Real Life studier av legemidler Pål Hasvold Nordic value demonstration manager AstraZeneca
Praktisk eksempel: Finnes det forskjeller mellom blodtrykksmedisiner innenfor en klasse?
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
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.
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.
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 100 80 telmisartan candesartan olmesartan EXP 3174 60 40 valsartan irbesartan 20 losartan 0 0 20 40 60 80 100 120 Dissociation t 1/2 *Van Liefde I, et al. Molecular and cellular endocrinology. 2008
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 2008. 2. Bhuiyan MA, et al. Life Sci. 2009. 3. Bakris G, et al. J Clin Hypertens. 2001. 4. Lacourcière Y, et al. Am J Hypertens 1999
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
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): 530-534 2. Ringborg A et al. Int J Clin Pract 2008; 62(5): 708-716, Ringborg A et al. Diabet Med 2008; 25(10): 1178-1186
Hvilke pasienter? 24,943 patients started prescription of losartan (13001) or candesartan (11942) from 1999 to 2007 10843 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
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
Baseline Characteristics Losartan Candesartan n=6771 n=7329 p Age (years) 62.4 (12) 61.7 (12) 0.0010 Women, n (%) 3723 (55.0) 4109 (56.1) 0.2030 Body mass index (kg/m2) 30.2 (5.3) 30.2 (5.4) 0.8463 Systolic blood pressure (mmhg) 159 (20) 160 (19) 0.0124 Diastolic blood pressure (mmhg) 89 (10) 90 (10) <0.0001 Total cholesterol (mmol/l) 5.7 (1.0) 5.7 (1.1) 0.2243 LDL cholesterol (mmol/l) 3.34 (0.81) 3.39 (0.81) 0.0647 HDL cholesterol (mmol/l) 1.38 (0.32) 1.37 (0.31) 0.4826 Triglycerides (mmol/l) 1.64 (0.81) 1.62 (0.78) 0.2965 Glucose (mmol/l) 6.3 (2.4) 6 2 (2.3) 0.0024 HbA1c (%) 5.9 (1.4) 5 8 (1.4) 0.0342 Diabetes, n (%) 1215 (17.9) 1112 (15.2) <0.0001 Serum creatinine (µmol/l) 84 (21) 84 (19) 0.6895 Potassium (mmol/l) 4.0 (0.4) 4.0 (0.4) 0.7452 Thiazides, n (%) 848 (12.5) 1087 (14.8) 0.0001 Calcium channel blockers, n (%) 968 (14.3) 1104 (15.1) 0.2071 Beta-blockers, n (%) 1605 (23.7) 1883 (25.7) 0.0066 Oral glucose lowering drugs, n (%) 628 (9.3) 559 (7.6) 0.0005 Statins, n (%) 727 (10.7) 688 (9.4) 0.0084 Antithrombotics, n (%) 421 (6.2) 395 (5.4) 0.0386 Angiotensin receptor blockers, n (%) 101 (1.5) 120 (1.6) 0.5301 Angiotensin converting enzyme inhibitors, n (%) 1361 (20.1) 1459 (19.9) 0.7906
mmhg Blood Pressure Reduction 180 160 Candesartan Losartan 140 120 Systolic 100 80 60 40 Diastolic 0 12 24 36 48 60 72 84 96 Months
Cumulative incidence (%) CVD Risk Primary composite endpoint 35 30 Losartan Candesartan 25 20 15 10 5-14.4%*, p=0.0062 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Time (months) Number at risk Los. Can. *Adjusted for age, gender, diabetes and index year
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 14,100 0.86 (95%CI 0.77 0.96) 14,100 0.84 (95%CI 0.75 0.94) 11,230 0.87 (95%CI 0.77 0.98) 11,596 0.86 (95%CI 0.76 0.98)
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 12 10 Losartan Candesartan 12 10 Losartan Candesartan 12 10 Losartan Candesartan 8-35.9% p=0.0004 8 8 6 4 2 6 4 2-20.0% p=0.0330 6 4 2-38.8% p=0.0140 0 0 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Time (months) 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Time (months) 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Time (months) 12 10 Chronic ischemic heart disease Losartan Candesartan 12 10 Myocardial infarction Losartan Candesartan 12 10 Stroke Losartan Candesartan 8 8 8 6 6 6 4 4 4 2-14.3% p=0.1400 2-7.0% p=0.5600 2-5.2% p=0.6400 0 0 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Time (months) 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Time (months) 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Time (months) *Adjusted for age, gender, diabetes and index year
Total Costs During the Study
Stepwise price reduction
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?
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
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], 171 11 Solna Växelnr: +46 8 568 420 50 Direktnr: +46 8 568 420 87 jeanette.lagerlund@tlv.se www.tlv.se
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External control/transparency Approval by ethics committee Approval by National Board of Health and Welfare Clinicaltrials.gov
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