Early Rheumatoid Arthritis COR Intervention

Study Overview
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Brief Summary
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The primary aim of our present study is to evaluate the effect of a targeted, intensified, multidimensional intervention compared to conventional treatment of modifiable risk factors for CVD in patients with early RA. The primary endpoint, a composite of death from cardiovascular causes, non-fatal MI, non-fatal stroke and re-vascularisation, will be assessed after 5years' follow-up.

Detailed Description
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The study is a prospective randomised open, blinded endpoint trial with balanced randomisation (1:1) conducted in seven outpatient clinics in Denmark. Follow-up visits for patients in the intervention group are scheduled to occur at baseline and then after 2, 4 and 12 weeks and thereafter every third month for 5 years after randomisation. The control group will be monitored for RA disease activity and comorbidity after 2, 4 weeks, 12 weeks and thereafter following national guidelines for RA. Prevention of CVD risk factors in the control group will be treated in general practice according to national guidelines for diabetes (2011), hypertension (2009) and CVD (2013).

Official Title
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Multifactorial Intervention to Prevent Cardiovascular Disease in Patients With Early Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis, Cardiovascular Diseases

Intervention / Treatment
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* Other: Simvastatin
* Other: Losartan
* Other: Losartan
* Other: Losartan
* Other: Metformin
* Other: Outpatient rheumatology department
* Other: Refered to general practice


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: RA according to the revised American College of Rheumatology (ACR) 2010 criteria and plasma LDL > 2.5mmol/l. Exclusion Criteria: Pregnancy Lactation Ongoing/previous DMARD therapy Ongoing/previous steorid therapy Contraindication to any of the trial drugs Current infection with parvovirus B19, hepatitis B, hepatitis C or human immune deficiency virus. Previous report of hospitalisation for myocardial ischaemia defined as follows: a) non-fatal myocardial infarction (MI) defined according to national and international guidelines. b) Acute coronary syndrome (ACS) including acute ischaemic symptoms with possible biomarker changes or elctrocardiographic changes that to not meet the criteria for MI, c) angina pectoris, d) revascularisation (percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG).

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Intervention<br>In the intervention group all patients will receive statins according to national guidelines. Stepwise introduction of pharmacological therapy targeting 1) hyperlipidaemia, 2) hypertension, 3) hyperglycaemia and 4) microalbuminuria and behaviour modification will be controlled by the project team in an outpatient rheumatology department. Hyperlipidaemia: LDL > 2.5 is treated with 40 mg Simvastatin; Hypertension: BT > 140/90 mmHg treated with 100 mg OD Losartan; Diabetes: DM BT > 130/80 mmHg treated with 100 mg OD Losartan; Microalbuminuria: Urinary albumin creatinin ratio > 30 mg treated with 100 mg OD Losartan; Hyperglycaemia: HBA1C > 48 mmol/mol treated with 500 mg increased dose to 2,000 mg in 4 weeks Metformin | Other: Simvastatin<br>* LDL > 2.5 is treated with 40 mg<br>* Other names: Hyperlipidaemia;Other: Losartan<br>* BT > 140/90 mmHg treated with 50 mg OD<br>* Other names: Hypertension;Other: Losartan<br>* DM BT > 130/80 mmHg treated with 50 mg OD<br>* Other names: Diabetes;Other: Losartan<br>* Microalbuminuria (urinary albumin creatinin ratio > 30 mg) treated with 100 mg OD<br>* Other names: Microalbuminuria;Other: Metformin<br>* HBA1C > 48 mmol/mol treated with 500 mg increased dose to 2,000 mg in 4 weeks<br>* Other names: Hyperglycaemia;Other: Outpatient rheumatology department<br>* (4 times yearly)<br>* Other names: Intervention;|
| Other: Control<br>In the control group patients will be refered to general practice for pharmacological therapy according to national guidelines targeting 1) hyperlipidaemia, 2) hypertension, 3) hyperglycaemia and 4) microalbuminuria. Hyperlipidaemia: LDL > 2.5 is treated with 40 mg Simvastatin; Hypertension: BT > 140/90 mmHg treated with 100 mg OD Losartan; Diabetes: DM BT > 130/80 mmHg treated with 100 mg OD Losartan; Microalbuminuria: Urinary albumin creatinin ratio > 30 mg treated with 100 mg OD Losartan; Hyperglycaemia: HBA1C > 48 mmol/mol treated with 500 mg increased dose to 2,000 mg in 4 weeks Metformin | Other: Simvastatin<br>* LDL > 2.5 is treated with 40 mg<br>* Other names: Hyperlipidaemia;Other: Losartan<br>* BT > 140/90 mmHg treated with 50 mg OD<br>* Other names: Hypertension;Other: Losartan<br>* DM BT > 130/80 mmHg treated with 50 mg OD<br>* Other names: Diabetes;Other: Losartan<br>* Microalbuminuria (urinary albumin creatinin ratio > 30 mg) treated with 100 mg OD<br>* Other names: Microalbuminuria;Other: Metformin<br>* HBA1C > 48 mmol/mol treated with 500 mg increased dose to 2,000 mg in 4 weeks<br>* Other names: Hyperglycaemia;Other: Refered to general practice<br> <br> * Other names: Control;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Major Cardiac Event (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke and cardiac revascularization) | Days from randomization to the first of cardiac event. If no event, censoring occurs at earliest of termination date or efficacy cut-off date of 31 December 2020. Events will be adjudicated by an endpoint committee. Kaplan-Meier estimate of the mean. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Death Due to Any Cause | Days from randomization to death. If no death then censoring occurs at earliest of termination date or efficacy cutoff date of 31 Dec 2020. Kaplan-Meier estimate of the mean | Up to 5 years | 
| Time to Non-cardiovascular Death | Days from randomization to death from a non-cardiovascular cause. If no event, then censoring occurs at earliest of termination date or efficacy cutoff date of 31 Dec 2020. Events will be adjudicated by an endpoint committee. Kaplan-Meier estimate of the mean | Up to 5 years | 
| Time to Serious Adverse Event (hospitalizations) | Time from randomization to the first venous thromboembolic event. Kaplan-Meier estimate of the mean | Up to 5 years | 
| The proportion of patients having a treatment success | LDL cholesterol < 2.5 mmol/l HbA1c < 48 mmol/mol (HbA1c < 6.5%), Blood pressure < 140/90 mmHg for non-diabetic patients and < 130/80 mm Hg for diabetic patients and normoalbuminuria (urinary albumin creatinine ratio < 30 mg/g) after 1-year of follow-up this in agreement with present national guidelines, which will be adjusted accordingly to any future changes in the respective national guidelines. Low RA disease activity DAS28-CRP < 3.2 and DAS28-CRP < 2.6 at 12, 24 and 60 months. Furthermore, all to hospitalisations will be adjudicated by the event committee | 1, 2 and 5 years |