Ferritin measurement IN Donors-Effectiveness of iron Monitoring to diminish iron deficiency and low haemoglobin in whole blood donors (FIND'EM): study protocol for a stepped wedge cluster randomised trial.

BACKGROUND: Blood donors are at risk for reduced iron stores, because of which donor iron monitoring received increased attention in the last decade. Despite the importance for donor health, international consensus on an appropriate policy for iron monitoring is lacking. Therefore, we conduct a trial to evaluate to what extent ferritin-guided donation intervals are effective in increasing haemoglobin and ferritin levels, decreasing low-haemoglobin deferral, increasing donor return and improving the health of whole blood donors in the Netherlands. METHODS: Sanquin Blood Bank is implementing ferritin-guided donation intervals to prevent donors from increasing iron loss at repeated donations. Using a stepped wedge cluster randomised trial approach, the design involves a random crossover of 29 clusters of blood collection centres from the existing policy without ferritin measurements to a ferritin-guided donation interval policy. This new policy includes ferritin measurements for all new donors and at every 5th whole blood donation, extending donation intervals to 6 months if ferritin is 15-≤ 30 ng/mL and to 12 months if ferritin is < 15 ng/mL. We measure ferritin levels of whole blood donors from stored plasma samples and collect haemoglobin levels and information on low-haemoglobin deferral and donor return from the donor database before, during and after the implementation period. We measure donor health during and after the implementation period using questionnaires, assessing physical and mental wellbeing and iron deficiency- and donation-related symptoms. We use multilevel analyses to investigate differences in ferritin and haemoglobin levels, low-haemoglobin deferral rates, donor return and donor health from whole blood donors, between blood collection centres that have versus those that have not yet implemented the ferritin-guided donation interval policy. DISCUSSION: This stepped wedge cluster randomised trial will provide insight into the effectiveness of ferritin-guided donation intervals in lowering iron deficiency, decreasing donor deferrals due to low haemoglobin and improving donor health. We will evaluate a policy that is implemented nationwide in a real-life setting. Our study is therefore not limited to a small experimental setting and the results will guide policymakers seeking an appropriate policy for iron monitoring. TRIAL REGISTRATION: The Dutch trial registry NTR6738 . Registered on 29 September 2017. Retrospectively registered.

Reperfusion ventricular arrhythmia 'bursts' predict larger infarct size despite TIMI 3 flow restoration with primary angioplasty for anterior ST-elevation myocardial infarction.

Aims Successful epicardial reperfusion with primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) can paradoxically evoke myocardial reperfusion injury, which may be signalled by temporally associated ventricular arrhythmias (VAs). We correlated reperfusion VA 'bursts' with final infarct size (IS) in patients with restored TIMI 3 flow following PCI for anterior STEMI. Methods and results All 128 anterior STEMI patients with final TIMI 3 flow had continuous 24 h digital 12-lead ECG with simultaneous Holter recording initiated prior to PCI, and Day 7/discharge SPECT imaging IS assessment. Angiography, SPECT imaging, continuous ST recovery, and quantitative rhythm analyses were performed. Reperfusion VA bursts were defined against patient-specific background VA rates and timed as concomitant with or following first angiographic TIMI 3 flow restoration associated with > or =50% stable ST recovery; they were then correlated with IS and global left ventricular ejection fraction (LVEF) at Day 7/discharge. Bursts occurred in 81/128 (63%) patients and were significantly correlated with larger IS and worse LVEF (median: 21.0 vs. 10.0%, P < 0.001; 35.5 vs. 46.5%, P < 0.001, respectively). In multivariable analyses that adjusted for known predictors of IS, the association of bursts with larger IS remained significant; similar results were seen for worse LVEF. Conclusion Reperfusion VA bursts predict larger IS despite TIMI 3 flow restoration with > or =50% stable ST recovery following PCI for anterior STEMI. Well-characterized reperfusion VAs may provide a novel biomarker of reperfusion injury.

Reperfusion ventricular arrhythmia 'bursts' in TIMI 3 flow restoration with primary angioplasty for anterior ST-elevation myocardial infarction: a more precise definition of reperfusion arrhythmias.

AIMS: We sought to define reperfusion-induced ventricular arrhythmias (VAs) more precisely through simultaneous angiography, continuous ST-segment recovery, and beat-to-beat Holter analyses in subjects with anterior ST-elevation myocardial infarction (STEMI) undergoing primary angioplasty [percutaneous coronary intervention (PCI)]. METHODS AND RESULTS: All 157 subjects with final TIMI 3 flow had continuous 12-lead electrocardiography with simultaneous Holter recording initiated prior to PCI for continuous ST-segment recovery and quantitative VA analyses. Ventricular arrhythmia bursts were detected against subject-specific background VA rates using a statistical outlier method. For temporal correlations, timing and quality of reperfusion were defined as first angiographic TIMI 3 flow with >or=50% stable ST-segment recovery. Almost all subjects had VAs [156/157 (99%)], whereas VA bursts during or subsequent to reperfusion occurred in 97/157 (62%). The majority of VA bursts (72%) arose within 20 min of reperfusion (95% CI: 26.7, 72), with onset at a median of 4 min post-reperfusion (IQR: 0-43) Bursts comprised a median of 1290 ventricular premature complexes (VPCs) (IQR: 415-4632) and persisted for a median of 105 min (IQR: 35-250). Most background VAs occurred as single VPCs; bursts typically comprised runs of three or more VPCs. Subjects with bursts had higher absolute peak ST segments and more frequent worsening of ST elevation immediately after reperfusion. CONCLUSION: Ventricular arrhythmia bursts temporally associated with TIMI 3 flow restoration and stable ST-segment recovery (reperfusion VA bursts) can be precisely defined in subjects with anterior STEMI and may constitute a unique electric biosignal of myocellular response to reperfusion.

Comparison of sirolimus-eluting and bare metal stents in coronary bifurcation lesions: subgroup analysis of the Stenting Coronary Arteries in Non-Stress/Benestent Disease Trial (SCANDSTENT).

BACKGROUND: Sirolimus-eluting stent implantation improves the outcome in simple coronary artery lesions compared with bare metal stents, but there is limited evidence of their safety and efficacy when implanted in complex lesions like coronary bifurcations. METHODS: SCANDSTENT was a randomized controlled study comparing implantation of sirolimus-eluting stents with bare-metal stents in patients with complex coronary artery disease. This substudy evaluates the angiographic and clinical outcome of 126 patients with lesions located in a coronary bifurcation. RESULTS: The baseline characteristics of the patients were comparable: 15% had diabetes, and 1.7 stents were implanted per lesion. At follow-up, the minimum lumen diameter of the main branch was 2.35 mm in patients who received sirolimus-eluting stents compared with 1.68 mm in those who received bare-metal stents, and that of the side branch was 1.70 versus 1.19 mm (both P < .001). The late lumen loss in the main branch was 0.12 mm in the sirolimus-eluting stent group versus 0.99 mm in the bare-metal stent group and 0.03 versus 0.56 mm in the side branch (both P < .001). Thus, sirolimus-eluting stents reduced the restenosis rate from 28.3% to 4.9% in the main branch and from 43.4% to 14.8% in the side branches (both P < .001). Major adverse cardiac events occurred in 9% with sirolimus-eluting stents versus 28% with bare-metal stents (P = .01), and stent thrombosis was observed in 0% versus 9% (P = .02). CONCLUSION: Sirolimus-eluting stent implantation improves both the angiographic and clinical outcomes considerably compared with that of bare-metal stents in patients with stenoses located in coronary bifurcations.

Lipid profile and carotid intima-media thickness in a prospective cohort of very preterm subjects at age 19 years: effects of early growth and current body composition.

Cardiovascular disease (CVD) risk is associated with prenatal and infancy growth. However, the relative importance of these time periods for the CVD risk is uncertain. To elucidate this, we tested in a very preterm cohort the effects of birth weight for gestational age and weight gain between birth and 3 mo post-term (early postnatal weight gain) and between 3 mo and 1 y post-term (late infancy weight gain) on the lipid profile and carotid intima-media thickness (CIMT) at age 19 y. A less favorable lipid profile was strongly associated with higher current body mass index (BMI), greater waist circumference, and greater absolute fat mass. CIMT was positively associated with current height, and with low-density lipoprotein (LDL) cholesterol and apolipoprotein B (ApoB) levels, and LDL/high-density lipoprotein (HDL) cholesterol and ApoB/apolipoprotein AI (ApoAI) ratios. Lipid profile and CIMT were unrelated to gestational age, birth weight standard deviation score (SDS) and early postnatal weight gain. CIMT was positively associated with late infancy weight gain, but the relationship disappeared after correction for current height. Our findings in 19 y olds born very preterm argue for an effect of current body composition, rather than of early growth, on the CVD risk. Attempts to reduce the CVD risk in this specific population should focus on weight reduction in young adulthood rather than on optimizing the early growth pattern.

Effectiveness of "direct" stenting without balloon predilatation (from the Multilink Tetra Randomised European Direct Stent Study [TRENDS]).

The purpose of the TRENDS trial was to assess the safety, efficacy, and cost effectiveness of a no-predilatation ("direct") stenting strategy in the treatment of de novo native coronary artery lesions using the Multilink Tetra stent system. In this multicenter, prospective clinical trial, 1,000 patients were randomized (1:1) to receive a Multilink Tetra stent with or without balloon predilatation. The primary outcome measurement was major adverse cardiac events (MACEs) at 30 days; secondary end points included resource utilization (including procedural duration, equipment use, and length of hospital stay), MACEs, and angiographic binary restenosis at 180 days. In the predilatation group, 587 stents were implanted in 499 patients; in the direct group, 579 stents were implanted in 501 patients. In the direct group, stents in 31 lesions (5.7%) required predilatation and multivariate analysis identified calcification (odds ratio 5.81), angulation (odds ratio 5.34), and preprocedural minimal lumen diameter (odds ratio 0.09) as direct stenting failure. MACEs at 30 days were similar in the 2 groups, with 19 (3.8%) in the predilatation group and 13 (2.6%) in the direct group (p = NS). Resource utilization favored the direct strategy, with decreases in balloon use, contrast media, and procedure time, but a larger number of guiding catheters was used. The 180-day MACE rate of 9.8% in the direct group was not significantly less than the rate of 10.8% in the predilatation group (p = NS). Quantitative angiographic follow-up at 6 months demonstrated in-stent binary restenotic rates of 11.4% in the predilatation group (late loss 0.88 +/- 0.53 mm) and 12.3% in the direct group (late loss 0.82 +/- 0.51 mm, p = NS) and in-segment restenosis rates of 12.2% and 13.4%, respectively (p = NS). In conclusion, a direct stenting strategy with the Multilink Tetra stent was feasible and safe in 94% of lesions and associated with lower resource utilization compared with a predilatation approach. Direct stenting was not associated with significantly lower MACE and target lesion revascularization rates and had no effect on late angiographic follow-up, with similar late loss reflecting an identical biologic response to bare metal stent placement.

The Stenting Coronary Arteries in Non-stress/benestent Disease (SCANDSTENT) trial.

OBJECTIVES: The purpose of the SCANDSTENT study was to evaluate the use of sirolimus-eluting stents (SES) in complex coronary lesions. BACKGROUND: The use of SES improves angiographic and clinical outcomes compared with bare-metal stents (BMS) in simple coronary artery lesions, but there is limited evidence of their safety and efficacy when implanted in complex lesions. METHODS: We randomly assigned 322 patients with symptomatic complex coronary artery disease to receive either SES or BMS. The lesions were occluded (36%), bifurcational (34%), ostial (22%), or angulated (8%) in morphology. The primary end point was the difference in minimal lumen diameter six months after stent implantation. RESULTS: The patients were well matched in terms of demographic and angiographic baseline characteristics; 18% had diabetes. The reference vessel diameter was 2.86 mm in mean, and the lesion length 18.0 mm. At follow-up, patients who received SES had a minimal lumen diameter of 2.48 mm compared with 1.65 mm in those who received BMS (p < 0.001), a diameter stenosis of 19.3% versus 43.8% (p < 0.001), and 2.0% versus 31.9% developed restenosis (p < 0.001). The rate of major adverse cardiac events was 4.3% with SES versus 29.3% with BMS (p < 0.001), and stent thrombosis was observed in 0.6% in the SES group versus 3.1% in the BMS group (p = 0.15). CONCLUSIONS: The use of SES markedly reduced restenosis and the occurrence of major adverse cardiac events in patients with complex coronary artery lesions without increasing the risk of stent thrombosis.

Frequency and time course of reocclusion and restenosis in coronary artery occlusions after balloon angioplasty versus Wiktor stent implantation: results from the Mayo-Japan Investigation for Chronic Total Occlusion (MAJIC) trial.

BACKGROUND: Compared with balloon angioplasty, stent implantation has been shown to reduce restenosis and reocclusion after treatment of chronic total coronary artery occlusions (CTOs). However, little is known about the time course of restenosis and reocclusion after the 2 procedures. The purpose of this study was to examine the frequency and time course of restenosis and reocclusion after treatment of CTOs with balloon angioplasty and Wiktor stent implantation. METHODS AND RESULTS: A total of 221 patients with successfully recanalized CTOs were randomly assigned to either treatment with a coil stent implantation (Wiktor stent, n = 110) or standard balloon angioplasty (n = 111). Repeat angiography was performed the day after treatment and at 6 months. Patients undergoing balloon angioplasty showed 29.8% restenosis and 1.1% reocclusion the following day versus 2% restenosis and no reocclusion in stent patients the following day. The cumulative reocclusion rate was significantly lower in the stent group than in the balloon group at 6 months (2.1% versus 9.3%, P <.05). As a result of the more frequent need of target vessel revascularization (49.5% in the balloon group and 30.6% in the stent group, P <.005) and earlier final follow-up angiography in the balloon group, the frequency of angiographic restenosis at 6 months was similar in both groups (57.3% in the stent group and 54.5% in the balloon group). CONCLUSIONS: The frequency and time course of reocclusion and restenosis after balloon angioplasty and stent placement differ within 24 hours of the procedure and remain different on angiography at 6 months.

Variability of quantitative coronary angiography: an evaluation of on-site versus core laboratory analysis.

To assess the validity of locally performed off-line quantitative coronary angiography (QCA) measurement in clinical trials, we carried out a comparative study between on-site QCA analysis and analysis performed at an independent external core laboratory. One local operator analyzed the pre, post and follow-up angiograms of 116 patients participating in the Stenting in Small Coronary Arteries Study (SISCA) prior to final QCA analysis in the core laboratory. The mean values of the reference diameter (RD), minimal lumen diameter (MLD) and diameter stenosis (DS) showed acceptable agreement between study site and core laboratory. However, on the level of individuals the interobserver differences were large, affecting the outcome of restenosis rate significantly, and in a such way that the conclusions in the SISCA trial might have come out differently if a core laboratory had not been used. This emphasizes the importance of using independent core laboratories in coronary interventional trials.

Low restenosis rate of the NIR coronary stent: results of the Danish multicenter stent study (DANSTENT)--a randomized trial comparing a first-generation stent with a second-generation stent.

BACKGROUND: Larger studies evaluating the angiographic results of second-generation stents are scarce. The objectives of this study were to assess current standards of angiographic and clinical outcomes after implantation of the second-generation stainless steel stent, NIR (Medinol Ltd, Tel Aviv, Israel), and to compare the outcomes with those of the first-generation Palmaz-Schatz (PS) stent (Johnson & Johnson, Warren, NJ). METHODS: Patients having coronary artery lesions that could be covered by a stent of 15 mm in length were randomly assigned to receive the NIR or the PS. Procedural success, 6-month angiographic findings, and 1-year clinical outcomes were determined. RESULTS: In 424 patients included in the study, the overall procedural success rate was high (NIR 98%, PS 99%, P =.90). Follow-up angiography was conducted in 91% of the patients. The overall rate of angiographic restenosis was low in both groups (NIR 9.9%, PS 12.6%, P =.35). We found a low restenosis rate in vessels with a minimal lumen diameter >3.1 mm after the procedure, particularly in the NIR group (<6%). The rate of target lesion revascularization after 1 year did not differ (NIR 12%, PS 10%, P =.47). CONCLUSIONS: The angiographic and clinical outcomes after implantation of the second-generation stainless steel stent were not significantly better than those of the first-generation stent. The low restenosis rates, particularly in patients with the largest minimal lumen diameters after stent implantation, warrants circumspection when planning the evaluation of newer stent technologies that aim to further reduce coronary restenosis.

One core laboratory at two international sites, is that feasible? An inter-core laboratory and intra-observer variability study.

To assess the magnitude of differences in QCA outcomes between two cooperating core laboratories in a single trial, we have carried out an inter-core laboratory variability study. Two QCA experts at the Montreal Heart Institute and Heart Core Leiden both analyzed 32 lesions (pre- and post-intervention) in accordance with previously agreed upon standard operating procedures. One of the experts analyzed the whole image set twice to determine the intraobserver variability. The inter-core laboratory differences in the acute gain (n = 31 pairs) are non-significant. The systematic errors of the individual measurements (n = 63 analyses) show an excellent intraclass correlation coefficient of reliability (>75%), except for the stent length (67.7%). The corresponding random errors are small. In general, the intra-observer systematic and random errors are both slightly smaller than those for the inter-core laboratory study. QCA analyses in clinical trials can be carried out in core laboratories at two different locations if and only if highly standardized conditions are maintained.

A novel measurement technique to assess the effects of coronary brachytherapy in clinical trials.

This paper presents a novel measurement technique to assess the effects of coronary brachytherapy. This new technique is based upon the conventional quantitative coronary analysis (QCA) technique, which is accepted worldwide as an accurate and reliable analysis tool for clinical trials. This paper provides the definitions and main issues important for correct brachytherapy analysis. Based on these definitions, this novel technique is implemented as an extension of conventional QCA software, as a multisegmental analysis tool. It allows to follow the influence of radiation on restenosis, and the mutual relation between intervention devices. A pilot interobserver study was performed to assess the reliability and reproducibility of the brachytherapy analysis tool, using 15 patient cases. The validation results show that the segment lengths, minimum lumen diameter, and reference diameters of the user-defined and derived (sub)segments can be assessed reproducible. However, these good results can only be obtained, when strict and extensive image acquisition and image analysis protocols are followed. From this pilot validation study presented in this paper and only based on a small number of patients, we may conclude that the software can be applied to clinical trials.