1. P H Y S I C I A N S ’ A C A D E M Y F O R C A R D I O V A S C U L A R E D U C A T I O N RAS blockade in the real world: Clinical lessons from recent trials Sverre Kjeldsen, MD Ullevaal University Hospital Oslo, Norway Cardio Diabetes Master Class Asian chapter January 28-30 2011, Shanghai Slide lecture prepared and held by: Presentation topic

2. LIFE: Primary Composite Endpoint 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0.14 0.16 Endpoint rate Intention-to-treat Losartan Atenolol Adjusted Risk Reduction 13·0%, p=0·021 Unadjusted Risk Reduction 14·6%, p=0·009 Dahlöf B, Devereux RB, Kjeldsen SE et al. Lancet 2002 Study Day0180360540720900108012601440162018001980 Study Month0612182430364248546066 Losartan (n)46054524446043924312424741894110404538951888901 Atenolol (n)45884494441443494289420541354066399238211854876 January 2011 Presented at Cardio Diabetes Master Class Shanghai

3. CHARM-Overall: CV death or CHF hosp. 0123years 0 10 20 30 40 50 % Placebo Candesartan HR 0.84 (95% CI 0.77-0.91), p<0.0001 HR 0.82, p<0.0001 (Adjusted) 3.5 Number at risk Candesartan 3803356332712215761 Placebo 3796346431702157743 1310 (34.5%) 1150 (30.2%) Pfeffer MA, Swedberg K, Granger CB, et al. Lancet. 2003;362:759-766

4. 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 *Van Liefde I, et al. Molecular and Cellular Endocrinology. 2008 020406080100120 0 20 40 60 80 100 telmisartan olmesartan valsartan losartan irbesartan candesartan Dissociation t 1/2 Insurmountability (%) EXP 3174 Large outcome trials comparing different ARBs for CV outcomes will probably never be done!

5. The Real Life Study: Hypothesis and Aim Candesartan binds longer and harder to the AT1 receptor and may be hypothesized to have a superior cardiovascular protection than other ARBsCandesartan 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 reductionThe 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 SwedenThe hypothesis was tested by setting up a large retrospective registration study in 72 Health Care Centres in the southern part of Sweden 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]

6. Health Care in Sweden All residents in Sweden have a unique identifiction numberAll residents in Sweden have a unique identifiction number Long traditions with mandatory national health registersLong traditions with mandatory national health registers Wide use of electronic patient journals in primary careWide use of electronic patient journals in primary care A patient is followed up by one and the same primary care physicianA patient is followed up by one and the same primary care physician The regulatories give permissions to use the registriesThe regulatories give permissions to use the registries January 2011 Presented at Cardio Diabetes Master Class Shanghai

7. Data Extraction in Primary Care Every primary care center had to be visitedEvery 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 studies 1,2 Patients were excluded if they hadPatients 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 Study Centre Number Losartan Candesartan January 2011 Presented at Cardio Diabetes Master Class Shanghai

9. Included Patients Per Year 10% 9% 8% 7% 6% 5% 4% 3% 2% 1% 0% 19992000 2001200220032004200520062007 Candesartan Losartan January 2011 Presented at Cardio Diabetes Master Class Shanghai

10. 6771 (52.1%) losartan patients 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%) 7329 (61.4%) candesartan patients 24,943 patients started prescription of losartan (13,001) or candesartan (11,942) from 1999 to 2007 Flow Chart January 2011 Presented at Cardio Diabetes Master Class Shanghai

11. ~15 years Two similar groups? Inclusion 1.3 years Drug history 5.8 years Primary care history ~15 years Hospital care history No patients hospitalised No of days in hospital per patient Losartan3,286 (48.6%)5.9 days Candesartan3,560 (48.5%)5.9 days

12. Baseline Characteristics Losartan (n=6771)Candesartan (n=7329) Age (years)61.7 (12)62.4 (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-C (mmol/L)3.34 (0.81)3·39 (0.81) HDL-C (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)

13. Up-titration of ARB Losartan mg/pas:Candesartan mg/pas: January 2011 Presented at Cardio Diabetes Master Class Shanghai

14. Ratio (candesartan/losartan) Index612243648607284 Ratio (mg candesartan / mg losartan) 0.19 0.20 0.21 0.00 0.05 0.10 0.15 0.20 0.25 January 2011 Presented at Cardio Diabetes Master Class Shanghai

15. Candesartan Follow-up Time (months) 7000 6000 5000 4000 3000 2000 1000 0 6 12 2436 4860 7284 Losartan Follow-up to 9 years (median 2.0 years; 36,339 patient years) January 2011 Presented at Cardio Diabetes Master Class Shanghai

16. Blood Pressure Reduction January 2011 Presented at Cardio Diabetes Master Class Shanghai

17. 96 months84726048362412Index 3624Index1296 months847260 0 10 20 30 40 50 60 70 % Candesartan dose titration % Losartan dose titration ARB Titration 50 mg100 mg50 mg/12.5 mg100 mg/25 mg 0 10 20 30 40 50 60 70 48 4 mg8 mg16 mg16 mg/12.5 mg January 2011 Presented at Cardio Diabetes Master Class Shanghai

18. Oral glucose lowering drugs Losartan Candesartan Betablockers Losartan Candesartan Calcium channel blockers † Months Thiazides * Losartan Candesartan Statins Losartan Candesartan Concomitant Medication 90 80 70 60 50 40 30 20 10 0 Index 1224364860728496 90 80 70 60 50 40 30 20 10 0 Index 1224364860728496 90 80 70 60 50 40 30 20 10 0 Index 1224364860728496 90 80 70 60 50 40 30 20 10 0 Index 1224364860728496 90 80 70 60 50 40 30 20 10 0 Index 1224364860728496 90 80 70 60 50 40 30 20 10 0 Index 1224364860728496 Antithrombotics January 2011 Presented at Cardio Diabetes Master Class Shanghai

19. Limitations The study was not randomizedThe 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 HCTZImbalance in use of HCTZ –May have favored losartan* Prescription behavior may change over time (marketing, scientific publications)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 feasibleThe 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 criteriaIt 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 groupsBlood 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 yearsAverage 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 deathWe 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 January 2011 Presented at Cardio Diabetes Master Class Shanghai

21. CVD Risk 0 5 10 15 20 25 30 35 Candesartan Losartan 06121824303642485460667278849096 Cumulative incidence (%) Time (months) Primary composite endpoint 6771581245483913318825912090173814581169 923715526385259183 95 73296291486040913385274222421875158013021021 794592436257152 78 Number at risk Los. Can. Adjusted risk reduction 14.4% p=0.0062 Unadjusted risk reduction 20.6% p<0.0001 January 2011 Presented at Cardio Diabetes Master Class Shanghai

22. Risk of Separate Endpoints B ArrhythmiasA Heart failureC Peripheral artery disease D Chronic ischemic heart disease F Stroke 0 2 4 6 8 10 12 06 1824303642485460667278849096 Candesartan Losartan Cumulative incidence (%) Time (months) 67715902466640573347276122521887160213171044 820611456314221126 73296385497542303529287523721998169314091113 878664496301175 89 Number at risk Los. Can. Adjusted risk reduction 35.9% p=0.0004 Unadjusted risk reduction 41.9% p<0.0001 0 2 4 6 8 10 12 06 1824303642485460667278849096 Cumulative incidence (%) Time (months) 67715909466640533337274522351874159113001041 814598439301212115 73296380496842163515285523511977167713901097 867654488294169 90 Number at risk Los. Can. Adjusted risk reduction 20.0% p=0.0330 Unadjusted risk reduction 26.7% p=0.0029 Candesartan Losartan 0 2 4 6 8 10 12 06 1824303642485460667278849096 Cumulative incidence (%) Time (months) 67715932469640873376278822731907161913311063 834624460320 225126 73296400498342443541288323822009170614241128 892677507307 179 91 Number at risk Los. Can. Adjusted risk reduction 38.8% p=0.0140 Unadjusted risk reduction 44.1% p=0.0035 Candesartan Losartan 0 2 4 6 8 10 12 06 1824303642485460667278849096 Cumulative incidence (%) Time (months) 67715903465940443335274122341872157712861021 798590431297208113 73296378495042053502284423451968167013841091 854644480290172 89 Number at risk Los. Can. Adjusted risk reduction 14.3% p=0.1400 Unadjusted risk reduction 19.6% p=0.0350 E Myocardial infarction 0 2 4 6 8 10 12 06 1824303642485460667278849096 Cumulative incidence (%) Time (months) 67715921468640793364278222721904161013181047 822612452312221123 73296387497242313516285823621992168814061113 876661494299175 91 Number at risk Los. Can. Adjusted risk reduction 7.0% p=0.5600 Unadjusted risk reduction 15.5% p=0.1800 0 2 4 6 8 10 12 06 1824303642485460667278849096 Cumulative Incidence (%) Time (months) 67715916468140643361276922511887159813091047 819609448307217118 73296374496342203515285923621991169114081113 877662489295172 89 Number at risk Los. Can. Adjusted risk reduction 5.2% p=0.6400 Unadjusted risk reduction 12.0% p=0.2600 January 2011 Presented at Cardio Diabetes Master Class Shanghai

23. Hazard Ratio Losartan (n=6771) Candesartan (n=7329) Hazard ratio (unadjusted) p Hazard ratio (adjusted*) p Primary composite endpoint676 (10.0)575 (7.8)0.79 (0.71–0.89)<0.00010·86 (0.77–0.96)0.0062 Heart failure164 (2.4)101 (1.4)0.58 (0.45–0.74)<0.00010·64 (0.50–0.82)0.0004 Cardiac arrhythmias210 (3.1)163 (2.2)0.73 (0.60–0.90)0.00290·80 (0.65–0.98)0.0330 Peripheral artery disease68 (1.0)40 (0.5)0.61 (0.38–0.83)0.00350·61 (0.41–0.91)0.0140 Chronic ischemic heart disease 202 (3.0)172 (2.3)0.80 (0.66–0.99)0.03500·86 (0.70–1.05)0.1400 Myocardial infarction138 (2.0)123 (1.7)0.85 (0.66–1.08)0.18000·93 (0.73–1.19)0.5600 Stroke157 (2.3)146 (2.0)0.88 (0.70–1.10)0.26000·95 (0.76–1.19)0.6400 Hosp. for unstable angina26 (0.4)21 (0.3)0.77 (0.43–1.36)0.36000·80 (0.45–1.42)0.4500 Elective PCI18 (0.3)14 (0.2)0.74 (0.37–1.48)0.39000·78 (0.39–1.58)0.4900 Cardiovascular mortality75 (1.1)66 (0.9)0.83 (0.60–1.16)0.28000·93 (0.66–1.29)0.6500 Total mortality155 (2.3)156 (2.1)0.96 (0.77–1.20)0.71001·06 (0.85–1.32)0.6200 New onset diabetes318 (4.7)309 (4.2)0.92 (0.79–1.08)0.30000·90 (0.77–1.05)0.1900 January 2011 Presented at Cardio Diabetes Master Class Shanghai

24. REAL LIFE: Conclusions No difference in blood pressure was observed during follow-upNo difference in blood pressure was observed during follow-up Frequently more use of thiazides in the losartan groupFrequently 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 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%) and heart failure (-36%)The primary result was driven by the risk reduction of arrhythmias (- 20%) and heart failure (-36%) January 2011 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 January 2011 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 January 2011 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. Tabell 1Losartan ( n=2500)Candesartan ( n=2639)p-value Mean age (yrs) ±SD75.3±10.272.0±11.5p<0.001 women1017(40.7%)1006(38.1%)p=0.061 NYHAp<0.001 I164(9.0%)234(10.9%) II734(40.3%)1068(50.0%) III840(46.2%)770(36.0%) IV82(4.5%)65(3.1%) EFp=0.035 >40%892(42.3%)992(41.6%) <40%1215(57.7%)1393(58.4%) Mean creatinine (mmol/l) ±SD120±13.4111.0±56.4p<0.001 Mean MAP (mmHg) ±SD91.5±13.492.6±13.9p=0.003 Hypertension1296(53.7%)1411(55.0%)p=0.365 IHD1461(60.6%)1286(50.7%)p<0.001 Diabetes mellitus844(34.0%)764(29.2%)p<0.001 ACE inhibitor76(3.1%)420(16.0%)p<0.001 Betablocker2049(82.3%)2295(87.1%)p<0.001 Aldosterone904(36.4%)802(30.6%)p<0.001 January 2011 Presented at Cardio Diabetes Master Class Shanghai

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

30. Survival in Days candesartan losartan Survival WomenSurvival Men candesartan losartan Survival in Days 90% 81% 89% 82% p<0.0001 January 2011 Presented at Cardio Diabetes Master Class Shanghai

31. EF >40%EF<40% candesartan losartan candesartan losartan p<0.0001 91% 85% 82% Survival in Days January 2011 Presented at Cardio Diabetes Master Class Shanghai

32. NYHA INYHA II NYHA IIINYHA IV candesartan losartan candesartan losartan candesartan losartan candesartan losartan 96% 94% 89% 87% 79% 63% 52% p=0.0230 p<0.0001 p=0.0672 January 2011 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