Coronary Collateral Function Long After Drug-Eluting Stent Implantation Pascal Meier, M.D.; Rainer Zbinden, M.D.; Mario Togni, M.D.; Peter Wenaweser, M.D.; Stephan Windecker, M.D.; Bernhard Meier, M.D., F.A.C.C., F.E.S.C.; and Christian Seiler, M.D., F.A.C.C., F.E.S.C Published in JACC January 2, 2007

Coronary Collateral Function Long After Drug-Eluting Stent Implantation : Background Drug-eluting stents (DES) have been demonstrated to decrease restenosis rates compared to bare-metal stents (BMS) and have diminished re-intervention rates. However, DES may have a heightened risk of late stent thrombosis and impairment of endothelial-dependent vasomotion. Meier et al. JACC. 2007 Jan; 49(1): 15 – 20.

Coronary Collateral Function Long After Drug-Eluting Stent Implantation: Background Togni et al. and Hofma et al. respectively described flow-induced (physical exercise) acetylcholine-induced endothelial dysfunction in only 3 of 16 patients following BMS implantation but in the vast majority (18 or 21) patients after DES implantation. Considering that endothelial dysfunction can be regarded as the earliest stage of atherosclerosis, and its presence predicts adverse cardiovascular events, an unfavorable clinical impact related to DES could be hypothesized. Meier et al. JACC. 2007 Jan; 49(1): 15 – 20.

Coronary Collateral Function Long After Drug-Eluting Stent Implantation : Background (cont.) In addition, DES have an inhibitory effect on the production of cytokines, chemotactic proteins, and growth factors, and thus may negatively affect coronary collateral growth. Therefore, this study was designed to quantitatively compare coronary collateral flow in patients six months after BMS or DES implantation. Meier et al. JACC. 2007 Jan; 49(1): 15 – 20.

Rise in Biomarkers by Use of Stent Type Rise in CRP After PCI In a recent study by Gibson et al, drug-eluting stent use was associated with reductions in peri-procedural markers of inflammation. PCI results in the upregulation of inflammatory cytokine production within the vessel wall which in turn results in the activation of inflammatory cells. Intereleukin-6 (IL-6) is a major stimulus of CRP production and local release of IL-6 release from the epicardial artery or myocardium in response to PCI could result in an increase in CRP production by the liver. Sirolimus reduces both inflammatory cytokine production and adhesion molecule expression by the endothelium in response to inflammatory stimuli. p=0.006 IQ 0.8, 11.1 CRP Rise post PCI (mg/L) IQ 0.5, 6.5 N=612 N=129 Drug-Eluting Stent Bare Metal Stent Gibson CM et al, Am J Cardiol. 2006; 97(10):1473-7.

Coronary Collateral Function Long After Drug-Eluting Stent Implantation : Study Design 120 patients 60+10 yrs old with 1- to 3-vessel long-term stable coronary artery disease (CAD) after stent implantation but excluding those with previous Q-wave infarction, baseline ECG ST-segment abnormalities, and non-stable CAD BMS Matched for: 1) stenosis severity of the vessel undergoing collateral flow index (CFI) measurement at baseline & 2) for the duration of follow-up n=60 DES Matched for: 1) stenosis severity of the vessel undergoing collateral flow index (CFI) measurement at baseline & 2) for the duration of follow-up n=60 6 mos. follow-up Primary Endpoint: Invasively determined coronary collateral function Meier et al. JACC. 2007 Jan; 49(1): 15 – 20.

Coronary Collateral Function Long After Drug-Eluting Stent Implantation: Baseline Characteristics BMS DES p value Age (yrsSD) 5910 6113 0.21 Male gender 51 50 1.0 Duration of Chest Pain (months) 1.22.2 1.42.5 0.63 Positive treadmill exercise ECG 26 28 0.82 BMI 283 3021 Smoking 20 19 0.85 Hypercholesterolemia 40 44 0.70 Hypertension 34 0.99 Obesity 21 0.23 Meier et al. JACC. 2007 Jan; 49(1): 15 – 20.

Coronary Collateral Function Long After Drug-Eluting Stent Implantation: Baseline Characteristics (cont.) Characteristic BMS DES p value Family History of CAD 16 17 0.45 Diabetes mellitus 8 4 0.24 Acetylsalicylic acid 56 1.0 Beta-blockers 45 52 0.17 Calcium antagonists 12 11 0.92 Nitrates 14 0.77 Angiotensin-converting enzyme inhibitor 19 21 0.88 Statin 46 Diuretics 9 0.65 Meier et al. JACC. 2007 Jan; 49(1): 15 – 20.

Coll. Flow Index Endpoint Coronary Collateral Function Long After Drug-Eluting Stent Implantation: Primary Endpoint Despite equal in-stent stenosis severity and equal follow-up duration for both groups, collateral flow index (CFI) was diminished in the DES versus BMS group. p =0.0049 0.224 ± 0.142 0.154 ± 0.097 Coll. Flow Index Endpoint Meier et al. JACC. 2007 Jan; 49(1): 15 – 20.

Insufficient collateral flow Coronary Collateral Function Long After Drug-Eluting Stent Implantation: Primary Endpoint p =0.001 In addition, the rate of collaterals insufficient to prevent ischemia during occlusion was higher in the DES group than in the BMS group. Insufficient collateral flow n=50 n=33 Meier et al. JACC. 2007 Jan; 49(1): 15 – 20.

Coronary Collateral Function Long After Drug-Eluting Stent Implantation: Limitations This study was a cross-sectional rather than longitudinal observation of collateral function. The ideal study design would have been a randomized group allocation with baseline and follow-up CFI measurement allowing intra- and inter-group comparisons; however, the ethics of such a design would have been questionable. The quality of matching was not absolute; however, it was so high that, statistically, an influence of stenosis severity and/or follow-up duration on the study’s main outcome can be excluded. Meier et al. JACC. 2007 Jan; 49(1): 15 – 20.

Coronary Collateral Function Long After Drug-Eluting Stent Implantation: Summary The novel result of this study is that coronary collateral function 6 months after implantation of a DES is 30% to 40% lower than that obtained equally long after BMS implantation. Considering the salvaging effect of well-grown collaterals, a potential clinical impact of this finding is that in the presence of stent thrombosis, myocardial infarct size and potentially mortality may be larger in DES- than in BMS-treated patients. Meier et al. JACC. 2007 Jan; 49(1): 15 – 20.

Coronary Collateral Function Long After Drug-Eluting Stent Implantation: Summary (cont.) Furthermore, an additional clinical risk could arise from endothelial dysfunction and a deficit of endothelial progenitor cells. In support of this notion, 6-month mortality after BMS stent thrombosis has been found to amount to 11% (10 of 95 stent thromboses in 6,058 patients) to 21% (11 of 53 stent thromboses in 6,219 patients), whereas that after DES-stent thrombosis has been 29% (2 of 7 stent thromboses in 2,006 patients) to 45% (13 of 29 stent thromboses in 2,229 patients). Meier et al. JACC. 2007 Jan; 49(1): 15 – 20.