HELicobacter Pylori Screening to Prevent Gastrointestinal Bleeding in MI Patients

Cardiovascular Diseases Clinical Trial

— HELP-MI  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05024864
• Other study ID #: HELP-SWEDEHEART
• Status: Recruiting
• Phase: N/A
• Start date: November 17, 2021
• Est. completion date: January 17, 2030

Study information

• Verified date: March 2023
• Source: Karolinska Institutet
• Contact: Robin Hofmann, MD, PhD
• Phone: +4681236161000
• Email: robin.hofmann[@]ki.se
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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:

1. 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.

2. 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.

3. 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 22000
• Est. completion date: January 17, 2030
• Est. primary completion date: January 17, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cardiovascular Diseases
• GastroIntestinal Bleeding
• Gastrointestinal Hemorrhage
• Helicobacter Pylori Infection
• Hemorrhage
• Infarction
• Myocardial Infarction

Intervention

Diagnostic Test:
• Urea breath test
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.

Locations

Country	Name	City	State
Sweden	Södra Älvsborg Hospital	Borås
Sweden	Eskilstuna Hospital	Eskilstuna
Sweden	Falun Hospital	Falun
Sweden	Gävle Hospital	Gävle
Sweden	Östra Hospital	Göteborg
Sweden	Sahlgrenska University Hospital	Göteborg
Sweden	Halmstad Hospital	Halmstad
Sweden	Helsingborg Hospital	Helsingborg
Sweden	Ryhov Hospital	Jönköping
Sweden	Karlskrona Hospital	Karlskrona
Sweden	Köping Hospital	Köping
Sweden	Kristianstad Hospital	Kristianstad
Sweden	Kungälv Hospital	Kungälv
Sweden	Lidköping Hospital	Lidköping
Sweden	Linköping University Hospital	Linköping
Sweden	Skåne University Hospital Lund	Lund
Sweden	Skåne University Hospital Malmö	Malmö
Sweden	Mölndal Hospital	Mölndal
Sweden	Mora Hospital	Mora
Sweden	Motala Hospital	Motala
Sweden	Vrinnevisjukhuset	Norrköping
Sweden	Norrtälje Hospital	Norrtälje
Sweden	Nyköping Hospital	Nyköping
Sweden	Örebro University Hospital	Örebro
Sweden	Sunderby Hospital	Södra Sunderbyn
Sweden	Danderyds University Hospital	Stockholm
Sweden	Karolinska University Hospital Huddinge	Stockholm
Sweden	Karolinska University Hospital Solna	Stockholm
Sweden	Sankt Görans Hospital	Stockholm
Sweden	Södersjukhuset	Stockholm
Sweden	Norra Älvsborgs Länssjukhus	Trollhättan
Sweden	Norrland University Hospital	Umeå
Sweden	Uppsala University Hospital	Uppsala
Sweden	Varberg Hospital	Varberg
Sweden	Västerås Hospital	Västerås

Sponsors (4)

Lead Sponsor	Collaborator
Karolinska Institutet	Region Stockholm, Swedish Heart Lung Foundation, The Swedish Research Council

Country where clinical trial is conducted

Sweden, 

References & Publications (12)

Capodanno D, Bhatt DL, Gibson CM, James S, Kimura T, Mehran R, Rao SV, Steg PG, Urban P, Valgimigli M, Windecker S, Angiolillo DJ. Bleeding avoidance strategies in percutaneous coronary intervention. Nat Rev Cardiol. 2022 Feb;19(2):117-132. doi: 10.1038/s — View Citation

Chey WD, Leontiadis GI, Howden CW, Moss SF. ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. Am J Gastroenterol. 2017 Feb;112(2):212-239. doi: 10.1038/ajg.2016.563. Epub 2017 Jan 10. Erratum In: Am J Gastroenterol. 2018 Jul;113(7):1102. — View Citation

Eikelboom JW, Connolly SJ, Bosch J, Shestakovska O, Aboyans V, Alings M, Anand SS, Avezum A, Berkowitz SD, Bhatt DL, Cook-Bruns N, Felix C, Fox KAA, Hart RG, Maggioni AP, Moayyedi P, O'Donnell M, Ryden L, Verhamme P, Widimsky P, Zhu J, Yusuf S. Bleeding a — View Citation

Fang Y, Fan C, Xie H. Effect of Helicobacter pylori infection on the risk of acute coronary syndrome: A systematic review and meta-analysis. Medicine (Baltimore). 2019 Dec;98(50):e18348. doi: 10.1097/MD.0000000000018348. — View Citation

Hellstrom PM, Benno P, Malfertheiner P. Gastrointestinal bleeding in patients with Helicobacter pylori and dual platelet inhibition after myocardial infarction. Lancet Gastroenterol Hepatol. 2021 Sep;6(9):684-685. doi: 10.1016/S2468-1253(21)00192-8. No ab — View Citation

Lindholm D, Sarno G, Erlinge D, Svennblad B, Hasvold LP, Janzon M, Jernberg T, James SK. Combined association of key risk factors on ischaemic outcomes and bleeding in patients with myocardial infarction. Heart. 2019 Aug;105(15):1175-1181. doi: 10.1136/he — View Citation

Malfertheiner P, Megraud F, O'Morain CA, Gisbert JP, Kuipers EJ, Axon AT, Bazzoli F, Gasbarrini A, Atherton J, Graham DY, Hunt R, Moayyedi P, Rokkas T, Rugge M, Selgrad M, Suerbaum S, Sugano K, El-Omar EM; European Helicobacter and Microbiota Study Group — View Citation

Ng JC, Yeomans ND. <em>Helicobacter pylori</em> infection and the risk of upper gastrointestinal bleeding in low dose aspirin users: systematic review and meta-analysis. Med J Aust. 2018 Sep 1;209(7):306-311. doi: 10.5694/mja17.01274. — View Citation

Sarajlic P, Simonsson M, Jernberg T, Back M, Hofmann R. Incidence, associated outcomes, and predictors of upper gastrointestinal bleeding following acute myocardial infarction: a SWEDEHEART-based nationwide cohort study. Eur Heart J Cardiovasc Pharmacothe — View Citation

Sarri GL, Grigg SE, Yeomans ND. Helicobacter pylori and low-dose aspirin ulcer risk: A meta-analysis. J Gastroenterol Hepatol. 2019 Mar;34(3):517-525. doi: 10.1111/jgh.14539. Epub 2018 Dec 17. — View Citation

Warme J, Sundqvist M, Mars K, Aladellie L, Pawelzik SC, Erlinge D, Jernberg T, James S, Hofmann R, Back M. Helicobacter pylori screening in clinical routine during hospitalization for acute myocardial infarction. Am Heart J. 2021 Jan;231:105-109. doi: 10. — View Citation

Xu Z, Li J, Wang H, Xu G. Helicobacter pylori infection and atherosclerosis: is there a causal relationship? Eur J Clin Microbiol Infect Dis. 2017 Dec;36(12):2293-2301. doi: 10.1007/s10096-017-3054-0. Epub 2017 Jul 27. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	CCS	Symptoms of angina and functional status (CCS class) at 2 months post index hospital admittance	2 months
Other	NYHA	Symptoms of dyspnea and functional status (NYHA class) at 2 months post index hospital admittance	2 months
Other	NYHA	Symptoms of dyspnea and functional status (NYHA class) at 12 months post index hospital admittance	12 months
Other	CCS	Symptoms of angina and functional status (CCS class) at 12 months post index hospital admittance	12 months
Other	EQ-5D	Health-related quality of life by EQ-5D at 12 months post index hospital admittance	12 months
Other	EQ-5D	Health-related quality of life by EQ-5D at 2 months post index hospital admittance	2 months
Other	Health care costs	Cost estimation with regard to consumed care	1 year
Other	Health care costs	Cost estimation with regard to consumed care	5 years
Other	Health care costs	Cost estimation with regard to consumed care	10 years
Primary	Upper gastrointestinal bleeding (UGIB)	Time from index hospital admittance to UGIB	1-2 years of follow-up
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Major Adverse Events (Bleeding)	Time from index hospital admittance to all-cause death or hospitalization for UGIB	1 year
Secondary	Major Adverse Events (Bleeding)	Time from index hospital admittance to all-cause death or hospitalization for UGIB	1-2 years
Secondary	Major Adverse Events (Bleeding)	Time from index hospital admittance to all-cause death or hospitalization for UGIB	1-3 years
Secondary	Major Adverse Events (Bleeding)	Time from index hospital admittance to all-cause death or hospitalization for UGIB	5 years
Secondary	Major Adverse Events (Bleeding)	Time from index hospital admittance to all-cause death or hospitalization for UGIB	10 years
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	All-cause death	Time from index hospital admittance to all-cause death	1 year
Secondary	All-cause death	Time from index hospital admittance to all-cause death	1-2 years of follow-up
Secondary	All-cause death	Time from index hospital admittance to all-cause death	1-3 years of follow-up
Secondary	All-cause death	Time from index hospital admittance to all-cause death	5 years
Secondary	All-cause death	Time from index hospital admittance to all-cause death	10 years
Secondary	Cardiovascular death	Time from index hospital admittance to cardiovascular death	1 year
Secondary	Cardiovascular death	Time from index hospital admittance to cardiovascular death	1-2 years of follow-up
Secondary	Cardiovascular death	Time from index hospital admittance to cardiovascular death	1-3 years of follow-up
Secondary	Cardiovascular death	Time from index hospital admittance to cardiovascular death	5 years
Secondary	Cardiovascular death	Time from index hospital admittance to cardiovascular death	10 years
Secondary	Rehospitalization with myocardial infarction	Time from index hospital admittance to rehospitalization with myocardial infarction	1 year
Secondary	Rehospitalization with myocardial infarction	Time from index hospital admittance to rehospitalization with myocardial infarction	1-2 years of follow-up
Secondary	Rehospitalization with myocardial infarction	Time from index hospital admittance to rehospitalization with myocardial infarction	1-3 years of follow-up
Secondary	Rehospitalization with myocardial infarction	Time from index hospital admittance to rehospitalization with myocardial infarction	5 years
Secondary	Rehospitalization with myocardial infarction	Time from index hospital admittance to rehospitalization with myocardial infarction	10 years
Secondary	Rehospitalization for heart failure	Time from index hospital admittance to rehospitalization for heart failure	1 years
Secondary	Rehospitalization for heart failure	Time from index hospital admittance to rehospitalization for heart failure	1-2 years of follow-up
Secondary	Rehospitalization for heart failure	Time from index hospital admittance to rehospitalization for heart failure	1-3 years of follow-up
Secondary	Rehospitalization for heart failure	Time from index hospital admittance to rehospitalization for heart failure	5 years
Secondary	Rehospitalization for heart failure	Time from index hospital admittance to rehospitalization for heart failure	10 years
Secondary	Rehospitalization for stroke	Time from index hospital admittance to rehospitalization for stroke	1 year
Secondary	Rehospitalization for stroke	Time from index hospital admittance to rehospitalization for stroke	1-2 years of follow-up
Secondary	Rehospitalization for stroke	Time from index hospital admittance to rehospitalization for stroke	1-3 years of follow-up
Secondary	Rehospitalization for stroke	Time from index hospital admittance to rehospitalization for stroke	5 years
Secondary	Rehospitalization for stroke	Time from index hospital admittance to rehospitalization for stroke	10 years
Secondary	UGIB requiring blood transfusion	Time from index hospital admittance to UGIB requiring blood transfusion	1 year
Secondary	UGIB requiring blood transfusion	Time from index hospital admittance to UGIB requiring blood transfusion	1-2 years of follow-up
Secondary	UGIB requiring blood transfusion	Time from index hospital admittance to UGIB requiring blood transfusion	1-3 years of follow-up
Secondary	UGIB requiring blood transfusion	Time from index hospital admittance to UGIB requiring blood transfusion	5 years
Secondary	UGIB requiring blood transfusion	Time from index hospital admittance to UGIB requiring blood transfusion	10 years
Secondary	Upper gastrointestinal bleeding (UGIB)	Time from index hospital admittance to UGIB	1 year
Secondary	Upper gastrointestinal bleeding (UGIB)	Time from index hospital admittance to UGIB	1-3 years
Secondary	Upper gastrointestinal bleeding (UGIB)	Time from index hospital admittance to UGIB	5 years
Secondary	Upper gastrointestinal bleeding (UGIB)	Time from index hospital admittance to UGIB	10 years