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Editorial
Coronary collaterals: an elusive network Franz Weidinger The role of coronary collaterals in protecting the myocardium from ischaemia and necrosis has been extensively investigated. Difficulties in assessing the true extent of collaterals relate in part to their capacity to rapidly adapt in size and function according to the demand of the ischaemic territory. Therefore, in addition to the angiographic quantification of collaterals by the Rentrop score,1 studies have used additional techniques such as collateral flow index to quantify collateral flow, albeit in an artificial situation of induced ischaemia or coronary occlusion.2 The protective effects of collateral arteries in the setting of acute myocardial infarction (MI) include a reduction in infarct size, prevention of fatal arrhythmias through QT interval prolongation, improved ventricular function and prevention of aneurysm formation.3 4 Perhaps due to the difficulties in correctly assessing collateral circulation, studies investigating the prognostic significance of coronary collaterals have yielded conflicting results. In particular, the influence on mortality is a matter of ongoing debate. Recently, a meta-analysis of 12 studies including 6529 patients analysed the impact of collateral circulation on allcause mortality in a mixed population of stable coronary artery disease (CAD) and acute and subacute MI.5 Results showed a reduced mortality in patients with ‘high collateralisation’ compared with patients with ‘low collateralisation’ (RR 0.64, 95% CI 0.45 to 0.91, p=0.012). Although the RR was statistically significant for patients with acute and subacute MI, the p value for interaction was not statistically significant. However, due to the small sample size of acute and subacute CAD and the lack of sufficient statistical power, no definite conclusion could be made on the role of collaterals in the setting of acute coronary syndromes (ACS). Meier and et al6 report a subgroup analysis of the ACUITY trial, addressing specifically the association of collateral circulation with mortality in patients with ACS. In this population of 5412 patients, the authors showed that mortality rate Correspondence to Professor Franz Weidinger, 2nd Medical Department (Cardiology), Krankenhaus Rudolfstiftung, Vienna 1030, Austria; [email protected] Weidinger F. Heart April 2014 Vol 100 No 8
was higher in the 858 patients (16% of the total population) with collaterals than in those without collaterals in univariable analysis. After multivariable adjustment for differences between the groups, including number and severity of coronary lesions, this difference was no longer significant (HR 0.94, 95% CI 0.76 to 1.16, p=0.55). The independent predictors of 1 year mortality were age, LVEF, jeopardy score and renal insufficiency. This study provides important information to the controversial area of the prognostic impact of coronary collaterals: first, it includes a large number of patients with a diagnosis of ACS from a single randomised trial. Previous studies were hampered by low statistical power for this subgroup of patients with acute CAD. Second, results are corrected for several important variables which may influence mortality in ACS. Previous studies, including meta-analyses,7 failed to adjust their findings for potential confounding factors. Indeed, after multivariable analysis, no significant difference was found in the present study by Meier et al between patients with and without collaterals in terms of 1-year mortality, MI and target vessel revascularisation. The authors conclude that no difference in outcome could be found between the groups with and without collaterals, but incomplete correction for all relevant covariables in multivariate analysis may account for these results. Can we conclude from this study that collaterals have no protective effects against major adverse clinical events in patients with ACS? Intuitively, visible collaterals in coronary angiograms may limit infarct size and prevent lethal arrhythmias by providing residual coronary flow to the jeopardised myocardium supplied by the acutely occluded coronary artery. In the long term, collaterals will likely prevent reinfarction, at least those of clinically relevant size. How can previous conflicting results of studies on the prognostic effects of collaterals be explained and why did the ACUITY authors fail to show an association between the presence of collaterals and outcome? Several limitations of the study of Meier et al, which may prevent the demonstration of such an association, have to be taken into account: first, angiographic visualisation of collaterals may be too insensitive to exclude
their presence or potential recruitment over time. The gold standard for collateral assessment, the measurement of collateral flow index,2 was not used in this study. The recruitment of visible collaterals is influenced by pre-existing high-grade stenosis and the duration of acute ischaemia.8 Thus, in the acute setting, the timing of angiographic assessment may be particularly relevant because collaterals may rapidly develop during ongoing ischaemia. Indeed, more patients with collaterals in the ACUITY substudy had cardiac biomarker and troponin elevation at baseline (73% vs 49%, p
Editorial
Coronary collaterals: an elusive network Franz Weidinger The role of coronary collaterals in protecting the myocardium from ischaemia and necrosis has been extensively investigated. Difficulties in assessing the true extent of collaterals relate in part to their capacity to rapidly adapt in size and function according to the demand of the ischaemic territory. Therefore, in addition to the angiographic quantification of collaterals by the Rentrop score,1 studies have used additional techniques such as collateral flow index to quantify collateral flow, albeit in an artificial situation of induced ischaemia or coronary occlusion.2 The protective effects of collateral arteries in the setting of acute myocardial infarction (MI) include a reduction in infarct size, prevention of fatal arrhythmias through QT interval prolongation, improved ventricular function and prevention of aneurysm formation.3 4 Perhaps due to the difficulties in correctly assessing collateral circulation, studies investigating the prognostic significance of coronary collaterals have yielded conflicting results. In particular, the influence on mortality is a matter of ongoing debate. Recently, a meta-analysis of 12 studies including 6529 patients analysed the impact of collateral circulation on allcause mortality in a mixed population of stable coronary artery disease (CAD) and acute and subacute MI.5 Results showed a reduced mortality in patients with ‘high collateralisation’ compared with patients with ‘low collateralisation’ (RR 0.64, 95% CI 0.45 to 0.91, p=0.012). Although the RR was statistically significant for patients with acute and subacute MI, the p value for interaction was not statistically significant. However, due to the small sample size of acute and subacute CAD and the lack of sufficient statistical power, no definite conclusion could be made on the role of collaterals in the setting of acute coronary syndromes (ACS). Meier and et al6 report a subgroup analysis of the ACUITY trial, addressing specifically the association of collateral circulation with mortality in patients with ACS. In this population of 5412 patients, the authors showed that mortality rate Correspondence to Professor Franz Weidinger, 2nd Medical Department (Cardiology), Krankenhaus Rudolfstiftung, Vienna 1030, Austria; [email protected] Weidinger F. Heart April 2014 Vol 100 No 8
was higher in the 858 patients (16% of the total population) with collaterals than in those without collaterals in univariable analysis. After multivariable adjustment for differences between the groups, including number and severity of coronary lesions, this difference was no longer significant (HR 0.94, 95% CI 0.76 to 1.16, p=0.55). The independent predictors of 1 year mortality were age, LVEF, jeopardy score and renal insufficiency. This study provides important information to the controversial area of the prognostic impact of coronary collaterals: first, it includes a large number of patients with a diagnosis of ACS from a single randomised trial. Previous studies were hampered by low statistical power for this subgroup of patients with acute CAD. Second, results are corrected for several important variables which may influence mortality in ACS. Previous studies, including meta-analyses,7 failed to adjust their findings for potential confounding factors. Indeed, after multivariable analysis, no significant difference was found in the present study by Meier et al between patients with and without collaterals in terms of 1-year mortality, MI and target vessel revascularisation. The authors conclude that no difference in outcome could be found between the groups with and without collaterals, but incomplete correction for all relevant covariables in multivariate analysis may account for these results. Can we conclude from this study that collaterals have no protective effects against major adverse clinical events in patients with ACS? Intuitively, visible collaterals in coronary angiograms may limit infarct size and prevent lethal arrhythmias by providing residual coronary flow to the jeopardised myocardium supplied by the acutely occluded coronary artery. In the long term, collaterals will likely prevent reinfarction, at least those of clinically relevant size. How can previous conflicting results of studies on the prognostic effects of collaterals be explained and why did the ACUITY authors fail to show an association between the presence of collaterals and outcome? Several limitations of the study of Meier et al, which may prevent the demonstration of such an association, have to be taken into account: first, angiographic visualisation of collaterals may be too insensitive to exclude
their presence or potential recruitment over time. The gold standard for collateral assessment, the measurement of collateral flow index,2 was not used in this study. The recruitment of visible collaterals is influenced by pre-existing high-grade stenosis and the duration of acute ischaemia.8 Thus, in the acute setting, the timing of angiographic assessment may be particularly relevant because collaterals may rapidly develop during ongoing ischaemia. Indeed, more patients with collaterals in the ACUITY substudy had cardiac biomarker and troponin elevation at baseline (73% vs 49%, p
