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RAS blockade in the real world: Clinical lessons from recent trials

Cardio Diabetes Master Class Asian chapter January 28-30 2011, Shanghai. Presentation topic. RAS blockade in the real world: Clinical lessons from recent trials. Slide lecture prepared and held by:. Sverre Kjeldsen, MD Ullevaal University Hospital Oslo, Norway.

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RAS blockade in the real world: Clinical lessons from recent trials

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  1. Cardio Diabetes MasterClass Asianchapter January 28-30 2011, Shanghai Presentation topic RAS blockade in the real world:Clinical lessons from recent trials Slide lecture prepared and held by: Sverre Kjeldsen, MD Ullevaal University Hospital Oslo, Norway

  2. LIFE: Primary Composite Endpoint 0.16 Intention-to-treat 0.14 Atenolol 0.12 0.10 Losartan 0.08 Endpoint rate 0.06 0.04 Adjusted Risk Reduction 13·0%, p=0·021 0.02 Unadjusted Risk Reduction 14·6%, p=0·009 0.00 Dahlöf B, Devereux RB, Kjeldsen SE et al. Lancet 2002 Presented at Cardio Diabetes Master Class Shanghai

  3. CHARM-Overall: CV death or CHF hosp. 50 40 1310 (34.5%) Placebo 1150 (30.2%) 30 % Candesartan 20 10 HR 0.84 (95% CI 0.77-0.91), p<0.0001HR 0.82, p<0.0001 (Adjusted) 0 0 1 2 3 3.5 years Number at risk Candesartan 3803 3563 3271 2215 761 Placebo 3796 3464 3170 2157 743 Pfeffer MA, Swedberg K, Granger CB, et al. Lancet. 2003;362:759-766

  4. Binding Ability to the AT1 Receptor 100 candesartan telmisartan 80 olmesartan EXP 3174 60 Insurmountability (%) valsartan 40 irbesartan 20 losartan 0 0 20 40 60 80 100 120 Dissociation t1/2 Large outcome trials comparing different ARBs for CV outcomes will probably never be done! Candesartan and losartan have significant pharmacological differences* • Candesartan binds harder to the AT1-receptor • Candesartan binds longer to the AT1-receptor *Van Liefde I, et al. Molecular and Cellular Endocrinology. 2008

  5. The Real Life Study: Hypothesis and Aim 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 5. Meredith PA et al, J Hum Hypertens. 2009 [Epub ahead of print] Candesartan binds longer and harder to the AT1 receptor and may be hypothesized to have a superior cardiovascular protection than other ARBs The aim of the Real Life study was to test the hypothesis that losartan and candesartan have different primary preventive effects on CVD risk, beyond BP reduction The hypothesis was tested by setting up a large retrospective registration study in 72 Health Care Centres in the southern part of Sweden

  6. Health Care in Sweden All residents in Sweden have a unique identifiction number Long traditions with mandatory national health registers Wide use of electronic patient journals in primary care A patient is followed up by one and the same primary care physician The regulatories give permissions to use the registries Presented at Cardio Diabetes Master Class Shanghai

  7. Data Extraction in Primary Care • Every primary care center had to be visited • Patients were extracted if they had an ARB precription • Computer specialists assessed all visits with diagnosis, all drug precriptions and available laboratory data • The computer programme and it’s use has been validated in previous published studies1,2 • Patients were excluded if they had • History of known CVD • Any CVD suspected drug Lindgren P et al. Eur J Cardiovasc Prev Rehabil 2005; 12(6): 530–534; Ringborg A et al. Int J Clin Pract 2008; 62(5): 708–716; Ringborg A et al. Diabet Med 2008; 25(10): 1178–1186

  8. Prescription Patterns at Study Centers Losartan Candesartan Study Centre Number Presented at Cardio Diabetes Master Class Shanghai

  9. Included Patients Per Year 10% Candesartan 9% Losartan 8% 7% 6% 5% 4% 3% 2% 1% 0% 1999 2000 2001 2002 2003 2004 2005 2006 2007 Presented at Cardio Diabetes Master Class Shanghai

  10. Flow Chart 24,943 patients started prescription of losartan (13,001) or candesartan (11,942) from 1999 to 2007 • 10,843 patients were excluded: • 5792 (44.6%) losartan and 4144 (34.7%) candesartan patients with a history of cardiovascular disease and/or prescription of warfarin / digitalis / nitrates before index prescription • 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 Presented at Cardio Diabetes Master Class Shanghai

  11. Two similar groups? Inclusion 1.3 years Drug history 5.8 years Primary care history Hospital care history ~15 years ~15 years

  12. Baseline Characteristics

  13. Up-titration of ARB Losartan mg/pas: Candesartan mg/pas: Presented at Cardio Diabetes Master Class Shanghai

  14. Ratio(candesartan/losartan) 0.25 0.21 0.21 0.20 0.20 0.20 0.20 0.20 0.20 0.19 0.20 0.15 0.10 0.05 0.00 Index 6 12 24 36 48 60 72 84 Ratio (mg candesartan / mg losartan) Presented at Cardio Diabetes Master Class Shanghai

  15. Follow-up Time (months) 7000 Losartan 6000 Candesartan 5000 4000 3000 2000 1000 0 24 36 72 84 12 48 60 6 Follow-up to 9 years (median 2.0 years; 36,339 patient years) Presented at Cardio Diabetes Master Class Shanghai

  16. Blood Pressure Reduction Presented at Cardio Diabetes Master Class Shanghai

  17. ARB Titration 70 60 50 40 % Losartandose titration 30 20 10 0 50 mg 100 mg 50 mg/12.5 mg 100 mg/25 mg Index 12 24 36 48 60 72 84 96 months 70 60 50 % Candesartandose titration 40 30 20 10 0 4 mg 8 mg 16 mg 16 mg/12.5 mg Index 12 24 36 48 60 72 84 96 months Presented at Cardio Diabetes Master Class Shanghai

  18. 90 90 90 90 90 90 80 80 80 80 80 80 70 70 70 70 70 70 60 60 60 60 60 60 50 50 50 50 50 50 40 40 40 40 40 40 30 30 30 30 30 30 20 20 20 20 20 20 10 10 10 10 10 10 0 0 0 0 0 0 12 12 12 12 12 12 24 24 24 24 24 24 36 36 36 36 36 36 48 48 48 48 48 48 60 60 60 60 60 60 72 72 72 72 72 72 84 84 84 84 84 84 96 96 96 96 96 96 Index Index Index Index Index Index Concomitant Medication Thiazides* Betablockers Calcium channel blockers† LosartanCandesartan LosartanCandesartan LosartanCandesartan Statins Antithrombotics Oral glucose lowering drugs LosartanCandesartan LosartanCandesartan LosartanCandesartan Months Months Months Months Months Months Presented at Cardio Diabetes Master Class Shanghai

  19. Limitations The study was not randomized Imbalance in baseline characteristics not seen No evidence of “confounding by indication”(in case, candesartan was considered as “heart failure medication”) Imbalance in use of HCTZ May have favored losartan* Prescription behavior may change over time (marketing, scientific publications) Adjustment for index year *Okin PM, Hille DA, Kjeldsen SE, Lindholm LH, Edelman JM, Dahlöf B, Devereux RB. Greater regression of electrocardiographic left ventricular hypertrophy during hydrochlorothiazide therapy in hypertensive patients and the interaction with losartan vs. atenolol therapy: The LIFE Study. Am J Hypertens 2010; online April 15.

  20. Conclusion – Conduct of Real Life The method used is cost effective and feasible It is possible to identify two similar groups from a large number of patient when applying identical selection and exclusion criteria Blood pressure treatment achieved identical reductions in both groups Average follow up was 2 years with maximal follow-up 9 years and accumulation of a total of 36,339 treatment years We detected 1251 patients with a primary CV event defined as a composite of heart failure, arrhythmias, coronary events, stroke, peripheral artery disease and CV death Presented at Cardio Diabetes Master Class Shanghai

  21. CVD Risk Primary composite endpoint 35 Losartan Candesartan 30 25 20 Cumulative incidence (%) 15 10 5 Adjusted risk reduction 14.4% p=0.0062 Unadjusted risk reduction 20.6% p<0.0001 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Time (months) Number at risk Los. 95 923 715 526 385 259 183 6771 5812 4548 3913 3188 2591 2090 1738 1458 1169 Can. 78 794 592 436 257 152 7329 6291 4860 4091 3385 2742 2242 1875 1580 1302 1021 Presented at Cardio Diabetes Master Class Shanghai

  22. Risk of Separate Endpoints A Heart failure B Arrhythmias C Peripheral artery disease Losartan Losartan Losartan 12 12 12 Candesartan Candesartan Candesartan 10 10 10 8 8 8 Cumulative incidence (%) Cumulative incidence (%) 6 6 6 Cumulative incidence (%) 4 4 4 2 2 2 Adjusted risk reduction 35.9% p=0.0004 Adjusted risk reduction 38.8% p=0.0140 Adjusted risk reduction 20.0% p=0.0330 Unadjusted risk reduction 41.9% p<0.0001 0 0 Unadjusted risk reduction 44.1% p=0.0035 Unadjusted risk reduction 26.7% p=0.0029 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Time (months) Time (months) Time (months) Number at risk Number at risk Number at risk Los. Los. 225 126 Los. 834 624 460 320 6771 5932 4696 4087 3376 2788 2273 1907 1619 1331 1063 820 611 456 314 221 126 6771 5902 4666 4057 3347 2761 2252 1887 1602 1317 1044 814 598 439 301 212 115 6771 5909 4666 4053 3337 2745 2235 1874 1591 1300 1041 Can. Can. Can. 179 91 892 677 507 307 878 664 496 301 175 89 7329 6400 4983 4244 3541 2883 2382 2009 1706 1424 1128 7329 6385 4975 4230 3529 2875 2372 1998 1693 1409 1113 90 867 654 488 294 169 7329 6380 4968 4216 3515 2855 2351 1977 1677 1390 1097 D Chronic ischemic heart disease E Myocardial infarction F Stroke 12 12 12 10 10 10 8 8 8 6 6 6 Cumulative incidence (%) Cumulative incidence (%) Cumulative Incidence (%) 4 4 4 2 2 2 Adjusted risk reduction 14.3% p=0.1400 Adjusted risk reduction 7.0% p=0.5600 Adjusted risk reduction 5.2% p=0.6400 0 Unadjusted risk reduction 19.6% p=0.0350 0 Unadjusted risk reduction 15.5% p=0.1800 Unadjusted risk reduction 12.0% p=0.2600 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Time (months) Time (months) Time (months) Number at risk Number at risk Number at risk Los. Los. Los. 798 590 431 297 208 113 6771 5903 4659 4044 3335 2741 2234 1872 1577 1286 1021 822 612 452 312 221 123 819 609 448 307 217 118 6771 5921 4686 4079 3364 2782 2272 1904 1610 1318 1047 6771 5916 4681 4064 3361 2769 2251 1887 1598 1309 1047 Can. Can. Can. 89 854 644 480 290 172 7329 6378 4950 4205 3502 2844 2345 1968 1670 1384 1091 91 89 876 661 494 299 175 877 662 489 295 172 7329 6387 4972 4231 3516 2858 2362 1992 1688 1406 1113 7329 6374 4963 4220 3515 2859 2362 1991 1691 1408 1113 Presented at Cardio Diabetes Master Class Shanghai

  23. Hazard Ratio Presented at Cardio Diabetes Master Class Shanghai

  24. REAL LIFE: Conclusions No difference in blood pressure was observed during follow-up Frequently more use of thiazides in the losartan group The risk of CVD was reduced by 14.4% when treated with candesartan compared to losartan (NNT=45) The primary result was driven by the risk reduction of arrhythmias (-20%) andheart failure (-36%) Presented at Cardio Diabetes Master Class Shanghai

  25. What was the main driver of the results? • Heart failure • Candesartan prevents the negative property of angiotensin II more effective than losartan • Less hypertrophy, increased cardiac remodelling • Arrhythmias • 90% of all arrhythmias were atrial fibrillation. • Atrial fibrillation is a common complication to heart failure. • Late development of arrhythmias Figure 4, page 6 Presented at Cardio Diabetes Master Class Shanghai

  26. No difference in CIHD, MI or stroke? • Why didn´t we observe differences in chronic ischemic heart disease, myocardial infarction or stroke? • Atherosclerotic disease takes longer time to develop Presented at Cardio Diabetes Master Class Shanghai

  27. Real Life – Outcomes in Subgroups J Clin Hypertens 2011; in press (online a head of print)

  28. Presented at Cardio Diabetes Master Class Shanghai

  29. Overall Survival (JAMA 2011; 305: 175-182 90% one year survival candesartan 82% one year survival 72% five year survival losartan 51% five year survival p<0,0001 Survival in Days Presented at Cardio Diabetes Master Class Shanghai

  30. Survival Men Survival Women 90% 89% candesartan candesartan 81% 82% losartan losartan p<0.0001 p<0.0001 Survival in Days Survival in Days Presented at Cardio Diabetes Master Class Shanghai

  31. EF >40% EF<40% 91% 85% candesartan candesartan 85% 82% losartan losartan p<0.0001 p<0.0001 Survival in Days Survival in Days Presented at Cardio Diabetes Master Class Shanghai

  32. NYHA I NYHA II 96% 94% candesartan candesartan 94% 89% losartan losartan p=0.0230 p<0.0001 NYHA III NYHA IV 87% candesartan 63% 79% 52% candesartan losartan losartan p<0.0001 p=0.0672 Presented at Cardio Diabetes Master Class Shanghai

  33. Conclusions Swedish Heart Failure Registry Study Candesartan is associated with longer survival than losartan: In univariate analysis In multivariate analysis, adjusted for age, gender, creatinine, EF, NYHA, diabetes, drug treatment Benefit of candesartan was seen in both genders, across NYHA classes and EF

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