Abstract

Objectives. Documentation on secondary prevention with statins in RA patients with coronary heart disease (CHD) is limited, despite the increased risk of CHD in RA. Our objective was to describe the effect of statin treatment on lipid levels and cardiovascular disease (CVD) events in patients with RA who participated in the incremental decrease in endpoints through aggressive lipid lowering (IDEAL) study.

Methods. Patients with previous myocardial infarction (MI) were randomly assigned to atorvastatin 80 mg daily or simvastatin 20–40 mg daily and followed for 4.8 years. We focused on changes in lipid levels in the current exploratory analyses and used the composite secondary endpoint in the IDEAL study: any CVD event. Out of the 8888 patients in the IDEAL study, 87 had RA.

Results. RA patients had significantly lower baseline levels of total- and low-density lipoprotein (LDL) cholesterol than patients without RA; 4.8 + 1.0 vs 5.1 + 1.0 (P = 0.023) and 2.9 + 0.9 vs 3.1 + 0.9 mmol/l (P = 0.034) for total cholesterol and LDL, respectively. The lipid reductions with either simvastatin or atorvastatin were comparable. Cardiovascular events occurred in 23/87 (26.4%) of the RA patients compared with 2523/8801 (28.7%; P = 0.70) in the general IDEAL population. The occurrence of these events was not related to the duration of RA, age, gender or treatment assignment.

Conclusion. Patients with RA and previous MI had comparable lipid-lowering effect and similar rates of cardiovascular events as those without RA, although the RA patients had lower baseline cholesterol levels than patients without RA.

Introduction

The risk of cardiovascular disease (CVD) in RA is >2-fold compared with the general population and is comparable with the increased CVD risk in diabetes mellitus type 2 [1]. In addition, as much as 50% of all deaths in those with RA are due to CVD [2]. Thus, there is a substantial need for cardiovascular risk intervention in patients with RA.

Lipid lowering with statins in patients both with and without signs of atherosclerotic disease significantly reduces the risk of CVD [3–5]. Indeed, in patients with CVD, intensive reductions of low-density lipoprotein (LDL) to levels of 1.6–1.8 mmol/l have demonstrated an additional protection against CVD risk compared with standard dosage of statins and moderate lipid reduction [6–8].

Despite the increased risk of CVD in RA, there are, to our knowledge, no reports on cardiovascular secondary prevention with statins or the statin effect on lipid lowering in RA patients with previous myocardial infarction (MI). Furthermore, no prospective randomized CVD endpoint trial has addressed the effects of lipid-lowering treatment in this patient group. The main focus in this exploratory analysis was to describe the effect of statin therapy on lipid levels and rates of CVD mortality and morbidity in the sub-group of patients with RA and previous MI [coronary heart disease (CHD)] who participated in the incremental decrease in endpoints through aggressive lipid lowering (IDEAL) study.

Methods

In the IDEAL study [6], 8888 patients aged ≤80 years with a history of acute MI received either atorvastatin 80 mg daily or simvastatin 20 mg daily (titrated up to 40 mg daily) in a prospective, randomized, open-label, blinded end-point evaluation (PROBE) design and with a median follow-up of 4.8 years. Written informed consent was obtained from all patients according to the Declaration of Helsinki, and the IDEAL study was approved by Regional Committees for Medical and Health Research Ethics in all countries and by governmental reimbursing institutions in countries where the main sponsor did not cover all costs.

All lipid and lipoprotein levels were measured from fasting blood samples, along with liver enzymes and other laboratory measurements. These measurements were performed at baseline, at 12 and 24 weeks, at 1 year and yearly thereafter. All measurements were made in a central laboratory.

To obtain the maximum number of CVD events, we used the secondary endpoint for the current exploratory analyses: any CVD event (hospitalization for angina pectoris and/or non-fatal and fatal acute MI, heart failure, interventions as percutaneous coronary intervention or coronary artery bypass graft operation, stroke or transitory ischaemic attacks).

When patients entered the IDEAL study, all current diseases in each individual were recorded and later coded according to the International Classification of Diseases (ICDs). Patients were classified to have RA according to the following ICD codes from the 8th, 9th and 10th revision: ICD-8 (from 1969 to 1986): 712.0; ICD-9 (from 1986 to 1998): 714.0 (RF-positive RA) and 714.8 (RF-negative RA); ICD-10 (from 1998 to present): M05.8, M05.9 (RF-positive RA) and M06.0 (RF-negative RA). We identified 87 patients with RA out of the 8888 patients participating in the IDEAL study, leaving 8801 patients being used as comparators to the RA patients in our exploratory analysis.

Statistics

Descriptive statistics with means (s.d.) are presented for the measurements of lipids. The median and inter-quartile range (IQR) are also presented for triglycerides (TG). Differences between lipids and lipoprotein components in RA and non-RA patients were tested by t-test or non-parametric Wilcoxon rank-sum test (for TG only) for baseline values, and an analysis of covariance (ANCOVA) model for changes from baseline to the last lipid measurement during follow-up (adjusting for baseline values). P-values were not adjusted for the number of comparisons (Bonferroni), since we performed an explorative analysis. Comparisons between side effects in RA and non-RA patients were done by a two-sided Fisher’s exact test. A Cox proportional hazards model was used to compare the occurrence of CVD events in the RA patients receiving atorvastatin vs simvastatin adjusted for age and gender. This model was also used to test the relationship between the duration of RA diagnosis (categorized below and above median length of having RA; 12 years) and the occurrence of CVD, adjusted for age and gender.

Results

Of the 87 patients with RA, 39 patients received atorvastatin 80 mg and 48 simvastatin 20–40 mg. Female gender was more frequent among the RA compared with the non-RA patients (P < 0.01; Table 1). Furthermore, RA patients had a greater degree of diabetes, were more often current smokers and had higher blood pressure. However, none of these differences was statistically significant, except that RA patients more frequently used warfarin (P < 0.05).

Table 1

Baseline patient characteristics

Characteristics RA (n = 87) non-RA (n = 8801) 
Age, years 62.6 (8.8) 63.2 (8.9) 
Female 37 (42.5)* 1664 (18.9) 
Blood pressure, mmHg   
 Systolic 140.1 (22.8) 136.9 (20.0) 
 Diastolic 78.9 (10.8) 80.4 (10.2) 
Cardiovascular history   
 ≤2 months since last MI 8 (9.2) 991 (11.3) 
 >1 Previous MIs 18 (20.7) 1476 (16.8) 
  One MI 69 (79.3) 7309 (83.2) 
  Two MIs 16 (18.4) 1192 (13.6) 
  Three or more MIs 2 (2.3) 284 (3.2) 
 Cerebrovascular disease 5 (5.7) 650 (7.4) 
 Congestive heart failure 5 (5.7) 532 (6.0) 
 Atrial fibrillation or flutter 9 (10.3) 659 (7.5) 
Risk factors   
 BMIa 27.2 (4.0) 27.3 (3.8) 
  Current smoker 19 (21.8) 1816 (20.6) 
  Former smoker 53 (60.9) 5138 (58.4) 
  Never smoker 15 (17.2) 1843 (20.9) 
 Hypertension 30 (34.5) 2894 (32.9) 
 Diabetes 16 (18.4) 1053 (12.0) 
Pre-randomization statin therapy 68 (78.2) 6645 (75.5) 
Concomitant therapy   
 Aspirin 65 (74.7) 6968 (79.2) 
 Warfarin 11 (12.6) 606 (6.9)** 
 β-blocker 68 (78.2) 6590 (74.9) 
 Calcium antagonist 14 (16.1) 1708 (19.4) 
 ACE inhibitors 27 (31.0) 2636 (29.9) 
 Angiotensin II blockers 4 (4.6) 529 (6.0) 
Characteristics RA (n = 87) non-RA (n = 8801) 
Age, years 62.6 (8.8) 63.2 (8.9) 
Female 37 (42.5)* 1664 (18.9) 
Blood pressure, mmHg   
 Systolic 140.1 (22.8) 136.9 (20.0) 
 Diastolic 78.9 (10.8) 80.4 (10.2) 
Cardiovascular history   
 ≤2 months since last MI 8 (9.2) 991 (11.3) 
 >1 Previous MIs 18 (20.7) 1476 (16.8) 
  One MI 69 (79.3) 7309 (83.2) 
  Two MIs 16 (18.4) 1192 (13.6) 
  Three or more MIs 2 (2.3) 284 (3.2) 
 Cerebrovascular disease 5 (5.7) 650 (7.4) 
 Congestive heart failure 5 (5.7) 532 (6.0) 
 Atrial fibrillation or flutter 9 (10.3) 659 (7.5) 
Risk factors   
 BMIa 27.2 (4.0) 27.3 (3.8) 
  Current smoker 19 (21.8) 1816 (20.6) 
  Former smoker 53 (60.9) 5138 (58.4) 
  Never smoker 15 (17.2) 1843 (20.9) 
 Hypertension 30 (34.5) 2894 (32.9) 
 Diabetes 16 (18.4) 1053 (12.0) 
Pre-randomization statin therapy 68 (78.2) 6645 (75.5) 
Concomitant therapy   
 Aspirin 65 (74.7) 6968 (79.2) 
 Warfarin 11 (12.6) 606 (6.9)** 
 β-blocker 68 (78.2) 6590 (74.9) 
 Calcium antagonist 14 (16.1) 1708 (19.4) 
 ACE inhibitors 27 (31.0) 2636 (29.9) 
 Angiotensin II blockers 4 (4.6) 529 (6.0) 

Values are given as mean (s.d.) for continuous variables and as counts in number (%) for categorical variables. No significant differences between groups were found, except RA was more frequently found in females (*P < 0.001) and non-RA patients used less warfarin (**P = 0.036). aBMI was calculated as weight in kilograms divided by the square of height in metres. AMI: acute MI; ACE: angiotensin-converting enzyme.

The lipids and lipoprotein components were normally distributed except for TG. Log transformation of TG did not yield further information. The RA patients had significantly lower baseline total cholesterol (Tot Chol), LDL cholesterol and apolipoprotein B (apoB) than patients without RA, while TG and the anti-atherogenic lipoprotein components, high-density lipoprotein (HDL) and apoA-1, where equal in RA and non-RA patients (Table 2). Both the lipid ratios (Tot Chol/HDL and LDL/HDL) and apoB/apoA-1 were significantly lower in RA compared with non-RA patients.

Table 2

Baseline lipids and apolipoproteins

Lipids and RA non-RA  
lipoproteins (n = 87) (n = 8801) P-value* 
Tot Chol, mmol/l 4.8 (1.0) 5.1 (1.0) 0.023 
LDL, mmol/l 2.9 (0.9) 3.1 (0.9) 0.034 
HDL, mmol/l 1.2 (0.3) 1.2 (0.3) 0.998 
TG, mmol/l 1.5 (1.1, 1.9) 1.5 (1.1, 2.0) 0.695 
ApoB, g/l 1.1 (0.3) 1.2 (0.3) 0.029 
ApoA-1, g/l 1.4 (0.2) 1.4 (0.2) 0.526 
Tot Chol/HDL 4.2 (1.1) 4.5 (1.4) 0.023 
LDL/HDL 2.6 (0.9) 2.8 (1.1) 0.033 
ApoB/apoA-1 0.8 (0.2) 0.9 (0. 3) 0.048 
Lipids and RA non-RA  
lipoproteins (n = 87) (n = 8801) P-value* 
Tot Chol, mmol/l 4.8 (1.0) 5.1 (1.0) 0.023 
LDL, mmol/l 2.9 (0.9) 3.1 (0.9) 0.034 
HDL, mmol/l 1.2 (0.3) 1.2 (0.3) 0.998 
TG, mmol/l 1.5 (1.1, 1.9) 1.5 (1.1, 2.0) 0.695 
ApoB, g/l 1.1 (0.3) 1.2 (0.3) 0.029 
ApoA-1, g/l 1.4 (0.2) 1.4 (0.2) 0.526 
Tot Chol/HDL 4.2 (1.1) 4.5 (1.4) 0.023 
LDL/HDL 2.6 (0.9) 2.8 (1.1) 0.033 
ApoB/apoA-1 0.8 (0.2) 0.9 (0. 3) 0.048 

Values are given as mean (s.d.), except for TG, which are presented as median (IQR). *P-values are based on two-sample t-tests for all lipids and apolipoproteins except TG. For TG, the P-value is based on a non-parametric Wilcoxon rank sum test.

The effect of both simvastatin and atorvastatin on lipids and apolipoproteins in RA patients were comparable with patients without RA (Table 3), with the exception of a significantly higher increase from baseline in HDL and apoA-1 levels in RA vs non-RA patients in the atorvastatin group. The changes in the lipid ratios and apolipoprotein ratio were similar in RA vs non-RA patients, both among those receiving atorvastatin and simvastatin.

Table 3

Changes in lipids from baseline to the last follow-up visit (after a median of 4.8 years)

Lipids and lipoproteins Atorvastatin, 80 mg
 
Simvastatin, 40 mg
 
 RA non-RA  RA non-RA  
 (n = 39) (n = 4 400) P-value* (n = 48) (n = 4401) P-value* 
Tot Chol, mmol/l −0.8 (1.2) −1.1 (1.1) 0.249 −0.3 (0.2) −0.5 (1.0) 0.977 
LDL, mmol/l −0.8 (1.0) −1.0 (1.0) 0.683 −0.4 (1.1) −0.5 (0.9) 0.722 
HDL, mmol/l 0.1 (0.3) 0.03 (0.2) 0.018 0.1 (0.2) 0.06 (0.2) 0.616 
TG, mmol/l −0.2 (−0.7, 0.2) −0.3 (−0.7, 0.0) 0.987 −0.1 (−0.4, 0.3) −0.1 (−0.4, 0.3) 0.543 
ApoB, g/l −0.2 (0.4) −0.3 (0.3) 0.960 −0.1 (0.3) −0.2 (0.3) 0.648 
ApoA-1, g/l 0.09 (0.2) 0.03 (0.2) 0.030 0.1 (0.2) 0.09 (0.2) 0.493 
Tot Chol/HDL −0.9 (1.3) −1.1 (1.3) 0.510 −0.6 (1.2) −0.6 (1.2) 0.734 
LDL/HDL −0.8 (0.9) −0.9 (1.0) 0.537 −0.5 (1.1) −0.6 (1.0) 0.796 
ApoB/apoA-1 −0.2 (0.3) −0.3 (0.3) 0.392 −0.1 (0.2) −0.16 (0.3) 0.558 
Lipids and lipoproteins Atorvastatin, 80 mg
 
Simvastatin, 40 mg
 
 RA non-RA  RA non-RA  
 (n = 39) (n = 4 400) P-value* (n = 48) (n = 4401) P-value* 
Tot Chol, mmol/l −0.8 (1.2) −1.1 (1.1) 0.249 −0.3 (0.2) −0.5 (1.0) 0.977 
LDL, mmol/l −0.8 (1.0) −1.0 (1.0) 0.683 −0.4 (1.1) −0.5 (0.9) 0.722 
HDL, mmol/l 0.1 (0.3) 0.03 (0.2) 0.018 0.1 (0.2) 0.06 (0.2) 0.616 
TG, mmol/l −0.2 (−0.7, 0.2) −0.3 (−0.7, 0.0) 0.987 −0.1 (−0.4, 0.3) −0.1 (−0.4, 0.3) 0.543 
ApoB, g/l −0.2 (0.4) −0.3 (0.3) 0.960 −0.1 (0.3) −0.2 (0.3) 0.648 
ApoA-1, g/l 0.09 (0.2) 0.03 (0.2) 0.030 0.1 (0.2) 0.09 (0.2) 0.493 
Tot Chol/HDL −0.9 (1.3) −1.1 (1.3) 0.510 −0.6 (1.2) −0.6 (1.2) 0.734 
LDL/HDL −0.8 (0.9) −0.9 (1.0) 0.537 −0.5 (1.1) −0.6 (1.0) 0.796 
ApoB/apoA-1 −0.2 (0.3) −0.3 (0.3) 0.392 −0.1 (0.2) −0.16 (0.3) 0.558 

Values are given as mean (s.d.), except for TG, which are presented as median (IQR). *P-values are based on ANCOVA adjusting for baseline lipid values.

Cardiovascular events occurred in 23/87 (26.4%) of the RA patients vs 2523/8801 (28.7%) in the non-RA IDEAL population (P = 0.70, adjusted for age and gender in a Cox regression). The rate of cardiovascular events was not significantly different in RA patients receiving atorvastatin (14/39, 35.9%) compared with simvastatin (9/48, 18.8%; P = 0.24, adjusted for age, gender and duration of RA diagnosis in a Cox regression). The time since RA was diagnosed was recorded in 74 patients. Among these, the occurrence of cardiovascular events was not found to be related to age, gender or disease duration (data not shown).

There were no statistically significant differences in frequency of any adverse events or serious adverse advents between RA and non-RA patients (supplementary Table 1, available as supplementary data at Rheumatology Online). However, RA patients reported myalgia more frequently (10.4% and 7.7% in RA patients vs 1.1% and 2.2% in non-RA patients receiving simvastatin and atorvastatin, respectively) and more diarrhoea/abdominal pain/nausea (10.4/10.4/4.2% and 7.7/12.8/10.3% in RA vs 0.2/0.2/0.1% and 0.9/0.8/0.5% in non-RA patients receiving simvastatin and atorvastatin, respectively), but these differences were not statistically significant.

Discussion

This analysis is the first report on the statin effect on lipids and cardiovascular endpoints in RA patients with a previous MI. The knowledge of statin effects in RA patients is modest. Patients with a previous MI and RA participating in the IDEAL study had lower lipids than patients with a previous MI without RA. There are inconsistencies in previous reports on lipid levels in RA patients. The levels of Tot Chol and LDL vary, while the level of HDL is frequently reported to be low [9–12]. In the apolipoprotein mortality risk study (AMORIS) register >480 000 healthy persons were followed for 11 years. In this register, RA patients had lower Tot Chol compared with persons without RA. At the same time, Tot Chol was not so strongly related to future MI in patients with RA as to MI in non-RA persons [13]. This difference in relationship between Tot Chol and MI may support the theory that lipid lowering in RA patients has relatively less effect as compared with non-RA persons. On the other side, RA patients have a higher absolute risk for MI than non-RA patients. Thus, a reduction of Tot Chol may be expected to reduce CVD events in RA similar to the reduction of CVD events in non-RA. More accurate estimates on cardiovascular risk reduction in RA will be elucidated when the cardiovascular hard endpoint study, Trace-RA, with atorvastatin vs placebo is published [14].

Statins have been shown to reduce cardiovascular mortality and morbidity by ∼30%. The rate of all cardiovascular events in RA patients was comparable with that in the general IDEAL population. The duration of RA has been related to severity of CVD [15]. We were not able to confirm this association in the RA subpopulation in the IDEAL study, but a type 2 error cannot be excluded.

Atherosclerosis can be regarded as a state of low-grade inflammation [16]. Statins have an anti-inflammatory effect in patients with and without CHD, but may not have the same anti-inflammatory or lipid-lowering effect in high-grade inflammatory states such as RA. Therefore, the lipid-lowering effect of statins in RA may not be as potent as in the general population. However, in the IDEAL study, patients with CHD and RA had a comparable reduction in lipids by statins as patients without RA. This observation is consistent with the findings in the trial of atorvastatin in rheumatoid arthritis (TARA) study on RA patients without CHD, where the LDL reduction was similar to observed reductions in the general population [17].

During the last few years, there has been a focus on lipid-transporting apolipoproteins as risk factors of CHD in the general population. ApoB and the apolipoprotein ratio apoB/apoA-1 have repeatedly been shown to be a better marker of future cardiovascular events than lipids and lipid ratios [18–21]. In statin-treated CHD patients in the IDEAL study, the apoB/apoA-1 was still the strongest predictor of major coronary events [22]. ApoB was lower, while apoA-1 was similar in RA and non-RA patients in the IDEAL study (Table 2). Furthermore, statins reduced the apolipoprotein ratio equally in RA patients as in the general IDEAL population (Table 3).

The mechanism underlying the high frequency of CVD in RA is not fully understood. Classical risk factors for CVD (high systolic blood pressure, smoking, diabetes mellitus and obesity) cannot alone explain the excess risk of CVD in RA [2, 15, 23]. However, the patients with RA participating in the IDEAL study had, compared with non-RA patients, somewhat higher blood pressure, greater degree of diabetes and were more frequently current smokers than the non-RA population (Table 1).

This study has some limitations. It was not designed specifically to investigate the effect of statins on lipids and CVD events in patients with RA. Furthermore, the study was not placebo controlled, but compared low- and high-dose statin treatment. A source of potential bias for our post hoc analysis where only 87 RA patients were retrieved is the inclusion and exclusion criteria in the IDEAL study. However, broad inclusion criteria were used in the IDEAL study, including patients up to 80 years of age and both patients with acute and chronic atherosclerotic disease. Another limitation is underscored by the higher event rate of atorvastatin compared with simvastatin. The small sample size and the small number of events render this study under-powered to draw conclusions regarding equivalence. To our knowledge, this is the first study to report the effect of statin treatment in RA patients with a CHD. Data on statin treatment in RA patients with previous MI are limited and there is no prospective CVD hard endpoint study available in RA patients with CHD. Therefore, any experience, such as the current data reported from 87 RA patients, will be of value until a stronger body of evidence is available. Patient groups with increased risk of CVD due to hyperlipidaemia, diabetes or hypertension have all been extensively investigated concerning CVD risk reduction, while this has still not been done for RA patients. There is a substantial unmet need in reducing the burden of CVD in RA patients, and thus long-term studies of CVD risk intervention are warranted. Interestingly, a European League Against Rheumatism (EULAR) task force has recently published recommendations for cardiovascular primary prevention in patients with inflammatory joint diseases [24].

The relatively larger number of adverse events experienced by RA patients may be due to increased susceptibility for adverse events because of a generally poorer health status than those without RA. Further, RA patients are possibly on more medications and may therefore be liable to medication interaction and hence adverse events.

The level of inflammation has been reported to influence lipid levels [25] and may be the reason for the low plasma lipid levels in RA patients [26, 27]. Thus, not surprisingly, anti-inflammatory treatment, such as HCQ, NSAID and anti-TNF treatment increases lipid levels [28–30]. Unfortunately, we have no information about inflammatory status (i.e. ESR or CRP) or anti-inflammatory medication in the RA patients participating in the IDEAL study. These variables may be confounders, and the lack of the opportunity to adjust for these variables is a limitation to this study. However, statins increase the anti-inflammatory capacity of HDL cholesterol [31], improve arterial stiffness [32, 33] and endothelial function [32, 34] and have a modest anti-inflammatory effect in RA [35], all of which fall in line with the effect statins have in the general population.

In conclusion, we found that in patients with CHD, RA patients had lower levels of lipids compared with non-RA patients and statins had the same lipid-lowering effect in both patient groups. Furthermore, the rate of CVD events after statin treatment appeared to be similar in RA and non-RA patients with CHD.

graphic

Disclosure statement: A.G.S. has received speaker's honoraria from Merck-Schering Plough, Abbott, Bristol-Myers Squibb and Wyeth and received speakers honoraria and consulting fees from Abbott and Roche. I.H. has received speaker’s honoraria and consulting fees from Pfizer and Merck-Schering Plough and consulting fees from AstraZeneca and Roche. T.K.K. has received speaker's and/or consulting honoraria and/or research grants from Abbott, Bristol-Myers Squibb, Merck-Schering Plough, Pfizer, Roche, Schering-Plough, UCB and Wyeth. T.R.P. has received speaker's honoraria and consulting fees from Pfizer and Merck-Schering Plough and speaker's honoraria from AstraZeneca AG.

Supplementary data

Supplementary data are available at Rheumatology Online.

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