Effects of dried bilberry dietary supplement after myocardial infarction: a multicenter, prospective, randomized, placebo-controlled trial.
Effects of dried bilberry dietary supplement after myocardial infarction: a multicenter, prospective, randomized, placebo-controlled trial.
Project number : 250001
Created by: Cecilia Bergh, 2018-07-01
Last revised by: Cecilia Bergh, 2018-07-03
Project created in: FoU Region Örebro län

PublishedPublished

Titel och sammanfattning

Populärvetenskaplig sammanfattning

Intag av vissa typer av bär är kopplat till flertalet biologiska processer som kan minska risken för hjärtkärlsjukdom. Tidigare studier har visat att bärkonsumtion kan användas som ett möjligt nytt effektivt och säkert tilläggsalternativ för att förebygga och förbättra kardiovaskulära riskfaktorer såsom LDL-kolesterol, inflammation samt fysisk förmåga. Personer med högst risk för tidig död, hjärtinfarkt och återinläggning är de med känd hjärtkärlsjukdom. Internationella riktlinjer förespråkar därför sekundärprevention med beprövade metoder som evidensbaserad farmakologisk behandling, kardiovaskulär riskoptimering, samt följsamhet till rekommendationer gällande kost och fysisk aktivitet. Bär rika på antocyaniner (färgämne) har visat samband med minskad dödlighet i hjärtkärlsjukdom, möjligen på gund av fördröjd eller reverserad plackprogression relaterad till lipidsänkning. Nordiska blåbär (bilberries har en hög koncentration av antocyaniner. Förhöjda kolesterolvärden samt ökad inflammation ökar risken betydligt för nya hjärtkärlhändelser och nya farmaka är både kostsamma samt förenade med allvarliga bieffekter. Om tillskott av blåbär ytterliga skulle kunna sänka dessa värden kan sådan behandling få betydande konsekvenser i klinisk praxis.Vi planerar en randomiserad, placebokontrollerad multicenter studie för att efter akut hjärtinfarkt utvärdera effekten av ett kosttillskott av torkade blåbär vad gäller lipidstatus, inflammationsmarkörer samt fysisk prestationsförmåga.

Sammanfattning på engelska

Background:
Berry consumption might be utilized as a new, effective and safe supplement for prevention and control of cardiovascular disease. Accumulating evidence show that ingestion of some types of berries is associated with a wide range of beneficial biological effects on cardiovascular parameters. However, clinical trials in patients with overt disease including acute myocardial infarction (AMI) are scarce, and bilberry rich in anthocyanins might be particularly useful following an AMI.
Methods:
This is a multicenter, prospective, randomized, placebo-controlled clinical trial assessing the efficacy of bilberry supplement initiated within 72 hours of percutaneous coronary intervention for AMI. Patients will be randomized 1:1 in a three-month intervention period to either bilberry powder/shake (40 g per day, equivalent to 480 g fresh berries) in combination with standard therapy or to a control group receiving placebo and standard therapy. The primary endpoint is low density lipoprotein (LDL) cholesterol change. The major secondary endpoint is exercise capacity assessed by a symptom-limited bicycle ergometer test. Other secondary endpoints include effects on inflammatory markers.
Clinical relevance:
Secondary prevention after AMI has improved during the last decades but readmissions and death following AMI remain large health care challenges. Hyperlipidemia and inflammation are believed to be critical for new cardiovascular events and novel pharmacological treatments for these conditions are prohibitively expensive and associated with serious side effects. Should a bilberry supplement be able to further lower LDL cholesterol and inflammation than is standard therapy, it would have wide clinical consequences.

Projektspecifik information

Ämnesord

checked Kardiologi


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Studietyp

Prövning av behandling

Fas

I

Randomiserad studie

Ja

Diagnoskod för huvuddiagnos

I20-I25 Ischemiska hjärtsjukdomar (sjukdomar orsakade av otillräcklig blodtillförsel till hjärtmuskeln)

Multicenterstudie

Ja

Startdatum för datainsamling

2018-11-01

Slutdatum för datainsamling

2021-12-31

Studiens status

Planering och förberedelse

Inklusionsstatus

 Planerat antalAntal tillfrågadeScreen-failureAntal randominserade
n=900   

Vetenskaplig sammanfattning

Background

Cardiovascular disease (CVD) is a leading cause of death and disability globally. 1 Despite multiple modifiable risk factors, dyslipidemia remains a key factor for the development of atherosclerotic plaques, 2 while systemic inflammation also plays a central role in the atherosclerotic process from initiation of atherosclerosis to progression and rupture of plaques. 3 4 Observational studies suggest that the risk of myocardial infarction in subjects with hyperlipidemia is 3 times higher than those in the general population with normal lipid status and that a 1% decrease in serum cholesterol is strongly associated with a 3% reduction in CVD risk 5 From a public health perspective, dietary intervention is considered a first approach in treating and controlling CVD. 6 However, patients at highest risk of premature death, myocardial infarction and re-hospitalization are those with known CVD. 7 Consequently, international guidelines advocate proven secondary prevention strategies such as evidence-based pharmacological therapy, cardiovascular risk factor optimization, cardiac rehabilitation and adherence to diet and physical activity recommendations. Both pharmacological therapy and dietary interventions have been used in CVD patients to improve lipid profiles.

Accumulating evidence show that ingestion of some types of berries is associated with a wide range of biological effects lowering CVD risk, 9 10 including anti-inflammatory, antihypertensive, hypoglycaemic and anticoagulant properties and improvement of lipid metabolism disorders. 11 12 Studies suggest that berry consumption might be utilized as a possible new, effective and safe supplementary option to better prevent and control CVD risk factors, such as low density lipoprotein (LDL) cholesterol 10 13 and improve exercise capacity. 14-18 Berries are rich in a number of polyphenols, and particularly anthocyanins (ACs). They also contain vitamin C, vitamin K, folic acid, carotenoids, and dietary fiber in varying proportions depending on species. Flavonoids, pigments found in plants, along with their subgroups, anthocyanidins, and their glycosylated form, ACs, which give plants blue or black color, have been the subject of research with respect to antioxidant properties. 19 A beneficial role of dietary antioxidants has recently been questioned 20 but ACs may have direct 21 or indirect positive effects on cardiovascular risk factors 22 23 and inflammation. 23 24 It has been suggested that consumption of flavonoids such as anthocyanidins, flavan-3-ols, flavanones, flavones, flavonols, proanthocyanidins, and isoflavones found in blueberries, red wine, spinach, onions, and herbal teas, may reduce the risk of death from CVD. 22 25

Further, berries such as blueberries, strawberries, lingonberries, black currants, raspberries, and chokeberries have beneficial effects on platelet function, increase high density lipoprotein (HDL) cholesterol, and may lower blood pressure. 26 27

Blueberries (Vaccinium corymbosum, Vaccinium ashei, and Vaccinium angustifolium) and bilberries Vaccinium myrtillus L. are often considered the same by laymen. Despite similarities, the berries differ in taste, pulp color, and nutritional content. The dominant ACs differ, the quantity of ACs in bilberries is more than twice that in blueberries, 28 and the AC content is typically higher in wild plants compared to cultivated. 28 The AC concentration in bilberries can be affected by climate, but the main determinants of AC concentration differences are genetic. Bilberries originating from high latitudes have a greater concentration of ACs than southern plants, even when grown under the same conditions for years. 29 In rat studies, blueberry-enriched diets prior to a myocardial infarction have shown cardioprotective properties, 30 31 and a protective effect may also be achieved when a blueberry diet is initiated after myocardial infarction. 31 This can be attributed, in part, to slowing or reversing atherosclerotic plaque progression, 32 33 possibly related to lipid lowering. 33 34. In vitro studies and studies in healthy subjects have demonstrated bilberries to have cardioprotective effects. 24 The ACs in bilberries show antioxidant properties in vascular endothelium and vascular smooth muscle, even at low concentrations. 35 They are reported to reduce inflammation in people with metabolic syndrome 36 and others at increased risk for CVD. 24

Evidence that dietary measures can prevent and combat CVD is accumulating, and in this respect, Mediterranean diets have attracted interest. 37 38 Clinical research on foods produced at higher latitudes are also of relevance. However, randomized controlled clinical trials of nutritional supplement interventions following acute CVD events are few. We have previously conducted a clinical trial (pilot study) of the effects of a dried bilberry dietary supplement after acute myocardial infarction (AMI), and our data (published in abstract form: Arevström L, Landberg R, Waldenborg M, Blanc S, Fröbert O.: Bilberry as a dietary supplement after myocardial infarction: the bear smart trial. J Am Coll Cardiol. 2016;67(13_S):539. doi:10.1016/S0735-1097(16)30540-X) indicate a larger reduction in LDL cholesterol in the intervention group compared to controls, which is remarkable considering that our study population received high-dose statin treatment.

Our pilot study also indicates an effect from bilberries on exercise capacity as indicated by a statistically significantly larger increase in walking distance in the intervention group. Because the pilot study was open-label by design, we now wish to conduct a large, placebo-controlled, multicenter, randomized, controlled clinical trial to assess true clinical impact.

Human gastrointestinal (gut and mouth) microbiota are linked to type 2 diabetes, 39 CVD 40 and metabolic events. 41 Associations between gastrointestinal microbiota and cardio-metabolic diseases have been shown in humans and causality has been demonstrated in animal models, mainly due to rapid development of modern molecular technologies. This has prompted a growing number of studies where bacterial taxa and their activities are characterized and studied in relation to disease and disease markers. Diet contributes in shaping the gut microbiota and gut microbiota at baseline modifies the effects on short to long term metabolic responses after intake of different dietary fibers and protein rich foods. 42-44 The numerous small molecules produced through primary and secondary metabolic pathways in bacteria 45 imply that specific diets, including berries, 46 47 in combination with specific microbiota, can potentially be reflected as metabolite profiles in plasma or other biospecimens. Thus, metabolomics could provide the means for effective characterization of microbiota composition through identification of such specific metabolite profiles. 45 48 This was confirmed in a very recent study by Zierer et al. (2018) 49 that showed that 68% of the variation in the gut microbiota composition was reflected in the fecal metabolome. Moreover, there was a good agreement between the fecal and plasma metabolomes. Thus, fecal and/or plasma metabolome are novel tools for exploring links between microbiome composition and host phenotypes and highly relevant when testing potential health benefits of specific food sources like bilberries.

Purpose of the study

The primary objective of the study is to assess the effect of bilberry supplement initiated within 72 hours of percutaneous coronary intervention (PCI) for AMI. We hypothesize that standard medical therapy supplemented with dried bilberriesEM after AMI will have a more beneficial effect than medical therapy alone on cardiovascular risk markers such as LDL cholesterol. Secondary objectives are to study the effect on exercise capacity and inflammatory biomarkers. We will also address to what extent gut microbiota composition and activity (addressed by untargeted metabolomics) may explain differences among responders and non-responders to the intervention.

Rationale

In this study, we test the primary hypothesis that standard therapy supplemented with dried bilberry is superior to standard therapy alone in reducing LDL cholesterol levels after three months in patients with AMI undergoing PCI treatment. Our secondary hypotheses to be tested are that a dried bilberry dietary supplement for three months will increase exercise capacity and have a lowering effect on inflammatory biomarkers compared to standard therapy alone. In an explorative analysis we hypothesize that differences in cardiometabolic risk profile may be modified by base-line gut microbiota as recently shown in two studies 42 50 (as well as in one of our yet unpublished studies).

Clinical relevance

The CVD event rate has been reported to be reduced by 1-3% for each 1% reduction in LDL cholesterol. 5 51 Although new lipid lowering drugs are effective in lowering LDL cholesterol levels, they are still not cost-effective, the yearly cost is as high as 14 000 US $. 52-55 Dried bilberry dietary supplement, with a potential LDL lowering effect in a patient population already undergoing statin treatment, might be utilized as a possible new cost-effective and safe supplementary option to better prevent future CVD events in a high-risk group of AMI patients.

Material and methods

Study design

This is a multicenter, prospective, randomized, placebo-controlled clinical with 900 patients. The study design is described in Figure 1.

Patient inclusion criteria

Study participants will be recruited among patients referred to the participating centers for coronary angiography/PCI due to ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation myocardial infarction (NSTEMI) (Figure 1).

Patients with a diagnosis of STEMI as defined by chest pain suggestive for myocardial ischemia for at least 30 minutes before hospital admission, time from onset of symptoms of less than 24 hours, and an ECG with new ST-segment elevation in two or more contiguous leads of ≥0.2 mV in leads V2-V3 and/or ≥0.1 mV in other leads or a probable new-onset left bundle branch block

Or:

Patients with a diagnosis of NSTEMI defined by a combination of: onset of symptoms such as central chest pain or an aggravated angina pectoris, with or without an ECG change with ST-segment lowering or an inverted T-wave, and at least two values with levels of troponin-T or troponin-I above the established margin of an AMI.

And:

- A finalized coronary angiography/PCI.

- Male or female subjects ≥18 years.

- Written informed consent.

Patient exclusion criteria

- Emergency coronary artery bypass grafting,

- Daily intake (or the intent to initiate daily intake) of bilberryEM in any form,

- Previous randomization in the study.

Randomization and blinding

After providing written informed consent, patients who fulfill the inclusion criteria with no exclusion criteria will be randomized according to a computer-generated random-number sequence.

Dietary intervention

The dietary intervention will be initiated within 72 hours of angiography / PCI and continued for three months. After randomization, subjects will be administered bilberry supplementation (active), or placebo supplementation containing no active bilberry. The patients will be instructed to use a dedicated 25 ml spoon, corresponding to ~13.3 g, to measure a dose of dehydrated bilberry to take with meals three times a day (t.i.d.), for a total of 40 g of powder per day, equaling approximately 480 g of fresh berries. The powder (Immune Skellefteå, Sweden, https://www.immun.se/) contains multiple ACs that are listed in table 1.

Nutritional value of the powder is, per 100 g: energy 377 kcal / 1600 kJ, protein 5 g, carbohydrates 82 g (sugars 30 g, fructose 19 g, glucose 11 g, sucrose < 2 g), dietary fiber 25 g (insoluble 19 g, soluble 6 g), fat 4 g, anthocyanins 2250 mg, ORAC value 45100 μmol TE/100 g. Subjects will be instructed to take the powder uncooked, mixed with food or beverage. A t.i.d. intake is considered appropriate given the relatively short metabolic half-life of ACs in blood. The patients will be instructed not to consume bilberry or blueberry during study.

Table 1.STRONG Anthocyanin compounds in V. myrtillus powder

Anthocyanins Average (mg/g)SD
peonidin-3-galactoside3.00.00
peonidin-3-glucoside0.000.00
cyanidin-3-galactoside3.110.04
cyanidin-3-glucoside0.000.00
cyanidin-3-arabinoside1.200.01
delphinidin-3-galactoside3.680.03
delphinidin-3-glucoside0.160.00
pelargonidin-3-galactoside0.870.01
pelargonidin-3-glucoside0.010.11
petunidin-3-galactoside4.70.02
malvinidin-3-galactoside6.260.04

Examinations and blood samples

Patients in the study will be assessed at baseline (as an inpatient), and at follow-up at three months as an outpatient. The following examinations will be performed:

Blood samples

Venous blood will be drawn according to hospital routine. Lipid profile, inflammatory markers, glycosylated hemoglobin (HbA1c), and heart function markers will be analyzed locally. Blood for later analysis will be centrifuged immediately and stored at -70°C. Analysis of samples will be conducted to assess compliance on the presumption that acid concentrations are higher in the bilberry group. Acid components of blood associated with bilberry consumption, 56-58 will be analyzed by a validated method combining liquid chromatography with mass spectrometry. 59 Analysis of total cholesterol (TC) (Vitros, Ortho), HDL cholesterol (Vitros, Ortho), LDL cholesterol (Vitros, Ortho), triglycerides (TGA) (Vitros, Ortho), HbA1c (Tosoh), BNP (Architecht, Abbott), troponin-I (Architecht, Abbott), high-sensitivity C-reactive protein (hs-CRP) (Advia 1800, Siemens), and high-sensitivity troponin-I (Architecht, Abbott) will be performed according to manufacturers’ instructions. Analysis of serum-oxidized low-density lipoprotein (LDL) will be performed with sandwich enzyme-linked immunosorbent assay (ELISA) according to manufacturer’s instructions. The assay will be performed blinded, without knowledge of the clinical diagnosis or randomization.

Fecal samples

Fecal samples will be collected at baseline and during intervention week 12. All samples will be processed and stored for metabolomics and microbiome analyses using a fecal collection kit.

Metabolomics and Microbiome Testing – plasma and fecal samples will be collected pre- and post-intervention and stored for untargeted metabolomics and microbiota analysis at Chalmers University in Gothenburg, Sweden. Plasma samples will be processed and analyzed in four different modes (reverse phase/HILIC chromatography in positive/negative ionization, respectively) on a LC-QTOF-MS instrument according to an established protocol. 60 This will ensure the most comprehensive collection of metabolite features. Data will be pre-processed according to a recently established data-treatment pipeline developed by our group. 61

Gut microbiome will be analyzed by sequencing of 16S rRNA amplicons using Illumina MiSeq. 62 Different data-analysis strategies such as PLS and random forests will be used to derive metabolites and microbiota that differ between treatments as well as derive metabolites and bacterial compositions that may be related to high vs low responders to treatment. 63

Transthoracic echocardiography (Philips CX50, Bothell, USA)

At baseline, left ventricular systolic function, expressed as global ejection fraction in percent, will be evaluated by the discharging physician. At follow-up, the procedure will be repeated by an experienced echocardiography technician or physician. Physicians and technicians will be blinded to the type of intervention. Two-dimensional biplane Simpson´s method will be used for ejection fraction assessment.

Heart rate and blood pressure

Heart rate and blood pressure will be measured after 15 minutes rest by an automatic sphygmomanometer at baseline and follow-up.

Clinical tests of physical fitness

For safety reasons, baseline recordings of clinical exercise tests will be obtained 1-2 weeks after the acute event; the absolute values for changes in exercise capacity after AMI may therefore be underestimated in both groups. The patient will, in good time prior to the test, receive information about no intake of coffee, tea, nicotine or other stimulants that activate the sympathetic nervous system within 2-3 hours prior to the test. The following tests are being used in standard clinical care for all AMI patients in Sweden.

The symptom-limited bicycle ergometer exercise test

The test-retest reliability of the symptom-limited bicycle ergometer exercise test in patients with acute coronary syndrome included in the SWEDEHEART registry is excellent. 64 This submaximal exercise test will be performed on a bicycle ergometer (Monark ProVO2, Monark, Varberg, Sweden) according to a WHO protocol, 65 and will be supervised by qualified physiotherapists blinded to the type of study intervention.

At rest, while sitting on the bicycle, patients will be informed of the symptom-limited exercise test protocol and how to rate their perceived exertion according to the Borg RPE-scale, 66 and dyspnea and possible chest pain according to Borg´s Category Ratio Scale (CR-10). 67 Heart rate will be registered at rest with a wireless heart rate sensor. Systolic and diastolic blood pressure will be measured in both arms and registered for the arm with the highest blood pressure. Initial starting load, 25W or 50 W, is based on the patient´s exertion history, with an increased workload of 25 W every 4.5 minutes. 68 At two and four minutes of each workload; heart rate and rating of Borg scales will be registered. At three minutes, the systolic blood pressure will be measured. The exercise test will be discontinued at 17 on Borg´s RPE-scale and/or 7 on Borg´s CR-10 scale. Other criteria for discontinuing the test are chest pain, drop in blood pressure, failure to increase heart rate, dizziness or other discomfort. Time at the last increment will be noted. If a patient does not complete full 4.5 minutes on the last increment a corrected maximal workload will be calculated using Strandell´s formula; 69 (submaximal workload)+(25xn/4.5), where submaximal workload is the Watt level prior to the step of termination, and (n) the number of minutes completed at the Watt level of the end-point of exercise. Maximal oxygen uptake (VO 2max) from final working load will be approximated with Ekblom-Bak test (www.gih.se/ekblombaktest).

The dynamic unilateral heel-lift and unilateral shoulder-flexion tests

These tests are designed to evaluate muscle endurance, and they are commonly used in exercise based cardiac rehabilitation settings and have excellent reliability for patients with coronary heart disease. 64 70

PEM[hysical activity scales]

The Frändin/Grimby activity scale and the Haskell physical activity scale will be used to subjectively measure physical activity level. 71 72

Primary outcome

Our primary endpoint is LDL cholesterol levels at three months.

Secondary outcomes

The major secondary endpoint is exercise capacity at 3 months. Other secondary endpoints include biochemical markers of inflammation. Table 2 summarizes the secondary outcomes of our study.

Table 2.Primary and secondary endpoints

Primary outcome
  • Change in LDL cholesterol levels
Secondary outcomes
  • Symptom-limited bicycle ergometer test (estimated VO 2max)
  • Dynamic unilateral heel-lift and unilateral shoulder-flexion tests (n)
  • Self-reported activity level (level 1-6, days/week)
  • Fasting lipid levels (TC, HDL, TGA)
  • HbA1c, hs-CRP, BNP
  • Resting heart rate and blood pressure
  • Left ventricular systolic function
  • Change in microbiota composition

Ethics approval

Application to be written during summer 2018.

Statistics and data management

The data will be passed on from the participating centers to Örebro University Hospital where data management work and statistical analyses will be performed. The accredited Swedish clinical research organization, Lytics will be in charge of external web-randomization (http://lytics.ai/company). The results will be analyzed according to the intention-to-treat principle, i.e. patients randomized to a certain group will be followed and assessed irrespectively of the actual treatment. Protocol violations will be monitored continuously and the responsible centers notified. Data collected during the study will be coded so that no subjects can be identified.

Statistical analysis

To assess compliance, we will compare polyphenolic metabolites in blood associated with V. myrtillus intake at baseline and at three months. For values that will fall below the limit of detection, an estimated concentration of 50% of the detection limit will be used. For our primary and main secondary outcome, (on original scale or on log scale as appropriate) a linear mixed model for repeated measurement will be used. Study groups and time (baseline, 3 months) will be used as factors together with the interaction term group x time to test for differences between bilberry and placebo. Ordinal variables will be assessed with chi-2 test for trend or Mann-Whitney U test, and Pearson’s chi-square test or Fisher's exact test when appropriate will be used to test differences between proportions. Two-sided statistical significance levels of 5% will be used and estimates will be presented with 95% confidence intervals. Analyses will be performed using IBM SPSS Statistics 22 (Armonk, NY, USA) or STATA release 14 (College Station, TX, USA)

Explorative analyses of microbiota (omics) data, will be conducted in R. Landbergs laboratory at the Department of Biology and Biological Engineering at Chalmers University of Technology. Instrumental analyses of microbiome and untargeted metabolomics in the project will generate raw data in the terabyte range. Bioinformatics for curation of data into tabular form for data analysis will be performed in direct relation to instrumental analysis by the service provider and additional data handling in-house. Data will be analyzed using primarily multivariate strategies, incorporating unsupervised PCA-based strategies and supervised PLS and random forest strategies. 60

The Landberg group has developed supervised methods to improve modelling accuracy while decreasing overfitting by incorporating unbiased variable selection within a nested cross-validation framework. 73 However, this comes at high computational cost and calculations are frequently performed in the national infrastructures for high-performance computing (SNIC-SENS), especially for more computationally demanding permutation analyses. These statistical analyses will be performed in R, using in house developed programs and scripts published in open access.

Interim Safety Analysis

From the literature and from our own pilot study we have no reason to expect serious side effects with bilberries. Therefore, an Interim Safety Analysis will not be conducted in the study.

Sample size calculations

As no previous intervention trial with bilberry and LDL as an endpoint in AMI patients is available at the time of designing this study, sample size is calculated on the basis of bilberry interventions from four smaller randomized studies in healthy populations, 10 and from our pilot study. With a 5% two-sided significance level, we calculated that 292 subjects would be needed to have a 90% statistical power to detect a -0.38mmol/L larger reduction in LDL cholesterol for the bilberry group compared to placebo, with a standard deviation of 1.0 mmol/L. With this estimation, 146 patients are needed per study group. Power calculations utilized STATA release 14 (College Station, TX, USA) and https://www.sealedenvelope.com/power/continuous-superiority/. In order to allow for dropouts, and especially for the fact that our study population will be receiving high-dose statin treatment, we plan to include 900 patients (equivalent to -0.22 mmol/L mean difference between the bilberry group and placebo). A 1mmol/L reduction in LDL cholesterol, regardless of type of treatment, is equivalent to a 19 % reduction in major vascular events. 74

Randomization procedure

Following written informed consent randomization is stratified by center with a 1:1 allocation within each stratum using predefined block sizes. Block randomization is by a computer generated random number list prepared by Lytics, the clinical research organization in charge of external web-randomization (http://lytics.ai/company). Patients, investigators and all other medical staff are kept blinded to the allocation.

Database and Case Report Form

A study data base with all patients included in the study will be generated based on the ordinary national registry process and a study specific randomization module. An electronic case report form (CRF) will be generated automatically based on the ordinary registration form and stored at Lytics for each patient included. The patient’s identity will always be confidential. Study data will be entered directly in the national SWEDEHEART registry. The investigators are responsible for ensuring the accuracy, completeness, legibility and timeliness of the data recorded in the CRFs.

Documentation and data collection

Criteria for inclusion, informed consent and the decision to include the patient will be documented in the patients’ hospital record. Also, the randomization number will be reported in the hospital record. Follow up data will be registered in the national databases. In the SWEDEHEART registry, detailed information on all patients undergoing coronary angiography in Sweden is registered. Although registry and database information by nature is retrospective, we will in the present study use national registries as prospective platforms for conducting a randomized clinical multicenter trial, the rationale being that with standardized and validated information coupled to health care registries by social security number, almost complete follow-up can be assured with limited extra work related to conducting a trial.

Monitoring

The study will be monitored using the ordinary SWEDEHEART monitoring system and registry monitoring systems in each participating hospital by independent professionals. Before starting the clinical trial all centers will have a telephone/web-based start meeting with presentation of the study, study procedures and documentation. During the study period, monitors will have regular telephone contact with the participating departments to ensure that the trial is conducted in compliance with the protocol and applicable regulatory requirements. The monitors will also provide information and support to the investigator(s) Monitoring will be performed according to risk-based monitoring and a study specific monitoring plan by personnel not otherwise involved in the study.

Administration

Organization

Swedish PCI centers with interest in the trial and willingness to include eligible STEMI and NSTEMI patients during the study period can participate in the study. There will be a local investigator for each center. The investigators will be responsible for the study in the respective centers.

Insurance

The patients in the study are covered by the Swedish patient insurances.

Economy

The trial is an academic study conceived and conducted by staff in the respective hospitals. The study is independent of commercial interests. Study logistics, handling of data and statistical assessments will be financed by the Department of Cardiology, Örebro University Hospital, Sweden. The steering committee will apply for grants from public funds. Possible external sponsors will have no influence on the conduct of the study.

Ethical considerations

The study will be conducted in accordance with the protocol, applicable regulatory requirements such as and the ethical principles of the Declaration of Helsinki as adopted by the 18th World Medical Assembly in Helsinki, Finland, in 1964 and subsequent versions. The study will be initiated when the Medical Ethical Committee of Uppsala, Sweden, has approved the protocol. Significant additions or changes to the protocol may be conducted after the application for amendment is approved by the Ethics Committee.

Timing of informed consent

Patients may be enrolled up to 72 hours following coronary angiography/PCI (NSTEMI and STEMI patients). This time window should allow patients sufficient time to read and consider the patient information and decide whether to participate in the trial or not.

Risks, side-effects, advantages and disadvantages in participation

Patients randomized to both intervention and placebo will be treated according to standard clinical practice. We do not expect that patients in the bilberry intervention group will have any disadvantages from participating. Bilberries are commonly consumed as fresh berries, jam or dried as in this study. We are not aware of any health risks from bilberry consumption. The intervention group may benefit from lower LDL cholesterol levels (the study hypothesis) although this cannot be guaranteed. Any side effect of the bilberry or placebo product will be registered according to 7b World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System: ( https://www.aaaai.org/Aaaai/media/MediaLibrary/PDF%20Documents/Immunotherapy%20Forms/7b-World-Allergy-Organization-Systemic-Reaction-Grading-systemx.pdf ).

Venous blood will be drawn for this study according to hospital routine, and the risk of complications during this procedure is considered low.

For safety reasons, baseline recordings of clinical exercise tests will be obtained 1-2 weeks after the acute event. The submaximal exercise tests are symptom-limited and will be supervised by qualified physiotherapists. This test is performed as standard clinical praxis.

Guidelines for obtaining informed consent

Patients will enter the study after signing the informed consent form. Candidate participants will receive written information of the study, and they will receive oral information by medical doctors participating in the study. The patients will be given time to think through the study participation and to ask questions. Informed consent shall be obtained by a Good Clinical Practice qualified medical doctor or research nurse participating in the study.

Withdrawal

A patient can be withdrawn from the study at any time, if it is the wish of the patient, or if it is medically indicated, as judged by the investigator. A patient’s participation in the study will be discontinued, if any of the following criteria applies: a) the patient’s general condition contraindicates continuing the study, b) non-eligible patient, c) protocol violation. Data collected up to the end of follow-up will be used in the final analysis of the study. If a patient wants to discontinue the study participation, data collected until that time point will be analyzed in the study.

Safety assessments

Any side effects of the bilberry or placebo product will be registered according to the World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System https://www.aaaai.org/Aaaai/media/MediaLibrary/PDF%20Documents/Immunotherapy%20Forms/7b-World-Allergy-Organization-Systemic-Reaction-Grading-systemx.pdf )

(See appendix 2). No other registration of adverse events or serious adverse events will be performed during the study.

Publication

Results, positive as well as negative or inconclusive, will be published in an international medical journal. Publication and author issues will be decided by the steering committee on basis of general involvement in the study (drafting of protocol, core laboratory. function, endpoint committee membership, etc.) and on number of included patients. The sequence of additional authors will be determined by the inclusion rates of the participating centers.

Sub-studies

Initiation of sub-studies are encouraged, but should be accepted by the steering committee. No sub-studies are part of the primary application for ethical approval of the study.

End of trial and archiving

The study will end when the last follow-up has been performed for the last subject. The steering committee reserves the right to terminate the study prematurely e.g. if study participant recruitment is too slow, if study participant retention in the study is insufficient or if undue risk related to the study intervention arises. Data collected during the study will be archived for at least 10 years after the study has been completed.

References

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Landsting - Region Örebro Län - Hälso- och sjukvård - Forskning och utbildning - Övrigt workplace verified by Region Örebro län on 2018-06-14

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Ole Fröbert
Överläkare, Adjungerad Professor, Hjärt-lung-fysiologiska kliniken

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David Erlinge
Professor/Överläkare, Universitetssjukhuset i Lund, Med. fak., Inst för kliniska vetenskaper, Lund

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Effects of dried bilberry dietary supplement after myocardial infarction: a multicenter, prospective, randomized, placebo-controlled trial., from FoU Region Örebro län
http://www.researchweb.org/is/fourol/project/250001