AHA 2012: Multiple Studies Provide Clinical Guidance for Interventional Community

LOS ANGELES, CA—From patients with diabetes to cutting-edge cell therapy to cost considerations, results from numerous trials presented November 4-7, 2012, at the American Heart Association (AHA) Scientific Sessions provided valuable guidance to interventional medicine specialists for their daily clinical practice.

FREEDOM

The headline trial for the interventional community was FREEDOM, which randomized 1,900 patients with diabetes and multivessel CAD to undergo either PCI with DES (n = 953) or CABG (n = 947). Led by Valentin Fuster, MD, PhD, of Mount Sinai Medical Center (New York, NY), the trial showed that after an early advantage with PCI, over 5 years the primary composite endpoint of death, stroke, and MI was lower with CABG, as were the individual component endpoints with the exception of stroke (table 1).

Table 1. FREEDOM: Five-Year Clinical Outcomes

“FREEDOM sends a strong message,” Robert A. Harrington, MD, of the Stanford University School of Medicine (Stanford, CA), told TCTMD. “For the interventional community it seems to me if you have a diabetic patient and you do angiography and they have multivessel coronary disease, in most cases it would not be appropriate to do ad hoc angioplasty. One should stop, think about it, get the patient engaged, get one of your surgical colleagues engaged, and take a page from the playbook of the TAVR experience with the heart team.”

The key, added Dr. Harrington, the vice chair of the scientific sessions program committee for AHA 2012, is how to address the patient. “We need to be more thoughtful in how we have those conversations, we need to be more fair to the data, and I think we need to get patients more engaged with that decision making,” he said. “That should constitute a major shift [in practice].”

The Cost of Care

FREEDOM included a built-in cost-effectiveness study. In the analysis, Elizabeth A. Magnuson, ScD, of Saint Luke’s Mid America Heart Institute (Kansas City, MO), and colleagues looked at the costs and long-term cost-effectiveness of the 2 strategies from FREEDOM, measuring quality adjusted life years (QALY) gained. They found that while CABG was more expensive than PCI, the gap narrowed from $7,878 at 1 year to $3,641 at 5 years. This translated to a cost of $8,132 per QALY gained with CABG, well under the generally accepted threshold of $50,000 per QALY gained.

In a separate analysis from the CPORT-E trial, Eric L. Eisenstein, DBA, of the Duke Clinical Research Institute (Durham, NC), and colleagues looked at the cost differences between PCI performed at centers with vs. without on-site cardiac surgery capabilities. There was no difference in index procedure medical costs, but there was a trend toward higher medical costs at 9 months at centers without on-site surgery, related to higher medical costs during follow-up. ICU room costs were also higher without on-site surgery, but patients seen at centers without such services were mandated by protocol to receive postprocedural care in the ICU or CCU. Overall costs at 9 months were 15% higher in sites without surgery.

In a third cost analysis, this one from the ASCERT trial, researchers found that much as with the FREEDOM subanalysis, CABG was more costly early on, but cost-effectiveness shifted in favor of bypass surgery over the long term for patients with nonemergent CAD.

“You absolutely need to have cost-effectiveness analyses built into these important policy questions,” Dr. Harrington commented, “because at the end of the day, in addition to making clinical practice recommendations, we as a community have got to make policy recommendations.”

The FREEDOM subanalysis results were “extraordinary in terms of cost-effectiveness if you think and if we still believe that our societal benchmark is somewhere around $50,000 per QALY,” he continued. “$8,000 is a pretty good buy.”

CPORT-E, meanwhile, raises some important questions. “If it’s okay from a clinical perspective to do PCI at sites without surgical backup, can we afford to do it?” Dr. Harrington asked. “What are the cost implications? There’s the suggestion that there are some increased costs of doing that. To me that says, as you make policy decisions, yes, you have to consider the clinical imperatives, but let’s not forget the cost imperatives and how we might translate that into policy.”

Taken together, the cost analyses represent “a good reminder that advances are not going to be cost saving necessarily,” Dr. Harrington said, “but advances should be cost effective, and society should know what it’s getting for its money.”

Cell Therapy Makes Headway

From cost to cutting-edge therapy, numerous cell therapy trials were presented at AHA 2012, showing both the promise and the problems inherent in myocardial regeneration. 

The POSEIDON trial, led by Joshua M. Hare, MD, of the University of Miami Miller School of Medicine (Miami, FL), found that both allogeneic and autologous mesenchymal stem cells are safe in patients with LV dysfunction due to ischemic cardiomyopathy. Allogeneic and autologous cell therapy reduced mean early enhancement defect by 33.21% (95% CI -43.61% to -22.81%; P < 0.001) and sphericity index but did not increase LVEF.

In the open-label single-center SCIPIO (Stem Cell Infusion in Patients with Ischemic cardiOmyopathy) trial, intracoronary infusion of autologous cardiac stem cells safely improved left ventricular systolic function and reduced infarct size up to 2 years after infusion in patients with heart failure after MI.

For the phase I ALCADIA (AutoLogous human CArdiac-Derived stem cell to treat Ischemic cArdiomyopathy) trial, Naofumi Takehara, MD, PhD, of Kyoto Prefectural University of Medicine (Kyoto, Japan), and colleagues used a unique hybrid strategy to treat 6 patients with ischemic cardiomyopathy following acute MI.

In addition to CABG, Dr. Takehara and colleagues administered autologous cardiac stem cells (5 x 10⁵ cell/kg) via intramyocardial injection combined with sustained release of basic fibroblast growth factor (bFGF; 200 µg) using a biodegradable scaffold. At 24 weeks, LVEF improved on cardiac MRI compared with baseline from roughly 22% to 35% (P = 0.0117). In addition, maximal oxygen consumption improved from roughly 12.5 ml/kg/min to 16.5 ml/kg/min (P = 0.0308).

However, 2 trials, TIME and SWISS-AMI found that early or late intracoronary bone marrow stem cell infusion failed to improve outcomes in patients with acute MI.

“Cell therapy came in like a lion,” Dr. Harrington commented. “This was going to change medicine. Now, the hard work continues. It’s not as easy as people thought. You can’t just squirt a bunch of cells in the human body and assume they’ll find where they’re supposed to go and organize themselves in a way that’s going to regenerate tissue.”

Nevertheless, the results represent a strong step forward. “We’ve made some progress,” Dr. Harrington said. “We’re learning more, it still looks promising, but we’re on a 5- to 10-year horizon, not a 1- to 3year horizon for cell therapy.”

Platelet Function Testing Fizzles

In results from the ARCTIC trial and a substudy of the TRILOGY ACS trial, platelet function results failed to show any association with clinical outcomes.

In ARCTIC, a strategy of therapy adjustment based on platelet function monitoring did not lead to any improvement in the primary composite endpoint of death, MI, stent thrombosis, stroke, or urgent revascularization at 1 year, or the secondary composite of stent thrombosis or urgent revascularization compared with patients who received no monitoring. The same was true for the individual component endpoints (table 2).

Table 2. Primary and Secondary Outcomes at 1 Year

In the TRILOGY ACS substudy, Kaplan-Meier estimates for the primary efficacy endpoint (composite of cardiovascular death, MI, or stroke through 30 months) were similar between medically managed ACS patients taking clopidogrel or prasugrel (17.2% vs. 18.9%; P = 0.29) despite lower platelet reactivity levels in patients receiving prasugrel. Likewise, estimates of all-cause death and all MI through 30 months were similar with both drugs (all-cause death 10.5% vs. 11.5%; P = 0.39; MI 10.5% vs. 10.0%; P = 0.83).

“This, to me, is one of the best examples of ‘it seems like it makes sense, but . . .’” Dr. Harrington said. “That is why we can’t rely on our intuition; we’ve got to test it.”

He called platelet function testing “not ready for prime time” in terms of widespread clinical use. “We should definitely keep going with the question, though, especially as the drugs change. We’re still in a clopidogrel-heavy world, and maybe platelet function testing will matter less with the new drugs, [or] maybe it will matter more.”

A third study, led by Stephen A. O’Connor, MD, of the Institute Cardiologie Hôpital Pitié-Salpêtrière (Paris, France), dealt with this scenario. Dr. O’Connor and colleagues found that in ACS patients who underwent PCI and received prasugrel, high platelet reactivity became more predictive of subsequent ischemic events with the use of multiple testing methods.

Next Renal Denervation Device

In what might be the next iteration of a device for renal denervation in resistant hypertension patients, the ENLIGHTN I trial showed positive results with a multi-electrode catheter. The EnligHTN catheter is 8-Fr compatible and features 4 electrodes on an expandable basket. Two rounds of ablation—the second after slight pull-back of the catheter—are performed at 90 seconds per round. The goal is to create a predictable pattern of transmural lesions circumferentially around the renal artery, causing renal fiber interruption without scarring.

In the trial, the primary endpoint of office BP reduction at 6 months maintained the positive results that were achieved at 1 and 3 months, as did 24-hour ambulatory BP (table 3).

Table 3. Blood Pressure Reductions from Baseline (Systolic/Diastolic)^a

^aAll P values are < 0.0001 except 24-hour diastolic at 1 month (P = 0.003) and 3 months (P = 0.0002).

Other studies from AHA 2012 of interest to the interventional community included:

• EMPIRE: The experimental agent exenatide reduced infarct size at 1 month compared with controls in STEMI patients.
• FAST-MI substudy: In a French nationwide registry of patients hospitalized within 48 hours of STEMI or NSTEMI, dual antiplatelet therapy use beyond 1 year was associated with slightly higher long-term mortality compared with patients on a single agent.
• OLIVE registry: In a Japanese registry of patients with critical limb ischemia, endovascular therapy achieved an amputation-free survival rate of 74% at 1 year, with a major adverse limb event (major amputation or surgical bypass of the index limb) -free survival rate of 88% at 1 year.
• RIME: Compared with CABG alone, bypass surgery with mitral valve annuloplasty improves functional capacity and symptoms at 1 year in patients with moderate functional mitral regurgitation.
• RELY-ABLE: Two different doses of dabigatran continued to be associated with low stroke and major bleeding rates in patients with nonvalvular A-fib.
• UMPIRE: A fixed dose ‘polypill’ including antiplatelet, statin, and antihypertensive drugs improved adherence, blood pressure, and cholesterol in a study of over 2,000 patients with cardiovascular disease.

 

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Sources:
Presentations at the American Heart Association Scientific Sessions 2012; November 4-7, 2012; Los Angeles, CA.

 

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