Ignite Creation Date:
2024-10-26 @ 3:42 PM
Last Modification Date:
2024-10-26 @ 3:42 PM
Study NCT ID:
NCT06637618
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-09-13
Brief Title:
Does the Sequence of Heart Failure Medication Matter
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Cluster and Registry Trial Of the Working Group of Heart Failure in Denmark Does the Strategy of Initiation of Heart Failure Medication Matter in the Real World
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This study will tests whether a strategy of upfront prescription of mineralocorticoid receptor antagonists MRA is different from usual care where MRA are usually prescribes as the last drug of the four drug classes used in the treatment of heart failure with reduced cardiac pump function ace-inhibitor beta blocker sodium-glucose-2 inhibitors MRA
The study is a national study that intends to include all adult Danish patients diagnosed with heart failure and reduced pump function from early 2025 til early 2029
Treatment strategy will be decided by randomisation where each heart failure clinic is randomised to one of the two strategies upfront MRA vs usual care for one year followed by cross-over to the other treatment strategy for one year
Patients will be followed according to usual care at their respective heart failure clinic Study-specific followup will be conducted through the Danish registries for a minimum of two years
The primary goal of the study is to evaluate whether one of the two treatment strategies leads to fewer hospitalisations for heart failure andor death at one year after study entry
Other goals of the study is to evaluate whether one of the two strategies leads to less kidney disease improved quality of life and improved cost-effectiveness
The study is a national study that intends to include all adult Danish patients diagnosed with heart failure and reduced pump function from early 2025 til early 2029
Treatment strategy will be decided by randomisation where each heart failure clinic is randomised to one of the two strategies upfront MRA vs usual care for one year followed by cross-over to the other treatment strategy for one year
Patients will be followed according to usual care at their respective heart failure clinic Study-specific followup will be conducted through the Danish registries for a minimum of two years
The primary goal of the study is to evaluate whether one of the two treatment strategies leads to fewer hospitalisations for heart failure andor death at one year after study entry
Other goals of the study is to evaluate whether one of the two strategies leads to less kidney disease improved quality of life and improved cost-effectiveness
Detailed Description:
This study aims to examine whether upfront initiation of MRA followed by usual care of HFrEF medication up-titration with ACE or ARB SGLT2 inhibitors and beta-blockers can improve clinical outcomes compared to the usual care approach ACEiARB or ARNi BB SGLT2i followed by MRA The investigators hypothesize that upfront initiation of MRA may enhance adherence to MRA therapy To test this hypothesis a cluster randomized controlled trial will be performed comparing two strategies 1 upfront initiation of MRA followed by usual care of up-titration of HFrEF medication versus usual car ACEiARB or ARNi BB SGLT2i followed by MRA This study will provide valuable insights into whether upfront initiation of MRA impacts patient outcomes potentially leading to a shift in HFrEF management
Methods
Design CROWD-Sequence is a cluster-randomized crossover comparative effectiveness study
Intervention All patients will receive treatment according to national guidelines which include all 4 pillars of modern HFrEF treatment The intervention is only whether the heart failure clinic initiates MRA upfront at the first visit compared with the initiation of MRA later in the up-titration of HFrEF medication
Cluster allocation Each participating heart failure clinic will be allocated to four periods clusters two periods with upfront initiation of MRA followed by usual care of HFrEF medication and two periods with usual care of up-titration of HFrEF medication with initiation of MRA at a later stage Heart failure clinics will be randomly allocated and alternate between the two strategies annually The estimated total participation time for each heart failure clinic is four years The randomization is unblinded Randomization of the heart failure clinics will be performed in a 11 fashion Details of randomization and allocation periods will be stored at the Sponsor
If a cluster is scheduled to stop before two years due to organizational changes eg if the heart failure clinic is closed or merged with another clinic the investigators may change the duration of the remaining periods for that cluster to get compatible allocation periods
Eligible departments Danish cardiology departments with a heart failure clinic reporting to the Danish Heart Failure Registry are eligible All responsible contact persons are listed in Appendix 1 Each contact person will comply with the protocol-requirements Further all 26 heart failure clinics will have the same inclusion and exclusion criteria regardless of their cluster allocation
Eligible patients
Patients will be identified when registered in the Danish Heart Failure Registry All patients 18 years old who are newly diagnosed with HFrEF and are allocated to an outpatient clinic for up-titration of guideline-directed medical therapy for HFrEF at participating cardiology departments are candidates for the study Patients will be informed about the study and given the option to opt out of all analyses
The criteria for being included in the Danish Heart Failure Registry are described in Schjoedt et al 2016 11 In brief patients enrolled in the registry must be 18 years or older and have a first-time hospital contact with heart failure as the primary diagnosis using the European Society of Cardiology criteria
Information to the patients
Eligible patients will be informed about the trial through posters and flyers within the department Their treating physician or nurse will inform them directly when initiating the HFrEF medication They will be informed that the department is part of a national effort to compare two similar strategies and will be briefed on the specific strategy currently employed by the heart failure clinic Patients will have the opportunity to opt out of all analyses Those who choose to opt out will be registered in a nationally accessible REDCap database
Treatment in allocation arms
Treatment in clusters will adhere to both Danish and European guidelines The treating physicians will treat patients according to general clinical practice The randomization is only regarding at what time point MRA is initiated not the actual drug prescribed The guideline-recommended treatment will adhere to both Danish and European guidelines The treating physicians will treat patients according to general clinical practice If a patient has a contraindication for a specific drug class eg hypersensitivity to the active substance etc then the patient will not be prescribed this class of drugs An instrumental variable analysis in the per-protocol analysis will be used to allow for this potential confounding by contraindication There will not be any extra patient visits due to the study and there will not be any increased economic burden on the patient
Information to the departments about activities in the trial and treatment allocation
Heart failure clinics will be instructed in the activities of the trial in three ways 1 all contact persons at each heart failure clinic will be sent the protocol together with written instructions on the conduct of the trial 2 all heart failure clinics will be offered an individual meeting on the conduct of the trial and 3 during the trial all heart failure clinics will be able to contact the primary investigators with questions regarding the conduct of the trial Heart failure clinics switch treatment strategies yearly The heart failure clinics will be contacted 3-4 weeks prior to the scheduled annual switch-over to remind them of the upcoming switch-over In addition all heart failure clinics will receive stickers to put on the computer monitors which state which strategy to use in the current period and when the next crossover occurs To handle questions all departments are offered a physical or online meeting before the annual switch-over
Data collection during the allocation period No study-related data on individual patients will be collected during the allocation period so there will be no case report forms
Follow-up Patients will be followed according to the usual standard of care at their respective heart failure clinics As there is no deviation from usual clinical practice except when to initiate MRA patients will not be seen or followed as part of a study protocol The treating physicians will discontinue treatment at their discretion according to usual practice Discontinuation or cross-over will not exempt patients from the study bring about additional procedures and will not be reported to the sponsor-investigator Hence there will be no protocol-specific follow-up Should new information emerge about one of the GDMTs including information that changes the risk-benefit-ratio for patients or patient subgroups treated for heart failure the patients will be informed about this via their local heart failure clinic
For study-specific follow-up data from the Danish Heart Failure Registry which is routinely uploaded to Statistics Denmark will be linked in anonymous form to hospital admissions diagnoses vital status cause of death dispensed descriptions and biochemistry from The Danish National Patient Registry The Danish Civil Registration System The Clinical Laboratory Information System and the Danish National Prescription Registry
All patients will be followed up regardless of whether they adhere to the allocation arm cross over to the other arm or discontinue medication Only patients who opt-out of the analysis will not be included in the follow-up
Concomitant treatment No other treatments before during or after the trial will exempt patients from participation Patients can be included in other research studies concomitantly and independently of this protocol
Data management plan Data will be collected and processed in compliance with Regulation EC No 452001 and national data protection legislation implementing Regulation EU 2016679 respectively The trial is registered with the Knowledge Centre on Data Protection Compliance in Central Denmark Region All data will be stored and analyzed on the Statistics Denmark servers through our agreement with the Division of Research Services at Statistics Denmark Registration of patients who opt out of the study will be collected on paper and entered in a REDcap database After the allocation period before any analyses are performed the REDcap database of patients who have opted out will be uploaded to the Statistics Denmark server and pseudo-anonymized This will allow investigators to exclude patients who have opted out from all analyses Data will be stored for 25 years after which opt out forms will be destroyed
Source data All data will be collected from central Danish registries Hence there will be no case report forms the only source data will be the opt-out forms from the patients who have opted out
Analysis Primary endpoint The primary endpoint will be a combined endpoint of all-cause mortality or first hospitalization for worsening heart failure
Secondary endpoints All-cause mortality First hospitalizations for heart failure Total hospitalizations Dialysis
Primary analysis Proportional hazard regression of time to the primary endpoint from the time of first claiming a prescription for HF medication comparing strategy clusters adjusted for the department of cardiology
Secondary analyses Cost-effectiveness analysis of each strategy The proportion of patients who remained on MRA treatment for a minimum of one year
Change in estimated glomerular filtration rate at one year Difference in GDMT adherence Difference in patient reported outcome
Patient cohort for analysis The patient cohort will consist of all patients registered in the Danish Heart Failure Registry during the allocation period with LVEF 40 excluding patients who had opted out of the study
Sample size considerations Based on data from the Danish Heart Failure Registry investigators expect that approximately 4000 patients will be enrolled in the heart failure registry annually In the Danish Heart Failure Registry 1-year mortality is 10 With 24 clusters four allocation periods and a mean cluster size per allocation period of 100 and assuming that 12 of patients in the control arm experience the primary outcome with an intraclass correlation of 003 and a cluster autocorrelation 0f 08 there will be a 91 power to detect a 15 reduction in the primary outcome in the intervention group
Statistics Analyses will be performed according to the recommendation of the CONSORT statement for cluster trials Primary results will be assessed as intention-to-treat An instrumental variable analysis will be performed where cluster randomization is used as an instrument for receiving treatment
Results for subgroups will be presented These will be prespecified before trial termination Already planned subgroup analyses are age gender NYHA class previous myocardial infarction previous revascularization hypertension type 2 diabetes chronic kidney disease stages atrial fibrillationflutter and socio-economic status A detailed statistical analysis plan will be prepared before study-termination
Safety Patients will be treated according to standard clinical practice Hence the safety of the study participants is equal to that of patients who are not participating in the study
All Danish heart failure clinics have strong experience initiating GDMT for HFrEF including monitoring patient safety as part of common practice Patients discharged from the outpatient clinics will be followed by their general practitioner with regular safety assessments as part of common practice As patients are prescribed the same medical therapy investigators do not expect any changes in the overall number of complications
Methods
Design CROWD-Sequence is a cluster-randomized crossover comparative effectiveness study
Intervention All patients will receive treatment according to national guidelines which include all 4 pillars of modern HFrEF treatment The intervention is only whether the heart failure clinic initiates MRA upfront at the first visit compared with the initiation of MRA later in the up-titration of HFrEF medication
Cluster allocation Each participating heart failure clinic will be allocated to four periods clusters two periods with upfront initiation of MRA followed by usual care of HFrEF medication and two periods with usual care of up-titration of HFrEF medication with initiation of MRA at a later stage Heart failure clinics will be randomly allocated and alternate between the two strategies annually The estimated total participation time for each heart failure clinic is four years The randomization is unblinded Randomization of the heart failure clinics will be performed in a 11 fashion Details of randomization and allocation periods will be stored at the Sponsor
If a cluster is scheduled to stop before two years due to organizational changes eg if the heart failure clinic is closed or merged with another clinic the investigators may change the duration of the remaining periods for that cluster to get compatible allocation periods
Eligible departments Danish cardiology departments with a heart failure clinic reporting to the Danish Heart Failure Registry are eligible All responsible contact persons are listed in Appendix 1 Each contact person will comply with the protocol-requirements Further all 26 heart failure clinics will have the same inclusion and exclusion criteria regardless of their cluster allocation
Eligible patients
Patients will be identified when registered in the Danish Heart Failure Registry All patients 18 years old who are newly diagnosed with HFrEF and are allocated to an outpatient clinic for up-titration of guideline-directed medical therapy for HFrEF at participating cardiology departments are candidates for the study Patients will be informed about the study and given the option to opt out of all analyses
The criteria for being included in the Danish Heart Failure Registry are described in Schjoedt et al 2016 11 In brief patients enrolled in the registry must be 18 years or older and have a first-time hospital contact with heart failure as the primary diagnosis using the European Society of Cardiology criteria
Information to the patients
Eligible patients will be informed about the trial through posters and flyers within the department Their treating physician or nurse will inform them directly when initiating the HFrEF medication They will be informed that the department is part of a national effort to compare two similar strategies and will be briefed on the specific strategy currently employed by the heart failure clinic Patients will have the opportunity to opt out of all analyses Those who choose to opt out will be registered in a nationally accessible REDCap database
Treatment in allocation arms
Treatment in clusters will adhere to both Danish and European guidelines The treating physicians will treat patients according to general clinical practice The randomization is only regarding at what time point MRA is initiated not the actual drug prescribed The guideline-recommended treatment will adhere to both Danish and European guidelines The treating physicians will treat patients according to general clinical practice If a patient has a contraindication for a specific drug class eg hypersensitivity to the active substance etc then the patient will not be prescribed this class of drugs An instrumental variable analysis in the per-protocol analysis will be used to allow for this potential confounding by contraindication There will not be any extra patient visits due to the study and there will not be any increased economic burden on the patient
Information to the departments about activities in the trial and treatment allocation
Heart failure clinics will be instructed in the activities of the trial in three ways 1 all contact persons at each heart failure clinic will be sent the protocol together with written instructions on the conduct of the trial 2 all heart failure clinics will be offered an individual meeting on the conduct of the trial and 3 during the trial all heart failure clinics will be able to contact the primary investigators with questions regarding the conduct of the trial Heart failure clinics switch treatment strategies yearly The heart failure clinics will be contacted 3-4 weeks prior to the scheduled annual switch-over to remind them of the upcoming switch-over In addition all heart failure clinics will receive stickers to put on the computer monitors which state which strategy to use in the current period and when the next crossover occurs To handle questions all departments are offered a physical or online meeting before the annual switch-over
Data collection during the allocation period No study-related data on individual patients will be collected during the allocation period so there will be no case report forms
Follow-up Patients will be followed according to the usual standard of care at their respective heart failure clinics As there is no deviation from usual clinical practice except when to initiate MRA patients will not be seen or followed as part of a study protocol The treating physicians will discontinue treatment at their discretion according to usual practice Discontinuation or cross-over will not exempt patients from the study bring about additional procedures and will not be reported to the sponsor-investigator Hence there will be no protocol-specific follow-up Should new information emerge about one of the GDMTs including information that changes the risk-benefit-ratio for patients or patient subgroups treated for heart failure the patients will be informed about this via their local heart failure clinic
For study-specific follow-up data from the Danish Heart Failure Registry which is routinely uploaded to Statistics Denmark will be linked in anonymous form to hospital admissions diagnoses vital status cause of death dispensed descriptions and biochemistry from The Danish National Patient Registry The Danish Civil Registration System The Clinical Laboratory Information System and the Danish National Prescription Registry
All patients will be followed up regardless of whether they adhere to the allocation arm cross over to the other arm or discontinue medication Only patients who opt-out of the analysis will not be included in the follow-up
Concomitant treatment No other treatments before during or after the trial will exempt patients from participation Patients can be included in other research studies concomitantly and independently of this protocol
Data management plan Data will be collected and processed in compliance with Regulation EC No 452001 and national data protection legislation implementing Regulation EU 2016679 respectively The trial is registered with the Knowledge Centre on Data Protection Compliance in Central Denmark Region All data will be stored and analyzed on the Statistics Denmark servers through our agreement with the Division of Research Services at Statistics Denmark Registration of patients who opt out of the study will be collected on paper and entered in a REDcap database After the allocation period before any analyses are performed the REDcap database of patients who have opted out will be uploaded to the Statistics Denmark server and pseudo-anonymized This will allow investigators to exclude patients who have opted out from all analyses Data will be stored for 25 years after which opt out forms will be destroyed
Source data All data will be collected from central Danish registries Hence there will be no case report forms the only source data will be the opt-out forms from the patients who have opted out
Analysis Primary endpoint The primary endpoint will be a combined endpoint of all-cause mortality or first hospitalization for worsening heart failure
Secondary endpoints All-cause mortality First hospitalizations for heart failure Total hospitalizations Dialysis
Primary analysis Proportional hazard regression of time to the primary endpoint from the time of first claiming a prescription for HF medication comparing strategy clusters adjusted for the department of cardiology
Secondary analyses Cost-effectiveness analysis of each strategy The proportion of patients who remained on MRA treatment for a minimum of one year
Change in estimated glomerular filtration rate at one year Difference in GDMT adherence Difference in patient reported outcome
Patient cohort for analysis The patient cohort will consist of all patients registered in the Danish Heart Failure Registry during the allocation period with LVEF 40 excluding patients who had opted out of the study
Sample size considerations Based on data from the Danish Heart Failure Registry investigators expect that approximately 4000 patients will be enrolled in the heart failure registry annually In the Danish Heart Failure Registry 1-year mortality is 10 With 24 clusters four allocation periods and a mean cluster size per allocation period of 100 and assuming that 12 of patients in the control arm experience the primary outcome with an intraclass correlation of 003 and a cluster autocorrelation 0f 08 there will be a 91 power to detect a 15 reduction in the primary outcome in the intervention group
Statistics Analyses will be performed according to the recommendation of the CONSORT statement for cluster trials Primary results will be assessed as intention-to-treat An instrumental variable analysis will be performed where cluster randomization is used as an instrument for receiving treatment
Results for subgroups will be presented These will be prespecified before trial termination Already planned subgroup analyses are age gender NYHA class previous myocardial infarction previous revascularization hypertension type 2 diabetes chronic kidney disease stages atrial fibrillationflutter and socio-economic status A detailed statistical analysis plan will be prepared before study-termination
Safety Patients will be treated according to standard clinical practice Hence the safety of the study participants is equal to that of patients who are not participating in the study
All Danish heart failure clinics have strong experience initiating GDMT for HFrEF including monitoring patient safety as part of common practice Patients discharged from the outpatient clinics will be followed by their general practitioner with regular safety assessments as part of common practice As patients are prescribed the same medical therapy investigators do not expect any changes in the overall number of complications
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None