Real Life studier av legemidler. Pål Hasvold Nordic value demonstration manager AstraZeneca

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1 Real Life studier av legemidler Pål Hasvold Nordic value demonstration manager AstraZeneca

2 Praktisk eksempel: Finnes det forskjeller mellom blodtrykksmedisiner innenfor en klasse?

3 Path way Renin angiotensin AT1 respetor blokkere? Angiotensinogen ARB Aprovel Atacand Cozaar Micardis Teveten Olmetec AT1 Renin ACE Angiotensin I Angiotensin II AT2 ACEi Capoten Enalapril Lisinopril Ramipril Triatec Vivatec Zestril

4 TLV granskar ARB-läkemedlen (2010) TLV har inlett en begränsad genomgång av samtliga ARB-läkemedel (angiotensin-receptor-blockerare). Vi startar genomgången med anledning av att ett av läkemedlen i gruppen, Cozaar (losartan), nyligen har förlorat sitt patentskydd och att generiskt losartan nu tillhandahålls. I genomgången utgår vi från det underlag som togs fram i samband med den omfattande genomgången av alla läkemedel mot högt blodtryck.

5 En genomgång av de läkemedel som sänker blodtrycket (2008) Alla företag har argumenterat starkt för sina produkter. Alla anför de argument och studier som talar till deras fördel. De direkt jämförande studier som företagen själva skickat in till oss bildar ett nät där det i princip är omöjligt att dra några säkra slutsatser. Det finns många jämförelser gjorda, men de flesta har gjorts på starkt begränsade och noga utvalda patientgrupper. Resultaten säger därför inte så mycket om hur läkemedlen fungerar i klinisk vardag.

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8 Insurmountability (%) Binding Ability to the AT1-receptor Candesartan and losartan have significant pharmacological differences * Candesartan binds harder to the AT1-receptor Candesartan binds longer to the AT1-receptor telmisartan candesartan olmesartan EXP valsartan irbesartan 20 losartan Dissociation t 1/2 *Van Liefde I, et al. Molecular and cellular endocrinology. 2008

9 Hypothesis and Aim Losartan and candesartan have different pharmacological properties and blood pressure lowering abilities 1-4 The aim of the this study was to test the hypothesis that losartan and candesartan have different primary preventive effects on CVD risk 1. Van Liefde I, et al. Molecular and cellular endocrinology Bhuiyan MA, et al. Life Sci Bakris G, et al. J Clin Hypertens Lacourcière Y, et al. Am J Hypertens 1999

10 Health Care in Sweden All residents in Sweden have a unique identification number Long traditions with mandatory national health registers Wide use of electronic patient journals in primary care and hospitals

11 Extraction Method 72 Primary Care Centers in Sweden 24,943 eligible patients Swedish National Discharge Register Mandatory since1984-1,2 14,100 included patients Swedish Cause of Death Register 1. Lindgren P et al. Eur J Cardiovasc Prev Rehabil 2005; 12(6): Ringborg A et al. Int J Clin Pract 2008; 62(5): , Ringborg A et al. Diabet Med 2008; 25(10):

12 Hvilke pasienter? 24,943 patients started prescription of losartan (13001) or candesartan (11942) from 1999 to patients were excluded: 5792 (44.6%) losartan and 4144 (34.7%) candesartan patients with a history of cardiovascular disease 386 (3.2%) losartan and 379 (2.9%) candesartan patients with malignancy Prescribed another RAAS* inhibitor in the first week after index prescription, losartan 59 (0.5%) and candesartan 83 (0.7%) 6771 (52.1%) losartan patients 7329 (61.4%) candesartan patients

13 Two similar groups at baseline? Drug history 1.3 years Hospital care history Primary care history ~15 years 5.8 years Inclusion No of patients hospitalised before index* Losartan Candesartan 3286 (48.5%) 3560 (48.6%) Mean days in hospital 5.9 days 5.9 days

14 Baseline Characteristics Losartan Candesartan n=6771 n=7329 p Age (years) 62.4 (12) 61.7 (12) Women, n (%) 3723 (55.0) 4109 (56.1) Body mass index (kg/m2) 30.2 (5.3) 30.2 (5.4) Systolic blood pressure (mmhg) 159 (20) 160 (19) Diastolic blood pressure (mmhg) 89 (10) 90 (10) < Total cholesterol (mmol/l) 5.7 (1.0) 5.7 (1.1) LDL cholesterol (mmol/l) 3.34 (0.81) 3.39 (0.81) HDL cholesterol (mmol/l) 1.38 (0.32) 1.37 (0.31) Triglycerides (mmol/l) 1.64 (0.81) 1.62 (0.78) Glucose (mmol/l) 6.3 (2.4) 6 2 (2.3) HbA1c (%) 5.9 (1.4) 5 8 (1.4) Diabetes, n (%) 1215 (17.9) 1112 (15.2) < Serum creatinine (µmol/l) 84 (21) 84 (19) Potassium (mmol/l) 4.0 (0.4) 4.0 (0.4) Thiazides, n (%) 848 (12.5) 1087 (14.8) Calcium channel blockers, n (%) 968 (14.3) 1104 (15.1) Beta-blockers, n (%) 1605 (23.7) 1883 (25.7) Oral glucose lowering drugs, n (%) 628 (9.3) 559 (7.6) Statins, n (%) 727 (10.7) 688 (9.4) Antithrombotics, n (%) 421 (6.2) 395 (5.4) Angiotensin receptor blockers, n (%) 101 (1.5) 120 (1.6) Angiotensin converting enzyme inhibitors, n (%) 1361 (20.1) 1459 (19.9)

15 mmhg Blood Pressure Reduction Candesartan Losartan Systolic Diastolic Months

16 Cumulative incidence (%) CVD Risk Primary composite endpoint Losartan Candesartan %*, p= Time (months) Number at risk Los. Can. *Adjusted for age, gender, diabetes and index year

17 Additional Adjustments Primary Analysis (age, gender, diabetes and prescription index year) Additional Drug Adjustments (+lipid lowering drugs, thiazides, beta-blockers and antithrombotics) Adjustment of blood pressure (+systolic blood pressure) Exclusion of diabetic patients (age, gender and prescription index year) Number of patients Hazard Ratio 14, (95%CI ) 14, (95%CI ) 11, (95%CI ) 11, (95%CI )

18 Cumulative incidence (%) Cumulative incidence (%) Cumulative Incidence (%) Cumulative incidence (%) Cumulative incidence (%) Cumulative incidence (%) Risk of Separate Endpoints Adjusted Risk Reduction* Heart failure Arrhythmias Peripheral artery disease Losartan Candesartan Losartan Candesartan Losartan Candesartan % p= % p= % p= Time (months) Time (months) Time (months) Chronic ischemic heart disease Losartan Candesartan Myocardial infarction Losartan Candesartan Stroke Losartan Candesartan % p= % p= % p= Time (months) Time (months) Time (months) *Adjusted for age, gender, diabetes and index year

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20 Total Costs During the Study

21 Stepwise price reduction

22 Konklusjon Skandinavia tilbyr unike muligheter til å genere real life data raskt og med høy kvalitet Vår mulighet til å benytte data fra allmennpraksis er unik Dette gjør det mulig for legemiddelindustrien å vise real life effekter av våre legemidler på et kostandseffektivt sett: Retrospektive studier I fremtiden: prospektive studier med randomisering?

23 Type of angiotensin receptor blocker affects mortality - analysis of 5823 patients in the Swedish heart failure registry The study identified patients treated with ARBs in the Swedish heart failure registry (RiksSvikt) 5823 patients (age 74±11; 39% women) were treated with ARB (2639 candesartan; 2500 losartan; 357 valsartan; and 327 other, excluded from the analysis) and were followed for 686±524 days One-year survival was 90% for candesartan and 82% for losartan (p<0.001) In multivariate analysis, hazard ratios for mortality compared to candesartan were 1.5 for losartan (p<0.001), after adjustment for all type of different covariates. As for example dose of ARB, age, etiology, NYHA class, presence or absence of diabetes etc Scandinavian Cardiovascular Journal 2010;44:16

24 Dental and Pharmaceutical Benefits Agency Hej, För en tid sedan fick ni ett brev där TLV upplyste om att PM med förslag till beslut för läkemedel inom gruppen ARB läkemedel skulle skickas ut under april månad. Vi är ännu inte redo att lägga fram ett förslag till beslut, och PM kommer därför inte att skickas ut i nuläget. Vi återkommer med en uppdaterad tidplan. Vänliga hälsningar Jeanette Lagerlund Medicinsk utredare TLV, Tandvårds- och läkemedelsförmånsverket Dental and Pharmaceutical Benefits Agency Box 55 [Sundbybergsvägen 1], Solna Växelnr: Direktnr: jeanette.lagerlund@tlv.se

25 BACK UP

26 Back up

27 Håndtering av pasientdata Data fra allmennpraksis Pasient data Studie database Studie database Kodenøkkel Hovedutprøver Kodenøkkel Pasient data Sosialstyrelsen Sykehusinnleggelser Dødsårsak

28 External control/transparency Approval by ethics committee Approval by National Board of Health and Welfare Clinicaltrials.gov

29 Klopidogrel og protonpumpehemmere unngå omeprazol og esomeprasol Etter en analyse av nye data om mulige interaksjoner mellom klopidogrel og protonpumpehemmere, har det europeiske legemiddelkontoret (EMA) anbefalt å begrense advarselen mot samtidig bruk. Det er omeprazol og esomeprazol som bør unngås, mens andre protonpumpehemmere kan brukes samtidig

30 Hvorfor Real Life studier på legemidler? Samfunnet stiller nye krav til dokumentasjonen av legemidler Nytteverdien vs annen behandling: Begrenset/individuell refusjon Foretrukket legemiddel Tidsbegrenset refusjon

31 Randomiserte head to head studier? Data skal benyttes til helseøkonomiske vurderinger Selekterte pasienter og leger Tar lang tid Ekstremt ressurskrevende Etisk forsvarlig?

32 Hvorfor Real Life studier i Skandinavia? Offentlig helsevesen Lang tradisjon med kvalitetsregister Lang tradisjon med offentligeregister Elektroniske pasientjournaler

33 TLV: Assessing Drug Effectiveness Common Opportunities and Challenges for Europe July 2009, Sweden The aim of the Swedish conference and the following pilot project is to find ways of cooperating systematically across Europe on the collection and sharing of data on the effectiveness of drugs. A better understanding of how well drug treatments work in everyday clinical use would benefit patients, pharmaceutical companies, government agencies and society as a whole