Mortality and cancer after 12 versus 30 months dual antiplatelet therapy

Serebruany, V. L.,Kim, M. H.,Cabrera-Fuentes, H. A.,Lee, K.,Cho, Y. R.,Park, K.,Park, T. H.,Kim, Y. D.,Yoon, S.-C. F K SCHATTAUER VERLAGSGESELLSCHAFT MBH 2017 Thrombosis and haemostasis Vol.117 No.5

<P>The optimal duration and cancer risks of antiplatelet therapy following percutaneous coronary intervention (PCI) are unclear. We compared cancer and all-cause mortality after dual antiplatelet therapy (DAPT) for the combination of clopidogrel and aspirin (ASA) versus ASA alone over 18 months follow-up in event-free patients at 12 months DAPT from the Health Insurance Review and Assessment (HIRA) dataset via the Korean Outcomes Registry Evaluating Antithrombotics (KOREA). We selected PCI patients who were event free for 12 months and maintained a consistent antiplatelet regimen for 18 more months. The primary endpoints were any cancer and all-cause mortality at 30 months follow-up after PCI. From 320,351 screened post-PCI patient HIRA records, we excluded 294,413 and qualified 25,938, constituting DAPT (n=10,992) and ASA (n=14,946) groups. The Propensity Score Matching (PSM), and Inverse Probability of Treatment Weighting (IPTW) revealed no significant differences in back-ground demographics and clinical characteristics for DAPT versus ASA patients. At 30-months post-PCI, after massive (>91 %) exclusions, cancer risk was higher for continuous DAPT [455 (4.15 %) vs 606 (4.04 %); HR=1.221; 95 % CI: 1.061-1.405; p=0.005], which remained significant by PSM (p=0.006) or IPTW (p=0.007), while all-cause mortality was similar [136 (1.24 %) vs 192 (1.28 %) HR=0.999; 95 % CI: 0.736-1.135; p=0.993]. This analysis suggests a potential mild excess cancer risk, but no mortality benefit in Korean post-PCI patients treated with DAPT for an additional 18 months beyond conventional 12 months DAPT. These data are not supporting continuing DAPT for more than one year in East Asians. Analysing cancer types and assessing potential cancer association with bleeding are warranted.</P>

The challenge for predicting bleeding events by assessing platelet reactivity following coronary stenting

Choi, S.Y.,Kim, M.H.,Serebruany, V. Elsevier/North-Holland Biomedical Press 2016 INTERNATIONAL JOURNAL OF CARDIOLOGY Vol.207 No.-

<P>Background: Predicting future bleeding events represents an unmet medical need that will ultimately improve outcomes during dual antiplatelet therapy (DAPT). Although low platelet reactivity (LPR) may be linked to bleeding, standardized and clinically validated threshold for reliable DAPT bleeding risk stratification is lacking. We sought to define the predictive value of LPR for future bleeding events in a large cohort of post-stenting single-center Korean patients. Methods: Consecutive patients (n = 800) who underwent coronary interventions with drug-eluting stents were enrolled from March 2010 to October 2014. Among them, 699 (80%) were treated with 75 mg/daily clopidogrel, 93 (19%) with 10 mg/daily prasugrel, and 8 (1%) with 180 mg/daily ticagrelor, all on top of 100 mg/daily aspirin. Bleeding was assessed by BARC 2-5 scale, and events were collected for 1-year post stenting. Platelet reactivity on DAPT was measured by the VerifyNow P2Y12 assay at 1 month following coronary intervention. Results: There were a total of 18 (2.1%) bleeding events. The LPR value defined as <= 139 PRU (AUC: 0.867, p < 0.0001) was an independent predictor for bleeding (HR = 21.26, 95% CI: 6.19-73.0, p < 0.0001) by univariate analysis, and remains significant (HR = 11.49; 95% CI: 2.89-45.67, p < 0.0004) following multivariate analysis adjustment. However, the specificity (81.7%) and sensitivity (83.3%) of the test was low challenging the assay utility to predict bleeding. Conclusion: Despite being an independent predictor for bleeding, LPR failed to reliably triage such patients due to low specificity and sensitivity of the test. There is an urgent need for a randomized trial with uniformed DAPT regimen, bleeding definition, and careful follow-up. (C) 2016 Elsevier Ireland Ltd. All rights reserved.</P>

Validation of Three Platelet Function Tests for Bleeding Risk Stratification During Dual Antiplatelet Therapy Following Coronary Interventions : Predicting bleeding during DAPT

Kim, Moo Hyun,Choi, Sun Young,An, Soo Yeon,Serebruany, Victor Foundation for Advances in Medicine and Science 2016 Clinical cardiology Vol.39 No.7

GW27-e0575 Impact of Renal Impairment on Platelet Reactivity and Clinical Outcomes During Chronic Dual Antiplatelet Therapy Following Coronary Stenting

Kim, Moo Hyun,Guo, Long Zhe,Shim, Chang Heon,Choi, Sun Young,Serebruany, Victor L. Elsevier 2016 JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY - Vol.68 No.16

Platelet microRNA for predicting acute myocardial infarction

Li, S.,Guo, L. Z.,Kim, M. H.,Han, J. Y.,Serebruany, V. Springer Science + Business Media 2017 Journal of thrombosis and thrombolysis Vol.44 No.4

Inhibition of Angiotensin II-Induced Cardiac Fibrosis by Atorvastatin in Adiponectin Knockout Mice

Choi, Sun Young,Park, Jong Sung,Roh, Mee Sook,Kim, Chong-Rak,Kim, Moo Hyun,Serebruany, Victor Wiley (John WileySons) 2017 Lipids Vol.52 No.5

<P>Adiponectin is a polypeptide known to inhibit cardiac fibrosis via the activation of aEuroZadenosine monophosphate-activated protein kinase (AMPK). Statins can also activate AMPK, resulting in the secretion of adiponectin. We determined whether atorvastatin inhibits angiotensin II-induced cardiac fibrosis (AICF) in the presence or absence of adiponectin. Adiponectin knockout (APN-KO, n = 44) and wild type (WT, n = 44) mice were received subcutaneous angiotensin II (1.5 mg/kg/day), and atorvastatin (10 mg/kg/day) was administered orally for 15 days. The mRNA expression levels of collagen type I and III, as well as AMPK phosphorylation levels in cardiac tissue were then measured. In the APN-KO mice, collagen type I (p < 0.001) and type III (p = 0.001) expression was significantly greater when treated with angiotensin II, while their expression was significantly reduced in the presence of angiotensin II and atorvastatin. Relative AMPK phosphorylation levels in APN-KO mice were also significantly higher in the angiotensin II + atorvastatin group when compared with angiotensin II group alone. We conclude that atorvastatin attenuates AICF independently from adiponectin by activating AMPK. These data suggest potential cardioprotection beyond lipid modulation potentially supporting statin pleiotropic hypothesis.</P>

Predicting Successful Recanalization in Patients with Native Coronary Chronic Total Occlusion: The Busan CTO Score

Jin, Cai De,Kim, Moo Hyun,Kim, Soo Jin,Lee, Kwang Min,Kim, Tae Hyung,Cho, Young-Rak,Serebruany, Victor L. S. Karger AG 2017 Cardiology Vol.137 No.2

<P><B><I>Background:</I></B> The optimal strategy to manage chronic total occlusion (CTO) remains unclear. The Japanese CTO multicenter registry (J-CTO) score is an established tool for predicting successful recanalization. However, it does not take into account nonangiographic predictors for final technique success. In the present study, we designed and tested a scoring model called the Busan single-center CTO registry (B-CTO) score combining clinical and angiographic characteristics to predict successful CTO recanalization in Korean patients. <B><I>Methods:</I></B> Prospectively enrolled CTO patients (<I>n</I> = 438) undergoing coronary intervention (1999-2015) were assessed. The B-CTO score comprises 6 independent predictors: age 60-74 years and lesion length ≥20 mm were assigned 1 point each, while age ≥75 years, female gender, lesion location in the right coronary artery, blunt stump, and bending >45° were assigned 2 points each. For each predictor, the points assigned were based on the associated odds ratio by multivariate analysis. The lesions were classified into 4 groups according to the summation of points scored to assess the probability of successful CTO recanalization: easy (score 0-1), intermediate (score 2-3), difficult (score 4-5), and very difficult (score ≥6). CTO opening was designated as the primary endpoint regardless of the interventional era or the skill of the operator. <B><I>Results:</I></B> The final success rate for B-CTO was 81.1%. The probability of successful recanalization for patient groups classified as easy (<I>n</I> = 64), intermediate (<I>n</I> = 148), difficult (<I>n</I> = 134), and very difficult (<I>n</I> = 92) was 95.3, 86.5, 79.1 and 65.2%, respectively (<I>p</I> for trend <0.001). When compared to the J-CTO, the B-CTO score demonstrated a significant improvement in discrimination as indicated by the area under the receiver-operator characteristic curve (AUC 0.083; 95% CI 0.025-0.141), with a positive integrated discrimination improvement of 0.042 and a net reclassification improvement of 56.0%. <B><I>Conclusions:</I></B> The B-CTO score has been designed and validated in Korean patients with native coronary CTO and is an improved tool for predicting successful recanalization. Wider application of the B-CTO score remains to be explored.</P>

Concomitant nitrates enhance clopidogrel response during dual anti-platelet therapy

Lee, D.H.,Kim, M.H.,Guo, L.Z.,De Jin, C.,Cho, Y.R.,Park, K.,Park, J.S.,Park, T.H.,Serebruany, V. Elsevier/North-Holland Biomedical Press 2016 INTERNATIONAL JOURNAL OF CARDIOLOGY Vol.203 No.-

<P>Background: Despite advances in modern anti-platelet strategies, clopidogrel still remains the cornerstone of dual anti-platelet therapy (DAPT) in patients undergoing percutaneous coronary interventions (PCI). There is some inconclusive evidence that response after clopidogrel may be impacted by concomitant medications, potentially affecting clinical outcomes. Sustained released nitrates (SRN) are commonly used together with clopidogrel in post-PCI setting for mild vasodilatation and nitric oxide-induced platelet inhibition. Methods: We prospectively enrolled 458 patients (64.5 +/- 9.6 years old, and 73.4% males) following PCI undergoing DAPT with clopidogrel and aspirin. Platelet reactivity was assessed by the VerifyNow (TM) P(2)Y12 assay at the maintenance outpatient setting. Results: Concomitant SRN (n = 266) significantly (p = 0.008) enhanced platelet inhibition after DAPT (251.6 +/- 80.9 PRU) when compared (232.1 +/- 73.5 PRU) to the SRN-free (n = 192) patients. Multivariate logistic regression analysis with the cut-off value of 253 PRU for defining heightened platelet reactivity confirmed independent correlation of more potent platelet inhibition during DAPT and use of SRN (Relative risk = 1.675; Odds ratio [1.059-2.648]; p = 0.027). In contrast, statins, calcium-channel blockers, beta blockers, angiotensin receptor blockers, ACE-inhibitors, diuretics, and anti-diabetic agents did not significantly impact platelet inhibition following DAPT. Conclusion: The synergic ability of SRN to enhance response during DAPT may have important clinical implications with regard to better cardiovascular protection, but extra bleeding risks, requiring further confirmation in a large randomized study. (C) 2015 Elsevier Ireland Ltd. All rights reserved.</P>

Thienopyridine reloading in clopidogrel-loaded patients undergoing percutaneous coronary interventions: The PRAISE study

Guo, Long Zhe,Kim, Moo Hyun,Shin, Eun Seok,Ann, Soe Hee,De Jin, Cai,Cho, Young-Rak,Park, Jong Sung,Park, Kyungil,Park, Tae-Ho,Lee, Michael S.,Serebruany, Victor L. Elsevier 2016 INTERNATIONAL JOURNAL OF CARDIOLOGY Vol.222 No.-

<P><B>Abstract</B></P> <P><B>Objective</B></P> <P>The impact of thienopyridine reloading on clinical outcomes, and residual high platelet reactivity (HPR) is unclear. We sought to compare the HRP-related effect of prasugrel and clopidogrel reloading in the already clopidogrel-loaded patients undergoing percutaneous coronary intervention (PCI).</P> <P><B>Materials and methods</B></P> <P>In this prospective, two-center, randomized, open-label study, patients with HPR who had undergone PCI after a clopidogrel (300–600mg) loading dose (LD) were enrolled. Among screened (n=153), HPR was determined in seventy-six patients, who were randomized to either repeated clopidogrel (300mg LD, followed by 75mg MD daily) or prasugrel (20mg LD, followed by 5mg MD daily). The primary endpoint was HPR at 24h after PCI, as determined by the VerifyNow assay. The rates of sustained high and low platelet reactivity, periprocedural myocardial injury (PMI) and 30-day clinical outcomes were also assessed.</P> <P><B>Results</B></P> <P>Higher inhibition of platelet reactive units (PRU) was observed in the prasugrel group than after clopidogrel reloading (Pre-PCI: 284.4±32.0 vs 279.5±32.5, p=0.504; Post-PCI: 100.0±67.0 vs 202.9±65.8, p<0.001; 30days: 170.8±69.8 vs 215.1±62.4, p=0.007). There were less HRP post-PCI after prasugrel compared with the clopidogrel group (2.7 vs 36.1%, p<0.001). However, reloading with prasugrel did not reduce PMI compared to clopidogrel (36.8% vs 39.5%, p=0.813).</P> <P><B>Conclusion</B></P> <P>Prasugrel reloading led to a greater reduction in HPR, but similar with clopidogrel PMI in post-PCI patients. Larger randomized evidence is needed for optimization of loading strategies with thienopyridines.</P> <P>Clinical Trial Registration Information: NCT01609647.</P>

Comparison of Three Tests to Distinguish Platelet Reactivity in Patients with Renal Impairment during Dual Antiplatelet Therapy

Guo, Long Zhe,Kim, Moo Hyun,Kim, Tae Hyung,Park, Jong Seong,Jin, Enze,Shim, Chang Heon,Choi, Sun Young,Serebruany, Victor L. S. Karger AG 2016 Nephron Vol.132 No.3

<P>Background: Clopidogrel and aspirin combination remains a cornerstone for modern dual antiplatelet therapy (DAPT) following coronary stenting. Although monitoring is not currently recommended, certain high-risk cohorts may benefit from tailoring antiplatelet options to reduce thrombotic or/and hemorrhagic risks. Patients with diminished estimated glomerular filtration rate (eGFR) are prone to both vascular occlusions and bleeding events in whom monitoring may be especially advantageous. We compared the residual platelet reactivity assessed by 3 conventional tests during the maintenance antiplatelet therapy dependent on eGFR. Methods: Post-stenting patients (n = 701) receiving aspirin 100 mg/ daily and clopidogrel 75 mg/daily were prospectively enrolled in the cross-sectional single-center study. Patients were dichotomized into 5 groups: eGFR >90, 60-89, 30-59, <30 ml/min/1.73 m(2), and dialysis. Platelet reactivity by VerifyNow (TM), light transmittance aggregometry (LTA), and Multiplate analyzer by multiple electrode platelet aggregometry (MEA) assays together with eGFR calculations were done simultaneously at 1 month after coronary stenting. Results: VerifyNow assay distinguished residual platelet reactivity dependent on eGFR deterioration (191 +/- 72 vs. 216 +/- 78 vs. 248 +/- 80 vs. 264 +/- 70 vs. 317 +/- 96 PRU; p < 0.001). In contrast, LTA (34.3 +/- 18.1 vs. 34.7 +/- 18.1 vs. 38.0 +/- 16.6 vs. 33.0 +/- 17.3 vs. 34.1 +/- 29.3%; p = 0.242), or MEA (37.2 +/- 19.6 vs. 33.8 +/- 18.4 vs. 38.6 +/- 21.4 vs. 36.5 +/- 20.5 vs. 38.3 +/- 28.3 AU/min; p = 0.086) failed to triage platelet reactivity in renal patients. Agreement among assays to identify patients with impaired platelet reactivity and eGFR during antiplatelet therapy was low. The multivariable regression analyses confirmed the VerifyNow advantage, since the differences in the platelet reactivity were highly significant for all renal impairment (RI) groups. In contrast, LTA did not distinguish RI patients, and for the MEA, only RI5 (dialysis) cohort exhibit borderline significant decline of residual platelet reactivity. Conclusion: Among 3 assays, VerifyNow was capable to reliably triage residual platelet reactivity in post-stenting DAPT patients dependent on the gradual decline of eGFR during therapy with clopidogrel and aspirin. These data should be confirmed in a large validation longitudinal trial, and may justify future platelet activity monitoring for potential regimen/dose adjustment in high-risk patients. The clinical implications of these data are still unclear, but may give an indication as to whether or when DAPT dose adjustment will become a reality. (C) 2016 S. Karger AG, Basel</P>