3. Insights
The things most hypertensives fear
• Heart attack
• Stroke
• Quality of life issues
• Impotence
4. Understanding
What doctors think while treating BP
• Getting the patients down to their BP targets
• Keeping BP on target
• Protect target organs from damage
• Preventing heart attacks
• Preventing strokes
• Step care approach
6. Observations
Key factor to ensuring compliance in BP
therapy
• Once daily dosing
• Favourable side effect profile
• Efficacy
• The security of round the clock BP control
• Protecting target organs
• Is it economical?
10. The sartan of today
Telmisartan CH3
CH3
N
N N
N O OH
CH3
Telmisartan
Let us now understand what sets Telmisartan
apart?
To know this, let us start at the clinical triggers
of cardiac events.
11. Blood pressure at early morning
Awaking Blood pressure
phase profile over 24 hours
180
Sleep
Blood pressure (mm Hg)
160
140
120
100
80
18:00 22:00 02:00 06:00 10:00 14:00 18:00
Time of the day Millar-Craig et al. Lancet 1978;1(8068):795–797
Mancia et al. Circ Res 1983;53:96–104
12. Events at early morning
Early morning rise in
180 BP 50
Stroke (n=1167)
Cerebrovascular incidents (every 2 hours.)
160 Myocardial infarction (n=2999) 45
Myocardial infarction (per hour.)
140 40
35
120
30
100
25
80
20
60
15
40 10
20 5
0 0
18:00 0:00 6:00 12:00
Increased Cardiovascular risks Time of day
Muller et al. N Engl J Med 1985;313:1315–1322
Marler et al. Stroke 1989;20:473–476
19. Hypertensive Damage to end
organs and clinical events
Endothelial dysfunction [ED] is the early
manifestation of impending end organ
damage and promotes various
cardiovascular ilnesses such as -
Atherosclerosis, Hypertension und Heart
Failure.
Early morning rise in BP can contribute to
the damage of end organs on account of the
raised haemodynamic load.
20. Hypertensive Damage to end
organs
Risk factors: Diabetes, Overweight, Smoking, Age
Arrhythmia
Apoptosis
Heart failure
LVH
Myocardial
Fibrosis
infarction
Vasoconstriction Hypertension
Vascular Hypertrophy Thrombosis
Disturbed Endothelial function Mortality
Stroke
Atherosclerosis Vascular
Cognitive
disorders
disturbances
Decline in GFR
Proteinuria/Albuminuria Renal failure
Glomerular sclerosis
21. More than one benefit
Telmisartan can be given with / without food
Antihypertensive activity begins within 3
hours and is maintained for 24 hours.
A maximum reduction in blood pressure is
evident in approximately 4 weeks.
Telmisartan is not eliminated by renal route
In the liver, as CYP isoenzymes are not
involved in metabolism of telmisartan, no
interactions happen with drugs that inhibit or
are metabolized by CYP isoenzymes.
Similar pharmakokinetic parameters in older
(> 65 years) and younger patients.
22. Trough/Peak-Ratio 180
Normal variation
Blood pressure (mmHg)
160
Trough
Antihypertensive A
(T/P-Ratio: .33 %)
140
Peak
120
100
Dosing
07:00 11:00 15:00 19:00 23:00 03:00
07:00
Time of the day
* Relation between minimum values and maximum values
Ellioit, Meredith. J Hypertension 1995;13:279–
23. Trough/Peak-Ratio 180
Normal variation
Blood pressure (mmHg)
160
Trough
Antihypertensive B
(T/P-Ratio: o.66 %)
140
Peak
120
100
Dosing
07:00 11:00 15:00 19:00 23:00 03:00
07:00
Time of the day
* Relation between minimum values and maximum values
Ellioit, Meredith. J Hypertension 1995;13:279–
24. Understanding TP ratio
Trough/Peak-Ratio ( Relation between
effect of minimum effect and the maximum
effect possible ) is preferred higher
► Trough/Peak-Ratio of A: 20 / 60
► Trough/Peak-Ratio of B: 20 / 30
► Which is better?
► Telmisartan has a very high TP ratio.
25. Telmisartan: the uniqueness
Convergence of reasons
Half life
• • • • • • • •
Distribution volumes
PPAR activity
TP ratio
Telride EMBPR
Dosage modification
Drug interactions
Safe in renal cases
26. Telmisartan: the summary
Longer half life
EMBPS Better
effectively distribution
blunted
Free from
drug Activates
interactions PPAR-gamma
No modification
Trough-Peak
of dosage
ratio
Beevers et al. BMJ 2001;322:912–916
Low renal excretion
27. Telmisartan: the indications
First line antihypertensive
Combination Type 2 diabetic
therapy nephropathy
Primary stroke
Diabetic
prevention
microalbuminuria
Intolerance to ACE
Proteinuria
inhibitors - cough
Beevers et al. BMJ 2001;322:912–916
Left ventricular ESH–ESC Guidelines. J Hypertens
hypertrophy 2003;21:1011–1053
29. Programme of Research tO show Telmisartan End-organ proteCTION
10 clinical Studies in > 6500 Patients from 32 countries
EMBPS Dysfunction of the renal endothelium
Telmisartan vs. Ramipril Telmisartan vs. Ramipril
Morning surge in BP Diabetic Nephropathy
Telmisartan + HCTZ Telmisartan vs. Placebo
vs. Losartan + HCTZ
Diabetic Nephropathy
Systolic Hypertension/ Telmisartan vs. Enalapril
elderly hypetensives
Telmisartan + HCTZ
vs. Amlodipine + HCTZ Diabetic Nephropathy
Telmisartan vs. Losartan
Diabetes + Overweight
Telmisartan + HCTZ Diabetic Nephropathy
vs. Valsartan + HCTZ Telmisartan vs. Valsartan
30. Telmisartan: the comparison
studies Losartan
Valsartan
Ramipril
Telmisartan
Perindopril
Comparison
Enalapril
with
Nifedipine
Amlodipine
Combinations
Beevers et al. BMJ 2001;322:912–916
33. Telmisartan: the comparison
studies Losartan
Valsartan
Ramipril
Telmisartan
Perindopril
Comparison
Enalapril
with
Nifedipine
Amlodipine
Combinations
Beevers et al. BMJ 2001;322:912–916
34. Telmisartan vs. Losartan - last 6 hrs
Mallion et al. (1999) Ding et al. (2004)
Diast. BP compared with initial value(mmHg)
0 0
-1 -2
-2
-4
-3
-6
-4
-8
-5
-10
-6
-7 -12
* *
-8 Losartan 50 mg -14
Telmisartan 40 mg
* P < 0,05 for Losartan Mallion et al .J Hum Hypertens 1999;13:657–664
Ding et al. Int J Clin Pract Suppl 2004;58:16–22
35. Telmisartan vs. Losartan - 24-hour
mean ABPM reduction
Diastol. BP compared with initial value (mmHg)
Mallion et al. (1999) Ding et al. (2004)
0 0
-1
-2
-2
-4
-3
-4 -6
-5
-8
-6 *
-10
-7
-8 * Losartan 50 mg -12 *
Telmisartan 40 mg
* P < 0,05 for Losartan Mallion et al .J Hum Hypertens 1999;13:657–664
Ding et al. Int J Clin Pract Suppl 2004;58:16–22
36. Telmisartan vs. Losartan -Systolic reduction
Systol. BP relative to the initial values (mmHg)
Lee et al. (2004) Zhu et al. (2004)
0 0
-2
-5
-4
-10 -6
-8
-15
-10
-20
-12
* *
-25 Losartan 50–100 mg -14
Telmisartan 40–80 mg
* P < 0,05 for Losartan Lee et al. Int J Clin Pract Suppl 2004;58:40–45
Zhu et al. Int J Clin Pract Suppl 2004;58:46–49
37. Telmisartan versus Losartan
over time Hourly course after dosing
Diast. BP relative to the initial values
0
2 4 6 8 10 12 14 16 18 20 22 24
-1
Losartan 50–100 mg
-2 Telmisartan 40–80 mg
P ≤ 0,01
(mmHg)
-3 Telmisartan vs. Losartan
-4
-5
-6
-7
-8
-9
Meta-analysis from 2 Studies (Titrated for similar response)
Smith et al. Blood Press Monit 2003;8:111–117
38. Telmisartan: the comparison
studies Losartan
Valsartan
Ramipril
Telmisartan
Perindopril
Comparison
with Enalapril
Nifedipine
Amlodipine
Combinations
Beevers et al. BMJ 2001;322:912–916
39. Telmisartan vs. Valsartan - last 6 hours
BP compared with initial value in the last 6 hrs
SBD DBD
0
before repeat dosing (mmHg)
-2
-4
-6
**
-8
-10 Valsartan 160 mg
*
Telmisartan 80 mg
-12
The MICADO-II-Study
* P = 0,02 versus Valsartan White et al. Am J Hypertens 2004;17:347–353
** P = 0,01 versus Valsartan
40. Telmisartan vs. Valsartan - after
dosing titration coursesimilar response
Hourly
for after dosing
Systol. BP relative to the initial values
2 4 6 8 10 12 14 16 18 20 22 24
0
Valsartan 160 mg
-2 Telmisartan 80 mg
-4
(mmHg)
-6
-8
-10
-12
-14
P = 0,02
-16 Telmisartan vs. Valsartan
The MICADO-II-Study
White et al. Am J Hypertens 2004;17:347–353
41. Telmisartan: the comparison
studies Losartan
Valsartan
Ramipril
Telmisartan
Perindopril
Comparison
with Enalapril
Nifedipine
Amlodipine
Combinations
Beevers et al. BMJ 2001;322:912–916
42. Telmisartan vs. Ramipril - last 6 hrs
Diastol. BP relative to the initial values (mmHg)
SBD DBD SBD DBD
0 0
-2 -2
-4 -4
-6 -6
-8 -8
*** ***
-10 -10
-12 -12
*** ***
-14 PRISMA I -14 PRISMA II
Ramipril 10 mg
Telmisartan 80 mg
* P < 0,0001 vs. Ramipril Williams et al. Hypertension 2004;44;576
Lacourcière et al. Hypertension 2004;44:576
43. Telmisartan vs. Ramipril - over time
Hourly course after dosing
2 4 6 8 10 12 14 16 18 20 22 24
0
BP relative to the initial values
Telmisartan 80 mg
-2 Ramipril 10 mg
-4
(mmHg)
-6
*
-8
-10
-12
-14
Data from the PRISMA-II-Study
* P < 0,0001 for Telmisartan versus Lacourcière et al. Hypertension 2004;44:576
Ramipril over 24 hours.
44. Telmisartan reduces EMBPS EMBPS
Changes in patients with
Definition
EMBPS ≥ 35 mmHg
105 Early morning average (EMA) 0
Morning BP (Diastolic BP mmHg)
100 -2
Diastol. BP (mmHg)
On -4
95
awakening
EMBPS = EMA – NL -6
90
-8
85 -10
*** P = 0,0001
for Ramipril
80 Night low (NL) -12
***
-14 Ramipril 10 mg
75
0 6 12 18 23 Telmisartan 80 mg
Hour of the day
In comparison to ramipril, Telmisartan is
more effective on EMBPS.
45. Telmisartan: the comparison
studies Losartan
Valsartan
Ramipril
Telmisartan
Perindopril
Comparison
with Enalapril
Nifedipine
Amlodipine
Combinations
Beevers et al. BMJ 2001;322:912–916
46. Telmisartan versus Perindopril
SBD DBD
0
Clinical BP lowering compared with initial
-2
-4
value(mmHg)
-6 *
-8
-10 Perindopril 4–8 mg
** Telmisartan 40–80 mg
-12
-14
* P < 0,01 vs. Perindopril Ragot et al. J Hum Hypertens 2002;16:865–873
** P < 0,005 vs. Perindopril
47. Telmisartan: the comparison
studies Losartan
Valsartan
Ramipril
Telmisartan
Perindopril
Comparison
Enalapril
with
Nifedipine
Amlodipine
Combinations
Beevers et al. BMJ 2001;322:912–916
48. Telmisartan versus EnalaprilSBD DBD
2
comparison to initial values (mm Hg)
0
**Trough** BP reduction in
-2
-4
-6
-8
-10
**
Placebo
-12
* Enalapril 20 mg
Telmisartan 40 mg
-14
Telmisartan 80 mg
* P = 0,03 vs. Enalapril Smith et al. Adv Ther 1998;15:229–240
** P = 0,01 vs. Enalapril
49. Telmisartan: the comparison
studies Losartan
Valsartan
Ramipril
Telmisartan
Perindopril
Comparison
with Enalapril
Nifedipine
Amlodipine
Combinations
Beevers et al. BMJ 2001;322:912–916
50. Telmisartan vs. Amlodipine - EMBPS
SBD DBD
BP reduction in comparison to initial values
0
-2
-4
-6
(mmHg)
-8
-10
*
-12
-14
-16 Amlodipine 5–10 mg
Telmisartan 40–120 mg
-18
-20
* P = 0,05 versus Amlodipine Lacourcière et al. Blood Press Monit 1998;3:295–302
51. Telmisartan versus Amlodipine
120
Diastol. BP versus initial values
100
(mmHg)
80
Placebo
Telmisartan (40–120 mg)
60 Amlodipine (5–10 mg)
P < 0,05
Telmisartan vs.
Amlodipine
0
Time of
08:00 12:00 16:00 20:00 24:00 04:00 08:00
the day
P < 0,05 Telmisartan vs. Amlodipine Lacourcière et al. Blood Press Monit 1998;3:295-302
52. Efficacy in terminal renal
states / Haemodialysis
DBD SBD
Changes in comparison to the initial values
0
-5
-10 *
(mmHg)
-15 *P < 0,05 vs. Losartan
-20
-25
Losartan 100 mg/day
-30 *
Telmisartan 80 mg/day
-35
Cice et al. XLI ERA. 2004
53. Summary of comparison trials
Prevention of EMBPS is an important beginning
point for prevention of cardiovascular mortality.
Qualities of Telmisartan:
• Effective lowering of EMBPS (the largest data on long
time ambulatory BP measurements in literature).
• More effective BP lowering during the last hours
before the next dose in comparison to Valsartan,
Losartan, Ramipril, Perindopril and Amlodipine.
• Early morning BP reduction especially in patients on
typical antihypertensive therapy who show EMBPS (in
comparison to Ramipril).
• Good efficacy and compatibility in patients with
Nephropathy (including dialysis patients).
56. Renoprotective Effect of
Telmisartan 14
Reduces Albuminuria
12
Albumin-excretion in the urine
earlier 9. weeks
10
*
8
6
4
2
0
Ramipril Telmisartan
* P < 0,05 for initial values Schmeider et al. XVIth IASH Meeting, 2005
57. Renoprotective Effect of
Telmisartan Reduced Microalbuminuria in
Hypertensives
35
30
Albuminuria (mg/24 h)
25
**
20
15 **
10
5
0
initial value 3 Months 12 Months
** P < 0,01 for initial values Redón et al. Pharmacogenomics J 2005;5:14–20
58. Renoprotective Effects of
Telmisartan
100
GFR (ml/min/1,73 m2)
90
80
70
60
50 No treatment
40 Telmisartan
30
20
10 Progress to renal insufficiency
0
0 1 2 3 4 5
Years
Barnett et al. N Engl J Med 2004;1952–1961
Parving et al. Semin Nephrol 2004;24:147–151
59. Telmisartan in LVH Continuous decrease of the Left
Ventricle mass index
125
120
LVMI (g/m2)
115
110 **
105
Treatment with Telmisartan
0 40–80 mg (Monthly)
0 3 6 12
** P < 0,01 for initial value Mattioli et al. Int J Cardiol 2004;97:383–388
60. Telmisartan in LVH Greater reduction of LVH
in comparison to HCTZ
145 initial after 12 Months
140
135
LVMI (g/m2)
130
*
125
*
120
0
Telmisartan 80 mg HCTZ 25 mg
(n=40) (n=25)
** p < 0,01 for initial values Galzerano et al. J Hum Hypertens 2004;18:53–59
61. Telmisartan in LVH Greater reduction than carvedilol
Carvedilol Telmisartan
0
Decline of the Left Ventricle mass
-5
index(LVMI, g/m2)
-10
-15
-20
***
-25
*** P < 0,0001 for Carvedilol
Galzerano et al. 53rd ACC, 2004, New Orleans, USA. 2004.
62. Telmisartan in LVH
Improvement of the LV-Function
Improved diastolic Function*
1.0
P < 0,05
0.9
0.8
DFV*
P < 0,05
0.7
0.6
0
0 3 6 12
Monthly Treatment with Telmisartan 40–80 mg
*Diastolisc filling relation (early atrial fill)
Mattioli et al. Int J Cardiol 2004;97:383–388
63. Effects on end organ damage
Improves the function of the renal endothelium as
well as the nephritic plasma flow and reduces the
vascular renal resistance more efficiently than
Ramipril.
Reduces Albuminuria (ongoing effect than with
ACE-Inhibitor).
Slows down the GFR declines with type 2 diabetes.
Causes ↓ of LVH than HCTZ and Carvedilol.
These effects occur independent of BP lowering.
Improves the Elasticity of the Arteries.
64. Telmisartan as safe as placebo
18 Placebo
Patients with undesirable events (%)
Telmisartan
16
14
12
10 *
8
6
4
2
0
Headache Dizziness Tiredness Failure Cough Muscle Oedema
pain
* P < 0,05 vs. Placebo
65. Summary of side effects
Placebo like side effect profile as
Monotherapy or in combination with
HCTZ
No significant side effects like cough as
seen with ACE-inhibitors
No significant side ffects of peripheral
oedema as with CCBs
Reduced possibility of hypokalaemia than
with HCTZ.
The renin-angiotensin system (RAS) has been implicated as an important participant in the development or maintenance of elevated blood pressure and in the damage that occurs to organs such as the brain, heart, and kidney in hypertensive patients. The RAS has been the target of intensive efforts by scientists to develop drugs that inhibit one or more steps of this important system. This schema illustrates the steps in the biochemical pathway that is involved in the formation of the most biologically potent of the angiotensin peptides, angiotensin II, and its interaction with the angiotensin receptor, the AT1 receptor, that mediates most of its actions. Inside the red lined circle are listed the enzymes, renin and angiotensin converting enzyme, that convert angiotensinogen or renin substrate and angiotensin I, to angiotensin I and angiotensin II, respectively. Components of the RAS are present not only in the circulation, but also in many tissues including the heart, brain, kidney, blood vessels and adrenal gland. Inhibitors of the enzyme renin have been developed and tested, but have never become commercially available because of their rather low potency and limited bioavailability. Among the most commonly used drugs to treat hypertension and concomitant conditions, such as renal insufficiency, proteinuria, and heart failure, are the angiotensin converting enzyme (ACE) inhibitors. Specific antagonists of the angiotensin AT1 receptor are commercially available, approved by the FDA for the treatment of hypertension, and hold the promise of having treatment benefits for patients with hypertension, renal insufficiency, and heart failure, either alone or in combination with ACE inhibitors.
Angiotensin Cascade This slide shows the renin-angiotensin cascade. There are at least 2 alternative pathways for angiotensin II formation that do no rely on either renin or angiotensin converting enzyme (ACE). In the non-renin pathway, tissue plasminogen activator (tPA) forms angiotensinsin II directly from angiotensinogen, bypassing the renin-mediated production of angiotensin I as an intermediate. A second alternative pathway involves enzymes like chymase that can form angiotensin II from angiotensin I via an ACE-independent mechanism. These alternative pathways are implicated in the gradual return toward pre-treatment angiotensin II concentrations during treatment of patients with ACE inhibitors, and provide a rationale for considering angiotensin receptor blockers (ARBs) that directly inhibit the binding of angiotensin II to the AT 1 receptor either in conjunction with or as an alternative to ACE inhibitor therapy. References: Balcells E, Meng QC, Johnson WH, Jr., Oparil S, and Dell'Italia LJ. Angiotensin II formation from ACE and chymase in human and animal hearts: methods and species considerations. Am J Physiol 1997;273(4 Pt 2):H1769-H1774. Petrie MC, Padmanabhan N, McDonald JE, Hillier C, Connell JM, and McMurray JJ. Angiotensin converting enzyme (ACE) and non-ACE dependent angiotensin II generation in resistance arteries from patients with heart failure and coronary heart disease. J Am Coll Cardiol 2001;37:1056-1061.
The answer is yes Let us now understand what sets Temisartan apart? To know this, let us start at the clinical triggers of cardiac events.
This slide shows the circadian rhythm of blood pressure in a normal individual. 1,2 Blood pressure falls during sleep and rises rapidly just before the time of awakening. The maximum is reached as people arise and begin their routine daytime activities. Millar-Craig M, et al. Circadian variation of blood pressure. Lancet 1978;1:795–797. Mancia G, et al. Blood pressure and heart rate variabilities in normotensive and hypertensive human beings. Circ Res 1983;53:96–104.
These data are from 2 studies that have analysed the circadian variation in the onset of acute myocardial infarction (n=2,999) or stroke (n=1,167). 1,2 Both studies found a notable increase in the number of events in the early morning period, the time that corresponds to the early morning blood pressure surge (EMBPS). Muller JE, et al. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med 1985;313:1315–1322. Marler JR, et al. Morning increase in onset of ischemic stroke. Stroke 1989;20:473–476.
Endothelial dysfunction contributes to cardiovascular disorders, such as atherosclerosis, 2 hypertension and heart failure. 3 In the kidney, endothelial dysfunction can result in intraglomerular hypertension and inflammation. 4 Annuk M, et al. Endothelium-dependent vasodilation and oxidative stress in chronic renal failure: impact on cardiovascular disease. Kidney Int Suppl 2003;84:50–53. Erhardt LR. Endothelial dysfunction and cardiovascular disease: the promise of blocking the renin-angiotensin system. Int J Clin Pract 2003;57:211–218. Vapaatalo H, Mervaala E. Clinically important factors influencing endothelial function. Med Sci Monit 2001;7:1075–1085. Klahr S, Morrissey JJ. The role of vasoactive compounds, growth factors and cytokines in the progression of renal disease. Kidney Int Suppl 2000;75:S7–S14.
The concept of a cardiovascular continuum was first published in 1991. 1 Factors such as hypertension can left ventricular hypertrophy (LVH), which increase the risk of cardio- and cerebrovascular events. 1 Ventricular wall remodelling, if untreated, may ultimately result in congestive heart failure, end-stage heart disease and death. These can be accompanied by cognitive dysfunction and, as the disease progresses, dementia. 2 Vascular remodelling, atherosclerosis and cardiac embolism can result in stroke. Hypertension and diabetes are also among the risk factors that lead to endothelial dysfunction. This can result in damage to the glomeruli, microalbuminuria and macroproteinuria, leading to progressive nephrosis and the development of renal failure. 3–5 Dzau V, Braunwald E. Resolved and unresolved issues in the prevention and treatment of coronary artery disease: a workshop consensus statement. Am Heart J 1991;121:1244–1263. Hofman A, et al. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer’s disease in the Rotterdam study. Lancet 1997;349:151–154. Cooper ME. Pathogenesis, prevention and treatment of diabetic nephropathy. Lancet 1998;352:213–219. Taylor AA. Pathophysiology of hypertension and endothelial dysfunction in patients with diabetes mellitus. Endocrinol Metabol Clin North Am 2001;30:983–997. Erhardt LR. Endothelial dysfunction and cardiovascular disease: the promise of blocking the renin-angiotensin system. Int J Clin Pract 2003;57:211–218.
Poor control in the morning hours in patients with controlled office blood pressure may be a consequence of antihypertensives that do not maintain full efficacy throughout the dosing period. Blood pressure may be normal when the patient visits the office several hours after taking their morning dose, but may not be controlled in the early morning period. Antihypertensive agents which have short elimination half-lives and wide fluctuations in plasma concentrations during a dosage interval (i.e. a greater trough-to-peak ratio) will produce greater variability in blood pressure compared with antihypertensive agents with lower trough:peak ratios. 1 Elliott HL, Meredith PA. Trough:peak ratio: clinically useful or practically irrelevant? J Hypertens 1995;13:279–283.
Antihypertensive agents which have short elimination half-lives and wide fluctuations in plasma concentrations during a dosage interval (i.e. a greater trough-to-peak ratio) will produce greater variability in blood pressure compared with antihypertensive agents with lower trough:peak ratios. 1 Elliott HL, Meredith PA. Trough:peak ratio: clinically useful or practically irrelevant? J Hypertens 1995;13:279–283.
Telmisartan is a unique ARB on account of its unparalleled features.
This slide gives a list of the conditions that favour the use of ARBs, according to the ESH guidelines. 1 2003 European Society of Hypertension – European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003;21:1011–1053.
Slide set includes notes.
The PROTECTION Programme 1 includes ten trials that will recruit a total of more than 6,500 patients. Broadly, these trials can be grouped into renal studies and at-risk hypertension studies. Six of these studies have been completed, and the results are provided in this slide kit. These studies are: PRISMA I & II ARBs FDC ATHOS TRENDY DETAIL Weber M. The telmisartan Programme of Research tO show Telmisartan End-organ proteCTION (PROTECTION) Programme. J Hypertens 2003;21 (Suppl 6):S37–S46.
This slide shows the result of a meta-analysis of five multicentre trials that used ABPM to compare the antihypertensive efficacy of telmisartan, losartan, valsartan and amlodipine. 1 Telmisartan 80 mg was significantly superior to losartan 50 mg and valsartan 80 mg in the reduction of 24-h mean SBP and DBP. Neutel JM, Smith DHG. Evaluation of angiotensin II receptor blockers for 24-hour blood pressure control: meta-analysis of a clinical database. J Clin Hypertens 2003;5:58–63.
This slide shows the result of a meta-analysis of five multicentre trials that used ABPM to compare the antihypertensive efficacy of telmisartan, losartan, valsartan and amlodipine. 1 The data show that telmisartan 80 mg was significantly superior to losartan and valsartan in the reduction of SBP and DBP during the risky, early morning period (06:00–11:59). Neutel JM, Smith DHG. Evaluation of angiotensin II receptor blockers for 24-hour blood pressure control: meta-analysis of a clinical database. J Clin Hypertens 2003;5:58–63.
Two fixed-dose studies have compared low doses of telmisartan and losartan. They both found telmisartan to be superior in the last 6 h of the dosing interval. Mallion et al. recruited 223 patients with mild-to-moderate hypertension for a 6-week trial of telmisartan 40 mg or 80 mg and losartan 50 mg. 1 Telmisartan 40 mg gave significantly superior reductions in SBP and DBP. The reduction in SBP in the last 6 h of the dosing interval was 10.7 mmHg with telmisartan 40 mg and 6.0 mg with losartan 50 mg (p<0.05). Telmisartan 80 mg was also superior to losartan 50 mg. Ding et al. compared telmisartan 40 mg with losartan 50 mg in 56 Taiwanese patients with mild-to-moderate hypertension. 2 The reduction in DBP in the last 6 h of the dosing interval was superior with telmisartan compared with losartan. Reductions in SBP in the last 6 h of the dosing interval (16.0 mmHg with telmisartan and 11.8 mmHg with losartan) did not reach statistical significance. Mallion JM, et al. ABPM comparison of the antihypertensive profiles of the selective angiotensin II receptor antagonists telmisartan and losartan in patients with mild-to-moderate hypertension. J Hum Hypertens 1999;13:657–664. Ding PY, et al. A double-blind ambulatory blood pressure monitoring study of the efficacy and tolerability of once-daily telmisartan 40 mg in comparison with losartan 50 mg in the treatment of mild-to-moderate hypertension in Taiwanese patients. Int J Clin Pract Suppl 2004;58:16–22.
The two fixed-dose studies comparing low doses of telmisartan and losartan also found telmisartan to be superior in 24-h mean ambulatory blood pressure reductions. Mallion et al. recruited 223 patients with mild-to-moderate hypertension for a 6-week trial of telmisartan 40 mg or 80 mg and losartan 50 mg. 1 Telmisartan 40 mg gave significantly superior reductions in SBP and DBP. The reduction in 24-h mean SBP was 11.5 mmHg with telmisartan 40 mg and 8.0 mg with losartan 50 mg (p<0.05). Telmisartan 80 mg was also superior to losartan 50 mg. Ding et al. compared telmisartan 40 mg with losartan 50 mg in 56 Taiwanese patients with mild-to-moderate hypertension. 2 The reduction in 24-h mean DBP was superior with telmisartan compared with losartan. Reductions in 24-h mean SBP (14.6 mmHg with telmisartan and 11.2 mmHg with losartan) did not reach statistical significance. Mallion JM, et al. ABPM comparison of the antihypertensive profiles of the selective angiotensin II receptor antagonists telmisartan and losartan in patients with mild-to-moderate hypertension. J Hum Hypertens 1999;13:657–664. Ding PY, et al. A double-blind ambulatory blood pressure monitoring study of the efficacy and tolerability of once-daily telmisartan 40 mg in comparison with losartan 50 mg in the treatment of mild-to-moderate hypertension in Taiwanese patients. Int J Clin Pract Suppl 2004;58:16–22.
In flexibly dosed studies using trough cuff blood pressure as the primary outcome, telmisartan was found to be superior to losartan. Lee et al. compared telmisartan 40–80 mg with losartan 50–100 mg in an 8-week study of 180 Taiwanese patients with mild-to-moderate hypertension. 1 Changes in SBP were statistically superior with telmisartan compared with losartan. Changes in DBP (amounting to 11.1 mmHg with telmisartan and 8.7 mmHg with losartan) did not reach statistical significance. Zhu et al. compared telmisartan 40–80 mg with losartan 50–100 mg in an 8-week study of 330 Chinese patients with mild-to-moderate hypertension. 2 Changes in SBP were statistically superior with telmisartan compared with losartan. Changes in DBP (amounting to 10.9 mmHg with telmisartan and 9.3 mmHg with losartan) were also statistically significant (p=0.03). Lee YT, et al. A double-blind comparison of the efficacy and tolerability of telmisartan 40-80 mg vs. losartan 50-100 mg in Taiwanese hypertensive patients. Int J Clin Pract Suppl 2004;58:40–45. Zhu JR, et al. Efficacy and safety of telmisartan vs. losartan in control of mild-to-moderate hypertension: a multicentre, randomised, double-blind study. Int J Clin Pract Suppl 2004;58:46–49.
In a meta-analysis of two flexible-dose studies, telmisartan-induced reductions in DBP during the last 6 h of the dosing interval were greater than those with losartan. 1 Reductions with telmisartan were greater than with losartan for the majority of the observed hourly mean values over the entire 24-h dosing interval. 1 These data are from two, 8-week studies in 720 patients with mild-to-moderate hypertension. 1 Patients were started at the lower dose, with up-titration to the higher dose allowed if seated trough cuff DBP was ≥90 mmHg at Week 4. The 24-h profiles of ambulatory SBP hourly mean reductions were similar to those for DBP . Smith DH, et al. Comparison of telmisartan versus losartan: meta-analysis of titration-to-response studies. Blood Press Monit 2003;8:111–117.
The results of a study comparing the effects of telmisartan (40–80 mg) with valsartan (80–160 mg) on BP in the last 6 hours of the dosing interval are shown here. 1 Telmisartan was superior to valsartan at reducing DBP and SBP at the end of the dosing interval. White WB, et al. Effects of the angiotensin II receptor blockers telmisartan versus valsartan on the circadian variation of blood pressure. Impact on the early morning period. Am J Hypertens 2004;17:347–353.
This was a double-blind, forced-titration, crossover, randomized trial that compared telmisartan 80 mg/day with valsartan 160 mg/day in 490 patients with hypertension. 1 Ambulatory blood pressure recordings were made at baseline and at 8 weeks. Telmisartan reduced SBP/DBP during the last 6 h of the dosing period by 11/7.6 mmHg, compared with 8.7/5.8 mmHg with valsartan (P=0.02). White WB, et al. Effects of the angiotensin II receptor blockers telmisartan versus valsartan on the circadian variation of blood pressure. Am J Hypertens 2004;17:347 – 353.
Telmisartan 80 mg provides superior reductions in SBP and DBP in the last 6 h of the dosing interval compared with ramipril 10 mg. Data shown are from two independent, fixed-dose, 14-week studies: Prospective, Randomized Investigation of the Safety and efficacy of Micardis versus ramipril using ABPM (PRISMA) I and II. PRISMA I was conducted in Europe and South Africa, and recruited 801 patients. 1 PRISMA II was conducted in the USA and Canada, and recruited 812 patients. 2 Patients were started on telmisartan 40 mg or ramipril 2.5 mg, and force titrated to telmisartan 80 mg or ramipril 5 mg after 2 weeks. At Week 8, ramipril was further up titrated to 10 mg. Blood pressure was measured using ABPM. As well as superiority in the early morning period, in both studies telmisartan was significantly superior to ramipril over the 24-h mean and other time periods: morning (06:00–11:59), daytime (06:00–21:59), and night-time (22:00–05:59). Williams B, et al. Superior blood pressure reduction in the last 6 h of the dosing interval with once-daily telmisartan versus ramipril. Hypertension 2004;44:576. Lacourcière Y, et al. A prospective, randomized investigation of the safety and efficacy of telmisartan vs ramipril in mild-to-moderate hypertensives using ambulatory blood pressure monitoring. Hypertension 2004;44:576 .
Telmisartan 80 mg reduces blood pressure over the full 24-h dosing interval compared with ramipril 10 mg. Data shown are from a fixed-dose, 14-week study: PRISMA II. 1 Patients were started on telmisartan 40 mg or ramipril 2.5 mg, force titrated to telmisartan 80 mg or ramipril 5 mg after 2 weeks. At Week 8, ramipril was further up titrated to 10 mg. Blood pressure was measured using ABPM. Telmisartan was significantly superior to ramipril (p<0.0001) over the 24-h mean and other time periods: morning (06:00–11:59), daytime (06:00–21:59), and night-time (22:00–05:59). Lacourcière Y, et al. A prospective, randomized investigation of the safety and efficacy of telmisartan vs ramipril in mild-to-moderate hypertensives using ambulatory blood pressure monitoring. Hypertension 2004;44:576.
Patients with a high EMBPS have been shown to be at increased risk of stroke. 1 In the study that demonstrated this connection, the EMBPS was defined as the difference between the early morning mean (the average blood pressure in the first 2 hours after waking) and the night-time low (the average of three blood pressure readings centred on the lowest night-time reading). 1 These definitions were used to calculate the EMBPS of patients in two studies of identical design that compared telmisartan 80 mg with ramipril 10 mg (PRISMA I and II). 2 The 25% of patients with the highest EMBPS of DBP all had an EMBPS ≥35 mmHg. 2 In these patients, telmisartan reduced the magnitude of the EMBPS by a significantly greater amount than did ramipril. 2 Kario K, et al. Morning surge in BP as a predictor of silent and clinical cerebrovascular disease in elderly hypertensives. Circulation 2003;107:1401–1406. Data on file. Boehringer Ingelheim GmbH.
The EValuation de l’Efficacité RESiduelle du Telmisartan (EVEREST) study compared telmisartan (n=217) with perindopril (n=218) over 12 weeks. 1 Initial treatment was telmisartan 40 mg and perindopril 4 mg, with the dose doubled at Week 6 for those patients who failed to reach target blood pressure (DBP <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.
The efficacy of telmisartan at doses of 40 mg and 80 mg was compared with that of enalapril 20 mg in a 12-week multicentre, randomized, parallel-group, placebo-controlled study that included 440 patients with mild-to-moderate hypertension. 1 The reduction in blood pressure with telmisartan was greater than with enalapril and reached statistical significance for the telmisartan 80 mg arm. Maximal blood pressure reductions were apparent by week 4 and were maintained through to week 12. Smith DHG, et al. Once-daily telmisartan compared with enalapril in the treatment of hypertension. Adv Ther 1998;15:229–240.
Telmisartan produced reductions in DBP in the last 4 h of the dosing interval that were superior to amlodipine in this 12-week, double-blind, titration-to-response, ABPM study. 1 Patients (n=232) had mild-to-moderate hypertension. They were randomized to placebo (n=81) or active dose, which comprised telmisartan 40 mg or amlodipine 5 mg titrated as required up to a maximum of telmisartan 120 mg or to amlodipine 10 mg. Compared with amlodipine, telmisartan resulted in a 26% reduction in SBP and an almost 40% reduction in DBP during the last 4 h of the dosing interval. Lacourcière Y, et al. A comparison of the efficacies and duration of action of the angiotensin II receptor blockers telmisartan and amlodipine. Blood Press Monit 1998;3:295–302.
Telmisartan produced reductions in DBP in the last 4 h of the dosing interval that were superior to amlodipine in this 12-week, double-blind, titration-to-response, ABPM study. 1 Patients (n=232) had mild-to-moderate hypertension. They were randomized to placebo (n=81) or active dose, which comprised telmisartan 40 mg or amlodipine 5 mg titrated as required up to a maximum of telmisartan 120 mg or to amlodipine 10 mg. Both telmisartan and amlodipine significantly reduced 24-h mean SBP and DBP (P<0.001) . 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.
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.
Slide set includes notes.
The TRENDY study also compared renal plasma flow and renal vascular resistance at rest (i.e. without stimulation by infusion of L-NMMA). 1 Telmisartan significantly improved renal plasma flow and decreased vascular resistance. Ramipril did not significantly change these parameters. Schmeider RE, et al. Effects of telmisartan versus ramipril on renal endothelial function in Type-2 diabetes. Presented at the XVIth Scientific Meeting of the Interamerican Society of Hypertension. Canc ún, México, April 17–21, 2005.
Patients in the TRENDY study had low levels of albuminuria at baseline. 1 Despite this, telmisartan still produced a significant reduction in albuminuria, whereas ramipril did not. Schmeider RE, et al. Effects of telmisartan versus ramipril on renal endothelial function in Type-2 diabetes. Presented at the XVIth Scientific Meeting of the Interamerican Society of Hypertension. Canc ún, México, April 17–21, 2005.
Red ó n et al. conducted a 12-month study to assess the interactions between RAAS gene polymorphisms and telmisartan therapy in patients with mild-to-moderate hypertension. 1 There was no correlation between RAAS gene polymorphisms and the response to telmisartan. Of the 206 patients, 28% had microalbuminuria (urinary albumin excretion [UAE] >30 mg/day), and mean UAE was 32.7 mg/day. After 3 months, telmisartan significantly reduced albuminuria by 52%, and this was reduced further to a 69% reduction by the end of the study. Redón J, et al. Renin-angiotensin system gene polymorphisms: relationship with blood pressure and microalbuminuria in telmisartan-treated hypertensive patients. Pharmacogenomics J 2005;5:14–20.
If diabetic nephropathy is left untreated, GFR declines steadily by 10–12 ml/min/1.73 m 2 /year. 1 In DETAIL, GFR declined over 5 years by 17.9 ml/min/1.73m 2 in the LOCF dataset and 18.7 ml/min/1.73 m 2 in completers. The rate of decline slowed over time. 2 Thus treatment with telmisartan halted the progression of diabetic nephropathy. Parving H-H, et al. Angiotensin receptor blockers in diabetic nephropathy: renal and cardiovascular endpoints. Semin Nephrol 2004;24:147–151. Barnett A, et al. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy . N Engl J Med 2004;351:1952–1961.
This clinical study assessed the effect of 12 months’ treatment with telmisartan 40–80 mg on left ventricular mass index (LVMI) in 90 patients with hypertension and echocardiographic evidence of mild-to-moderate LVH. 1 Mean SBP was reduced from 167 mmHg at baseline to 126 mmHg at treatment end (p<0.001) and mean DBP from 104 mmHg to 86 mmHg (p<0.001). There was a concomitant decrease in LVMI, from 121 ± 7 g/m 2 at baseline to 109 ± 3 g/m 2 at treatment end (p<0.01). Mattioli AV, et al. Regression of left ventricular hypertrophy and improvement of diastolic function in hypertensive patients treated with telmisartan. Int J Cardiol 2004;97:383–388.
This study used a freehand three-dimensional echocardiographic technique to evaluate the effect of telmisartan on left ventricular mass (LVM). 1 The technique employs a magnetic sensor attached to an ultrasound probe to aid spatial location, which enables calculation of LVM without geometric assumptions. In this multicentre, randomized, double-blind study, 65 patients with hypertension received 12 months of treatment with either telmisartan 80 mg (n=40) or HCTZ 25 mg (n=25). Both drugs lowered blood pressure significantly: mean 24-h ambulatory SBP/DBP was reduced from baseline by 24/13 mmHg with telmisartan and by 10/8 mmHg with HCTZ. There was also a significant 16 g/m 2 decrease in LVMI (from 141 ± 16 g/m 2 to 125 ± 19 g/m 2 ; p<0.02) in the telmisartan treatment group. However, the 4 g/m 2 reduction in LVMI (from 139 ± 20 g/m 2 to 135 ± 22 g/m 2 ) observed in the HCTZ group was not statistically significant. Galzerano D, et al. Freehand three-dimensional echocardiographic assessment of efficacy of telmisartan on left ventricular mass in hypertensive patients: a multicentre study. J Hum Hypertens 2004;18:53 –5 9.
Telmisartan reduced LVH compared with carvedilol despite similar reductions in blood pressure. 1 The 84 patients in this study had hypertension and LVH, and received telmisartan 80 mg or carvedilol 25 mg for 44 weeks. LVM was measured by MRI (results shown in this slide) and three-dimensional echocardiography. Both treatments reduced 24-h mean SBP/DBP by similar amounts (telmisartan by 31/19 mmHg, carvedilol by 29/17 mmHg, P=ns). However, telmisartan reduced LVM significantly more than did carvedilol. Similar effects were seen using echocardiography. Galzerano D, et al. Three-dimensional echocardiographic and magnetic resonance assessment of the effect of telmisartan compared to carvedilol on left ventricular mass: a multicenter randomized study. 53rd Annual Scientific Session of the American College of Cardiology, 2004, New Orleans, USA. 2004.
This clinical study assessed the effect of 12 months’ treatment with telmisartan 40–80 mg on LVMI in 90 patients with hypertension and echocardiographic evidence of mild-to-moderate LVH. 1 There was a significant improvement in diastolic filling: the early to atrial filling ratio increased from 0.59 ± 0.2 at baseline to 0.88 ± 0.2 at study end (P<0.05). Mattioli AV, Zennaro M, Bonatti S, Bonetti L, Mattioli G. Regression of left ventricular hypertrophy and improvement of diastolic function in hypertensive patients treated with telmisartan. Int J Cardiol 2004;97:383–388.
Telmisartan has been evaluated for safety in 27 studies in a total of 5363 patients with essential hypertension, including 2921 patients treated for up to 6 months, 888 patients treated between 6 and 12 months, and 1554 patients treated for 1 year or more. 1 Adverse events were typically mild and transient in nature. In placebo-controlled trials that included 1758 patients treated with doses ranging from 20 mg to 160 mg ( 1344 patients received telmisartan monotherapy, 414 received telmisartan/HCTZ combination) , the incidence of adverse events was comparable to that of placebo. 1 Headache was the most frequently reported adverse event (7.1% in telmisartan-treated patients vs 15.1% in the placebo group). 1 Data on file. Boehringer Ingelheim GmbH.
