Jin Yong Hwang

Ischemic postconditioning during primary percutaneous coronary intervention: the effects of postconditioning on myocardial reperfusion in patients with ST-segment elevation myocardial infarction (POST) randomized trial.

Background— Ischemic postconditioning has been reported to reduce infarct size in patients with ST-segment–elevation myocardial infarction. However, cardioprotective effects of postconditioning have not been demonstrated in a large-scale trial. Methods and Results— We performed a multicenter, prospective, randomized, open-label, blinded end-point trial. A total of 700 patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment–elevation myocardial infarction within 12 hours after symptom onset were randomly assigned to the postconditioning group or to the conventional primary PCI group in a 1:1 ratio. Postconditioning was performed immediately after restoration of coronary flow as follows: The angioplasty balloon was positioned at the culprit lesion and inflated 4 times for 1 minute with low-pressure (<6 atm) inflations, each separated by 1 minute of deflation. The primary end point was complete ST-segment resolution (percentage resolution of ST-segment elevation >70%) measured at 30 minutes after PCI. Complete ST-segment resolution occurred in 40.5% of patients in the postconditioning group and 41.5% of patients in the conventional PCI group (absolute difference, −1.0%; 95% confidence interval, −8.4 to 6.4; P=0.79). The rate of myocardial blush grade of 0 or 1 and the rate of major adverse cardiac events (a composite of death, myocardial infarction, severe heart failure, or stent thrombosis) at 30 days did not differ significantly between the postconditioning group and the conventional PCI group (17.2% versus 22.4% [P=0.20] and 4.3% versus 3.7% [P=0.70], respectively). Conclusion— Ischemic postconditioning did not improve myocardial reperfusion in patients with ST-segment–elevation myocardial infarction undergoing primary PCI with current standard practice. Clinical Trial Registration— URL: http://clinicaltrials.gov. Unique identifier: NCT00942500.Background —Ischemic postconditioning has been reported to reduce infarct size in patients with ST-segment elevation myocardial infarction (STEMI). However, cardioprotective effects of postconditioning have not been demonstrated in a large-scale trial. nnMethods and Results —We performed a multicenter, prospective, randomized, open-label, blinded endpoint trial. A total of 700 patients undergoing primary percutaneous coronary intervention (PCI) for STEMI within 12 hours after symptom onset were randomly assigned to the postconditioning group or the conventional primary PCI group in a 1:1 ratio. Postconditioning was performed immediately after restoration of coronary flow as follows: the angioplasty balloon was positioned at the culprit lesion, and inflated 4 times for 1 minute with low-pressure ( 70%) measured at 30 minutes after PCI. Complete ST-segment resolution occurred in 40.5% of patients in the postconditioning group and 41.5% of patients in the conventional PCI group (absolute difference, -1.0%; 95% confidence interval, -8.4% to 6.4%; P =0.79). The rate of myocardial blush grade of 0 or 1 and the major adverse cardiac events (a composite of death, myocardial infarction, severe heart failure, or stent thrombosis) at 30 days did not differ significantly between the postconditioning group and the conventional PCI group (17.2% versus 22.4%, P =0.20, and 4.3% versus 3.7%, P =0.70, respectively). nnConclusions —Ischemic postconditioning did not improve myocardial reperfusion in patients with STEMI undergoing primary PCI with current standard practice. nnClinical Trial Registration Information —http://ClinicalTrials.gov. Identifier: [NCT00942500][1].nn [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00942500&atom=%2Fcirculationaha%2Fearly%2F2013%2F09%2F25%2FCIRCULATIONAHA.113.001690.atom

Effect of CYP2C19*2 and *3 Loss-of-Function Alleles on Platelet Reactivity and Adverse Clinical Events in East Asian Acute Myocardial Infarction Survivors Treated With Clopidogrel and Aspirin

Background— As compared with whites, East Asians more often carry the cytochrome P450 (CYP) 2C19 loss-of-function (LOF) allele with the CYP2C19*3 variant. The influence of the CYP2C19 LOF alleles (*2 and *3) on clopidogrel response and clinical outcomes in East Asians with acute myocardial infarction (AMI) has not been reported. We sought to evaluate the effect of the CYP2C19 variants on clopidogrel pharmacodynamics and long-term prognosis in these patients. Methods and Results— Patients who survived an AMI (n=266) were enrolled in a single-center registry. Predischarge platelet reactivity was assessed with light transmittance aggregometry and the VerifyNow P2Y12 assay; the CYP2C19*2, *3, *17 and ABCB1 3435C>T variants were determined. The primary clinical end point was the composite of cardiovascular death, nonfatal MI, and ischemic stroke. The median exposure to clopidogrel was 21 months (interquartile range, 13–29). The ABCB1 3435C>T was not related to clopidogrel response or cardiovascular events. Carriage of the CYP2C19 LOF variant allele was relatively high (60.9%, n=162; *2/*17=2, *3/*17=1, *1/*2=96, *1/*3=29, *2/*2=20, and *2/*3=14). Platelet reactivity increased proportionally according to the number of the CYP2C19 LOF alleles. In a multivariate regression analysis, the risk of high on-treatment platelet reactivity (HPR) increased depending on the number of CYP2C19 LOF allele [1 LOF allele; odds ratio (OR), 1.8; 95% confidence interval (CI), 0.8 to 4.2, P=0.152; and 2 LOF alleles; OR, 2.8; 95% CI, 1.2 to 6.5; P=0.016]; platelet reactivity and the rate of HPR did not differ between the CYP2C19*2 versus *3 allele carriage. In addition, cardiovascular event occurrence increased according to the number of the CYP2C19 LOF allele; compared with noncarriers, carriers of 1 [hazard ratio (HR), 3.1; 95% CI, 0.8 to 11.6; P=0.089] and 2 CYP2C19 LOF allele(s) (HR, 10.1; 95% CI, 1.8–58.8; P=0.008) were associated with clinical end point. The clinical impact of the CYP2C19*2 versus *3 allele carriage also did not differ. Conclusions— Among East Asian patients who survived an AMI, the CYP2C19 LOF allele carriage appears to affect clopidogrel pharmacodynamics and cardiovascular events according to the number of the CYP2C19 LOF allele; the influence of the CYP2C19*2 and *3 alleles on clopidogrel response and long-term outcomes does not differ.

Accelerated platelet inhibition by switching from atorvastatin to a non-CYP3A4-metabolized statin in patients with high platelet reactivity (ACCEL-STATIN) study

AIMSnCYP3A4-metabolized statins can influence the pharmacodynamic effect of clopidogrel. We sought to assess the impact of switching to a non-CYP3A4-metabolized statin on platelet function among patients receiving clopidogrel and atorvastatin with high on-treatment platelet reactivity (HPR).nnnMETHODS AND RESULTSnPercutaneous coronary intervention (PCI)-treated patients (n= 50) with HPR [20 μM adenosine diphosphate (ADP)-induced maximal platelet aggregation (MPA) >50%] were enrolled during chronic administration of atorvastatin (10 mg/day) and clopidogrel (75 mg/day) (≥6 months). They were randomly assigned to a 15-day therapy with either rosuvastatin 10 mg/day (n= 25) or pravastatin 20 mg/day (n= 25). Platelet function was assessed before and after switching by conventional aggregometry and the VerifyNow P2Y12 assay. Genotyping was performed for CYP2C19*2/*3, CYP3A5*3, and ABCB1 C3435T alleles. The primary endpoint was the absolute change in 20 μM ADP-induced MPA. After switching, MPAs after stimuli with 20 and 5 μM ADP were decreased by 6.6% (95% confidence interval: 3.2-10.1%; P < 0.001), and 6.3% (95% confidence interval: 2.5-10.2%; P = 0.002), respectively. Fifty-two P2Y12 reaction units fell (95% confidence interval: 35-70; P < 0.001) and the prevalence of HPR decreased (24%; P < 0.001). Pharmacodynamic effects were similar after rosuvastatin and pravastatin therapy. In addition to smoking status, the combination of calcium channel blocker usage and ABCB1 C3435T genotype significantly affected the change of 20 μM ADP-induced MPA.nnnCONCLUSIONSnAmong PCI-treated patients with HPR during co-administration of clopidogrel and atorvastatin, switching to a non-CYP3A4-metabolized statin can significantly decrease platelet reactivity and the prevalence of HPR. This switching effect appears similar irrespective of the type of non-CYP3A4-metabolized statin.

Three-Year Patient-Related and Stent-Related Outcomes of Second-Generation Everolimus-Eluting Xience V Stents Versus Zotarolimus-Eluting Resolute Stents in Real-World Practice (from the Multicenter Prospective EXCELLENT and RESOLUTE-Korea Registries)

Long-term outcomes are imperative to confirm safety of drug-eluting stents. There have been 2 randomized controlled trials comparing everolimus-eluting stents (EESs) and Resolute zotarolimus-eluting stents (ZES-Rs). To date, long-term clinical outcomes of these stents were limited to only 1 report, which has recently reported 4-year comparisons of these stents. Therefore, more evidence is needed regarding long-term clinical outcomes of the second-generation stents. This study compared the long-term clinical outcomes of EES with ZES-R in all-comer cohorts up to 3-year follow-up. The EXCELLENT and RESOLUTE-Korea registries prospectively enrolled 3,056 patients treated with EES and 1,998 with ZES-R, respectively, without exclusions. Stent-related composite outcomes (target lesion failure) and patient-related composite events up to 3-year follow-up were compared in crude and propensity score-matched analyses. Of 5,054 patients, 3,830 patients (75.8%) had off-label indication (2,217 treated with EES and 1,613 treated with ZES-R). The stent-related outcome (189 [6.2%] vs 127 [6.4%], pxa0= 0.812) and the patient-related outcome (420 [13.7%] vs 250 [12.5%], pxa0= 0.581) did not differ between EES and ZES-R, respectively, at 3xa0years, which was corroborated by similar results from the propensity score-matched cohort (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.70 to 1.20, pxa0= 0.523 and 0.85, 95% CI 0.70 to 1.02, pxa0= 0.081, for stent- and patient-related outcomes, respectively). The rate of definite or probable stent thrombosis up to 3xa0years (22 [0.7%] vs 10 [0.5%], pxa0=xa00.370) was also similar. The rate of very late definite or probable stent thrombosis was very low and comparable between the 2 stents (3 [0.1%] vs 1 [0.1%], pxa0= 0.657). In multivariate analysis, chronic renal failure (adjusted HR 3.615, 95% CI 2.440 to 5.354, pxa0<0.001) and off-label indication (adjusted HR 1.782, 95% CI 1.169 to 2.718, pxa0= 0.007) were the strongest predictors of target lesion failure at 3 years. In conclusion, both stents showed comparable safety and efficacy at 3-year follow-up in this robust real-world registry with unrestricted use of EES and ZES-R. Overall incidences of target lesion failure and definite stent thrombosis, including very late stent thrombosis, were low, even in the patients with off-label indications, suggesting excellent long-term safety and sustained efficacy of both types of second-generation drug-eluting stents.

Relation between the vasodilator-stimulated phosphoprotein phosphorylation assay and light transmittance aggregometry in East Asian patients after high-dose clopidogrel loading

OBJECTIVESnWe analyzed the relation between platelet aggregation measured by light transmittance aggregometry (LTA) and platelet reactivity index (PRI) measured by vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) assay.nnnBACKGROUNDnIt has been suggested that LTA and VASP-P assay correlate differently according to the level of P2Y12 receptor blockade by thienopyridines.nnnMETHODSnWe simultaneously measured platelet function by LTA and VASP-P assay in 466 East Asians undergoing elective percutaneous coronary intervention after a 600-mg clopidogrel loading. High on-clopidogrel platelet reactivity (HPR) was defined by published consensus criteria.nnnRESULTSnThe degree of correlation between LTA and the VASP-P assay was different according to PRI levels. The correlation was lower in patients with poor responsiveness (PRI >60%) (n = 216) (0.035 ≤ r(2) ≤ 0.047), which was greater in responsive patients (PRI ≤60%) (n = 250) (0.315 ≤ r(2) ≤ 0.526). Despite a 600-mg loading, East Asians had a high prevalence of HPR (40.1%-63.5%), and the prevalence of HPR also differed between LTA and VASP-P assay. A PRI cutoff of >58% (area under curve, 0.829; 95% confidence intervals, 0.792-0.862; P < .001) corresponded to the published HPR cutoff by 5-μM adenosine diphosphate-induced maximal platelet aggregation >46%.nnnCONCLUSIONSnThis is the largest study correlating platelet reactivity measured by LTA and VASP-P assay in a percutaneous coronary intervention-treated cohort. The correlation is dependent on the level of responsiveness. Future investigations are needed to better define the optimal cutoffs of HPR measured by LTA and VASP-P assay for personalized antiplatelet therapy.

Long-term effects of ischemic postconditioning on clinical outcomes: 1-year follow-up of the POST randomized trial

BACKGROUNDnIn the Effects of Postconditioning on Myocardial Reperfusion in Patients with ST-segment Elevation Myocardial Infarction (POST) trial, ischemic postconditioning failed to improve myocardial reperfusion. However, long-term effects of ischemic postconditioning on clinical outcomes are not known in patients with ST-segment elevation myocardial infarction.nnnMETHODSnA total of 700 patients undergoing primary percutaneous coronary intervention (PCI) were randomly assigned to the postconditioning group or the conventional primary PCI group in a 1:1 ratio. Postconditioning was performed immediately after restoration of coronary flow by balloon occlusion 4 times for 1 minute. Complete follow-up data for major clinical events at 1 year were available in 695 patients (99.3%), and analyses were done by the intention to treat principle. The primary outcome was a composite of death, myocardial infarction, severe heart failure, or stent thrombosis at 1 year.nnnRESULTSnAt 1 year, a composite of death, myocardial infarction, severe heart failure, or stent thrombosis occurred in 21 patients (6.1%) in the postconditioning group and 16 patients (4.6%) in the conventional PCI group (hazard ratio [HR] 1.32, 95% CI 0.69-2.53, P = .40). The risk of death (4.9% vs 3.7%, HR 1.32, 95% CI 0.64-2.71, P = .46), heart failure (2.6% vs 2.3%, HR 1.13, 95% CI 0.44-2.94, P = .80), and stent thrombosis (2.3% vs 1.7%, HR 1.34, 95% CI 0.46-3.85, P = .59) did not differ significantly between the 2 groups.nnnCONCLUSIONSnIschemic postconditioning does not seem to improve the 1-year clinical outcomes in patients with ST-segment elevation myocardial infarction undergoing primary PCI.

Pharmacodynamic Effect of Cilostazol Plus Standard Clopidogrel Versus Double-Dose Clopidogrel in Patients With Type 2 Diabetes Undergoing Percutaneous Coronary Intervention

OBJECTIVE To determine the effect of adding cilostazol (100 mg b.i.d.) to standard-dose clopidogrel (75 mg/d) (TRIPLE) compared with double-dose clopidogrel (150 mg/d) (DOUBLE) and the influence of the cytochrome P450 (CYP2C19*2/*3, CYP3A5*3)and ATP-binding cassette subfamily B1(ABCB1 C3435T) genetic polymorphisms in type 2 diabetes (T2DM) patients. RESEARCH DESIGN AND METHODS T2DM patients were treated with TRIPLE (n = 41) or DOUBLE (n = 39) after percutaneous coronary intervention. Conventional aggregometry and VerifyNow were performed at baseline and at 30 days. The primary end point was absolute change in 20-μM ADP-induced maximal platelet aggregation (ΔMPA20) between baseline and switching values. RESULTS TRIPLE versus DOUBLE showed greater ΔMPA20 (22.9 ± 11.6 vs.12.7 ± 15.5%; difference, 10.2% [95% CI 4.2–16.3]; P < 0.001). Carriage of one (β coefficient, −5.4%; P = 0.162) and two CYP2C19 loss-of-function allele(s) (−8.3%; P = 0.007) were associated with lower ΔMPA20 in DOUBLE–treated patients, but not in TRIPLE-treated patients. CONCLUSIONS Among T2DM patients, adding cilostazol achieves greater platelet inhibition compared with clopidogrel (150 mg/d), which is not influenced by genetic polymorphisms.

Novel role of platelet reactivity in adverse left ventricular remodelling after ST-segment elevation myocardial infarction: The REMODELING Trial

The role of platelet-leukocyte interaction in the infarct myocardium still remains unveiled. We aimed to determine the linkage of platelet activation to post-infarct left ventricular remodelling (LVR) process. REMODELING was a prospective, observational, cohort trial including patients (n = 150) with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. Patients were given aspirin plus clopidogrel therapy (600 mg loading and 75 mg daily). Platelet reactivity (PRU: P2Y12 Reaction Units) was assessed with VerifyNow P2Y12 assay on admission. Transthoracic echocardiography was performed on admission and at one-month follow-up. The primary endpoint was the incidence of LVR according to PRU-based quartile distribution. LVR was defined as a relative ≥ 20u2009% increase in LV end-diastolic volume (LVEDV) between measurements. Adverse LVR was observed in 36 patients (24.0u2009%). According to PRU quartile, LVR rate was 10.8u2009% in the first, 23.1u2009% in the second, 27.0u2009% in the third, and 35.1u2009% in the fourth (p = 0.015): the optimal cut-off of PRU was ≥ 248 (area under curve: 0.643; 95u2009% confidence interval: 0.543 to 0.744; p = 0.010). LVR rate also increased proportionally according to the level of high sensitivity-C reactive protein (hs-CRP) (p = 0.012). In multivariate analysis, the combination of PRU (≥ 248) and hs-CRP (≥ 1.4 mg/l) significantly increased the predictive value for LVR occurrence by about 21-fold. In conclusion, enhanced levels of platelet activation and inflammation determined the incidence of adverse LVR after STEMI. Combining the measurements of these risk factors increased risk discrimination of LVR. The role of intensified antiplatelet or anti-inflammatory therapy in post-infarct LVR process deserves further study.

Influence of platelet reactivity on BARC classification in East Asian patients undergoing percutaneous coronary intervention. Results of the ACCEL-BLEED study.

An increasing body of data suggests that East Asian patients have differing risk profiles for both thrombophilia and bleeding compared with Western population. This study was designed to evaluate the relationship of bleeding to platelet function in East Asians undergoing percutaneous coronary intervention (PCI). Patients who had undergone uneventful PCI (n= 301) were prospectively enrolled and bleeding events were evaluated during dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. Platelet function was measured during hospitalisation and at 30-day follow-up by light transmittance aggregometry (LTA) and vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) assay. During 30-day follow-up, 29.2u2009% of patients (n= 88) experienced post-discharge Bleeding Academic Research Consortium (BARC) complications (24.6u2009% and 7.0u2009% of BARC type 1 and 2, respectively). Patients presenting with acute myocardial infarction had fewer episodes of type 1 BARC bleeding (odds ratio: 0.41; 95u2009% confidence interval: 0.22 to 0.76; p= 0.005). The cut-off of low platelet reactivity (LPR) (20 µM ADP-induced platelet aggregation ≤u200946.1u2009%; platelet reactivity index ≤u200945.1u2009%) was the independent determinant of type 2 BARC bleeding (odds ratio: 3.55 and 4.44; p= 0.009 and 0.002, respectively). The first 30-day BARC bleeding episodes were associated with an increased rate of subsequent premature DAPT discontinuation during one-year follow-up (4.7u2009% vs 11.4u2009%; odds ratio: 2.60; 95u2009% confidence interval: 1.04 to 6.50; p= 0.035). In conclusion, among East Asians, mild bleeding episodes are common early after PCI and are associated with premature DAPT discontinuation. Type 2 BARC bleeding episodes are associated with LPR cut-offs measured at 30 days post-discharge.

A Randomized, Double-blind, Candesartan-controlled, Parallel Group Comparison Clinical Trial to Evaluate the Antihypertensive Efficacy and Safety of Fimasartan in Patients with Mild to Moderate Essential Hypertension

PURPOSEnA new antihypertensive drug that selectively blocks angiotensin II receptor type 1, fimasartan, has a potent and rapidly acting antihypertensive effect. We investigated the antihypertensive effects of fimasartan 60 and 120 mg and its safety in comparison to 8 mg of candesartan.nnnMETHODSnThis clinical trial is a multicenter, randomized, double-blind, active comparator, and parallel group study. Three hundred sixty-two individuals were screened, and 290 patients aged 19 to 75 years with mild to moderate hypertension (diastolic blood pressure [DBP], 90-110 mm Hg) were randomly assigned to 60 to 120 mg/d of fimasartan or 8 mg/d of candesartan after a 2-week placebo run-in period. Treatments were administered for 12 weeks without dosage adjustment. The primary end point was the differences in DBP changes at week 12.nnnFINDINGSnAfter 12 weeks of treatment, DBP and systolic blood pressure (SBP) decreased significantly in all 3 groups. The decrease in DBP at week 12 was larger but not statistically significant in the fimasartan 60 mg compared with the candesartan 8 mg group with a mean (SD) difference of 1.72 (8.32) mm Hg (95% CI, -0.71 to 4.15 mm Hg; P = 0.17). The lower margin of the CI (-0.71 mm Hg) exceeded the noninferiority margin (-3.5 mm Hg). The DBP-lowering effect of fimasartan 120 mg was also nonsignificantly larger than candesartan 8 mg (difference, 1.58 [8.27] mm Hg; P = 0.20). The decrease in SBP was also nonsignificantly larger in the fimasartan 60 mg group compared with the candesartan 8 mg group (difference, 3.50 [12.63] mm Hg; P = .06). The SBP-lowering effect of fimasartan 120 mg was statistically larger than candesartan 8 mg (difference, 4.98 [13.99] mm Hg; P = .02). Response rate (DBP <90 mm Hg or DBP lowering >10 mm Hg at week 12) was also nonsignificantly greater in both fimasartan groups (Fimasartan 60 mg, 81%; fimasartan 120 mg, 72%; candesartan 8 mg, 71%). The safety profile of the fimasartan 60 mg and 120 mg was similar to candesartan 8 mg, with a slightly higher, but statistically not significant, incidence of hepatic enzyme elevation in fimasartan 120 mg.nnnIMPLICATIONSnThe antihypertensive effect of fimasartan, a newly available angiotensin II receptor type 1 blocker, is comparable, although not superior, to candesartan with a good safety profile. ClinicalTrials.gov identifier: NCT01135212.