The effect of renal denervation on arterial stiffness, central blood pressure and heart rate variability in treatment resistant essential hypertension: a substudy of a randomized sham-controlled double-blinded trial (the ReSET trial).

OBJECTIVES: To investigate, whether renal denervation (RDN) improves arterial stiffness, central blood pressure (C-BP) and heart rate variability (HRV) in patients with treatment resistant hypertension. METHODS: ReSET was a randomized, sham-controlled, double-blinded trial (NCT01459900). RDN was performed by a single experienced operator using the Medtronic unipolar Symplicity FlexTM catheter. C-BP, carotid-femoral pulse wave velocity (PWV), and HRV were obtained at baseline and after six months with the SphygmoCor®-device. RESULTS: Fifty-three patients (77% of the ReSET-cohort) were included in this substudy. The groups were similar at baseline (SHAM/RDN): n = 27/n = 26; 78/65% males; age 59 ± 9/54 ± 8 years (mean ± SD); systolic brachial BP 158 ± 18/154 ± 17 mmHg; systolic 24-hour ambulatory BP 153 ± 14/151 ± 13 mmHg. Changes in PWV (0.1 ± 1.9 (SHAM) vs. -0.6 ± 1.3 (RDN) m/s), systolic C-BP (-2 ± 17 (SHAM) vs. -8 ± 16 (RDN) mmHg), diastolic C-BP (-2 ± 9 (SHAM) vs. -5 ± 9 (RDN) mmHg), and augmentation index (0.7 ± 7.0 (SHAM) vs. 1.0 ± 7.4 (RDN) %) were not significantly different after six months. Changes in HRV-parameters were also not significantly different. Baseline HRV or PWV did not predict BP-response after RDN. CONCLUSIONS: In a sham-controlled setting, there were no significant effects of RDN on arterial stiffness, C-BP and HRV. Thus, the idea of BP-independent effects of RDN on large arteries and cardiac autonomic activity is not supported.

Coronary plaque quantification and fractional flow reserve by coronary computed tomography angiography identify ischaemia-causing lesions.

AIMS: Coronary plaque characteristics are associated with ischaemia. Differences in plaque volumes and composition may explain the discordance between coronary stenosis severity and ischaemia. We evaluated the association between coronary stenosis severity, plaque characteristics, coronary computed tomography angiography (CTA)-derived fractional flow reserve (FFRCT), and lesion-specific ischaemia identified by FFR in a substudy of the NXT trial (Analysis of Coronary Blood Flow Using CT Angiography: Next Steps). METHODS AND RESULTS: Coronary CTA stenosis, plaque volumes, FFRCT, and FFR were assessed in 484 vessels from 254 patients. Stenosis >50% was considered obstructive. Plaque volumes (non-calcified plaque [NCP], low-density NCP [LD-NCP], and calcified plaque [CP]) were quantified using semi-automated software. Optimal thresholds of quantitative plaque variables were defined by area under the receiver-operating characteristics curve (AUC) analysis. Ischaemia was defined by FFR or FFRCT ≤0.80. Plaque volumes were inversely related to FFR irrespective of stenosis severity. Relative risk (95% confidence interval) for prediction of ischaemia for stenosis >50%, NCP ≥185 mm(3), LD-NCP ≥30 mm(3), CP ≥9 mm(3), and FFRCT ≤0.80 were 5.0 (3.0-8.3), 3.7 (2.4-5.6), 4.6 (2.9-7.4), 1.4 (1.0-2.0), and 13.6 (8.4-21.9), respectively. Low-density NCP predicted ischaemia independent of other plaque characteristics. Low-density NCP and FFRCT yielded diagnostic improvement over stenosis assessment with AUCs increasing from 0.71 by stenosis >50% to 0.79 and 0.90 when adding LD-NCP ≥30 mm(3) and LD-NCP ≥30 mm(3) + FFRCT ≤0.80, respectively. CONCLUSION: Stenosis severity, plaque characteristics, and FFRCT predict lesion-specific ischaemia. Plaque assessment and FFRCT provide improved discrimination of ischaemia compared with stenosis assessment alone.

Zotarolimus-eluting durable-polymer-coated stent versus a biolimus-eluting biodegradable-polymer-coated stent in unselected patients undergoing percutaneous coronary intervention (SORT OUT VI): a randomised non-inferiority trial.

BACKGROUND: New-generation drug-eluting coronary stents have reduced the risk of coronary events, especially in patients with complex disease or lesions. To what extent different stent platforms, polymers, and antiproliferative drugs affect outcomes, however, is unclear. We investigated the safety and efficacy of a third-generation stent by comparing a highly biocompatible durable-polymer-coated zotarolimus-eluting stent with a biodegradable-polymer-coated biolimus-eluting stent. METHODS: This open-label, randomised, multicentre, non-inferiority trial was done at three sites across western Denmark. All patients who presented with stable coronary artery disease or acute coronary syndromes and at least one coronary artery lesion (more than 50% stenosis) from March, 2011, to August, 2012, were assessed for eligibility. Patients were randomly assigned in a 1:1 ratio to receive either the durable-polymer zotarolimus-eluting stent or the biodegradable-polymer biolimus-eluting stent. The primary endpoint was a composite of safety (cardiac death and myocardial infarction not clearly attributable to a non-target lesion) and efficacy (target-lesion revascularisation) at 12 months, analysed by intention to treat. The trial was powered to assess non-inferiority of durable-polymer zotarolimus-eluting stent compared with the biodegradable-polymer biolimus-eluting stent with a predetermined non-inferiority margin of 0·025. This trial is registered with ClinicalTrials.gov, number NCT01956448. FINDINGS: Of 7103 screened, 1502 patients with 1883 lesions were assigned to receive the durable-polymer zotarolimus-eluting stent and 1497 patients with 1791 lesions to receive the biodegradable-polymer biolimus-eluting stent. 79 (5·3%) and 75 (5·0%) patients, respectively, met the primary endpoint (absolute risk difference 0·0025, upper limit of one-sided 95% CI 0·016%; p=0·004). The individual components of the primary endpoint did not differ significantly between stent types at 12 months. INTERPRETATION: The durable-polymer-coated zotarolimus-eluting stent was non-inferior to the biodegradable-polymer-coated biolimus-eluting stent in unselected patients. FUNDING: Medtronic Cardiovascular and Biosensors Interventional Technologies.

Differential clinical outcomes after 1 year versus 5 years in a randomised comparison of zotarolimus-eluting and sirolimus-eluting coronary stents (the SORT OUT III study): a multicentre, open-label, randomised superiority trial.

BACKGROUND: In head-to-head comparisons of coronary drug-eluting stents, the primary endpoint is traditionally assessed after 9-12 months. However, the optimum timepoint for this assessment remains unclear. In this study, we assessed clinical outcomes at up to 5 years' follow-up in patients who received two different types of drug-eluting stents. METHODS: We undertook this multicentre, open-label, randomised superiority trial at five percutaneous coronary intervention centres in Denmark. We randomly allocated 2332 eligible adult patients (≥18 years of age) with an indication for drug-eluting stent implantation to the zotarolimus-eluting Endeavor Sprint stent (Medtronic, Santa Rosa, CA, USA) or the sirolimus-eluting Cypher Select Plus stent (Cordis, Johnson & Johnson, Warren, NJ, USA). Randomisation of participants was achieved by computer-generated block randomisation and a telephone allocation service. The primary endpoint of the SORT OUT III study was a composite of major adverse cardiac events-cardiac death, myocardial infarction, and target vessel revascularisation-at 9 months' follow-up. In this study, endpoints included the occurrence of major adverse cardiac events and definite stent thrombosis at follow-up times of up to 5 years. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00660478. FINDINGS: We randomly allocated 1162 patients to receive the zotarolimus-eluting stent and 1170 to the sirolimus-eluting stent. At 5-year follow-up, rates of major adverse cardiac events were similar in patients treated with both types of stents (zotarolimus-eluting stents 197/1162 [17.0%] vs sirolimus-eluting stents 182/1170 [15.6%]; odds ratio [OR] 1.10, 95% CI 0.88-1.37; p=0.40). This finding was indicative of the directly contrasting results for rates of major adverse cardiac events at 1-year follow up (zotarolimus 93/1162 [8.0%] vs sirolimus 46/1170 [3.9%]; OR 2.13, 95% CI 1.48-3.07; p<0.0001) compared with those at follow-up between 1 and 5 years (104 [9.0%] vs 136 [11.6%]; OR 0.78, 95% CI 0.59-1.02; p=0.071). At 1-year follow-up, definite stent thrombosis was more frequent after implantation of the zotarolimus-eluting stent (13/1162 [1.1%]) than the sirolimus-eluting stent (4/1170 [0.3%]; OR 3.34, 95% CI 1.08-10.3; p=0.036), whereas the opposite finding was recorded for between 1 and 5 years' follow-up (zotarolimus-eluting stent 1/1162 [0.1%] vs sirolimus-eluting stent 21/1170 [1.8%], OR 0.05, 95% CI 0.01-0.36; p=0.003). 26 of 88 (30%) target lesion revascularisations in the zotarolimus-eluting stent group occurred between 1 and 5 years' follow-up, whereas 54 of 70 (77%) of those in the sirolimus-eluting stent group occurred during this follow-up period. INTERPRETATION: The superiority of sirolimus-eluting stents compared with zotarolimus-eluting stents at 1-year follow-up was lost after 5 years. The traditional 1-year primary endpoint assessment therefore might be insufficient to predict 5-year clinical outcomes in patients treated with coronary drug-eluting stent implantation. FUNDING: Cordis and Medtronic.

A 10-month angiographic and 4-year clinical outcome of everolimus-eluting versus sirolimus-eluting coronary stents in patients with diabetes mellitus (the DiabeDES IV randomized angiography trial).

OBJECTIVE: We aimed to compare angiographic and clinical outcomes after the implantation of everolimus-eluting (EES) and sirolimus-eluting (SES) stents in patients with diabetes. BACKGROUND: There are limited data on long-term outcome after EES vs SES implantation in diabetic patients. METHODS: We randomized 213 patients with diabetes and coronary artery disease to EES (n = 108) or SES (n = 105) implantation. Angiographic follow-up was performed 10 months after the index procedure and all patients were followed clinically for 4 years. The primary endpoint was angiographic in-stent late luminal loss at 10-month follow-up. Secondary endpoints included angiographic restenosis rate, the need for target lesion revascularization (TLR) and major adverse cardiac events (MACE; defined as cardiac death, myocardial infarction, definite stent thrombosis, or TLR) at 4-year follow-up. RESULTS: At 10-month angiographic follow-up, in-stent late lumen loss was 0.20 ± 0.53 mm and 0.11 ± 0.49 mm (P = 0.28), and angiographic restenosis rate was 3.8% and 5.2% (P = 0.72) in the EES and SES groups, respectively. At 4-year clinical follow-up, MACE had occurred in 22 (20.4%) patients in the EES group and 25 (23.8%) patients in SES group (HR 0.84, 95% CI 0.47-1.49; P = 0.55), with TLR performed in 6 (5.6%) and 10 (9.5%) patients in the two groups (HR 0.57, 95% CI 0.21-1-58; P = 0.28). CONCLUSION: EES and SES had comparable 10-month angiographic and 4-year clinical outcomes in patients with diabetes mellitus and coronary artery disease.

Biolimus-eluting biodegradable polymer-coated stent versus durable polymer-coated sirolimus-eluting stent in unselected patients receiving percutaneous coronary intervention (SORT OUT V): a randomised non-inferiority trial.

BACKGROUND: Third-generation biodegradable polymer drug-eluting stents might reduce the risk of stent thrombosis compared with first-generation permanent polymer drug-eluting stents. We aimed to further investigate the effects of a biodegradable polymer biolimus-eluting stent compared with a durable polymer-coated sirolimus-eluting stent in a population-based setting. METHODS: This randomised, multicentre, all-comer, non-inferiority trial was undertaken at three sites across western Denmark. Eligible patients were aged 18 years or older with chronic stable coronary artery disease or acute coronary syndromes, and at least one coronary artery lesion (>50% diameter stenosis). We randomly assigned patients (1:1) using an independently managed computer-generated allocation sequence to receive either a biolimus-eluting biodegradable polymer stent (Nobori, Terumo, Tokyo, Japan) or a sirolimus-eluting permanent polymer stent (Cypher Select Plus, Cordis, Johnson & Johnson, Warren, NJ, USA). The primary endpoint was a composite of safety (cardiac death, myocardial infarction, definite stent thrombosis) and efficacy (target vessel revascularisation) at 9 months, analysed by intention to treat (non-inferiority margin of 0·02). This trial is registered with ClinicalTrials.gov, number NCT01254981. FINDINGS: From July, 2009, to January, 2011, we assigned 1229 patients (1532 lesions) to receive the biolimus-eluting stent and 1239 (1555 lesions) to receive the sirolimus-eluting stent. One patient was lost to follow-up because of emigration. Intention-to-treat analysis showed that 50 (4·1%) patients who were assigned the biolimus-eluting stent and 39 (3·1%) who were assigned the sirolimus-eluting stent met the primary endpoint (risk difference 0·9% [upper limit of one-sided 95% CI 2·1%]; p(non-inferiority)=0·06). Significantly more patients in the biolimus-eluting stent group had definite stent thrombosis at 12 months than did those in the sirolimus-eluting stent group (9 [0·7%] vs 2 [0·2%], risk difference 0·6% [95% CI 0·0-1·1]; p=0·034). Per-protocol analysis showed that 45 (3·8%) of 1193 patients who received a biolimus-eluting stent and 39 (3·2%) of 1208 who received a sirolimus-eluting stent met the primary endpoint (risk difference 0·5% [upper limit of one-sided 95% CI 1·8%]; p(non-inferiority)=0·03). INTERPRETATION: At 1 year follow-up, the biodegradable polymer biolimus-eluting Nobori stent did not improve clinical results compared with a first-generation sirolimus-eluting stent. We will need to obtain long-term data before we can make recommendations for the role of this biolimus-eluting stent in routine clinical practice. FUNDING: Terumo and Cordis (Johnson & Johnson).

Intimal hyperplasia and vascular remodeling after everolimus-eluting and sirolimus-eluting stent implantation in diabetic patients: the randomized Diabetes and Drug-Eluting Stent (DiabeDES) IV Intravascular Ultrasound trial.

OBJECTIVE: To evaluate the effects of the everolimus-eluting Xience™/Promus™ stent (EES) and the sirolimus-eluting Cypher™ stent (SES) on intimal hyperplasia (IH) in diabetic patients. BACKGROUND: Patients with diabetes mellitus have increased risk of in-stent restenosis after coronary stent implantation due to intimal hyperplasia (IH). METHODS: In a sub study of the Randomized Comparison of Everolimus-Eluting and Sirolimus-Eluting Stents in Patients Treated with Percutaneous Coronary Intervention (SORT OUT IV trial), serial intravascular ultrasound (IVUS) 10-month follow-up data were available in 88 patients, including 48 EES and 40 SES treated patients. IVUS endpoints included IH volume, in-stent % volume obstruction and changes in external elastic membrane (EEM) volume. RESULTS: Compared with the SES group, IH volume was increased in the EES group [median (interquartile range): 2.8 mm(3) (0.0-12.6) vs. 0.0 mm(3) (0.0-1.1), P = 0.001]. In-stent % volume obstruction was increased in EES compared to SES [median (interquartile range): 1.6% (0.0-8.2) vs. 0.0% (0.0-1.0), P = 0.001]. Peri-stent external elastic membrane (EEM) volume: (post procedure vs. follow-up EES [300 mm(3) (219-491) vs. 307 mm(3) (223-482), P = 0.73] and SES [316 mm(3) (235-399) vs. 323 mm(3) (246-404), P = 0.05]) and peri-stent plaque volume: EES [163 mm(3) (103-273) vs. 184 mm(3) (115-291), P = 0.18] and SES [186 mm(3) (139-248) vs. 175 mm(3) (153-243), P = 0.26]) were unchanged in both groups. In the proximal reference segment a significant increase in plaque area was seen in the EES group only, without vascular remodeling. CONCLUSION: In diabetic patients, EES stent implantation was associated with increased IH volume obstruction without involvement of vascular remodeling.

Long-term outcome following percutaneous coronary intervention with drug-eluting stents compared with bare-metal stents in saphenous vein graft lesions: from Western Denmark Heart Registry.

OBJECTIVES: We used the Western Denmark Heart Registry to assess one-year and long-term all-cause mortality and stent failure following Percutaneous Coronary Intervention (PCI) with drug-eluting stents (DES) or bare-metal stents (BMS). BACKGROUND: The use of DES compared with BMS during PCI has reduced the risk of restenosis in native coronary artery lesions. In saphenous vein grafts (SVG) the outcome after DES compared with BMS is insufficiently described. METHODS: From January 1, 2002 to December 31, 2010 all patients with PCI of SVG lesions were identified among 3.0 million inhabitants. Stent failure was defined as clinically driven target lesion revascularization, graft occlusion without intervention, or stent thrombosis. RESULTS: The study cohort consisted of 529 patients with 755 SVG lesions (348 DES patients with 510 lesions and 181 BMS patients with 245 lesions). Mean age did not differ between patients with DES-treated lesions compared to patients with BMS-treated lesions (67.5 ± 9.1 years vs. 67.6 ± 9.3 years; P = 0.85). The median follow-up time was 3.0 years (25th-75th percentile: 1.4-5.1 years). One-year (n = 27 (8.2%) vs. n = 12 (6.7%), log rank P = 0.60) and 3-year cumulative mortality (n = 31 (18.8%) vs. n = 59 (21.8%), log rank P = 0.64) did not differ significantly between DES- and BMS-treated patients. One-year cumulative stent failure was seen in 39 (6.6%) DES-treated lesions vs. 24 (10.8%) BMS-treated lesions (P = 0.088), and 3-year cumulative stent failure in 48 (15.4%) vs. 34 (18.8%) lesions (P = 0.25), respectively. CONCLUSION: In SVG lesions, DES showed no long-term benefit compared to BMS in rates of all-cause mortality or stent failure.

Clopidogrel discontinuation within the first year after coronary drug-eluting stent implantation: an observational study.

BACKGROUND: The impact of adherence to the recommended duration of dual antiplatelet therapy after first generation drug-eluting stent implantation is difficult to assess in real-world settings and limited data are available. METHODS: We followed 4,154 patients treated with coronary drug-eluting stents in Western Denmark for 1 year and obtained data on redeemed clopidogrel prescriptions and major adverse cardiovascular events (MACE, i.e., cardiac death, myocardial infarction, or stent thrombosis) from medical databases. RESULTS: Discontinuation of clopidogrel within the first 3 months after stent implantation was associated with a significantly increased rate of MACE at 1-year follow-up (hazard ratio (HR) 2.06; 95% confidence interval (CI): 1.08-3.93). Discontinuation 3-6 months (HR 1.29; 95% CI: 0.70-2.41) and 6-12 months (HR 1.29; 95% CI: 0.54-3.07) after stent implantation were associated with smaller, not statistically significant, increases in MACE rates. Among patients who discontinued clopidogrel, MACE rates were highest within the first 2 months after discontinuation. CONCLUSIONS: Discontinuation of clopidogrel was associated with an increased rate of MACE among patients treated with drug-eluting stents. The increase was statistically significant within the first 3 months after drug-eluting stent implantation but not after 3 to 12 months.

Pre-hospital evaluation of electrocardiographic grade 3 ischemia predicts infarct progression and final infarct size in ST elevation myocardial infarction patients treated with primary percutaneous coronary intervention.

BACKGROUND: In STEMI, grade-3 ischemia (G3) on admission ECG predicts larger infarct size (IS) than grade-2 (G2). We evaluated whether pre-hospital G3 and its temporal behavior are associated with IS and salvage after pPCI. METHODS: In 401 STEMI patients, pre-hospital and pre-PCI ECGs were classified as G3 or G2. IS was assessed by single-photon emission computed tomography (SPECT) at 30days. In 245 patients, pre-PCI SPECT was available to determine myocardium at risk (MaR). RESULTS: G3 criteria were met by 88, and G2 by 313 patients. G3 was independently associated with IS (p=0.006). With ST resolution (STR) group as a reference, G2->G2, G2->G3 and G3->G3 were associated with larger IS (B=4.4, p=0.004; B=5.4, p=0.01; B=10.2, p<0.001, respectively), whereas G3->G2 was not. Salvage was similar between G3 and G2 on pre-hospital ECG if treated early, however lower for G3 when treated later (>2.5h); 48% (35-78) vs 62% (40-87); p=0.04. CONCLUSION: Development or persistence of G3 is associated with larger IS and less salvage, but decreasing grade G3->G2 was not.

Randomized comparison of everolimus-eluting and sirolimus-eluting stents in patients treated with percutaneous coronary intervention: the Scandinavian Organization for Randomized Trials with Clinical Outcome IV (SORT OUT IV).

BACKGROUND: Among drug-eluting stents released to date, the sirolimus-eluting stent has demonstrated the least amount of late lumen loss, but its efficacy and safety have not been compared head-to-head with the next-generation everolimus-eluting stent. METHODS AND RESULTS: The Scandinavian Organization for Randomized Trials with Clinical Outcome IV (SORT OUT IV) trial was a randomized multicenter, single-blind, all-comer, 2-arm, noninferiority trial comparing the everolimus-eluting stent with the sirolimus-eluting stent in patients with coronary artery disease. The primary end point was a composite of safety (cardiac death, myocardial infarction, definite stent thrombosis) and efficacy (target vessel revascularization) parameters. The noninferiority criterion was a risk difference of 0.015. Intention-to-treat analyses were done at 9- and 18-month follow-ups. A total of 1390 patients were assigned to receive the everolimus-eluting stent and 1384 patients to the sirolimus-eluting stent. At the 9-month follow-up, 68 patients (4.9%) treated with the everolimus-eluting stent compared with 72 patients (5.2%) treated with the sirolimus-eluting stent experienced the primary end point (hazard ratio, 0.94; 95% confidence interval, 0.67-1.31; P for noninferiority=0.01). At the 18-month follow-up, this differential remained: 99 patients (7.2%) treated with the everolimus-eluting stent versus 105 (7.6%) treated with the sirolimus-eluting stent (hazard ratio, 0.94; 95% confidence interval, 0.71-1.23). At the 9-month follow-up, the rate of definite stent thrombosis was higher in the sirolimus-eluting group (2 patients [0.1%] versus 9 patients [0.7%]; hazard ratio, 0.22; 95% confidence interval, 0.05-1.02). At the 18-month follow-up, this difference was sustained (3 patients [0.2%] versus 12 patients [0.9%]; hazard ratio, 0.25; 95% confidence interval, 0.07-0.88). CONCLUSION: The everolimus-eluting stent was found to be noninferior to the sirolimus-eluting stent. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00552877.

Consideration of QRS complex in addition to ST segment abnormalities in the estimation of the 'risk region' during acute inferior myocardial infarction.

BACKGROUND: The myocardial area at risk (MaR) has been estimated in patients with acute myocardial infarction (AMI) by using ST segment based ECG methods. However, as the process from ischemia to infarction progresses, the ST segment deviation is typically replaced by QRS abnormalities, causing a falsely low estimation of the total MaR if determined by using ST segment based methods. A previous study showed the value of the consideration of the abnormalities in the QRS complex, in addition to those in the ST segment estimating the total MaR for patients with anterior AMI. The purpose of this study was to investigate the same method for patients with inferior AMI. METHODS: Thirty-two patients with acute inferior ST elevation myocardial infarction received (99m)Tc-Sestamibi before percutaneous coronary intervention. SPECT was performed within 2 hours after treatment and was used as a gold standard for the estimation of the total MaR. The ECG recorded at admission in the hospital was used for the ECG estimates of the total MaR. This included a ST segment estimation of the ischemic component of the total MaR (Aldrich score) and an estimation of the infarcted component of the total MaR in the acute phase of AMI by QRS abnormalities (Selvester score). These scores were added for the combined ECG score. RESULTS: The ischemic component of the total MaR estimated by the Aldrich score alone no statistically significant correlation with SPECT (r=0.17, p=0.36). The infarcted component of the total MaR estimated by the Selvester score showed a significant correlation with SPECT (r=0.55, p=0.001). When the Aldrich and Selvester scores were combined, the correlation with SPECT improved (r=0.58, p<0.001). Both the Aldrich and Selvester score alone underestimated the mean MaR measured by SPECT (respectively p=0.007 and p<0.0001). There was no statistically significant difference between the mean MaR estimated by the sum of Aldrich and Selvester and the MaR measured by SPECT (p=0.636). CONCLUSION: The estimation of the total MaR was more accurate by taking both ST deviation and QRS abnormalities in account than by using either method alone. A new ECG method to determine the total MaR during acute coronary occlusion should consider both its ischemic and infarcted components.

Zotarolimus-eluting vs. sirolimus-eluting coronary stents in patients with and without acute coronary syndromes: a SORT OUT III substudy.

OBJECTIVES: To compare clinical outcomes among patients with acute coronary syndrome treated with zotarolimus-eluting and sirolimus-eluting stents in the SORT OUT III trial. BACKGROUND: Currently, only limited data allow direct comparison of clinical outcomes among patients with acute coronary syndrome treated with a second-generation drug-eluting stent (DES) eluting zotarolimus vs. a first-generation DES eluting sirolimus. METHODS: Patients with acute coronary syndrome (n=1052) were randomized to treatment with zotarolimus-eluting (n=506) or sirolimus-eluting (n=546) stents and followed for 18 months. The primary composite endpoint, major adverse cardiac events (MACE), was defined as a composite of cardiac death, myocardial infarction or target vessel revascularization. RESULTS: Zotarolimus-eluting stent treatment compared to sirolimus-eluting stent treatment was associated with increased rates of MACE (8·7% vs. 5·0%; hazard ratio (HR), 1·78; 95% confidence interval (CI), 1·10-2·88; P=0·02) and TVR (6·8% vs. 3·9%; HR, 1·77; 95% CI, 1·03-3·04; P=0·04), while all-cause death, cardiac death, myocardial infarction and definite stent thrombosis did not differ significantly. In the same trial, stable angina pectoris patients (n=1206) were randomized to zotarolimus-eluting (n=614) and sirolimus-eluting (n=592) stents with similar results. CONCLUSIONS: With and without acute coronary syndromes, patients treated with the sirolimus-eluting stent had better clinical outcomes than those treated with the zotarolimus-eluting stent.

Use of clopidogrel and calcium channel blockers and risk of major adverse cardiovascular events.

BACKGROUND: The CYP3A4 inhibition by calcium channel blockers (CCBs) may attenuate the effectiveness of clopidogrel. Using time-varying drug exposure ascertainment, we examined whether CCB use modified the association between clopidogrel use and major adverse cardiovascular events (MACE) after coronary stent implantation. DESIGN: We conducted this population-based cohort study in western Denmark (population 3 million) using medical databases. We identified all 13,001 patients with coronary stent implantation between 2002 and 2005 and their comorbidities. During 12-month follow-up, we tracked the use of clopidogrel and CCBs and the rate of MACE (composite of myocardial infarction, ischaemic stroke, stent thrombosis, target lesion revascularization, or cardiac death). We used Cox regression to compute hazard ratios, controlling for potential confounders. RESULTS: Overall, the 12-month risk for MACE was 14·5%. The rate was 130 per 1000 person years for concomitant clopidogrel and CCB use, 106 for clopidogrel without CCB use, 213 for CCB without clopidogrel use, and 248 for no use of either drug. The adjusted hazard ratio for MACE comparing clopidogrel use with nonuse was 0·52 [95% confidence interval (CI): 0·42-0·64] for CCB users and 0·48 (95% CI: 0·42-0·54) for nonusers, yielding an interaction effect, i.e. relative rate increase, of 1·09 (95% CI: 0·86-1·38). The adjusted hazard ratio for MACE comparing CCB use with nonuse was 1·06 (95% CI: 0·89-1·25) among clopidogrel users. CONCLUSIONS: Concomitant use of CCBs as a class did not modify the protective effect of clopidogrel and was not associated with increased cardiovascular risk among patients using clopidogrel after coronary stent implantation.

Concomitant use of clopidogrel and statins and risk of major adverse cardiovascular events following coronary stent implantation.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • The CYP3A4 inhibition by lipophilic statins may attenuate the effectiveness of clopidogrel. • No studies have measured drug exposure in a time-varying manner that detects discontinuation and restart of clopidogrel and statin therapy, allowing clinical quantification of the interaction effect. WHAT THIS STUDY ADDS: • Clopidogrel and CYP3A4-metabolizing statin use were each associated with a substantially reduced rate of major adverse cardiovascular events within 12 months after coronary stent implantation. • Although we observed an interaction between use of clopidogrel and statins, statin use vs. non-use was not associated with an increased rate of major adverse cardiovascular events in patients using clopidogrel after coronary stent implantation. AIMS: To examine whether CYP3A4-metabolizing statin use modified the association between clopidogrel use and major adverse cardiovascular events (MACE) after coronary stent implantation, using time-varying drug exposure ascertainment. METHODS: We conducted this population-based cohort study in Western Denmark (population: 3 million) using medical databases. We identified all 13 001 patients with coronary stent implantation between 2002 and 2005 and their comorbidities. During 12 months of follow-up, we tracked the use of clopidogrel and CYP3A4-metabolizing statins and the rate of MACE. We used Cox regression to compute hazard ratios (HRs) controlling for potential confounders. RESULTS: The rate of MACE per 1000 person years was 104 for concomitant clopidogrel and statin use, 130 for clopidogrel without statin use, 108 for statin without clopidogrel use and 446 for no use of either drug. The adjusted HR comparing clopidogrel use with non-use was 0.68 (95% confidence interval (CI) 0.58, 0.79) among statin users and 0.34 (95% CI 0.29, 0.40) among statin non-users, yielding an interaction effect (i.e. relative rate increase) of 1.97 (95% CI 1.59, 2.44). The adjusted HR for MACE comparing statin use with non-use was 0.97 (95% CI 0.83, 1.13) among clopidogrel users and 0.49 (95% CI 0.42, 0.57) among clopidogrel non-users. CONCLUSIONS: Clopidogrel and CYP3A4-metabolizing statin use were each associated with a substantially reduced rate of MACE within 12 months after coronary stent implantation. Although we observed an interaction between use of clopidogrel and statins, statin use vs. non-use was not associated with an increased rate of MACE in patients using clopidogrel after coronary stent implantation.

Clinical outcomes after treatment of multiple lesions with zotarolimus-eluting versus sirolimus-eluting coronary stents (a SORT OUT III substudy).

BACKGROUND: Data on clinical outcomes among patients treated with the zotarolimus-eluting Endeavor™ stent versus the sirolimus-eluting Cypher™ stent favor the sirolimus-eluting stent. However, a separate comparison of clinical outcome among patients treated for multiple lesions with these stents is lacking. We performed this comparison within the SORT OUT III trial data set. METHODS: Among 2332 patients randomized in SORT OUT III, 695 were treated for multiple lesions with zotarolimus-eluting (n = 350) or sirolimus-eluting (n = 345) stents and followed for 18 months. Major adverse cardiac events (MACE); composite of cardiac death, myocardial infarction, or target vessel revascularization (TVR); was the primary endpoint. RESULTS: Zotarolimus-eluting compared to sirolimus-eluting stent treatment was associated with increased MACE rate (13.2% vs. 2.6%; hazard ratio 5.29 with 95% confidence interval: 2.59-10.8). All secondary endpoints; all cause death, cardiac death, myocardial infarction, TVR, target lesion revascularization, in-stent restenosis, and definite stent thrombosis; were observed more frequently among zotarolimus-eluting stent treated patients. For all endpoints, hazard ratios were 1.6 to 4.6 times higher than in the overall results of the SORT OUT III trial. CONCLUSIONS: We observed better clinical outcomes among patients treated for multiple lesions with the sirolimus-eluting stent compared to those treated with the zotarolimus-eluting stent.

Comparison of zotarolimus-eluting and sirolimus-eluting coronary stents: a study from the Western Denmark Heart Registry.

BACKGROUND: We evaluated the effectiveness and safety of a zotarolimus-eluting (ZES) versus a sirolimus-eluting (SES) coronary stent in a large cohort of patients treated with one of these stents in Western Denmark. METHODS: A total of 6,122 patients treated with ZES (n=2,282) or SES (n=3,840) were followed for up to 27 months. We ascertained clinical outcomes based on national medical databases. RESULTS: Incidence of target lesion revascularization (no. per 100 person-years) was 5.3 in the ZES group compared to 1.9 in the SES group (adjusted hazard ratio (HR)=2.19, 95% confidence intervals (CI): 1.39-3.47; p=0.001). All-cause mortality was also higher in the ZES group (ZES: 6.3; SES: 3.3; adjusted HR=1.34, 95% CI: 1.05-1.72; p=0.02), while stent thrombosis (ZES: 1.2; SES: 0.5; adjusted HR=1.98, 95% CI: 0.75-5.23; p=0.14) did not differ significantly. CONCLUSIONS: In agreement with previously published randomised data, this observational study indicated that the ZES was associated with an increased risk of death and TLR in a large cohort of consecutive patients.

Efficacy and safety of zotarolimus-eluting and sirolimus-eluting coronary stents in routine clinical care (SORT OUT III): a randomised controlled superiority trial.

BACKGROUND: In low-risk patients, the zotarolimus-eluting stent has been shown to reduce rates of restenosis without increasing the risk of stent thrombosis. We compared the efficacy and safety of the zotarolimus-eluting stent versus the sirolimus-eluting stent in patients with coronary artery disease who were receiving routine clinical care with no direct follow-up. METHODS: We did a single-blind, all-comer superiority trial in adult patients with chronic stable coronary artery disease or acute coronary syndromes, and at least one target lesion. Patients were treated at one of five percutaneous coronary intervention centres between January, 2006, and August, 2007. Computer-generated block randomisation and a telephone allocation service were used to randomly assign patients to receive the zotarolimus-eluting or the sirolimus-eluting stent. Data for follow-up were obtained from national Danish administrative and health-care registries. The primary endpoint was a composite of major adverse cardiac events within 9 months: cardiac death, myocardial infarction, and target vessel revascularisation. Intention-to-treat analyses were done at 9-month and 18-month follow-up. This trial is registered with ClinicalTrials.gov, number NCT00660478. FINDINGS: 1162 patients (1619 lesions) were assigned to receive the zotarolimus-eluting stent, and 1170 patients (1611 lesions) to receive the sirolimus-eluting stent. 67 patients (72 lesions) had stent failure, and six patients were lost to follow-up. All randomly assigned patients were included in analyses at 9-month follow-up; 2200 patients (94%) had completed 18-month follow-up by the time of our assessment. At 9 months, the primary endpoint had occurred in a higher proportion of patients treated with the zotarolimus-eluting stent than in those treated with the sirolimus-eluting stent (72 [6%] vs 34 [3%]; HR 2.15, 95% CI 1.43-3.23; p=0.0002). At 18-month follow-up, this difference was sustained (113 [10%] vs 53 [5%]; 2.19, 1.58-3.04; p<0.0001). For patients receiving the zotarolimus-eluting stent and those receiving the sirolimus-eluting stent, all cause-mortality was similar at 9-month follow-up (25 [2%] vs 18 [2%]; 1.40, 0.76-2.56; p=0.28), but was significantly different at 18-month follow-up (51 [4%] vs 32 [3%]; 1.61, 1.03-2.50; p=0.035). INTERPRETATION: The sirolimus-eluting stent is superior to the zotarolimus-eluting stent for patients receiving routine clinical care. FUNDING: Cordis and Medtronic.

Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial.

BACKGROUND: Remote ischaemic preconditioning attenuates cardiac injury at elective surgery and angioplasty. We tested the hypothesis that remote ischaemic conditioning during evolving ST-elevation myocardial infarction, and done before primary percutaneous coronary intervention, increases myocardial salvage. METHODS: 333 consecutive adult patients with a suspected first acute myocardial infarction were randomly assigned in a 1:1 ratio by computerised block randomisation to receive primary percutaneous coronary intervention with (n=166 patients) versus without (n=167) remote conditioning (intermittent arm ischaemia through four cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff). Allocation was concealed with opaque sealed envelopes. Patients received remote conditioning during transport to hospital, and primary percutaneous coronary intervention in hospital. The primary endpoint was myocardial salvage index at 30 days after primary percutaneous coronary intervention, measured by myocardial perfusion imaging as the proportion of the area at risk salvaged by treatment; analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00435266. FINDINGS: 82 patients were excluded on arrival at hospital because they did not meet inclusion criteria, 32 were lost to follow-up, and 77 did not complete the follow-up with data for salvage index. Median salvage index was 0.75 (IQR 0.50-0.93, n=73) in the remote conditioning group versus 0.55 (0.35-0.88, n=69) in the control group, with median difference of 0.10 (95% CI 0.01-0.22; p=0.0333); mean salvage index was 0.69 (SD 0.27) versus 0.57 (0.26), with mean difference of 0.12 (95% CI 0.01-0.21; p=0.0333). Major adverse coronary events were death (n=3 per group), reinfarction (n=1 per group), and heart failure (n=3 per group). INTERPRETATION: Remote ischaemic conditioning before hospital admission increases myocardial salvage, and has a favourable safety profile. Our findings merit a larger trial to establish the effect of remote conditioning on clinical outcomes. FUNDING: Fondation Leducq.

Consideration of QRS complex in addition to ST-segment abnormalities in the estimated "risk region" during acute anterior myocardial infarction.

BACKGROUND: The myocardial area at risk (MaR) has been estimated in patients with acute myocardial infarction (AMI) by using ST segment-based electrocardiographic (ECG) methods. As the process from ischemia to infarction progresses, the ST-segment deviation is typically replaced by QRS abnormalities causing a falsely low estimated total MaR if determined by using ST segment-based methods. The purpose of this study was to investigate if consideration of the abnormalities in the QRS complex, in addition to those in the ST segment, provides a more accurate estimated total MaR during anterior AMI than by considering the ST segment alone. METHODS: Twenty-five patients with acute anterior ST elevation myocardial infarction (STEMI) received technetium Tc 99m-sestamibi before percutaneous coronary intervention. Single photon emission computed tomography (SPECT) was performed within 2 hours after treatment and was used as a criterion standard for the estimated total MaR. The ECG recorded at admission in the hospital was used for the ECG estimated total MaR. This included an ST-segment estimated ischemic component of the total MaR (Aldrich score) and an estimated infarcted component of the total MaR in the acute phase of AMI by QRS abnormalities (Selvester score). These scores were added for the combined ECG score. RESULTS: The ischemic component of the total MaR estimated by the Aldrich score alone had no statistically significant correlation with SPECT (r = 0.21, P = .32). The infarcted component of the total MaR estimated by the Selvester score showed a significant correlation with SPECT (r = 0.49, P = .01). Each score gave a significant underestimated total MaR measured by SPECT (P < .01). When the Aldrich and Selvester scores were combined, the correlation with SPECT was r = 0.47, P = .02. The combined score still underestimated the total MaR by SPECT (P < .01), though the difference was smaller in comparison to either method alone (P < .01). CONCLUSION: The ECG estimated total MaR was more accurate by taking both ST deviation and QRS abnormalities into account than by using either method alone. A new ECG method to determine the total MaR during acute coronary occlusion should consider both its ischemic and infarcted components.