Anton Boel Villadsen

Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3—PRIMULTI): an open-label, randomised controlled trial.

BACKGROUND Patients with acute ST-segment elevation myocardial infarction (STEMI) and multivessel coronary disease have a worse prognosis compared with individuals with single-vessel disease. We aimed to study the clinical outcome of patients with STEMI treated with fractional flow reserve (FFR)-guided complete revascularisation versus treatment of the infarct-related artery only. METHODS We undertook an open-label, randomised controlled trial at two university hospitals in Denmark. Patients presenting with STEMI who had one or more clinically significant coronary stenosis in addition to the lesion in the infarct-related artery were included. After successful percutaneous coronary intervention (PCI) of the infarct-related artery, patients were randomly allocated (in a 1:1 ratio) either no further invasive treatment or complete FFR-guided revascularisation before discharge. Randomisation was done electronically via a web-based system in permuted blocks of varying size by the clinician who did the primary PCI. All patients received best medical treatment. The primary endpoint was a composite of all-cause mortality, non-fatal reinfarction, and ischaemia-driven revascularization of lesions in non-infarct-related arteries and was assessed when the last enrolled patient had been followed up for 1 year. Analysis was on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01960933. FINDINGS From March, 2011, to February, 2014, we enrolled 627 patients to the trial; 313 were allocated no further invasive treatment after primary PCI of the infarct-related artery only and 314 were assigned complete revascularization guided by FFR values. Median follow-up was 27 months (range 12–44 months). Events comprising the primary endpoint were recorded in 68 (22%) patients who had PCI of the infarct-related artery only and in 40 (13%) patients who had complete revascularisation (hazard ratio 0∙56, 95% CI 0∙38–0∙83; p=0∙004). INTERPRETATION In patients with STEMI and multivessel disease, complete revascularisation guided by FFR measurements significantly reduces the risk of future events compared with no further invasive intervention after primary PCI. This effect is driven by significantly fewer repeat revascularisations, because all-cause mortality and non-fatal reinfarction did not differ between groups. Thus, to avoid repeat revascularisation, patients can safely have all their lesions treated during the index admission. Future studies should clarify whether complete revascularization should be done acutely during the index procedure or at later time and whether it has an effect on hard endpoints. FUNDING Danish Agency for Science, Technology and Innovation and Danish Council for Strategic Research.

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).

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 S candinavian O rganization for R andomized T rials with Clinical O utcome IV trial was a randomized multicenter, single-blind, all-comer, two-arm, non-inferiority 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 non-inferiority criterion was a risk difference of 0.015. Intention-to-treat analyses were done at 9-month and 18-month follow-up. 1,390 patients were assigned to receive the everolimus-eluting stent, and 1,384 patients were assigned to receive the sirolimus-eluting stent. At 9-month follow-up, 68 \[4.9%] patients treated with the everolimus-eluting stent versus 72 [5.2%] patients treated with the sirolimus-eluting stent experienced the primary end point (hazard ratio (HR) =0.94; 95% confidence interval (CI): 0.67-1.31) ( p for non-inferiority=0.01). At 18-month follow-up, this differential remained: 99 [7.2%] patients treated with the everolimus-eluting stent versus 105 [7.6%\] (HR=0.94, 95% CI: 0.71-1.23). At 9-month follow-up, rate of definite stent thrombosis was higher in the sirolimus-eluting group (2 [0.1%] patients versus 9 [0.7%] patients, (HR=0.22, 95% CI:0.05-1.02)).At 18-monthfollow-up, this difference was sustained (3 [0.2%] patients versus 12 [0.9%] patients; (HR=0.25, 95% CI:0.07-0.88). Conclusions —The everolimus-eluting stent was found to be non-inferior to the sirolimus-eluting stent. Clinical Trial Registration Information —ClinicalTrials.gov; [NCT00552877][1] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00552877&atom=%2Fcirculationaha%2Fearly%2F2012%2F02%2F03%2FCIRCULATIONAHA.111.063644.atomBackground— 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.

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.

System Delay and Timing of Intervention in Acute Myocardial Infarction (from the Danish Acute Myocardial Infarction-2 [DANAMI-2] Trial)

The interval from the first alert of the healthcare system to the initiation of reperfusion therapy (system delay) is associated with mortality in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention (pPCI). The importance of system delay in patients treated with fibrinolysis versus pPCI has not been assessed. We obtained data on system delay from the Danish Acute Myocardial Infarction-2 study, which randomized 1,572 patients to fibrinolysis or pPCI. The study end points were 30-day and 8-year mortality. The short system delays were associated with reduced absolute mortality in both the fibrinolysis group (<1 hour, 5.6%; 1 to 2 hours, 6.9%; 2 to 3 hours, 9.5%; and >3 hours, 11.5%; test for trend, p = 0.08) and pPCI group (<1 hour, not assessed; 1 to 2 hours, 2.6%; 2 to 3 hours, 7.5%; >3 hours, 7.7%; test for trend, p = 0.02). The lowest 30-day mortality was obtained with pPCI and a system delay of 1 to 2 hours (vs fibrinolysis within <1 hour, adjusted hazard ratio 0.33; 95% confidence interval 0.10 to 1.10; p = 0.07; vs fibrinolysis within 1 to 2 hours, adjusted hazard ratio 0.37; 95% confidence interval 0.14 to 0.95; p = 0.04). pPCI and system delay >3 hours was associated with a similar 30-day and 8-year mortality as fibrinolysis within 1 to 2 hours. In conclusion, short system delays are associated with reduced mortality in patients with ST-segment elevation myocardial infarction treated with fibrinolysis as well as pPCI. pPCI performed with a system delay of <2 hours is associated with lower mortality than fibrinolysis performed with a faster or similar system delay.

3-Year clinical outcomes in the randomized SORT OUT III superiority trial comparing zotarolimus- and sirolimus-eluting coronary stents.

OBJECTIVES This study sought to examine the 3-year clinical outcomes in patients treated with the Endeavor (Medtronic, Santa Rosa, California) zotarolimus-eluting stent (ZES) or the Cypher (Cordis, Johnson & Johnson, Warren, New Jersey) sirolimus-eluting stent (SES) in routine clinical practice. BACKGROUND The long-term clinical outcome in patients treated with ZES in comparison with SES is unclear. METHODS The authors randomized 2,332 patients to ZES (n = 1,162) or SES (n = 1,170) implantation. Endpoints included major adverse cardiac events (MACE), a composite of cardiac death, myocardial infarction, or target vessel revascularization; the individual endpoints of MACE; and definite stent thrombosis. RESULTS At 3-year follow-up, the MACE rate was higher in patients treated with ZES than in patients treated with SES (148 [12.9%] vs. 116 [10.1%]; hazard ratio [HR]: 1.33, 95% confidence interval [CI]: 1.04 to 1.69; p = 0.022). Target vessel revascularization was more frequent in the ZES group compared with the SES group (103 [9.1%] vs. 76 [6.7%]; HR: 1.40, 95% CI: 1.04 to 1.89; p = 0.025), whereas the occurrence of myocardial infarction (3.8% vs. 3.3%) and cardiac death (2.8% vs. 2.8%) did not differ significantly. Although the rate of definite stent thrombosis was similar at 3-year follow-up (1.1% vs. 1.4%), very late (12 to 36 months) definite stent thrombosis occurred in 0 (0%) patients in the ZES group versus 12 (1.1%) patients in the SES group (p = 0.0005). CONCLUSIONS Although the 3-year MACE rate is higher in patients treated with ZES versus SES, our data highlight a late safety problem concerning definite stent thrombosis with the use of SES. This finding underscores the importance of long-term follow-up in head-to-head comparisons of drug-eluting stents. (Randomized Clinical Comparison of the Endeavor and the Cypher Coronary Stents in Non-selected Angina Pectoris Patients [SORT OUT III]; NCT00660478).

Outcome of sirolimus-eluting versus zotarolimus-eluting coronary stent implantation in patients with and without diabetes mellitus (a SORT OUT III Substudy).

Diabetes is associated with an increased risk of major adverse cardiac events after percutaneous coronary intervention. We compared clinical outcomes in patients with and without diabetes mellitus treated with the second-generation Endeavor zotarolimus-eluting stent (ZES) or the first-generation Cypher Select+ sirolimus-eluting stent (SES). We randomized 2,332 patients to treatment with ZESs (n = 1,162, n = 169 diabetics) or SESs (n = 1,170, n = 168 diabetics) and followed them for 18 months. Randomization was stratified by presence/absence of diabetes. The primary end point was major adverse cardiac events defined as a composite of cardiac death, myocardial infarction, or target vessel revascularization. Secondary end points included these individual end points plus all-cause mortality and target lesion revascularization. In diabetic patients, use of ZES compared to SES was associated with an increased risk of major adverse cardiac events (18.3% vs 4.8%, hazard ratio 4.05, 95% confidence interval 1.86 to 8.82), myocardial infarction (4.7% vs 0.6%, hazard ratio 8.09, 95% confidence interval 1.01 to 64.7), target vessel revascularization (14.2% vs 3.0%, hazard ratio 4.99, 95% confidence interval 1.90 to 13.1), and target lesion revascularization (12.4% vs 1.2%, hazard ratio 11.0, 95% confidence interval 2.59 to 47.1). In patients without diabetes differences in absolute risk decrease were smaller but similarly favored SES. In conclusion, implantation of ZESs compared to SESs is associated with a considerable increased risk of adverse events in patients with diabetes at 18-month follow-up.

Randomized Comparison of a Biodegradable Polymer Ultrathin Strut Sirolimus-Eluting Stent With a Biodegradable Polymer Biolimus-Eluting Stent in Patients Treated With Percutaneous Coronary Intervention The SORT OUT VII Trial

Background—Coronary drug-eluting stents with biodegradable polymers have been designed to improve safety and efficacy. Methods and Results—The Scandinavian Organization for Randomized Trials With Clinical Outcome (SORT OUT) VII trial—a large-scale registry-based randomized, multicenter, single-blind, 2-arm, noninferiority trial—compared 2 biodegradable polymer drug-eluting stents: the thin-strut cobalt–chromium sirolimus-eluting Orsiro stent and the stainless steel biolimus-eluting Nobori stent in an all-comer patient population. The primary end point target lesion failure was a composite of cardiac death, myocardial infarction (not related to other than index lesion), or target lesion revascularization within 1 year, analyzed by intention to treat (noninferiority margin of 3.0%). Clinically driven event detection based on Danish registries was used. A total of 1261 patients were assigned to receive the sirolimus-eluting stent (1590 lesions) and 1264 patients to the biolimus-eluting stent (1588 lesions). At 1 year, the composite end point target lesion failure occurred in 48 patients (3.8%) in the sirolimus-eluting group and in 58 patients (4.6%) in the biolimus-eluting group (absolute risk difference, −0.78% [upper limit of 1-sided 95% confidence interval, 0.61%]; P<0.0001). Rates of definite stent thrombosis occurred in 5 (0.4%) of the sirolimus-eluting group compared with 15 (1.2%) biolimus-eluting stent–treated patients (rate ratio, 0.33; 95% confidence interval, 0.12–0.92; P=0.034), which largely was attributable to a lower risk of subacute definite stent thrombosis: 0.1% versus 0.6% (rate ratio, 0.12; 95% confidence interval, 0.02–1.00; P=0.05). Conclusions—The thin-strut sirolimus-eluting Orsiro stent was noninferior to the biolimus-eluting Nobori stent in unselected patients for target lesion failure at 1 year. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01879358.

Late lumen loss and intima hyperplasia after sirolimus-eluting and zotarolimus-eluting stent implantation in diabetic patients: the diabetes and drug-eluting stent (DiabeDES III) angiography and intravascular ultrasound trial

AIMS Patients with diabetes mellitus have increased risk of in-stent restenosis after coronary stent implantation due to neointimal hyperplasia (NIH). The aim of this study was to use quantitative coronary angiography (QCA) and volumetric intravascular ultrasound (IVUS) to evaluate the effects of the sirolimus-eluting Cypher® stent (SES) and the zotarolimus-eluting Endeavor® stent (ZES) on angiographic late lumen loss and intima hyperplasia in diabetic patients. METHODS AND RESULTS In the DiabeDES III trial, 127 patients were randomised to SES or ZES stent implantation. Angiographic 10-month follow-up data were available in 105 patients, including 48 SES and 57 ZES treated patients. Angiographic endpoints were in-stent late lumen loss and minimal lumen diameter. IVUS endpoints included NIH volume and in-stent percent volume obstruction. Baseline clinical characteristics and lesion parameters were similar in the two groups. At 10-month follow-up, angiographic in-stent late lumen loss (0.14±0.37 mm vs. 0.74±0.45 mm, p<0.001) was reduced and minimum lumen diameter was higher (2.36±0.53 mm vs. 1.96±0.65, p<0.001) in the SES group as compared to the ZES group. As compared to the ZES group, NIH volume was significantly reduced in the SES group (median [interquartile range]: 0.0 mm3 [0.0 to 1.2] vs. 16.5 mm3 [6.2 to 31.1], p<0.001). In-stent% volume obstruction was significantly reduced in SES as compared to ZES (median [interquartile range]: 0.0% [0.0-0.7] vs. 13.0% [6.7-20.8], p<0.001). CONCLUSIONS In diabetic patients, the SES reduced angiographic late lumen loss and inhibited NIH more effectively than ZES.

Outcome in high risk patients with unprotected left main coronary artery stenosis treated with percutaneous coronary intervention

Objective: We examined mortality, risk of myocardial infarction (MI), and target lesion revascularization (TLR) in high‐risk patients with unprotected left main (LM) percutaneous coronary intervention (PCI) in Western Denmark. Background: PCI of left main coronary artery lesions may be an alternative to coronary artery bypass grafting in high‐risk surgical patients. Methods: From January 2005 to May 2007, all patients who had unprotected LM PCI with stent implantation were identified in the Western Denmark Heart Registry. The indications for PCI were: (1) ST segment elevation MI (STEMI), (2) non‐STEMI (NSTEMI) or unstable angina, and (3) stable angina. All patients were followed up for 18 months. Results: A total of 344 patients were treated with LM PCI (STEMI: 71, NSTEMI/unstable angina: 157, and stable angina: 116). In STEMI patients, the median logistic EuroSCORE was 22.5 (interquartile range 12.5–39.5), in non‐STEMI (NSTEMI)/unstable angina patients 13.8 (4.8–23.9), and in stable angina patients 4.8 (2.2–10.4). Mortality after 18 months 38.0, 18.5, and 11.2% (P < 0.001) in patients with STEMI, NSTEMI/unstable angina, and stable angina, respectively. MI after 18 months was 9.9, 6.4, and 6.0% (P = ns), respectively. Four subacute and one late definite stent thrombosis were seen. TLR occurred in 5.6, 4.5, and 6.9% (P = ns) of patients, respectively. Conclusion: After PCI, patients with STEMI and LM culprit lesion have a high‐mortality risk, whereas long‐term outcome for patients with NSTEMI and stable angina pectoris is comparable with other high surgical risk patients with unprotected left main lesion. Further, TLR rates and risk of stent thrombosis were low.