Pawel Buszman

Guidelines on the management of stable angina pectoris: executive summary

We thank the authors for raising the interesting discussion regarding the treatment of hypertension in patients with concomitant coronary disease. The J-shaped association between on-treatment blood pressure and risk has been described in longitudinal cohorts of patients with treated hypertension as well as in clinical trial populations, both in on-treatment and control arms. However, it is not absolutely clear that the association is treatmentrelated; in fact, one meta-analysis of seven randomized controlled trials including data on more than 40 000 patients has shown that the J-shaped relationship between blood pressure and mortality was not related to antihypertensive treatment. In this meta-analysis, noncardiovascular death was inversely related to blood pressure (both systolic and diastolic) in contrast to the J-shaped relationships for cardiovascular and total mortality, leading the authors to hypothesize that poor health conditions leading to low blood pressure and an increased risk of death might in part explain the J-shaped curve. Secondly, as discussed in the full-text version of the guidelines, there is accumulating evidence that blood pressure lowering in the ‘normal’ range is associated with improved cardiovascular outcomes in the population with known coronary disease. In the CAMELOT study, patients with coronary disease and mean blood pressure of 129/78 were randomized to enalapril, amlodipine, or placebo. Blood pressure reductions were similar (5/2 mm) in both treatment groups and associated with similar relative reductions in the composite endpoint of cardiovascular death, MI, and stroke, although not statistically significant in either group because of the small sample size. An intravascular ultrasound substudy demonstrated a significant inverse correlation between progression of atherosclerosis and blood pressure reduction even in this normal blood pressure range, with the greatest benefit observed in patients whose blood pressure fell below 120/80. Thus, the task force has felt it important, in the absence of unequivocal evidence to the contrary, to preserve consistency between guidelines on prevention and angina with regard to targets for institution of therapy for hypertension in the presence of coronary disease. No lower limit has yet been identified as a definite cutoff beyond which blood pressure should not be lowered further, although, clearly, symptomatic hypotension or postural hypotension will limit aggressive blood pressure lowering in the lower range.

Biolimus-eluting stent with biodegradable polymer versus sirolimus-eluting stent with durable polymer for coronary revascularisation (LEADERS): a randomised non-inferiority trial

BACKGROUND A novel stent platform eluting biolimus, a sirolimus analogue, from a biodegradable polymer showed promising results in preliminary studies. We compared the safety and efficacy of a biolimus-eluting stent (with biodegradable polymer) with a sirolimus-eluting stent (with durable polymer). METHODS We undertook a multicentre, assessor-blind, non-inferiority study in ten European centres. 1707 patients aged 18 years or older with chronic stable coronary artery disease or acute coronary syndromes were centrally randomised by a computer-generated allocation sequence to treatment with either biolimus-eluting (n=857) or sirolimus-eluting (n=850) stents. The primary endpoint was a composite of cardiac death, myocardial infarction, or clinically-indicated target vessel revascularisation within 9 months. Analysis was by intention to treat. 427 patients were randomly allocated to angiographic follow-up, with in-stent percentage diameter stenosis as principal outcome measure at 9 months. The trial is registered with ClinicalTrials.gov, number NCT00389220. FINDINGS We analysed all randomised patients. Biolimus-eluting stents were non-inferior to sirolimus-eluting stents for the primary endpoint at 9 months (79 [9%] patients vs 89 [11%], rate ratio 0.88 [95% CI 0.64-1.19], p for non-inferiority=0.003, p for superiority=0.39). Frequency of cardiac death (14 [1.6%] vs 21 [2.5%], p for superiority=0.22), myocardial infarction (49 [5.7%] vs 39 [4.6%], p=0.30), and clinically-indicated target vessel revascularisation (38 [4.4%] vs 47 [5.5%], p=0.29) were similar for both stent types. 168 (79%) patients in the biolimus-eluting group and 167 (78%) in the sirolimus-eluting group had data for angiographic follow-up available. Biolimus-eluting stents were non-inferior to sirolimus-eluting stents in in-stent percentage diameter stenosis (20.9%vs 23.3%, difference -2.2% [95% CI -6.0 to 1.6], p for non-inferiority=0.001, p for superiority=0.26). INTERPRETATION Our results suggest that a stent eluting biolimus from a biodegradable polymer represents a safe and effective alternative to a stent eluting sirolimus from a durable polymer in patients with chronic stable coronary artery disease or acute coronary syndromes. FUNDING Biosensors Europe SA, Switzerland.

Comparison of zotarolimus-eluting and everolimus-eluting coronary stents.

BACKGROUND New-generation coronary stents that release zotarolimus or everolimus have been shown to reduce the risk of restenosis. However, it is unclear whether there are differences in efficacy and safety between the two types of stents on the basis of prospectively adjudicated end points endorsed by the Food and Drug Administration. METHODS In this multicenter, noninferiority trial with minimal exclusion criteria, we randomly assigned 2292 patients to undergo treatment with coronary stents releasing either zotarolimus or everolimus. Twenty percent of patients were randomly selected for repeat angiography at 13 months. The primary end point was target-lesion failure, defined as a composite of death from cardiac causes, any myocardial infarction (not clearly attributable to a nontarget vessel), or clinically indicated target-lesion revascularization within 12 months. The secondary angiographic end point was the extent of in-stent stenosis at 13 months. RESULTS At least one off-label criterion for stent placement was present in 66% of patients. The zotarolimus-eluting stent was noninferior to the everolimus-eluting stent with respect to the primary end point, which occurred in 8.2% and 8.3% of patients, respectively (P<0.001 for noninferiority). There were no significant between-group differences in the rate of death from cardiac causes, any myocardial infarction, or revascularization. The rate of stent thrombosis was 2.3% in the zotarolimus-stent group and 1.5% in the everolimus-stent group (P=0.17). The zotarolimus-eluting stent was also noninferior regarding the degree (+/-SD) of in-stent stenosis (21.65+/-14.42% for zotarolimus vs. 19.76+/-14.64% for everolimus, P=0.04 for noninferiority). In-stent late lumen loss was 0.27+/-0.43 mm in the zotarolimus-stent group versus 0.19+/-0.40 mm in the everolimus-stent group (P=0.08). There were no significant between-group differences in the rate of adverse events. CONCLUSIONS At 13 months, the new-generation zotarolimus-eluting stent was found to be noninferior to the everolimus-eluting stent in a population of patients who had minimal exclusion criteria. (ClinicalTrials.gov number, NCT00617084.)

Intracoronary infusion of bone marrow-derived selected CD34+CXCR4+ cells and non-selected mononuclear cells in patients with acute STEMI and reduced left ventricular ejection fraction: results of randomized, multicentre Myocardial Regeneration by Intracoronary Infusion of Selected Population of Stem Cells in Acute Myocardial Infarction (REGENT) Trial

AIMS Comparison of intracoronary infusion of bone marrow (BM)-derived unselected mononuclear cells (UNSEL) and selected CD34(+)CXCR4(+) cells (SEL) in patients with acute myocardial infarction (AMI) and reduced <40% left ventricular ejection fraction (LVEF). METHODS AND RESULTS Two hundred patients were randomized to intracoronary infusion of UNSEL (n = 80) or SEL (n = 80) BM cells or to the control (CTRL) group without BM cell treatment. Primary endpoint: change of LVEF and volumes measured by magnetic resonance imaging before and 6 months after the procedure. After 6 months, LVEF increased by 3% (P = 0.01) in patients treated with UNSEL, 3% in patients receiving SEL (P = 0.04) and remained unchanged in CTRL group (P = 0.73). There were no significant differences in absolute changes of LVEF between the groups. Absolute changes of left ventricular end-systolic volume and left ventricular end-diastolic volume were not significantly different in all groups. Significant increase of LVEF was observed only in patients treated with BM cells who had baseline LVEF < median (37%). Baseline LVEF < median and time from the onset of symptoms to primary percutaneous coronary intervention > or = median were predictors of LVEF improvement in patients receiving BM cells. There were no differences in major cardiovascular event (death, re-infarction, stroke, target vessel revascularization) between groups. CONCLUSION In patients with AMI and impaired LVEF, treatment with BM cells does not lead to a significant improvement of LVEF or volumes. There was however a trend in favour of cell therapy in patients with most severely impaired LVEF and longer delay between the symptoms and revascularization.

Acute and Late Outcomes of Unprotected Left Main Stenting in Comparison With Surgical Revascularization

OBJECTIVES The purpose of this study was to compare the early and late results of percutaneous and surgical revascularization of left main coronary artery stenosis. BACKGROUND Unprotected left main coronary artery (ULMCA) stenting is being investigated as an alternative to bypass surgery. METHODS We randomly assigned 105 patients with ULMCA stenosis to percutaneous coronary intervention (PCI; 52 patients) or coronary artery bypass grafting (CABG; 53 patients). The primary end point was the change in left ventricular ejection fraction (LVEF) 12 months after the intervention. Secondary end points included 30-day major adverse events (MAE), major adverse cardiac and cerebrovascular events (MACCE), length of hospitalization, target vessel failure (TVF), angina severity and exercise tolerance after 1 year, and total and MACCE-free survival. RESULTS A significant increase in LVEF at the 12-month follow-up was noted only in the PCI group (3.3 +/- 6.7% after PCI vs. 0.5 +/- 0.8% after CABG; p = 0.047). Patients performed equally well on stress tests, and angina status improved similarly in the 2 groups. PCI was associated with a lower 30-day risk of MAE (p < 0.006) and MACCE (p = 0.03) and shorter hospitalizations (p = 0.0007). Total and MACCE-free 1-year survival was comparable. Left main TVF was similar in the 2 groups. During the 28.0 +/- 9.9-month follow-up, there were 3 deaths in the PCI group and 7 deaths in the CABG group (p = 0.08). CONCLUSIONS Patients with ULMCA disease treated with PCI had favorable early outcomes in comparison with the CABG group. At 1 year, LVEF had improved significantly only in the PCI group. After more than 2 years, MACCE-free survival was similar in both groups with a trend toward improved survival after PCI.

Long-term clinical outcomes of biodegradable polymer biolimus-eluting stents versus durable polymer sirolimus-eluting stents in patients with coronary artery disease (LEADERS): 4 year follow-up of a randomised non-inferiority trial.

BACKGROUND The effectiveness of durable polymer drug-eluting stents comes at the expense of delayed arterial healing and subsequent late adverse events such as stent thrombosis (ST). We report the 4 year follow-up of an assessment of biodegradable polymer-based drug-eluting stents, which aim to improve safety by avoiding the persistent inflammatory stimulus of durable polymers. METHODS We did a multicentre, assessor-masked, non-inferiority trial. Between Nov 27, 2006, and May 18, 2007, patients aged 18 years or older with coronary artery disease were randomly allocated with a computer-generated sequence to receive either biodegradable polymer biolimus-eluting stents (BES) or durable polymer sirolimus-eluting stents (SES; 1:1 ratio). The primary endpoint was a composite of cardiac death, myocardial infarction, or clinically-indicated target vessel revascularisation (TVR); patients were followed-up for 4 years. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00389220. FINDINGS 1707 patients with 2472 lesions were randomly allocated to receive either biodegradable polymer BES (857 patients, 1257 lesions) or durable polymer SES (850 patients, 1215 lesions). At 4 years, biodegradable polymer BES were non-inferior to durable polymer SES for the primary endpoint: 160 (18·7%) patients versus 192 (22·6%) patients (rate ratios [RR] 0·81, 95% CI 0·66-1·00, p for non-inferiority <0·0001, p for superiority=0·050). The RR of definite ST was 0·62 (0·35-1·08, p=0·09), which was largely attributable to a lower risk of very late definite ST between years 1 and 4 in the BES group than in the SES group (RR 0·20, 95% CI 0·06-0·67, p=0·004). Conversely, the RR of definite ST during the first year was 0·99 (0·51-1·95; p=0·98) and the test for interaction between RR of definite ST and time was positive (p(interaction)=0·017). We recorded an interaction with time for events associated with ST but not for other events. For primary endpoint events associated with ST, the RR was 0·86 (0·41-1·80) during the first year and 0·17 (0·04-0·78) during subsequent years (p(interaction)=0·049). INTERPRETATION Biodegradable polymer BES are non-inferior to durable polymer SES and, by reducing the risk of cardiac events associated with very late ST, might improve long-term clinical outcomes for up to 4 years compared with durable polymer SES. FUNDING Biosensors Europe SA, Switzerland.

Mobilization of bone marrow-derived Oct-4+ SSEA-4+ very small embryonic-like stem cells in patients with acute myocardial infarction.

OBJECTIVES This study sought to assess of the mobilization of nonhematopoietic very small embryonic-like stem cells (VSELs) in acute myocardial infarction (MI). BACKGROUND Acute MI induces mobilization of bone marrow stem cells. Recently, a rare population of VSELs, expressing markers of embryonic pluripotent stem cells (PSCs), was identified in adult murine bone marrow and human umbilical cord blood. METHODS Thirty-one patients with acute MI and 30 healthy subjects were enrolled. Blood was sampled on admission, after 24 h, and 5 days later. Erythrocytes were lysed and lin(-)CD45(-) VSELs were isolated using a live cell sorting system (FACSAria, Beckton Dickinson, San Jose, California). RESULTS In healthy subjects the median number of circulating VSELs was very low (median 0.8 [range 0 to 1.3]) cells/microl. In acute MI, VSELs were mobilized early (median 2.7 [range 0.2 to 3.9] cells/microl; p < 0.001) and remained elevated after 24 h and 5 days (median 4.7 [range 0.2 to 6.4] cells/microl; p < 0.003, and median 2.6 [range 0.3 to 3.6] cells/microl; p < 0.03, respectively). The mobilization of VSEL was significantly reduced in patients older than 50 years and with diabetes in comparison with younger and nondiabetic patients. Circulating VSELs were small (7 to 8 microm) and enriched in the messenger ribonucleic acid of PSC markers (Oct-4, Nanog), cardiac lineage (GATA-4, Nkx2.5/Csx, MEF2C), and endothelial (VE-cadherin) markers. The presence of PSC markers (Oct-4, SSEA-4) and the chemokine receptor CXCR4 in circulating VSELs was confirmed at the protein level by immunofluorescent staining and ImageStream system (Amnis Corporation, Seattle, Washington) analysis. CONCLUSIONS Acute MI induced mobilization of VSELs expressing pluripotent markers, early cardiac and endothelial markers, and chemokine receptor CXCR4.

Value of the SYNTAX score for risk assessment in the all-comers population of the randomized multicenter LEADERS (Limus Eluted from A Durable versus ERodable Stent coating) trial

OBJECTIVES We aimed to assess the predictive value of the SYNTAX score (SXscore) for major adverse cardiac events in the all-comers population of the LEADERS (Limus Eluted from A Durable versus ERodable Stent coating) trial. BACKGROUND The SXscore has been shown to be an effective predictor of clinical outcomes in patients with multivessel disease undergoing percutaneous coronary intervention. METHODS The SXscore was prospectively collected in 1,397 of the 1,707 patients enrolled in the LEADERS trial (patients after surgical revascularization were excluded). Post hoc analysis was performed by stratifying clinical outcomes at 1-year follow-up, according to 1 of 3 SXscore tertiles. RESULTS The 1,397 patients were divided into tertiles based on the SXscore in the following fashion: SXscore<or=8 (SXlow) (n=464), SXscore>8 and <or=16 (SXmid) (n=472), and SXscore>16 (SXhigh) (n=461). At 1-year follow-up, there was a significantly lower number of patients with major cardiac event-free survival in the highest tertile of SXscore (SXlow=92.2%, SXmid=91.1%, and SXhigh=84.6%; p<0.001). Death occurred in 1.5% of SXlow patients, 2.1% of SXmid patients, and 5.6% of SXhigh patients (hazard ratio [HR]: 1.97, 95% confidence interval [CI]: 1.29 to 3.01; p=0.002). The myocardial infarction rate tended to be higher in the SXhigh group. Target vessel revascularization was 11.3% in the SXhigh group compared with 6.3% and 7.8% in the SXlow and SXmid groups, respectively (HR: 1.38, 95% CI: 1.1 to 1.75; p=0.006). Composite of cardiac death, myocardial infarction, and clinically indicated target vessel revascularization was 7.8%, 8.9%, and 15.4% in the SXlow, SXmid, and SXhigh groups, respectively (HR: 1.47, 95% CI: 1.19 to 1.81; p<0.001). CONCLUSIONS The SXscore, when applied to an all-comers patient population treated with drug-eluting stents, may allow prospective risk stratification of patients undergoing percutaneous coronary intervention. (LEADERS Trial Limus Eluted From A Durable Versus ERodable Stent Coating; NCT00389220).

Randomized Trial of Percutaneous Coronary Intervention for Subacute Infarct-Related Coronary Artery Occlusion to Achieve Long-Term Patency and Improve Ventricular Function. The Total Occlusion Study of Canada (TOSCA)-2 Trial

Background— In the present study, we sought to determine whether opening a persistently occluded infarct-related artery (IRA) by percutaneous coronary intervention (PCI) in patients beyond the acute phase of myocardial infarction (MI) improves patency and indices of left ventricular (LV) size and function. Methods and Results— Between May 2000 and July 2005, 381 patients with an occluded native IRA 3 to 28 days after MI (median 10 days) were randomized to PCI with stenting (PCI) or optimal medical therapy alone. Repeat coronary and LV angiography was performed 1 year after randomization (n=332, 87%). Coprimary end points were IRA patency and change in LV ejection fraction. Secondary end points included change in LV end-systolic and end-diastolic volume indices and wall motion. PCI was successful in 92%. At 1 year, 83% of PCI versus 25% of medical therapy–only patients had a patent IRA (P<0.001). LV ejection fraction increased significantly (P<0.001) in both groups, with no between-group difference: PCI 4.2±8.9 (n=150) versus medical therapy 3.5±8.2 (n=136; P=0.47). Median change (interquartile range) in LV end-systolic volume index was −0.5 (−9.3 to 5.0) versus 1.0 (−5.7 to 7.3) mL/m2 (P=0.10), whereas median change (interquartile range) in LV end-diastolic volume index was 3.2 (−8.2 to 13.3) versus 5.3 (−4.6 to 23.2) mL/m2 (P=0.07) in the PCI (n=86) and medical therapy–only (n=76) groups, respectively. Conclusions— PCI with stenting of a persistently occluded IRA in the subacute phase after MI effectively maintains long-term patency but has no effect on LV ejection fraction. On the basis of these findings and the lack of clinical benefit in the main Occluded Artery Trial, routine PCI is not recommended for stable patients with a persistently occluded IRA after MI.

Early and Long-Term Results of Unprotected Left Main Coronary Artery Stenting: The LE MANS (Left Main Coronary Artery Stenting) Registry

OBJECTIVES The aim of the study was to evaluate early and late outcomes after percutaneous coronary intervention (PCI) of unprotected left main coronary artery disease (ULMCA) and to compare bare-metal stent (BMS) and drug-eluting stent (DES) subgroups. BACKGROUND PCI is an increasingly utilized method of revascularization in patients with ULMCA. METHODS This multicenter prospective registry included 252 patients after ULMCA stenting enrolled between March 1997 and February 2008. Non-ST-segment elevation acute coronary syndrome was diagnosed in 58% of patients; ST-segment elevation myocardial infarction cases were excluded. Drug-eluting stents were implanted in 36.2% of patients. RESULTS Major adverse cardiovascular and cerebral events (MACCE) occurred in 12 (4.8%) patients during the 30-day period, which included 4 (1.5%) deaths. After 12 months there were 17 (12.1%) angiographically confirmed cases of restenosis. During long-term follow-up (1 to 11 years, mean 3.8 years) there were 64 (25.4%) MACCE and 35 (13.9%) deaths. The 5- and 10-year survival rates were 78.1% and 68.9%, respectively. Despite differences in demographical and clinical data in favor of BMS patients, unmatched analysis showed a significantly lower MACCE rate in DES patients (25.9% vs. 14.9%, p = 0.039). This difference was strengthened after propensity score matching. The DES lowered both mortality and MACCE for distal ULMCA lesions when compared with BMS. Ejection fraction <50% was the only independent risk factor influencing long-term survival. CONCLUSIONS Stenting of ULMCA is feasible and offers good long-term outcome. Implantation of DES for ULMCA decreased the risk of long-term MACCE, and particularly improved survival in patients with distal ULMCA disease.