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COlchicine to Prevent PeriprocEdural Myocardial Injury in Percutaneous Coronary Intervention (COPE-PCI): Coronary Microvascular Physiology Pilot Substudy

COlchicine to Prevent PeriprocEdural Myocardial Injury in Percutaneous Coronary Intervention... Hindawi Journal of Interventional Cardiology Volume 2022, Article ID 1098429, 10 pages https://doi.org/10.1155/2022/1098429 Research Article COlchicine to Prevent PeriprocEdural Myocardial Injury in Percutaneous Coronary Intervention (COPE-PCI): Coronary Microvascular Physiology Pilot Substudy 1,2 1,2 1 1 3 Justin Cole , Nay Htun, Robert Lew, Mark Freilich, Stephen Quinn, 1,2 and Jamie Layland Peninsula Heart Service, Peninsula Health, Frankston, Australia Peninsula Clinical School, Monash University, Melbourne, Australia Department of Health Science and Biostatistics, Swinburne University of Technology, Melbourne, Australia Correspondence should be addressed to Jamie Layland; jlayland@phcn.vic.gov.au Received 9 February 2022; Accepted 22 April 2022; Published 29 May 2022 Academic Editor: Alessandro Sciahbasi Copyright © 2022 Justin Cole et al. %is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Aim. In this randomized pilot trial, we aimed to assess the anti-inflammatory effect of preprocedural colchicine on coronary microvascular physiology measurements before and after PCI. Methods. Patients undergoing PCI for stable angina (SA) or non- ST-elevation myocardial infarction (NSTEMI) were randomized to oral colchicine or placebo, 6- to 24-hours before the pro- cedure. Strict prespecified inclusion/exclusion criteria were set to ensure all patients were given the study medication, had a PCI, and had pre- and post-PCI culprit vessel invasive coronary physiology measurements. Fractional flow reserve (FFR), Index of Microvascular Resistance (IMR), Coronary Flow Reserve (CFR), and Resistive Reserve Ratio (RRR) were measured immediately before and after PCI. CMVD was defined as any one of post-PCI IMR>32 or CFR<2 or RRR<2. High-sensitive-(hs)-troponin-I, hsCRP, and leucocyte count were measured before and 24 hours after PCI.Results. A total of 50 patients were randomized and met the strict prespecified inclusion/exclusion criteria: 24-colchicine and 26-placebo. Pre-PCI coronary physiology measurements, hs- troponin-I, and hsCRP were similar between groups. Although numerically lower in patients given colchicine, the proportion of patients who developed CMVD was not significantly different between groups (colchicine: 10 (42%) vs placebo: 16 (62%), p � 0.16). Colchicine patients had higher post-PCI CFR and RRR vs placebo (respectively: 3.25 vs 2.00, p � 0.03 & 4.25 vs 2.75, p<0.01). Neutrophil count was lower after PCI in the colchicine arm (p � 0.02), and hsCRP post-PCI remained low in both treatment arms (1.0mg/L vs 1.7mg/L, p � 0.97). Patients randomized to colchicine had significantly less PCI-related absolute hs- troponin-I change (46ng/L vs 152ng/L, p � 0.01). Conclusion. In this pilot randomized substudy, colchicine given 6 to 24 hours before PCI did not statistically impact the post-PCI CMVD definition used in this study, yet it did improve post-PCI RRR and CFR measurements, with less procedure-related troponin release and less inflammation. CMVD is defined by impaired response of coronary 1. Introduction/Background microvascular flow to vasodilator stimuli [5] which can Percutaneous coronary intervention (PCI), of a functionally occur through many pathways as a consequence of PCI [3, 5] significant epicardial artery stenosis, is one of the main and is associated with myocardial injury [4, 6, 7], yet the treatments for symptomatic patients with either stable underlying mechanisms of this association remain under coronary disease or acute coronary syndromes (ACSs) [1, 2]. investigation. Small trials offering targeted treatment aimed However, PCI can activate multiple pathways leading to at reducing PCI-related CMVD have been performed and coronary microvascular dysfunction (CMVD) [3] with as- have shown promise. Both ACE inhibitors and statins have sociated adverse clinical outcomes [3, 4]. demonstrated improved measures of microvascular function 2 Journal of Interventional Cardiology in patients undergoing PCI [8–12], and a strategy of direct involved in the invasive protocol. Randomization was simple stenting has also been shown to have favorable effects on and not stratified. Study medication was denoted Drug A or Drug B throughout the trial. Both Drug A and Drug B were PCI-related coronary microvascular dysfunction, as mea- sured by IMR [13]. in labeled bottles and looked identical. %is was a double- In the COPE-PCI Pilot Trial [14], we have previously blind randomized placebo-controlled trial. All parties in- demonstrated that when colchicine is given before PCI, it is volved were blinded to the treatment allocation until the trial associated with reductions in periprocedural myocardial had finished. %e study protocol was approved by the injury and in a subsequent study is associated with nu- Human Research Ethics Committee at St Vincent’s Hospital merically lower pre-PCI levels of inflammation [15]. Melbourne and Frankston Hospital Melbourne, Australia. Moreover, we have previously demonstrated a relationship %e trial was publicly registered (COPE-PCI Trial ANZCTR between pre-PCI microvascular function and inflammation Trial ID: ACTRN12615000485538). %e trial ran from 1 December 2017 to 30 December 2019. [16]. %us, in this substudy of the COPE-PCI Pilot Trial, we aimed to assess the anti-inflammatory effect of colchicine, given 6–24 hours before PCI, on coronary microvascular 2.3. PCI Procedure. All patients received weight-adjusted physiology measurements before and after PCI. We hy- bolus (100 Units/kg) intravenous heparin, immediately prior pothesized that colchicines’ anti-inflammatory effect would to PCI, and additional bolus dosing to maintain an attenuate PCI-associated impairment in coronary micro- activated clotting time of >250secs. Technical aspects of vascular function. the PCI procedure were determined by the practicing interventionalist. 2. Methods 2.1. Study Population. %e study population consisted of 2.4. Invasive Coronary Physiological Measurements both stable angina (SA) patients intended for elective PCI [3, 17–19]. We performed invasive interrogation of the and patients presenting with non-ST-elevation myocardial culprit vessel coronary circulation as previously described infarction (NSTEMI) planned for in-patient coronary an- [20]. Measurements were taken both before and after PCI. In giography and PCI. Patients were assessed against strict brief, a dual temperature and pressure-sensing guidewire inclusion and exclusion criteria (see below) and must have was used to cross the lesion, measuring distal pressure (Pd) had a lesion appropriate for invasive coronary physiological and transit time (Tmn) of 3ml of room temperature hep- measurements, deemed by the interventional cardiologist at arinized saline-injected intracoronary. %ree reproducible the time of the index PCI. Notable inclusion criteria were and consistent thermodilution curves were performed be- patients with a de novo lesion amenable to PCI, and patients fore and after PCI, both at rest ( ) and at maximal hy- Rest with high-sensitive (hs) troponin-I and creatinine kinase peremia ( ). Maximal hyperemia was induced by the Hyp (CK) that had peaked and stabilized prior to PCI. Patients administration of intravenous adenosine at 140ug/kg/min were excluded if they had left main disease and required for up to 2 minutes and confirmed by clinical response and bifurcation lesion PCI, or the culprit’s vessel was completely hemodynamic changes. Proximal pressure was obtained occluded. Additionally, patients were excluded if they had from the guiding catheter (Pa). Coronary artery wedge heavily calcified or tortuous vessels such that safe passage of pressure (Pw) was obtained during a 20-second balloon the pressure wire could not be guaranteed. Furthermore, occlusion of the culprit’s vessel during the initial balloon patients were excluded if they had active inflammation or inflation. infection or were taking anti-inflammatory medications, had prior ACS within 12-months, had severe renal impairment (i) Fractional Flow Reserve myocardial (FFRmyo) [17] (creatinine clearance <45ml/min), and developed ST-ele- was measured at maximal hyperemia, defined as vation prior to PCI or troponin increase after randomization follows: FFRmyo �Pd /Pa Hyp Hyp. and prior to PCI. Patients received dual antiplatelet therapy (ii) Coronary Flow Reserve (CFR ) was defined as thermo prior to PCI. We prespecified that patients who were initially CFR �Tmn /Tmn [19] thermo Rest Hyp enrolled in the trial but who did not go on to PCI or invasive (iii) In the presence of severe epicardial stenosis, the coronary physiological measurements were excluded from index of microvascular resistance (IMR) was de- statistical analysis. fined by incorporating Pw via the following equa- tion:IMR �Pa ×Tmn ×FFRcor [18]. FFR Hyp Hyp coronary (FFRcor) was defined by the following 2.2. Study Protocol. All patients reviewed and signed an equation: FFRcor �(Pd -Pw)/(Pa −Pw) [18], Hyp Hyp informed consent prior to randomization and PCI. where Pw was not recorded and FFRcor was pre- Consenting patients were randomized 1:1 to oral col- dicted by FFRmyo using the following equation chicine (1mg followed by 0.5mg one hour later [14]) or [17]:FFRcor �(1.34 ×FFRmyo) −0.32. %erefore, in placebo, 6 to 24 hours prior to a coronary angiogram. Se- the absence of Pw: IMR �Pa ×Tmn × Hyp Hyp quential randomization was performed using proprietary ((1.34 ×FFRmyo) −0.32). software (https://www.sealedenvelope.com). Study patients were assigned to colchicine or placebo prior to coronary (iv) Baseline Resistance Index (BRI) [20] was defined as angiography by an independent research assistant not per IMR; however, baseline measures were used: Journal of Interventional Cardiology 3 (a) BRI �Pa ×Tmn ×((Pd −Pw)/ normal data or a Spearman Correlation Coefficient for Rest Rest Rest (Pa −Pw)). skewed data. A p value <0.05 (two-sided) was considered Rest statistically significant. Statistical analyses were performed (b) Or in the absence of Pw: BRI �Pa × Rest Tmn ×(((1.34 ×(Pd /Pa )) −0.32) with IBM SPSS Statistics for Windows, Version 25.0 Rest Rest Rest (Armonk, NY: IBM Corp). (v) Resistive Reserve Ratio (RRR) [20] was defined by the following equation: RRR �BRI/IMR. 3. Results 2.5. Blood Sampling. All patients had study blood samples 3.1.StudyPopulation. A total of 196 patients were screened. collected immediately prior to PCI (before administration of Of these, 14 patients (7%) developed clinical criteria ex- PCI procedure-related medications) and 24 hours later. All cluding them, 107 (54%) did not have PCI, and 25 (13%) did patients also had standard routine clinical blood tests. Study not have invasive coronary physiological measurements (see blood samples were assessed for high sensitivity (hs)-tro- Figure 1). %us, the final population was 50 patients, thereby ponin-I (ng/L), hsCRP (mg/L), and leucocyte count. Serum ensuring all analyzed patients fulfilled the prespecified cri- hsCRP level was quantified using a Human CRP Simplex teria: (1) received the study medication, (2) PCI procedure ProcartaPlex performed, and (3) complete pre- and post-PCI invasive immunoassay that utilizes Luminex xMAP ™ ™ technology for protein detection/quantitation. We pre- coronary physiological measurements performed. Twenty- specified that patients enrolled in the trial who had in- four (11 (46) NSTEMI, 13 (54) SA) were randomized to complete blood sampling were excluded from statistical colchicine, 26 (12 (46) to NSTEMI, and 14 (54) SA) to analysis. placebo (Table 1). Patients were well matched, without significant differ- ences, for baseline characteristics and pre-PCI medication 2.6.StudyEndpoints. %e primary outcome of this study was use (Table 1). %ere was no significant difference in PCI the difference in proportion between treatment arms, of characteristics between treatment arms (Table 2). patients with coronary microvascular dysfunction, defined Prior to PCI, there was no statistical difference in the as any one of the following: post-PCI RRR<2.0, CFR<2.0, or invasive coronary physiological measurements between IMR >32. treatment groups (Table 3). FFR was similar and functionally Additionally, colchicines’ effect on coronary microvas- significant in both treatment arms before PCI (0.65 vs 0.72, cular function was assessed by comparing pre- and post-PCI p � 0.42), and IMR measures were low (<22). invasive coronary physiological measurements (listed above) Post-PCI patients randomized to colchicine had higher between the treatment arms of this study. CFR and RRR compared to placebo (respectively: 3.25 Demographic, clinical, medication use, and PCI pro- (2.08–4.40) vs 2.00 (1.48–3.30), p � 0.03 and 4.25 cedure data were recorded. (2.45–5.24) vs 2.75 (1.67–3.44), p<0.01, Table 3). Median Inflammation was assessed by measuring pre-PCI and IMR remained low in both treatment arms (IMR <20). 24-hour post-PCI hsCRP and leucocyte count, comparing Comparing change between pre- and post-PCI invasive treatment arms. coronary physiological measurements, patients randomized Myocardial injury was assessed by measuring pre-PCI to colchicine had significantly less change in Tmn Rest and 24-hour post-PCI hs-troponin-I and calculating abso- measurements (0.01 vs −0.31, p � 0.03) and significantly lute hs-troponin-I change: calculated as post-PCI mea- greater change in CFR (1.20 (−0.30–2.10) vs 0.10 surements minus pre-PCI measurements, in each treatment (−0.70–0.63), p � 0.03) (Table 3). %ere was a trend in favor arm of this study. of a change in RRR being numerically higher in the col- Patients were followed up for 24 hours after the pro- chicine arm (p � 0.054, Table 3). cedure. All patients received standard medical and PCI Following PCI, there was no statistical difference in the therapy and were reviewed by their referring cardiologist proportion of patients with CMVD between those ran- within 30 days after PCI. domized to colchicine or placebo (colchicine: 10 (42%) vs placebo: 16 (62%), p � 0.16, Table 4). %is was also true for 2.7. Statistical Analysis. Continuous variables are reported the proportion of patients with individual measures of CFR as mean±SD or median (LQ-UQ) according to whether the <2.0, IMR >32, or RRR <2.0 (Table 4). variable is normal or skewed, and categorical variables are as Troponin measures prior to PCI were similar and low in numbers (n (%)). Differences in continuous variables were both treatment groups (<13, Table 3). Most patients had a tested via an independent-samples t-test (normal data) or troponin elevation of any magnitude after PCI (colchicine: Mann–Whitney U test (skewed data). Similarly, paired 75% vs placebo 92%, p � 0.13). Patients randomized to variables were tested via a paired-samples t-test (normal colchicine had significantly less absolute troponin change data) or Wilcoxon signed-rank test (skewed data). Pro- after PCI (46 (1–154) vs 152 (48–633), p � 0.01), compared portional differences in categorical variables were compared to placebo (Table 3). No correlation was found between using the Chi-Square test or the Fisher’s-Exact Test (Fisher’s measurements of post-PCI troponin or absolute change in Exact Test was used when one or more cell frequencies were troponin with any invasive coronary physiological mea- less than five). Assessment of bivariate correlation was surements comparing treatment groups. A weak negative performed using a Pearson Correlation Coefficient for correlation was found between absolute troponin change 4 Journal of Interventional Cardiology Screened And Randomised Pre-PCI (n = 196) Exclusion Pre -Angiogram: (i) Unstable Troponin (n = 3) (ii) Anti-inflammatory Medication Given (n = 3) (iii) Active Infection/Inflammation (n = 2) (iv) Inappropriate Blood Sampling (n = 6) Coronary Angiogram Exclusion Post -Angiogram: No PCI (n = 107) (i) Minor CAD (n = 39) (ii) Cardiac Conference Discussion (n = 22) (iii) FFR Negative Lesion (n = 15) (iv) Other PCI Exclusion Criteria (n = 31) No Coronary Circulation Physiology Measurements at time of PCI (n = 25): (i) Complex PCI case (n = 9) Percutaneous Coronary (ii) Artery Occlusion (n = 8) Intervention (iii) Measurement Error (n = 3) (iv) Other (n = 5) Study Population (n = 50) Figure 1: Overview of study design and patient allocation. (i) Development of unstable troponin or active in‰ammation/infection, anti- in‰ammatory medications given, or inappropriate blood sampling occurred in 14 patients after randomization. (ii) Cardiac conference discussion  patient had severe CAD at coronary angiography. ”e procedure was therefore stopped, and the patient’s case was discussed at a later date at a combined cardiology/cardiothoracic surgical meeting to determine an optimal revascularization strategy. Most patients were sent for coronary artery bypass grafting. (iii) Other PCI exclusion criteria  see “exclusion criteria” in the supplemental material. (iv) Complex PCI case  as deemed by the interventional cardiologist, not appropriate for coronary artery physiology measurements. Table 1: Baseline patient characteristics and pre-PCI medication use, by study drug randomization. Baseline characteristics Colchicine (n  24) Placebo (n  26) NSTEMI vs. SA presentation NSTEMI 11 (46) 12 (46) SA 13 (54) 14 (54) Baseline patient characteristics Age, y 67.0 ± 10.2 62.6 ± 11.7 Male 16 (67) 18 (69) Obese (BMI >30) 12 (50) 19 (73) Current smoker 4 (17) 6 (23) Hypertension 13 (54) 15 (58) Dyslipidaemia 15 (63) 20 (77) Diabetes mellitus 8 (33) 5 (19) Prior myocardial infarction 4 (17) 4 (15) Prior percutaneous coronary intervention 3 (13) 4 (15) Family history of ischaemic heart disease 11 (46) 18 (69) Pre-PCI medication use Aspirin 24 (100) 26 (100) P2Y inhibitor 23 (96) 25 (96) Statins 23 (96) 22 (85) Beta-blockers or/& Ca-channel blocker 16 (67) 22 (85) Angiotensin-converting enzyme inhibitors 9 (38) 12 (46) Angiotensin–II–receptor antagonists 5 (21) 7 (27) Nitrates 2 (8) 2 (8) Values are n (%) or mean ± SD. and change in Tmn , in the overall cohort: Spearman’s degree of in‰ammation was low and similar between Rest Correlation Coecient: −0.31, p  0.03. treatment arms (median hsCRP  1.1 mg/L). Neutrophil Patients randomized to colchicine had signicantly count was lower after PCI in the colchicine arm (p  0.02). lower pre-PCI total white blood cell (WBC) count: 6.7 ± 1.3 Total WBC count and hsCRP were similar between treat- vs 7.7 ± 1.5, p  0.02 (Table 3). However, prior to PCI, the ment groups after PCI (Table 3), and hsCRP remained low. Journal of Interventional Cardiology 5 Table 2: PCI characteristics, by study drug randomization. PCI characteristics Colchicine (n �24) Placebo (n �26) p value Access || Radial 20 (83) 21 (81) 1 || Femoral 4 (17) 5 (19) 1 PCI artery Left anterior descending 13 (54) 12 (46) 0.57 || Intermediate 2 (8) 0 (0) 0.23 || Left circumflex 5 (21) 6 (23) 1 || Right coronary artery 4 (17) 8 (31) 0.33 PCI procedure duration (minutes) 55 (47–69) 62 (51–70) 0.25 Contrast volume (mL) 150 (120–200) 160 (120–193) 0.86 Total number of balloon inflations 7.0 (5.0–11.0) 6.0 (5.0–9.0) 0.86 Total time of balloon inflations (seconds) 66 (48–80) 69 (51–91) 0.78 Total stent length (mm) 18 (15–24) 23 (18–32) 0.07 Maximum stent diameter (mm) 3.28 (2.95–3.99) 3.33 (3.00–3.64) 0.88 Stent type || Drug-eluting stent 23 (96) 26 (100) 0.48 || Bare metal stent 1 (4) 0 (0) 0.48 || Pre-PCI balloon dilation 23 (96) 25 (96) 1 || Post-PCI balloon dilation 22 (92) 24 (92) 1 Use of OCT or IVUS 0 0 PCI complications || Stent dissection 1/23 (4) 1 (4) 1 No reflow 0 0 Values are n/N (%), mean±SD or median (LQ-UQ), stent dissection assessed by angiography, denotes comparison between colchicine vs placebo group, † denotes independent-samples t-test, ‡ denotes Mann–Whitney-U test, § denotes Chi-squared test, and || denotes Fisher’s exact test. Comparing patients who developed after PCI CMVD to after PCI, and so the true effect size of colchicine may have those without CMVD, regardless of study drug treatment, been attenuated. However, an interesting observation in our there was no statistical difference in absolute troponin change study was that preprocedural colchicine seemed to improve (p � 0.66), pre- or post-PCI neutrophil count (p � 0.06 or post-PCI CFR and RRR, had no effect on FFR or IMR, and 0.42), pre- or post-PCI WBC count (p � 0.23 or 0.99), or pre- had a muted effect on change in Tmn compared to the Rest or post-PCI hsCRP (p � 0.95 or 0.91). However, in the subset placebo group whereas FFR assesses the functional signifi- of patients who develop CMVD after PCI, absolute troponin cance of epicardial stenosis [17], and CFR and to a lesser change was less if they were given colchicine vs placebo extent RRR are influenced by both functional changes in (29ng/L (−197-108) vs 189 (52–687), p � 0.01, Figure 2). epicardial and microcirculation compartments, yet CFR is not microvascular specific [21]. On the other hand, IMR assesses coronary microvascular resistance independent of 3.2. Safety and Adverse Events. No adverse events were re- epicardial arterial stenosis [18], under only hyperaemic ported in any study participants. conditions. Resistive Reserve Ratio, a newer marker of coronary physiology, represents the dynamic vasodilatory capacity [20] of the coronary microcirculation and the 4. Discussion cumulative functional disease burden throughout the in- In this study, we found several pertinent and important terrogated vessel [22]. Additionally, in this study, change in findings. Firstly, preprocedural administration of colchicine Tmn was reduced by a greater magnitude in the placebo Rest had no impact on the development of PCI-induced coronary arm compared to the colchicine arm. %is may represent a microvascular dysfunction (as defined in our study by any nondynamic static increase in resting coronary vascular flow one of the following: post-PCI RRR <2.0, CFR <2.0, or IMR after PCI in the placebo group who had increased proce- >32), yet colchicine was found to improve post-PCI CFR and dural-related myocardial injury, compared to the colchicine RRR measures. Additionally, patients randomized to col- group who appear to retain a dynamic functional coronary chicine had less procedurally related absolute troponin vasculature. %us, this study alludes to colchicine’s im- change and lower neutrophil count. Furthermore, of the proved functional effect on vascular dynamics (RRR), rather subset of patients who had CMVD after the procedure, those than influencing microvascular resistance at maximal hy- given colchicine had significantly lower absolute troponin peremia (IMR). change after PCI. In the long term, therapies that improve RRR may have Although colchicine failed to reach its primary endpoint prognostic benefits, highlighted by recent studies showing by modifying PCI-related CMVD in this pilot substudy, this the superior ability of RRR to have a prognostic role in both may be explained by the fact that this patient group was stable [22] and unstable [6, 23] coronary artery diseases, lower in risk, as reflected by low levels of IMR before and particularly in STEMI patients [20]. 6 Journal of Interventional Cardiology Table 3: Combined pre-PCI, post-PCI, and change in invasive coronary physiological and laboratory measurements, by study drug randomization. Colchicine (n �24) Placebo (n �26) p value Invasive coronary physiological measurements FFR Pre-PCI 0.65 (0.47–0.79) 0.72 (0.52–0.80) 0.42 Post-PCI 0.88 (0.83–0.93) 0.90 (0.81–0.93) 0.79 Change 0.19 (0.09–0.38) 0.13 (0.07–0.33) 0.45 Tmn rest Pre-PCI 0.82 (0.57–1.55) 1.19 (0.54–1.59) 0.73 Post-PCI 0.89 (0.52–1.44) 0.64 (0.39–1.09) 0.16 Change 0.01 (−0.30–0.23) −0.31 (−0.80–0.01) 0.03 Tmn hyperaemia Pre-PCI 0.38 (0.31–0.69) 0.45 (0.20–0.78) 0.87 Post-PCI 0.26 (0.14–0.45) 0.26 (0.16–0.46) 0.57 Change −0.12 (−0.43–0.11) −0.12 (−0.43–0.04) 0.84 CFR Pre-PCI 2.10 (1.40–2.70) 1.95 (1.38–3.30) 0.92‡ Post-PCI 3.25 (2.08–4.40) 2.00 (1.48–3.30) 0.03 Change 1.20 (−0.30–2.10) 0.10 (−0.70–0.63) 0.03 BRI Pre-PCI 54.40 (21.83–96.63) 47.65 (26.63–106.00) 0.79 Post-PCI 73.55 (44.05–122.67) 54.37 (30.73–95.52) 0.25 Change 15.86 (−1.53–40.29) −5.16 (−41.10–17.76) 0.052 IMR Pre-PCI 21.30 (11.50–26.80) 18.05 (9.95–32.28) 0.97 Post-PCI 17.02 (10.40–31.43) 19.92 (14.30–34.18) 0.27 Change 0.91 (−6.88–12.37) 4.90 (−11.34–11.66) 0.58 RRR Pre-PCI 3.26 (1.86–4.15) 2.75 (2.04–4.31) 0.94 Post-PCI 4.25 (2.45–5.24) 2.75 (1.67–3.44) <0.01 Change 1.05 (−0.91–2.64) −0.09 (−1.34–0.88) 0.054 Laboratory results hs-troponin-I (ng/L) Pre-PCI 9 (3–769) 13 (3–93) 0.88 Post-PCI 184 (60–643) 259 (139–779) 0.55 Absolute change 46 (1–154) 152 (48–633) 0.01 WBC count Pre-PCI 6.7± 1.3 7.7± 1.5 0.02 Post-PCI 7.6±1.6 8.5±1.7 0.06 Change 0.9±1.6 0.8±1.0 0.84 Neutrophil count Pre-PCI 4.0±1.1 4.7±1.3 0.06 Post-PCI 4.7± 1.1 5.6± 1.4 0.02 Change 0.6±1.3 0.9±1.0 0.48 hsCRP (mg/L) Pre-PCI 1.1 (0.5–5.7) 1.1 (0.6–4.3) 0.78 Post-PCI 1.0 (0.5–5.9) 1.7 (0.8–2.7) 0.97 Change 0.0 (−0.1–0.1) 0.2 (0.0–0.4) 0.21 Values are mean±SD or median (LQ-UQ), denotes comparison between colchicine vs placebo group, † denotes independent-samples t-test, and ‡ denotes Mann–Whitney U test. Table 4: Primary study endpoint, by study drug randomization. Primary endpoint Colchicine (n �24) Placebo (n �26) p value Combined CMVD: (CFR <2.0 or RRR <2.0 or IMR >32) 10 (42) 16 (62) 0.16 RRR <2.0 or IMR >32 8 (33) 14 (54) 0.14 CFR or RRR <2.0 5 (21) 12 (46) 0.06 || RRR <2.0 3 (13) 9 (35) 0.10 CFR <2.0 5 (21) 12 (46) 0.06 IMR >32 6 (25) 8 (31) 0.65 Values are n (%), denotes comparison between colchicine vs placebo group, § denotes Chi-squared test, and || denotes Fisher’s exact test. Journal of Interventional Cardiology 7 ‡ ‡ Colchicine’s e¨ect on the arteriolar function is supported by 800.00 p=0.29 p=0.59 studies showing improvement of arterial wall sti¨ness in patients with Familial Mediterranean Fever, given higher 550.00 doses of colchicine [30], and improvement of Flow-Medi- ated Vasodilation in patients with coronary artery disease 300.00 and a higher degree of in‰ammation dened by a high white cell count [31]. ”ese ndings of improved vascular tone and 50.00 improvements in endothelial function in colchicine-treated patients may partly explain the improvements seen in our -200.00 study, namely, higher CFR and RRR after PCI among pa- p=0.01 tients treated with preprocedural colchicine. -450.00 p=0.34 Not only does colchicine exert its e¨ects through the inhibition of the NLRP3 in‰ammasome, but colchicine also -700.00 Colchicine Placebo suppresses neutrophil extracellular traps (NETs) formation in patients presenting with ACS treated with PCI [32]. ”is CMVD novel anti-in‰ammatory e¨ect of colchicine may also assist NO in improving periprocedural coronary microvascular YES function and reducing periprocedural myocardial injury. Figure 2: Boxplot of absolute hs-Troponin-I change in patients In these COPE-PCI trials, we have shown that when with or without post-PCI CMVD, according to study drug colchicine is given before PCI, it is associated with reduc- randomization. tions in periprocedural myocardial injury [14] and nu- merically lower pre-PCI levels of in‰ammation [15]. In this nal study, we show targeting in‰ammation with pre- Results of published therapies aimed at attenuating measures of coronary microvascular function have been procedural colchicine, which is associated with improved coronary microvascular function as measured by RRR and mixed, most have not assessed RRR, and as yet specic targeted anti-in‰ammatory medications have not been tri- CFR; however, it did not attenuate PCI-related CMVD. aled. A recent meta-analysis found overall long-term use of calcium channel blocking medications improves CFR [24], and results with beta-blocker medications are mixed 5. Limitations [24–26]. ACE inhibitors are e¨ective at improving CFR [8, 9, 24] and IMR [9] alone. Statin therapy has been shown In this pilot study, the patient population consisted of a low- to (1) improve CFR with reduced in‰ammatory cytokines risk cohort for coronary microvascular dysfunction, with a [10] and (2) improve IMR with reduced post-PCI troponin combined high use of calcium channel and/or beta-blocker [11]. However, other statin studies have not been as con- medications in the 24 hours prior to PCI. Additionally, we vincing. A recent trial of women, without obstructive cor- cannot comment on preprocedural drug posology. Pre-PCI onary disease, demonstrated no change in IMR and only an IMR measures were low indicating that patients were at low improvement in CRP after pretreatment with rosuvastatin risk of myocardial injury [7] and in‰ammation [16]. Also, [12]. Furthermore, a strategy of direct stenting has been notably, this study population had low levels of in‰am- shown to attenuate PCI-related CMVD [13] without an mation after the procedure, denoted by low hsCRP levels. associated impact on troponin release. Additionally, Tica- ”erefore, in our study population, the possible e¨ect size of grelor given for 6 months after PCI among patients with colchicine on coronary microvascular function may have ACS improved CFR and IMR [27] compared to clopidogrel. been attenuated. Also, in patients presenting with STEMI, both intracoronary Due to the small population size in this pilot study, we nicorandil and streptokinase have been shown to improve had a lower number of patients with abnormal coronary IMR [28, 29]. While these trialed therapies are not in- microvascular function. It is possible that we would have ‰ammation specic, there are many in‰ammatory mecha- observed a di¨erent result where there had been a larger nisms activated as a consequence of PCI that disturb number of patients with abnormal microvasculature. microvascular function, such as endothelial dysfunction, A number of patients were randomized to study med- increased oxidative stress, embolization of immunogenic ication who ultimately were excluded due to prespecied debris, and induction of distal and systemic in‰ammation inclusion/exclusion criteria, procedural necessities, and time [3, 5]. Moreover, we have previously demonstrated a positive frames. ”is was unavoidable and expected. In this pilot correlation between pre-PCI microvascular function (as study, the coronary anatomy was not known prior to ran- measured by IMR) and in‰ammation [16]. ”us, strategies domization and many patients evidently did not require PCI aimed at targeting in‰ammation before PCI may also at- or have a suitable lesion to perform invasive coronary tenuate PCI-related CMVD. physiology measurements. ”is was anticipated prior to the In our study, involving both stable patients and those commencement of this study, and it was prespecied that the with NSTEMI, colchicine appeared to aid in the restoration nal trial analysis would not include these patients, a of PCI-related microvascular reactivity and coronary methodology that has previously been published by other vascular ‰ow reserve, seen as improved RRR and CFR. authors assessing PCI-induced periprocedural myocardial Absolute Troponin-I Change (ng/L) 8 Journal of Interventional Cardiology injury [33]. %e reported results should therefore be 7.2. Exclusion Criteria interpreted with this in mind. (i) Pregnant females or lactating females (ii) Age younger than 18 years 6. Conclusion (iii) Evidence of active infection/inflammatory condi- In this pilot substudy, administration of preprocedural tions that might be associated with markedly el- colchicine improved post-PCI RRR and CFR, with less evated CRP levels or other inflammatory markers periprocedural absolute troponin change and lowered in the blood (e.g., active rheumatoid arthritis) neutrophil count, without effect on the development of post- (iv) Taking anti-inflammatory therapies (e.g., PCI Coronary Microvascular Dysfunction (defined in this corticosteroids) study as any one of post-PCI IMR >32 or CFR <2 or RRR (a) Including colchicine <2). (v) Known hypersensitivity to colchicine (vi) Noncompliance with medications 6.1. Impact on Daily Practice. Treatment of inflammation and impaired coronary microvascular function at the time of (vii) Patients not on or unable to take aspirin before or percutaneous coronary intervention (PCI) could improve after PCI outcomes. Based on this small, randomized placebo-con- (viii) Patients unable to take a second antiplatelet agent trolled trial, improvements in post-PCI coronary micro- and/or statin therapy after PCI vascular function (Resistive Reserve Ratio (RRR) and (ix) Moderate renal impairment defined as creatinine Coronary Flow Reserve (CFR)), inflammation, and troponin clearance <45ml/min release were seen in patients treated with preprocedural (x) Hepatic dysfunction defined as alanine amino- colchicine compared to placebo. Importantly, an improved transferase 1.5 ×upper limit of the normal range RRR represents an improved vasodilatory capacity of the coronary microcirculation and improved functional disease (xi) %rombocytopenia or leucopenia burden throughout the interrogated vessel. Improved RRR (xii) Already on moderate-strong CYP3A4 inhibitors in other studies has shown prognostic utility. (xiii) Severe left ventricular function defined as LVEF <35% 7. Inclusion and Exclusion Criteria (xiv) Acute Myocardial Infarction in the last 12 months 7.1. Inclusion Criteria (xv) Cardiogenic shock or hemodynamic instability (xvi) ST-elevation myocardial infarction (STEMI) (i) Male or female over 18years of age (ii) Stable angina (SA) patients: symptomatic patients (xvii) Patients who do not go on to PCI and/or patients who have PCI immediately prior to coronary with stable angina or asymptomatic patients with positive functional tests (requiring elective PCI) artery bypass grafting (xviii) Significant complex disease as deemed by (iii) Non-ST-elevation myocardial infarction (NSTEMI) patients: defined as the recent onset of chest pain interventionalist associated with ST-segment and/or T-wave ECG (a) Bifurcation lesions changes and positive cardiac enzymes (high sen- (b) Left main PCI or left main >50% stenosis sitivity troponin) (c) Chronic total occlusion of a vessel requiring PCI (a) Troponin must have peaked and stabilized prior to PCI, as defined by two serial Troponin (d) Side branch involvement or occlusion measures (xix) PCI to a small caliber vessel (<2.5mm in diam- (b) Stable troponins are defined by≤20% variation eter), distal vessel, or vessel supplying a small between troponin measurements distal territory (iv) Must be taking aspirin prior to PCI (xx) Incomplete blood sampling (v) Must be prescribed a second antiplatelet agent and (xxi) PCI performed outside the allowed time frame of statin therapy prior to PCI colchicine or placebo before treatment (6 to 24 (vi) PCI vessel caliber>2.5mm diameter vessels hours prior to PCI) (vii) Obstructive coronary artery disease (defined as (xxii) Unstable troponins or new ST elevation prior to PCI and after randomization diameter stenosis >70%) (vii) De novo lesion: defined by interventionalist (xxiii) Unable to perform invasive coronary physio- logical measurements (viii) Patient and coronary lesion appropriate for In- vasive Coronary Physiological Measurements, (xxiv) Heavily calcified or tortuous vessels such that safe passage of the pressure wire could not be deemed by the interventional cardiologist at the time of index PCI guaranteed Journal of Interventional Cardiology 9 (xxv) Contraindications to adenosine also had less PCI procedure-related troponin release and less inflammation. 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COlchicine to Prevent PeriprocEdural Myocardial Injury in Percutaneous Coronary Intervention (COPE-PCI): Coronary Microvascular Physiology Pilot Substudy

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Copyright © 2022 Justin Cole et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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10.1155/2022/1098429
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Abstract

Hindawi Journal of Interventional Cardiology Volume 2022, Article ID 1098429, 10 pages https://doi.org/10.1155/2022/1098429 Research Article COlchicine to Prevent PeriprocEdural Myocardial Injury in Percutaneous Coronary Intervention (COPE-PCI): Coronary Microvascular Physiology Pilot Substudy 1,2 1,2 1 1 3 Justin Cole , Nay Htun, Robert Lew, Mark Freilich, Stephen Quinn, 1,2 and Jamie Layland Peninsula Heart Service, Peninsula Health, Frankston, Australia Peninsula Clinical School, Monash University, Melbourne, Australia Department of Health Science and Biostatistics, Swinburne University of Technology, Melbourne, Australia Correspondence should be addressed to Jamie Layland; jlayland@phcn.vic.gov.au Received 9 February 2022; Accepted 22 April 2022; Published 29 May 2022 Academic Editor: Alessandro Sciahbasi Copyright © 2022 Justin Cole et al. %is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Aim. In this randomized pilot trial, we aimed to assess the anti-inflammatory effect of preprocedural colchicine on coronary microvascular physiology measurements before and after PCI. Methods. Patients undergoing PCI for stable angina (SA) or non- ST-elevation myocardial infarction (NSTEMI) were randomized to oral colchicine or placebo, 6- to 24-hours before the pro- cedure. Strict prespecified inclusion/exclusion criteria were set to ensure all patients were given the study medication, had a PCI, and had pre- and post-PCI culprit vessel invasive coronary physiology measurements. Fractional flow reserve (FFR), Index of Microvascular Resistance (IMR), Coronary Flow Reserve (CFR), and Resistive Reserve Ratio (RRR) were measured immediately before and after PCI. CMVD was defined as any one of post-PCI IMR>32 or CFR<2 or RRR<2. High-sensitive-(hs)-troponin-I, hsCRP, and leucocyte count were measured before and 24 hours after PCI.Results. A total of 50 patients were randomized and met the strict prespecified inclusion/exclusion criteria: 24-colchicine and 26-placebo. Pre-PCI coronary physiology measurements, hs- troponin-I, and hsCRP were similar between groups. Although numerically lower in patients given colchicine, the proportion of patients who developed CMVD was not significantly different between groups (colchicine: 10 (42%) vs placebo: 16 (62%), p � 0.16). Colchicine patients had higher post-PCI CFR and RRR vs placebo (respectively: 3.25 vs 2.00, p � 0.03 & 4.25 vs 2.75, p<0.01). Neutrophil count was lower after PCI in the colchicine arm (p � 0.02), and hsCRP post-PCI remained low in both treatment arms (1.0mg/L vs 1.7mg/L, p � 0.97). Patients randomized to colchicine had significantly less PCI-related absolute hs- troponin-I change (46ng/L vs 152ng/L, p � 0.01). Conclusion. In this pilot randomized substudy, colchicine given 6 to 24 hours before PCI did not statistically impact the post-PCI CMVD definition used in this study, yet it did improve post-PCI RRR and CFR measurements, with less procedure-related troponin release and less inflammation. CMVD is defined by impaired response of coronary 1. Introduction/Background microvascular flow to vasodilator stimuli [5] which can Percutaneous coronary intervention (PCI), of a functionally occur through many pathways as a consequence of PCI [3, 5] significant epicardial artery stenosis, is one of the main and is associated with myocardial injury [4, 6, 7], yet the treatments for symptomatic patients with either stable underlying mechanisms of this association remain under coronary disease or acute coronary syndromes (ACSs) [1, 2]. investigation. Small trials offering targeted treatment aimed However, PCI can activate multiple pathways leading to at reducing PCI-related CMVD have been performed and coronary microvascular dysfunction (CMVD) [3] with as- have shown promise. Both ACE inhibitors and statins have sociated adverse clinical outcomes [3, 4]. demonstrated improved measures of microvascular function 2 Journal of Interventional Cardiology in patients undergoing PCI [8–12], and a strategy of direct involved in the invasive protocol. Randomization was simple stenting has also been shown to have favorable effects on and not stratified. Study medication was denoted Drug A or Drug B throughout the trial. Both Drug A and Drug B were PCI-related coronary microvascular dysfunction, as mea- sured by IMR [13]. in labeled bottles and looked identical. %is was a double- In the COPE-PCI Pilot Trial [14], we have previously blind randomized placebo-controlled trial. All parties in- demonstrated that when colchicine is given before PCI, it is volved were blinded to the treatment allocation until the trial associated with reductions in periprocedural myocardial had finished. %e study protocol was approved by the injury and in a subsequent study is associated with nu- Human Research Ethics Committee at St Vincent’s Hospital merically lower pre-PCI levels of inflammation [15]. Melbourne and Frankston Hospital Melbourne, Australia. Moreover, we have previously demonstrated a relationship %e trial was publicly registered (COPE-PCI Trial ANZCTR between pre-PCI microvascular function and inflammation Trial ID: ACTRN12615000485538). %e trial ran from 1 December 2017 to 30 December 2019. [16]. %us, in this substudy of the COPE-PCI Pilot Trial, we aimed to assess the anti-inflammatory effect of colchicine, given 6–24 hours before PCI, on coronary microvascular 2.3. PCI Procedure. All patients received weight-adjusted physiology measurements before and after PCI. We hy- bolus (100 Units/kg) intravenous heparin, immediately prior pothesized that colchicines’ anti-inflammatory effect would to PCI, and additional bolus dosing to maintain an attenuate PCI-associated impairment in coronary micro- activated clotting time of >250secs. Technical aspects of vascular function. the PCI procedure were determined by the practicing interventionalist. 2. Methods 2.1. Study Population. %e study population consisted of 2.4. Invasive Coronary Physiological Measurements both stable angina (SA) patients intended for elective PCI [3, 17–19]. We performed invasive interrogation of the and patients presenting with non-ST-elevation myocardial culprit vessel coronary circulation as previously described infarction (NSTEMI) planned for in-patient coronary an- [20]. Measurements were taken both before and after PCI. In giography and PCI. Patients were assessed against strict brief, a dual temperature and pressure-sensing guidewire inclusion and exclusion criteria (see below) and must have was used to cross the lesion, measuring distal pressure (Pd) had a lesion appropriate for invasive coronary physiological and transit time (Tmn) of 3ml of room temperature hep- measurements, deemed by the interventional cardiologist at arinized saline-injected intracoronary. %ree reproducible the time of the index PCI. Notable inclusion criteria were and consistent thermodilution curves were performed be- patients with a de novo lesion amenable to PCI, and patients fore and after PCI, both at rest ( ) and at maximal hy- Rest with high-sensitive (hs) troponin-I and creatinine kinase peremia ( ). Maximal hyperemia was induced by the Hyp (CK) that had peaked and stabilized prior to PCI. Patients administration of intravenous adenosine at 140ug/kg/min were excluded if they had left main disease and required for up to 2 minutes and confirmed by clinical response and bifurcation lesion PCI, or the culprit’s vessel was completely hemodynamic changes. Proximal pressure was obtained occluded. Additionally, patients were excluded if they had from the guiding catheter (Pa). Coronary artery wedge heavily calcified or tortuous vessels such that safe passage of pressure (Pw) was obtained during a 20-second balloon the pressure wire could not be guaranteed. Furthermore, occlusion of the culprit’s vessel during the initial balloon patients were excluded if they had active inflammation or inflation. infection or were taking anti-inflammatory medications, had prior ACS within 12-months, had severe renal impairment (i) Fractional Flow Reserve myocardial (FFRmyo) [17] (creatinine clearance <45ml/min), and developed ST-ele- was measured at maximal hyperemia, defined as vation prior to PCI or troponin increase after randomization follows: FFRmyo �Pd /Pa Hyp Hyp. and prior to PCI. Patients received dual antiplatelet therapy (ii) Coronary Flow Reserve (CFR ) was defined as thermo prior to PCI. We prespecified that patients who were initially CFR �Tmn /Tmn [19] thermo Rest Hyp enrolled in the trial but who did not go on to PCI or invasive (iii) In the presence of severe epicardial stenosis, the coronary physiological measurements were excluded from index of microvascular resistance (IMR) was de- statistical analysis. fined by incorporating Pw via the following equa- tion:IMR �Pa ×Tmn ×FFRcor [18]. FFR Hyp Hyp coronary (FFRcor) was defined by the following 2.2. Study Protocol. All patients reviewed and signed an equation: FFRcor �(Pd -Pw)/(Pa −Pw) [18], Hyp Hyp informed consent prior to randomization and PCI. where Pw was not recorded and FFRcor was pre- Consenting patients were randomized 1:1 to oral col- dicted by FFRmyo using the following equation chicine (1mg followed by 0.5mg one hour later [14]) or [17]:FFRcor �(1.34 ×FFRmyo) −0.32. %erefore, in placebo, 6 to 24 hours prior to a coronary angiogram. Se- the absence of Pw: IMR �Pa ×Tmn × Hyp Hyp quential randomization was performed using proprietary ((1.34 ×FFRmyo) −0.32). software (https://www.sealedenvelope.com). Study patients were assigned to colchicine or placebo prior to coronary (iv) Baseline Resistance Index (BRI) [20] was defined as angiography by an independent research assistant not per IMR; however, baseline measures were used: Journal of Interventional Cardiology 3 (a) BRI �Pa ×Tmn ×((Pd −Pw)/ normal data or a Spearman Correlation Coefficient for Rest Rest Rest (Pa −Pw)). skewed data. A p value <0.05 (two-sided) was considered Rest statistically significant. Statistical analyses were performed (b) Or in the absence of Pw: BRI �Pa × Rest Tmn ×(((1.34 ×(Pd /Pa )) −0.32) with IBM SPSS Statistics for Windows, Version 25.0 Rest Rest Rest (Armonk, NY: IBM Corp). (v) Resistive Reserve Ratio (RRR) [20] was defined by the following equation: RRR �BRI/IMR. 3. Results 2.5. Blood Sampling. All patients had study blood samples 3.1.StudyPopulation. A total of 196 patients were screened. collected immediately prior to PCI (before administration of Of these, 14 patients (7%) developed clinical criteria ex- PCI procedure-related medications) and 24 hours later. All cluding them, 107 (54%) did not have PCI, and 25 (13%) did patients also had standard routine clinical blood tests. Study not have invasive coronary physiological measurements (see blood samples were assessed for high sensitivity (hs)-tro- Figure 1). %us, the final population was 50 patients, thereby ponin-I (ng/L), hsCRP (mg/L), and leucocyte count. Serum ensuring all analyzed patients fulfilled the prespecified cri- hsCRP level was quantified using a Human CRP Simplex teria: (1) received the study medication, (2) PCI procedure ProcartaPlex performed, and (3) complete pre- and post-PCI invasive immunoassay that utilizes Luminex xMAP ™ ™ technology for protein detection/quantitation. We pre- coronary physiological measurements performed. Twenty- specified that patients enrolled in the trial who had in- four (11 (46) NSTEMI, 13 (54) SA) were randomized to complete blood sampling were excluded from statistical colchicine, 26 (12 (46) to NSTEMI, and 14 (54) SA) to analysis. placebo (Table 1). Patients were well matched, without significant differ- ences, for baseline characteristics and pre-PCI medication 2.6.StudyEndpoints. %e primary outcome of this study was use (Table 1). %ere was no significant difference in PCI the difference in proportion between treatment arms, of characteristics between treatment arms (Table 2). patients with coronary microvascular dysfunction, defined Prior to PCI, there was no statistical difference in the as any one of the following: post-PCI RRR<2.0, CFR<2.0, or invasive coronary physiological measurements between IMR >32. treatment groups (Table 3). FFR was similar and functionally Additionally, colchicines’ effect on coronary microvas- significant in both treatment arms before PCI (0.65 vs 0.72, cular function was assessed by comparing pre- and post-PCI p � 0.42), and IMR measures were low (<22). invasive coronary physiological measurements (listed above) Post-PCI patients randomized to colchicine had higher between the treatment arms of this study. CFR and RRR compared to placebo (respectively: 3.25 Demographic, clinical, medication use, and PCI pro- (2.08–4.40) vs 2.00 (1.48–3.30), p � 0.03 and 4.25 cedure data were recorded. (2.45–5.24) vs 2.75 (1.67–3.44), p<0.01, Table 3). Median Inflammation was assessed by measuring pre-PCI and IMR remained low in both treatment arms (IMR <20). 24-hour post-PCI hsCRP and leucocyte count, comparing Comparing change between pre- and post-PCI invasive treatment arms. coronary physiological measurements, patients randomized Myocardial injury was assessed by measuring pre-PCI to colchicine had significantly less change in Tmn Rest and 24-hour post-PCI hs-troponin-I and calculating abso- measurements (0.01 vs −0.31, p � 0.03) and significantly lute hs-troponin-I change: calculated as post-PCI mea- greater change in CFR (1.20 (−0.30–2.10) vs 0.10 surements minus pre-PCI measurements, in each treatment (−0.70–0.63), p � 0.03) (Table 3). %ere was a trend in favor arm of this study. of a change in RRR being numerically higher in the col- Patients were followed up for 24 hours after the pro- chicine arm (p � 0.054, Table 3). cedure. All patients received standard medical and PCI Following PCI, there was no statistical difference in the therapy and were reviewed by their referring cardiologist proportion of patients with CMVD between those ran- within 30 days after PCI. domized to colchicine or placebo (colchicine: 10 (42%) vs placebo: 16 (62%), p � 0.16, Table 4). %is was also true for 2.7. Statistical Analysis. Continuous variables are reported the proportion of patients with individual measures of CFR as mean±SD or median (LQ-UQ) according to whether the <2.0, IMR >32, or RRR <2.0 (Table 4). variable is normal or skewed, and categorical variables are as Troponin measures prior to PCI were similar and low in numbers (n (%)). Differences in continuous variables were both treatment groups (<13, Table 3). Most patients had a tested via an independent-samples t-test (normal data) or troponin elevation of any magnitude after PCI (colchicine: Mann–Whitney U test (skewed data). Similarly, paired 75% vs placebo 92%, p � 0.13). Patients randomized to variables were tested via a paired-samples t-test (normal colchicine had significantly less absolute troponin change data) or Wilcoxon signed-rank test (skewed data). Pro- after PCI (46 (1–154) vs 152 (48–633), p � 0.01), compared portional differences in categorical variables were compared to placebo (Table 3). No correlation was found between using the Chi-Square test or the Fisher’s-Exact Test (Fisher’s measurements of post-PCI troponin or absolute change in Exact Test was used when one or more cell frequencies were troponin with any invasive coronary physiological mea- less than five). Assessment of bivariate correlation was surements comparing treatment groups. A weak negative performed using a Pearson Correlation Coefficient for correlation was found between absolute troponin change 4 Journal of Interventional Cardiology Screened And Randomised Pre-PCI (n = 196) Exclusion Pre -Angiogram: (i) Unstable Troponin (n = 3) (ii) Anti-inflammatory Medication Given (n = 3) (iii) Active Infection/Inflammation (n = 2) (iv) Inappropriate Blood Sampling (n = 6) Coronary Angiogram Exclusion Post -Angiogram: No PCI (n = 107) (i) Minor CAD (n = 39) (ii) Cardiac Conference Discussion (n = 22) (iii) FFR Negative Lesion (n = 15) (iv) Other PCI Exclusion Criteria (n = 31) No Coronary Circulation Physiology Measurements at time of PCI (n = 25): (i) Complex PCI case (n = 9) Percutaneous Coronary (ii) Artery Occlusion (n = 8) Intervention (iii) Measurement Error (n = 3) (iv) Other (n = 5) Study Population (n = 50) Figure 1: Overview of study design and patient allocation. (i) Development of unstable troponin or active in‰ammation/infection, anti- in‰ammatory medications given, or inappropriate blood sampling occurred in 14 patients after randomization. (ii) Cardiac conference discussion  patient had severe CAD at coronary angiography. ”e procedure was therefore stopped, and the patient’s case was discussed at a later date at a combined cardiology/cardiothoracic surgical meeting to determine an optimal revascularization strategy. Most patients were sent for coronary artery bypass grafting. (iii) Other PCI exclusion criteria  see “exclusion criteria” in the supplemental material. (iv) Complex PCI case  as deemed by the interventional cardiologist, not appropriate for coronary artery physiology measurements. Table 1: Baseline patient characteristics and pre-PCI medication use, by study drug randomization. Baseline characteristics Colchicine (n  24) Placebo (n  26) NSTEMI vs. SA presentation NSTEMI 11 (46) 12 (46) SA 13 (54) 14 (54) Baseline patient characteristics Age, y 67.0 ± 10.2 62.6 ± 11.7 Male 16 (67) 18 (69) Obese (BMI >30) 12 (50) 19 (73) Current smoker 4 (17) 6 (23) Hypertension 13 (54) 15 (58) Dyslipidaemia 15 (63) 20 (77) Diabetes mellitus 8 (33) 5 (19) Prior myocardial infarction 4 (17) 4 (15) Prior percutaneous coronary intervention 3 (13) 4 (15) Family history of ischaemic heart disease 11 (46) 18 (69) Pre-PCI medication use Aspirin 24 (100) 26 (100) P2Y inhibitor 23 (96) 25 (96) Statins 23 (96) 22 (85) Beta-blockers or/& Ca-channel blocker 16 (67) 22 (85) Angiotensin-converting enzyme inhibitors 9 (38) 12 (46) Angiotensin–II–receptor antagonists 5 (21) 7 (27) Nitrates 2 (8) 2 (8) Values are n (%) or mean ± SD. and change in Tmn , in the overall cohort: Spearman’s degree of in‰ammation was low and similar between Rest Correlation Coecient: −0.31, p  0.03. treatment arms (median hsCRP  1.1 mg/L). Neutrophil Patients randomized to colchicine had signicantly count was lower after PCI in the colchicine arm (p  0.02). lower pre-PCI total white blood cell (WBC) count: 6.7 ± 1.3 Total WBC count and hsCRP were similar between treat- vs 7.7 ± 1.5, p  0.02 (Table 3). However, prior to PCI, the ment groups after PCI (Table 3), and hsCRP remained low. Journal of Interventional Cardiology 5 Table 2: PCI characteristics, by study drug randomization. PCI characteristics Colchicine (n �24) Placebo (n �26) p value Access || Radial 20 (83) 21 (81) 1 || Femoral 4 (17) 5 (19) 1 PCI artery Left anterior descending 13 (54) 12 (46) 0.57 || Intermediate 2 (8) 0 (0) 0.23 || Left circumflex 5 (21) 6 (23) 1 || Right coronary artery 4 (17) 8 (31) 0.33 PCI procedure duration (minutes) 55 (47–69) 62 (51–70) 0.25 Contrast volume (mL) 150 (120–200) 160 (120–193) 0.86 Total number of balloon inflations 7.0 (5.0–11.0) 6.0 (5.0–9.0) 0.86 Total time of balloon inflations (seconds) 66 (48–80) 69 (51–91) 0.78 Total stent length (mm) 18 (15–24) 23 (18–32) 0.07 Maximum stent diameter (mm) 3.28 (2.95–3.99) 3.33 (3.00–3.64) 0.88 Stent type || Drug-eluting stent 23 (96) 26 (100) 0.48 || Bare metal stent 1 (4) 0 (0) 0.48 || Pre-PCI balloon dilation 23 (96) 25 (96) 1 || Post-PCI balloon dilation 22 (92) 24 (92) 1 Use of OCT or IVUS 0 0 PCI complications || Stent dissection 1/23 (4) 1 (4) 1 No reflow 0 0 Values are n/N (%), mean±SD or median (LQ-UQ), stent dissection assessed by angiography, denotes comparison between colchicine vs placebo group, † denotes independent-samples t-test, ‡ denotes Mann–Whitney-U test, § denotes Chi-squared test, and || denotes Fisher’s exact test. Comparing patients who developed after PCI CMVD to after PCI, and so the true effect size of colchicine may have those without CMVD, regardless of study drug treatment, been attenuated. However, an interesting observation in our there was no statistical difference in absolute troponin change study was that preprocedural colchicine seemed to improve (p � 0.66), pre- or post-PCI neutrophil count (p � 0.06 or post-PCI CFR and RRR, had no effect on FFR or IMR, and 0.42), pre- or post-PCI WBC count (p � 0.23 or 0.99), or pre- had a muted effect on change in Tmn compared to the Rest or post-PCI hsCRP (p � 0.95 or 0.91). However, in the subset placebo group whereas FFR assesses the functional signifi- of patients who develop CMVD after PCI, absolute troponin cance of epicardial stenosis [17], and CFR and to a lesser change was less if they were given colchicine vs placebo extent RRR are influenced by both functional changes in (29ng/L (−197-108) vs 189 (52–687), p � 0.01, Figure 2). epicardial and microcirculation compartments, yet CFR is not microvascular specific [21]. On the other hand, IMR assesses coronary microvascular resistance independent of 3.2. Safety and Adverse Events. No adverse events were re- epicardial arterial stenosis [18], under only hyperaemic ported in any study participants. conditions. Resistive Reserve Ratio, a newer marker of coronary physiology, represents the dynamic vasodilatory capacity [20] of the coronary microcirculation and the 4. Discussion cumulative functional disease burden throughout the in- In this study, we found several pertinent and important terrogated vessel [22]. Additionally, in this study, change in findings. Firstly, preprocedural administration of colchicine Tmn was reduced by a greater magnitude in the placebo Rest had no impact on the development of PCI-induced coronary arm compared to the colchicine arm. %is may represent a microvascular dysfunction (as defined in our study by any nondynamic static increase in resting coronary vascular flow one of the following: post-PCI RRR <2.0, CFR <2.0, or IMR after PCI in the placebo group who had increased proce- >32), yet colchicine was found to improve post-PCI CFR and dural-related myocardial injury, compared to the colchicine RRR measures. Additionally, patients randomized to col- group who appear to retain a dynamic functional coronary chicine had less procedurally related absolute troponin vasculature. %us, this study alludes to colchicine’s im- change and lower neutrophil count. Furthermore, of the proved functional effect on vascular dynamics (RRR), rather subset of patients who had CMVD after the procedure, those than influencing microvascular resistance at maximal hy- given colchicine had significantly lower absolute troponin peremia (IMR). change after PCI. In the long term, therapies that improve RRR may have Although colchicine failed to reach its primary endpoint prognostic benefits, highlighted by recent studies showing by modifying PCI-related CMVD in this pilot substudy, this the superior ability of RRR to have a prognostic role in both may be explained by the fact that this patient group was stable [22] and unstable [6, 23] coronary artery diseases, lower in risk, as reflected by low levels of IMR before and particularly in STEMI patients [20]. 6 Journal of Interventional Cardiology Table 3: Combined pre-PCI, post-PCI, and change in invasive coronary physiological and laboratory measurements, by study drug randomization. Colchicine (n �24) Placebo (n �26) p value Invasive coronary physiological measurements FFR Pre-PCI 0.65 (0.47–0.79) 0.72 (0.52–0.80) 0.42 Post-PCI 0.88 (0.83–0.93) 0.90 (0.81–0.93) 0.79 Change 0.19 (0.09–0.38) 0.13 (0.07–0.33) 0.45 Tmn rest Pre-PCI 0.82 (0.57–1.55) 1.19 (0.54–1.59) 0.73 Post-PCI 0.89 (0.52–1.44) 0.64 (0.39–1.09) 0.16 Change 0.01 (−0.30–0.23) −0.31 (−0.80–0.01) 0.03 Tmn hyperaemia Pre-PCI 0.38 (0.31–0.69) 0.45 (0.20–0.78) 0.87 Post-PCI 0.26 (0.14–0.45) 0.26 (0.16–0.46) 0.57 Change −0.12 (−0.43–0.11) −0.12 (−0.43–0.04) 0.84 CFR Pre-PCI 2.10 (1.40–2.70) 1.95 (1.38–3.30) 0.92‡ Post-PCI 3.25 (2.08–4.40) 2.00 (1.48–3.30) 0.03 Change 1.20 (−0.30–2.10) 0.10 (−0.70–0.63) 0.03 BRI Pre-PCI 54.40 (21.83–96.63) 47.65 (26.63–106.00) 0.79 Post-PCI 73.55 (44.05–122.67) 54.37 (30.73–95.52) 0.25 Change 15.86 (−1.53–40.29) −5.16 (−41.10–17.76) 0.052 IMR Pre-PCI 21.30 (11.50–26.80) 18.05 (9.95–32.28) 0.97 Post-PCI 17.02 (10.40–31.43) 19.92 (14.30–34.18) 0.27 Change 0.91 (−6.88–12.37) 4.90 (−11.34–11.66) 0.58 RRR Pre-PCI 3.26 (1.86–4.15) 2.75 (2.04–4.31) 0.94 Post-PCI 4.25 (2.45–5.24) 2.75 (1.67–3.44) <0.01 Change 1.05 (−0.91–2.64) −0.09 (−1.34–0.88) 0.054 Laboratory results hs-troponin-I (ng/L) Pre-PCI 9 (3–769) 13 (3–93) 0.88 Post-PCI 184 (60–643) 259 (139–779) 0.55 Absolute change 46 (1–154) 152 (48–633) 0.01 WBC count Pre-PCI 6.7± 1.3 7.7± 1.5 0.02 Post-PCI 7.6±1.6 8.5±1.7 0.06 Change 0.9±1.6 0.8±1.0 0.84 Neutrophil count Pre-PCI 4.0±1.1 4.7±1.3 0.06 Post-PCI 4.7± 1.1 5.6± 1.4 0.02 Change 0.6±1.3 0.9±1.0 0.48 hsCRP (mg/L) Pre-PCI 1.1 (0.5–5.7) 1.1 (0.6–4.3) 0.78 Post-PCI 1.0 (0.5–5.9) 1.7 (0.8–2.7) 0.97 Change 0.0 (−0.1–0.1) 0.2 (0.0–0.4) 0.21 Values are mean±SD or median (LQ-UQ), denotes comparison between colchicine vs placebo group, † denotes independent-samples t-test, and ‡ denotes Mann–Whitney U test. Table 4: Primary study endpoint, by study drug randomization. Primary endpoint Colchicine (n �24) Placebo (n �26) p value Combined CMVD: (CFR <2.0 or RRR <2.0 or IMR >32) 10 (42) 16 (62) 0.16 RRR <2.0 or IMR >32 8 (33) 14 (54) 0.14 CFR or RRR <2.0 5 (21) 12 (46) 0.06 || RRR <2.0 3 (13) 9 (35) 0.10 CFR <2.0 5 (21) 12 (46) 0.06 IMR >32 6 (25) 8 (31) 0.65 Values are n (%), denotes comparison between colchicine vs placebo group, § denotes Chi-squared test, and || denotes Fisher’s exact test. Journal of Interventional Cardiology 7 ‡ ‡ Colchicine’s e¨ect on the arteriolar function is supported by 800.00 p=0.29 p=0.59 studies showing improvement of arterial wall sti¨ness in patients with Familial Mediterranean Fever, given higher 550.00 doses of colchicine [30], and improvement of Flow-Medi- ated Vasodilation in patients with coronary artery disease 300.00 and a higher degree of in‰ammation dened by a high white cell count [31]. ”ese ndings of improved vascular tone and 50.00 improvements in endothelial function in colchicine-treated patients may partly explain the improvements seen in our -200.00 study, namely, higher CFR and RRR after PCI among pa- p=0.01 tients treated with preprocedural colchicine. -450.00 p=0.34 Not only does colchicine exert its e¨ects through the inhibition of the NLRP3 in‰ammasome, but colchicine also -700.00 Colchicine Placebo suppresses neutrophil extracellular traps (NETs) formation in patients presenting with ACS treated with PCI [32]. ”is CMVD novel anti-in‰ammatory e¨ect of colchicine may also assist NO in improving periprocedural coronary microvascular YES function and reducing periprocedural myocardial injury. Figure 2: Boxplot of absolute hs-Troponin-I change in patients In these COPE-PCI trials, we have shown that when with or without post-PCI CMVD, according to study drug colchicine is given before PCI, it is associated with reduc- randomization. tions in periprocedural myocardial injury [14] and nu- merically lower pre-PCI levels of in‰ammation [15]. In this nal study, we show targeting in‰ammation with pre- Results of published therapies aimed at attenuating measures of coronary microvascular function have been procedural colchicine, which is associated with improved coronary microvascular function as measured by RRR and mixed, most have not assessed RRR, and as yet specic targeted anti-in‰ammatory medications have not been tri- CFR; however, it did not attenuate PCI-related CMVD. aled. A recent meta-analysis found overall long-term use of calcium channel blocking medications improves CFR [24], and results with beta-blocker medications are mixed 5. Limitations [24–26]. ACE inhibitors are e¨ective at improving CFR [8, 9, 24] and IMR [9] alone. Statin therapy has been shown In this pilot study, the patient population consisted of a low- to (1) improve CFR with reduced in‰ammatory cytokines risk cohort for coronary microvascular dysfunction, with a [10] and (2) improve IMR with reduced post-PCI troponin combined high use of calcium channel and/or beta-blocker [11]. However, other statin studies have not been as con- medications in the 24 hours prior to PCI. Additionally, we vincing. A recent trial of women, without obstructive cor- cannot comment on preprocedural drug posology. Pre-PCI onary disease, demonstrated no change in IMR and only an IMR measures were low indicating that patients were at low improvement in CRP after pretreatment with rosuvastatin risk of myocardial injury [7] and in‰ammation [16]. Also, [12]. Furthermore, a strategy of direct stenting has been notably, this study population had low levels of in‰am- shown to attenuate PCI-related CMVD [13] without an mation after the procedure, denoted by low hsCRP levels. associated impact on troponin release. Additionally, Tica- ”erefore, in our study population, the possible e¨ect size of grelor given for 6 months after PCI among patients with colchicine on coronary microvascular function may have ACS improved CFR and IMR [27] compared to clopidogrel. been attenuated. Also, in patients presenting with STEMI, both intracoronary Due to the small population size in this pilot study, we nicorandil and streptokinase have been shown to improve had a lower number of patients with abnormal coronary IMR [28, 29]. While these trialed therapies are not in- microvascular function. It is possible that we would have ‰ammation specic, there are many in‰ammatory mecha- observed a di¨erent result where there had been a larger nisms activated as a consequence of PCI that disturb number of patients with abnormal microvasculature. microvascular function, such as endothelial dysfunction, A number of patients were randomized to study med- increased oxidative stress, embolization of immunogenic ication who ultimately were excluded due to prespecied debris, and induction of distal and systemic in‰ammation inclusion/exclusion criteria, procedural necessities, and time [3, 5]. Moreover, we have previously demonstrated a positive frames. ”is was unavoidable and expected. In this pilot correlation between pre-PCI microvascular function (as study, the coronary anatomy was not known prior to ran- measured by IMR) and in‰ammation [16]. ”us, strategies domization and many patients evidently did not require PCI aimed at targeting in‰ammation before PCI may also at- or have a suitable lesion to perform invasive coronary tenuate PCI-related CMVD. physiology measurements. ”is was anticipated prior to the In our study, involving both stable patients and those commencement of this study, and it was prespecied that the with NSTEMI, colchicine appeared to aid in the restoration nal trial analysis would not include these patients, a of PCI-related microvascular reactivity and coronary methodology that has previously been published by other vascular ‰ow reserve, seen as improved RRR and CFR. authors assessing PCI-induced periprocedural myocardial Absolute Troponin-I Change (ng/L) 8 Journal of Interventional Cardiology injury [33]. %e reported results should therefore be 7.2. Exclusion Criteria interpreted with this in mind. (i) Pregnant females or lactating females (ii) Age younger than 18 years 6. Conclusion (iii) Evidence of active infection/inflammatory condi- In this pilot substudy, administration of preprocedural tions that might be associated with markedly el- colchicine improved post-PCI RRR and CFR, with less evated CRP levels or other inflammatory markers periprocedural absolute troponin change and lowered in the blood (e.g., active rheumatoid arthritis) neutrophil count, without effect on the development of post- (iv) Taking anti-inflammatory therapies (e.g., PCI Coronary Microvascular Dysfunction (defined in this corticosteroids) study as any one of post-PCI IMR >32 or CFR <2 or RRR (a) Including colchicine <2). (v) Known hypersensitivity to colchicine (vi) Noncompliance with medications 6.1. Impact on Daily Practice. Treatment of inflammation and impaired coronary microvascular function at the time of (vii) Patients not on or unable to take aspirin before or percutaneous coronary intervention (PCI) could improve after PCI outcomes. Based on this small, randomized placebo-con- (viii) Patients unable to take a second antiplatelet agent trolled trial, improvements in post-PCI coronary micro- and/or statin therapy after PCI vascular function (Resistive Reserve Ratio (RRR) and (ix) Moderate renal impairment defined as creatinine Coronary Flow Reserve (CFR)), inflammation, and troponin clearance <45ml/min release were seen in patients treated with preprocedural (x) Hepatic dysfunction defined as alanine amino- colchicine compared to placebo. Importantly, an improved transferase 1.5 ×upper limit of the normal range RRR represents an improved vasodilatory capacity of the coronary microcirculation and improved functional disease (xi) %rombocytopenia or leucopenia burden throughout the interrogated vessel. Improved RRR (xii) Already on moderate-strong CYP3A4 inhibitors in other studies has shown prognostic utility. (xiii) Severe left ventricular function defined as LVEF <35% 7. Inclusion and Exclusion Criteria (xiv) Acute Myocardial Infarction in the last 12 months 7.1. Inclusion Criteria (xv) Cardiogenic shock or hemodynamic instability (xvi) ST-elevation myocardial infarction (STEMI) (i) Male or female over 18years of age (ii) Stable angina (SA) patients: symptomatic patients (xvii) Patients who do not go on to PCI and/or patients who have PCI immediately prior to coronary with stable angina or asymptomatic patients with positive functional tests (requiring elective PCI) artery bypass grafting (xviii) Significant complex disease as deemed by (iii) Non-ST-elevation myocardial infarction (NSTEMI) patients: defined as the recent onset of chest pain interventionalist associated with ST-segment and/or T-wave ECG (a) Bifurcation lesions changes and positive cardiac enzymes (high sen- (b) Left main PCI or left main >50% stenosis sitivity troponin) (c) Chronic total occlusion of a vessel requiring PCI (a) Troponin must have peaked and stabilized prior to PCI, as defined by two serial Troponin (d) Side branch involvement or occlusion measures (xix) PCI to a small caliber vessel (<2.5mm in diam- (b) Stable troponins are defined by≤20% variation eter), distal vessel, or vessel supplying a small between troponin measurements distal territory (iv) Must be taking aspirin prior to PCI (xx) Incomplete blood sampling (v) Must be prescribed a second antiplatelet agent and (xxi) PCI performed outside the allowed time frame of statin therapy prior to PCI colchicine or placebo before treatment (6 to 24 (vi) PCI vessel caliber>2.5mm diameter vessels hours prior to PCI) (vii) Obstructive coronary artery disease (defined as (xxii) Unstable troponins or new ST elevation prior to PCI and after randomization diameter stenosis >70%) (vii) De novo lesion: defined by interventionalist (xxiii) Unable to perform invasive coronary physio- logical measurements (viii) Patient and coronary lesion appropriate for In- vasive Coronary Physiological Measurements, (xxiv) Heavily calcified or tortuous vessels such that safe passage of the pressure wire could not be deemed by the interventional cardiologist at the time of index PCI guaranteed Journal of Interventional Cardiology 9 (xxv) Contraindications to adenosine also had less PCI procedure-related troponin release and less inflammation. Abbreviations Conflicts of Interest ACS: Acute coronary syndrome BMS: Bare metal stent %e authors declare that they have no conflicts of interest. BRI: Baseline resistance index CAD: Coronary artery disease Authors’ Contributions CFR: Coronary flow reserve CRP: C-reactive protein All authors have read and approved the manuscript. DES: Drug-eluting stent FFR: Fractional flow reserve Acknowledgments hs: High-sensitive IHD: Ischaemic heart disease %is trial was supported by Peninsula Health and the Faculty IL: Interleukin of Medicine, Nursing and Health Sciences, Monash Uni- IM: Intermediate versity. %ere are no relationships with the industry. IMR: Index of microvascular resistance IVUS: Intravascular ultrasound LAD: Left anterior descending References LCx: Left circumflex [1] W. E. Boden, R. A. O’Rourke, K. K. 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Published: May 29, 2022

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