Slide set includes notes.

Slide set includes notes.
Telmisartan zur Behandlung von Hypertonie und gegen die Risiken des morgendlichen Blutdruckanstiegs

Hypertonie Definition, Prognose und Behandlung

Hypertension: Ursachen
In über 90 % aller Fälle kann eine primäre Ursache nicht festgestellt werden. Diese Fälle bezeichnet man als essenzielle Hypertonie. Bei 2–5 % aller Hypertoniker liegt die Ursache in einer Erkrankung der Niere oder Nebenniere. Bei essenzieller Hypertonie spielen eine Reihe von Faktoren zusammen: Ernährung Bewegungsmangel Stress Alkohol Auch genetische Faktoren spielen eine Rolle: Etwa 30 % der Fälle in jeder Population sind auf genetische Faktoren zurückzuführen. There is no single identifiable cause for most cases of hypertension.1 Hypertension is known to be a product of genetic predisposition with environmental and lifestyle factors.1 Beevers G, et al. The pathophysiology of hypertension. BMJ 2001;322:912–916. Beevers et al. BMJ 2001;322:912–916

Hypertonie: Pathophysiologie
Die Pathophysiologie von Bluthochdruck umfasst zahlreiche Faktoren: Systemisches und lokales Renin-Angiotensin-System: Sympathisches Nervensystem Insulin-Resistenz Übergewicht Unelastische Gefäße Vasoaktive Substanzen (z.B. Stickoxid und Endothelin) Funktion des Endothels Kallikrein-Kinin-System Natriuretische Peptide Numerous physiological systems contribute to determine an individual’s blood pressure.1 The environmental and genetic factors described in the previous slide cause hypertension by interacting with this physiological systems. Antihypertensives modulate one or more of these to reduce blood pressure. Beevers G, et al. The pathophysiology of hypertension. BMJ 2001;322:912–916. Beevers et al. BMJ 2001;322:912–916

Hypertonie: Klassifikation
JNC 7 ESH Normal SBD <120 und Normal SBD 120–129 od. DBD <80 DBP 80–84 Vorstadium SBD 120–139 od. Hoch normal SBD 130–139 od. DBD 80–89 DBD 85–89 Stadium 1 SBD 140–149 od. Grad 1 SBD 140–159 od. DBD 90–99 DBD 90–99 Stadium 2 SBD ≥160 od. Grad 2 SBD 160–179 od. DBD ≥100 DBD 100–109 Grad 3 SBD ≥180 od. DBD ≥110 Recent US and European guidelines have extended the range of blood pressure that is considered to be greater than optimal. JNC 7 introduced the concept of ‘pre-hypertension’, which indicates those patients who are at increased risk of progression to true hypertension.1 The European Society of Hypertension (ESH) guidelines introduced the concept of ‘high-normal’, to reinforce the idea that the real threshold for a ‘safe’ level of blood pressure depends on the total cardiovascular risk profile of each individual.2 Total cardiovascular risk is a product of the level of blood pressure and the presence of other risk factors, such as obesity, diabetes and albuminuria, as well as the presence of target-organ damage. Chobanian AV, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. JAMA 2003;289:2560–2572. 2003 European Society of Hypertension – European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003;21:1011–1053. ESH Guidelines. J Hypertens 2003;21:1011–1053 JNC 7. JAMA 2003;289:2560–2572

Prävalenz von Hypertonie*
Steigende Prävalenz mit zunehmendem Alter These data are from a meta-analysis of cross-sectional studies on the prevalence of hypertension around the world.1 Overall, 26% of adults have hypertension, with similar proportions for men and women.1 The prevalence of hypertension increases strongly with age, especially for women.1 Worldwide, the number of adults with hypertension is predicted to increase from 972 million in 2002 to 1,560 million in 2025, as the proportion of elderly people increases.1 Kearney PM et al. Global burden of hypertension: analysis of worldwide data. Lancet 2005;365:217–223. *SBD >140 mmHg oder DBD >90 mmHg oder antihypertensive Behandlung Kearney et al. Lancet 2005;365:217–223

Blutdruckmessung Die Methode der ersten Wahl in der Arztpraxis ist Auskultieren mit einem Quecksilber-Sphygmomanometer. Häusliche Blutdruckkontrollen vermeiden nervositätsbedingten Bluthockdruck beim Arzt, außerdem können die Messungen zu verschiedenen Tageszeiten durchgeführt werden. Besser einschätzen lässt sich das Risikoprofil durch eine ambulante 24-Stunden-Langzeitmesssung. Es handelt sich dabei um ein nicht invasives automatisches Verfahren, bei dem häufig eine oszillometrische Methode zum Einsatz kommt. Die durchschnittlichen 24-Stunden-Werte sind gewöhnlich niedriger als die beim Arzt gemessenen Werte. Optimal sind 24-Stunden-Durchschnittswerte von < 125/73 mmHg. The most accurate method to measure blood pressure in the office is to listen for Korotkoff sounds in the brachial artery as cuff pressure is reduced. A mercury sphygmomanometer is very reliable, although aneroid devices, if regularly maintained, can also provide accurate pressure readings.1 White-coat hypertension is common, and occurs when a patient’s blood pressure increases in the presence of a physician.1 Blood pressure can also be assessed by the patient at home. This avoids the potential for white-coat hypertension, and makes the measure of early morning blood pressure more feasible. HBPM typically uses aneroid or oscillometric devices and may be semi-automated.1 The best technique for measuring blood pressure is to use an ambulatory monitor, which is typically a small, fully automatic device which can be worn on a belt around the waist.1 ABPM allows blood pressure to be measured several times an hour over a 24-h period, and provides an assessment of the patient’s circadian rhythm. 24-h mean blood pressure is typically lower than office blood pressure, partly due to white-coat hypertension in the office but mostly because blood pressure drops at night in most people.1 Pickering TG, et al. Recommendations for blood pressure measurement in humans and experimental animals. Part 1: blood pressure measurement in humans. Hypertension. 2005;45:142–161. Pickering et al. Hypertension. 2005;45:142–161

24-h-Messungen sind genauer als Messungen beim Arzt
OvA-Studie Ambulanter SBD über 24 Stunden: <135 mmHg Ambulanter SBD über 24 Stunden: ≥ 135 mmHg 25 20 15 Ereignisse pro Personenjahre 10 The Office versus Ambulatory (OvA) study looked at cardiovascular risk over 5 years in 1,963 patients subdivided at baseline according to their 24-h mean ambulatory blood pressure and their office blood pressure.1 Overall, the risk of a cardiovascular event was 3.2-fold higher in patients with a 24-h mean SBP ≥135 mmHg compared with a 24-hour ambulatory SBP <135 mmHg.1 Even after adjusting for office blood pressure, a 24-h mean SBP ≥135 mmHg indicated a 1.3-fold higher risk.1 The 24-h mean blood pressure is therefore an important independent indicator of cardiovascular risk.1 Clement DL, et al. Prognostic value of ambulatory blood-pressure recordings in patients with treated hypertension. N Engl J Med 2003;348:2407–2415. 5 <140 140–159 >160 Systolischer Blutdruck beim Arzt (mmHg) Clement et al. N Engl J Med 2003;348:2407–2415

Blutdruckanstieg am frühen Morgen
Blutdruckprofil über 24 Stunden Aufwach- phase 180 Schlaf 160 Blutdruck (mm Hg) 140 120 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. 100 80 18: : : : : : :00 Tageszeit Millar-Craig et al. Lancet 1978;1(8068):795–797 Mancia et al. Circ Res 1983;53:96–104

Morgenhochdruck bei Normo- und Hypertonikern Unbehandelte Hypertoniker Normotoniker Morgen Morgen 200 Systolisch (MW ± SEM) 150 Blutdruck (mmHg) 100 This figure shows the range of blood pressure over 24 hours in normotensives and patients with hypertension.1 In both groups, blood pressure shows a circadian rhythm, with a rapid increase in the early morning. Millar-Craig MW, et al. Circadian variation of blood-pressure. Lancet 1978;1:795–797. 50 Diastolisch (MW ± SEM) 9 12 15 18 21 24 3 6 9 12 15 18 21 24 3 6 Tageszeit (Std.) Tageszeit (Std.) Millar-Craig et al. Lancet 1978;1:795–797 Reproduced with permission from Elsevier

Häufung von kardiovaskulären Komplikationen Plötzlicher Tod1 Akuter Myokardinfarkt1 Typische Angina pectoris2 Stumme Ischämie1 Ischämische Gesamtbelastung1 Ischämischer Insult3 Angina pectoris durch Koronarspasmen (variant angina pectoris; 02:00-04:00 Uhr)4 Thrombozytenaggregation5 06:00-12:00 Uhr The early morning blood pressure surge has been shown to coincide with the peak incidence of a multitude of cardiovascular events. One study revealed that most (68%) ischaemic episodes occurred between 07:30 and 19:30, with a peak in the morning and a lesser peak in the evening, a rhythm that resembles the occurrence of myocardial infarction and sudden death.1 The circadian rhythm of angina likewise follows a similar pattern to that of myocardial infarction.2 The incidence of stroke rises by around 60% in the early morning period.3 The circadian rhythm of variant angina peaks in the morning, coupled with a peak in plasma levels of fibrinopeptide A.4 The morning rise in blood pressure is also accompanied by a rise in platelet aggregability.5 Mulcahy D, et al. Circadian variation of total ischaemic burden and its alteration with anti-anginal agents. Lancet 1988;2:755–759. Taylor CR, et al. Circadian rhythm of angina: similarity to circadian rhythms of myocardial infarction, ischemic ST segment depression, and sudden cardiac death. Am Heart J 1989;118:1098–1099. Marler JR, et al. Morning increase in onset of ischemic stroke. Stroke 1989;20:473–476. Ogawa H, et al. Circadian variation of plasma fibrinopeptide A level in patients with variant angina. Circulation 1989;80:1617–1626. Oshchepkova EV, et al. [Morning rise of systolic blood pressure (by 24-hour ambulatory monitoring) and platelet aggregability in essential hypertension patients]. Ter Arkh 2000;72:47–51. 1Mulcahy et al. Lancet. 1988;2:755–759; 2Taylor et al. Am Heart J. 1989;118:1098–1099; 3Marler et al. Stroke. 1989;20:473–476; 4Ogawa et al. Circulation. 1989;80:1617–1626; Oshchepkova et al. Ter Arkh 2000;72:47–51

Morgendlicher Blutdruckanstieg
Blutdruckanstieg am frühern Morgen Erhöhtes kardiovaskuläres Risiko Morgendlicher Blutdruckanstieg 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. 18:00 0:00 6:00 12:00 Tageszeit Muller et al. N Engl J Med 1985;313:1315–1322 Marler et al. Stroke 1989;20:473–476

Erhöhtes Risiko von plötzlichem Herztod und Ischämie Plötzlicher Herztod Todesfälle (n) 20 10 0– – – – –15 15–18 18– –24 Myokardiale Ischämie A significant (p<0.05) circadian pattern of cardiac death was apparent in a retrospective analysis of 94 cases of sudden cardiac death.1 The incidence of cardiac death peaked in the morning between 09:00 and 12:00 h and was lowest in the evening (18:00 to 21:00 h).1 There was an even stronger relationship with the time of waking, with a 2.6-fold increase in risk in the first 3 hours after waking compared with other times of the day.1 The peak incidence of cardiovascular events also occurs at the time of the EMBPS.2 Willich SN, et al. Increased onset of sudden cardiac death in the first three hours after awakening. Am J Cardiol 1992;70:65-68. Rocco MB, et al. Circadian variation of transient myocardial ischaemia in patients with coronary artery disease. Circulation 1987;75:395–400. Dauer (min) 300 200 100 01: : : : : :00 Tageszeit Willich et al. Am J Cardiol 1992;70:65–68 Rocco et al. Circulation 1987;75:395–400

Erhöhtes Risiko von ischämischem/hämorrhagischem Insult Ischämisch (n = 8250) Hämorrhagisch (n = 1801) Prozentsatz der zu erwartenden Schlaganfälle Temporärer ischämischer Insult (n=405) Gesamt (n = 11816) These data are from a meta-analysis of 31 publications reporting the circadian timing of 11,816 strokes.1 There was a 79% increase in the incidence of stroke in the period 06:00–12:00 compared with other hours of the day. This increase in the morning period was found in all three stroke subtypes. Elliott WJ. Circadian variation in the timing of stroke onset. Stroke 1998;29:992–996. 00:00– 06:00 06:00– 12:00 12:00– 18:00 18:00– 00:00 00:00– 06:00 06:00– 12:00 12:00– 18:00 18:00– 00:00 Elliott. Stroke 1998;29:992–996

Tagesrhythmische Schwankungen
Auch das RAAS ist am Morgen aktiviert. Schlaf Blutdruck -15 % Herzfrequenz -10 % Hämodynamisch Periph. Gesamtwiderstand -10 % Herzzeitvolumen -5 % Glomeruläre Filtrationsrate -5 % NaCl -67 % Elektrolyt- ausscheidung The EMBPS is accompanied by a surge in many other important physiological factors. This slide shows the percent change in key haemodynamic, electrolyte excretion and hormonal factors in the early morning period.1 A sharp increase in RAS activity contributes to the EMBPS. White WB. Relevance of blood pressure variation in the circadian onset of cardiovascular events. J Hypertens 2003;21 (Suppl 6):S9–S15. KHCO3 -50 % Renin-Aktivität im Plasma Aldosteron im Plasma +200 % Hormonell Cortisol +100 % 8 12 16 20 24 4 8 Zeit (Std.) White. J Hypertens 2003;21 (Suppl 6):S9–S15

Schädigung von Zielorganen vor klinischen Ereignissen
Risikofaktoren: Diabetes, Übergewicht, Rauchen, Alter Apoptose LVH Fibrose Arrhythmia Herzversagen Myokardinfarkt Hypertonie Thrombose Vasokonstriktion Vaskuläre Hypertrophie Gestörte Endothelfunktion Atherosklerose Tod The concept of a cardiovascular continuum was first published in 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. Schlaganfall Kognitive Störungen Vaskuläre Er- krankungen Rückgang der GFR Proteinurie/Albuminurie Glomerulosklerose Nierenversagen

Morgenhochdruck führt zur Schädigung von Zielorganen
Morgendlicher Blutdruckanstieg kann aufgrund der erhöhten hämodynamischen Belastung zur Schädigung von Zielorganen beitragen. Patienten mit Morgenhochdruck weisen gehäuft eine linksventrikuläre Hypertrophie auf. Der Morgenblutdruck sagt über die folgenden Parameter mehr aus als die in der Arztpraxis gemessenen Werte: Rückgang der GFR Albuminurie bei Patienten mit Typ-1-Diabetes Albuminurie bei Patienten mit Typ-2-Diabetes The EMBPS causes stress to the cardiovascular system, leading to target-organ damage and pathological responses. For example, in a study of 507 untreated hypertensives, the magnitude of the EMBPS was found to be positively correlated with left ventricular mass, as well as with the risk of future cardiovascular complications.1 In 113 hypertensives with chronic renal insufficiency, followed for 3 years, the decline in GFR was most strongly correlated with morning SBP measured using HBPM (r=0.64, compared with r=0.43 for office SBP).2 A study in 170 type 2 diabetics found that hypertension in the morning (measured using HBPM) was linked to a significantly greater incidence of proteinuria. Office blood pressure was not found to be linked to proteinuria.3 Similar results were also found in patients with type 1 diabetes.4 Gosse P, et al. Blood pressure surge on rising. J Hypertens 2004;22:1113–1118. Suzuki H, et al. Self-measured systolic blood pressure in the morning is a strong indicator of decline of renal function in hypertensive patients with non-diabetic chronic renal insufficiency. Clin Exp Hypertens 2002;24:249–260. Kamoi K, et al. Usefulness of home blood pressure measurement in the morning in type 2 diabetic patients. Diabetes Care 2002;25:2218–2223. Kamoi K, et al. Usefulness of home blood pressure measurement in the morning in type 1 diabetic patients. Diabetes Care 2003;26:2473–2475. Gosse et al. J Hypertens 2004;22:1113–1118 Suzuki et al. Clin Exp Hypertens 2002;24:249–260 Kamoi et al. Diabetes Care 2002;25:2218–2223 Kamoi et al. Diabetes Care 2003;26:2473–2475

Geschädigte Zielorgane steigern das kardiovaskuläre Risiko
Funktionsstörung des Endothels Das Endothel spielt bei der Steuerung des peripheren Arterienwiderstands eine zentrale Rolle. Funktionsstörungen des Endothels können als unerwünschte Reaktionen auf Vasodilatatoren/Vasokonstriktoren gelten. Stickoxid spielt als endogener Vasodilatator eine Schlüsselrolle. Funktionsstörungen des Endothels zeigen frühzeitig das Vorliegen einer Zielorganschädigung an. Sie fördern kardiovaskuläre Erkrankungen wie Atherosklerose, Hypertonie und Herzversagen. In der Niere können sie Fibrosen verursachen, die glatte Gefäßmuskulatur zum Proliferieren bringen und schließlich die Organfunktion beeinträchtigen. The endothelium responds to endogenous vasodilators and vasoconstrictors, and can play an important role in maintaining blood pressure and peripheral circulation. Endothelial dysfunction is an early marker of vascular disease in a range of different diseases, including diabetes, hypertension, hypercholesterolaemia and coronary heart disease.1 It 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. Klahr, Morrissey. Kidney Int Suppl 2000;75:S7–S14

Linksventrikuläre Hypertrophie Patients with hypertension have an elevated risk of cardiovascular events compared with normotensive individuals. However, if hypertension is associated with LVH, the overall risk of cardiovascular morbidity and mortality increases even more. Data from the 32-year Framingham Heart Study follow-up of men aged 32–64 years show that the presence of LVH in patients with established hypertension nearly triples the incidence of coronary heart disease and stroke, and increases the incidence of heart failure by about 7-fold.1 Kannel WB. Left ventricular hypertrophy as a risk factor in arterial hypertension. Eur Heart J 1992; (Suppl D):82–88. Kannel. Eur Heart J 1992;13 (Suppl D):82–88

Albuminurie (bei Typ-2-Diabetes) * * 463 patients with type 2 diabetes and normoalbuminuria (n=330), microalbuminuria (n=106) or macroproteinuria (n=27) were followed for an average of 4.64 years.1 The overall cardiovascular morbidity and mortality rate was 3.7%/year.1 After multiple adjustment for co-existing risk factors, microalbuminuria was associated with a 1.9-fold increase in relative risk, and macroproteinuria with a 4.1-fold increase.1 Gimeno Orna JA, et al. [Microalbuminuria and clinical proteinuria as the main predictive factors of cardiovascular morbidity and mortality in patients with type 2 diabetes]. Rev Clin Esp 2003;203:526–531. *P < 0,05 gegenüber Normoalbuminurie nach Berichtigung hinsichtlich anderer Risikoindikatoren Gimeno Orna et al. Rev Clin Esp 2003;203:526–531

Blutdrucksenkung verringert das kardiovaskuläre Risiko
Deutliche Verbesserungen durch geringfügige Senkungen des SBD Metaanalyse von 61 prospektiven Beobachtungsstudien 1 Mio. Erwachsene – 12,7 Mio. Personenjahre Mortalitätsrisiko durch ischämische Herzerkrankung um 7 % geringer. Senkung des mittleren SBD um 2 mmHg A meta-analysis of 61 prospective, observational studies has shown that a 10 mmHg lower S BP is associated over the long term with a 40% lower risk of stroke death and a 30% lower risk of death from ischaemic heart disease (IHD) or other vascular causes.1 Even a small, 2 mmHg fall in mean S BP was associated with large reductions in premature deaths and disabling strokes.1 There was no evidence of a J-curve (i.e. a threshold of reduction beyond which risk begins to increase).1 The reduction in risk associated with a given reduction in mean blood pressure is approximately constant down to at least an SBP of 115 mmHg and a DBP of 75 mmHg – well beyond what is normally achieved.1 The reduction in risk holds for all age groups assessed from 40 up to 89 years old.1 Lewington S, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903–1913. Mortalitätsrisiko durch Schlaganfall um 10 % geringer. Lewington et al. Lancet. 2002;360:1903–1913

Eindämmen der Zielorganschädigung
Blutdrucksenkung verlangsamt GFR-Rückgänge Mittlerer Arteriendruck (mmHg) 95 98 101 104 107 110 113 116 119 -2 r = 0,69; P < 0,05 -4 -6 GFR-Rückgänge (ml/min/Jahr) This meta-analysis of clinical trials in diabetic and non-diabetic renal disease shows the direct and continuous relationship between the achieved blood pressure and the decline in GFR.1 In patients with proteinuria >1 g/day and renal insufficiency (GFR 13–55 mL/min/1.73 m2), optimal blood pressure is <125/75 mmHg.2 Bakris GL, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis 2000;36:646–661. Lazarus JM, et al. Achievement and safety of a low blood pressure goal in chronic renal disease. The Modification of Diet in Renal Disease Study Group. Hypertension 1997;29:641–650. Unbehandelte Hypertonie -8 -10 -12 130/85 140/90 -14 Bakris et al. Am J Kidney Dis 2000;36:646–661

Vorteile einer intensiven Blutdrucksenkung
Intensive Blutdrucksenkung verringert Risiko† (Nichtraucher) ** * Intensive antihypertensive treatment (i.e. with a target DBP ≤85 mmHg) can significantly reduce the risk of a major cardiovascular event compared with less intensive treatment (target DBP ≤90 mmHg). The data shown in this slide are from the Hypertension Optimal Treatment (HOT) study of 18,790 hypertensives treated for an average 3.8 years.1 Benefits were greatest in diabetics (relative risk = 0.53 for cardiovascular events).1 In non-smokers, there was reduced risk in many important patient groups, including those with a global risk considered to be high or very high.1 In smokers, more intensive DBP lowering was associated with increased risk of all types of cardiovascular event.1 Zanchetti A, et al. Benefits and risks of more intensive blood pressure lowering in hypertensive patients of the HOT study with different risk profiles: does a J-shaped curve exist in smokers? J Hypertens 2003;21:797–804. * P ≤ 0,05 gegenüber weniger intensiver Behandlung ** P ≤ 0,01 gegenüber weniger intensiver Behandlung † Intensiv = DBD ≤ 85 mmHg; weniger intensiv = DBD < 90 mmHg Zanchetti et al. J Hypertens 2003;21:797–804

Antihypertensive Behandlungsziele
Die Langzeitrisiken hinsichtlich kardiovaskulärer Morbidität und Mortalität sollten auf ein Mindestmaß reduziert werden. Der SBD/DBD sollte auf < 140/90 mmHg gesenkt werden (bei guter Verträglichkeit noch tiefer) Bei Diabetikern sind < 130/80 mmHg anzustreben. The treatment of patients with hypertension requires the identification of all reversible risk factors (for example, smoking and diabetes), as well as antihypertensive therapy.1 The target should be to reduce SBP and DBP to at least 140/90 mmHg. However, there is convincing evidence that further reductions, if they can be achieved without causing side effects, are beneficial in most patients. Diabetics are at increased risk of cardiovascular events, and so blood pressure should be reduced to at least 130/80 mmHg.1 2003 European Society of Hypertension – European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003;21:1011–1053. ESH–ESC Guidelines. J Hypertens 2003;21:1011–1053

Behandlungsschema (JNC 7)
Hypertonie ohne zwingende Indikationen Hypertonie mit zwingenden Indikationen Hypertonie Stadium 1 Meist thiazidartiges Diuretikum Evtl. ACE-I-Hemmer, AT1-Rezeptorblocker, b-Blocker, Ca-Kanalblocker oder Kombinationstherapie Hypertonie Stadium 2 Kombination aus zwei Medikamenten Meist thiazidartiges Diuretikum und ACE-I, AT1R, b-Blocker oder Ca-Kanalblocker Medikament(e) für zwingende Indikationen Andere Antihypertensiva nach Bedarf (thiazid-artiges Diuretikum und ACE-I, AT1R, b-Blocker, Ca-Kanalblocker) This is a section of the full treatment algorithm, focussing on the choice of antihypertensive class.1 The JNC 7 guidelines recommend lifestyle modifications as an intervention in all patients.1 Patients with Stage 2 hypertension (SBP/DBP ≥160/≥100 mmHg) should receive initial therapy with combination treatment.1 Although diuretics are the drugs of choice for uncomplicated hypertension, the presence of ‘compelling indications’ (see next slide) can dictate the initial use of other drug classes.1 Chobanian AV, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. JAMA 2003;289:2560–2572. JNC 7. JAMA 2003;289:2560–2572

Behandlungsschema (ESH–ESC)
Behandlung je nach Blutdruck und sonstigen Risikofaktoren Absolutes Risiko SBD 130–139 DBD 85–89 SBD 140–179 DBD 90–109 SBD ≥180 DBD ≥110 Niedrig Keine Senkung Bei anhaltend hohem BD evtl. medikamen- töse Behandlung Unverzüglich medikamentöse Behandlung Mittelhoch Häufiges Messen Bei anhaltend hohem BD medikamentöse Behandlung Hoch Sehr hoch ESH–ESCguidelines also emphasize the need to consider ancillary risk factors when setting treatment goals.1 Shown in this table is the blood pressure at diagnosis. Risk factors include diabetes, smoking, abdominal obesity and target-organ damage (such as LVH, microalbuminuria or increased serum creatinine), as well as associated clinical conditions such as cardiovascular or renal disease. Patients at high risk or very high risk should have their blood pressure treated if it is above 130/85 mmHg. Patients with blood pressure that is consistently >140/90 mmHg should usually have it treated, regardless of the presence of other risk factors. 2003 European Society of Hypertension – European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003;21:1011–1053. ESH–ESC Guidelines. J Hypertens 2003;21:1011–1053

Hypertonie – Bewusstsein, Behandlung und Einstellung
Schlechte Blutdruck-Einstellung* in den westlichen Staaten Hypertension is poorly controlled, even in western industrialized societies, as revealed in a survey of studies on hypertension treatment and control.1 Many patients, especially in Europe, are not even aware that they have hypertension. Many patients are not treated even when they have been diagnosed. Fewer than 30% of patients have their blood pressure reduced to recommended levels (i.e. <140/90 mmHg). Wolf-Maier K et al. Hypertension Treatment and Control in Five European Countries, Canada, and the United States. Hypertension 2004;43:10–17. * Schwellenwert SBP/DBP = 140/90 mm Hg Wolf-Maier et al. Hypertension 2004;43:10–17

Einstellung des Blutdrucks in den riskanten Morgenstunden
Ambulante 24-Stunden-Werte aussagekräftiger als klinische Werte Zwei Studien zu Hypertonikern zeigen trotz vermeintlich guter Kontrolle schlechte Durchschnittswerte beim Morgendruck. Even when patients have controlled office blood pressure, their blood pressure in the early morning hours often is not controlled. Shown here are data from two studies: Analysis of the control of blood pressure using ambulatory blood pressure monitoring (ACAMPA) study in Spain in 290 treated hypertensives.1 Jichi Morning-Hypertension Research (J-MORE) study in 1027 treated hypertensives.2 Both studies found that 60% of treated and apparently well-controlled hypertensive patients still show high blood pressure levels in the morning hours. Redón J, et al. Uncontrolled early morning blood pressure in medicated patients: the ACAMPA study. Blood Press Monit 2002;7:111–116. Kario K et al. Morning Surge in Blood Pressure as a Predictor of Silent and Clinical Cerebrovascular Disease in Elderly Hypertensives. Circulation 2003;108:72e–73e. Redón et al. Blood Press Monit 2002;7:111–116 Kario et al. Circulation 2003;108:72e–73e

Trough/Peak-Ratio* und Blut-drucksenkung über 24 Stunden
180 Placebo Blutdruck (mmHg) 160 Trough Medikament A (T/P-Ratio: 75 %) 140 Peak 120 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. Medikament B (T/P-Ratio: 45 %) 100 Dosis 07: : : : : : :00 Tageszeit * Verhältnis zwischen Minimal- und Maximalwerten Ellioit, Meredith. J Hypertension 1995;13:279–283

Bessere Resultate bei Hypertonikern
Größere Behandlungstreue bei Einnahme 1× täglich * *** Failure to achieve target blood pressure can also result when patients do not adhere to their treatment regimen. One reason for non-adherence is multiple daily dosing. This meta-analysis of 8 studies shows that adherence to a once-daily dosing regimen is significantly greater than that to a twice-daily or multiple-daily dosing regimen.1 Iskedjian M, et al. Relationship between daily dose frequency and adherence to antihypertensive pharmacotherapy: evidence from a meta-analysis. Clin Ther 2002;24:302–316. * P < 0,05 gegenüber 2× täglich *** P < 0,001 gegenüber mehrmals täglich Iskedjian et al. Clin Ther 2002;24:302–316

Selektive Angiotensin-I-Rezeptorblockade Bradykinin/NO Inaktive Fragmente ANGIOTENSIN I ANGIOTENSIN II AT1R-Blocker AT1-Rezeptor Vasokonstriktion Natriumretention SNS-Aktivierung Entzündung Wachstumsförderung AT2-Rezeptor Vasodilatation Natriurie Geweberegeneration Hemmung von schädlichem Zellwachstum Chymase, tPA, Cathepsin ‘Angiotensin II escape’ ACE-Hemmer The RAAS, in particular angiotensin II, contributes to cardiovascular disease by increasing blood pressure and also by causing inflammation, leading to sclerosis and tissue hypertrophy. ARBs and angiotensin-converting enzyme (ACE) inhibitors block the RAAS by different mechanisms. ACE inhibitors block the conversion of angiotensin I to angiotensin II. However, angiotensin II can be formed by other pathways. This can lead to a gradual return of angiotensin levels to baseline, a phenomenon termed ‘angiotensin II escape’.1 ACE inhibitors also have other physiological effects, some beneficial,2 but which can also result in cough. Two principal receptors mediate the effects of angiotensin II in humans. The AT1 receptor is responsible for most of the pathological effects associated with angiotensin II, whereas the AT2 receptor counteracts these effects.3 ARBs specifically block the AT1 receptor. Because ARBs specifically block the AT1 receptor but allow continued activation of the AT2 receptor, they can provide tissue-protective effects beyond their effects on blood pressure. Hanon S, et al. Persistent formation of angiotensin II despite treatment with maximally recommended doses of angiotensin converting enzyme inhibitors in patients with chronic heart failure. J Renin Angiotensin Aldosterone Syst 2000;1:147–150. Chen R, et al. Important role of nitric oxide in the effect of angiotensin-converting enzyme inhibitor imidapril on vascular injury. Hypertension 2003;42:542–547. Hurairah H, Ferro A. The role of the endothelium in the control of vascular function. Int J Clin Pract 2004;58:173–183.

Nebenwirkungen von Antihypertensiva
A1-Rezeptorhemmer sind nebenwirkungsarm. Klasse Wichtige Nebenwirkungen Diuretika (thiazidartige) Verlust von Extrazellularflüssigkeit. Anstieg von Cholesterin, Glukose, Harnsäure, Kalzium, Lithium. Abfall von Kalium, Natrium und Magnesium. b-Blocker Bradykardie, maskierte Hypoglykämie. Auch Impotenz, Müdigkeit, Schlaflosigkeit, Bronchospasmus, periphere Kreislaufschwäche. Ca-Kanalblocker (Dihydropyridin) Periphere Ödeme, Hautröte, Kopfschmerzen, Gingivahypertrophie. ACE-Hemmer Husten, Angioödem (sehr selten), Hyperkalämie, Ausschläge, Geschmacksverlust, Leukopenie, erhöhte Lithium-Werte. AT1R-Blocker Angioödem (sehr selten), erhöhte Lithium-Werte. Auch Husten und Hyperkalämie (geringerer Schweregrad als bei ACE-Hemmern). Another common reason for poor patient adherence is side effects. Because hypertension is largely asymptomatic, and because treatment can often last years or decades, good tolerability is essential. This slide lists some of the side effects commonly associated with widely used antihypertensive classes.1 National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39(2 Suppl 1):S1–S266. National Kidney Foundation. Am J Kidney Dis 2002;39(2 Suppl 1):S1–S266

Bessere Behandlungstreue mit AT1-Rezeptorblockern Patients prescribed ARBs as their initial medication are more likely to persist with treatment than patients prescribed other classes of antihypertensive medication. This study followed 14,062 newly-diagnosed hypertensives for 273 days.1 The slide shows the percentage of patients who received initial monotherapy and did not discontinue (i.e. did not stop medication or switch to another class) within the 9-month follow-up. Patients who continued their monotherapy but added an agent from another class were considered to be persistent. Since drugs were provided free by the Italian Health Service, the cost of medication is unlikely to have contributed to the discontinuation rates. Esposti LD et al. Pharmacoeconomics of antihypertensive drug treatment: an analysis of how long patients remain on various antihypertensive therapies. J Clin Hypertens 2004;6:76–84. Diuretika CaK-Blocker b-Blocker ACE-Hemmer AT1R-Blocker Esposti et al. J Clin Hypertens 2004;6:76–84

Wünschenswerte Eigenschaften von Antihypertensiva
Blockade des Renin–Angiotensin–Aldosteron-Systems Renoprotektiver Effekt nicht auf Blutdrucksenkung beschränkt. Einnahme 1× täglich Bessere Behandlungstreue 24-Stunden-Effekt bis in die Morgenstunden (größte Häufigkeit von kardiovaskulären Ereignissen) Parameter: Trough/Peak-Ratio (Verhältnis zwischen Wirkung vor täglicher Einnahme und größter Wirkung) Ambulante 24-Stunden-Messung (mit 24-Stunden-Mittelwert sowie Mittelwert in den letzten 6 Stunden vor der nächsten Einnahme) Keine Nebenwirkungen Bessere Behandlungstreue und konsequentere Einnahme Blockade of the renin–angiotensin–aldosterone system (RAAS) is a potent way to reduce hypertension, and the RAAS forms a target for modern antihypertensive therapy.1 Patient compliance with antihypertensive medication is significantly improved if it requires only once-daily administration.2 Increased compliance, coupled with a 24-h efficacy, may be expected to improve patient outcomes. The ideal antihypertensive should also provide round-the-clock activity, especially in the early morning hours when blood pressure increases and cardiovascular events are at their most frequent.3 As with any drug, the therapeutic objectives should be achieved with a minimum of side effects. Weinen W, et al. A review on telmisartan: a novel, long-acting angiotensin II-receptor antagonist. Cardivasc Drug Rev 2000;18:127–156. Iskedjian M, et al. Relationship between daily dose frequency and adherence to antihypertensive pharmacotherapy: evidence from a meta-analysis. Clin Ther 2002;23:302–316. Mulcahy D. Circadian variation in cardiovascular events. Blood Press Monit 1998;3:29–34. Mulcahy. Blood Press Monit 1998;3:29–34 Iskedjian et al. Clin Ther 2002;23:302–316

Richtlinien zur Behandlung von Hypertonie (JNC-VI)
Antihypertensiva sollten möglichst lange wirken. Lang wirksame (d.h. über 24 Stunden) Medikamente sind gegenüber kurz wirksamen Medikamenten aus vielen Gründen zu bevorzugen: Bessere Behandlungstreue bei Einnahme 1× täglich. Niedrigere Kosten durch weniger Tabletten (bei manchen Medikamenten). Der Blutdruck ist nicht phasenweise, sondern durchgängig unter Kontrolle. Schutz gegen alle Risiken (plötzlicher Tod, Herzinfarkt, Schlaganfall) im Zusammenhang mit abrupten Blutdruckanstiegen morgens nach dem Aufwachen. Das optimale Antihypertensivum sollte 1× täglich eingenommen werden, 24 Stunden lang wirksam sein und zum Zeitpunkt der nächsten Einnahme noch mindestens 50 % seiner größten Wirkung haben. Sinnvoll erscheinen auch Antihypertensiva mit einer Wirkungsdauer von über 24 Stunden, weil viele Patienten die Einnahme des Medikaments mindestens einmal pro Woche vergessen. The benefits of long-acting drugs were listed in the JNC 6 guidelines, as quoted on this slide.1 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997;157:2413–2446. JNC 6. Arch Intern Med 1997;157:2413–2446

Zwingende Indikationen (JNC 7)
Diuretikum b-Blocker ACE-I AT1R CaK Herzversagen ● Nach Myokardinfarkt Koronare Hochrisikogruppen Diabetes Chronische Nierenerkrankung Prophylaxe nach Schlaganfall Clinical trials have shown that some classes of antihypertensives can reduce the cardiovascular morbidity in patients with specific indications. The JNC 7 guidelines recommend the use of specific antihypertensive classes in such patient groups, based on such evidence.1 ARBs are recommended for patients with heart failure, diabetes and chronic kidney disease. Note that a lack of recommendation for a specific indication does not mean that the class has been shown to be non-beneficial. It may simply mean that large-scale trials have not yet been conducted. Chobanian AV, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. JAMA 2003;289:2560–2572. JNC 7. JAMA 2003;289:2560–2572

Vorteilhafte Einsatzbereiche für AT1-Rezeptorblocker (ESH–ESC)
Diabetische Nephropathie (Typ 2) Diabetische Mikroalbuminurie Proteinurie Linksventrikuläre Hypertrophie Schlechte Verträglichkeit von ACE-Hemmern (Husten) 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. ESH–ESC Guidelines. J Hypertens 2003;21:1011–1053

Zusammenfassung Hypertonie
Hypertonie ist eine häufige Erkrankung. Hypertoniker haben ein erhöhtes Risiko von kardiovaskuläre Erkrankungen. Insbesondere die morgendlichen Blutdruckanstiege erhöhen das kardiovaskuläre Risiko. Bei schlecht eingestelltem Blutdruck (insbesondere in den Morgenstunden) besteht Handlungsbedarf. Hypertonie verursacht Zielorganschäden. Die Prognose verbessert wich, wenn sich die Schäden durch Blutdrucksenkung zurückbilden. Bei Patienten mit zusätzlichen Risikofaktoren sind die Behandlungsziele strenger. Für Patienten mit Typ-2-Diabetes, Herzversagen oder Nierenerkrankungen weden in den vorliegenden Behandlungsrichtlinien AT1-Rezeptorblocker empfohlen.

Pharmakologie

Chemische Verbindungen
Telmisartan und andere Angiotensin-II-Antagonisten N COOH CI H N HOOC NH OCH2CH3 COCH S N Eprosartan Losartan (aktiv) Candesartan (aktiv) N CH3 O OH N COOH C H OH CH3 H3C Telmisartan, a potent and highly selective AT1 receptor antagonist, displays a novel bis-benzimidazole structure. This unique feature of telmisartan accounts for both its high receptor affinity and its excellent pharmacokinetic properties.1 This slide shows the active metabolites of losartan, candesartan and olmesartan. The chemical structures of valsartan, irbesartan and eprosartan are also shown. Ries UJ, et al. 6-Substituted benzimidazoles as new nonpeptide angiotensin II receptor antagonists: synthesis, biological activity, and structure–activity relationships. J Med Chem 1993;36:4040–4051. N NH O Telmisartan N NH O CO2H Irbesartan Olmesartan (aktiv) Valsartan

Röntgenstruktur von Telmisartan
X-ray crystallography of telmisartan shows that it adopts a triangular configuration closely resembling the proposed conformations of ideal receptor-bound AT1 antagonists. The heteroaromatic substituent in the structural conformation of telmisartan may account for its high receptor affinity.

Bindung an AT1-Rezeptor
Telmisartan bindet unüberwindlich an den AT1-Rezeptor. AII-induzierte Kontraktilität in isolierten Aorta-Ringen beim Kaninchen Telmisartan 10 nM Telmisartan 100 nM Telmisartan 1000 nM Control Eindämmung der Kontraktilität (%) 100 75 50 In vivo studies show that telmisartan is a potent and long-acting antagonist of the hypertensive effects of exogenously administered angiotensin II. In the rabbit aorta, the maximal contractile response to angiotensin II was dose-dependently decreased by 40% to 50% across a dose range of 10 to 1000 nM. No agonist activity was detected at any concentration.1 Even high concentrations of angiotensin II were unable to overcome the receptor blockade, demonstrating that telmisartan manifests an insurmountable AT1 receptor antagonism. Wienen W, et al. Pharmacological characterization of the novel nonpeptide angiotensin II receptor antagonist, BIBR 277. Br J Pharmacol 1993;110:245–252. 25 Angiotensin II log (M) Wienen et al. Br J Pharmacol 1993;110:245–252

Plasma-Halbwertzeit Halbwertzeiten der klinisch verfügbaren AT1-Rezeptorblocker Telmisartan has a 24-h plasma half-life, which is the longest any ARB.1,2 The long plasma half-life ensures that the antihypertensive efficacy is maintained for the full 24-h dosing interval, including into the early morning hours. Burnier M, Brunner HR. Angiotensin II receptor antagonists. Lancet 2000;355:637–645. Brunner HR. The new oral angiotensin II antagonist olmesartan medoxomil: a concise overview. J Hum Hypertens 2002;16 (Suppl 2):S13–S16. Burnier, Brunner. Lancet 2000;355:637–645 Brunner. J Hum Hypertens 2002;16 (Suppl 2):S13–S16

Verteilungsvolumen Verteilungsvolumina von AT1-Rezeptorblockern
Telmisartan also has the largest volume of distribution of any ARB.1 A large volume of distribution signifies that telmisartan penetrates the tissue compartment, ensuring that local as well as systemic RAAS is blocked. Because the AT1 receptor has pathological effects that include cell hypertrophy and fibrosis, blocking AT1 at the tissue level may help to reduce target-organ damage. Song JC, White CM. Olmesartan medoxomil (CS-866). An angiotensin II receptor blocker for treatment of hypertension. Formulary 2001;36:487–499. Song, White. Formulary 2001;36:487–499

Telmisartan aktiviert PPAR-g
Aktivierung von PPAR-g in zellbasiertem Transfektionsassay PPAR-g agonists can improve insulin sensitivity, reduce triglyceride levels and decrease the risk for atherosclerosis. This study examined the ability of different ARBs to activate PPAR-g in a cell-based transient transfection assay.1 This assay eliminates interference from endogenous nuclear receptors. In the results shown here, each ARB was applied at 10 mmol/L. Telmisartan was the only ARB to show strong (27-fold) activation, although irbesartan showed a slight activation (two- to three-fold). By comparison, full PPAR-g agonists show ~140-fold activation in this assay.1 Telmisartan was also the only ARB that activated PPAR-g when tested at lower concentrations that can be achieved physiologically (1–5 mmol/L).1 Telmisartan therefore acts as a partial agonist of PPAR-g. Benson SC, Pershadsingh HA, Ho CI et al. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARg-modulating activity. Hypertension 2004;43:993–1002. Telmisartan Candesartan Olmesartan EXP (losartan) Irbesartan Valsartan Eprosartan Benson et al. Hypertension 2004;43:993–1002

Verhältnis zwischen Minimal- und Maximalwert
SBD DBD Empfehlung (JNC VI) >50 % >50 % Losartan 50 mg 35 % 51 % Telmisartan 40 mg 66 % ~100 % Telmisartan 80 mg 92 % ~100 % The trough:peak ratio is a method for assessing the duration of effect of an antihypertensive.1 The mean 24-h ambulatory blood pressure is considered the gold standard for testing the duration of antihypertensive effect, although trough:peak ratios can still provide valuable guidance.2 Losartan provides a trough:peak ratio of 35% SBP and 51% DBP.3 Telmisartan once daily provides clinically significant reductions in trough (i.e., 24 h after last dose) SBP and DBP that are comparable to the peak reductions.4 The trough:peak ratio for the 40 mg dose is around 66% (SBP) and 100% (DBP), and around 92% (SBP) and 100% (DBP) for the 80-mg dose. Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997;157:2413–2446. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Principles for clinical evaluation of new antihypertensive drugs Available at: Stergiou GS, et al. Comparison of the smoothness index, the trough : peak ratio and the morning : evening ratio in assessing the features of the antihypertensive drug effect. J Hypertens 2003;21:913–920 Neutel JM. Ambulatory blood pressure monitoring to assess the comparative efficacy and duration of action of a novel new angiotensin II receptor blocker—telmisartan. Blood Press 2001;10(suppl 4):27–32. JNC VI. Arch Intern Med 1997;157:2413–2446 Stergiou et al. J Hypertens 2003;21:913–920 Neutel. Blood Press 2001;10(suppl 4):27–32

Normaldosierung Die empfohlene Anfangsdosis für Erwachsene beträgt 40 mg Telmisartan 1× täglich. Die größte Blutdrucksenkung wird bei einer Dosierung von 80 mg Telmisartan 1× täglich erreicht. Die antihypertensive Wirkung ist nach 2 Wochen weitestgehend hergestellt. Die maximale Wirkung wird gewöhnlich nach 4–8 Wochen erreicht. Telmisartan kann auch fix mit 12,5 bzw. 25 mg Hydrochlorthiazid (HCTZ) kombiniert werden. Telmisartan produces substantial antihypertensive efficacy with a dose of 40 mg, and so this is the recommended starting dose.1,2 Further blood pressure reductions can be achieved with the 80 mg dose.1,2 If additional blood-pressure lowering power is needed, telmisartan can be given in fixed-dose combination with the diuretic HCTZ. Blood pressure reductions are achieved smoothly but quickly, with most of the response apparent within 2 weeks.1,2 Micardis Prescribing Information. Available at Micardis Summary of Product Characteristics. Available at Micardis® SPC Micardis® USPI

Dosierung je nach Alter und Geschlecht
Keine Dosisanpassung je nach Alter oder Geschlecht erforderlich. Telmisartan besitzt bei älteren ( 65 Jahren) und jüngeren (< 65 years) Patienten vergleichbare pharmakokinetische Eigenschaften. Die Telmisartan-Konzentrationen im Plasma sind bei Frauen 2–3× höher als bei Männern. Aber: Es waren keine nennenswerte Unterschiede zwischen Frauen und Männern bei der diastolischen Blutdrucksenkung und beim Unbedenklichkeitsprofil zu beobachten. Eine Dosisanpassung je nach Alter oder Geschlecht ist nicht zu verzeichnen. The pharmacokinetics of telmisartan in the elderly (≥65 years) is similar to that in younger patients, with no accumulation.1 This indicates that changes in hepatic function with increasing age do not affect the clearance of telmisartan. Although plasma concentrations of telmisartan are higher in women, this does not affect the antihypertensive effect nor does it increase the risk for adverse events.1,2 Stangier J, et al. Pharmacokinetics of orally and intravenously administered telmisartan in healthy young and elderly volunteers and in hypertensive patients. J Int Med Res 2000;28:149–167. Smith DHG, et al. Dose response and safety of telmisartan in patients with mild to moderate hypertension. J Clin Pharmacol 2000;40:1380–1390. Stangier J et al. J Int Med Res 2000;28:149–167 Smith et al. J Clin Pharmacol 2000;40:1380–1390

Ausscheidung durch die Niere
Geringste Harnausscheidung unter allen AT1R-Blockern* Unlike other ARBs, only 1% of a telmisartan dose in excreted by the kidney.1 Up to 50% of the dose of other ARBs is excreted by the kidney.1 Renal impairment is unlikely to affect the pharmacokinetics of telmisartan. Song JC, White CM. Olmesartan medoxomil (CS-866). An angiotensin II receptor blocker for treatment of hypertension. Formulary 2001;36:487–499. * Telmisartan wird über die Leber metabolisiert. Bei leichter bis mittelschwerer Leberfunktionsstörung ist daher Vorsicht geboten. Song, White. Formulary 2001;36:487–499

Dosierung bei Nephropathien
Bei Nierenerkrankungen ist keine Dosisanpassung erforderlich. Telmisartan wird fast ausschließlich über die Galle ausgeschieden; somit ist bei Nephropathien keine Dosisanpassung erforderlich. Telmisartan bindet zu 99,5 % an Serumproteine; somit ist keine Dosisanpassung nach Dialyse erforderlich. Telmisartan reduziert bei Patienten mit leichter, mittelschwerer oder schwerer Nephropathie (bis hin zu terminaler Niereninsuf- fizienz) wirksam den systolischen und diastolischen Blutdruck. Because telmisartan is 99.5% bound to serum protein, it is not dialysable, and as a result there is no requirement for post-dialysis supplementation.1 Valsartan and eprosartan show notably lower binding (95% and 90%, respectively).1 Telmisartan has been shown to reduce blood pressure in patients with renal disease in the Efficacy and Safety in Patients with Renal Impairment treated with Telmisartan (ESPRIT) study.2 ESPRIT was a 12-week, open-label study of telmisartan 40–80 mg in 82 patients with hypertension (DBP 90–109 mmHg) and chronic mild/moderate (GFR 30–74 ml/min/1.73 m2) or severe renal impairment (GFR <30 ml/min/1.73 m2), or requiring maintenance haemodialysis. There was greater effect in patients with greater renal impairment (a common finding in this patient population). Song JC, White CM. Olmesartan medoxomil (CS-866). An angiotensin II receptor blocker for treatment of hypertension. Formulary 2001; 36: Sharma AM, et al. Telmisartan in patients with mild/moderate hypertension and chronic kidney disease. Clin Nephrol 2005;63:250–257. Song, White. Formulary 2001;36:487–499 Sharma et al. Clin Nephrol 2005;63:250–257

Wechselwirkungen mit anderen Arzneimitteln
Telmisartan zeigt keine nennenswerten Wechselwirkungen. Kein Metabolisierung über Cytochrom P450 Wechselwirkungen mit oxidativ metabolisierten Arzneimitteln sind unwahrscheinlich. Keine klinisch relevanten Wechselwirkungen mit HCTZ Simvastatin Amlodipin Warfarin Glibenclamid Paracetamol Ibuprofen Keine Anhaltspunkte für Digoxin-Toxizität aus klinischen Studien und Pharmakovigilanz-Studien. Telmisartan is not metabolized by cytochrome P450, an enzyme that is important for the oxidative metabolism of a number of other drugs. Therefore, the potential for interaction with drugs metabolized by this pathway is low.1 Telmisartan is primarily metabolized by glucuronidation.2 Other drugs metabolized by glucuronidation include paracetamol (acetaminophen) and ibuprofen. There is no effect of telmisartan on the pharmacokinetics of these drugs.3 Telmisartan has been assessed for interaction with a number of other drugs that are likely to be used concomitantly, with no evidence of a significant effect.4–7 Telmisartan can result in elevated serum digoxin in some patients. However, clinical trials and post-marketing surveillance has revealed no evidence of a clinically significant interaction.8 Wienen W, et al. A review on telmisartan: a novel, long-acting angiotensin II-receptor antagonist. Cardiovasc Drug Rev 2000;18:127–156. Stangier J, et al. Absorption, metabolism and excretion of intravenously and orally administered [14C]telmisartan in healthy volunteers. J Clin Pharmacol 2000;40:1312–1322. Stangier J, et al. Pharmacokinetics of acetaminophen and ibuprofen when coadministered with telmisartan in healthy volunteers. J Clin Pharmacol 2000;40:1338–1346. Stangier J, Su CAPF. Pharmacokinetics of repeated oral doses of amlodipine and amlodipine plus telmisartan in healthy volunteers. J Clin Pharmacol 2000;40:1338–1346. Heuer HJ, et al. Influence of repeated oral doses of telmisartan on the clinical pharmacology of glibenclamide in healthy volunteers. Eur J Clin Pharmacol 1998;54:A12 (abstract 38). Stangier J, et al. Steady-state pharmacodynamics and pharmacokinetics of warfarin in the presence and absence of telmisartan in healthy volunteers. J Clin Pharmacol 2000;40:1331–1337. Dunselman PHJM, and the replacement of angiotensin converting enzyme inhibition (REPLACE) investigators. Effects of the replacement of the angiotensin converting enzyme inhibitor enalapril by the angiotensin II receptor blocker telmisartan in patients with congestive heart failure. Int J Cardiol 2001;77:131–138. Unger T, Kaschina E. Drug interactions with angiotensin receptor blockers: a comparison with other antihypertensives. Drug Safety 2003;26:707–720. Wienen et al. Cardiovasc Drug Rev 2000;18:127–156; Stangier, Su. J Clin Pharmacol 2000;40:1338–1346; Heuer et al. Eur J Clin Pharmacol 1998;54:A12 (abstract 38); Stangier et al. J Clin Pharmacol 2000;40:1331–1337; Stangier et al. J Clin Pharmacol 2000;40:1338–1346; Dunselman et al. Int J Cardiol 2001;77:131–138; Unger, Kaschina. Drug Safety 2003;26:707–720

Pharmakologie: Zusammenfassung
Telmisartan bindet unüberwindlich (aber reversibel) an den AT1-Rezeptor. Telmisartan hat von allen AT1-Rezeptorblockern die längste Plasmahalbwertzeit und das größte Verteilungsvolumen. Im Gegensatz zu anderen AT1-Rezeptorblockern bewirkt Telmisartan schon in physiologisch erreichbaren Konzentrationen eine Aktivierung von PPAR-g. Eine Dosisanpassung je nach Alter oder Geschlecht ist nicht erforderlich. Telmisartan wird über die Leber metabolisiert, sodass bei Patienten mit Nephropathie keine Dosisanpassung erforderlich ist. Telmisartan zeigt keine Wechselwirkungen mit anderen Arzneimitteln.

Klinische Wirksamkeit

In Vergleichsstudien ausführlich getestet
Vergleichssubstanzen in klinischen Studien zu Micardis® Diuretika HCTZ b-Blocker Atenolol Carvedilol Ca-Kanalblocker Amlodipin / Amlodipin + HCTZ Lercanidipin Nifedipin ACE-Hemmer Enalapril Lisinopril Perindopril Ramipril AT1-Rezeptorblocker Losartan / Losartan + HCTZ Valsartan / Valsartan + HCTZ Eprosartan Telmisartan has be extensively studied in comparative clinical trials. This slide provides a summary of the comparisons that have been assessed. The results are provided in the following slides.

Größter Datenbestand aus ambulanten Langzeitmessungen
Umfangreiche 24-Stunden-Daten und morgendliche Blutdruckwerte Patienten mit leichter bis mittelschwerer Hypertonie AT1-Rezeptorblocker Losartan (letzte 6 Std) Losartan + HCTZ (letzte 6 Std) Valsartan (letzte 6 Std) ACE-Hemmer Perindopril (letzte 8 Std) Ramipril (letzte 6 Std, 24 Std) Ca-Kanalblocker Amlodipin (letzte 4 Std) Amlodipin + HCTZ (24 Std) Nifedipin GITS (24 Std) Patienten mit Zielorganschädidung (LVH) Diuretika HCTZ (24 Std und letzte 6 Std) Clinical trials of telmisartan have extensively used ABPM, which is widely considered to be the most relevant measure of blood pressure. This extensive use of ABPM has resulted in the largest body of ABPM data currently available. This slide provides a list of studies that have been conducted to date, and which are detailed in the following slides. Additional ABPM studies are ongoing, which will increase further the body of available data.

Wirksame Blutdrucksenkung über 24 Stunden
Ambulante Langzeitmessungen bei Hypertonikern - Metaanalyse 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. * * * P < 0,0125 gegenüber Losartan und Valsartan Neutel, Smith. J Clin Hypertens 2003;5:58–63

Wirksamere Senkung des Blutdrucks am Vormittag
Vormittagsdruck bei Hypertonikern (6–12 Uhr) * 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. * * * P < 0,0125 gegenüber Losartan und Valsartan Neutel, Smith. J Clin Hypertens 2003;5:58–63

Morgendliche Blutdrucksenkung mit AT1-Rezeptorblockern
Telmisartan gegenüber Losartan Bessere systolische/diastolische Blutdrucksenkung in den letzten 6 Studen vor der nächsten Einnahme Äquivalente Wirksamkeit von Monotherapie mit Telmisartan und Kombinationstherapie mit Losartan + HCTZ Telmisartan + HCTZ gegenüber Losartan + HCTZ Telmisartan gegenüber Valsartan Bessere Senkung nach getätigter und versäumter Einnahme Bessere Senkung in den letzten 6 Std. vor der nächsten Einnahme Bessere durchschnittliche Blutdrucksenkung über 24 Stunden Telmisartan has consistently shown superior reductions in blood pressure in the last 6 h of the dosing interval compared with other ARBs. This superiority is a consequence of telmisartan’s long duration of action. The evidence for this superiority is detailed in the following slides.

Telmisartan gegenüber Losartan in den letzten 6 Stunden
Daten aus zwei unabhängigen Studien 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. * * Losartan 50 mg Telmisartan 40 mg * P < 0,05 gegenüber Losartan Mallion et al .J Hum Hypertens 1999;13:657–664 Ding et al. Int J Clin Pract Suppl 2004;58:16–22

Telmisartan gegenüber Losartan Mittelwerte über 24 Stunden
Daten aus zwei unabhängigen Studien 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. * * * Losartan 50 mg Telmisartan 40 mg * P < 0,05 gegenüber Losartan Mallion et al .J Hum Hypertens 1999;13:657–664 Ding et al. Int J Clin Pract Suppl 2004;58:16–22

Daten nach dem Studienprinzip Titrieren bis zum Ansprechen The superiority of telmisartan over losartan is also evident when a flexible-dosing regimen is employed. This slide shows the results of an 8-week study in 331 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. By Week 8, the reduction in SBP and DBP in the last 6 h of the dosing interval was greater in the telmisartan arm than in the losartan arm. Data on file. Boehringer Ingelheim GmbH. * * Losartan 50–100 mg Telmisartan 40–80 mg * P < 0,05 gegenüber Losartan Data on file, Boehringer Ingelheim GmbH

Metaanalyse von 2 Studien (Titrieren bis zum Ansprechen) In a meta-analysis of two flexible-dose studies, telmisartan produced superior reductions in blood pressure than losartan. 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. By Week 8, the reduction in SBP and DBP in the last 6 h of the dosing interval was greater in the telmisartan arm than in the losartan arm. Telmisartan-induced reductions were also greater for the majority of the observed hourly mean ambulatory SBP and DBP values over the entire 24-h dosing interval. Smith DH, et al. Comparison of telmisartan versus losartan: meta-analysis of titration-to-response studies. Blood Press Monit 2003;8:111–117. ** Losartan 50–100 mg Telmisartan 40–80 mg ** ** P ≤ 0,01 gegenüber Losartan Smith et al. Blood Press Monit 2003;8:111–117

Telmisartan gegenüber Losartan Stundenverlauf
Metaanalyse von 2 Studien (Titrieren bis zum Ansprechen) Stundenverlauf nach Einnahme 2 4 10 14 12 6 8 16 18 20 22 24 P ≤ 0,01 Telmisartan vs. Losartan 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. Smith et al. Blood Press Monit 2003;8:111–117

Telmisartan gegenüber Losartan Systol. Minimaldruck am Oberarm
Metaanalyse von zwei Studien (Titrieren bis zum Ansprechen) 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 mg vs. losartan 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. * * Losartan 50–100 mg Telmisartan 40–80 mg * P < 0,05 gegenüber 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 gegenüber Valsartan in den letzten 6 Stunden
MICADO-II-Studie 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. ** Valsartan 160 mg Telmisartan 80 mg * * P = 0,02 gegenüber Valsartan ** P = 0,01 gegenüber Valsartan White et al. Am J Hypertens 2004;17:347–353

Telmisartan gegenüber Valsartan nach getätigter Einnahme
The MICADO II study Stundenverlauf nach Einnahme 2 4 10 14 12 6 8 16 18 20 22 24 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. P = 0,02 Telmisartan vs. Valsartan White et al. Am J Hypertens 2004;17:347–353

Telmisartan gegenüber Valsartan nach versäumter Einnahme
Metaanalyse aus zwei unabhängigen Studien Stundenverlauf nach Einnahme 2 4 10 14 12 6 8 16 18 20 22 24 P < 0,05 P < 0,005 P < 0,0001 P < 0,001 Telmisartan 80 mg provides superior blood pressure reductions than valsartan 160 mg following a missed dose. The combined data from two, double-blind, crossover, forced-titration studies are shown.1 Patients with hypertension (n=877) received either telmisartan 80 mg/day or valsartan 160 mg/day. After 4-weeks’ treatment, patients received either double-blind active therapy or placebo (missed dose) for 1 day. After a further 2 weeks’ therapy, patients were crossed over and again received either active therapy or placebo for 1 day. After a missed dose, 24-h mean SBP/DBP was reduced by 10.7/7.2 mmHg with telmisartan, compared with 8.7/5.5 mmHg with valsartan (P<0.05). Lacourcière Y, et al. Sustained antihypertensive activity of telmisartan compared with valsartan. Blood Press Monit 2004;9:203–210. P-Werte = Telmisartan versus Valsartan Lacourcière et al. Blood Press Monit 2004:9;203–210

Telmisartan gegenüber Ramipril in den letzten 6 Stunden
Daten aus zwei unabhängigen Studien PRISMA I PRISMA II 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. *** *** *** *** Ramipril 10 mg * P < 0,0001 vs. Ramipril Telmisartan 80 mg Williams et al. Hypertension 2004;44;576 Lacourcière et al. Hypertension 2004;44:576

Telmisartan gegenüber Ramipril Stundenverlauf
Daten aus der PRISMA-II-Studie Stundenverlauf nach Einnahme 2 4 10 14 12 6 8 16 18 20 22 24 * 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. * P < 0,0001 für Telmisartan versus Ramipril über 24 Std. Lacourcière et al. Hypertension 2004;44:576

Telmisartan reduziert morgendlichen Blutdruckanstieg
Telmisartan ist bei starkem Morgenhochdruck wirksamer als Ramipril. Morgendlicher Blutdruckanstieg: Definition Veränderungen bei Patienten mit morgendlichem Anstieg von ≥ 35 mmHg Morgendlicher Mittelwert (MMW) Aufwachen 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. Morgendlicher Anstieg = MMW – NTP Nächtlicher Tiefpunkt (NTP) *** 6 12 18 23 Ramipril 10 mg Hour of the day Telmisartan 80 mg *** P = 0,0001 gegenüber Ramipril Data on file, Boehringer Ingelheim GmbH

Telmisartan gegenüber Perindopril in den letzten 8 Stunden
Vergleichende Doppelblindstudie P < 0,05 für Telmisartan vs. Perindopril über 24 Std. Vor Behandlung P ≤ 0,05 für Telmisartan vs. Perindopril Nach Behandlung Telmisartan 80 mg reduced mean DBP in the last 8 h of the dosing interval compared with perindopril 4 mg (P≤0.05).1 This study was a 6-week, double-blind, ABPM trial in 60 patients with mild-to-moderate hypertension. DBP control (24-h mean DBP <85 mmHg) was observed in 66.6% of telmisartan-treated patients but only 46.6% of perindopril-treated patients (P<0.05). Nalbantgil I, et al. The efficacy of telmisartan compared with perindopril in patients with mild-to-moderate hypertension. Int J Clin Pract 2004;58:50–54. Telmisartan 80 mg Perindopril 4 mg 8 10 12 14 16 18 20 22 24 2 4 6 8 Tageszeit (Std.) Nalbantgil et al. Int J Clin Pract 2004;58:50–54

Telmisartan gegenüber Perindopril
Größere maximale Blutdrucksenkungen zu Hause * 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 <90 mmHg). More patients required a dose doubling of perindopril (55%) than of telmisartan (41%, p=0.005) Despite the higher rate of dose doubling with perindopril, telmisartan still reduced blood pressure measured at home compared with perindopril. Telmisartan also significantly reduced clinic blood pressure compared with perindopril. More patients had a clinic DBP <90 mm Hg with telmisartan than with perindopril (58% versus 46%, respectively, P<0.01), and more patients had an SBP <140 mmHg (46% versus 32%, respectively, P<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. ** * P < 0,01 vs. Perindopril ** P < 0,005 vs. Perindopril Ragot et al. J Hum Hypertens 2002;16:865–873

Telmisartan gegenüber Enalapril
Signifikant größere maximale Blutdrucksenkungen 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. ** * * P = 0,03 vs. Enalapril ** P = 0,01 vs. Enalapril Smith et al. Adv Ther 1998;15:229–240

Schutz gegen Morgenhochdruck Telmisartan versus Amlodipin
Letzte 4 Stunden vor der nächsten Einnahme 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. * * P = 0,05 versus Amlodipin Lacourcière et al. Blood Press Monit 1998;3:295–302

Telmisartan gegenüber Amlodipin
Größere diastolische Blutdrucksenkung nachts und morgens Diastol. BD gegenüber Ausgangswert (mmHg) 120 P < 0,05 Telmisartan vs. Amlodipin 100 80 Placebo Telmisartan (40–120 mg) 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<0.001) . DBP reductions were greater with telmisartan compared with amlodipine (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. 60 Amlodipin (5–10 mg) P < 0,05 Telmisartan vs. Amlodipin 08: : : : : :00 08:00 Tageszeit Lacourcière et al. Blood Press Monit 1998;3:

Wirksamkeit bei eingeschränkter Nierenfunktion
Blutdrucksenkung in allen nephropathischen Stadien Schweregrad der Nierenfunktionsstörung The Efficacy and Safety in Patients with Renal Impairment treated with Telmisartan (ESPRIT) trial was an 8-week, open-label study of telmisartan 40–80 mg in 82 patients with hypertension (DBP 90–109 mmHg) and chronic mild/moderate (GFR 30–74 ml/min/1.73 m2) or severe renal impairment (GFR <30 ml/min/1.73 m2), or requiring maintenance haemodialysis.1 Blood pressure was significantly reduced in all groups, and there were no statistically significant between-group differences in the magnitude of the reduction. Drug-related adverse events were uncommon, and were typical class effects of ARBs. There were few notable changes in laboratory parameters following telmisartan treatment. Sharma AM, et al. Telmisartan in patients with mild/moderate hypertension and chronic kidney disease. Clin Nephrol 2005;63:250–257. Sharma et al. Clin Nephrol 2005;63:250–257

Wirksamkeit bei terminaler Niereninsuffizienz/Hämodialyse
Größere Wirksamkeit als Losartan bei chronischem Nierenversagen * 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). The superiority of telmisartan increased by Week 8 (-30.6/-10.9 versus -12.3/-4.9 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. * *P < 0,05 vs. Losartan Cice et al. XLI ERA. 2004

Zusammenfassung Morgendlicher Blutdruckanstieg ist ein wichtiges Ansatzpunkt zur Verhinderung von kardiovaskulärer Mortalität. Eigenschaften von Telmisartan: Wirksame Blutdrucksenkung am Morgen (größter Datenbestand zu ambulanten Langzeitmessungen in der medizinischen Literatur). Wirksamere Blutdrucksenkung in den letzten Stunden vor der täglichen Einnahme als Valsartan, Losartan, Ramipril, Perindopril und Amlodipin. Morgendliche Blutdrucksenkung bei Patienten mit Morgenhochdruck (im Vergleich zu Ramipril). Gute Wirksamkeit und Verträglichkeit bei Patienten mit Nephropathie (einschließlich Dialysepatienten).

Wirksame Blutdrucksenkung am Morgen - Zusammenfassung
Telmisartan: Größere Wirksamkeit als andere Antihypertensiva Vergleichssubstanzen Telmisartan (Dosis) Differenz zugunsten Telmisartan (mmHg) SBD DBD AT1-Rezeptorblocker Losartan 50 mg 40 mg 4,2 5,1* Losartan 50–100 mg 40–80 mg 2,1* 1,5** Valsartan 160 mg 80 mg 2,3* 1,8* 2,0** 1,8** Ca-Kanalblocker Amlodipin 5–10 mg† 40–120 mg 3,9 3,4* ACE-Hemmer Perindopril 4–8 mg‡ 3,4** 1,4* Ramipril 10 mg 4,7*** 3,4*** 3,7*** 2,7*** This slide gives a summary of the benefits of telmisartan over active comparators in the early morning period. Except where indicated, all these studies used ABPM to measure the changes from baseline in the last 6 h of the dosing interval. Telmisartan was superior to losartan in a fixed-dose1 and a titration-to-response study.2 Telmisartan was superior to valsartan in two forced-titration studies.3,4 Telmisartan reduced DBP compared with amlodipine in the last 4 h of the dosing interval (assessed using ABPM).5 Telmisartan reduced trough blood pressure measured at home in the morning compared with perindopril.6 Two studies showed that telmisartan reduces early morning blood pressure compared with ramipril.7,8 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. Smith DH, et al. Comparison of telmisartan versus losartan: meta-analysis of titration-to-response studies. Blood Press Monit 2003;8:111–117. 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. Lacourcière Y, et al. Sustained antihypertensive activity of telmisartan compared with valsartan. Blood Press Monit 2004;9:203–210. 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. 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. 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. *P < 0,05; **P < 0.01; ***P < 0,001 † Letzte 4 Stunden vor täglicher Einnahme (ambulante Langezeitmessung) ‡ Messung der Minimalwerte (häusliche Blutdruckmesssungen)

Klinische Wirksamkeit

Faktorenstudie zu Telmisartan + HCTZ
Mittlere systolische Blutdruckveränderungen über 8 Wochen Reported here are selected arms from an 8-week, 4 x 5 factorial, multicentre, double-blind, placebo-controlled, dose-finding study conducted in 818 patients with mild-to-moderate hypertension.1 Patients were randomized to telmisartan 20 mg, 40 mg, 80 mg or 160 mg alone or in combination with HCTZ 6.25 mg, 12.5 mg, or 25 mg, giving a total of 20 treatment groups. SBP was significantly lowered with telmisartan 40 mg/HCTZ 12.5 mg compared with telmisartan 40 mg or HCTZ 12.5 mg monotherapies (P<0.01), and was significantly lowered with telmisartan 80 mg/HCTZ 12.5 mg compared with telmisartan 40/80 mg or HCTZ 12.5 mg monotherapies (P<0.01). McGill JB, Reilly PA. Telmisartan plus hydrochlorothiazide versus telmisartan or hydrochlorothiazide monotherapy in patients with mild to moderate hypertension: a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. Clin Ther 2001;23:833–850. ** T: Telmisartan H: HCTZ ** **P < 0,01 gegenüber äquivalenten Monotherapien McGill, Reilly. Clin Ther 2001;23:833–850

Faktorenstudie zu Telmisartan + HCTZ
Ansprechrate beim systolischen BD† nach 8 Wochen ** ** T: Telmisartan H: HCTZ Reported here are selected arms from an 8-week, 4 x 5 factorial, multicentre, double-blind, placebo-controlled, dose-finding study conducted in 818 patients with mild-to-moderate hypertension.1 Patients were randomized to telmisartan 20 mg, 40 mg, 80 mg or 160 mg alone or in combination with HCTZ 6.25 mg, 12.5 mg, or 25 mg, giving a total of 20 treatment groups. Combination therapy significantly improved the SBP response rate compared with monotherapy (P<0.01). McGill JB, Reilly PA. Telmisartan plus hydrochlorothiazide versus telmisartan or hydrochlorothiazide monotherapy in patients with mild to moderate hypertension: a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. Clin Ther 2001;23:833–850. ** P < 0,01 gegenüber äquivalanten Monotherapien † Anprechen: Systol. BD-Senkung gegenüber Ausgangswert um 10 mmHg McGill, Reilly. Clin Ther 2001;23:833–850

Erhöhtes Ansprechen auf Telmisartan + HCTZ
Weitere BD-Senkungen ohne Monotherapie-Kontrollgruppen† 85 90 95 100 135 140 145 150 SBD ** ** Mittlerer BD (mmHg) Telmisartan 80 mg (n = 230) Telmisartan 80 mg/HCTZ 12,5 mg (n = 235) This was an 8-week study in 491 patients with mild-to-moderate hypertension who were non-responders (DBP 90 mmHg) in an open-label period of telmisartan 80 mg monotherapy.1 Patients were randomized to either continuation of monotherapy or fixed-dose combination with HCTZ 12.5 mg. After 8 weeks, mean DBP changes were -4.9 and -8.0 mmHg in the monotherapy and combination therapy groups, respectively (p<0.01). Mean SBP changes were -7.0 and mmHg in the monotherapy and combination therapy groups, respectively (p<0.01). Most of the relative improvements with combination therapy occurred in the first 4 weeks. By endpoint, blood pressure was normalized (SBP/DBP <140/<90 mmHg) in 41.5% of patients on combination therapy and 26.1% of patients on monotherapy (P<0.05). Lacourcière Y, et al. Efficacy and tolerability of a fixed-dose combination of telmisartan plus hydrochlorothiazide in patients uncontrolled with telmisartan monotherapy. J Hum Hypertens 2001;15:763–770. DBD ** ** 4 8 Wochen ** P < 0,01 gegenüber Monotherapie mit Telmisartan †DBD-Kontrolle (< 90 mmHg nach 8 Wochen Monotherapie) Lacourcière et al. J Hum Hypertens 2001;15:763–770

Telmisartan + HCTZ wirksamer als Losartan + HCTZ
Daten aus zwei unabhängigen Studien Telmisartan 40 mg in combination with HCTZ was superior to losartan 50 mg in combination with HCTZ in two 6-week, prospective, randomized, open-label, blinded endpoint (PROBE) studies.1,2 The studies compared telmisartan 40 mg + HCTZ 12.5 mg, telmisartan 80 mg + HCTZ 12.5 mg and losartan 50 mg + HCTZ 12.5 mg. Both telmisartan groups were also significantly superior to losartan in the mean change from baseline in SBP in the last 6 h of the dosing interval. Neutel JM, et al. Telmisartan 40 or 80 mg/HCT 12.5 mg fixed-dose combinations provide superior BP reductions compared with losartan 50 mg/HCT 12.5 mg fixed-dose combination: an ABPM comparison. Am J Hypertens 2004;17(5 pt 2):118A. Lacourcière Y, et al. Efficacy and tolerability of fixed-dose combinations of telmisartan plus HCTZ compared with losartan plus HCTZ in patients with essential hypertension. Int J Clin Pract 2003;57:273–279. ** * *** *** Losartan 50/HCTZ 12.5 Telmisartan 40/HCTZ 12.5 Telmisartan 80/HCTZ 12.5 *P < 0,01; **P < 0,01; ***P < 0,001 vs. Losartan/HCTZ Neutel et al. Am J Hypertens 2004;17(5 pt 2):118A; Lacourcière et al. Int J Clin Pract 2003;57:273–279

Telmisartan + HCTZ wirksamer als Losartan + HCTZ
Ansprechdaten (2 unabhängige Studien mit festen Dosierungen) *** * Shown here are the combined data from two 6-week, prospective, randomized, open-label, blinded endpoint (PROBE) study comparing telmisartan 40 mg + HCTZ 12.5 mg (n=485), telmisartan 80 mg + HCTZ 12.5 mg (n=356) and losartan 50 mg + HCTZ 12.5 mg (n=489).1 Control/response rates were defined as follows: DBP control = 24-h mean DBP <85 mmHg DBP response = 24-h mean DBP <85 mmHg or reduction from baseline ≥10 mmHg SBP response = 24-h mean SBP <130 mmHg or reduction from baseline ≥10 mmHg There was a trend towards superiority in DBP control, DBP response and SBP response rates with telmisartan/HCTZ, and telmisartan 80 mg/HCTZ produced significantly greater DBP control and SBP response rates than losartan/HCTZ. Data on file. Boehringer Ingelheim, GmbH. *P = 0,016; ***P = 0,0005 gegenüber Losartan/HCTZ Data on file, Boehringer Ingelheim GmbH

Telmisartan + HCTZ 25 mg Valsartan + HCTZ 25 mg
Größere maximale Blutdrucksenkungen The fixed-dose combination of telmisartan 80 mg/HCTZ 25 mg has been compared with valsartan 160 mg/HCTZ 25 mg in an 8-week placebo-controlled study.1 The study recruited 1109 patients with mild-to-moderate hypertension. Telmisartan/HCTZ significantly reduced trough cuff SBP and DBP compared with valsartan/HCTZ. Data on file. Boehringer Ingelheim GmbH. ** ** ** P < 0,01 vs. Valsartan + HCTZ Data on file, Boehringer Ingelheim GmbH

Telmisartan + HCTZ bei systolischer Hypertonie
Wirksamere systolische BD-Senkungen als Amlodipin + HCTZ This study, A comparison of Telmisartan plus HCTZ with amlodipine plus HCTZ in Older patients with predominantly Systolic hypertension (ATHOS) compared telmisartan 40–80 mg + HCTZ 12.5 mg with amlodipine 5–10 mg + HCTZ 12.5 mg.1 On entry, the patients had seated SBP >140 mmHg, seated DBP ≤95 mmHg and 24-h mean ambulatory SBP 125 mmHg. They were elderly (≥60 years old). The primary endpoint, the change from baseline in SBP in the last 6 h of the dosing interval, was not significantly different between the two groups. However, SBP was significantly reduced with telmisartan + HCTZ compared with amlodipine + HCTZ over the 24 h, morning and daytime periods. SBP control rates (24-h mean SBP <140 mmHg) were also significantly greater (p=0.0175) with telmisartan + HCTZ (65.9%) than with amlodipine + HCTZ (58.3%). Data on file. Boehringer Ingelheim, GmbH. *** *** * * P < 0,05 T+H vs. A+H *** P < 0,001 T+H vs. A+H Data on file, Boehringer Ingelheim GmbH

Telmisartan + HCTZ bei älteren Patienten
Telmisartan + HCTZ 12,5 mg senkt den Blutdruck noch stärker. Senkung des SBD/DBD um 10,1/6,6 mmHg Ältere Menschen sprechen auf Telmisartan + HCTZ ähnlich gut an wie jüngere Patienten. In einer Faktorenstudie betrugen die systolischen Blutdrucksenkungen 25,3 bzw. 23,5 mmHg. ATHOS-Studie: Größere Wirksamkeit von Telmisartan + HCTZ als von Amlodipin + HCTZ bei älteren Patienten mit isolierter systolischer Hypertonie. In a study comparing enalapril with telmisartan in the elderly, patients were given HCTZ 12.5–25 mg in addition to study medication if their response was insufficient (trough DBP ≥90 mmHg) after Week 12.1 In patients who received add-on HCTZ to telmisartan, SBP/DBP was significantly reduced. In a factorial study comparing different doses of telmisartan, HCTZ and the combination, the blood pressure response to telmisartan/HCTZ in elderly patients was similar to that in younger patients.2 SBP was reduced by 25.3 mmHg in elderly patients, compared with 23.5 mmHg in younger patients. In the ATHOS trial of elderly patients with ISH, 24-h mean reductions in SBP were greater with telmisartan/HCTZ than with amlodipine/HCTZ.3 Karlberg BE, et al. Efficacy and safety of telmisartan, a selective AT1 receptor antagonist, compared with enalapril in elderly patients with primary hypertension. J Hypertens 1999;17:293–302. Fenton C, et al. Telmisartan/hydrochlorothiazide: in the treatment of essential hypertension. Drugs 2003;63:2013–2026. Data on file, Boehringer Ingelheim, GmBH. Fenton et al. 2003;63:2013–2026; Karlberg et al. J Hypertens 1999;17:293–302; Data on file, Boehringer Ingelheim GmBH

Telmisartan +Temisartan/HCTZ bei Diabetikern
Wirksam als Telmisartan-Monotherapie und in Kombination In a pooled analysis of randomized clinical trials, mean reductions in SBP/DBP were 26.1/12.6 mmHg in diabetic patients treated with telmisartan 80 mg/HCTZ 12.5 mg for a mean of 148 days.1 This compares with mean reductions of 15.9/9.4 mmHg with telmisartan 80 mg monotherapy for a mean of days. Fenton C, et al. Telmisartan/hydrochlorothiazide: in the treatment of essential hypertension. Drugs 2003;63:2013–2026. Fenton et al. 2003;63:2013–2026

Telmisartan + HCTZ bei Afro-Amerikanern
Wirksame Senkung SBD und DBD * ** Because African-American (black) patients may have low plasma renin activity, they can show an especially improved response to ARBs when HCTZ is added. Reported here are the results from 222 African-American patients who took part in an 8-week, 4 x 5 factorial, multicentre, double-blind, placebo-controlled, dose-finding study conducted in patients (total n=818) with mild-to-moderate hypertension.1 Patients were randomized to telmisartan 20 mg, 40 mg, 80 mg or 160 mg alone or in combination with HCTZ 6.25 mg, 12.5 mg, or 25 mg, giving a total of 20 treatment groups. Key arms are shown in this slide. Telmisartan/HCTZ reduced blood pressure compared with HCTZ monotherapy. The magnitude of the response was similar to that observed in the full patient population. McGill JB, Reilly PA. Combination treatment with telmisartan and hydrochlorothiazide in black patients with mild to moderate hypertension. Clin Cardiol 2001;24:66–72. ** *P  0,05 vs. HCTZ 12,5 mg **P  0,01 vs. HCTZ 12,5 mg McGill, Reilly. Clin Cardiol 2001;24:66–72

Telmisartan + HCTZ Zusammenfassung
Telmisartan + HCTZ führt zu noch stärkeren Blutdrucksenkungen (auch bei ungenügendem Ansprechen auf Monotherapie). Stärkere Wirksamkeit bei Afroamerikanern, Senioren und Diabetikern. Telmisartan 80 mg + HCTZ 12,5 mg bewirkt stärkere systolische Blutdrucksenkungen als Losartan 50 mg + HCTZ 12.5 mg. Telmisartan 80 mg + HCTZ 25 mg bewirkt stärkere systolische Maximalsenkungen (Oberarmmanschette) als Valsartan 160 mg + HCTZ 25 mg. Bei Patienten mit systolischer Hypertonie bewirkt Telmisartan 80 mg + HCTZ 12,5 mg im Durchschnitt größere Senkungen des systolischen Blutdrucks über 24 Stunden als Amlodipin 10 mg + HCTZ 12,5 mg.

Effekte bei Zielorganschädigung

Renoprotektiver Effekt von Telmisartan
Telmisartan verbessert Funktionsstörungen des Endothels ** * Erhöhtes Ansprechen des Nierenplasmastroms auf L-NMMA (%) The Telmisartan versus Ramipril in renal ENdothelial DYsfunction (TRENDY) study showed that telmisartan improves endothelial function in the kidneys of patients with type 2 diabetes, good renal function and low or absent microalbuminuria.1 The 96 patients had mild-to-moderate hypertension (seated SBP/DBP 140–180/90–110 mmHg), normo- or microalbuminuria and GFR >80 mL/min/1.73 m2. They received telmisartan 40 mg or ramipril 5 mg for 3 weeks, followed by telmisartan 80 mg or ramipril 10 mg for 6 weeks, with add-on therapy (HCTZ, metoprolol or atenolol) to ensure blood pressure control. Endothelial function was assessed by measuring renal plasma flow in response to the infusion of N(G)-monomethyl-L-arginine acetate (L-NMMA). The percentage change from baseline in endothelial function is shown in this slide. 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. Cancún, México, April 17–21, 2005. * P < 0,05 gegenüber Ausgangswert ** P < 0,001 gegenüber Ausgangswert Schmeider et al. XVIth IASH Meeting, 2005

Verbessert Nierenplasmastrom und reduziert Gefäßwiderstand Nierenplasmastrom Nierengefäßwiderstand Vorher 9. Woche * * ml/min RU 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. Cancún, México, April 17–21, 2005. * P<0.05 vs baseline Schmeider et al. XVIth IASH Meeting, 2005

Reduziert Albuminurie Vorher 9. Woche Albumin-Ausscheidung im Harn (mg/24 h) * 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. Cancún, México, April 17–21, 2005. * P < 0,05 gegenüber Ausgangswert Schmeider et al. XVIth IASH Meeting, 2005

Reduziert Mikroalbuminurie bei Hypertonikern ** Redón 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. ** ** P < 0,01 gegenüber Ausgangswert Redón et al. Pharmacogenomics J 2005;5:14–20

Weiterer Albuminurie-Rückgang in Kombination mit ACE-Hemmer Ucak et al. conducted an open-label study comparing lisinopril 20 mg as monotherapy and in combination with telmisartan 80 mg in 100 type 2 diabetics with microalbuminuria (30–300 mg/24 h) who had been receiving ACE inhibitors for at least 6 months previously.1 At baseline, albuminuria was 264 mg/24 h in the lisinopril group and 256 mg/24 h in the combination therapy group. After 12 months, albuminuria had decreased to 186 mg/24 h with lisinopril and 144 mg/24 h with combination therapy (P<0.001). Both treatment arms had a similar decrease in blood pressure (SBP/DBP decreased by 1/2 and 1/4 mmHg in the lisinopril monotherapy and lisinopril/telmisartan combination therapy, respectively). Ucak S, et al. Combination of telmisartan and ACE-I significantly reduces urinary albumin excretion in hypertensive patients with type 2 diabetes. Program and abstracts of the 38th Annual Meeting of the European Association for the Study of Diabetes Budapest, Hungary: September 1–5, 2002. *** Zusätzlicher Rückgang von durchschnittlich 44 % *** P < 0,001 gegenüber Monotherapie mit Lisinopril Ucak et al. EASD, 2002

Rückgang der glomerulären Filtrationsrate GFR gesamt GFR Veränderungen p= n.s.† ml/min/1,73 m2 ml/min/1,73 m2 The Diabetics Exposed to Telmisartan And enalaprIL (DETAIL) study assessed the decline in renal function over 5 years in 250 patients with type 2 diabetes, mild-to-moderate hypertension, and GFR that was either normal or only mildly impaired.1 It employed a 1-month run-in period, followed by up-titration over a period of 1 month to either telmisartan 80 mg or enalapril 20 mg. Add-on antihypertensive therapy (- or -blocker, CCB, diuretic) was allowed after 2 months of double-blind treatment if seated DBP was >100 mmHg or SBP was >160 mmHg. There were no significant differences in GFR at 5 years, or in the change in GFR over 5 years. At endpoint, the difference (telmisartan minus enalapril) in GFR was –3.0 ml/min/1.73 m2, with 95% confidence interval –7.6 to +1.6. Telmisartan was comparable to enalapril (i.e. met the statistical test for non-inferiority), since the 95% confidence interval of the difference was <–10 mL/min/1.73 m2. 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. p = n.s.* Vorher Nach 5 Jahren * P = n.s. (Telmisartan versus Enalapril) Barnett et al. N Engl J Med 2004;351:1952–1961

Reduziert langfristig den Rückgang der GFR Veränderungen der GFR (ml/min/1,73 m2) In DETAIL, the steepest decline in GFR was seen in the first year.1 This was probably a haemodynamic effect, associated with the lowering of systemic blood pressure that results in reduced intraglomerular pressure.2 Thereafter, the rate of decline was markedly reduced with a consistent, year-on-year effect. The mean decline in GFR of patients in the telmisartan group was 3.7 ml/min/1.73 m2/year in those who completed the study, and 3.6 ml/min/1.73 m2/year in the LOCF dataset. In the enalapril group, the mean rate of GFR decline was 3.3 ml/min/1.73 m2/year in those who completed the study, and 3.1 ml/min/1.73 m2/year in the last observation carried forward dataset. 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. Levey AS, et al. Short-term effects of protein intake, blood pressure, and antihypertensive therapy on glomerular filtration rate in the Modification of Diet in Renal Disease Study. J Am Soc Nephrol 1996;7:2097–2109. Barnett et al. N Engl J Med 2004;351:1952–1961

GFR (ml/min/1,73 m2) If diabetic nephropathy is left untreated, GFR declines steadily by 10–12 ml/min/1.73 m2/year.1 In DETAIL, GFR declined over 5 years by 17.9 ml/min/1.73m2 in the LOCF dataset and 18.7 ml/min/1.73 m2 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. Übergang zu terminaler Niereninsuffizienz Barnett et al. N Engl J Med 2004;1952–1961 Parving et al. Semin Nephrol 2004;24:147–151

Behandlungsdauer mit Telmisartan 40–80 mg (Monate)
Telmisartan bei LVH Kontinuierliche Abnahme des linksventrikulären Masseindex 125 120 115 LVMI (g/m2) 110 ** 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<0.001) and mean DBP from 104 mmHg to 86 mmHg (p<0.001). There was a concomitant decrease in LVMI, from 121 ± 7 g/m2 at baseline to 109 ± 3 g/m2 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. 105 3 6 12 Behandlungsdauer mit Telmisartan 40–80 mg (Monate) ** P < 0,01 versus Ausgangswert Mattioli et al. Int J Cardiol 2004;97:383–388

Telmisartan bei LVH Reduktion der LVH im Vergleich zu HCTZ 145 140 135
Vorher Nach 12 Monaten 140 135 LVMI (g/m2) 130 ** 125 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/m2 decrease in LVMI (from 141 ± 16 g/m2 to 125 ± 19 g/m2; p<0.02) in the telmisartan treatment group. However, the 4 g/m2 reduction in LVMI (from 139 ± 20 g/m2 to 135 ± 22 g/m2) 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;18:53–59. 120 Telmisartan 80 mg (n=40) HCTZ 25 mg (n=25) ** p < 0,01 gegenüber Ausgangswert Galzerano et al. J Hum Hypertens 2004;18:53–59

Rückgänge des linksventrikulären Masseindex (LVMI, g/m2)
Telmisartan bei LVH Größere LVH-Rückgänge als mit Carvedilol Rückgänge des linksventrikulären Masseindex (LVMI, g/m2) 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 *** *** P < 0,0001 gegenüber Carvedilol Galzerano et al. 53rd ACC, 2004, New Orleans, USA

Behandlungsmonate mit Telmisartan 40–80 mg
Telmisartan bei LVH Verbessert diastolische Funktion* 1.0 P < 0,05 0.9 0.8 P < 0,05 Verbesserung der LV-Funktion DFV* 0.7 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. 0.6 3 6 12 Behandlungsmonate mit Telmisartan 40–80 mg *Diastolisches Füllungsverhältnis (früh:atrial) Mattioli et al. Int J Cardiol 2004;97:383–388

Telmisartan verbessert Elastizität der Arterien
Impulswellen-Verlangsamung bei Hypertonikern mit Typ-2-Diabetes * Arterial stiffness is an independent risk factor for cardiovascular mortality.1 Pulse wave velocity increases as vascular stiffness increases, and can cause increased SBP. In this study, 28 patients with type 2 diabetes and mild-to-moderate hypertension were given placebo or telmisartan 40 mg for 3 weeks in a cross-over design with 2-week placebo wash-out.2 Telmisartan significantly reduced pulse wave velocity along the carotid-femoral route, with improvements along the carotid-radial route approaching significance. Laurent S, et al. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 2001;37:1236–1241. Asmar R, et al. Effects of telmisartan on arterial stiffness in Type 2 diabetes patients with essential hypertension. J Renin Angiotensin Aldosterone Syst 2002;3:176–180. Placebo Telmisartan 40 mg * P ≤ 0,05 gegenüber Placebo Asmar et al. J Renin Angiotensin Aldosterone Syst 2002;3:176–180

Telmisartan verbessert Elastizität der Arterien
Impulswellen-Verlangsamung bei Hypertonikern ** Impulswellen-Geschwindigkeit (cm/s) In this study, 24 patients with hypertension received telmisartan 40 mg/day for 3 months.1 Brachial-ankle pulse wave velocity (ba-PWV) was significantly reduced. Office blood pressure was also reduced. However, the improvement in ba-PWV was greater than predicted on the basis of blood pressure changes. Uchida H, et al. Practical efficacy of telmisartan for decreasing morning home blood pressure and pulse wave velocity in patients with mild-to-moderate hypertension. Hypertens Res 2004;27:545–550. ** P < 0,01 gegenüber Ausgangswert Uchida et al. Hypertens Res 2004;27:545–550

Effekte bei Zielorganschädigung Zusammenfassung
Verbessert die Funktion des Nierenendothels wie auch den Nierenplasmastrom und reduziert den Gefäßwiderstand in der Niere wirksamer als Ramipril. Reduziert Albuminurie (weitergehende Effekte als bei ACE- Hemmern). Verlangsamt die GFR-Rückgänge bei Typ-2-Diabetes. Bewirkt stärkere Rückgänge der linksventrikulären Hypertrophie als HCTZ und Carvedilol. Die Effekte gehen über die Blutdrucksenkung hinaus. Verbessert die Elastizität der Arterien

Verträglichkeit

Verträglichkeit von Telmisartan ähnlich gut wie bei Placebo
* 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. * P < 0,05 vs. Placebo Data on file, Boehringer Ingelheim GmbH

Gute Verträglichkeit von Telmisartan
Urteil der meisten Patienten = Verträglichkeit gut bis sehr gut A German post-marketing surveillance study followed 19,870 patients treated with telmisartan for 6 months.1 Data were not available for 2% of patients. Of the rest, 98.8% gave a global rating of tolerability of good or very good. Adverse events were reported by 1.9% of patients, the most frequent being headache (0.3%), dizziness (0.2%) and nausea (0.2%). Age, gender and comorbidities had no effect on global tolerability. Michel MC, et al. Safety of telmisartan in patients with arterial hypertension. An open-label observational study. Drug Saf 2004;27:335–344. Michel et al. Drug Saf 2004;27:335–344

Verträglichkeit von Telmisartan + HCTZ ähnlich wie bei Placebo
Geringe Häufigkeit von unerwünschten Ereignissen Safety data were collected from 34 multicentre randomized studies, the majority of which were double-blind, which recruited 6,915 patients.1 Patients received placebo, telmisartan 10–160 mg, or telmisartan 10–160 mg + HCTZ 6.25–25 mg for a minimum of 7 days and up to >2 years. 819 patients were treated with placebo, 6575 treated with telmisartan, and 2180 patients were treated with telmisartan + HCTZ. When calculated according to exposure to study drug, treatment-related adverse events were low with both telmisartan monotherapy and combination therapy. The incidence of adverse events were similar in younger (< 65 years) and elderly (≥ 65 years) patients. Mancia G. Tolerability and safety of telmisartan as monotherapy or combined with hydrochlorothiazide compared with placebo. Am J Hypertens 2002;15 (Supp 1):A54. Mancia. Am J Hypertens 2002;15 (Supp 1):A54

Verträglichkeitsprofil
Zusammenfassung Ähnliche Häufigkeit von unerwünschten Ereignissen wie bei Placebo (laut klinischen Studien) Unerwünschte Ereignisse traten dosisunabhängig auf und zeigten keinen Zusammenhang mit Geschlcht, Alter oder Rasse. In Pharmakovigilanz-Studien wurden 19,870 Patienten 6 Monate lang nachbeobachtet. 98,8 % dieser Patienten bewerteten die Verträglichkeit als gut bis sehr gut. Telmisartan SPC Michel et al. Drug Saf 2004;27:335–344

Besseres Verträglichkeitsprofil als ACE-Hemmer
Weniger Husten als bei Behandlung mit Lisinopril * In this study, 578 patients with mild-to-moderate hypertension received telmisartan 40–160 mg or lisinopril 10–40 mg once daily for 52 weeks.1 At the end of the maintenance period, mean SBP/ DBP reductions were 23.8/16.6 mmHg and 19.9/15.6 mmHg in the telmisartan and lisinopril arms, respectively. Treatment-related side effects occurred in fewer telmisartan-treated patients (28%) than in lisinopril-treated patients (40%, P=0.001), principally due to an increase in cough with lisinopril. There were also two cases of angioedema, both in the lisinopril group. Similar results were seen in an 8-week comparison of telmisartan with enalapril in 86 patients with severe hypertension.2 No patients on telmisartan experienced cough during this study, compared with 7% of patients on enalapril. Neutel JM, Frishman WH, Oparil S, et al. Comparison of telmisartan with lisinopril in patients with mild-to-moderate hypertension. Am J Therapeutics 1999;6:161–166. Neutel JM, Smith DHG, Reilly PA. The efficacy and safety of telmisartan compared to enalapril in patients with severe hypertension. Int J Clin Pract 1999;53:175–178. ** * P < 0,05 gegenüber Lisinopril ** P < 0,01 gegenüber Lisinopril Neutel et al. Am J Therapeutics 1999;6:161–166

Besseres Verträglichkeitsprofil als Amlodipin
Weniger periphere Ödeme als bei Behandlung mit Amlodipin *** This study, A comparison of Telmisartan plus HCTZ with amlodipine plus HCTZ in Older patients with predominantly Systolic hypertension (ATHOS), compared telmisartan 40–80 mg + HCTZ 12.5 mg and amlodipine 5–10 mg + HCTZ 12.5 mg.1 There were more adverse events in the amlodipine group than in the telmisartan group. The most frequently reported adverse event was peripheral oedema, reported in 6 (1.2%) patients taking telmisartan + HCTZ, compared with 122 (24.3%) patients taking amlodipine + HCTZ. This led to a higher overall discontinuation rate from adverse events in the amlodipine group compared with the telmisartan group. Data on file. Boehringer Ingelheim, GmbH. *** *** *** P < 0,0001 gegenüber Amlodipin + HCTZ Data on file, Boehringer Ingelheim GmbH

Reduziert die hypokaliämischen Einflüsse von HCTZ
Thiazide therapy can cause hypokalaemia, which can, potentially, trigger adverse cardiac events.1,2 Reported here are selected arms from an 8-week, 4 x 5 factorial, multicentre, double-blind, placebo-controlled, dose-finding study conducted in 818 patients with mild-to-moderate hypertension.3 Patients were randomized to telmisartan 20 mg, 40 mg, 80 mg or 160 mg alone or in combination with HCTZ 6.25 mg, 12.5 mg, or 25 mg, giving a total of 20 treatment groups. HCTZ caused a dose-related decrease in serum potassium. Combination with telmisartan tended to offset the effects of HCTZ on serum potassium levels. Beermann B, Groschinsky-Grind M. Pharmacokinetics of hydrochlorothiazide in man. Eur J Clin Pharmacol 1977;12:297–303. Siscovick D, et al. Diuretic therapy for hypertension and the risk of primary cardiac arrest. N Engl J Med 1994;330:1852–1857. McGill JB, Reilly PA. Telmisartan plus hydrochlorothiazide versus telmisartan or hydrochlorothiazide monotherapy in patients with mild to moderate hypertension: a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. Clin Ther 2001;23:833–850. T: Telmisartan H: HCTZ McGill, Reilly. Clin Ther 2001;23:833–850

Verträglichkeit Zusammenfassung
Placeboähnliches Verträglichkeitsprofil als Monotherapie oder in Kombination mit HCTZ Keine signifikante Zunahme von Husten wie bei ACE-Hemmern Keine signifikante Zunahme bei peripheren Ödemen wie bei Ca- Kanalblockern Verringerung des hypokaliämischen Effekts von HCTZ

Laufende Studien

10 klinische Studien zu > 6500 Patienten aus 32 Staaten
Programme of Research tO show Telmisartan End-organ proteCTION 10 klinische Studien zu > 6500 Patienten aus 32 Staaten Morgendlicher Blutdruckanstieg Telmisartan vs. Ramipril Funktionsstörung des Nierenendothels Telmisartan vs. Ramipril Morgendlicher Blutdruckanstieg Telmisartan + HCTZ vs. Losartan + HCTZ Diabetische Nephropathie Telmisartan vs. Placebo Diabetische Nephropathie Telmisartan vs. Enalapril The PROTECTION Programme1 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. Systol. Hypertonie/ ältere Hypertoniker Telmisartan + HCTZ vs. Amlodipine + HCTZ Diabetische Nephropathie Telmisartan vs. Losartan Diabetes + Übergewicht Telmisartan + HCTZ vs. Valsartan + HCTZ Diabetische Nephropathie Telmisartan vs. Valsartan

Prevention Regimen For Effectively avoiding Second Strokes
15000 Patienten kurz nach ischämischen Schlaganfällen 32 Staaten, 600 Zentren Weltweit größte Studie zur Verhinderung von Schlaganfällen Ausgewertete Hauptkriterien: Telmisartan + standardmäßige antithrombozytäre Behandlung versus antithrombozytäre Behandlung als Monotherapie ER-DP + ASA im Vergleich zu Clopidogrel Behandlungsdauer: bis zu 4 Jahre Primäres Zielkriterium: Dauer bis zum zweiten Schlaganfall (Ziel: 2280 Schlaganfälle) The PRoFESS® study is a randomized, controlled, double-blind study featuring an innovative 2 x 2 factorial design.1 There will be four treatment groups, each enrolling a planned 3875 patients. Each of the primary comparisons will compare patient populations of 7750 patients. The 2 x 2 factorial design provides high power to detect primary end-points. Telmisartan vs placebo. ER-DP + ASA versus clopidogrel. The inclusion criteria are: Ischaemic stroke within 90 days prior to study entry Neurologically and clinically stable Age >55 y Secondary outcomes are: Vascular events (composite of time to first stroke, myocardial infarction, or vascular death) Vascular events or congestive heart failure New onset diabetes The PRoFESS Collaborative Group. Presented at the 30th International Stroke Conference, 2–4 February 2005, New Orleans, Louisiana, USA. The PRoFESS Collaborative Group. Presented at the 30th ISC, New Orleans, USA. 2005

Größte Studie zu kardiovaskulären Schutzeffekten von AT1R
patients (Alter: 55 years) über 5,5 Jahre Vergleich zwischen Telmisartan, Ramipril u. Kombinationstherapie Die parallele TRANSCEND-Studie vergleicht Telmisartan mit Placebo bei Patienten mit Unverträglichkeit gegen ACE-Hemmer. Kardiovaskuläre Hochrisikopatienten mit vorangegangener koronararterieller Erkrankung peripherer Gefäßerkrankung Schlaganfall oder kurz zurückliegender ischämischer Insult Diabetes mellitus (Typ 1 oder 2) mit Zielorganschädigung Primäres Zielkriterium: Kombination aus kardiovaskulärem Tod, Schlaganfall, akutem Myokardinfarkt und Hospitalisierung wegen dekompensierter Rechtsherzinsuffizienz. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) Programme is one of the largest cardiovascular protection trials ever undertaken.1,2 ONTARGET will compare telmisartan, ramipril and the combination over a study period of 5.5 years. The parallel Telmisartan Randomized AssessmeNt Study in ACE inhibitor-iNtolerant subjects with cardiovascular Disease (TRANSCEND) will compare telmisartan with placebo in patients intolerant of ACE inhibitors, and has the same endpoints. Patients enrolled are aged 55 years and are at high risk of cardiovascular events (i.e., they have a history of coronary artery disease, peripheral vascular disease, stroke or recent ischaemic attack, or diabetes mellitus type 1 or 2 with target-organ damage). ONTARGET will incorporate a number of endpoints, including cardiovascular mortality and morbidity, new cases of diabetes, nephropathy and cognitive decline. Zimmerman M, Unger T. Challenges in improving prognosis and therapy: the Ongoing Telmisartan Alone and in Combination with Ramipril Global End point Trial Programme. Exp Opin Pharmacother 2004;5:1201–1208. The ONTARGET/TRANSCEND Investigators. Rationale, design and baseline characteristics of two, large, simple, randomized trials evaluating telmisartan, ramipril and their combination in high-risk patients: the ONTARGET/TRANSCEND trials. Am Heart J 2004;148:52–61. Zimmerman, Unger. Expert Opin Pharmacother 2004;5:1201–1208 The ONTARGET/TRANSCEND Investigators. Am Heart J 2004;148:52–61

Telmisartan Von zu Neubildung Ventrikuläre Erweiterung/
Kognitive Störungen Stauungsinsuffizienz/ erneuter Schlaganfall Myokardinfarkt und Schlaganfall Makro- proteinurie Mikro- albuminurie This slide illustrates the cardiovascular continuum.1 Factors such as hypertension can trigger atherosclerosis and LVH.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 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 The studies of the PROTECTION Programme, along with the PRoFESS study and The ONTARGET Programme, are investigating the effects of telmisartan at many stages of this continuum. 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. Nephrotische Proteinurie Terminale Herzerkrankung/ Hirnschaden und Demenz Atherosklerose und LVH Endotheliale Funktionsstörung Terminale Nieren-insuffizienz Risikofaktoren Diabetes Hypertonie Kardio-/zerebro- vaskulärer Tod Adapted from Dzau, Braunwald. Am Heart J 1991;121:1244–1263

Zusammenfassung Die laufende Telmisartan-Studie umfasst über Patienten. Das PROTECTION-Programm umfasst 10 Studien zu Telmisarten mit AT1- Rezeptorblockern, ACE-Hemmern und Ca-Kanalblockern (Patienten mit erhöhtem Risiko einer Zielorganschädigung oder mit Nierenerkrankung). In der PROFESS-Studie wird Telmisartan bei antithrombozytär behandelten Schlaganfallpatienten mit einem Placebo (und anderen Antihypertensiva außer AT1-Rezeptorblockern oder ACE-Hemmern) verglichen. In ONTARGET/TRANSCEND werden bei kardiovaskulären Hochrisikopatienten (Hyper- und Normotoniker) Telmisartan und Ramipril als Monotherapie und in Kombination erprobt. Das Studienprogramm wird umfassend zeigen, wie Telmisartan auf das kardiovaskuläre Kontinuum Einfluß nimmt.

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