HELicobacter Pylori Screening to Prevent Gastrointestinal Bleeding in MI Patients

Study Overview
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Brief Summary
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Background: Potent antithrombotic therapy has improved prognosis for patients with acute myocardial infarction (MI) significantly, however, at a price of increased bleeding risk. Helicobacter pylori (H. pylori) infection commonly causes upper gastrointestinal bleeding (UGIB). If systematic screening for H. pylori and subsequent eradication therapy significantly reduces the risk of UGIB and improves outcomes is unknown. Study design: A cluster randomized, cross-over, registry-based clinical trial using nationwide Swedish registries for patient enrollment and data collection. Population: Patients hospitalized for MI at up to 40 hospitals across Sweden. Regional PCI networks comprise 18 clusters. Clusters will be randomized to H. pylori screening or no screening for 1 year after which cross-over to the opposite strategy for 1 year is followed by 1-year follow-up. Intervention: All MI patients will be routinely screened for H. pylori. Patients diagnosed with active H. pylori infection will receive eradication therapy. All follow-up by data collection from national registries. Controls: Standard clinical practice. Data will be collected from national registries. Outcome: Primary outcome is the incidence of hospitalization for UGIB. Secondary outcomes include mortality (all-cause, cardiovascular), cardiovascular endpoints (rehospitalization for MI, heart failure or stroke), or UGIB requiring blood transfusion.

Detailed Description
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Background: Despite progressively reduced mortality over the last decades, cardiovascular disease remains the most common cause of death in both men and women in Sweden and the world. Ischemic heart disease with its acute presentation myocardial infarction (MI) accounts for the majority of cases, approximately 25000 hospitalized patients in Sweden annually. In addition to early revascularization therapy, potent antithrombotic therapy is the basis for the reduction in cardiovascular events, however, at a price of increased risk of bleeding, typically upper gastrointestinal bleeding (UGIB) that result in substantial morbidity, mortality, and medical care cost. Consequently, antithrombotic therapy may be interrupted in these cases leading to an excessive risk of cardiovascular events; in particular in patients with high age or comorbidities who - by fear of bleeding - rarely receive full recommended treatment from the start. It is recognized that major bleeding events affect prognosis comparably to spontaneous ischemic complications. To optimize the sensitive trade-off between ischemia and bleeding, risk factor management is crucial. On top of established risk factors - high age, male sex, smoking, dyslipidemia, hypertension, hyperglycemia, physical inactivity - chronic active infection with Helicobacter pylori (H. pylori) may be important for two reasons: First, as it commonly causes acute and chronic gastroduodenal lesions, concomitant anticoagulation or antithrombotic therapy aggravates the risk for bleeding, 2-fold with low dose aspirin, and 7-fold with dual antiplatelet therapy, which today is standard treatment for 12 months post MI.2 Non-invasive screening for H. pylori can be performed easily with high accuracy by urea breath test (UBT). If found positive, eradication by triple therapy is well established, recommended in risk individuals and believed to reverse the bleeding risk almost completely. Second, H. pylori has been proposed as a causal factor between atherosclerosis progression and plaque instability associated with a two-fold increased risk. However, as no data from contemporary randomized trials are available, controversy remains due to conflicting results caused by limitations in sample size, observational study design, lack of information on H. pylori virulence factors, and different methods of detection of H. pylori status. H. pylori may hence be an overlooked risk factor for bleeding complications in MI patients, which potentially could be eliminated by H. pylori eradication treatment. This would be anticipated not only to reduce the UGIB complications after MI but also to improve the adherence to dual antiplatelet therapy and consequently potentially also improve the cardiovascular prognosis in this group. H. pylori screening in a contemporary MI population has to our knowledge never been performed. Hence, it remains unknown if systematic screening and subsequent eradication therapy significantly reduces the risk of bleeding and improves prognosis. OBJECTIVE - paradigm and main hypothesis The aim of this main trial is to determine whether systematic screening for (H. pylori) and subsequent eradication therapy significantly reduces the risk of hospitalization for UGIB and cardiovascular events including death in patients after myocardial infarction (MI) The investigators hypothesize that H. pylori screening and eradication in MI patients tested positive reduces bleeding and improves cardiovascular outcomes. STUDY POPULATIONS: PRIMARY INTENTION-TO-TREAT (ITT) POPULATION All patients 18 years of age or older registered in SWEDEHEART as admitted at an active study site and with a discharge diagnosis of MI (including ICD-10 code I21 or I22) irrespective of Hp diagnostics performed or possible eradication treatment if tested positive. MATCHED SECONDARY PER-PROTOCOL (MPP) POPULATION All patients 18 years of age or older registered in SWEDEHEART as admitted at a study site randomized to screening and with a discharge diagnosis of MI (including ICD-10 code I21 or I22) who were screened for HP are compared to matched patients from the control group from study sites randomized to no-screening. TERTIARY POPULATIONS 3.1 MATCHED SCREENED POPULATION (MS) All patients 18 years of age or older registered in SWEDEHEART as admitted at a study site randomized to screening and with a discharge diagnosis of MI (including ICD-10 code I21 or I22) who were screened positive for HP are compared to matched patients from the control group from study sites randomized to no-screening. 3.2 MATCHED TREATED POPULATION (MT) All patients 18 years of age or older registered in SWEDEHEART as admitted at a study site randomized to screening and with a discharge diagnosis of MI (including ICD-10 code I21 or I22) who were screened positive for HP and had eradication therapy dispensed are compared to matched patients from the control group from study sites randomized to no-screening. In matched populations, treatment effects will be estimated using latent subgroup methods based on randomization as an instrumental variable and respecting the cluster structure. OUTCOMES As specified below. Pre-specified subgroups are: Age Sex Smoking status Hypertension Diabetes Previous cardiovascular disease (MI, HF, stroke, peripheral arterial disease [PAD]) Anemia (previous diagnosis and at arrival during index hospitalization) Previous gastroduodenal disease (UGIB, peptic ulcer disease [PUD], atrophic gastritis, mucosa-associated lymphoid tissue [MALT] lymphoma, gastric cancer) Chronic kidney disease (CKD) MI patients by subtype MI patients according to revascularization status MI patients according to revascularization technique Concomitant medication (antithrombotic, anticoagulation, NSAID, serotonin reuptake inhibitors, cortisone, proton pump inhibitors) Stratified according to time on DAPT Stratified according to antithrombotic therapy Stratified according to trial site Stratified according to socioeconomic and sociodemographic parameters All described endpoints will be analyzed in all subgroups and study populations and reported during short-term (30 days), medium-term (1,1-2,1-3 years) and, at a later stage, long-term (5 years, 10 years) follow-up (chapter 6). The primary analysis will use 1-2 years of follow-up.

Official Title
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HELicobacter Pylori Screening to Prevent Gastrointestinal Bleeding in Patients With Acute Myocardial Infarction Trial Based on the SWEDEHEART Registry (HELP-SWEDEHEART)

Conditions
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Myocardial Infarction, Helicobacter Pylori Infection, GastroIntestinal Bleeding, Cardiovascular Diseases

Intervention / Treatment
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* Diagnostic Test: Urea breath test


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 Registered in SWEDEHEART as admitted at an active study site and with a discharge diagnosis of myocardial infarction including ICD-10 code I21 or I22. Exclusion Criteria: None

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Cluster randomized, crossover, registry-based clinical trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Helicobacter pylori screening<br>At centers randomized to screening, all patients with confirmed MI will be tested H. pylori infection with a bedside UBT incorporated into MI routine care during the hospitalization period. In patients tested H. pylori positive, standard triple eradication therapy according to the national society of gastroenterology guidelines will be prescribed at the caring physician's discretion. | Diagnostic Test: Urea breath test<br>* After fasting for six hours prior to testing, the patient swallows a C13 Urea tablet or solution and waits. After 10 minutes, the patient exhales and breath is collected (breath bag). The production of 13CO2 is measured by a desktop analyzer (infrared mass spectrometry) and active H. pylori infection diagnosis is made based on previously established cut-off levels for H. pylori infection. In patients tested positive, eradication therapy according to the national society of gastroenterology guidelines will be prescribed at the caring physician's discretion. Control of successful H. pylori eradication 6 weeks after completed eradication therapy is recommended to the treating physician.<br>|
| No Intervention: Usual care without Helicobacter pylori screening<br>At centers randomized to no screening, all MI patients will receive usual care and will be followed in national registries. Concerning the use of eradication therapy and other relevant medication), follow-up is performed in the National Drug Prescription Registry. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Upper gastrointestinal bleeding (UGIB) | Time from index hospital admittance to UGIB | 1-2 years of follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Net Adverse Clinical Events (NACE) | Time from index hospital admittance to all-cause death, UGIB, rehospitalization with MI, hospitalization for HF or stroke (NACE) | 1 year | 
| Net Adverse Clinical Events (NACE) | Time from index hospital admittance to all-cause death, UGIB, rehospitalization with MI, hospitalization for HF or stroke (NACE) | 1-2 years of follow-up | 
| Net Adverse Clinical Events (NACE) | Time from index hospital admittance to all-cause death, UGIB, rehospitalization with MI, hospitalization for HF or stroke (NACE) | 1-3 years of follow-up | 
| Net Adverse Clinical Events (NACE) | Time from index hospital admittance to all-cause death, UGIB, rehospitalization with MI, hospitalization for HF or stroke (NACE) | 5 years | 
| Net Adverse Clinical Events (NACE) | Time from index hospital admittance to all-cause death, UGIB, rehospitalization with MI, hospitalization for HF or stroke (NACE) | 10 years | 
| Major Adverse Events (Bleeding) | Time from index hospital admittance to all-cause death or hospitalization for UGIB | 1 year | 
| Major Adverse Events (Bleeding) | Time from index hospital admittance to all-cause death or hospitalization for UGIB | 1-2 years | 
| Major Adverse Events (Bleeding) | Time from index hospital admittance to all-cause death or hospitalization for UGIB | 1-3 years | 
| Major Adverse Events (Bleeding) | Time from index hospital admittance to all-cause death or hospitalization for UGIB | 5 years | 
| Major Adverse Events (Bleeding) | Time from index hospital admittance to all-cause death or hospitalization for UGIB | 10 years | 
| Major Adverse Cardiac or Cerebrovascular Events (MACCE) 1 | Time from index hospital admittance to all-cause death, rehospitalization with MI, or hospitalization for HF, or stroke (MACCE 1) | 1 year | 
| Major Adverse Cardiac or Cerebrovascular Events (MACCE) 1 | Time from index hospital admittance to all-cause death, rehospitalization with MI, or hospitalization for HF, or stroke (MACCE 1) | 1-2 years of follow-up | 
| Major Adverse Cardiac or Cerebrovascular Events (MACCE) 1 | Time from index hospital admittance to all-cause death, rehospitalization with MI, or hospitalization for HF, or stroke (MACCE 1) | 1-3 years of follow-up | 
| Major Adverse Cardiac or Cerebrovascular Events (MACCE) 1 | Time from index hospital admittance to all-cause death, rehospitalization with MI, or hospitalization for HF, or stroke (MACCE 1) | 5 years | 
| Major Adverse Cardiac or Cerebrovascular Events (MACCE) 1 | Time from index hospital admittance to all-cause death, rehospitalization with MI, or hospitalization for HF, or stroke (MACCE 1) | 10 years | 
| Major Adverse Cardiac or Cerebrovascular Events (MACCE) 2 | Time from index hospital admittance to CV death, rehospitalization with MI, or hospitalization for HF, or stroke (MACCE 2) | 1 year | 
| Major Adverse Cardiac or Cerebrovascular Events (MACCE) 2 | Time from index hospital admittance to CV death, rehospitalization with MI, or hospitalization for HF, or stroke (MACCE 2) | 1-2 years | 
| Major Adverse Cardiac or Cerebrovascular Events (MACCE) 2 | Time from index hospital admittance to CV death, rehospitalization with MI, or hospitalization for HF, or stroke (MACCE 2) | 1-3 years | 
| Major Adverse Cardiac or Cerebrovascular Events (MACCE) 2 | Time from index hospital admittance to CV death, rehospitalization with MI, or hospitalization for HF, or stroke (MACCE 2) | 5 years | 
| Major Adverse Cardiac or Cerebrovascular Events (MACCE) 2 | Time from index hospital admittance to CV death, rehospitalization with MI, or hospitalization for HF, or stroke (MACCE 2) | 10 years | 
| All-cause death | Time from index hospital admittance to all-cause death | 1 year | 
| All-cause death | Time from index hospital admittance to all-cause death | 1-2 years of follow-up | 
| All-cause death | Time from index hospital admittance to all-cause death | 1-3 years of follow-up | 
| All-cause death | Time from index hospital admittance to all-cause death | 5 years | 
| All-cause death | Time from index hospital admittance to all-cause death | 10 years | 
| Cardiovascular death | Time from index hospital admittance to cardiovascular death | 1 year | 
| Cardiovascular death | Time from index hospital admittance to cardiovascular death | 1-2 years of follow-up | 
| Cardiovascular death | Time from index hospital admittance to cardiovascular death | 1-3 years of follow-up | 
| Cardiovascular death | Time from index hospital admittance to cardiovascular death | 5 years | 
| Cardiovascular death | Time from index hospital admittance to cardiovascular death | 10 years | 
| Rehospitalization with myocardial infarction | Time from index hospital admittance to rehospitalization with myocardial infarction | 1 year | 
| Rehospitalization with myocardial infarction | Time from index hospital admittance to rehospitalization with myocardial infarction | 1-2 years of follow-up | 
| Rehospitalization with myocardial infarction | Time from index hospital admittance to rehospitalization with myocardial infarction | 1-3 years of follow-up | 
| Rehospitalization with myocardial infarction | Time from index hospital admittance to rehospitalization with myocardial infarction | 5 years | 
| Rehospitalization with myocardial infarction | Time from index hospital admittance to rehospitalization with myocardial infarction | 10 years | 
| Rehospitalization for heart failure | Time from index hospital admittance to rehospitalization for heart failure | 1 years | 
| Rehospitalization for heart failure | Time from index hospital admittance to rehospitalization for heart failure | 1-2 years of follow-up | 
| Rehospitalization for heart failure | Time from index hospital admittance to rehospitalization for heart failure | 1-3 years of follow-up | 
| Rehospitalization for heart failure | Time from index hospital admittance to rehospitalization for heart failure | 5 years | 
| Rehospitalization for heart failure | Time from index hospital admittance to rehospitalization for heart failure | 10 years | 
| Rehospitalization for stroke | Time from index hospital admittance to rehospitalization for stroke | 1 year | 
| Rehospitalization for stroke | Time from index hospital admittance to rehospitalization for stroke | 1-2 years of follow-up | 
| Rehospitalization for stroke | Time from index hospital admittance to rehospitalization for stroke | 1-3 years of follow-up | 
| Rehospitalization for stroke | Time from index hospital admittance to rehospitalization for stroke | 5 years | 
| Rehospitalization for stroke | Time from index hospital admittance to rehospitalization for stroke | 10 years | 
| UGIB requiring blood transfusion | Time from index hospital admittance to UGIB requiring blood transfusion | 1 year | 
| UGIB requiring blood transfusion | Time from index hospital admittance to UGIB requiring blood transfusion | 1-2 years of follow-up | 
| UGIB requiring blood transfusion | Time from index hospital admittance to UGIB requiring blood transfusion | 1-3 years of follow-up | 
| UGIB requiring blood transfusion | Time from index hospital admittance to UGIB requiring blood transfusion | 5 years | 
| UGIB requiring blood transfusion | Time from index hospital admittance to UGIB requiring blood transfusion | 10 years | 
| Upper gastrointestinal bleeding (UGIB) | Time from index hospital admittance to UGIB | 1 year | 
| Upper gastrointestinal bleeding (UGIB) | Time from index hospital admittance to UGIB | 1-3 years | 
| Upper gastrointestinal bleeding (UGIB) | Time from index hospital admittance to UGIB | 5 years | 
| Upper gastrointestinal bleeding (UGIB) | Time from index hospital admittance to UGIB | 10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myocardial infarction, Helicobacter Pylori Infection, GastroIntestinal Bleeding, Cardiovascular Diseases, Eradication therapy, Registry based randomized clinical trial, Mortality, Cluster-randomized crossover trial