Maria Wanitschek

Long-Term Efficacy and Safety of Biodegradable-Polymer Biolimus-Eluting Stents: Main Results of the Basel Stent Kosten-Effektivitäts Trial- PROspective Validation Examination II (BASKET-PROVE II), A Randomized, Controlled Noninferiority 2-Year Outcome Trial

Background— Biodegradable-polymer drug-eluting stents (BP-DES) were developed to be as effective as second-generation durable-polymer drug-eluting stents (DP-DES) and as safe >1 year as bare-metal stents (BMS). Thus, very late stent thrombosis (VLST) attributable to durable polymers should no longer appear. Methods and Results— To address these early and late aspects, 2291 patients presenting with acute or stable coronary disease needing stents ≥3.0 mm in diameter between April 2010 and May 2012 were randomly assigned to biolimus-A9–eluting BP-DES, second-generation everolimus-eluting DP-DES, or thin-strut silicon-carbide–coated BMS in 8 European centers. All patients were treated with aspirin and risk-adjusted doses of prasugrel. The primary end point was combined cardiac death, myocardial infarction, and clinically indicated target-vessel revascularization within 2 years. The combined secondary safety end point was a composite of VLST, myocardial infarction, and cardiac death. The cumulative incidence of the primary end point was 7.6% with BP-DES, 6.8% with DP-DES, and 12.7% with BMS. By intention-to-treat BP-DES were noninferior (predefined margin, 3.80%) compared with DP-DES (absolute risk difference, 0.78%; −1.93% to 3.50%; P for noninferiority 0.042; per protocol P=0.09) and superior to BMS (absolute risk difference, −5.16; −8.32 to −2.01; P=0.0011). The 3 stent groups did not differ in the combined safety end point, with no decrease in events >1 year, particularly VLST with BP-DES. Conclusions— In large vessel stenting, BP-DES appeared barely noninferior compared with DP-DES and more effective than thin-strut BMS, but without evidence for better safety nor lower VLST rates >1 year. Findings challenge the concept that durable polymers are key in VLST formation. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01166685.

Comparison of peripheral endothelial function in shift versus nonshift workers.

Shift working is related to increased cardiovascular morbidity. Peripheral endothelial dysfunction, an inherent feature of early atherosclerosis, has been suggested as a surrogate marker of cardiovascular risk. Whether shift working is associated with peripheral endothelial dysfunction has not been investigated to date. A total of 48 male shift workers (SWs) and 47 male nonshift workers (NSWs) (mean age 43 ± 5 years) were recruited from a glass manufactory. The SWs and NSWs were matched according to age, body mass index, smoking habits, family history of premature coronary artery disease, prevalence of hypercholesterolemia and hypertension, and work place. Their sport habits were also documented. Peripheral endothelial function was assessed using the EndoPAT technique to determine the peripheral arterial tone (PAT) index. According to the study design, no difference was found in the risk factor profiles between the SWs and NSWs. Despite a greater percentage of regular physical activity among the SWs (16.7 vs 4.3%, p = 0.05), shift working was associated with a reduced PAT index compared to working only on the day shift (PAT index 1.73 ± 0.4 vs 1.94 ± 0.5, p = 0.03). In the NSW group, the participants with regular physical training (n = 16) had a greater PAT index than those without regular physical activity (n = 12; PAT index 2.28 ± 0.45 vs 1.86 ± 0.51, p = 0.03). No such difference was found in the SWs. In conclusion, SWs had a reduced PAT index compared with NSWs, suggesting endothelial dysfunction. Therefore, the known increased cardiovascular risk in those shift working might be related to endothelial dysfunction.

Neopterin, CD4+CD28− lymphocytes and the extent and severity of coronary artery disease

OBJECTIVES Macrophages and pro-inflammatory CD3+CD4+CD28- T lymphocytes are involved in atherosclerotic plaque destabilization. Whether neopterin, a macrophage-specific activation-marker, and circulating CD3+CD4+CD28- cells are also related to the severity and extent of coronary artery disease (CAD) in stable patients is still unclear. METHODS Coronary angiograms of 30 patients with stable angina pectoris were graded using the Gensini severity and an extent score. Patients were grouped according to the median of each score. Lymphocyte subsets were determined by FACS analysis and neopterin by radioimmunoassay. Peripheral endothelial function of the brachial artery (FMD) shown to correlate with cardiovascular risk factors was evaluated using high-resolution ultrasound. RESULTS More extensive CAD was associated with increased neopterin levels (8.3 +/- 3.3 vs. 5.5 +/- 1.2 nmol/L, p < 0.001) and increased CD3+CD4+CD28- cells (3.1 +/- 1.6 vs. 2.0 +/- 1.2%, p < 0.05). A high Gensini severity score was associated with increased neopterin levels (7.8 +/- 2.7 vs. 6.3 +/- 1.7 nmol/L, p < 0.05), but not with CD3+CD4+CD28- cells. Neopterin correlated with both the extent (r = 0.59, p < 0.001) and the Gensini score (r = 0.57, p < 0.003). FMD was not correlated with both scores. CONCLUSIONS Neopterin and CD3+CD4+CD28- lymphocytes are associated with CAD extent in stable patients, thereby emphasizing the inherent role of inflammation in atherogenesis itself beyond plaque destabilization. Neopterins correlation with CAD severity might be additionally useful in identifying patients eligible for revascularization procedures.

Heart rate at discharge and long-term prognosis following percutaneous coronary intervention in stable and acute coronary syndromes — results from the BASKET PROVE trial☆☆☆

BACKGROUND Elevated heart rate (HR) is associated with mortality in a number of heart diseases. We examined the long-term prognostic significance of HR at discharge in a contemporary population of patients with stable angina (SAP), non-ST-segment elevation acute coronary syndromes (NSTE-ACS), and ST-segment elevation myocardial infarction (STEMI) revascularized with percutaneous coronary intervention (PCI). METHODS Patients from the BASKET-PROVE trial, an 11-center randomized all-comers trial comparing bare-metal and drug-eluting stenting in large coronary vessels, were included. Discharge HR was determined from a resting ECG. Long-term outcomes (7 days to 2 years) were evaluated for all-cause mortality and cardiovascular death and non-fatal myocardial infarction. RESULTS A total of 2029 patients with sinus rhythm were included, 722 (35.6%) SAP, 647 (31.9%) NSTE-ACS, and 660 (32.5%) STEMI. Elevated discharge HR was associated significantly with all-cause mortality: when compared to a reference of <60 beats per minute (bpm), the adjusted hazard ratios were (95% CI) 4.5 (1.5-13.5, p=0.006) for 60-69 bpm, 3.8 (1.2-11.9, p=0.022) for 70-79 bpm, 4.3 (1.2-15.6, p=0.025) for 80-89 bpm, and 16.9 (5.2-55.0, p<0.001) for >90 bpm. For cardiovascular death/myocardial infarction, a discharge HR >90 bpm was associated with a hazard ratio of 6.2 (2.5-15.5, p<0.001) compared to a HR <60 bpm. No interaction was found for disease presentation, diabetes or betablocker use. CONCLUSION In patients revascularized with PCI for stable angina or acute coronary syndromes an elevated discharge HR was independently associated with poor prognosis. Conversely, a HR <60 bpm at discharge was associated with a good long-term prognosis irrespective of indication for PCI.

Long-term benefits and risks of drug-eluting compared to bare-metal stents in patients with versus without chronic kidney disease

AIMS Chronic kidney disease (CKD) is associated with worse outcomes in patients with coronary artery disease (CAD). How CKD influences the benefit-risk balance of drug-eluting stents (DES) versus bare-metal stents (BMS) is less known. METHODS AND RESULTS In the multicentre BASKET-PROVE trial, 2314 patients in need of large coronary stenting (≥ 3.0mm) were randomised 2:1 to DES or BMS. In an a priori planned secondary analysis, outcomes were evaluated according to renal function defined by estimated glomerular filtration rates (eGFR; normal: eGFR ≥ 60 ml/min/1.73 m(2); CKD: eGFR<60 ml/min/1.73 m(2)). The primary endpoint was the first major adverse cardiac event (MACE: cardiac death, myocardial infarction, target vessel revascularisation) up to 2 years. A Cox proportional-hazard model was used to evaluate adjusted relative risks (hazard rates, HRs) for BMS versus DES. The interaction of stent type and renal function was tested. CKD patients (189 (11.2%)/1681 with such data) had a 2-year MACE rate of 8.5% versus 7.4% in those without CKD [HR 0.98 (0.56-1.72), p=0.95] with cardiac mortalities of 5.3% and 1.5%, respectively (p=0.002, non-significant after baseline adjustments). The MACE rate was lower in CKD patients with DES than with BMS [4.9% versus 15.2%, p=0.017, HR 0.29(0.10-0.80)] as was the MACE rate in patients without CKD [5.6% with DES versus 11.1% with BMS, p<0.0001, HR 0.51(0.35-0.75)]. No significant interaction between stent type and renal function was found. CONCLUSIONS This analysis of patients needing large coronary artery stenting confirms the increased mortality of CKD patients and documents a long-term benefit of DES compared to BMS irrespective of kidney function.

External validation and extension of a diagnostic model for obstructive coronary artery disease: a cross-sectional predictive evaluation in 4888 patients of the Austrian Coronary Artery disease Risk Determination In Innsbruck by diaGnostic ANgiography (CARDIIGAN) cohort

Objective To externally validate and extend a recently proposed prediction model to diagnose obstructive coronary artery disease (CAD), with the ultimate aim to better select patients for coronary angiography. Design Analysis of individual baseline data of a prospective cardiology cohort. Setting Single-centre secondary and tertiary cardiology clinic. Participants 4888 patients with suspected CAD, without known previous CAD or other heart diseases, who underwent an elective coronary angiography between 2004 and 2008 as part of the prospective Coronary Artery disease Risk Determination In Innsbruck by diaGnostic ANgiography (CARDIIGAN) cohort. Relevant data were recorded as in routine clinical practice. Main outcome measures The probability of obstructive CAD, defined as a stenosis of minimally 50% diameter in at least one of the main coronary arteries, estimated with the predictors age, sex, type of chest pain, diabetes status, hypertension, dyslipidaemia, smoking status and laboratory data. Missing predictor data were multiply imputed. Performance of the suggested models was evaluated according to discrimination (area under the receiver operating characteristic curve, depicted by the c statistic) and calibration. Logistic regression modelling was applied for model updating. Results Among the 4888 participants (38% women and 62% men), 2127 (44%) had an obstructive CAD. The previously proposed model had a c statistic of 0.69 (95% CI 0.67 to 0.70), which was lower than the expected c statistic while correcting for case mix (c=0.80). Regarding calibration, there was overprediction of risk for high-risk patients. All logistic regression coefficients were smaller than expected, especially for the predictor ‘chest pain’. Extension of the model with high-density lipoprotein and low-density lipoprotein cholesterol, fibrinogen, and C reactive protein led to better discrimination (c=0.72, 95% CI 0.71 to 0.74, p<0.001 for improvement). Conclusions The proposed prediction model has a moderate performance to diagnose obstructive CAD in an unselected patient group with suspected CAD referred for elective CA. A small, but significant improvement was attained by including easily available and measurable cardiovascular risk factors.

Sekundärpräventive Antiplättchentherapie in der kardiologischen Rehabilitation

The long-term increased cardiovascular risk of patients with an acute coronary syndrome (ACS) is a challenging and common clinical problem. Recent evidence demonstrated an ischemic benefit for a prolonged dual antiplatelet therapy beyond the initial 12 months at the cost of an increased bleeding risk. Individual, careful and repeated risk-benefit analyses are essential for an optimized patient management in which cardiovascular rehabilitation providers may play a central role.ZusammenfassungDas über Jahre langfristig erhöhte kardiovaskuläre Risiko von Patienten/innen mit einem akuten Koronarsyndrom (ACS) ist eine Herausforderung. Rezente Resultate für eine über ein Jahr hinaus prolongierte duale Antiplättchentherapie haben einen ischämische Nutzen zum Preis einer erhöhten Blutungsgefahr aufgezeigt. Daher ist eine individuelle, sorgfältige und wiederholte Risiko-Nutzen-Abwägung essentieller Bestandteil eines optimierten Patientenmanagements, in dem Rehabilitationsärzte/innen eine zentrale Rolle spielen können.SummaryThe long-term increased cardiovascular risk of patients with an acute coronary syndrome (ACS) is a challenging and common clinical problem. Recent evidence demonstrated an ischemic benefit for a prolonged dual antiplatelet therapy beyond the initial 12 months at the cost of an increased bleeding risk. Individual, careful and repeated risk-benefit analyses are essential for an optimized patient management in which cardiovascular rehabilitation providers may play a central role.

An ordinal prediction model of the diagnosis of non-obstructive coronary artery and multi-vessel disease in the CARDIIGAN cohort

Abstract Background The extent of coronary artery disease (CAD) is relevant for the evaluation and the choice of treatment of patients and consists of the severity of stenoses and their distribution within the coronary tree. Diagnosis is not easy and severe CAD should not be missed. For low-risk patients one wants to avoid the invasive angiography. We aim to propose a diagnostic prediction model of CAD respecting the degree of disease severity. Methods We included 4888 patients from the Coronary Artery disease Risk Determination In Innsbruck by diaGnostic ANgiography (CARDIIGAN) cohort. An ordinal regression model was applied to estimate the probabilities of five incrementally disease categories: no CAD, non-obstructive stenosis, and one-, two- and three-vessel disease. We included 11 predictors in the model: age, sex, chest pain, diabetes, hypertension, dyslipidaemia, smoking, HDL and LDL cholesterol, fibrinogen, and C-reactive protein. Bootstrapping was used to validate model performance (discrimination and calibration). Results Age, sex, and three laboratory measures had a large predictive effect. The model poorly separated most adjacent disease categories, but performed well for categories far apart, with little optimism. The overall discrimination added up to a c statistic of 0.71 (95% CI 0.69 to 0.73). The model enables the estimation of individual patient probabilities of disease severity categories. Conclusions The proposed ordinal diagnostic risk model, employing routinely obtainable variables, allows distinguishing the extent of CAD and can especially discriminate between non-obstructive stenosis and multi-vessel disease in our CARDIIGAN patients. This can help to decide on treatment strategy and thereby reduce the number of unnecessary angiographies.

Cohort profile: the Coronary Artery disease Risk Determination In Innsbruck by diaGnostic ANgiography (CARDIIGAN) cohort

Purpose The Coronary Artery disease Risk Determination In Innsbruck by diaGnostic ANgiography (CARDIIGAN) cohort is aimed to gain a better understanding of cardiovascular risk factors and their relation to the diagnosis and severity of coronary artery disease, as well as to the long-term prognosis in consecutive (including revascularised) patients referred for elective coronary angiography. Participants The included patients visited the University Clinic of Cardiology at Innsbruck (Austria), which fulfils a secondary and tertiary hospital function. Inclusion took place in the period between February 2004 and April 2008 and resulted in a total of 8296 patients aged 18–91 years; 65% of them were men. Findings to date There was one follow-up round on vital status through record linkage for 84% of the cohort (those with residence in Tyrol), resulting in a follow-up duration of over 5.5 to nearly 10.0 years among survivors. The data contain basic patient characteristics, cardiovascular risk factors, laboratory measurements, medications, detailed information on the extent and severity of coronary artery disease, revascularisation history, treatment strategy and mortality specifics. A few studies have already been published. Future plans Various diagnostic and prognostic studies are planned, also concerning complications, competing risks and cost-effectiveness. Collaboration with other research groups is welcomed.

Long-Term Efficacy and Safety of Biodegradable-Polymer Biolimus-Eluting Stents

Background— Biodegradable-polymer drug-eluting stents (BP-DES) were developed to be as effective as second-generation durable-polymer drug-eluting stents (DP-DES) and as safe >1 year as bare-metal stents (BMS). Thus, very late stent thrombosis (VLST) attributable to durable polymers should no longer appear. Methods and Results— To address these early and late aspects, 2291 patients presenting with acute or stable coronary disease needing stents ≥3.0 mm in diameter between April 2010 and May 2012 were randomly assigned to biolimus-A9–eluting BP-DES, second-generation everolimus-eluting DP-DES, or thin-strut silicon-carbide–coated BMS in 8 European centers. All patients were treated with aspirin and risk-adjusted doses of prasugrel. The primary end point was combined cardiac death, myocardial infarction, and clinically indicated target-vessel revascularization within 2 years. The combined secondary safety end point was a composite of VLST, myocardial infarction, and cardiac death. The cumulative incidence of the primary end point was 7.6% with BP-DES, 6.8% with DP-DES, and 12.7% with BMS. By intention-to-treat BP-DES were noninferior (predefined margin, 3.80%) compared with DP-DES (absolute risk difference, 0.78%; −1.93% to 3.50%; P for noninferiority 0.042; per protocol P=0.09) and superior to BMS (absolute risk difference, −5.16; −8.32 to −2.01; P=0.0011). The 3 stent groups did not differ in the combined safety end point, with no decrease in events >1 year, particularly VLST with BP-DES. Conclusions— In large vessel stenting, BP-DES appeared barely noninferior compared with DP-DES and more effective than thin-strut BMS, but without evidence for better safety nor lower VLST rates >1 year. Findings challenge the concept that durable polymers are key in VLST formation. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01166685.