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Triple Drug Combination For Hypertension
Triple Drug Combination For Hypertension
Triple Drug Combination For Hypertension
for Hypertension
Dr. Devendra Khandke MD
Head- Medical Services
Alembic Pharmaceutical
Limited
1
Global mortality
16 million
128 million
78 million
59 million
39 million
30 million
43 million
All cardiovascular
High BP
High cholesterol
Overweight and obesity
23 million
High BMI
Physical inactivity
Alcohol
Indoor smoke from solid fuels
Iron deficiency
0
Attributable Mortality
WHO 2000 Report. Lancet. 2002;360:1347-1360.
Renin
Na+
+
Beta-blockers
Renin
Kidney
Angiotensin I
Diuretic
Calcium
channel
ACE
ACE inhibitor
Angiotensin II
blocker
AT1 receptor
Angiotensin receptor
blocker
Vasoconstriction
Sodium retention
SNS activation
Inflammation
Growth-promoting effects
Aldosterone 5
Apoptosis
Smoking
Diseases Attributable to
Hypertension
Left Ventricular
Heart
Gangrene of the
Failure
Lower Extremities
Hypertrophy Myocardial
Infarction
Hypertensive
Encephalopathy
Aortic
Aneurym
HYPERTENSION
Blindness
Coronary
Heart Disease
Cerebral
Chronic
Preeclampsi Hemorrhage
Kidney Stroke
a/Eclampsia
Failure
Adapted from Dustan HP et al. Arch Intern Med. 1996; 156: 1926-1935
Risk of Hypertension
9
Lancet
2002;360:1903-13.
115/75
135/85
155/95
175/105
SBP/DBP, mmHG
* Individuals aged 4069 years (N = 1 million).
Lewington S, et al. Lancet. 2002;360:19031913.
11
2 mmHg
decrease in
mean SBP
12
Prevalence %
Before
Intervention
Reduction in BP
Reduction
in SBP
% Reduction in Mortality
(mmHg)
Stroke
CHD
Total
2
3
-6
-8
-4
-5
-3
-4
-14
-9
-7
13
14
2.
3.
4.
5.
6.
7.
8.
15
Diuretics
16
Calcium Antagonists
CCBs block the L type calcium channels present within blood vessels- prevent entry of calcium ions into vascular
smooth muscle fibers
relaxing large and small arteries and reducing peripheral resistance ( PVR )
Reduce force of contraction of myocardium
Drawbacks
Indications
Hypertension
Angina
Myocardial Infarction
17
Therapeutic effects
18
19
CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney
disease; DM, diabetes mellitus; HTN, hypertension; PAD, peripheral arterial
disease.
* Based on BP target <130/80 mmHg
20
Not treated
48%
(n = 2,458)
BP
uncontrolled
35%
(n = 1,756)
BP controlled
17%
(n = 872)
21
22
23
ESH/ESC
JNC VII
NICE
JSH
Many patients will require more than one drug to achieve adequate BP
control
Pathophysiological reasoning suggests that adding an ACE-I/ARB to a CCB
or a diuretic (or vice versa in the younger group) are logical combinations
24
Chobanian et al. JAMA. 2003;289:25602572; Mancia et al. Eur Heart J. 2007;28:14621536; http://www.nice.org.uk/
download.aspx?o=CG034fullguideline (accessed January 2010); Ogihara et al. Hypertens Res. 2009;32:3107.
24
Lifestyle modifications
Not at goal BP*
Hypertension without
compelling indications
Stage 1
Stage 2
Thiazide-type diuretics
for most. May consider
ACE-I, ARB, B, CCB or
combination
Two-drug combination
for most
(usually including
thiazide-type diuretic)
Hypertension with
compelling indications
If not at goal, optimize dosages or add additional drugs until goal BP is achieved.
Consider consultation with hypertension specialist
25 Chobanian et al. JAMA. 2003;289:25602572.
25
- Marked BP elevation
- High/very high CV risk
- Lower BP target
Not at BP goal
Full dose of
single agent
Switch to
different agent
at low dose
Full dose of
two-drug
combination
Add a
third drug
at low dose
Not at BP goal
Two/three-drug
combination
at full dose
Full-dose
single agent
Full doses of
two/three-drug combination
26
Step 1
< 55 y
55 y or Black
patients at any age
Step 2
Step 3
Step 4
27
2007
Diuretics
Diuretics
B
ARB
ARB
ONTARGET
ACCOMPLISH
HYVET
CCB
CCB
-blockers
ACE-I
ACE-I
28
of regime
Improved adherence
Reduced pill burden
30
31
1.83
Total n = 445,356
-blockers
1.64
-blockers
1.23
1.08
ACE inhibitors
1.00
ARBs
0.92
0.5
1.0
2.0
32
33
Telmisartan
A Unique ARB
Novel AT1 receptor
antagonist
34
35
Number of patients
44,264
19,335
12,565
1,405
Eprosartan
MOSES1
4,449
Olmesartan
ROADMAP2
6,405
Irbesartan
Losartan
Valsartan
Telmisartan
IRMA II3
SCOPE6
RENAAL8
Val-HeFT12
TRANSCEND16
IDNT4
CHARM7
ELITE II9
NAVIGATOR13
PRoFESS16
I-Preserve
36
Candesartan
OPTIMAAL10
VALIANT
LIFE11
VALUE15
1. Schrader et al. Stroke. 2005;36:12181226; 2. http://www.roadmapstudy.org/resident.aspx; 3. Parving et al. N Engl J Med. 2001;345:870878; 4. Lewis et al. N Engl J Med. 2001;345:851860; 5.
Carson et al. J Card Fail. 2005;11:576585; 6. Papademetriou et al. J Am Coll Cardiol. 2004;44:11751180; 7. www.atacand.com; 8. Brenner et al. N Engl J Med. 2001;345:861869; 9. Pitt et al.
Lancet. 2000;355:15821587; 10. Dickstein et al. Lancet. 2002;360:752760; 11. Dahlof et al. Lancet. 2002;359:9551003; 12. Cohn et al. N Engl J Med. 2001;345:16671675; 13.
www.novartis.com; 14. Pfeffer et al. N Engl J Med. 2003;349:18931906; 15. Julius et al. Lancet. 2004;363:20222031; 15. www.ontarget-micardis.com.
14
ONTARGET16
36
Telmisartan
Mechanism Of action
9
24
10-15
Losartan
11-15
Irbesartan
5-9
Eprosartan
10
Telmisartan
Olmesartan
2.5-9
Valsartan
Candesartan
15
20
25
High affinity towards AT1 receptor (telmisartan > olmesartan > candesartan >
valsaratan > losartan)
Very slow dissociation rate
Long terminal half-life supports a once-daily dosing regimen and suggests that
drug concentrations do not decline below therapeutic levels even if a dose is
delayed
These unique properties of Telmisartan ensure improved 24- hr control of blood
pressure as compared to other ARBs
Goodman & Gilman p 812-813 11th edition
38
Telmisartan
39
range
Eprosartan
500
range
Cande- Olme- ValLoIrbeEpro- Telmisartan sartan sartan sartan sartan sartan sartan
Valsartan
PPAR fold activation
Receptor dissociation
half life (min)
Longest half life, Highest receptor affinity, Highest tissue penetration and selective PPAR
activation
Losartan
Candesartan
Olmesartan
Telmisartan
Burnier M. & Brunner H.R., Lancet 2000;355:637645; Brunner H.R., J Hum Hypertens 2002;16(Suppl
2):S13S16; Kakuta H., et al. Int J Clin Pharmacol Res 2005;25:4146; Wienen W., et al. Br J
Pharmacol 1993;110:245-252; Song J.C. & White C.M., Formulary 2001;36:487499; Asmar,R., Int J
Clin Pract. 2006;60:315-320; Israili,Z.H., J Hum.Hypertens. 2000;14 Suppl 1: S73-S86; Benson S.C. et
al. Hypertension 2004;43:9931002
40
Telmisartan
INDICATIONS
Telmisartan is indicated for the treatment of hypertension
US FDA has approved it for the reduction of the risk of
myocardial infarction (heart attack), stroke, or death from
cardiovascular (CV) causes in patients 55 years of age or
older at high risk of developing major CV events who are
unable to take ACE inhibitors
European Commission has approved telmisartan for the
reduction of cardiovascular morbidity in patients with:
I. manifest atherothrombotic cardiovascular disease (history
of coronary heart disease, stroke, or peripheral arterial
disease) or,
II. type 2 diabetes mellitus with documented target organ
damage.
Telmisartan is the first treatment in its class to be approved for this indication.
41
< 65 year
(n = 921)
65 year
(n = 246)
Placebo
< 65 year
(n = 3817)
65 year
(n = 1196)
Telmisartan
< 65 year
(n = 1444)
65 year
(n = 399)
Telmisartan/HCTZ
42
ONTARGET Trial
Blood Pressure Control:
Mean blood pressure was lower in both the
telmisartan group (a 0.9/0.6 mm Hg greater
reduction) and the combination-therapy group (a
2.4/1.4 mm Hg greater reduction) than in the ramipril
group.
N Engl J Med 2008;358:1547-59
43
ONTARGET
44
ONTARGET
Conclusion:
45
47
LoEprosarta
sartan
n
Hypertension
- Treatment of renal disease
- Prevention of stroke in LVH
Irbesartan
Olmesartan
Valsartan
Candesartan
Telmisartan
CV high risk
Atherothrombotic CV
disease such as:
- Peripheral vascular
disease
- Stroke
Type
2 diabetes with
target organ damage
Heart failure or LV
dysfunction
49
Heart failure
Hypertension
MI and
stroke
LIFE
VALUE
Microalbuminuria
Atherosclerosis
and LVH
Endothelial
dysfunction
Risk factors:
hypertension, diabetes,
obesity, smoking, age
50
VALIANT
CHARM
Val-HeFT
ELITE II
Remodelling
Macroproteinuria
Ventricular dilation/
cognitive dysfunction
Nephrotic
proteinuria
ESRD
CHF/
secondary stroke
Cardio/
cerebrovascular
death
50
Telmisartan
Olmesartan
24 hr control of BP*
66 -100 %
60 -80%
More Lipophilic
tissue penetration
better inhibition
RAAS
so
and
of
Renal Insufficiency
No dosage adjustment
better
hence
tissue
20 mg maximum in
severe disease
51
***
***
***
***
***
12.5 mg (n=412)
12.5 mg (n=428)
52
AMLODIPINE
53
Is
Acts
54
Other
55
1. Mancia et al. J Hypertens Suppl. 2006;24(1):S51S56; 2. Robertson and Robertson. In: Hardman JG, Limbard JG, eds-in-chief. Goodman
& Gilmans The Pharmacological Basis of Therapeutics. 9th ed. 1996. p759779; 3. Prisant. In: Oparil S, Weber MA,
eds. Hypertension: Companion to Brenner & Rectors The Kidney. 2nd ed. 2005. p683704.
55
Lercanidipine
Nifedipine
Nimodipine
Nisoldipine
Nicardipine
Felodipine
Lacidipine
Amlodipine
56
CCB + ARB:
The Synergies of Counter-Regulation (1)
CCB
Arteriodilation
Peripheral oedema
Effective in low-renin patients
Reduces cardiac ischaemia
BP
Synergistic
BP reduction
Complementary
clinical benefits
57
CCB
RAS activation
No renal or CHF
benefits
57
CCB + ARB:
The Synergies of Counter-Regulation (2)
CCB
Arteriodilation
Peripheral oedema
Effective in low-renin patients
Reduces cardiac ischaemia
ARB
Venodilation
Attenuates peripheral oedema
Effective in high-renin patients
No effect on cardiac ischaemia
58
BP
Synergistic
BP reduction
Complementary
clinical benefits
ARB
RAS blockade
CHF and renal
benefits
CCB
RAS activation
No renal or CHF
benefits
58
as Initial Therapy
59
59
(n = 13)
(n = 31)
Severe HTN
60
1. Littlejohn et al. J Clin Hypertens. 2009;11:207213; 2. Neutel et al. J Clin Hypertens. 2010: In press; ASH 2010
poster presentation (LB-PO-10) & data on file
60
Patients (%)
A10
(n = 65)
(n = 183)
(n = 37)
(n = 117)
(n = 20)
(n = 61)
55 mmHg
60 mmHg
50 mmHg
Mean SBP reductions from baseline*
* Mean baseline BP = 185.4/103.2 mmHg
61 Neutel et al. J Clin Hypertens. 2010: In press; ASH 2010 poster presentation (LB-PO-10).
61
Diabetic
Obese
BMI 30kg/m1
(n = 175)
Metabolic
syndrome1*
(n = 36)
Elderly
65 y1
Black
(n = 100)
(n = 30)
Severe HTN
180/95 mmHg2
(n = 379)
(n = 62)
T80/A10
Mean baseline BP = 185.4/103.2 mmHg
* Diabetes, obesity (BMI 30kg/m2), and HTN
62
1. TEAMSTA Severe HTN study (data on file; Boehringer Ingelheim Pharmaceuticals, Inc);
2. Neutel et al. J Clin Hypertens. 2010: In press; ASH 2010 poster presentation (LB-PO-10).
62
185.4
T80/A5
T80/A10
(n = 405)
(n =379)
Baseline
80%*
147.7
137.9
37.9 mmHg
Week 2
47.5 mmHg
Week 8
63
24-h ABPM
64
64
p < 0.0001
A10
T80/A10
(n = 58)
(n = 52)
65
66
66
Patients with
AEs > 1% incidence (%)
Placebo (n = 46)
A mono (n = 319)
NasoUpper Influenza
pharyn- respiratory
gitis
tract
infection
T/A (n = 789)
Back
pain
Dizziness
Headache Peripheral
oedema
67
Fluid leakage
Arterial
dilation
(CCBs)
No
venous
dilation
Fluid leakage
Capillary bed
68
Opie et al. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:4273; White et al. Clin Pharmacol Ther.
1986;39:4348; Gustaffson. J Cardiovasc Pharmacol. 1987;10:S121S131.
68
Arterial
dilation
(CCB and
ARB)
Venous
dilation
(ARB)
Capillary bed
69
Opie et al. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:4273; White et al. Clin Pharmacol Ther. 1986;39:4348;
Gustaffson. J Cardiovasc Pharmacol. 1987;10:S121S131; Messerli et al. Am J Cardiol. 2000;86:11821187.
69
* p <0.05; p <0.0001
Littlejohn TW et al. J Clin Hypertension. 2009;11(4):207-213
70
p < 0.0001
A10
(n = 124)
90%
71%
T4080+A5
T4080+A5A10
(n = 264)
(n = 543)
71
72
1. Neutel et al. J Clin Hypertens. 2010: In press; 2. White et al. Blood Press Monit. 2010: In press; 3. Littlejohn et al. J Hypertens.
2008;26(suppl 1):S494; 4. Neldam, Lang. J Clin Hypertens. 2009;11(Suppl s1):114 (P279); 5. Littlejohn et al.
J Clin Hypertens 2009:11:207213.
72
73
Benefits
Patients
Combinations
Limitations
74
Telmisartan/Amlodipine/Hydrochlorothiazide
Parameter
Telmisartan
Amlodipine
HCTZ
Tellzy-AH
MOA
AT1 Receptor
Blocker
Block the L
type calcium
channels
Diuretic
Complementary
effect
Decrease
--------------
Decrease
Additive effect
After Load
(PVR)
Decrease
Decrease
Decrease
Additive effect
RAAS
Suppression
Activation
Activation
Neutral effect
Dosing
OD
OD
OD
OD
75
Telmisartan/Amlodipine/Hydrochlorothiazide
Parameter
Telmisartan
Amlodipine
HCTZ
Tellzy-AH
Renin Levels
Decrease
Increase
Increase
No Change
Potassium
Levels
Increase
No change
Decrease
No Change
Edema
Decreased
Increased
No Change
Less effect
Reflex
Tachycardia
No change
May be
present
No change
Less effect
76
Conclusions
There is still a huge unmet medical need in the treatment of hypertension, with many
patients being uncontrolled
ARB + CCB + Diuretic combination exhibit complementary and synergistic MoA with high BP
reductions and a good safety and tolerability profile
All 3 components have a huge clinical evidence-based database for CV protection, and
Telmisartan is the only ARB with a CV protection indication
77
77
Thank You
78