The presence of coronary collateral circulation should be cardioprotective and beneficial, but the demonstration of such benefit has been more challenging.
Glen N. Levine, MD, FAHA, FACC
Meier P, Lansky AJ, Fahy M, et al. The impact of the coronary collateral circulation on outcomes in patients with acute coronary syndromes: results from the ACUITY trial. Heart. 2014;100(8):647-651.
The impact of the presence of coronary collateral circulation on a variety of “soft” end points in patients with coronary artery disease (CAD) has previously undergone investigation. However, data on its impact on hard end points in patients with non—ST-elevation acute coronary syndromes (NSTE-ACS) is limited. Meier et al1sought to assess the impact of visible coronary collateral arteries on prognosis in patients with NSTE-ACS who were enrolled in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial.
The design2and primary findings3of the ACUITY trial have been previously published. In brief, patients with moderate- to high-risk NSTE-ACS were randomized to 1 of 3 antithrombotic regimens. As specified in the study design, all patients underwent cardiac catheterization and, when appropriate, revascularization. An angiographic substudy was performed on the first 7000 patients enrolled in the United States.
In this substudy, coronary angiograms of 5412 patients were visually assessed for the presence or absence of coronary collaterals. Sixteen percent (858) of patients had such collaterals, while 84% (4554) had no visible collaterals. While the unadjusted 1-year mortality rate was actually higher in those with collaterals (hazard ratio [HR], 1.66; 95% confidence interval [CI], 1.15-2.40; P = .007), there was no difference in mortality after multivariable adjustment (HR, 1.03; 95% CI, 0.65-1.62; P = .905). There were also no significant differences after multivariable adjustment in major adverse cardiac events (MACE) (HR, 0.94; 95% CI, 0.76-1.16; P = .55), myocardial infarction (MI) (HR, 1.07; 95% CI, 0.83-1.38; P = .60), or unplanned target vessel revascularization (TVR) (HR, 0.95; 95% CI, 0.71-1.28; P = .75).
Independent predictors of 1-year mortality included age, left ventricular ejection fraction, jeopardy score, and renal insufficiency, but not the presence of collaterals. Independent predictors for TVR included previous percutaneous coronary intervention (PCI), 3-vessel CAD, PCI treatment compared with medical therapy or coronary artery bypass graft (CABG), diameter stenosis degree and age, but not the presence of collaterals.
A subgroup analysis of only those who underwent PCI found no difference in adjusted HR for mortality, MI, or MACE. A significantly elevated HR for unplanned TVR was found (HR, 2.74; 95% CI, 1.48-5.10; P = .004).
Further study needed for this complex process
It is intuitive that the presence of coronary collateral circulation should be cardioprotective and beneficial. In the presence of acute coronary vessel occlusion, such as may occur in ACS, and in the absence of collateral circulation, myocyte cell death in the subtended area of myocardium begins after approximately 60 minutes and is complete within a period of time measured in hours. The presence of collateral vessels subtending the area of jeopardized myocardium should provide at least some blood flow, which may prevent irreversible myonecrosis, or at least delay or mitigate myonecrosis until a time in which an occlusion may become at least partially patent again, via either administered anticoagulant or thrombolytic therapy, mechanical intervention, or spontaneously.
This should lead to avoidance of MI or a smaller degree of myonecrosis, greater preservation of left ventricular function, and improved prognosis.
While the above line of reasoning seems logical, the demonstration of such benefit has been more challenging. Although several studies have demonstrated a correlation in patients with ACS between the presence of collateral circulation and end points such as infarct size, left ventricular function, and left ventricular remodeling, as well as reduction in QT prolongation with acute myocardial ischemia, studies of the benefits in terms of hard end points were less consistent and conclusive.1,4,5
In a meta-analysis of studies examining the relationship between collateral circulation and outcome, Meier and colleagues (including several authors of the ACUITY substudy) identified 12 studies for inclusion.4Most studies used a visual assessment of collateral vessels, and classified collateralization based on the Rentrop Score. Five of the studies were of patients with acute MI and 2 had patients with “subacute MI.” Half of the studies involved patients undergoing PCI and 1 study involved patients treated with thrombolysis. Overall, patients with “high collateralization” had a significantly reduced risk of mortality (relative risk [RR], 0.64; 95% CI, 0.45-0.91; P = .012) compared with those with “low collateralization.” The relative risks were comparable for those studies of patients with stable CAD, subacute MI, and acute MI. The beneficial effect of collaterals was more pronounced in the studies in which patients underwent PCI (RR, 0.42; 95% CI, 0.32-0.56; P <.001).
The protective effect of collaterals was found to be more pronounced in 1 of the 12 studies that measured collaterals via intracoronary pressure measurements and collateral flow index (considered to be the “gold standard” for assessing collateral flow).
The current study by Meier and colleagues, in which angiograms from patients enrolled in the ACUITY trial were studied, represents the largest study to date on collateral circulation and outcome. In contrast to the meta-analysis discussed above, no benefit of collateral circulation on hard end points was detected. Attempting to explain this discrepancy, the ACUITY substudy authors postulate that in the current ACUITY population analysis there may have been better adjustment for potential confounding variables.
Interestingly, a recent meta-analysis by this same group found that the presence of collateral vessels increased the risk of restenosis after PCI.6In that meta-analysis, involving a total of 7 studies and 1425 patients, the presence of good collateralization was associated with a RR for restenosis of 1.40 (95% CI, 1.09-1.80; P = .009). The finding in the present study of an increased risk of TVR in patients with collaterals undergoing PCI must be viewed with caution, however, as this increased risk was not found in the study population as a whole, and is only one of several endpoints studied in a subgroup of a substudy in which the overall results were “negative.”
Thus, the true impact of the presence of collateral circulation requires further study. Even if clearly found to be beneficial, it is unclear how this information can be used to improve outcome and prognosis in patients with CAD. Formation and maturation of collateral vessels is a complex process, often involving increased fluid shear stress, attraction of bone marrow-derived mononuclear cells, and stimulation of these cells.5Attempts to improve collateral circulation via angiogenesis have been disappointing.5Ongoing research may better clarify the true benefits (or detriments) of collateral circulation, and the means of improving such circulation in patients with CAD.
1. Meier P, Lansky AJ, Fahy M, et al. The impact of the coronary collateral circulation on outcomes in patients with acute coronary syndromes: results from the ACUITY trial. Heart. 2014;100(8):647-651.
2. Stone GW, Bertrand M, Colombo A, et al. Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial: study design and rationale. Am Heart J. 2004;148(5):764-775.
3. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006;355(21):2203-2216.
4. Meier P, Hemingway H, Lansky AJ, Knapp G, Pitt B, Seiler C. The impact of the coronary collateral circulation on mortality: a meta-analysis. Eur Heart J. 2012;33(5):614-621.
5. Schaper W. Collateral vessels reduce mortality. Eur Heart J. 2012;33(5):564-566.
6. Meier P, Indermuehle A, Pitt B, et al. Coronary collaterals and risk for restenosis after percutaneous coronary interventions: a meta-analysis. BMC Med. 2012;10:62.
About the Author
Glenn N. Levine, MD, FAHA, FACC, is professor of medicine at Baylor College of Medicine, and director of the Cardiac Care Unit at Michael E. DeBakey Medical Center in Houston, TX. He received his MD from Columbia University College of Physicians and Surgeons in New York City and completed postdoctoral training in advanced cardiovascular imaging at Baylor College of Medicine/Texas Heart Institute. Dr Levine’s internship, residency, and fellowships in interventional cardiology and cardiology were at Boston University Medical Center. He has coauthored numerous published clinical trials, guidelines, and textbook chapters.