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 , Shanghai Slide lecture prepared and held by: Presentation topic

LIFE: Primary Composite Endpoint 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 Day Study Month Losartan (n) Atenolol (n) January 2011 Presented at Cardio Diabetes Master Class Shanghai

CHARM-Overall: CV death or CHF hosp. 0123years % Placebo Candesartan HR 0.84 (95% CI ), p< HR 0.82, p< (Adjusted) 3.5 Number at risk Candesartan Placebo (34.5%) 1150 (30.2%) Pfeffer MA, Swedberg K, Granger CB, et al. Lancet. 2003;362:

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 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!

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 Bhuiyan MA, et al. Life Sci Bakris G, et al. J Clin Hypertens Lacourcière Y, et al. Am J Hypertens Meredith PA et al, J Hum Hypertens [Epub ahead of print]

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

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

Prescription Patterns at Study Centers Study Centre Number Losartan Candesartan January 2011 Presented at Cardio Diabetes Master Class Shanghai

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

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

~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

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)

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

Ratio (candesartan/losartan) Index Ratio (mg candesartan / mg losartan) January 2011 Presented at Cardio Diabetes Master Class Shanghai

Candesartan Follow-up Time (months) Losartan Follow-up to 9 years (median 2.0 years; 36,339 patient years) January 2011 Presented at Cardio Diabetes Master Class Shanghai

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

96 months Index 3624Index1296 months % Candesartan dose titration % Losartan dose titration ARB Titration 50 mg100 mg50 mg/12.5 mg100 mg/25 mg mg8 mg16 mg16 mg/12.5 mg January 2011 Presented at Cardio Diabetes Master Class Shanghai

Oral glucose lowering drugs Losartan Candesartan Betablockers Losartan Candesartan Calcium channel blockers † Months Thiazides * Losartan Candesartan Statins Losartan Candesartan Concomitant Medication Index Index Index Index Index Index Antithrombotics January 2011 Presented at Cardio Diabetes Master Class Shanghai

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.

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

CVD Risk Candesartan Losartan Cumulative incidence (%) Time (months) Primary composite endpoint Number at risk Los. Can. Adjusted risk reduction 14.4% p= Unadjusted risk reduction 20.6% p< January 2011 Presented at Cardio Diabetes Master Class Shanghai

Risk of Separate Endpoints B ArrhythmiasA Heart failureC Peripheral artery disease D Chronic ischemic heart disease F Stroke Candesartan Losartan Cumulative incidence (%) Time (months) Number at risk Los. Can. Adjusted risk reduction 35.9% p= Unadjusted risk reduction 41.9% p< Cumulative incidence (%) Time (months) Number at risk Los. Can. Adjusted risk reduction 20.0% p= Unadjusted risk reduction 26.7% p= Candesartan Losartan Cumulative incidence (%) Time (months) Number at risk Los. Can. Adjusted risk reduction 38.8% p= Unadjusted risk reduction 44.1% p= Candesartan Losartan Cumulative incidence (%) Time (months) Number at risk Los. Can. Adjusted risk reduction 14.3% p= Unadjusted risk reduction 19.6% p= E Myocardial infarction Cumulative incidence (%) Time (months) Number at risk Los. Can. Adjusted risk reduction 7.0% p= Unadjusted risk reduction 15.5% p= Cumulative Incidence (%) Time (months) Number at risk Los. Can. Adjusted risk reduction 5.2% p= Unadjusted risk reduction 12.0% p= January 2011 Presented at Cardio Diabetes Master Class Shanghai

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)< ·86 (0.77–0.96) Heart failure164 (2.4)101 (1.4)0.58 (0.45–0.74)< ·64 (0.50–0.82) Cardiac arrhythmias210 (3.1)163 (2.2)0.73 (0.60–0.90) ·80 (0.65–0.98) Peripheral artery disease68 (1.0)40 (0.5)0.61 (0.38–0.83) ·61 (0.41–0.91) Chronic ischemic heart disease 202 (3.0)172 (2.3)0.80 (0.66–0.99) ·86 (0.70–1.05) Myocardial infarction138 (2.0)123 (1.7)0.85 (0.66–1.08) ·93 (0.73–1.19) Stroke157 (2.3)146 (2.0)0.88 (0.70–1.10) ·95 (0.76–1.19) Hosp. for unstable angina26 (0.4)21 (0.3)0.77 (0.43–1.36) ·80 (0.45–1.42) Elective PCI18 (0.3)14 (0.2)0.74 (0.37–1.48) ·78 (0.39–1.58) Cardiovascular mortality75 (1.1)66 (0.9)0.83 (0.60–1.16) ·93 (0.66–1.29) Total mortality155 (2.3)156 (2.1)0.96 (0.77–1.20) ·06 (0.85–1.32) New onset diabetes318 (4.7)309 (4.2)0.92 (0.79–1.08) ·90 (0.77–1.05) January 2011 Presented at Cardio Diabetes Master Class Shanghai

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

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

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

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

Tabell 1Losartan ( n=2500)Candesartan ( n=2639)p-value Mean age (yrs) ±SD75.3± ±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± ±56.4p<0.001 Mean MAP (mmHg) ±SD91.5± ±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

Overall Survival (JAMA 2011; 305: candesartan losartan p<0, % 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

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

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

NYHA INYHA II NYHA IIINYHA IV candesartan losartan candesartan losartan candesartan losartan candesartan losartan 96% 94% 89% 87% 79% 63% 52% p= p< p= January 2011 Presented at Cardio Diabetes Master Class Shanghai

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