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J Am Coll Cardiol, 2007; 50:852-858, doi:10.1016/j.jacc.2007.04.076 (Published online 10 August 2007).
© 2007 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: METABOLIC SYNDROME

Ezetimibe and Simvastatin Reduce Inflammation, Disease Activity, and Aortic Stiffness and Improve Endothelial Function in Rheumatoid Arthritis

Kaisa M. Mäki-Petäjä, BSc*,1,*, Anthony D. Booth, MD, MRCP2,*, Frances C. Hall, DPhil, FRCP{dagger},3, Sharon M.L. Wallace, BA, RN*, John Brown, DM, FRCP{ddagger}, Carmel M. McEniery, PhD* and Ian B. Wilkinson, DM, FRCP2,*

* Clinical Pharmacology Unit, University of Cambridge, Cambridge, United Kingdom
{dagger} Department of Clinical Medicine, Addenbrooke’s Hospital, University of Cambridge, Cambridge, United Kingdom
{ddagger} Trinity College, University of Cambridge, Cambridge, United Kingdom.

Manuscript received February 6, 2007; revised manuscript received April 20, 2007, accepted April 22, 2007.

* Reprint requests and correspondence: Kaisa Mäki-Petäjä, Clinical Pharmacology Unit, University of Cambridge, Addenbrooke’s Hospital, BOX 110, Cambridge CB2 0QQ, United Kingdom. (Email: km391{at}cam.ac.uk).


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 Conclusions
 References
 
Objectives: The aim of this study was to investigate the effect of simvastatin and ezetimibe on inflammation, disease activity, endothelial dysfunction, and arterial stiffness in a cohort of rheumatoid arthritis (RA) patients.

Background: Rheumatoid arthritis is a chronic inflammatory condition associated with increased cardiovascular risk. Statins reduce inflammation and disease activity in RA patients, but whether this is due to pleiotropism or cholesterol lowering per se is unclear.

Methods: Twenty patients received 20 mg simvastatin or 10 mg ezetimibe each for 6 weeks in a randomized double-blind crossover study. Disease activity, blood pressure, aortic pulse wave velocity (PWV), brachial artery flow-mediated dilation (FMD), and serum inflammatory markers were measured before and after each treatment.

Results: Both ezetimibe and simvastatin significantly reduced total cholesterol (–0.62 ± 0.55 mmol/l and –1.28 ± 0.49 mmol/l, respectively; p < 0.001), low-density lipoprotein cholesterol (–0.55 ± 0.55 mmol/l and –1.28 ± 0.49 mmol/l; p < 0.0001), and C-reactive protein (–5.35 ± 9.25 mg/l and –5.05 ± 6.30 mg/l; p < 0.001). Concomitantly, Disease Activity Score (–0.55 ± 1.01 and –0.67 ± 0.91; p = 0.002), aortic PWV (–0.69 ± 1.15 m/s and –0.71 ± 0.71 m/s; p = 0.001), and FMD (1.37 ± 1.17% and 2.51 ± 2.13%; p = 0.001) were significantly improved by both drugs.

Conclusions: This study demonstrates that both ezetimibe and simvastatin reduce disease activity and inflammatory markers to a similar extent in patients with RA. Therapy is also associated with a concomitant reduction in aortic PWV and improvement in endothelial function. This suggests that cholesterol lowering per se has anti-inflammatory effects and improves vascular function in RA.

Abbreviations and Acronyms
  AIx = augmentation index
  CRP = C-reactive protein
  DAS = Disease Activity Score
  ESR = erythrocyte sedimentation rate
  FMD = flow-mediated dilatation
  GTN = glyceryl trinitrate
  oxLDL = oxidized low-density lipoprotein
  PWV = pulse wave velocity
  RA = rheumatoid arthritis

Rheumatoid arthritis (RA) is associated with increased mortality and comorbidity, mostly owing to an excess of cardiovascular disease (1). This cannot solely be explained by traditional cardiovascular risk factors (2), which has led to the suggestion that the chronic systemic inflammation characterizing RA may accelerate the atherosclerotic process either directly by contributing to plaque formation and destabilization or indirectly via endothelial dysfunction and aortic stiffening. Aortic stiffening increases wave reflection, thus increases pulse pressure, leading to elevated left ventricular (LV) load and a possible LV hypertrophy, thus increased cardiovascular risk. Both aortic stiffening and endothelial dysfunction predict future cardiovascular risk in other patient groups (3,4) and may play a pathophysiologic role in atheroma formation. Moreover, we and others have demonstrated both endothelial dysfunction (5,6) and increased arterial stiffness (7–9) in RA, which can be reversed by successful anti-inflammatory therapy (9,10).

Statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors) are effective in reducing cardiovascular morbidity and mortality in a variety of populations (11,12). In addition to cholesterol reduction, a number of other pleiotropic effects have been described with statins that may improve outcome independently of cholesterol reduction (13). One such effect is a reduction in inflammation (14), which is increasingly thought to play an important role in the pathogenesis of atherosclerosis. The TARA (Trial of Atorvastatin in Rheumatoid Arthritis) study assessed the effect of 6 months’ treatment with atorvastatin in patients with RA. Statin therapy was associated with a marked reduction in inflammatory markers (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) as well as with a reduction of disease activity (15). That study did not include any control cholesterol-lowering therapy and it is therefore unclear whether the observed anti-inflammatory properties were a pleiotropic effect of statins or simply due to a reduction in cholesterol. Moreover, the authors did not assess the effect of therapy on vascular function.

The aim of the present study was to test the hypothesis that cholesterol reduction per se reduces inflammation, disease activity, and surrogate measures of cardiovascular risk in patients with RA, by examining the effect of simvastatin and a nonstatin, ezetimibe, which acts locally by inhibiting cholesterol absorption from the small intestine, in a randomized double-blind crossover study.


   Methods
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 Abstract
 Methods
Results
 Discussion
 Conclusions
 References
 
Study population.   Twenty patients with active RA who met the 1987 American Rheumatism Association criteria were recruited from the rheumatology clinics at Addenbrooke’s Hospital, Cambridge, United Kingdom. Inclusion criteria included a Disease Activity Score (DAS)-28 >3.5 and a serum CRP >6 mg/l. Individuals with cardiovascular disease, untreated hypertension (blood pressure ≥140/90 mm Hg), diabetes, hypercholesterolemia (total cholesterol ≥6.5 mmol/l), renal disease, and current smokers were excluded, because these conditions are associated with endothelial dysfunction and arterial stiffening. Patients on vasoactive drugs were also excluded. We also randomly selected 20 age- and gender-matched control subjects from our database to compare the baseline arterial stiffness and endothelial function between patients with RA and healthy individuals. Approval was obtained from the Local Research Ethics Committee, and written informed consent was obtained from each participant.

Hemodynamic measurements.   All studies were conducted in a quiet temperature-controlled room. Blood pressure was recorded in the brachial artery using a validated oscillometric technique (HEM-705CP, Omron Corp., Kyoto, Japan). Radial artery waveforms were obtained with a high-fidelity micromanometer (SPC-301, Millar Instruments, Houston, Texas) from the wrist, and a corresponding central waveform was generated using a validated transfer function (Sphygmocor, AtCor Medical, Sydney, Australia). Augmentation index (AIx), a composite measure of systemic arterial stiffness and wave reflection, mean arterial pressure, and heart rate was determined using the integrated software. Aortic (carotid to femoral) pulse wave velocity (PWV) was measured as previously described (16).

Endothelial function was assessed in the brachial artery using the technique of flow-mediated dilatation (FMD) (17). Vessel diameter was measured using high-resolution vascular ultrasound (Acuson 128XP/10, Siemens, Erlangen, Germany) with a 10-MHz linear array transducer. Brachial artery diameter was measured continuously for 1 min at baseline and for a further 5 min after cuff deflation. The cuff was placed below (distal to) the ultrasound transducer and inflated to 200 mm Hg for 5 min. After return to baseline, vessel diameter was again measured continuously for 5 min after administration of 25 µg sublingual glyceryl trinitrate (GTN). The FMD was defined as the maximum percentage increase in vessel diameter during reactive hyperemia; GTN-mediated dilatation was defined as the maximum percentage increase in vessel diameter after sublingual GTN. The FMD recordings were analyzed off line by a blinded operator unfamiliar with the study.

Laboratory measurements.   Fasting lipid profile, blood glucose, and high-sensitivity CRP, ESR, and rheumatoid factor were determined using standard methodology. Oxidized low-density lipoprotein (oxLDL) was measured in stored serum samples (–80°C) by a commercially available solid-phase two-site enzyme immunoassay (Mercodia, Uppsala, Sweden). The samples were measured in a single analytical run.

Disease Activity Score.   The DAS-28 is a validated composite Disease Activity Score (18). The components of DAS-28 include the number of swollen and tender joints from 28 assessed joints, ESR, and patient-assessed visual analog score of overall well-being (scaled 0 to 100). The DAS-28 was calculated as previously described (18).

Experimental protocol.   The present study was conducted in a randomized double-blind crossover manner. Following a 2-week placebo run-in, patients received 10 mg ezetimibe or 20 mg simvastatin, in random order, each for 6 weeks, with a 6-week washout between drugs (Fig. 1). All hemodynamic measurements were assessed at baseline, following the end of the placebo run-in, and at the end of each 6-week period (drug 1, washout, and drug 2). Blood was drawn at each time point for the measurement of biochemical markers, and DAS-28 was calculated.


Figure 1
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  		Figure 1 The Study Design

Following 2-week placebo run-in, patients received simvastatin or ezetimibe in a randomized double-blinded manner, each for 6 weeks, with a 6-week washout between the drugs.

 
Data analysis.   Data were analyzed using SPSS software (version 12, SPSS Inc., Chicago, Illinois). Two-way repeated measures analysis of variance was used to investigate the effect of the drugs. Custom hypothesis testing (simple) of within-subject contrasts was performed for the ezetimibe-simvastatin comparison, where treatment order was entered as a between-subject factor. In post hoc tests, the effect of individual treatments was determined using paired Student t tests with Bonferroni adjustment for 2 comparisons. For the skewed variables (CRP and ESR) log-transformed values were used for the analyses. The carryover effect of the drugs was assessed with paired Student t tests between the baseline measurements at week 2 (baseline 2) and week 14 (end of washout period). Pearson correlations were calculated between absolute changes in lipid parameters and anti-inflammatory markers, hemodynamic measures and disease activity. A probability of <0.05 was considered to be significant. Data are given as mean ± SD.


   Results
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 Abstract
 Methods
 Results
Discussion
 Conclusions
 References
 
A total of 20 patients with active rheumatoid arthritis completed the study. The demographic variables and biochemical and hemodynamic characteristics of patients at entry are shown in Table 1. There was no difference in the lipid profile between patients with RA and control subjects (total cholesterol 5.3 ± 0.9 mmol/l vs. 4.9 ± 1.3 mmol/l; LDL 3.1 ± 0.9 mmol/l vs. 2.8 ± 0.9 mmol/l, respectively; both p = 0.3). The current therapy included methotrexate (n = 13), other disease-modifying drug (n = 7), nonsteroidal anti-inflammatory drug (n = 14), and prednisolone (n = 9) (mean dose 6.7 ± 3.2 mg). Most patients were taking 2 or more drugs concomitantly (n = 18), and none were free from medication. None of the patients were receiving medication for hypertension or hypercholesterolemia. Patients remained on their existing therapy, and they did not receive corticosteroid injections throughout the study period.


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  		Table 1 Baseline Demographics, Biochemical, and Hemodynamic Characteristics of Subjects With Rheumatoid Arthritis (n = 20)
 
Table 2 shows the effect of ezetimibe and simvastatin on lipids, inflammatory markers, disease activity, and hemodynamic parameters after 6 weeks of each drug therapy; the presented p values in the "Between Drugs" column are Bonferroni adjusted. Both ezetimibe and simvastatin produced a significant reduction in total cholesterol, LDL cholesterol, and oxLDL. The reduction was more pronounced with simvastatin than with ezetimibe. Baseline oxLDL was significantly higher in patients with RA compared with control subjects (62.8 ± 16.6 U/l vs. 43.6 ± 12.9 U/l, respectively; p < 0.001). The ESR and CRP were reduced by both ezetimibe and simvastatin. There were no significant differences in the reduction in inflammatory markers between the 2 treatments.


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  		Table 2 Effect of Treatment on Lipids, Inflammation, Disease Activity, and Hemodynamics After 6 Weeks of Treatment
 
Disease activity, assessed by DAS-28, fell by a similar degree following both ezetimibe and simvastatin, and there was no significant difference between the treatments. When looking at the individual components of DAS-28, the only parameters that reached statistical significance were ESR and tender joints count. Neither mean arterial pressure nor AIx was significantly affected by either drug. However, aortic PWV was significantly reduced (Fig. 2) and FMD increased (Fig. 3) following both drugs, and there was no change in the GTN response. (The p values in Figures 2 and 3 are Bonferroni adjusted.) There were no significant differences in the hemodynamic effects of the 2 treatments.


Figure 2
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  		Figure 2 Effect of 10 mg Ezetimibe and 20 mg Simvastatin on Aortic PWV

Measurements were taken after 6 weeks of each treatment. Bars show mean and standard error of mean (n = 20). The omnibus significance for the trend was p = 0.001. The significance was determined by 2-way repeated measures analysis of variance with post hoc testing with Bonferroni adjustment. PWV = pulse wave velocity.

 

Figure 3
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  		Figure 3 Effect of 10 mg Ezetimibe and 20 mg Simvastatin on FMD

Measurements were taken after 6 weeks of each treatment. Bars show mean and standard error of mean (n = 20). The omnibus significance for the trend was p < 0.001. The significance was determined by 2-way repeated measures analysis of variance with post hoc testing with Bonferroni adjustment. FMD = flow-mediated dilation.

 
Custom hypothesis testing for the effect of treatment order showed that the order in which the drugs were received did not affect any of the outcomes (p < 0.05) and there was no carryover effect of the previous treatment after the 6-week washout period (unpaired t test between 2 baselines: p < 0.05). In pooled data of both treatments, a reduction in total, LDL, and oxLDL cholesterol were found to correlate with the improvement of FMD (r = –0.5, –0.5, and –0.6, respectively; all p < 0.05). We did not find a correlation between cholesterol reduction and improvement of inflammatory markers or disease activity. There was a significant correlation between baseline CRP and change in CRP (r = –0.8; p < 0.001) and between baseline ESR and change in aortic PWV, with greatest reductions in PWV occurring in subjects with the highest baseline ESR (Fig. 4).


Figure 4
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  		Figure 4 Relationship Between Baseline ESR and Change in Aortic PWV Following Ezetimibe and Simvastatin

The change in aortic pulse wave velocity (PWV) following drug treatment was significantly associated with the baseline erythrocyte sedimentation rate (ESR); r = –0.416; p = 0.008. Solid circles = ezetimibe; open circles = simvastatin.

 
The baseline aortic PWV was significantly increased in patients with RA compared with control subjects (9.42 ± 2.42 m/s vs. 7.69 ± 1.18 m/s, respectively; p = 0.005) and FMD was reduced (3.70 ± 2.32% vs. 6.74 ± 3.78%, respectively; p = 0.01). Following ezetimibe and simvastatin, FMD improved to a level similar to the control subjects (p = 0.2 and p = 0.8, respectively), but aortic PWV remained elevated (p = 0.02). There was no significant change in AIx following either drug.


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
Conclusions
 References
 
In the present study, we demonstrated that short-term therapy with both ezetimibe and simvastatin significantly reduces cholesterol, inflammatory markers, and disease activity in patients with active RA. Interestingly, despite a significantly greater reduction in cholesterol following treatment with simvastatin, the anti-inflammatory effects of the two drugs were similar. Moreover, we have shown for the first time, in a single cohort of RA patients, that both ezetimibe and simvastatin reduce aortic PWV and improve endothelial function.

The recent TARA study showed that statins reduce inflammation and disease activity in patients with RA (15). However, it is unclear to what extent this effect is due to cholesterol reduction or true pleiotropism, because there was no control cholesterol-lowering therapy. It is also unclear whether treatment is associated with any improvement in surrogate measures of cardiovascular risk. Therefore, in the present study we assessed the effect of simvastatin as well as of the nonstatin cholesterol-lowering agent ezetimibe on inflammation, disease activity, and surrogate measures of cardiovascular risk, such as endothelial function and aortic PWV, in a cohort of subjects with active RA.

Anti-inflammatory effects.   Treatment with ezetimibe and simvastatin produced similar reductions in inflammatory markers and disease activity. The improvement of DAS-28 was mostly due to the reduction of ESR, but there was also a significant reduction in tender joints count. Although, the reduction in inflammatory markers correlated with the degree of baseline inflammation, there was no correlation between the extent of cholesterol reduction and fall in CRP or DAS-28, which was also the case in the TARA study (15). This suggests either a potential "threshold effect" or that the reduction in cholesterol induced by ezetimibe and simvastatin was not sufficiently different, or indeed large, to unmask such a relationship.

Treatment with statins has been consistently associated with a decrease in inflammatory markers (14,19,20) in a variety of patient groups, including subjects with RA (15). However, previous data suggest that ezetimibe only reduces CRP when given in combination with other agents (19,20). Indeed, the present study is the first to show an anti-inflammatory effect of ezetimibe per se. This may relate to the relatively high level of systemic inflammation associated with RA patients compared with subjects with pure hypercholesterolemia or cardiovascular disease included in earlier studies (19,20). The present data are also the first to show that ezetimibe produces a clinical reduction of inflammation and disease activity in subjects with RA. It is unlikely that any such effects of ezetimibe are pleiotropic, because it is not absorbed into the circulation but acts locally by inhibiting cholesterol absorption from the small intestine. Taken together, these observations suggest that cholesterol reduction per se has anti-inflammatory effects in patients with RA. This notion is supported by previous observations that fibrates (21) and systemic Acyl-CoA cholesterol acyltransferase (ACAT) inhibition (22) reduce inflammatory markers in other patient groups.

Reduction of oxLDL.   The anti-inflammatory effects seen in the present study may be mediated by the reduction in oxLDL. Indeed, oxLDL is known to increase the expression of proinflammatory genes, leading to monocyte adhesion to arterial endothelial cells (23,24). Moreover, recent evidence from cultured human coronary artery endothelial cells indicates that oxLDL, through its receptor LOX-1, activates an inflammatory reaction by up-regulating CD40 and CD40L signaling pathways, and CD40 antibody reduces oxLDL-induced tumor necrosis factor (TNF)-alpha production (25). This may be especially important in RA, which is associated with elevated TNF-alpha signaling and increased oxidative stress driven by high inflammation (26). This could initiate a vicious circle, where inflammation-driven oxidation of LDL leads to further increases in inflammation, worsening of disease activity, and yet further oxidation, ultimately leading to endothelial dysfunction and cardiovascular disease. The present results support this theory by demonstrating that despite having LDL levels similar to control subjects, RA patients had higher oxLDL levels and worse endothelial function at baseline.

Reduction of arterial stiffness.   We confirmed our original observations of increased aortic PWV in RA and for the first time demonstrated a significant reduction in aortic PWV with antihyperlipidemic drugs in patients with RA. The reduction in aortic PWV correlated with the baseline ESR, with greatest reductions in PWV occurring in subjects with the highest ESR. This finding is in line with other studies, where greater clinical benefits of statins have been demonstrated in patients with high levels of inflammation (27,28). These data also extend our previous observations that anti–TNF-alpha therapy improves endothelial function and reduces aortic stiffness in RA (9) and suggest that even modest reductions in systemic inflammation may lead to beneficial effects on surrogates of cardiovascular risk.

We did not find any significant change in AIx following either drug. This suggests that despite reduction in wave speed, there was no reduction in the impact of wave reflection. This could be due to a fall in inflammation and subsequent peripheral vasoconstriction, which would lead to increased impedance mismatch at the point of reflection, and therefore the net effect on AIx would remain unchanged. Our data contradict those of Efrati et al. (29), who demonstrated that 40 mg simvastatin, but not 80 mg simvastatin, 10 mg ezetimibe, or combination of 40 mg simvastatin and 10 mg ezetimibe, reduces AIx. However, those data were based on small parallel groups (n = 10).

Improvement of endothelial function.   Statins improve endothelial function in patients with hypercholesterolemia (30), heart failure (31), coronary artery disease (CAD) (32), and RA (33). Most authors have ascribed this to the pleiotropic effect of statins, but, with the exception of 3 studies (29,31,32), investigators have not controlled for the cholesterol reduction. In the present study, we demonstrated for the first time that both ezetimibe and simvastatin significantly improve endothelial function in RA to a level similar to healthy control subjects. Although the improvement in FMD following simvastatin appeared greater than that following ezetimibe, it did not reach statistical significance. However, we cannot rule out the possibility that we would have reached a statistical significance if a larger number of patients were studied. Importantly, there was no change in the GTN response or baseline diameter of the brachial artery between visits, suggesting that smooth muscle susceptibility to nitric oxide (NO) was not altered. The reduction of total, LDL, and oxLDL cholesterol significantly correlated with the improvement of FMD, suggesting that cholesterol, and especially oxLDL, reduction per se improves endothelial function. Our findings contradict those of Landmesser et al. (31) and Fichtlscherer et al. (32), who showed that only simvastatin and not ezetimibe improved endothelial function. However, those studies were performed in patients with heart failure and CAD, not RA, which may explain the different findings. Moreover, although anti-TNF therapy has been associated with improved cardiovascular outcome in patients with RA (34), it worsens outcome in heart failure (35). Furthermore, the study by Landmesser et al. (31) included only 20 patients in a parallel group design, whereas ours employed the same number of subjects in a crossover design, providing greater power.

Possible mechanisms behind the improvement of endothelial function.   Support for the notion that cholesterol reduction per se may improve endothelial vasomotor function comes from in vivo and in vitro observations. A number of nonstatin therapies, such as a single LDL apheresis (36), fibrates (21,37), and systemic ACAT inhibition (22) have already been linked with improved endothelial function in hypercholesterolemic patients. Moreover, in vitro LDL itself inhibits endothelium-dependent vasodilatation (38). The composition of lipid rafts within the plasma membrane is also dependent on the circulating lipid profile. Indeed, the expression of scaffolding protein caveolin is increased in hypercholesterolemia (39). Caveolin functions as an inhibitor of endothelial nitric oxide synthase (eNOS) by blocking access of eNOS to its cofactor and substrate, thus reducing NO production (40) and possibly leading to endothelial dysfunction. Therefore, lipid reduction may lead to decreased expression of caveolin and to restoration of normal transport of substrate L-arginine for eNOS (41).

Study limitations.   This study was powered to detect a change in CRP and DAS-28 with statin therapy, and our power calculations were based on the reductions seen in the TARA study, but it was not powered to detect a difference of <50% between the 2 treatments. The crossover design of the study is an obvious strength, but also a weakness owing to a potential carryover effect. Nevertheless, we did not find a carryover effect after a 6-week washout period, and the order of the drugs did not affect the outcome. We did not have a combined simvastatin and ezetimibe treatment period and therefore we cannot answer whether this would have added to the effect we observed.

Furthermore, as with all chronic diseases, the disease activity can fluctuate markedly during the course of a study, especially if the duration is long. Therefore, our treatment period was relatively short.


   Conclusions
Top
 Abstract
 Methods
 Results
 Discussion
 Conclusions
References
 
We have shown that both ezetimibe and simvastatin reduce inflammatory markers ESR and CRP as well as disease activity to a similar degree in patients with RA. We have also shown, for the first time in a randomized double-blind study, that endothelial function and concomitantly arterial stiffness were improved by both drugs. These results suggest that the reduction of cholesterol per se ameliorates aortic stiffness and endothelial dysfunction. Our data also suggest that cholesterol-reducing therapies may be beneficial for RA patients, because they are well tolerated, improve clinical outcome. and reduce surrogates of cardiovascular risk. Future studies are needed to establish whether a reduction of arterial stiffness and improvement of endothelial function with antihyperlipidemic agents translates to an improvement in cardiovascular outcome in patients with RA.


   Acknowledgments
 
The authors gratefully thank Mrs. Anita Furlong for the recruitment of the participants and Mr. Mike Ashby for technical assistance with ELISA.


   Footnotes
 
The laboratory in which this work was carried out is sponsored by the British Heart Foundation.

1 Kaisa Mäki-Petäjä’s doctoral studies are funded by GlaxoSmithKline. Back

2 Drs. Booth and Wilkinson are supported by grants from the British Heart Foundation. Back

3 Dr. Hall is supported by the British Medical Association’s Doris Hillier Prize and has received an unrestricted grant from Pfizer for the development of a cardiovascular risk reduction website. Back


   References
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 Discussion
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 References
 

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