal medical therapy alone in patients with stable coronary disease, according to the results of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial[1]. The much-anticipated results add fat to the mounting fire over whether stents, including drug-eluting stents, are being overused for the treatment of stable CAD or for the prevention of future cardiac events.

After embargo break, COURAGE results released early

Originally slated for presentation on the final day of the American College of Cardiology 2007 Scientific Sessions, COURAGE trial results were published in the online edition of the Wall Street Journal on Monday, prompting the ACC to permit early publication of the results by other news organizations. According to the Journal, results of the study were discussed at a Boston Scientific-sponsored symposium Sunday night; perhaps not surprisingly, the Journal story is largely dismissive of the trial results. The Journal story quotes Dr Martin Leon as calling COURAGE a "critically flawed study." The article also states that Leon "had reviewed the COURAGE study after it was submitted to a medical journal."

In an interview with heart wire , Leon was adamant that the material discussed at last night's symposium did not constitute an embargo break. "[My] comments . . . were taken out of context and woven into a story that is a distortion of what went on at that meeting," Leon told heart wire . "Nothing went on at that meeting that should justify the embargo having been broken. People commented on the trial design and what they expected the results to show, and everyone agreed we expected that there would be no difference."

Lead investigator Dr William E Boden (Buffalo General Hospital, NY) will present the results Tuesday morning, with full results of the study published simultaneously online March 27, 2007 in the New England Journal of Medicine.

"Although the addition of PCI to optimal medical therapy reduced the prevalence of angina, it did not reduce long-term rates of death, nonfatal myocardial infarction, and hospitalization for acute coronary syndromes," Boden et al conclude in the published paper.

In an editorial accompanying the study, Drs Judith S Hochman (New York University School of Medicine, NY) and P Gabriel Steg (Université Paris, France) say the study findings are practice-changing[2].

 
PCI has an established place in treating angina but is not superior to intensive medical therapy to prevent myocardial infarction and death.
 

"The COURAGE trial should lead to changes in the treatment of patients with stable coronary artery disease, with expected substantial healthcare savings," they write. "PCI has an established place in treating angina but is not superior to intensive medical therapy to prevent myocardial infarction and death in symptomatic or asymptomatic patients such as those in this study."

Other commentators suggested the findings are not unexpected. "PCI has never been shown to reduce death or MI compared with medical therapy," Dr Eric Topol (Scripps Translational Science Institute, La Jolla, CA) told heart wire . "COURAGE really does not present anything new but simply reinforces that the basis for revascularization is for control of ischemia. There is no surprise with this trial."

Likewise, Dr Christopher Cannon (Brigham and Women's Hospital, Boston, MA) called the trial confirmation of a "back-to-basics approach."

"This is actually what many people would have expected, thinking about the pathophysiology of stable CAD, but it runs a little bit counter to the current sucking sound of patients being drawn to the cath lab," he told heart wire . "Anyone with ACS ends up being cathed appropriately, but many other people have ended up in the cath lab as well."

But many cardiologists—interventionalists in particular—may not be easily persuaded by the results. "The real question is whether cardiologists will have the 'courage' to change the way they practice, which in 2007 flies in the face of the evidence," said Dr James Stein (University of Wisconsin, Madison). "We know PCI in the setting of an acute coronary syndrome saves lives, but 85% of PCIs in the US are done in stable patients, and of those I'd bet that at least 25% are asymptomatic patients. This study clearly shows something we all knew—but many did not want to believe—that angioplasties don't save lives, except in acutely ill patients, and don't prevent heart attacks. Cardiologists say yes, we know that, we are relieving symptoms, but why are so many done on people who are asymptomatic? And why all the 'screening' stress tests?"

Dr Eric Cohen (Sunnybrook Health Sciences Centre, Toronto, ON), who was a site investigator for COURAGE, commented, "COURAGE does not tell us that there is no role for PCI in the management of stable CAD, but I think it is telling us to be more selective in targeting only those patients with very significant symptoms and to be more modest in our expectation of what is achieved."

Cohen also pointed out that Canadian centers made a "disproportionately large" contribution to the COURAGE study, "perhaps because the momentum leading directly to PCI was slightly less intense in Canada at the time and thus patients and physicians were somewhat more amenable to randomization."

The implications from COURAGE are good news for Canada and other countries where PCI is not available to large portions of the population. "Utilization of PCI has grown substantially in Canada during the [duration] of the COURAGE trial but remains below most of the US.  The results of COURAGE suggest that despite a lower rate of PCI in Canada, our patients with stable CAD are not being disadvantaged in terms of hard outcomes. It also suggests that in the US, particularly in some regions with very high rates of PCI, utilization could likely be reduced without a detrimental impact on clinical outcome."

Summoning COURAGE

Between 1999 and 2004, the COURAGE trial enrolled and randomized 2287 patients either to PCI plus optimal medical therapy or to optimal medical therapy alone. Over a follow-up period ranging from 2.5 to 7.0 years, a total of 211 all-cause deaths or nonfatal MIs (the primary outcome of COURAGE) occurred in the PCI group, compared with 202 in the medical-therapy group, a statistically nonsignificant difference. When stroke was added to the composite end point, again there were no differences seen between the two groups. When outcomes were analyzed individually, there were no differences in rates of deaths, MI, stroke, or hospitalization for acute coronary syndromes between the PCI and medical-therapy groups.

COURAGE: Cumulative event rates*

Outcome PCI (%) Medical therapy (%) Hazard ratio 95% CI p
Death, MI 19 18.5 1.05 0.87-1.27 0.62
Death, MI, stroke 20 19.5 1.05 0.87-1.27 0.62
Death 7.6 8.3 0.87 0.65-1.16 0.38
Nonfatal MI 13.2 12.3 1.13 0.89-1.43 0.33
Stroke 2.1 1.8 1.56 0.80-3.04 0.19
Hospitalization for ACS 12.4 11.8 1.07 0.84-1.37 0.56
Revascularization (PCI or CABG) 21.1 32.6 0.60 0.51-0.71 <0.001
*At a median of 4.6 years

Over the median 4.6 years of follow-up, more medical-therapy patients than PCI-treated patients underwent subsequent revascularization, usually due to refractive angina or objective, noninvasive evidence of worsening ischemia.

The only statistically significant difference between the two treatment strategies was reduced prevalence of angina, which was greater in the PCI group at one and three years. However, by five years—in part a reflection of subsequent revascularization in the medical-therapy group—there was no significant difference in freedom from angina, with roughly 73% of both groups reporting no angina at five years.

COURAGE: Freedom from angina

Time point (y) PCI (%) Medical therapy (%) p
Baseline 12 13 NS
1 66 58 <0.001
3 72 67 0.02
5 74 72 NS

Boden and colleagues propose that their findings can be explained, in part, by the fact that plaque morphology and vascular remodeling are different in ACS—where stenting has proved superior to medical therapy—than in stable coronary disease. Focal management of stable lesions through PCI would not lead to a reduction of clinical events if the lesions themselves were in no danger of triggering an acute coronary event, they explain; by contrast, systemic medical therapy and risk-factor management may have the effect of reducing plaque vulnerability.

While the authors identify the low numbers of women and nonwhites in COURAGE as limitations of the study, they reject the idea that the lack of drug-eluting stents (DES) should restrict the generalizability of their results to current-day PCI. "Published data indicate no benefit (either short-term or long-term) with respect to death and MI in patients with stable CAD who receive DES, as compared with those who receive bare-metal stents," they write.

Shaking things up

Commenting on the study, Cannon predicted that COURAGE "is going to shake things up in the cath labs," pointing out that the trial addresses a very important segment of the population: the 30% to 40% of patients undergoing catheterization and PCI for stable disease.

But the results will be viewed differently for patients with and without manageable symptoms, Cannon emphasized. While freedom from angina was similar in both groups in COURAGE at five years, a full third of medically managed patients underwent PCI or CABG during the follow-up period, he noted. As such, COURAGE specifically showed a lack of benefit for PCI over medical therapy for preventing future events but did not speak to the treatment of patients with refractory symptoms.

"Many people undergo stenting for symptoms, and that's appropriate," says Cannon. "So of the stable 30% to 40% of patients undergoing cath, many should continue to do so; it's perfectly valid for them to undergo revascularization to improve their symptoms. If patients have real angina, and if they're on one or two meds, or they're very bothered by their symptoms, and if the goal is to relieve those symptoms, not prevent future events, then that's okay."

Several experts emphasized to heart wire that the COURAGE results will provide hard data for physicians concerned about the medicolegal repercussions of not opting to revascularize on the basis of screening results.

"The problem is fear of malpractice: docs are afraid of getting sued if they don't do a stress test and if they don't do a cath in response to an abnormality," Stein explained.

Cannon agreed: "Now we have something to fall back on," he told heart wire .

Whether PCI rates take a dip based on COURAGE remains to be seen. "Economic incentives favor procedures rather than medical therapy with lifestyle and medications. PCIs are very lucrative for hospitals and doctors; talking to patients and taking care of their risk factors, unfortunately, is not," Stein said.

Patients, too, may not want to accept that drugs may be all they need, Stein added. "Patients don't understand that minor blockages, not seen on stress tests or opened by PCI, cause the vast majority of heart attacks. Most docs know that, but many don't practice that way. A major educational effort is needed."

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