Fokus på hjerte-kar sykdom ved revmatisk leddsykdom:

Fokus på hjerte-kar sykdom ved revmatisk leddsykdom: Forebygging og behandling av Kardiovaskulær sykdom AG Semb, overlege dr med Forebyggende Hjerte Revma Klinikk Revma i Nord 2.12 2011

Fokus på hjerte-kar sykdom ved inflammatorisk leddsykdom: 1. Kardiovaskulær sykdom hos pasienter med inflammatorisk leddsykdom RA revmatoid artritt AS - Mb. Bekterev PsA psoriasis artritt 2. Forebygging av kardiovaskulær sykdom

Kardiovaskulær sykdom hos pasienter med inflammatorisk leddsykdom Risiko hos RA, AS, PsA Risiko faktorer forebygging og behandling

Dødsårsaker WHO 2006

Fra Nasjonalt Folkehelseinstitutt. Kilde: WHO A fabulous decrease in Mortality by AMI and stroke for men 0-64 yrs -Cholesterol is redused from ~6.8 to 5.8 mmol/l - Reduced smoking

Revmatoid Arthritt (RA) Prevalence 0.5-1.0% i populasjonen 165 million i verden har RA I Norge 25 000 ~ like mange som FH - 50 000 personer med inflammatorisk leddsykdom Pincus T, et al. J Rheumatol. 1989;79(suppl):67-95. Pincus T, et al. J Rheumatol. 1987;14:240-251.

Mortalitet hos pasienter med RA Survival (%) 100 80 60 40 20 0 0 2 4 6 8 10 Years < 10 joints (n=12) < 11-12 joints (n=16) < 21-30 joints (n=16) >30 joints (n=9) Pasienter med RA har dobbelt så høy mortalitets risiko enn den generelle befolkningen 50% skyldes CVD Livslengden er nedsatt 3 til 18 år Pincus & Callahan. Scand J Rheumatol Suppl.1989;79:67-96 Koopman. Arthritis and Allied Conditions.13th ed. 1997

Ann Rheum Dis 2011;70:929-34

Lindhardsen et al. Ann Rheum Dis 2011;70:929-34

ARD 2006;65:1608-12

A&R 2006;54:2061-8

A&R 2005;52:402-11

Ankyloserende Spondylit Mb Bekterev

Comparison of myocardial infarction risk between AS and controls Mathieu S et al Arthritis Care & Rheum 2011

Comparison of prevalence of metabolic syndrome between AS and controls Mathieu S et al Arthritis Care & Rheum 2011

Psoriasis & PsA Prevalence: 2-3% av verdens befolkning 20-30% har psoriasis arthropathi Gelfand JAMA 2006 Mease Bull NYU Hosp Jt Dis 2010 Inkonsistente data vedr øket risiko for CVD

review There is a paucity on info on the effects of LL agents and a HT on CV risk and no data on aspirin Large prospective cohort studies necessary are required to produce evidence based guidelines Lack of data on nonconvential risk factors impact on CV outcomes in Ps and PsA Important to define patients at risk and id potential biomarkers of CV risk

Psoriasis and CVD Ps/PsA er forbundet med øket risiko for kardiovaskulær sykdom Ung alder, alvorlighetsgrad av Ps, og PsA har høyest risiko - ikke justert for K-V risiko faktorer Pas med Ps/PsA er kandidater for tidlig innsetting av forebyggende K-V intervensjon J Int Med 2011;270:147-157

RA, AS & PsA pas dør av sykdom og ikke sin immunsykdom

Høy y RISIKO

Traditional Risk factors 1. Age 2. Cholesterol 3. Smoking 4. Diabetes 5. HT 6. Weight, BMI, waist circumference: menn >102 cm woman >88 cm 7. Fam VD 8. Fysical activity 9. Alcohol

Traditional Risk factors 1. Age 2. Cholesterol 3. Smoking 4. Diabetes 5. HT 6. Weight, BMI, waist circumference: menn >102 cm woman >88 cm 7. Fam VD 8. Fysical activity 9. Alcohol

Moderne Human beeing is the only mammal with total cholesterol > 4,0 mmol/l A reflection of sedentary lifestyle O Keefe et al. JACC 2004;43:2142-46

Despite low lipids There is an increased rate of CVD Ann Rheu Dis 2010; 69: 1996-2001

Increasing CRP reduces lipid levels i RA CRP- groups Group 0: 0-3 Group 1: 3-10 Group 2: >10 Peters M Clin Pract 2010

LIPID PARADOX IN RA Myasoedova E Ann Rheum Dis 2010;69(Suppl3):495

Guidelines for the management of dyslipidemias 2007 Atherosclerosis 2011; 217:S1-44 Identify autoimmune disorders as high risk (Ps, RA, SLE, mm) but no indication for LL on basis of the presence of autoimmune disease alone Id carotid plaques as high risk factor Treatment target LDL < 1.8 mmol /l

0 3 5 140 5 3 0 People who stay healthy tend to have certain characteristics: 0 No tobacco 3 Walk 3 km daily, or 30 mins any moderate activity 5 Portions of fruit and vegetables a day 140 Blood pressure less than 140 mm Hg systolic 5 Total blood cholesterol <5mmol/l 3 LDL cholesterol <3 mmol/l 0 Avoidance of overweight and diabetes

KARDIOVASKULÆR RISIKO STRATIFISERING: Kjent hjerte-kar sykdom Ikke kjent hjerte-karsykdom, men SCORE > 5% sekundær prevensjon primær prevensjon Behandlings mål: Primær Prevensjon Ingen hjerte kar sykdom SCORE>5% Sekundær Prevensjon Kjent hjerte kar sykdom Total Cholmmol/l 4.5 4.0 LDL mmol/l 2.5 1.8 HDL mmol/l Males : 1.0 Females: 1.1 Males : 1.0 Females: 1.1 TG mmol/l 1.7 1.7 BP, mmhg Glucose < 140/80 <6.0 < 130/80 <6.0

Hvorfor viktig at LDL og HDL guideline nivå oppnåes?

Forhindre fremtidige KV hendelser

50 Proportional Reduction in MCE by Mean Reduction in LDL-C 40 % 30 20 10 1mmol/L reduction 22% risk reduction 0 0,5 1.0 1.5 2.0 Reduction in LDL cholesterol (mmol/l) CTT Collaborators. Lancet 2005;366:1267-78

Fordi... Utover RR for fremtidige hendelser.. Atheroma volume reduksjon

LDL-C og % forandring i Atheroma Volume i IVUS studier Median change in percent atheroma volume (%) 1.8 1.2 0.6 0-0.6 R 2 = 0.97 P<0.001 REVERSAL atorvastatin ASTEROID rosuvastatin A-Plus placebo CAMELOT placebo REVERSAL pravastatin Progression Regression -1.2 50 60 70 80 90 100 110 120 1.6 1.8 Mean LDL-C (mg/dl)mmol/l Nissen S et al. JAMA 2006;295:e-publication ahead of print

Uavhengig av statin, LDL-C 50% for atheroma vol reduksjon Change in Atheroma Volume, mm 3 20 15 10 5 0-5 -10-15 -80-70 -60-50 -40-30 -20-10 0 10 20 Reverseal: Pravastatin 40 mg vs atorvastatin 80mg N=502 x 2 18 months IVUS % Change in Low-Density Lipoprotein Cholesterol Nissen S 2004

Fordi... Utover RR for fremtidige hendelser.. Atheroma volume reduksjon Courage studien viser at medikamentell behandling er like bra som PCI/CABG

Gjelder dette for RA, AS & PsA?

Ubesvarte spm: Har lipid senkning samme effekt hos RA/AS/PsA pasienter som i den generelle befolkningen? Høyerer absolutt K-V risiko Bakgrunns systemisk inflammasjon Høyere lipider Har de flere bivirkinger av statiner?

Mindre enn halvparten av pas når lipid målene 60 55 LDL-C Goal Attainment % Patients at Goal 50 40 30 20 10 24 14 26 34 40.5 0 France a Germany a Italy a Spain a Switzerland b OVERALL a LDL-C goal of <100 mg/dl (2.6 mmol/l) per ATP III guidelines b LDL-C goal of <100 mg/dl (2.6 mmol/l) per ATP III guidelines or at discretion of individual physician Adapted from Van Ganse E, et al. Curr Med Opin, 2005;21(9):1389-1400.

LDL-C C Reductions with Different Statin Strategies Change in LDL-C from baseline (%) 0-5 -10-15 20-25 -30-35 -40-45 -50-55 -60 10 mg 20 mg 40 mg CRESTOR 10 mg 20 mg 40 mg 80 mg atorvastatin 10 mg 20 mg 40 mg 80 mg simvastatin 10 mg 20 mg 40 mg pravastatin P<0.002 vs CRESTOR 10 mg P<0.002 vs CRESTOR 20 mg P<0.002 vs CRESTOR 40 mg Adapted from Jones PH, et al Am J Cardiol 2003;92:152 160

Doubling a Statin Dose Generally Yields Only a 6% Incremental Drop in LDL-C Reduction of LDL-C (%) 6% drop Statin Rule of 6 6% drop 6% drop 0 10 20 30 40 50 60 70 80 Statin (mg) Adapted from Knopp RH, et al. N Engl J Med. 1999;341:498 509; Stein E. Am J Cardiol. 2002;89(suppl):50C 57C.

Hva gjør man da? Dual lipidmodulerende behandling

Lipid senkende behandling Fibrates Cholesterol absorption inhibitor Ezetemibe Ezetrol

Higher LDL-C Goal Attainment by co-administration Ezetimibe & statin % Patients at LDL-C Goal at 6 Weeks. a 100 80 60 40 20 0 Study 1 80% b 17% 100 80 60 40 20 0 Study 2 74% b 17% 100 80 60 40 20 0 Studies 3 and 4 (pooled) 81% b 22%. Ezetimibe + simvastatin 10 20 mg (n=208) Placebo + simvastatin 10 20 mg (n=210) Ezetimibe + atorvastatin 10 20 mg (n=219) Placebo + atorvastatin 10 20 mg (n=225) Adapted from Brohet C, et al. Curr Med Res Opin. 2005;21:571 578; Cruz-Fernández JM, et al. Int J Clin Pract. 2005;59:619 627.

Statiner er trygge og effektive Muskel smerter 1-5% i RCT 5-10% i klinisk praksis ca 0.1% pr 1/1000 000 rhabdomyolyse

Risk of Cancer in Statin Versus Control Cohorts for Any Given Level of On-Treatment LDL-C 15 randomiserte Pbo statin trials 437 017 persons yrs 5 752 incident cancers Statins not related to cancers Alsheikh-Ali et al JACC 2008; Vol. 52, No. 14, 2008 Low LDL not related to liver enzyme elevations or rhabomylysis

SåhvorforerikkeK V risiko redusert med 100% med disse behandlingsprogammene i den generelle befolkningen?

Kolesterol Det dårlige kolesterol LDL Det gode kolesterol - HDL Triglycerider

HDL

Low HDL-c: a strong risk factor Risk CVD 4.0 3.0 4.0 For any level of LDL-C, HDL-C is inversely related to CVD risk 2.0 1.0 2.0 1.0 Rule of 1 s For every 1% shift in HDL-C or LDL-C, event rates are ~1% lower 0.65 1.17 1.68 HDL-c Kannel et al. Am J Cardiol 1983

How does HDL protect against atherosclerosis? Anti-oxidant properties Anti-coagulant properties Anti-inflammatory properties Protection/maintenance of endothelial function Key role player in Reverse Cholesterol Transport

Risikofaktorer: 1. Alder 2. Kolesterol 3. Røyk 4. Diabetes 5. Høyt Blodtrykk 6. Vekt 7. Fysisk aktivitet Røyk assosiert med RA Røyk er assosiert med dårligere behandlings effekt ved RA Interheart studien, Salim Yusuf, 2004

Lifestyle Changes Lifestyle change MOA HDL Efficacy Comments Diet & Exercise Change in free fatty acid metabolism +5-15% Lack of compliance impacts efficacy HERITAGE trial only showed 3% increase Smoking Cessation Unknown +5% Compliance is very difficult Although other lifestyle approaches (e.g. High fat diet; Alcohol) can raise HDL, they are associated with different risks. Source: Product PIs, LIPITOR consumer research, Circulation June 2003

Traditional Risk factors 1. Age 2. Cholesterol 3. Smoking 4. Diabetes 5. HT 6. Weight, BMI, waist 7. Fam VD 8. Fysical activity 9. Alcohol

Ola Nordmanns vekt økt 6-8 kg siste 25 år da får vi mange med helseskadelig overvekt! Diagrammet viser andel (%) av befolkningen som har BMI > 30 (fra Folkehelseinstituttet)

Psoriasis, PsA og fedme Adipositas-Ps link Setty et al Arch Inern med 2007 Fedme utvikling av Ps Herron et al Arch Dermatol 2005 PASI relatert til vekt Bardazzi et al Dermatol Ther 2010 Bedre medikamentell effekt ved vekt tap Gisondi et al Am J Clin Nutr 2008 Gastric banding Hossler et al Acad Dermatol 2010

Diabetes Kardiometabolsk syndrome Høyt Livvidde mål Plus 2 av følgende Triglycerider ( 1.7 mmol/l) HDL kolesterol Menn < 1.0 mmol/l Kvinner < 1.3 mmol/l Blod trykk 130 / >85 mm Hg FPG 5.6 mmol/l eller diabetes

Lave triglyserider er assosiert med redusert risiko for død, hjerteinfarkt og sykehusinnleggelser 0.20 0.15 HR: 0.73 (0.62, 0.87) P < 0.001 TG > 1,7 mmol/l Tilfeller (%) 0.10 0.05 TG < 1,7 mmol/l 0.00 0 150 300 510 700 Dager n=3718 Miller M. et al, JACC Vol 51, No 7: 2008

Omacor Effektiv senkning av høye triglyserider 12 Triglyserider mmol/l 10 8 6 4 2-45% * P<0.0001 0 Baseline 4 gram Omacor * Change from baseline for placebo versus change from baseline for Omacor Harris WS et at, J Cardiovasc Risk 1997; 4: 385-91

To Decrease TG To Decrease Inflammation To Decrease Platelet Function To Decrease Vascular Reactivity DHA+EPA Daily dose needed, gram 3-4 3-4 6 3-4

Utradisjonelle Risiko faktorer Immunsykdommen Totale inflammasjons byrde Systemisk steroide bruk Biologiske midler

Sammenhengen mellom inflammasjon og atherosklerose? CRP nivået er assosiert med K-V sykdom i den generelle befolkningen Sammenheng mellom inflammatorisk aktivitet atherosklerose/k-v sykdom

Results from the Women s Health Study suggest CRP determinations will be of value in primary prevention Risk level Low < 1 Average 1-3 High >3 CRP(mg/L) Ridker PM Circulation 2003; 107:391-397 CVD Event Free Survival Probability 1.00 0.99 0.98 0.97 0.96 0.95 0 2 4 6 8 Years of Follow-Up CRP < 1.0 mg/l CRP 1.0-3.0 mg/l CRP > 3.0 mg/l

Biologics and CRP-Levels: Mean CRP at Baseline and Endpoint of Study (All +MTX) Agent Baseline (mg/dl) Endpoint (mg/dl) Change (% reduction) Tocilizumab 2.6 0.2 96% Infliximab 4.7 1.2 74% Etanercept 4.3 1.2 73% Abatacept 3.4 1.3 62% Rituximab 3.7 1.6 57% Quinn MA, et al. Arthritis Rheum 2005; 52:27 35 Klareskog L, et al. Ann Rheum Dis 2006; 65:1578 1584 Schiff M, et al. Ann Rheum Dis 2005; 64(Suppl III): 435 Cohen SB, et al. Arthritis Rheum 2006; 54:2793 2806

TNF blockers & CVD in RA SMR 300 250 200 150 100 50 0 No Yes Anti-TNF treatment Jacobson TH et al. J Rheumatol 2005;32:1213

RA - Changes in lipids and CRP with biologics CRP - inflammation baseline Lipid levels pre-ra untreated RA RA treated with biologics

Sex 2 uker etter AMI + en trapp

Samliv - SEX Viagra Levitra - Cialis er OK Ikke sammen med nitroglycerin preparater

Er klassiske risiko faktorer økt ved RA? Røyking Arterial hypertension Diabetes mellitus Dyslipidemi

Er klassiske risiko faktorer økt ved RA? Røyking Risiko faktor for RA

Er klassiske risiko faktorer økt ved RA? Arteriell hypertension NSAID, leflunomide, cyclosporin Diabetes mellitus Corticosteroider Dyslipidaemi Inflammation, corticosteroids

Økt risiko... Hvordan sette dette i klinisk perspektiv?

No CV hard end point studies - yet primary prevention awaiting results fromtrace-ra secondary prevention - few reports» Semb et al Rheumatology 2011;50(2)324-329» Semb et al Abstract Eular 2011 THU0042

All Cardiovascular Events in a pooled analysis IDEAL and TNT trials CVMM % 30 Intensive lipid lowering atorva 80 Conventional LL simva 40 or atorva 10 25 20 15 10 5 0 RA/AS/PsA non-ijd n=280 n=18 609 Semb, Ann Rheum Dis 2011;70(Suppl3):193

Conclusion Patients with and without IJD had comparable lipid lowering effect and risk reduction of CVMM after intensive treatment with statins. Patients with AS had low atherogenic lipids at baseline compared to the other groups, but intensive lipid lowering seemed to be more protective concerning CVMM in this patient group. These observations needs replication in other studies.

Guidelines for the management of dyslipidemias Atherosclerosis 2011; 217:S1-44 2007 Identify autoimmune disorders as high risk (Ps, RA, SLE, mm) but no indication for LL on basis of the presence of autoimmune disease alone Treatment target LDL < 1.8 mmol /l Recognize asymp CP high risk RF for CVD

Risk score models should be adapted for RA patients by introducing a 1.5 multiplication factor. The accuracy of using a simple multiplier to improve the risk assessment is unknown And a comment has been made from prof Gabriels group on this in ARD spring 2011

CAROTID ATHEROSCLEROSIS PREDICTS INCIDENT ACUTE CORONARY SYNDROMES IN RHEUMATOID ARTHRITIS Evans et al Arthritis & Rheum 2011 FU: 3402 person years without prev. CVD with prev. CVD n=599 n=636

CAROTID ATHEROSCLEROSIS PREDICTS INCIDENT ACUTE CORONARY SYNDROMES IN RHEUMATOID ARTHRITIS Evans et al Arthritis & Rheum 2011

Traditional Risk factors 1. Age 2. Cholesterol 3. Smoking 4. Diabetes 5. HT 6. Weight, BMI, waist circumference: menn >102 cm woman >88 cm 7. Fam VD 8. Fysical activity 9. Alcohol

Hva skal/bør en lege gjøre? Spør pas: har du hjerte-kar sykdom; selv/fam vet ditt kol nivå hva er BT ditt har du diabetes Henvise til kardiovaskulær risiko stratifisering?

Treatment targets: Primary Prevention No CVD SCORE>5% Secondary Prevention CVD or CP or both Total Chol mmol/l 4.5 4.0 LDL mmol/l 2.5 1.8 HDL mmol/l Males: 1.0 Females: 1.1 Males: 1.0 Females: 1.1 TG mmol/l 1.7 1.7 BP < 140/80 < 130/80 Glucose <6.0 <6.0

Hvem skal henvises til kardiovaskulær risikostratifisering: 1. Når en person ber om vurdering av sin risiko eller Risiko Faktorer 2. Når legen eller pas har kunnskap om høyt nivå av en eller fler RF 3. Symptomer eller tegn forenlig med en risikotilstand, - feks hodepine pga HT 4. Tidlig sykdom i familien

Hva gjøres Forebyggende Hjerte Revma klinikk 1. Spørreskjema 2. Lipider / glucose / BT og EKG 3. BMode US art carotis 4. Ekkokardiografi

KARDIOVASKULÆR RISIKO STRATIFISERING VED IKKE KJENT HJERTE-KARSYKDOM: Det beregnes 10 års risiko for fatalt hjerteinfarkt i høy risiko regioner i Europa 1 Alder Kjønn Røyk +/- BT Kol or Kol/HDL Terskel verdi for intervensjon: > 5 %

B-Mode Ultrasound of Carotid artery To detect carotid plaques

ICA ECA Bulb CCA Longitudinal view

Treatment to Lipid Targets in patients with inflammatory arthrits in a Preventive Cardio-Rheuma Unit A.G. Semb, S. Rollefstad, A. Eirheim, T. R. Pedersen, I. Holme, T. K. Kvien Rollefstad S et al Ann Rheum Dis 2011;70(Suppl3):131

Preventive Cardio-Rheuma Clinic Referred 239 pat with IJD referred from the rheumatologic out patient clinic 1.3 2009 30.6 2010 No preventive LL treatment SCORE<5% n=72 (30.1%) Categorized to preventive LL treatment n=167 (69.9%) LL treatment was either simvastatin, atorvastatin or rosuvastatin 1 prevention no CVD SCORE>5% n=42 (25.1%) 2 prevention n=125(74.9%) CVD n=70 CP no CVD n=55 CVD + CP n=112 Rollefstad S et al Ann Rheum Dis 2011;70(Suppl3):131 Accepted lipid targets n=112 Still under treatment n=55

Patient charcteristics at first consultation

Patient charcteristics at first consultation Rollefstad S et al Ann Rheum Dis 2011;70(Suppl3):131

Patient charcteristics at first consultation Rollefstad S et al Ann Rheum Dis 2011;70(Suppl3):131

Percent change in lipids first to final consultation in IJD were highly significant 50 45 40 35 30 25 20 15 10 5 0 primary prevention % % p<0.0001 p<0.0001 p=0.01 p=0.06 TC LDL TG HDL 50 45 40 35 30 25 20 15 10 5 0 secondary prevention p<0.0001 p<0.0001 p=0.03 p=0.6 TC LDL TG HDL The relative change in lipids were larger in 1 prevention compared to 2 because some patients were already on statins when referred, but had not reached lipid targets RA: 7 (17.9%), AS: 4 (30.8%), PsA: 3 (37.5%) Rollefstad S et al Ann Rheum Dis 2011;70(Suppl3):131

% 100 90 Proportion of patients reaching at least 2 lipid targets 90,3 92,6 84,6 80 70 60 50 RA AS PsA Rollefstad S et al Ann Rheum Dis 2011;70(Suppl3):131

100 90 80 70 60 50 40 30 20 10 0 60 50 40 Proportion of patients reaching at least 2 lipid targets 90,3 92,6 84,6 RA AS PsA 55 Current Therapies Provide Suboptimal Results Van Ganse E, et al. Curr Med Opin, 2005 Eurospire I, II, III Kotseva et al Lancet 2009;379(9667):929-40 Dysis reports Germany 2010 & 2011, Netherlands 2010, Spain 2011, Portugal 2011, Ireland 2011, Canada 2010 LDL-C Goal Attainment 34 40.5 30 24 26 20 14 10 0 France a Germany a Italy a Spain a Switzerland b OVERALL Rollefstad S et al Ann Rheum Dis 2011;70(Suppl3):131

% 100 90 80 70 Proportion of patients reaching at least 2 lipid targets 90,3 92,6 84,6 Number of consultations needed to obtain target: 2.59+0.97 3.30+1.43 3.00+1.16 60 50 RA AS PsA Rollefstad S et al Ann Rheum Dis 2011;70(Suppl3):131

The proportion of IJD patients reaching each lipid target % 100 90 80 70 60 50 40 30 20 10 1 prev: all 4 lipid targets was reached >76% 2 prev: targets for LDL/HDL was reached > 81%, except TC target 54% due to HDL 1 prev 2 prev 0 TC LDL HDL TG Rollefstad S et al Ann Rheum Dis 2011;70(Suppl3):131

Adverse events tolerable minor side effects mostly GIT no increase in CPK, AST, ALT > 2xULN No serious adverse events were observed Rollefstad S et al Ann Rheum Dis 2011;70(Suppl3):131

Conclusion Patients with IJD referred to the Preventive Cardio- Rheuma Clinic had a high probability for the need of CV prevention Treatment to lipid targets was succesful in ~ 90% This experience support the importance and relevance of establishing Preventive Cardio-Rheuma Clinics Rollefstad S et al Ann Rheum Dis 2011;70(Suppl3):131

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