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C omparison O f R ecommended D ose s

C omparison O f R ecommended D ose s. Outcomes of the non-interventional clinical trial CORD – pilot data analysis J. Špinar , P rof . MD. , J. Vítovec, Prof. MD., M. Souček, Prof. MD., D. Tomčíková, MSc., T. Pavlík , MSc. , K. Chroust , PhD. , L. Dušek , A ss oc. prof. PhD.

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C omparison O f R ecommended D ose s

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  1. Comparison Of Recommended Doses Outcomes of the non-interventional clinical trial CORD – pilot data analysis J. Špinar,Prof. MD., J. Vítovec, Prof. MD., M. Souček, Prof. MD., D. Tomčíková, MSc., T. Pavlík, MSc., K. Chroust, PhD.,L. Dušek,Assoc. prof. PhD.

  2. VVZ MŠMT 0021 622 402 Prevention of cardiovascular diseases

  3. CORD A Journal of hypertension 2008; 56, Suppl 1, PS32/WED/57: 464 CORD B Journal of hypertension 2008; 56, Suppl 1, PS33/THU/43: 475 CORD Late breaking clinical trials

  4. International Journal of Cardiology 2009; 144 (2): 293-4; IF 2,9

  5. Hypotheses of ACE-I – AIIA noninferiority 6 Mentioned are only trials comparing ACE-I and AIIA • Chronic heart failure • The ELITE, ELITE II and Val Heft trials have shown similar effect on mortality and morbidity. • Post MI • The OPTIMAAL and VALIANT trials have shown similar effect on mortality and morbidity. • Stable IHD • The ON TARGET trial has shown similar effect on morbidity and mortality. • Renal Functions • The COOPERATE trial has shown similar effect on renal functions.

  6. Hypotheses of ACE-I – AIIA superiority 7 Mentioned are trials comparing ACE-I and AIIA with other antihypertensive drugs • LIFE • Losartan is superior to atenolol in stroke, mortality and onset of new diabetes mellitus. • ASCOT • Perindopril is superior to atenolol in stroke, mortality and onset of new diabetes mellitus. • VALUE • Valsartan is not superior to amlodipin with the exception of onset of new diabetes mellitus. • ALLHAT, STOP I + II • Lisinopril (enalapril) in not superior to other antihypertensive drugs with the exception of onset of new diabetes mellitus .

  7. Hypotheses of the clinical trial CORD 8 A B • Hypothesis 1. • AIIA losartan in dosage 25-100 mg has the same effect on blood pressure as ACE-I in an appropriate dose. • Hypothesis 2. • The change in medication from ACE-I to losartan in comparable doses isn’t associated with an increase of adverse events. • Hypothesis3. • The treatment with the adequate dose of Iosartan or ACE-I results in a similar decrease of the blood pressure. • Hypothesis 4. • The treatment with the adequate dose of Iosartan or ACE-I is associated with less frequent demonstration of adverse events (cough).

  8. Categorization of patients in clinical trial CORD 9 • Group A • Substitution of AIIA losartan for ACE-I treatment in patients with well or marginally controlled hypertension (BP < 160/100 mmHg). • Patients treated with ACE-I for > 3months. • Group B • Addition of AIIA to ACE-I treatment in the case of insufficiently controlled hypertension (BP > 140/90 mmHg). • Patients treated or untreated with antihypertensive drugs but no ACE-I or AIIA allowed. • Patients born on the even day randomised to AIIA losartan 50 mg. • Patients born on the odd day randomised to ACE-I ramipril 5 mg. • Increasing dosing in case of not reaching normotension.

  9. Numbers of screened patients • 585 centres • 11 284 screened Czech Republic Screening started in January 2006 and continued till December 2006. 11 284 patients in 585 centres were screened, 7 829 patients were randomised and included into the trial.

  10. Flow diagram of the study N = 11 284 pts screened Group A Group B From January to December 2006 Ramipril Losartan 72pts excluded due to AE » examinations in the 1st and 3rd month during follow-up « 3 383 pts not randomised 6th month N = 4016 N = 1926 N = 1887 Follow – up period 1 997 pts not randomised 12th month N = 3022 N = 1416 N = 1394

  11. Risk factors in patients history (n = 7 829)

  12. Co - medication (n = 7 829)

  13. Chapter 1Analysis of change in target parameters in time 0 and 6 months • Systolic blood pressure • Diastolic blood pressure • Heart rate

  14. 95% percentile mean 5% percentile Clinical parameters in time – group A Parameters measured in sitting position - 13.9 mmHg SBP mmHg. min-1 - 8.9 mmHg DBP HR -2.4 /min N0-6 = 4 016 N12 = 3 022

  15. 95% percentile mean 5% percentile Clinical parameters in time – group B Parameters measured in sitting position - 22.1 mmHg SBP mmHg. min-1 - 13.8 mmHg DBP HR -3.3 /min N0-6 = 3 813 N12 = 2 810

  16. 95% percentile mean 5% percentile Clinical parameters in time – group B Ramipril Parameters measured in sitting position - 22.2 mmHg SBP mmHg. min-1 -14.0 mmHg DBP HR -3.0 /min N0-6 = 1 926 N12 = 1 416

  17. 95% percentile mean 5% percentile Clinical parameters in time – group B Losartan Parameters measured in sitting position -22.0 mmHg SBP mmHg. min-1 -13.6 mmHg DBP HR -3.5 /min N0-6 = 1 887 N12 = 1 394

  18. Summary of parameter change over time (0 and12 months) Parameters measured in sitting position Difference in parametermeans in time 0 and 12 months Group A Systolic BP (mmHg) Group B B - Ramipril B - Losartan Group A Diastolic BP (mmHg) Group B B - Ramipril B - Losartan Group A Heart rate (min-1) Group B B - Ramipril B - Losartan

  19. Chapter 2 Analysis of secondary parameter in time • Biochemistry • Renal functions • Haematology

  20. Biochemical parameters in time 0 and 12 months

  21. Biochemical parameters in time 0 and 12 months

  22. Ionts, renal functions in time 0 and 12 months

  23. Ionts, renal functions in time 0 and 12 months

  24. Haematology in time 0 and 12 months

  25. Haematology in time 0 and 12 months

  26. Chapter 3Analysis of serious adverse events • Death • Myocardial infarction • Stroke • New diabetes mellitus • Cough

  27. Serious adverse events All AE < 1%. 25 patients in group A and 47 patients in group B discontinuated due to AE. 21 (1%) patients discontinuated ramipril due to cough in group B, no patient discontinuated losartan due to cough. These patients are not included into the final analysis and are mentioned as not randomised at baseline.

  28. Chapter 4Analysis of dose • Initial dose of ACE-I – group A • 6 month dose of losartan – group A • 6 month dose of losartan – group B • 6 month dose of ramipril – group B

  29. Dose of ACE-I - group A – at month 0 N = 4 016 % of patients N = 1 725 N = 2 038 N = 253

  30. Dose of Losartan - group A - at month 6 N = 4 016 % of patients N = 4 N = 1 525 N = 1 938 N = 549

  31. Dose of Ramipril - group B Ramipril - at month 6 N = 1 926 % of patients N = 30 N = 641 N = 721 N = 534

  32. Dose of Losartan - group B Losartan - at month 6 N = 1 887 % of patients N = 38 N = 690 N = 760 N = 399

  33. Chapter 5Summary – group A • Switching from an ACE-I to losartan is safe and effective • Effectiveness : dose effect placebo (trial) effect • Safety : no increase in AE or BP

  34. Chapter 6Summary – group B • Ramipril and losartan have comparable effect on BP • 5mg ramipril is equivalent to 50mg losartan • 10mg ramipril is equivalent to 100mg losartan • Adverse effects are similar, with the exception of cough, which is 8x higher after ramipril

  35. Chapter 6Summary – secondary endpoints • Both ramipril and losartan have favorable metabolic effect. • We observed no deterioration of renal functions or pottasium increase. • We observed NO decrease in blood count.

  36. Summary – message from the CORD study • Can you imagine, that the ARB would be first on the market – before ACE-I ?

  37. Summary – message from the CORD study Do you beleive, that FDA or any other institution would allow ACE-I, if they are as effective as ARB, but with 8 times higher adverse events (dry cough)? B. Pitt after the presentation of ELITE II study.

  38. Summary – message from the CORD study • What is the drug of first choice in the treatment of hypertension ACE-I or ARB ?

  39. Summary – message from the CORD study • In the case of dry cough after ACE-I we must prescribe ARB. If there is NO cough and we know, that both groups are similarly effective, than the price will play the main role. And the prices differe in various countries. So if in your country the ARB are cheaper – choose ARB, if the ACE-I are cheaper – choose ACE-I. G. Mancia after the first presentation of ESC guidelines 2007.

  40. Chapter 5Summary – secondary enpoints

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