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Telmisartan
 

Telmisartan

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  • The renin-angiotensin system (RAS) has been implicated as an important participant in the development or maintenance of elevated blood pressure and in the damage that occurs to organs such as the brain, heart, and kidney in hypertensive patients. The RAS has been the target of intensive efforts by scientists to develop drugs that inhibit one or more steps of this important system. This schema illustrates the steps in the biochemical pathway that is involved in the formation of the most biologically potent of the angiotensin peptides, angiotensin II, and its interaction with the angiotensin receptor, the AT1 receptor, that mediates most of its actions. Inside the red lined circle are listed the enzymes, renin and angiotensin converting enzyme, that convert angiotensinogen or renin substrate and angiotensin I, to angiotensin I and angiotensin II, respectively. Components of the RAS are present not only in the circulation, but also in many tissues including the heart, brain, kidney, blood vessels and adrenal gland. Inhibitors of the enzyme renin have been developed and tested, but have never become commercially available because of their rather low potency and limited bioavailability. Among the most commonly used drugs to treat hypertension and concomitant conditions, such as renal insufficiency, proteinuria, and heart failure, are the angiotensin converting enzyme (ACE) inhibitors. Specific antagonists of the angiotensin AT1 receptor are commercially available, approved by the FDA for the treatment of hypertension, and hold the promise of having treatment benefits for patients with hypertension, renal insufficiency, and heart failure, either alone or in combination with ACE inhibitors.
  • Angiotensin Cascade This slide shows the renin-angiotensin cascade. There are at least 2 alternative pathways for angiotensin II formation that do no rely on either renin or angiotensin converting enzyme (ACE). In the non-renin pathway, tissue plasminogen activator (tPA) forms angiotensinsin II directly from angiotensinogen, bypassing the renin-mediated production of angiotensin I as an intermediate. A second alternative pathway involves enzymes like chymase that can form angiotensin II from angiotensin I via an ACE-independent mechanism. These alternative pathways are implicated in the gradual return toward pre-treatment angiotensin II concentrations during treatment of patients with ACE inhibitors, and provide a rationale for considering angiotensin receptor blockers (ARBs) that directly inhibit the binding of angiotensin II to the AT 1 receptor either in conjunction with or as an alternative to ACE inhibitor therapy. References: Balcells E, Meng QC, Johnson WH, Jr., Oparil S, and Dell'Italia LJ. Angiotensin II formation from ACE and chymase in human and animal hearts: methods and species considerations. Am J Physiol 1997;273(4 Pt 2):H1769-H1774. Petrie MC, Padmanabhan N, McDonald JE, Hillier C, Connell JM, and McMurray JJ. Angiotensin converting enzyme (ACE) and non-ACE dependent angiotensin II generation in resistance arteries from patients with heart failure and coronary heart disease. J Am Coll Cardiol 2001;37:1056-1061.
  • The answer is yes Let us now understand what sets Temisartan apart? To know this, let us start at the clinical triggers of cardiac events.
  • This slide shows the circadian rhythm of blood pressure in a normal individual. 1,2 Blood pressure falls during sleep and rises rapidly just before the time of awakening. The maximum is reached as people arise and begin their routine daytime activities. Millar-Craig M, et al. Circadian variation of blood pressure. Lancet 1978;1:795–797. Mancia G, et al. Blood pressure and heart rate variabilities in normotensive and hypertensive human beings. Circ Res 1983;53:96–104.
  • These data are from 2 studies that have analysed the circadian variation in the onset of acute myocardial infarction (n=2,999) or stroke (n=1,167). 1,2 Both studies found a notable increase in the number of events in the early morning period, the time that corresponds to the early morning blood pressure surge (EMBPS). Muller JE, et al. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med 1985;313:1315–1322. Marler JR, et al. Morning increase in onset of ischemic stroke. Stroke 1989;20:473–476.
  • Endothelial dysfunction contributes to cardiovascular disorders, such as atherosclerosis, 2 hypertension and heart failure. 3 In the kidney, endothelial dysfunction can result in intraglomerular hypertension and inflammation. 4 Annuk M, et al. Endothelium-dependent vasodilation and oxidative stress in chronic renal failure: impact on cardiovascular disease. Kidney Int Suppl 2003;84:50–53. Erhardt LR. Endothelial dysfunction and cardiovascular disease: the promise of blocking the renin-angiotensin system. Int J Clin Pract 2003;57:211–218. Vapaatalo H, Mervaala E. Clinically important factors influencing endothelial function. Med Sci Monit 2001;7:1075–1085. Klahr S, Morrissey JJ. The role of vasoactive compounds, growth factors and cytokines in the progression of renal disease. Kidney Int Suppl 2000;75:S7–S14.
  • The concept of a cardiovascular continuum was first published in 1991. 1 Factors such as hypertension can left ventricular hypertrophy (LVH), which increase the risk of cardio- and cerebrovascular events. 1 Ventricular wall remodelling, if untreated, may ultimately result in congestive heart failure, end-stage heart disease and death. These can be accompanied by cognitive dysfunction and, as the disease progresses, dementia. 2 Vascular remodelling, atherosclerosis and cardiac embolism can result in stroke. Hypertension and diabetes are also among the risk factors that lead to endothelial dysfunction. This can result in damage to the glomeruli, microalbuminuria and macroproteinuria, leading to progressive nephrosis and the development of renal failure. 3–5 Dzau V, Braunwald E. Resolved and unresolved issues in the prevention and treatment of coronary artery disease: a workshop consensus statement. Am Heart J 1991;121:1244–1263. Hofman A, et al. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer’s disease in the Rotterdam study. Lancet 1997;349:151–154. Cooper ME. Pathogenesis, prevention and treatment of diabetic nephropathy. Lancet 1998;352:213–219. Taylor AA. Pathophysiology of hypertension and endothelial dysfunction in patients with diabetes mellitus. Endocrinol Metabol Clin North Am 2001;30:983–997. Erhardt LR. Endothelial dysfunction and cardiovascular disease: the promise of blocking the renin-angiotensin system. Int J Clin Pract 2003;57:211–218.
  • Poor control in the morning hours in patients with controlled office blood pressure may be a consequence of antihypertensives that do not maintain full efficacy throughout the dosing period. Blood pressure may be normal when the patient visits the office several hours after taking their morning dose, but may not be controlled in the early morning period. Antihypertensive agents which have short elimination half-lives and wide fluctuations in plasma concentrations during a dosage interval (i.e. a greater trough-to-peak ratio) will produce greater variability in blood pressure compared with antihypertensive agents with lower trough:peak ratios. 1 Elliott HL, Meredith PA. Trough:peak ratio: clinically useful or practically irrelevant? J Hypertens 1995;13:279–283.
  • Antihypertensive agents which have short elimination half-lives and wide fluctuations in plasma concentrations during a dosage interval (i.e. a greater trough-to-peak ratio) will produce greater variability in blood pressure compared with antihypertensive agents with lower trough:peak ratios. 1 Elliott HL, Meredith PA. Trough:peak ratio: clinically useful or practically irrelevant? J Hypertens 1995;13:279–283.
  • Telmisartan is a unique ARB on account of its unparalleled features.
  • This slide gives a list of the conditions that favour the use of ARBs, according to the ESH guidelines. 1 2003 European Society of Hypertension – European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003;21:1011–1053.
  • Slide set includes notes.
  • The PROTECTION Programme 1 includes ten trials that will recruit a total of more than 6,500 patients. Broadly, these trials can be grouped into renal studies and at-risk hypertension studies. Six of these studies have been completed, and the results are provided in this slide kit. These studies are: PRISMA I & II ARBs FDC ATHOS TRENDY DETAIL Weber M. The telmisartan Programme of Research tO show Telmisartan End-organ proteCTION (PROTECTION) Programme. J Hypertens 2003;21 (Suppl 6):S37–S46.
  • This slide shows the result of a meta-analysis of five multicentre trials that used ABPM to compare the antihypertensive efficacy of telmisartan, losartan, valsartan and amlodipine. 1 Telmisartan 80 mg was significantly superior to losartan 50 mg and valsartan 80 mg in the reduction of 24-h mean SBP and DBP. Neutel JM, Smith DHG. Evaluation of angiotensin II receptor blockers for 24-hour blood pressure control: meta-analysis of a clinical database. J Clin Hypertens 2003;5:58–63.
  • This slide shows the result of a meta-analysis of five multicentre trials that used ABPM to compare the antihypertensive efficacy of telmisartan, losartan, valsartan and amlodipine. 1 The data show that telmisartan 80 mg was significantly superior to losartan and valsartan in the reduction of SBP and DBP during the risky, early morning period (06:00–11:59). Neutel JM, Smith DHG. Evaluation of angiotensin II receptor blockers for 24-hour blood pressure control: meta-analysis of a clinical database. J Clin Hypertens 2003;5:58–63.
  • Two fixed-dose studies have compared low doses of telmisartan and losartan. They both found telmisartan to be superior in the last 6 h of the dosing interval. Mallion et al. recruited 223 patients with mild-to-moderate hypertension for a 6-week trial of telmisartan 40 mg or 80 mg and losartan 50 mg. 1 Telmisartan 40 mg gave significantly superior reductions in SBP and DBP. The reduction in SBP in the last 6 h of the dosing interval was 10.7 mmHg with telmisartan 40 mg and 6.0 mg with losartan 50 mg (p<0.05). Telmisartan 80 mg was also superior to losartan 50 mg. Ding et al. compared telmisartan 40 mg with losartan 50 mg in 56 Taiwanese patients with mild-to-moderate hypertension. 2 The reduction in DBP in the last 6 h of the dosing interval was superior with telmisartan compared with losartan. Reductions in SBP in the last 6 h of the dosing interval (16.0 mmHg with telmisartan and 11.8 mmHg with losartan) did not reach statistical significance. Mallion JM, et al. ABPM comparison of the antihypertensive profiles of the selective angiotensin II receptor antagonists telmisartan and losartan in patients with mild-to-moderate hypertension. J Hum Hypertens 1999;13:657–664. Ding PY, et al. A double-blind ambulatory blood pressure monitoring study of the efficacy and tolerability of once-daily telmisartan 40 mg in comparison with losartan 50 mg in the treatment of mild-to-moderate hypertension in Taiwanese patients. Int J Clin Pract Suppl 2004;58:16–22.
  • The two fixed-dose studies comparing low doses of telmisartan and losartan also found telmisartan to be superior in 24-h mean ambulatory blood pressure reductions. Mallion et al. recruited 223 patients with mild-to-moderate hypertension for a 6-week trial of telmisartan 40 mg or 80 mg and losartan 50 mg. 1 Telmisartan 40 mg gave significantly superior reductions in SBP and DBP. The reduction in 24-h mean SBP was 11.5 mmHg with telmisartan 40 mg and 8.0 mg with losartan 50 mg (p<0.05). Telmisartan 80 mg was also superior to losartan 50 mg. Ding et al. compared telmisartan 40 mg with losartan 50 mg in 56 Taiwanese patients with mild-to-moderate hypertension. 2 The reduction in 24-h mean DBP was superior with telmisartan compared with losartan. Reductions in 24-h mean SBP (14.6 mmHg with telmisartan and 11.2 mmHg with losartan) did not reach statistical significance. Mallion JM, et al. ABPM comparison of the antihypertensive profiles of the selective angiotensin II receptor antagonists telmisartan and losartan in patients with mild-to-moderate hypertension. J Hum Hypertens 1999;13:657–664. Ding PY, et al. A double-blind ambulatory blood pressure monitoring study of the efficacy and tolerability of once-daily telmisartan 40 mg in comparison with losartan 50 mg in the treatment of mild-to-moderate hypertension in Taiwanese patients. Int J Clin Pract Suppl 2004;58:16–22.
  • In flexibly dosed studies using trough cuff blood pressure as the primary outcome, telmisartan was found to be superior to losartan. Lee et al. compared telmisartan 40–80 mg with losartan 50–100 mg in an 8-week study of 180 Taiwanese patients with mild-to-moderate hypertension. 1 Changes in SBP were statistically superior with telmisartan compared with losartan. Changes in DBP (amounting to 11.1 mmHg with telmisartan and 8.7 mmHg with losartan) did not reach statistical significance. Zhu et al. compared telmisartan 40–80 mg with losartan 50–100 mg in an 8-week study of 330 Chinese patients with mild-to-moderate hypertension. 2 Changes in SBP were statistically superior with telmisartan compared with losartan. Changes in DBP (amounting to 10.9 mmHg with telmisartan and 9.3 mmHg with losartan) were also statistically significant (p=0.03). Lee YT, et al. A double-blind comparison of the efficacy and tolerability of telmisartan 40-80 mg vs. losartan 50-100 mg in Taiwanese hypertensive patients. Int J Clin Pract Suppl 2004;58:40–45. Zhu JR, et al. Efficacy and safety of telmisartan vs. losartan in control of mild-to-moderate hypertension: a multicentre, randomised, double-blind study. Int J Clin Pract Suppl 2004;58:46–49.
  • In a meta-analysis of two flexible-dose studies, telmisartan-induced reductions in DBP during the last 6 h of the dosing interval were greater than those with losartan. 1 Reductions with telmisartan were greater than with losartan for the majority of the observed hourly mean values over the entire 24-h dosing interval. 1 These data are from two, 8-week studies in 720 patients with mild-to-moderate hypertension. 1 Patients were started at the lower dose, with up-titration to the higher dose allowed if seated trough cuff DBP was ≥90 mmHg at Week 4. The 24-h profiles of ambulatory SBP hourly mean reductions were similar to those for DBP . Smith DH, et al. Comparison of telmisartan versus losartan: meta-analysis of titration-to-response studies. Blood Press Monit 2003;8:111–117.
  • The results of a study comparing the effects of telmisartan (40–80 mg) with valsartan (80–160 mg) on BP in the last 6 hours of the dosing interval are shown here. 1 Telmisartan was superior to valsartan at reducing DBP and SBP at the end of the dosing interval. White WB, et al. Effects of the angiotensin II receptor blockers telmisartan versus valsartan on the circadian variation of blood pressure. Impact on the early morning period. Am J Hypertens 2004;17:347–353.
  • This was a double-blind, forced-titration, crossover, randomized trial that compared telmisartan 80 mg/day with valsartan 160 mg/day in 490 patients with hypertension. 1 Ambulatory blood pressure recordings were made at baseline and at 8 weeks. Telmisartan reduced SBP/DBP during the last 6 h of the dosing period by 11/7.6 mmHg, compared with 8.7/5.8 mmHg with valsartan (P=0.02). White WB, et al. Effects of the angiotensin II receptor blockers telmisartan versus valsartan on the circadian variation of blood pressure. Am J Hypertens 2004;17:347 – 353.
  • Telmisartan 80 mg provides superior reductions in SBP and DBP in the last 6 h of the dosing interval compared with ramipril 10 mg. Data shown are from two independent, fixed-dose, 14-week studies: Prospective, Randomized Investigation of the Safety and efficacy of Micardis versus ramipril using ABPM (PRISMA) I and II. PRISMA I was conducted in Europe and South Africa, and recruited 801 patients. 1 PRISMA II was conducted in the USA and Canada, and recruited 812 patients. 2 Patients were started on telmisartan 40 mg or ramipril 2.5 mg, and force titrated to telmisartan 80 mg or ramipril 5 mg after 2 weeks. At Week 8, ramipril was further up titrated to 10 mg. Blood pressure was measured using ABPM. As well as superiority in the early morning period, in both studies telmisartan was significantly superior to ramipril over the 24-h mean and other time periods: morning (06:00–11:59), daytime (06:00–21:59), and night-time (22:00–05:59). Williams B, et al. Superior blood pressure reduction in the last 6 h of the dosing interval with once-daily telmisartan versus ramipril. Hypertension 2004;44:576. Lacourcière Y, et al. A prospective, randomized investigation of the safety and efficacy of telmisartan vs ramipril in mild-to-moderate hypertensives using ambulatory blood pressure monitoring. Hypertension 2004;44:576 .
  • Telmisartan 80 mg reduces blood pressure over the full 24-h dosing interval compared with ramipril 10 mg. Data shown are from a fixed-dose, 14-week study: PRISMA II. 1 Patients were started on telmisartan 40 mg or ramipril 2.5 mg, force titrated to telmisartan 80 mg or ramipril 5 mg after 2 weeks. At Week 8, ramipril was further up titrated to 10 mg. Blood pressure was measured using ABPM. Telmisartan was significantly superior to ramipril (p<0.0001) over the 24-h mean and other time periods: morning (06:00–11:59), daytime (06:00–21:59), and night-time (22:00–05:59). Lacourcière Y, et al. A prospective, randomized investigation of the safety and efficacy of telmisartan vs ramipril in mild-to-moderate hypertensives using ambulatory blood pressure monitoring. Hypertension 2004;44:576.
  • Patients with a high EMBPS have been shown to be at increased risk of stroke. 1 In the study that demonstrated this connection, the EMBPS was defined as the difference between the early morning mean (the average blood pressure in the first 2 hours after waking) and the night-time low (the average of three blood pressure readings centred on the lowest night-time reading). 1 These definitions were used to calculate the EMBPS of patients in two studies of identical design that compared telmisartan 80 mg with ramipril 10 mg (PRISMA I and II). 2 The 25% of patients with the highest EMBPS of DBP all had an EMBPS ≥35 mmHg. 2 In these patients, telmisartan reduced the magnitude of the EMBPS by a significantly greater amount than did ramipril. 2 Kario K, et al. Morning surge in BP as a predictor of silent and clinical cerebrovascular disease in elderly hypertensives. Circulation 2003;107:1401–1406. Data on file. Boehringer Ingelheim GmbH.
  • The EValuation de l’Efficacité RESiduelle du Telmisartan (EVEREST) study compared telmisartan (n=217) with perindopril (n=218) over 12 weeks. 1 Initial treatment was telmisartan 40 mg and perindopril 4 mg, with the dose doubled at Week 6 for those patients who failed to reach target blood pressure (DBP <0.005). Ragot S, et al. Comparison of trough effect of telmisartan vs perindopril using self blood pressure measurement: EVERESTE study. J Hum Hypertens 2002;16:865–873.
  • The efficacy of telmisartan at doses of 40 mg and 80 mg was compared with that of enalapril 20 mg in a 12-week multicentre, randomized, parallel-group, placebo-controlled study that included 440 patients with mild-to-moderate hypertension. 1 The reduction in blood pressure with telmisartan was greater than with enalapril and reached statistical significance for the telmisartan 80 mg arm. Maximal blood pressure reductions were apparent by week 4 and were maintained through to week 12. Smith DHG, et al. Once-daily telmisartan compared with enalapril in the treatment of hypertension. Adv Ther 1998;15:229–240.
  • Telmisartan produced reductions in DBP in the last 4 h of the dosing interval that were superior to amlodipine in this 12-week, double-blind, titration-to-response, ABPM study. 1 Patients (n=232) had mild-to-moderate hypertension. They were randomized to placebo (n=81) or active dose, which comprised telmisartan 40 mg or amlodipine 5 mg titrated as required up to a maximum of telmisartan 120 mg or to amlodipine 10 mg. Compared with amlodipine, telmisartan resulted in a 26% reduction in SBP and an almost 40% reduction in DBP during the last 4 h of the dosing interval. Lacourcière Y, et al. A comparison of the efficacies and duration of action of the angiotensin II receptor blockers telmisartan and amlodipine. Blood Press Monit 1998;3:295–302.
  • Telmisartan produced reductions in DBP in the last 4 h of the dosing interval that were superior to amlodipine in this 12-week, double-blind, titration-to-response, ABPM study. 1 Patients (n=232) had mild-to-moderate hypertension. They were randomized to placebo (n=81) or active dose, which comprised telmisartan 40 mg or amlodipine 5 mg titrated as required up to a maximum of telmisartan 120 mg or to amlodipine 10 mg. Both telmisartan and amlodipine significantly reduced 24-h mean SBP and DBP (P<0.05) during the night-time interval and over the last 4 h of the dosing period. Lacourcière Y, et al. A comparison of the efficacy and duration of action of the angiotensin II receptor blocker telmisartan to amlodipine. Blood Press Monit 1998;3:295–302.
  • 148 haemodialysis patients with chronic renal failure and arterial hypertension were given telmisartan 80 mg or losartan 100 mg daily at 08:00 for 8 weeks. 1 Telmisartan provided a better and faster antihypertensive effect than losartan. At 4 weeks, the reduction in SBP/DBP was significantly greater with telmisartan than with losartan (-11.1/-6.2 mmHg versus -4.6/+0.3 mmHg, P<0.05). Cice G, et al. Unexpected heart rate reduction and antihypertensive efficacy of telmisartan in haemodialysis patients. Presented at the XLI Congress of the European Renal Association, Lisbon, Portugal. May 15–18, 2004.
  • Slide set includes notes.
  • The TRENDY study also compared renal plasma flow and renal vascular resistance at rest (i.e. without stimulation by infusion of L-NMMA). 1 Telmisartan significantly improved renal plasma flow and decreased vascular resistance. Ramipril did not significantly change these parameters. Schmeider RE, et al. Effects of telmisartan versus ramipril on renal endothelial function in Type-2 diabetes. Presented at the XVIth Scientific Meeting of the Interamerican Society of Hypertension. Canc ún, México, April 17–21, 2005.
  • Patients in the TRENDY study had low levels of albuminuria at baseline. 1 Despite this, telmisartan still produced a significant reduction in albuminuria, whereas ramipril did not. Schmeider RE, et al. Effects of telmisartan versus ramipril on renal endothelial function in Type-2 diabetes. Presented at the XVIth Scientific Meeting of the Interamerican Society of Hypertension. Canc ún, México, April 17–21, 2005.
  • Red ó n et al. conducted a 12-month study to assess the interactions between RAAS gene polymorphisms and telmisartan therapy in patients with mild-to-moderate hypertension. 1 There was no correlation between RAAS gene polymorphisms and the response to telmisartan. Of the 206 patients, 28% had microalbuminuria (urinary albumin excretion [UAE] >30 mg/day), and mean UAE was 32.7 mg/day. After 3 months, telmisartan significantly reduced albuminuria by 52%, and this was reduced further to a 69% reduction by the end of the study. Redón J, et al. Renin-angiotensin system gene polymorphisms: relationship with blood pressure and microalbuminuria in telmisartan-treated hypertensive patients. Pharmacogenomics J 2005;5:14–20.
  • If diabetic nephropathy is left untreated, GFR declines steadily by 10–12 ml/min/1.73 m 2 /year. 1 In DETAIL, GFR declined over 5 years by 17.9 ml/min/1.73m 2 in the LOCF dataset and 18.7 ml/min/1.73 m 2 in completers. The rate of decline slowed over time. 2 Thus treatment with telmisartan halted the progression of diabetic nephropathy. Parving H-H, et al. Angiotensin receptor blockers in diabetic nephropathy: renal and cardiovascular endpoints. Semin Nephrol 2004;24:147–151. Barnett A, et al. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy . N Engl J Med 2004;351:1952–1961.
  • This clinical study assessed the effect of 12 months’ treatment with telmisartan 40–80 mg on left ventricular mass index (LVMI) in 90 patients with hypertension and echocardiographic evidence of mild-to-moderate LVH. 1 Mean SBP was reduced from 167 mmHg at baseline to 126 mmHg at treatment end (p<0.01). Mattioli AV, et al. Regression of left ventricular hypertrophy and improvement of diastolic function in hypertensive patients treated with telmisartan. Int J Cardiol 2004;97:383–388.
  • This study used a freehand three-dimensional echocardiographic technique to evaluate the effect of telmisartan on left ventricular mass (LVM). 1 The technique employs a magnetic sensor attached to an ultrasound probe to aid spatial location, which enables calculation of LVM without geometric assumptions. In this multicentre, randomized, double-blind study, 65 patients with hypertension received 12 months of treatment with either telmisartan 80 mg (n=40) or HCTZ 25 mg (n=25). Both drugs lowered blood pressure significantly: mean 24-h ambulatory SBP/DBP was reduced from baseline by 24/13 mmHg with telmisartan and by 10/8 mmHg with HCTZ. There was also a significant 16 g/m 2 decrease in LVMI (from 141 ± 16 g/m 2 to 125 ± 19 g/m 2 ; p<0.02) in the telmisartan treatment group. However, the 4 g/m 2 reduction in LVMI (from 139 ± 20 g/m 2 to 135 ± 22 g/m 2 ) observed in the HCTZ group was not statistically significant. Galzerano D, et al. Freehand three-dimensional echocardiographic assessment of efficacy of telmisartan on left ventricular mass in hypertensive patients: a multicentre study. J Hum Hypertens 2004;18:53 –5 9.
  • Telmisartan reduced LVH compared with carvedilol despite similar reductions in blood pressure. 1 The 84 patients in this study had hypertension and LVH, and received telmisartan 80 mg or carvedilol 25 mg for 44 weeks. LVM was measured by MRI (results shown in this slide) and three-dimensional echocardiography. Both treatments reduced 24-h mean SBP/DBP by similar amounts (telmisartan by 31/19 mmHg, carvedilol by 29/17 mmHg, P=ns). However, telmisartan reduced LVM significantly more than did carvedilol. Similar effects were seen using echocardiography. Galzerano D, et al. Three-dimensional echocardiographic and magnetic resonance assessment of the effect of telmisartan compared to carvedilol on left ventricular mass: a multicenter randomized study. 53rd Annual Scientific Session of the American College of Cardiology, 2004, New Orleans, USA. 2004.
  • This clinical study assessed the effect of 12 months’ treatment with telmisartan 40–80 mg on LVMI in 90 patients with hypertension and echocardiographic evidence of mild-to-moderate LVH. 1 There was a significant improvement in diastolic filling: the early to atrial filling ratio increased from 0.59 ± 0.2 at baseline to 0.88 ± 0.2 at study end (P<0.05). Mattioli AV, Zennaro M, Bonatti S, Bonetti L, Mattioli G. Regression of left ventricular hypertrophy and improvement of diastolic function in hypertensive patients treated with telmisartan. Int J Cardiol 2004;97:383–388.
  • Telmisartan has been evaluated for safety in 27 studies in a total of 5363 patients with essential hypertension, including 2921 patients treated for up to 6 months, 888 patients treated between 6 and 12 months, and 1554 patients treated for 1 year or more. 1 Adverse events were typically mild and transient in nature. In placebo-controlled trials that included 1758 patients treated with doses ranging from 20 mg to 160 mg ( 1344 patients received telmisartan monotherapy, 414 received telmisartan/HCTZ combination) , the incidence of adverse events was comparable to that of placebo. 1 Headache was the most frequently reported adverse event (7.1% in telmisartan-treated patients vs 15.1% in the placebo group). 1 Data on file. Boehringer Ingelheim GmbH.

Telmisartan Telmisartan Presentation Transcript

  • TelmisartanThe master sartan
  • Session Module 1  RAAS & Angiotensin Module 2  Morning events Module 3  Telmisartan Module 4  Comparison studies
  • Insights The things most hypertensives fear • Heart attack • Stroke • Quality of life issues • Impotence
  • 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
  • Step care approach
  • 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?
  • RAAS and morningeventsTelride
  • Angiotensin cascade Angiotensin cascade Renin ACE ARBs.
  • Angiotensin cascade AngiotensinogenNon-renin Renin (eg tPA) ⇑ Angiotensin I Bradykinin Non-ACE (eg chymase) ACE ⇑ Angiotensin II Inactive ARB peptides AT1 AT2 ATn
  • 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.
  • 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
  • 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
  • TemisartanWhy is it the better sartan?
  • Comparing the sartans
  • Comparing the sartans
  • Comparing the sartans
  • Comparing the sartans
  • Comparing the sartans
  • 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.
  • 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
  • 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.
  • 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–
  • 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–
  • 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.
  • Telmisartan: the uniqueness Convergence of reasons Half life • • • • • • • • Distribution volumes PPAR activity TP ratio Telride EMBPR Dosage modification Drug interactions Safe in renal cases
  • 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
  • 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
  • TelmisartanComparison studies
  • 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
  • Telmisartan: the comparisonstudies Losartan Valsartan RamiprilTelmisartan PerindoprilComparison Enalapril with Nifedipine Amlodipine Combinations Beevers et al. BMJ 2001;322:912–916
  • 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–
  • 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
  • Telmisartan: the comparisonstudies Losartan Valsartan RamiprilTelmisartan PerindoprilComparison Enalapril with Nifedipine Amlodipine Combinations Beevers et al. BMJ 2001;322:912–916
  • 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
  • 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
  • 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
  • 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
  • Telmisartan: the comparisonstudies Losartan Valsartan RamiprilTelmisartan PerindoprilComparison with Enalapril Nifedipine Amlodipine Combinations Beevers et al. BMJ 2001;322:912–916
  • 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
  • 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
  • Telmisartan: the comparisonstudies Losartan Valsartan RamiprilTelmisartan PerindoprilComparison with Enalapril Nifedipine Amlodipine Combinations Beevers et al. BMJ 2001;322:912–916
  • 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
  • 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.
  • 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.
  • Telmisartan: the comparisonstudies Losartan Valsartan RamiprilTelmisartan PerindoprilComparison with Enalapril Nifedipine Amlodipine Combinations Beevers et al. BMJ 2001;322:912–916
  • 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
  • Telmisartan: the comparisonstudies Losartan Valsartan RamiprilTelmisartan PerindoprilComparison Enalapril with Nifedipine Amlodipine Combinations Beevers et al. BMJ 2001;322:912–916
  • 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
  • Telmisartan: the comparisonstudies Losartan Valsartan RamiprilTelmisartan PerindoprilComparison with Enalapril Nifedipine Amlodipine Combinations Beevers et al. BMJ 2001;322:912–916
  • 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
  • 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
  • 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
  • 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).
  • Telmisartan effectson end organ damage
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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.
  • 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
  • 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.
  • 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
  • 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.
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