Objectives To perform cardiovascular risk stratification in patients with inflammatory joint diseases (IJD) and treat to lipid targets according to recommendations.
Methods We initiated a preventive cardio-rheuma clinic based on the unmet need of adequate cardiovascular prevention in IJD patients. A full cardiovascular risk stratification was performed at the first consultation (history of conventional risk factors and of cardiovascular disease, lipid measurement, blood pressure and ultrasound examination of both carotid arteries), and the patient was classified to either a primary or secondary cardiovascular prevention regime, or to have a low risk (no intervention). Lipid-lowering treatment was adjusted until at least two lipid targets were achieved.
Results Of the 426 patients referred, 36.6% had a systematic coronary risk evaluation less than 5% (no lipid-lowering intervention). The remaining 270 patients ((rheumatoid arthritis (RA), n=165; ankylosing spondylitis (AS), n=70; and psoriatic arthritis (PsA), n=35) were assigned to either primary (n=63) or secondary prevention (n=207). There were significant differences between the patient groups regarding age (p<0.001), sex (p<0.001) and disease duration (p<0.001). Lipid changes in IJD patients were: total cholesterol −1.86±1.20 mmol/l (p<0.001); low-density lipoprotein cholesterol −1.74±1.11 (p<0.001); high-density lipoprotein cholesterol 0.01±0.30 (p=0.61); triglycerides −0.28±0.72 (p<0.001). The proportions of patients reaching at least two lipid targets were for RA 92.1%, AS 90.0% and PsA 82.9%. No serious adverse events were observed.
Conclusions There was indication for cardiovascular prevention in a high proportion of IJD patients referred for cardiovascular risk stratification. Treatment to lipid targets was successful in approximately 90% of patients with IJD.
- Rheumatoid Arthritis
- Ankylosing Spondylitis
- Psoriatic Arthritis
- Cardiovascular Disease
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In industrialised countries cardiovascular disease is the number one cause of death, and cardiovascular prevention programmes have been evolved. There is no longer doubt that patients with inflammatory joint diseases (IJD) have an increased risk of cardiovascular disease. Within the IJD group, patients with rheumatoid arthritis (RA) have been most extensively investigated concerning cardiovascular risk,1 2 but the cardiovascular burden of patients with psoriatic arthritis (PsA)3 4 and ankylosing spondylitis (AS)5 6 has also been documented to be increased compared to the general population. RA is associated with the same risk of myocardial infarction as patients with diabetes mellitus.1 In the latest European Society of Cardiology (ESC) guidelines for cardiovascular disease prevention,7 immunological diseases such as RA is for the first time mentioned as a high risk factor. RA alone is not an indication for lipid-lowering treatment, but is recommended to be taken into consideration as part of the cardiovascular risk stratification.
For several decades the increased cardiovascular risk in IJD has been known, but this knowledge has not been implemented in clinical practice. There is still a lack of cardiovascular hard endpoint trials with statins for this patient group, although some post hoc analyses from large statin/placebo controlled trials with cardiovascular outcomes have reported that patients with and without IJD have comparable cardioprotective effects with statins.8 9
A multicentre audit recording cardiovascular risk in patients with RA and systemic lupus erythematosus concluded that cardiovascular risk factors are inadequately managed in these diseases.10 Furthermore, Toms et al11 reported that there was a substantial undertreatment of cardiovascular risk in patients with RA. There is thus an unmet need for systematic cardiovascular prevention in patients with IJD. We have initiated a preventive cardio-rheuma clinic for patients with IJD. The objective of this report is to evaluate the proportion of patients with IJD in need of cardiovascular prevention, and the clinical effects of lipid-lowering therapy with regard to the achievement of guideline-recommended lipid targets.
Patients and methods
Patients with IJD were referred for cardiovascular risk stratification from a rheumatology outpatient clinic or from general practitioners, to the preventive cardio-rheuma clinic during the period March 2009 and July 2012. Referral criteria were diagnosed IJD, age between 25 and 85 years and fulfilment of at least one of the following criteria: known cardiovascular risk factor(s); symptoms/signs of a risk factor; familial premature cardiovascular disease or simply that a patient wished to undergo cardiovascular risk stratification. At the first consultation cardiovascular risk stratification was performed. The patient was classified to either primary or secondary cardiovascular prevention with lipid-lowering treatment, or to have a low risk with no indication for medical intervention. Lipid-lowering treatment was adjusted until at least two lipid targets were achieved (or at the nearest possible level to the lipid targets).
This was an observational study. Ethical approval and informed patient consent was therefore not required. The data collection/publication has been recommended and approved by the office of the hospital's privacy and data protection officer (2011/7318) of the Oslo University Hospitals.
Recording of cardiovascular risk factors
When the patients received a letter regarding the date/time for the consultation, they also received a cardiovascular questionnaire, which was completed and returned at the consultation. The following risk factors were recorded: smoking status, diabetes, medication history, family history of premature cardiovascular disease in first-degree relatives (male/female <55/<65 years) and the presence of established cardiovascular disease as well as history of stroke, transient ischaemic attack, or peripheral vascular disease.
Laboratory tests included total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, liver enzymes, creatine kinase (CK), creatinine, haemoglobin and C-reactive protein (CRP). All were measured at the hospital laboratory (European standard accredited 2009) by routine procedures in a COBAS 600.12 The erythrocyte sedimentation rate (ESR) was analysed by the Westergren method.
Brachial blood pressure (BP) was measured using an Omron M7 after a 5 min rest in a supine position. If the BP exceeded 140/90 mm Hg, three consecutive measurements were performed and a mean was calculated. A 12-lead electrocardiogram was recorded digitally.
Bilateral B-mode ultrasonography examination of the carotid arteries was performed with a Vivid-7 ultrasound scanner (General Electrics Vingmed ultrasound) using a 12 MHz probe (9–14) linear matrix array transducer. The ultrasonography examinations were all performed by one sonographer (ASE) supervised by a cardiologist (AGPS). Atherosclerotic plaque(s) in the common carotid artery, bulb and the internal carotid artery in the far and near wall were identified. This was performed by revealing protrusions ≥1.4 mm or greater into the lumen or more than a doubling of the adjacent intimamedia thickness, when both intima media of the far and near wall had sharp edges in the longitudinal view. If there was any doubt about the plaque, it was verified by a cross-sectional image by turning the probe 90° to the longitudinal axis of the vessel.13
Management of cardiovascular risk factors
All patients received advice about cholesterol-friendly food choices (including a brochure) and physical activity. Smokers were advised to stop and were offered the opportunity to join smoking cessation support programmes and/or the use of appropriate medications. Patients with diabetes in need of optimised glucose control were referred to an outpatient diabetic clinic. If antihypertension treatment was initiated the BP goals were less than 140/90 mm Hg or 125/80 mm Hg in a 24-h recording.
Individual cardiovascular risk stratification was done by using the systematic coronary risk evaluation (SCORE) for high-risk countries,14 which is recommended by the ESC. Patients without established cardiovascular disease with a SCORE of 5% or greater (10-year risk of fatal myocardial infarction), received lipid-lowering treatment. The lipid goals were as follows: total cholesterol 4.5 mmol/l or less, LDL-cholesterol 2.5 mmol/l or less, HDL-cholesterol 1.0/1.2 mmol/l or greater for men/women, triglycerides 1.7 mmol/l or less. In this paper we refer to these lipid levels as targets. However, lower HDL-cholesterol or higher triglyceride levels than mentioned are described as markers of increased risk, but there is not sufficient evidence to consider these specific levels of HDL-cholesterol and triglycerides as recommended targets according to the ESC guidelines.7
Patients in the very high risk group are, according to the latest ESC guidelines for cardiovascular prevention,7 those with documented cardiovascular disease by invasive or non-invasive testing (such as coronary angiography or carotid plaque on ultrasound), previous myocardial infarction, acute coronary syndrome, coronary/arterial revascularisation, ischaemic stroke, peripheral artery disease, diabetes mellitus with one or more cardiovascular risk factors and/or target organ damage, and patients with severe chronic kidney disease. A calculated SCORE of 10% or greater also indicates a very high risk of cardiovascular disease. Those patients have the highest priority for treatment, and the recommended lipid targets are lower. We implemented the following lipid goals: total cholesterol 4.0 mmol/l or less, LDL-cholesterol 1.8 mmol/l or less or a 50% or greater reduction from baseline LDL-cholesterol if the LDL-cholesterol goal of 1.8 mmol/l or less could not be obtained. HDL-cholesterol and triglyceride levels were the same as in primary prevention.
Follow-up until treatment goals were reached
The cardiologist initiated the lipid-lowering intervention with statins and continued or changed the lipid-lowering treatment until at least two lipid targets were achieved (or at the nearest possible level of the lipid targets), before the patients were discharged for further follow-up by the general practitioner.
The data are presented as crude data and the results are expressed as mean±SD and median (IQR) for normally and non-normally distributed characteristics, respectively. The data were compared using paired samples t test, analysis of variance, Kruskal–Wallis and χ2 tests as appropriate. Data analyses were performed using IBM SPSS version 20.
Four hundred and twenty-six patients with IJD (RA n=257, AS n=108 and PsA n=61) were referred to the preventive cardio-rheuma clinic (figure 1). Patients with RA were older than the other patient groups, p<0.001 (table 1). The RA patients were mostly women (73.2%) and the majority of the AS patients were, as expected, men (68.5%). In the PsA patient group the gender distribution was more equal (55.7% women). The median disease duration was approximately 15 years in patients with RA and PsA, but 22.5 years in AS patients. As expected, the PsA patients had a slightly higher body mass index (p=0.003). Approximately 6–10% of all the patients had established cardiovascular disease (RA 9.7%, AS 10.2%, PsA 6.6%) (table 1). The lipid profile in IJD patients was comparable, although there was a significant difference in HDL-cholesterol between the groups (p<0.001), possibly due to there being more women in the RA population. Almost half of all referred patients had atherosclerotic plaque(s) in the carotid arteries (carotid plaques) (RA 46.3%, AS 44.4%, PsA 41.0%). Despite established cardiovascular disease, or carotid plaques on ultrasound, a high proportion of patients was not using lipid-lowering treatment at when referred (RA 81.0%, AS 83.3%, PsA 64.3%).
Cardiovascular risk stratification
Of the 426 patients, 270 were assigned to preventive lipid-lowering treatment (63.4%) (figure 1). The proportions of patients having a SCORE of 5% or greater (assigned to primary prevention) were similar across the patient groups (RA 13.6%/AS 16.4%/PsA 14.3%, p=0.80). More than three-quarters (76.7%) of the patients in need of lipid-lowering intervention had either cardiovascular disease, carotid plaques or both, and were assigned to secondary preventive treatment.
Treatment to target
An indication for lipid-lowering intervention was found in approximately 60% of all the referred patients. Initiation of lipid-lowering treatment was done with statins (atorvastatin, simvastatin, rosuvastatin or pravastatin). Patients reaching at least two lipid targets were for RA 92.1%, AS 90.0%, and for PsA 82.9% (figure 2). In the combined IJD group, 40.4% reached all four lipid targets, 30.4% reached three lipid targets and 19.6% only obtained two of the targets. Lipid-lowering treatment was unsuccessful in 26 patients (9.6%) and there were various reasons for this. Two patients did not reach lipid targets at the highest possible dose of statins. Three patients did not reach lipid goals, but were so close to targets that the lipid profile was accepted by the cardiologist. One patient had an unacceptable CK increase and two patients had a rise in liver enzymes, and statin treatment was stopped. The increase in liver enzymes and CK was not three times or more above the upper normal limit. Five patients died (n=4 outside the hospital, n=1 of colon cancer with liver metastasis), one patient was diagnosed with lymphoma and was lost to follow-up. Nine patients preferred follow-ups by their general practitioner, one did not want to take statins, and another patient did not obtain targets due to poor compliance. After a carotid endarterectomy, one patient was followed by the vascular surgery clinic at Oslo University Hospital, and was therefore lost to follow-up at the preventive cardio-rheuma clinic. Some patients did experience tolerable minor side effects such as muscle tenderness or symptoms from the gastrointestinal tract. These were not recorded systematically in our clinical setting if the statin treatment was not changed. There were no serious adverse events concerning statin medications. The patients needed on average less than three consultations to reach at least two lipid targets.
Lipid attainment in primary prevention
A total of 23.3% of the patients was in need of lipid-lowering intervention and they were assigned to primary prevention (figure 1). Baseline total cholesterol and LDL-cholesterol were higher in RA compared to AS and PsA patients (p=0.17 and p=0.11, respectively). Before the patients were discharged for further follow-up by the general practitioner, the lipid profile was lower than or at target values in all patients, except for triglycerides in PsA (table 2). Twenty per cent of the PsA patients, who were assigned to lipid-lowering intervention, had combined dyslipidaemias, which includes elevated triglycerides and low HDL-cholesterol levels. This may have influenced the incompleteness in reaching the triglyceride targets. In the combined patient group with IJD, there was a significant change in all lipids from first to final consultation, except for HDL-cholesterol (figure 2). When evaluating the three patient groups separately, there was not a significant change in LDL-cholesterol in patients with PsA concerning primary prevention (table 2). This may be a reflection of the low number of PsA patients (n=9). There was no significant change in triglyceride levels among AS and PsA patients. As in the combined IJD group, HDL-cholesterol did not change significantly for RA, AS and PsA patients (table 2). The proportion of patients assigned to primary prevention reaching each lipid target was for total cholesterol 60.3%, LDL-cholesterol 66.7%, HDL-cholesterol 82.5% and triglycerides 69.8% (figure 3).
Lipid attainment in secondary prevention
Baseline lipids were lower in patients who had established cardiovascular disease and who were assigned to secondary preventive treatment, compared to patients assigned to primary prevention (table 2). This was probably due to the fact that some patients (RA n=8 (14.0%), AS n=7 (13.5%) and PsA n=8 (30.3%)) were already statin users when referred to the clinic, although the statin dosage was inadequate for reaching the recommended lipid targets. It may also reflect the fact that patients receiving primary prevention were selected based on their risk profiles, including lipids, in contrast to those selected based on carotid plaques and previous cardiovascular events. Patients who were statin users when referred were also included in the analysis, because one of our aims was to evaluate whether attainment of lipid targets was possible. For all the patient groups, the final mean levels for all the lipids were under or at goal values, except for TC, which were close to target (table 2). This was only so for patients with RA and was due to the higher HDL-cholesterol level in this patient group. The percentage change in lipids from first to final consultation was significant except for HDL-cholesterol, as in primary prevention, in the combined IJD group (figure 2) and for the separate patient groups: RA, AS and PsA (table 2). The proportion of patients with secondary prevention goals reaching each lipid target was for total cholesterol 57.0%, LDL-cholesterol 73.9%, HDL-cholesterol 83.1% and triglycerides 81.2% (figure 3).
Overall, lipid targets were reached in approximately 90% of all three patients groups combined (figure 4), using on average less than three consultations to obtain this. When being referred to the clinic, 12.9% of the patients were already using a statin, but had not reached lipid targets. This did not influence the number of consultations needed to obtain lipid goals, because patients who used statins when referred needed on average 2.80±1.10 versus 2.70±1.19 consultations for patients who did not use statins (p=0.62) to obtain lipid targets.
In 426 patients referred to cardiovascular risk stratification, more than 60% were in need of lipid-lowering intervention. Of these, two-thirds were assigned to intensive lipid-lowering treatment and one-third to primary prevention. The lipid targets were not reached in 10% of the patients. On average, only three consultations were needed to obtain two recommended lipid goals.
In the general population approximately 40% have been reported to obtain lipid targets.15 ,16 This was to a great extent due to the suboptimal use of lipid-lowering treatment. There are several potential reasons for this unsuccessful result. Physicians may be concerned about possible side effects or that increasing statin doses only results in a marginal lipid-lowering effect, and there is the issue of compliance. In our report a very high proportion of the patients reached recommended goals, but over time this goal attainment may be lower. Future studies are warranted to reveal this. Lindhardsen et al17 also reported that physicians less often initiate secondary prevention in RA patients compared to non-RA patients, with statins being the most underused drug. A large number of our patients did not receive lipid-lowering treatment at baseline despite established cardiovascular disease or asymptomatic carotid plaques. These patients as well as those with carotid intima media thickness greater than 0.90 mm have a very high risk of future fatal myocardial infarction.7 ,18 ,19
Patients with IJD have a systemic inflammation and lower lipids compared to the general population. Hypothetically, the systemic inflammation may be a reason for the need for higher statin doses to obtain the same lipid-lowering effect as the general population. Contradicting this are the lower lipid levels. These factors illuminate the difficulties in cardiovascular risk stratification and prevention in IJD patients. Recent published data indicate that the lipid-lowering effect of statins in RA, AS and PsA patients are comparable to non-IJD patients.9 ,20
Patients with IJD have a severe chronic and disabling disease, and for that reason often use several medications. Polypharmacy increases the risk of drug interactions, and may therefore potentially lead to more side effects. We did not observe this in our patients, which fall in line with the recently reported comparable side effects from statins in patients with and without IJD,9 ,20 although the patients with IJD had somewhat more side effects from the gastrointestinal tract.
Our focus has been to evaluate the cardiovascular risk in IJD patients, and initiate optimal preventive treatment when needed in accordance with guidelines for the general population. Ultrasound of the carotid arteries has been an important part of the risk stratification as we found that almost half of the patients had asymptomatic carotid plaques. These patients were therefore correctly assigned to secondary prevention instead of incorrectly receiving primary or no lipid-lowering prevention. This illuminates the importance of performing carotid ultrasound to identify carotid plaques during cardiovascular risk stratification. B-mode ultrasound of the carotid arteries has several advantages in that it is inexpensive, takes a short time and there is no radiation exposure as with a CT scan.
RA patients have a significantly shortened life expectancy, which is mainly due to cardiovascular disease.21 ,22 The background inflammation is most likely an important reason for the substantially increased risk of cardiovascular disease in RA. Statins reduces the systemic inflammation in addition to the lipid-lowering effect,23–26 and have been shown to reduce joint inflammation in RA.27 Furthermore, statins may have a beneficial effect on endothelial function,23 arterial stiffness28 and in improving HDL-cholesterol anti-inflammatory properties in patients with RA.29 A cost-effectiveness analysis concluded that the dual effect of statins (lipid-lowering and anti-inflammatory) makes this therapy highly cost effective in RA patients.30 Hypothetically this would also apply to AS and PsA patients.
A placebo controlled study (TARA) showed that treatment with atorvastatin 40 mg resulted in a reduction in CRP and ESR, and a significant lower swollen joint count compared to placebo.27 Due to our cardiovascular focus, swollen joint count was not recorded and thus we could not relate statins to disease activity. This is an observational report, and not as well controlled as experimental studies, which is an obvious limitation. The recruitment of patients who wished to undergo cardiovascular risk assessment may have some impact on compliance and the attainment of lipid targets. Finally, most patients had long-standing disease. The results may therefore not be applicable to patients with recent-onset arthritis, who could potentially benefit the most from prevention.
The strengths of our clinical data are the relatively large number of IJD patients and that all have been treated by the same physician. A further strength is that the three patient groups were comparable regarding cardiovascular risk factors.
In conclusion, more than 60% of IJD patients who were referred to cardiovascular risk stratification were in need of preventive treatment with statins, supporting the importance and relevance of establishing preventive cardio-rheuma clinics. Of these patients, 90% obtained lipid targets in less than three consultations. No serious adverse side effects were observed. Our data illustrate that lipid-lowering medication such as statins is effective and safe in patients with IJD. Longitudinal data are needed to demonstrate whether lipid-lowering in patients with IJD can also reduce the risk of cardiovascular disease and improve outcomes.
Handling editor Dr Hans Bijlsma
Contributors All authors met the criteria for authorship, they critically reviewed the manuscript and agreed to publish this work.
Funding This project was supported by the Grethe Harbitz legacy.
Competing interests TKK has received speaker and/or consulting honoraria and/or research grants from Abbott, BMS, Merck/Schering-Plough, Pfizer/Wyeth, Roche and UCB. IH has received speaker honoraria and consulting fees from Pfizer and Merck/Schering Plough and consulting fees from AstraZeneca and Roche. TRP has received speaker honoraria and consulting fees from Pfizer and Merck/Schering-Plough and speaker honoraria from AstraZeneca. AGPS has received speaker honoraria from Merck/Schering Plough, Abbott, Pfizer, BMS and Wyeth, and has received speaker honoraria and consulting fees from Abbott and Roche. SR and ASE declare no competing interests. The authors alone are responsible for the content and writing of this paper.
Provenance and peer review Not commissioned; externally peer reviewed.
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