The year 2013 has brought us several important clinical trials that have changed the way interventional cardiologists approach and treat patients with stable coronary artery disease. These trials were a major focus at the “Hottest Topics 2013” session at the Society for Cardiovascular Angiography and Interventions (SCAI) 2013 Scientific Sessions, in May in Orlando, Fla.
The session was moderated by Peter Block, M.D., FSCAI, director of interventional research at the Andreas Gruentzig Research Center at Emory University School of Medicine, Ga., and Roxana Mehran, M.D., FSCAI, director of interventional cardiovascular research and clinical trials at The Zena and Michael A. Weiner Cardiovascular Institute at The Icahn School of Medicine at Mount Sinai, N.Y. The trials provide important insight into the best treatment strategy for patients with complex multivessel disease, examine the utility of fractional flow reserve (FFR) and intravascular ultrasound (IVUS) when deciding which lesions should be treated, and evaluate the use of platelet function testing to tailor antiplatelet therapy for patients undergoing percutaneous coronary intervention (PCI).
SYNTAX Trial Five-Year Follow-Up
Ted Feldman, M.D., FSCAI, director of the cardiac catheterization laboratory, University of Chicago, focused on five-year results of SYNTAX. This multicenter, randomized trial evaluated patients with de-novo three-vessel or left main disease, with randomization to either PCI with first-generation paclitaxel-eluting stents or to coronary artery bypass graft (CABG) surgery. Overall, Kaplan-Meier estimates of major adverse cardiac and cerebral events (MACCE) were 26.9% in the CABG group and 37.3% in the PCI group (p<0.0001), driven by increased estimated rates of myocardial infaction (MI) and repeat revascularization. All-cause mortality rates were not different between two groups, with a trend toward more strokes (3.7 vs. 2.4%, p=0.09) in the CABG group. The MACCE rates did not differ in subgroups of patients with low SYNTAX scores or left main artery disease, whereas those with intermediate or high SYNTAX scores had greater MACCE in the PCI group.
The SYNTAX score has become an important risk score that allows clinicians to stratify patients into low, intermediate, or high-score groups based on angiographic complexity of coronary artery disease (CAD). Once SYNTAX score is calculated, decisions about appropriateness of PCI versus CABG can be made on individual patient basis, taking into account clinical factors as well as patient/family preference.
Feldman concluded that, based on data from SYNTAX trial, patients with complex multivessel coronary disease should be evaluated by a cardiac team of physicians (the “heart team”) that includes an interventionalist and cardiac surgeon prior to undergoing ad hoc multivessel PCI. For patients with less complex disease (low SYNTAX scores) or left main coronary disease (low or intermediate SYNTAX scores), PCI may be a reasonable alternative to CABG surgery. For patients with high or intermediate SYNTAX scores, CABG may be the preferable revascularization option, given angiographic and clinical suitability for surgery.
George Dangas, M.D., Ph.D., FSCAI, director of cardiovascular innovation, Icahn School of Medicine at Mount Sinai, N.Y., reviewed the results of the FREEDOM trial, which is the largest prospective trial addressing the best revascularization approach for patients with diabetes and multivessel disease. Prior data from the BARI trial suggested that a subgroup of diabetics with multivessel coronary disease lived longer after undergoing CABG versus PCI. Therefore, FREEDOM was a randomized, multicenter trial that evaluated patients with diabetes and multivessel coronary artery disease undergoing either PCI with drug-eluting stents or CABG surgery. Patients were followed for more than two years. All patients were prescribed currently recommended medical therapies for the control of hyperlipidemia, hypertension, and diabetes.
The primary outcome (a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke) occurred more frequently in the PCI group (p=0.005), with five-year rates of 26.6% in the PCI group and 18.7% in the CABG group. The benefit of CABG was driven by differences in rates of both myocardial infarction (p<0.001) and death from any cause (p=0.049). Stroke was more frequent in the CABG group, with 5-year rates of 2.4% in the PCI group and 5.2% in the CABG group (p=0.03). The benefit of CABG was consistent across prespecified subgroups according to the category of SYNTAX score (interaction p=0.58).
Dangas concluded that the results of this important trial suggest that for patients with diabetes and multivessel CAD, CABG is the preferred option given reductions in all-cause mortality and myocardial infarction, despite higher rates of strokes.
FAME II Trial
William Fearon, M.D., FSCAI, associate professor at Stanford University Medical Center, Calif., and senior author of the FAME and FAME II trials, discussed the findings of the FAME II trial. Given the results of the COURAGE trial, medical therapy is considered to be the best initial strategy for treatment of patients with stable CAD, as determined by angiography to be severe. However, angiographic severity does not always correlate with physiological significance of coronary stenoses, which can be determined by fractional flow reserve (FFR) measurements. Therefore, FAME II trial examined patients with functionally significant stenoses (FFR, ?0.80) who were randomized to FFR-guided PCI plus the best available medical therapy or the optimal medical therapy alone, Fearon explained. Patients with functionally non-significant stenoses were entered into a registry and received the best available medical treatment.
The primary endpoint was a composite of death, myocardial infarction, or urgent revascularization. The trial was terminated early, because of a significant between-group difference in primary endpoint events: 4.3% in the PCI group and 12.7% in the medical-therapy group (hazard ratio with PCI 0.32; p<0.001). The difference was driven by a lower rate of urgent revascularization in the PCI group compared with the medical-therapy group (1.6 vs. 11.1%; hazard ratio 0.13; p<0.001). The results of this trial suggest that in patients with stable coronary artery disease and functionally significant stenoses by FFR, PCI plus the best available medical therapy offers patients better outcomes when compared with best medical therapy, said Fearon. Patients with FFR stenoses >0.80 should be treated with optimal medical therapy given excellent clinical outcome in such patients.
Ron Waksman, M.D., FSCAI, professor of medicine and associate director of the division of cardiology at Washington Hospital Center, Washington, D.C., discussed the results of the FIRST trial. Controversy exists regarding the appropriateness of PCI for intermediate coronary stenoses and how anatomical IVUS parameters (e.g., minimal luminal area) correlate with functional FFR. Minimal luminal area (MLA) less than 4 mm2 has been commonly used in interventional practice as a cutoff for anatomically significant lesions. FIRST (Fractional Flow Reserve and Intravascular Ultrasound Relationship Study) was performed to determine the optimal minimal luminal area by IVUS that correlates with FFR in patients with intermediate (40-80% stenosis) coronary lesions. Three-hundred-fifty patients were studied in 10 U.S. and European centers.
Waksman noted that overall correlation between IVUS and FFR was moderate, an MLA <3.07 mm2 was found to be the best threshold correlating with FFR <0.8. The accuracy improved when the reference vessel was taken into consideration: an MLA <2.4 mm2 correlated best for reference vessel diameters <3 mm, an MLA <2.7 mm2 for reference diameters 3-3.5 mm, and MLA <3.6 mm2 for reference diameters >3.5mm2. Waksman concluded that the results of the FIRST trial suggest a new MLA cutoff, which would be dependent on size of coronary vessels. Waksman also noted that the utility of using IVUS MLA as a guide to intervention in indeterminate coronary lesions needs to be further tested clinically.
Roxana Mehran discussed the findings and take-home messages of the ARCTIC trial. High platelet reactivity measurements in clopidogrel-treated patients have been shown to be predictive of higher rates of future cardiovascular events. However, prior randomized trials (GRAVITAS and TRIGGER-PCI) did not demonstrate any benefit of platelet function-guided therapy to improve clinic outcomes in PCI patients. The ARCTIC trial evaluated the benefit of bedside platelet monitoring to adjust antiplatelet therapy after coronary stenting.
In this multicenter randomized trial, 2,440 patients were assigned to either a strategy of platelet function monitoring (via the VerifyNow P2Y12 and aspirin point-of-care assays) and then drug adjustment in poor responders or to a conventional strategy without monitoring. The platelet function monitoring was performed prior to stenting and then two to four weeks later on an outpatient basis. In the platelet-monitoring group, high platelet reactivity in those taking clopidogrel (35%) or aspirin (7.6%) resulted in additional dosing of clopidogrel, prasugrel, aspirin, or glycoprotein IIb/IIIa inhibitors periprocedurally.
The combined primary endpoint of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization at one year occurred with similar frequency in both groups (34.6% monitoring group vs. 31.1% conventional group); the secondary endpoint of stent thrombosis or any urgent revascularization (4.9 vs. 4.6%) also did not differ between two groups.
Mehran noted that the results of this trial, in addition to the prior negative GRAVITAS and TRIGGER PCI studies, suggest no utility of routine platelet function testing and adjusting antiplatelet therapy based on the results of such testing in patients with stable coronary artery disease. Further studies are needed to evaluate in which patients and clinical scenarios platelet function testing may be appropriate. ARCTIC-2 will evaluate a second randomization occurring one year after the first randomization to determine the effect of continuation versus interruption of clopidogrel therapy.
Editor’s note: Dmitriy N. Feldman, M.D., FACC, FSCAI, is director of endovascular services and assistant professor of medicine, interventional cardiology and endovascular laboratory, Weill Cornell Medical College/The New York Presbyterian Hospital, New York. His clinical expertise extends from the performance of complex coronary interventions to endovascular treatment of peripheral and carotid disease. His areas of research interest include percutaneous coronary and endovascular intervention outcomes research. He has performed extensive work with the New York State Department of Health PCI database, American College of Cardiology National Cardiovascular Data Registry as well as the Cornell Catheterization Laboratory institutional database.
1. Mohr FW, Morice MC, Kappetein AP, Feldman TE, et al. “Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial.” Lancet 2013;381:629-38.
2. Farkouh ME, Domanski M, Sleeper LA, Siami FS, et al. “FREEDOM Trial Investigators. Strategies for multivessel revascularization in patients with diabetes.” N Engl J Med 2012;367:2375-84.
3. De Bruyne B, Pijls NH, Kalesan B, Barbato E, Fearon WF, et al. “FAME 2 Trial Investigators. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease.” N Engl J Med 2012;367:991-1001.
4. Waksman R, Legutko J, Singh J, Orlando Q, et al. “FIRST: Fractional Flow Reserve and Intravascular Ultrasound Relationship Study.” J Am Coll Cardiol 2013;61:917-23.
5. Collet JP, Cuisset T, Rangé G, Cayla G, et al. “ARCTIC Investigators. Bedside monitoring to adjust antiplatelet therapy for coronary stenting.” N Engl J Med 2012;367:2100-9.