Telmisartan

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Telmisartan

  1. 1. TelmisartanThe master sartan
  2. 2. Session Module 1  RAAS & Angiotensin Module 2  Morning events Module 3  Telmisartan Module 4  Comparison studies
  3. 3. Insights The things most hypertensives fear • Heart attack • Stroke • Quality of life issues • Impotence
  4. 4. Understanding What doctors think while treating BP • Getting the patients down to their BP targets • Keeping BP on target • Protect target organs from damage • Preventing heart attacks • Preventing strokes • Step care approach
  5. 5. Step care approach
  6. 6. Observations Key factor to ensuring compliance in BP therapy • Once daily dosing • Favourable side effect profile • Efficacy • The security of round the clock BP control • Protecting target organs • Is it economical?
  7. 7. RAAS and morningeventsTelride
  8. 8. Angiotensin cascade Angiotensin cascade Renin ACE ARBs.
  9. 9. Angiotensin cascade AngiotensinogenNon-renin Renin (eg tPA) ⇑ Angiotensin I Bradykinin Non-ACE (eg chymase) ACE ⇑ Angiotensin II Inactive ARB peptides AT1 AT2 ATn
  10. 10. The sartan of today Telmisartan CH3 CH3 N N N N O OH CH3 Telmisartan Let us now understand what sets Telmisartan apart? To know this, let us start at the clinical triggers of cardiac events.
  11. 11. Blood pressure at early morning Awaking Blood pressure phase profile over 24 hours 180 SleepBlood pressure (mm Hg) 160 140 120 100 80 18:00 22:00 02:00 06:00 10:00 14:00 18:00 Time of the day Millar-Craig et al. Lancet 1978;1(8068):795–797 Mancia et al. Circ Res 1983;53:96–104
  12. 12. Events at early morning Early morning rise in 180 BP 50 Stroke (n=1167) Cerebrovascular incidents (every 2 hours.) 160 Myocardial infarction (n=2999) 45 Myocardial infarction (per hour.) 140 40 35 120 30 100 25 80 20 60 15 40 10 20 5 0 0 18:00 0:00 6:00 12:00Increased Cardiovascular risks Time of day Muller et al. N Engl J Med 1985;313:1315–1322 Marler et al. Stroke 1989;20:473–476
  13. 13. TemisartanWhy is it the better sartan?
  14. 14. Comparing the sartans
  15. 15. Comparing the sartans
  16. 16. Comparing the sartans
  17. 17. Comparing the sartans
  18. 18. Comparing the sartans
  19. 19. Hypertensive Damage to end organs and clinical events Endothelial dysfunction [ED] is the early manifestation of impending end organ damage and promotes various cardiovascular ilnesses such as - Atherosclerosis, Hypertension und Heart Failure. Early morning rise in BP can contribute to the damage of end organs on account of the raised haemodynamic load.
  20. 20. Hypertensive Damage to end organs Risk factors: Diabetes, Overweight, Smoking, Age Arrhythmia Apoptosis Heart failure LVH Myocardial Fibrosis infarctionVasoconstriction HypertensionVascular Hypertrophy ThrombosisDisturbed Endothelial function Mortality StrokeAtherosclerosis Vascular Cognitive disorders disturbances Decline in GFR Proteinuria/Albuminuria Renal failure Glomerular sclerosis
  21. 21. More than one benefit Telmisartan can be given with / without food Antihypertensive activity begins within 3 hours and is maintained for 24 hours.  A maximum reduction in blood pressure is evident in approximately 4 weeks. Telmisartan is not eliminated by renal route In the liver, as CYP isoenzymes are not involved in metabolism of telmisartan, no interactions happen with drugs that inhibit or are metabolized by CYP isoenzymes. Similar pharmakokinetic parameters in older (> 65 years) and younger patients.
  22. 22. Trough/Peak-Ratio 180 Normal variation Blood pressure (mmHg) 160 Trough Antihypertensive A (T/P-Ratio: .33 %) 140 Peak 120 100 Dosing 07:00 11:00 15:00 19:00 23:00 03:00 07:00 Time of the day* Relation between minimum values and maximum values Ellioit, Meredith. J Hypertension 1995;13:279–
  23. 23. Trough/Peak-Ratio 180 Normal variation Blood pressure (mmHg) 160 Trough Antihypertensive B (T/P-Ratio: o.66 %) 140 Peak 120 100 Dosing 07:00 11:00 15:00 19:00 23:00 03:00 07:00 Time of the day* Relation between minimum values and maximum values Ellioit, Meredith. J Hypertension 1995;13:279–
  24. 24. Understanding TP ratio Trough/Peak-Ratio ( Relation between effect of minimum effect and the maximum effect possible ) is preferred higher► Trough/Peak-Ratio of A: 20 / 60► Trough/Peak-Ratio of B: 20 / 30► Which is better?► Telmisartan has a very high TP ratio.
  25. 25. Telmisartan: the uniqueness Convergence of reasons Half life • • • • • • • • Distribution volumes PPAR activity TP ratio Telride EMBPR Dosage modification Drug interactions Safe in renal cases
  26. 26. Telmisartan: the summary Longer half life EMBPS Better effectively distribution blunted Free from drug Activates interactions PPAR-gamma No modification Trough-Peak of dosage ratio Beevers et al. BMJ 2001;322:912–916 Low renal excretion
  27. 27. Telmisartan: the indications First line antihypertensive Combination Type 2 diabetic therapy nephropathy Primary stroke Diabetic prevention microalbuminuriaIntolerance to ACE Proteinuria inhibitors - cough Beevers et al. BMJ 2001;322:912–916 Left ventricular ESH–ESC Guidelines. J Hypertens hypertrophy 2003;21:1011–1053
  28. 28. TelmisartanComparison studies
  29. 29. Programme of Research tO show Telmisartan End-organ proteCTION 10 clinical Studies in > 6500 Patients from 32 countries EMBPS Dysfunction of the renal endothelium Telmisartan vs. Ramipril Telmisartan vs. Ramipril Morning surge in BP Diabetic Nephropathy Telmisartan + HCTZ Telmisartan vs. Placebo vs. Losartan + HCTZ Diabetic Nephropathy Systolic Hypertension/ Telmisartan vs. Enalapril elderly hypetensives Telmisartan + HCTZ vs. Amlodipine + HCTZ Diabetic Nephropathy Telmisartan vs. LosartanDiabetes + Overweight Telmisartan + HCTZ Diabetic Nephropathy vs. Valsartan + HCTZ Telmisartan vs. Valsartan
  30. 30. Telmisartan: the comparisonstudies Losartan Valsartan RamiprilTelmisartan PerindoprilComparison Enalapril with Nifedipine Amlodipine Combinations Beevers et al. BMJ 2001;322:912–916
  31. 31. Antihypertensive efficacy over 24 hours - ABPM comparison SBD DBDChanges compared with initial value(mmHg) 0 -2 -4 -6 * -8 -10 Losartan 50 mg Valsartan 80 mg -12 * Amlodipine 5 mg Telmisartan 80 mg -14* P < 0,0125 for Losartan & Valsartan Neutel, Smith. J Clin Hypertens 2003;5:58–
  32. 32. Antihypertensive efficacy in earlymorning - ABPM comparison SBD DBD Changes compared with initial value(mmHg) 0 -2 -4 -6 * * -8 -10 Losartan 50 mg Valsartan 80 mg -12 * Amlodipin 5 mg Telmisartan 80 mg -14* P < 0,0125 for Losartan & Valsartan Neutel, Smith. J Clin Hypertens 2003;5:58–63
  33. 33. Telmisartan: the comparisonstudies Losartan Valsartan RamiprilTelmisartan PerindoprilComparison Enalapril with Nifedipine Amlodipine Combinations Beevers et al. BMJ 2001;322:912–916
  34. 34. Telmisartan vs. Losartan - last 6 hrs Mallion et al. (1999) Ding et al. (2004) Diast. BP compared with initial value(mmHg) 0 0 -1 -2 -2 -4 -3 -6 -4 -8 -5 -10 -6 -7 -12 * * -8 Losartan 50 mg -14 Telmisartan 40 mg* P < 0,05 for Losartan Mallion et al .J Hum Hypertens 1999;13:657–664 Ding et al. Int J Clin Pract Suppl 2004;58:16–22
  35. 35. Telmisartan vs. Losartan - 24-hour mean ABPM reduction Diastol. BP compared with initial value (mmHg) Mallion et al. (1999) Ding et al. (2004) 0 0 -1 -2 -2 -4 -3 -4 -6 -5 -8 -6 * -10 -7 -8 * Losartan 50 mg -12 * Telmisartan 40 mg* P < 0,05 for Losartan Mallion et al .J Hum Hypertens 1999;13:657–664 Ding et al. Int J Clin Pract Suppl 2004;58:16–22
  36. 36. Telmisartan vs. Losartan -Systolic reduction Systol. BP relative to the initial values (mmHg) Lee et al. (2004) Zhu et al. (2004) 0 0 -2 -5 -4 -10 -6 -8 -15 -10 -20 -12 * * -25 Losartan 50–100 mg -14 Telmisartan 40–80 mg* P < 0,05 for Losartan Lee et al. Int J Clin Pract Suppl 2004;58:40–45 Zhu et al. Int J Clin Pract Suppl 2004;58:46–49
  37. 37. Telmisartan versus Losartanover time Hourly course after dosingDiast. BP relative to the initial values 0 2 4 6 8 10 12 14 16 18 20 22 24 -1 Losartan 50–100 mg -2 Telmisartan 40–80 mg P ≤ 0,01 (mmHg) -3 Telmisartan vs. Losartan -4 -5 -6 -7 -8 -9 Meta-analysis from 2 Studies (Titrated for similar response) Smith et al. Blood Press Monit 2003;8:111–117
  38. 38. Telmisartan: the comparisonstudies Losartan Valsartan RamiprilTelmisartan PerindoprilComparison with Enalapril Nifedipine Amlodipine Combinations Beevers et al. BMJ 2001;322:912–916
  39. 39. Telmisartan vs. Valsartan - last 6 hoursBP compared with initial value in the last 6 hrs SBD DBD 0 before repeat dosing (mmHg) -2 -4 -6 ** -8 -10 Valsartan 160 mg * Telmisartan 80 mg -12 The MICADO-II-Study* P = 0,02 versus Valsartan White et al. Am J Hypertens 2004;17:347–353** P = 0,01 versus Valsartan
  40. 40. Telmisartan vs. Valsartan - after dosing titration coursesimilar response Hourly for after dosingSystol. BP relative to the initial values 2 4 6 8 10 12 14 16 18 20 22 24 0 Valsartan 160 mg -2 Telmisartan 80 mg -4 (mmHg) -6 -8 -10 -12 -14 P = 0,02 -16 Telmisartan vs. Valsartan The MICADO-II-Study White et al. Am J Hypertens 2004;17:347–353
  41. 41. Telmisartan: the comparisonstudies Losartan Valsartan RamiprilTelmisartan PerindoprilComparison with Enalapril Nifedipine Amlodipine Combinations Beevers et al. BMJ 2001;322:912–916
  42. 42. Telmisartan vs. Ramipril - last 6 hrs Diastol. BP relative to the initial values (mmHg) SBD DBD SBD DBD 0 0 -2 -2 -4 -4 -6 -6 -8 -8 *** *** -10 -10 -12 -12 *** *** -14 PRISMA I -14 PRISMA II Ramipril 10 mg Telmisartan 80 mg* P < 0,0001 vs. Ramipril Williams et al. Hypertension 2004;44;576 Lacourcière et al. Hypertension 2004;44:576
  43. 43. Telmisartan vs. Ramipril - over time Hourly course after dosing 2 4 6 8 10 12 14 16 18 20 22 24 0BP relative to the initial values Telmisartan 80 mg -2 Ramipril 10 mg -4 (mmHg) -6 * -8 -10 -12 -14 Data from the PRISMA-II-Study * P < 0,0001 for Telmisartan versus Lacourcière et al. Hypertension 2004;44:576 Ramipril over 24 hours.
  44. 44. Telmisartan reduces EMBPS EMBPS Changes in patients with Definition EMBPS ≥ 35 mmHg 105 Early morning average (EMA) 0 Morning BP (Diastolic BP mmHg) 100 -2Diastol. BP (mmHg) On -4 95 awakening EMBPS = EMA – NL -6 90 -8 85 -10 *** P = 0,0001 for Ramipril 80 Night low (NL) -12 *** -14 Ramipril 10 mg 75 0 6 12 18 23 Telmisartan 80 mg Hour of the day In comparison to ramipril, Telmisartan is more effective on EMBPS.
  45. 45. Telmisartan: the comparisonstudies Losartan Valsartan RamiprilTelmisartan PerindoprilComparison with Enalapril Nifedipine Amlodipine Combinations Beevers et al. BMJ 2001;322:912–916
  46. 46. Telmisartan versus Perindopril SBD DBD 0Clinical BP lowering compared with initial -2 -4 value(mmHg) -6 * -8 -10 Perindopril 4–8 mg ** Telmisartan 40–80 mg -12 -14 * P < 0,01 vs. Perindopril Ragot et al. J Hum Hypertens 2002;16:865–873 ** P < 0,005 vs. Perindopril
  47. 47. Telmisartan: the comparisonstudies Losartan Valsartan RamiprilTelmisartan PerindoprilComparison Enalapril with Nifedipine Amlodipine Combinations Beevers et al. BMJ 2001;322:912–916
  48. 48. Telmisartan versus EnalaprilSBD DBD 2comparison to initial values (mm Hg) 0 **Trough** BP reduction in -2 -4 -6 -8 -10 ** Placebo -12 * Enalapril 20 mg Telmisartan 40 mg -14 Telmisartan 80 mg * P = 0,03 vs. Enalapril Smith et al. Adv Ther 1998;15:229–240 ** P = 0,01 vs. Enalapril
  49. 49. Telmisartan: the comparisonstudies Losartan Valsartan RamiprilTelmisartan PerindoprilComparison with Enalapril Nifedipine Amlodipine Combinations Beevers et al. BMJ 2001;322:912–916
  50. 50. Telmisartan vs. Amlodipine - EMBPS SBD DBDBP reduction in comparison to initial values 0 -2 -4 -6 (mmHg) -8 -10 * -12 -14 -16 Amlodipine 5–10 mg Telmisartan 40–120 mg -18 -20 * P = 0,05 versus Amlodipine Lacourcière et al. Blood Press Monit 1998;3:295–302
  51. 51. Telmisartan versus Amlodipine 120 Diastol. BP versus initial values 100 (mmHg) 80 Placebo Telmisartan (40–120 mg) 60 Amlodipine (5–10 mg) P < 0,05 Telmisartan vs. Amlodipine 0Time of 08:00 12:00 16:00 20:00 24:00 04:00 08:00the day P < 0,05 Telmisartan vs. Amlodipine Lacourcière et al. Blood Press Monit 1998;3:295-302
  52. 52. Efficacy in terminal renal states / Haemodialysis DBD SBDChanges in comparison to the initial values 0 -5 -10 * (mmHg) -15 *P < 0,05 vs. Losartan -20 -25 Losartan 100 mg/day -30 * Telmisartan 80 mg/day -35 Cice et al. XLI ERA. 2004
  53. 53. Summary of comparison trials Prevention of EMBPS is an important beginning point for prevention of cardiovascular mortality. Qualities of Telmisartan: • Effective lowering of EMBPS (the largest data on long time ambulatory BP measurements in literature). • More effective BP lowering during the last hours before the next dose in comparison to Valsartan, Losartan, Ramipril, Perindopril and Amlodipine. • Early morning BP reduction especially in patients on typical antihypertensive therapy who show EMBPS (in comparison to Ramipril). • Good efficacy and compatibility in patients with Nephropathy (including dialysis patients).
  54. 54. Telmisartan effectson end organ damage
  55. 55. Renoprotective Effect of Telmisartan Improved renal plasma flow and reduced renal resistance Renal plasma flow Renal vessel resistance 800 earlier 120 9. weeks 700 * 100 600 * 80 500ml/min RU 400 60 300 40 200 20 100 0 0 Ramipril Telmisartan Ramipril Telmisartan* P<0.05 vs baseline Schmeider et al. XVIth IASH Meeting, 2005
  56. 56. Renoprotective Effect of Telmisartan 14 Reduces Albuminuria 12Albumin-excretion in the urine earlier 9. weeks 10 * 8 6 4 2 0 Ramipril Telmisartan* P < 0,05 for initial values Schmeider et al. XVIth IASH Meeting, 2005
  57. 57. Renoprotective Effect of Telmisartan Reduced Microalbuminuria in Hypertensives 35 30 Albuminuria (mg/24 h) 25 ** 20 15 ** 10 5 0 initial value 3 Months 12 Months** P < 0,01 for initial values Redón et al. Pharmacogenomics J 2005;5:14–20
  58. 58. Renoprotective Effects ofTelmisartan100GFR (ml/min/1,73 m2) 90 80 70 60 50 No treatment 40 Telmisartan 30 20 10 Progress to renal insufficiency 0 0 1 2 3 4 5 Years Barnett et al. N Engl J Med 2004;1952–1961 Parving et al. Semin Nephrol 2004;24:147–151
  59. 59. Telmisartan in LVH Continuous decrease of the Left Ventricle mass index 125 120LVMI (g/m2) 115 110 ** 105 Treatment with Telmisartan 0 40–80 mg (Monthly) 0 3 6 12 ** P < 0,01 for initial value Mattioli et al. Int J Cardiol 2004;97:383–388
  60. 60. Telmisartan in LVH Greater reduction of LVH in comparison to HCTZ 145 initial after 12 Months 140 135LVMI (g/m2) 130 * 125 * 120 0 Telmisartan 80 mg HCTZ 25 mg (n=40) (n=25) ** p < 0,01 for initial values Galzerano et al. J Hum Hypertens 2004;18:53–59
  61. 61. Telmisartan in LVH Greater reduction than carvedilol Carvedilol Telmisartan 0Decline of the Left Ventricle mass -5 index(LVMI, g/m2) -10 -15 -20 *** -25 *** P < 0,0001 for Carvedilol Galzerano et al. 53rd ACC, 2004, New Orleans, USA. 2004.
  62. 62. Telmisartan in LVH Improvement of the LV-Function Improved diastolic Function* 1.0 P < 0,05 0.9 0.8 DFV* P < 0,05 0.7 0.6 0 0 3 6 12 Monthly Treatment with Telmisartan 40–80 mg*Diastolisc filling relation (early atrial fill) Mattioli et al. Int J Cardiol 2004;97:383–388
  63. 63. Effects on end organ damage Improves the function of the renal endothelium as well as the nephritic plasma flow and reduces the vascular renal resistance more efficiently than Ramipril. Reduces Albuminuria (ongoing effect than with ACE-Inhibitor). Slows down the GFR declines with type 2 diabetes. Causes ↓ of LVH than HCTZ and Carvedilol. These effects occur independent of BP lowering. Improves the Elasticity of the Arteries.
  64. 64. Telmisartan as safe as placebo 18 Placebo Patients with undesirable events (%) Telmisartan 16 14 12 10 * 8 6 4 2 0 Headache Dizziness Tiredness Failure Cough Muscle Oedema pain* P < 0,05 vs. Placebo
  65. 65. Summary of side effects Placebo like side effect profile as Monotherapy or in combination with HCTZ No significant side effects like cough as seen with ACE-inhibitors No significant side ffects of peripheral oedema as with CCBs Reduced possibility of hypokalaemia than with HCTZ.
  66. 66. Thanks

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