COURAGE quality-of-life analysis: Slim early gains with PCI soon disappear

August 13, 2008

Boston, MA - The results of their quality-of-life (QoL) analysis from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial[1]] are consistent with the message from its primary outcomes[2] and other secondary results, conclude researchers. That message: PCI can often be deferred in patients with stable CAD and significant coronary lesions without adding risk while optimal medical therapy (OMT) is given a chance to work, and it can be considered later if the patient still develops significant symptoms, according to the group.

In the trial's QoL analysis, published in the August 14, 2008 issue of the New England Journal of Medicine, OMT either with or without routine early PCI rapidly improved the patients' Seattle Angina Questionnaire (SAQ) scores for physical limitation, angina frequency, overall QoL, and other outcome domains.

The gains with routine PCI were significantly greater than those for OMT-only throughout the first one to two years of follow-up. But the PCI advantages had dissipated by three years, when no significant differences in QoL scores were seen between the two treatment strategies.

The new report does little to settle controversies ignited when the COURAGE primary outcome—similar composite rates of mortality or MI over four to five years for the routine-PCI and OMT-only groups—became public last year. As extensively reported by heart wire , proponents of early routine intervention have questioned the quality of PCI in COURAGE, the relevance of the trial's exceptionally good medical therapy, its statistical power for prespecified end points, other ways it was designed and executed, the authors' interpretation of the data, and their conclusions; but both detractors and defenders of the trial abound.

No additional risk from deferring PCI

According to the QoL report's lead author, Dr William S Weintraub (Christiana Care Health System, Newark, DE), the new analysis is consistent with the trial's primary-outcomes message and the results of its "nuclear substudy"[3], which provided objective evidence that the early PCI strategy was better than first-line OMT at relieving myocardial ischemia. COURAGE, he told heart wire , shows that there is some relief of angina with routine early PCI and that about a third of OMT-only patients will cross over to invasive management. "But lots of patients get better without PCI. So it doesn't mean we shouldn't do PCI, it means that people will not be put at additional risk if PCI is deferred to see [whether] they get better with just medical therapy."

If the patient reports debilitating symptoms on OMT, Weintraub added, "it's reasonable" to go right to PCI. One finding of the study, he said, is that the QoL benefits of PCI were proportional to the severity of angina.

 
The most remarkable observation from COURAGE is the stellar performance of optimal medical therapy, which not only affected hard outcomes, but more impressively affected outcomes for which PCI clearly was thought to have an advantage, which is relief of angina and ischemia.
 

Weintraub had presented a preliminary version of the QoL subanalysis at the American College of Cardiology (ACC) 2007 Scientific Sessions, the meeting at which the trial's primary results were also first formally reported. Both analyses were covered at the time by heart wire .

Dr Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA), who has defended COURAGE in the literature[4], said to heart wire that "the most remarkable observation from COURAGE is the stellar performance of optimal medical therapy, which not only affected hard outcomes, but more impressively affected outcomes for which PCI clearly was thought to have an advantage, which is relief of angina and ischemia."

Although PCI did show significant QoL advantages during the first two years, there is a "disconnect between statistical significance and clinical importance," Kaul said. "While the difference in health status and anginal frequency in COURAGE is unequivocally significant in favor of PCI plus OMT, it is likely too small to be judged as being clinically important."

He continued, "if OMT is just as good and doesn't have the drawbacks of being invasive and associated with some periprocedural complications and added cost, then it stands to reason that the initial treatment strategy should then be optimal medical therapy, failing which PCI can be considered."

Angina frequency: Mean SAQ scores* by randomization group in COURAGE

Follow-up time>, mo PCI + OMT OMT p
3 85 80 <0.001
12 87 84 0.003
24 89 86 0.002
36 89 88 0.37
SAQ=Seattle Angina Questionnaire. OMT=optimal medical therapy
*No significant differences between groups at baseline

In an editorial accompanying the QoL analysis[5], Dr Eric D Peterson (Duke Clinical Research Institute, Durham, NC) and Dr John S Rumsfeld (University of Colorado Denver Health Sciences Center) also questioned the clinical importance of PCI's early edge. "Depending on the domain evaluated," they write, "the health-status advantages associated with PCI persisted for six to 24 months. However, although the benefits were significant, the comparative differences were small, leaving open the question of whether a PCI-first strategy is justified."

As most patients in the OMT-only group showed symptomatic improvement within three months while 21% crossed over to PCI, observe Peterson and Rumsfeld, "a very reasonable take-home message from the COURAGE trial is to pursue optimal medical therapy initially and if this is ineffective, turn to PCI."

But interpretations of the QoL analysis vary, as they did for the trial's primary outcomes. The QoL data, Dr Bonnie Weiner (Worcester Medical Center, MA) told heart wire , "clearly shows the symptomatic benefit and the quality-of-life benefit for PCI, and I think that's what the interventional community has been saying all along. I think that actually it's a positive trial from that perspective. . . . I think it reaffirms that patients with more frequent and more severe angina do better with PCI than those with little or no angina. I think that's always been the case, and I don't think any of us have suggested otherwise." Weiner is the immediate past-president of the Society for Cardiovascular Angiography and Interventions.

Stepping back a bit . . . 
 
The quality-of-life data . . . clearly show the symptomatic benefit and the quality-of-life benefit for PCI, and I think that's what the interventional community has been saying all along.
 

COURAGE had randomized 2287 patients with stable CAD, at least one angiographically significant coronary stenosis, and inducible ischemia to either OMT plus PCI or OMT alone at centers in the US and Canada. Stents were used in the overwhelming majority of PCI cases, and they were bare-metal stents in all but a handful. OMT consisted of agents typical of today: nitrates, beta blockers, calcium-channel blockers, statins, and ACE inhibitors or angiotensin-receptor blockers.

With 1149 patients assigned to early PCI, the 1138 randomized to OMT-only went to revascularization if their angina failed to respond "or when there was objective evidence of worsening ischemia on noninvasive testing, at the discretion of the patient's physician," the primary report notes[2].

The groups didn't differ significantly in the primary end point of death or MI over a median follow-up of 4.6 years; it was 19.0% for early PCI and 18.5% for first-line OMT (p=0.62).

In the trial's 313-patient nuclear imaging substudy[3], the PCI-based approach significantly reduced the total burden of ischemia as judged by stress-single photon emission computed tomography (SPECT) myocardial perfusion imaging. The difference was most profound among patients initially with moderate-to-severe ischemia.

Quality of life: Mean SAQ scores* by randomization group in COURAGE

Follow-up time, mo PCI + OMT OMT p
3 73 68 <0.001
12 76 73 0.008
24 77 76 0.10
36 79 77 0.32
SAQ=Seattle Angina Questionnaire. OMT=optimal medical therapy
*No significant differences between groups at baseline

In the current analysis, SAQ scores for the two groups were similar at baseline for all domains and improved significantly by one to three months (p<0.001 for all improvements), write Weintraub et al. "This finding with respect to the benefit of OMT alone shows that PCI is not always essential for the relief of symptoms in patients with stable angina."

That observation also intrigued the editorialists. "A remarkable finding from the COURAGE study was the rapidity of improvement in health status in both treatment groups. This should serve as encouraging news to patients with coronary disease," they write.

"With contemporary treatment, the majority of patients had substantial improvements in health status that were sustained for several years. At the same time, the rapid improvement with optimal medical therapy alone suggests that antianginal medications are underused in practice."

According to Weintraub et al, "Scores were higher in the PCI group than in the medical-therapy group for six to 24 months, depending on the domain. By 36 months, the addition of PCI to optimal medical therapy no longer provided a significant advantage for any domain."

That eventual QoL parity between COURAGE groups also has more than one interpretation. While some see it as evidence for only a slim practical difference between the strategies, if any, others point to PCI's early advantage as fundamental to the study's message.

PCI's performance in COURAGE was attenuated because DES were only rarely used, observed Weiner. "But for two years or more, the PCI patients felt better, had fewer symptoms, and had a better quality of life," she said. "I do think that's a significant finding."

"Bad PCI and unrealistically good medicine"

PCI didn't surpass OMT more decisively because the trial used "bad PCI and unrealistically good medicine," Dr Dean J Kereiakes (Christ Hospital Heart and Vascular Center, Cincinnati, OH), coauthor of a published critique of the trial's methods[6], told heartwire .

Physical limitation: Mean SAQ scores* by randomization group in COURAGE

Follow-up time, mo PCI + OMT OMT p
3 76 72 0.004
12 75 73 0.21
24 74 72 0.16
36 74 74 0.68
SAQ=Seattle Angina Questionnaire. OMT=optimal medical therapy
*No significant differences between groups at baseline

"I'm amazed PCI as performed in this trial maintained superiority through two years, because of the extremely high frequency of bare-metal stents, high frequency of standard balloon angioplasty, and the incomplete revascularization in the PCI cohort," Kereiakes said.

According to the trial's primary report, "complete revascularization was performed as clinically appropriate." But it also notes that 69% and 70% of routine-PCI and OMT-only patients, respectively, had two- or three-vessel disease, whereas only 41% of routine-PCI patients received more than one stent[2]. Only 31 patients received DES, which for most of the study had yet to become available, the report notes.

 
These data contribute to my enthusiasm for doing PCI better than was done in this trial.
 

"Think of what could have been achieved if more complete PCI had been performed, with optimal technology—that is, with drug-eluting stents. You would have had a more durable benefit of PCI," Kereiakes said.

Excellent medical therapy and a high level of compliance within the confines of the clinical trial also narrowed the outcomes gap between the two patient groups, Kereiakes said. "The level of medication and even the goals achieved, as far as blood-pressure control, cholesterol levels, etc, were truly remarkable in this trial. It's admirable, I think it's inspirational, but it's unrealistic."

In the eye of the beholder

He added, "Patients with objective evidence of ischemia, absolutely, if feasible, should have PCI plus OMT, unless there are mitigating circumstances." PCI wouldn't be required, he said, if medication completely controls both symptoms and objectively documented ischemia, whether symptomatic or silent.

"These data contribute to my enthusiasm for doing PCI better than was done in this trial," Kereiakes said. "Still giving optimal medications to the extent that they're tolerated and the patients are compliant, I have no doubt that a strategy of complete revascularization with optimal technologies would provide a significantly greater gap than was demonstrated to two years in this trial and would extend that benefit beyond two years."

On the latter point, Weiner seemed to agree. If recurrent symptoms after PCI are often due to restenosis and DES can "virtually eliminate" restenosis—both ideas are borne out by the data—and then if DES are used in COURAGE-like patients, "it's not unreasonable to think that the separation between the two groups would be wider, and it would be maintained for a longer period of time," she said.

 
High-risk anatomy and a high-risk functional stress test—a large amount of myocardial ischemia and compromised LV function—those would be reasons why I would offer PCI over medical therapy.
 

More conservative about when to perform PCI in COURAGE-like patients, Kaul outlined a scenario he thinks might indicate invasive management. "If on objective assessment you demonstrate a substantial degree of myocardial ischemia in association with reduced LV systolic function, that would be a case where I could justify an initial PCI strategy," he said.

"I would say, high-risk anatomy and a high-risk functional stress test—a large amount of myocardial ischemia and compromised LV function—those would be reasons why I would offer PCI over medical therapy [only]."

Editorialists Peterson and Rumsfeld emphasize that OMT and PCI aren't actually competitors. "The COURAGE trial redefines the contemporary roles of optimal medical therapy and PCI in the management of patients with stable angina. Rather than one victor, COURAGE demonstrates that both treatment strategies can have a profoundly positive effect on patients' health status and suggests complementary roles—optimal medical therapy as first-line therapy, with PCI reserved for patients who do not have a response or who have severe baseline symptoms."

Weintraub reports receiving "consulting fees from Sanofi-Aventis, GlaxoSmithKline, Indigo Pharmaceuticals, and CV Therapeutics and grant support from Sanofi-Aventis, AstraZeneca, Otsuka, and Bristol-Myers Squibb"; disclosures for the other COURAGE coauthors and for the two editorialists are listed in the papers. Kaul and Weiner say they have no conflicts to disclose. Kereiakes reports grant and/or research support from Abbott/Bioabsorbable Vascular Solutions, Amylin Pharmaceuticals, Cordis/Johnson & Johnson, Boston Scientific, Medtronic, and Daiichi Sanyko; receiving consulting fees from Devax, Eli Lilly, Boston Scientific, Abbott Vascular Solutions, Medpace, and Cordis/Johnson & Johnson; and being on the Eli Lilly speakers' bureau.

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