Franciscus Rheumatoid Arhtritis and Cardiovascular Intervention Study

Recent studies have shown without doubt, that inflammation is closely linked to
atherosclerosis. Inflammatory markers such as C-reactive protein (CRP),
leukocyte count and complement component 3 (C3) have been linked to coronary
heart disease (CHD) as well as to hyperlipidemia, insulin resistance, the
metabolic syndrome and type 2 diabetes mellitus. Elevation of these
inflammatory markers is associated to activation of endothelial cells and
leukocytes and/or disturbances in adipose tissue fatty acid metabolism, which
in turn are closely, associated to the well-known CHD risk factors like for
example dyslipidemia, hypertension and obesity and even atherosclerotic plaque
progression. It has been shown that lipoproteins, triglycerides (TG), fatty
acids and glucose can activate endothelial cells in part due to the production
of reactive oxygen species. Elevated TG, disturbances of fatty acid metabolism
and glucose are frequently found in many disorders related to premature
atherosclerosis such as the metabolic syndrome and type 2 diabetes. All of
these have been shown to lead to leukocyte activation in vitro and in vivo,
which is obligatory for the development of atherosclerosis. Therefore,
inhibition of leukocyte activation and/or endothelial cell activation is a
promising target for intervention in the struggle against atherosclerosis.
Patients with RA have an increased risk for atherosclerosis and cardiovascular
death. Recent studies suggest that the risk may be comparable to patients with
type 2 diabetes mellitus. One of the causes of the increased risk in RA may be
leukocyte activation, which is part of the disease. The generation of oxidative
stress by this widespread inflammation may be one of the mechanisms. Recent
studies also suggest an impaired capacity to support vascular regeneration.
Inflammatory mediators such as TNF alpha and IL-6 are associated with the
severity of subclinical atherosclerosis. It has been suggested that a better
treatment of RA and a lower disease activity score could reduce the
cardiovascular risk. Data regarding cardiovascular risk reduction with changed
treatment options have been conflicting. So far there are no clinical studies
available investigating the clinical outcome of patients with RA treated
according current guidelines as proposed in patients with type 2 DM. It is well
known that multiple risk intervention in the latter group can result in
impressive risk reduction, even for cardiovascular mortality, within a short
follow up period. These results have been achieved in type DM in groups of a
few hundred subjects.

The primary aim of this study is to investigate if a tight multiple
cardiovascular risk reduction program is effective in reducing progression of
Intima media thickness progression (subclinical atherosclerosis) in patients
with RA compared to usual care.
The secondary aims are:
(1) to investigate if a tight multiple cardiovascular risk reduction program
is effective in reducing the number of cardiovascular events (clinical
atherosclerosis) in patients with RA compared to usual care.
(2) To investigate if there is any difference in reducing progression of
clinical and subclinical atherosclerosis between the tight control group and
the parallel cohort of RA patients with a cardiovascular risk >10% at baseline.
Cardiovascular risk is determined by using the score model (72)
(3) To investigate if cell-bound apoB (e.g. apoB bound to leukocytes and
erythrocytes) can be used
as marker of risk in these patients;
(4) To evaluate if apoB is a modifiable marker in RA;
(5) To investigate the relationship between leukocyte activation, skin AGEs and
atherosclerosis.


Primary endpoint:
Primary outcome measure is the progression of the carotid artery intima media
thickness (IMT) at 5 years follow-up.

Secondary endpoints:
Secondary outcome measures are the following:
1) cardiovascular mortality
2) cardiovascular events, i.e. nonfatal stroke, nonfatal myocardial infarction,
coronary artery bypass grafting, percutaneous coronary intervention,
revascularisation for peripheral atherosclerotic arterial disease, amputation
because of ischaemia.

The study is designed as a randomized, open, parallel clinical trial and a
prospective cohort. RA patients with a cardiovascular mortality risk >10% at
study entry are, after proper assessment of inclusion and exclusion criteria,
included in the prospective cohort, and monitored and treated according to the
tight multiple cardiovascular risk reduction program. RA patients with a
cardiovascular mortality risk <10% at study entry, eligible for study
participation, are randomly (1:1) assigned either of two strategies: (1)
conventional therapy for multiple risk factors (*usual care*) or (2) the tight
multiple cardiovascular risk reduction program, i.e. intensive multifactorial
intervention involving strict treatment goals. Patients receiving usual care
will be treated by there general practitioner for cardiovascular risk factors
and patients receiving tight control will be treated according to a well
defined program. The rheumatoid arthritis will be treated by patients own
rheumatology. Treatment goals is a disease activity score <2,6 measured by the
DAS 28. Written informed consent will be obtained from each subject.

Participants are recruited at the outpatient clinic of the Departments of
Rheumatology and Internal Medicine, Sint Franciscus Gasthuis, Rotterdam.
At study entry before randomization, subjects will be asked for their medical
history, medication use and family history. Furthermore, they are physically
examined and undergo conventional anthropometric determinations; weight,
length, BMI, waist, waist-hip ratio and blood pressure. A rheumatoid arthritis
disease activity score will be recorded once a year using the DAS28.
Primary outcome measure is increase in Intima media thickness (IMT). Secondary
outcome measures are measures of cardiovascular disease activity at the both on
clinical and laboratory level. Patients in de tight control are offered three
individual outpatient consultations annually at which blood is sampled.
Patients in the usual care group will be offered a consulation once a year.
Intima media thickness (IMT) is measured once a year . In order to be informed
about patient adherence to therapy, patients are asked to fill out a
questionnaire regarding adherence once a year. The follow-up period will be 5
years.

Patients with a cardiovascular risk <10% will be randomized into two groups. A
usual care group and a tight control group. The tight control group will be
followed 3 times a year (or more often when necessary because of treatment) in
the outpatient clinic for vascular medicine and treated according to the
treatment algorithm described below.. Patients in the usual care group will be
followed once a year in the outpatient clinic. Cardiovascular risk factors will
be determined, but treatment will be left to the general practitioner.
Treatment target levels in the tight multiple cardiovascular risk reduction
program (see below and attachment 1).
Treatment goals for blood pressure, cholesterol and triglyceride levels are
determined using the current NIV guidelines for cardiovascular risk management.
- Blood pressure: In the intensive therapy group systolic blood pressure <130
and diastolic blood pressure <85.
- HbA1c: Metformin therapy will be initialized when HbA1c is > 6.4%. When Hba1c
is above 7.0% sitagliptine is added. When HbA1c stays above 7.0% treatment may
be altered as seen fit. To minimize the burden for patients participating HbA1c
is chosen as parameter for glucose tolerance and diabetes. Target levels for
HbA1c are not well defined. A HbA1c level of > 6,5% is considered diabetes,
HbA1c Levels of Metformin therapy will be initialized when HbA1c is > 6.4%.
When Hba1c is above 7.0% sitagliptine is added. When HbA1c stays above 7.0%
treatment may be altered as seen fit. To minimize the burden for patients
participating HbA1c is chosen as parameter for glucose tolerance and diabetes.
Target levels for HbA1c are not well defined. A HbA1c level of > 6,5% is
considered diabetes, HbA1c Levels of 5,7-6,5% are considered pre diabetes. For
diabetes the advised HbA1c level is 7.0%. It is well known that metformin may
reduce the risk to develop diabetes/ further glucose intolerance.
- HDL-C: In male patients > 1mmol/l, in female patients >1,2 mmol/l.
- LDL-C: <3,0 mmol/L
- TG: <2.2 mmol/l
-apoB: 0.9 g/l (76).

If a patient has a blood pressure above targets, on two consecutive
consultations treatment will be started or intensified. The antihypertensive
drug of first choice is an ACE inhibitor due to the cardiovascular protective
effect, The first step is an ACE-inhibitor, perindopril 4mg. Second step
perindopril 8mg. When blood pressure stays above the target with therapy,
indapamide 1,25 will be added, Epitizide is chosen as second drug because of
the known combination with perindopril (Coversyl plus®) If the target values
are not reached a calcium channel blocker, a beta-blocker or an alfa blocker
will be added. This choice is up to the treating physician/research physician.
If a patient has a total cholesterol or LDL cholesterol above target, dietary
measures will be taken, as well as the consultation of a dietitian and
simvastatine 40mg will be started. When there are contra indications or side
effects for simvastatin an equivalent will be chosen (first choice is
atorvastatin 20mg, second choice is fluvastatin 40mg). If targets are not met
on next consultation simvastatin 80mg (or equivalent) will be prescribed. When
targets are not met with maximum statin therapy ezetimibe may be added when
seen fit. Fibrates are only given in cases of isolated hypertrigliceridemia
with levels above target or are added to a statin treatment if the non fasting
serum triglyceride concentration is above 2,2 mmol/L on two consecutive
meetings under optimal statin treatment. When HbA1c levels are above targets,
the first choice treatment will be metformin 2x500mg. When HbA1C stays above 7%
despite a maximum dosage of metformin (i.e. 3x1000mg), sitagliptine 100mg once
a day will be started. If targets are not achieved, the treatment may be
altered as seen fit by the physician. The start of a statin, fibrate and/
antidiabetic medication will always be accompanied by lifestyle and dietary
advice and the advice to go to a dietician. Steroid induced hyperglycemia will
be treated by the general practitioner in case of usual care randomization (as
currently done in daily clinical practice). Patients in the tight control group
will be followed and treated as stated above. Participants that smoke will be
advised to stop. Participants in the tight control group and participants with
a cardiovascular mortality risk >10% will be offered a consultation at the
smoking cessation outpatient clinic.
As stated before, it is well known that a tight, multiple cardiovascular risk
intervention in type 2 diabetes mellitus can result in impressive risk
reduction, even for cardiovascular mortality, within a short follow up period.
Since there will be no use of experimental medication or treatments, both
treatment strategies will be relatively safe. Adverse events that can be
expected are well documented. The general risk for patients participating will
not exceed the risk for patients in daily clinical practice.

Since the majority of the interventions done in this trial is part of routine
clinical practice, the nature of the burden will be primarily time investment.
Medications used are routinely used medications. blood test will be combined
with test done by the rheumatologist because of follow up. Test such as AGE,
IMT are without risk and take only a couple of minutes.