TELBLOK-H

Telmisartan/Hydrochlorothiazide combination

Hypertension is best managed by maintaining blood pressure below 140/90

mmHg.Individuals with persistent resting diastolic blood pressure (DBP) > 90
mmHg and or systolic blood pressure ( SBP) > 140 mmHg are at increased risk
of cardiovascular morbidity and mortality.It has been estimated that a 5-6 mmHg
reduction in DBP and 10 mmHg reduction in systolic BP lowers the risk of stroke
by approximately 33% and of coronary events by approximately 17%.
Blood pressure lowering effect may be enhanced when two
classes of antihypertensive agents are coadministered.To achieve the
recommended blood pressure targets, it is now acknowledged that many
patients require a combination of antihypertensive agents.
The combination of an ARB and a low dose of thiazide diuretic
increases the antihypertensive efficacy, but not at the expense of tolerability,
compared with the individual components administered alone.

Hydrochlorothiazide belongs to thiazide group of diuretics.Thiazide diuretics

inhibit the Na+-Cl- transport in distal convoluted tubule and therefore increase
Na+ and Cl- excretion.

Thiazide diuretics are widely used for the treatment of hypertension, either alone
or in combination with other antihypertensive drugs.Thiazide diuretics are
inexpensive, as efficacious as other classes of antihypertensive agents, and well
tolerated.Thiazides can be administered once daily and do not require dose
titration. Moreover, thiazides have additive or synergistic effects when combined
with other classes of antihypertensive agents.

Rationale of Telmisartan and Hydrochlorothiazide combination

™ Complementry mechanism of action

1.Reduction in peripheral resistence with ARB

2.Reduction of fluid volume with Diuretics

™ ARBs counteract reactive increase in blood pressure related to

diuretic induced renin secretion

™ ARBs ameliorates diuretic induced potassium depletion

™ Well tolerated; fewer metabolic disturbances

 ™ No significant variation in pharmacokinetic parameters of
telmisartan in presence of hydrochlorothiazide

Combination of telmisartan with hydrochlorothiazide was found to be more

effective than each agent alone in lowering blood pressure.Indeed ,
combining telmisartan with hydrochlorothiazide enhances the
antihypertensive efficacy of telmisartan in patients not adequately controlled
with telmisartan alone.

Study 1

Comparison of a Fixed-Dose Combination of 40 mg Telmisartan Plus

12.5 mg Hydrochlorothiazide With 40 mg Telmisartan in the Control of
Mild to Moderate Hypertension. (19)

Objective:To investigate whether a fixed-dose combination of 40 mg of the

angiotensin II antagonist telmisartan plus 12.5 mg of the diuretic
hydrochlorothiazide (HCTZ) was superior to 40 mg telmisartan in patients with
mild to moderate hypertension who failed to respond adequately to 40 mg
telmisartan monotherapy.

Methods: Nonresponders (n = 327) were double blind and randomized to 40

mg telmisartan + 12.5 mg HCTZ (n = 160) or 40 mg telmisartan (n = 167).

Results:After 8 weeks of treatment, 40 mg telmisartan + 12.5 mg HCTZ

lowered diastolic blood pressure (DBP) by an additional 3.5 mm Hg (P < .01) and
systolic blood pressure (SBP) by 7.4 mm Hg (P < .01) compared with 40 mg
telmisartan. Most of the additional effect of the combination was seen after 4
weeks of treatment. At week 8, blood pressure was normalized (SBP <140 mm
Hg and DBP <90 mm Hg) in 51.6% of patients on 40 mg telmisartan + 12.5 mg
HCTZ compared with 23.5% on 40 mg telmisartan (P < .05). The combination of
40 mg telmisartan + 12.5 mg HCTZ normalized DBP in 64.8% of patients,
whereas 40 mg telmisartan normalized DBP in 40.1% (P < .05). SBP decreased
by >=10 mm Hg from baseline in 63.5% of patients receiving the fixed-dose
combination compared with 42.6% of those receiving 40 mg telmisartan (P <
.05). Both treatments were well tolerated.

Conclusion: fixed-dose combination of 40 mg telmisartan + 12.5 mg HCTZ is

clinically and statistically superior to 40 mg telmisartan in patients with mild to
moderate hypertension failing to respond to 40 mg telmisartan alone.
Study 2

Telmisartan/Hydrochlorothiazide in Comparison with

Losartan/Hydrochlorothiazide in Managing Patients with Mild-to-
Moderate Hypertension(20)

Objective: To evaluate the antihypertensive efficacies of fixed-dose

combinations of angiotensin II receptor blockers with hydrochlorothiazide (HCTZ)
12.5 mg

Methods: a multicenter, randomized, prospective, open-label, blinded-endpoint

study was performed in 805 patients with mild-to-moderate hypertension
randomized to once-daily treatment with telmisartan 40 mg plus HCTZ
(T40/H12.5), losartan 50 mg plus HCTZ (L50/H12.5), or telmisartan 80 mg plus
HCTZ (T80/H12.5), with the primary objective of comparing T40/H12.5 with
L50/H12.5 and evaluating the additional response of T80/H12.5. Efficacy was
assessed by ambulatory blood pressure monitoring (ABPM), clinic seated cuff
sphygmomanometry and calculated responder rates after 6 weeks' active
treatment. The primary endpoint was reduction from baseline in the last 6-h
mean (relative to dosing) diastolic blood pressure (DBP) measured using 24-h
ABPM. Results:Compared with the L50/H12.5 group, the mean reductions in the
last 6-h mean DBP for the T40/H12.5 and T80/H12.5 groups were significantly
greater: -2.0 mmHg (p=0.0031) and -2.8 mmHg (p=0.0003), respectively.

Conclusion: T40/H12.5 provided clinically and statistically significantly superior

blood pressure reductions compared with L50/H12.5 during the last 6 h of the
24-h dosing interval.
Study 3

Efficacy and tolerability of a fixed-dose combination of telmisartan plus

hydrochlorothiazide in patients uncontrolled with telmisartan
monotherapy(21)

Objective:The antihypertensive effects of a telmisartan 80

mghydrochlorothiazide (HCTZ) 12.5 mg fixed-dose combination and
telmisartan 80 mg monotherapy were compared in patients with a history of
mild-to-moderate essential hypertension and inadequate BP control (DBP >90
mm Hg) following 8 weeks of telmisartan monotherapy.

Methods:At the end of 8 weeks, 491 patients (62.9% men; mean age 55.3
years) whose DBP was >90 mm Hg were double-blind randomized to once-daily
telmisartan 80 mgHCTZ 12.5 mg (n = 246) or telmisartan 80 mg (n = 245).
Trough (24 h post-dose) clinic BP was measured after 4 and 8 weeks of double-
blind therapy.

Results: At the end of double-blind treatment, patients receiving telmisartan 80

mgHCTZ 12.5 mg had significant additional decrements in clinic SBPDBP over
telmisartan 80 mg of -5.7-3.1 mm Hg (P < 0.01). The proportion of patients with
normalised BP (SBP <140 mm Hg and DBP <90 mm Hg) was significantly greater
in the telmisartan 80 mgHCTZ 12.5 mg group than the telmisartan 80 mg group
(41.5%vs 26.1%;P < 0.05). Both treatments were well tolerated.

Conclusion: Telmisartan 80 mgHCTZ 12.5 mg fixed-dose combination confers

significant additional BP reductions compared with continuation of telmisartan
monotherapy in non-responders.

Telmisartan with hydrochlorothiazide ( Telblok-H) is indicated in

• Moderate to severe hypertension

• Patients not controlled with monotherapy

Dosage : Telblok-H tablet contains telmisartan 40mg with hydrochlorothiazide

12.5 mg for once daily administration.

Clinical trials with telmisartan :

The Telmisartan versus Ramipril in renal ENdothelium DYsfunction (TRENDY)

trial examined endothelial function of the renal vasculature as a therapeutic
target in patients with hypertension and type 2 diabetes, but without
albuminuria. The rationale was that blockade of the renin-angiotensin system
(RAS) is cardio- and renoprotective at later stages of the disease, but the impact
of blockade of the RAS at earlier stages of disease is unknown. The results of
TRENDY indicate that the endothelial function, as assessed by basal nitric oxide
activity, can be improved after RAS blockade. These data complement the results
of the Diabetics Exposed to Telmisartan And enalaprIL (DETAIL) trial, which
demonstrated that telmisartan and enalapril similarly decelerate the progression
of overt diabetic nephropathy.(22)

AMADEO

The Efficacy of Telmisartan Compared With Losartan in Reducing Proteinuria in

Hypertensive Type 2 Diabetic Patients With Overt Nephropathy (AMADEO) study
results showed that telmisartan reduced creatinine and BP levels after one year
of treatment compared with losartan.

Researchers enrolled 860 patients with hypertension (BP >130 mm Hg/ 80 mm

Hg) and overt nephropathy defined as proteinuria (spot urine >700 mg/g
creatinine), serum creatinine <3 mg/dL in women and <3.2 mg/dL in men. After
a run-in period, they randomly assigned 419 patients to 40 mg of telmisartan
and 441 patients to 50 mg of losartan for two weeks, and then titrated the doses
to 80 mg of telmisartan and 100 mg of losartan, for 50 weeks.

The average age of the patients in both arms was 60. Serum creatinine was 1.54
in the telmisartan group and 1.55 in the losartan group.

The primary endpoint was change from baseline in morning spot urinary protein
creatinine; the telmisartan group was superior to losartan (0.71; 95% CI, 0.66-
0.77 vs. 0.80; 95% CI, 0.74-0.87). No significant BP reductions were noted
between the two medications.

“Telmisartan provides greater reduction in proteinuria over losartan,”

-The Ongoing Telmisartan Clinical trial Programme include over 54000 patients.

The PROTECTION programme

( Programme of research to show Telmisartan End-organ protection )

The objective is to assess the benefits of the drug in patients at high risk of
renal,cardiac and vascular damage.It involves more than 6500 patients in more
than 30 countries.This programme comprises 10 trials comparing telmisartan
with ARBs, ACE inhibitors and CCBs in patients at risk of target organ damage or
with renal disease. 5 studies will evaluate the effects of telmisartan on early
morning bloodpressure BP control.3 of them will examine the effects of a fixed
dose combination of telmisartan and hydrochlorothiazide in patients with mild to
moderate hypertension, and in hard to treat,at risk populations such as patients
with diabetes,obesity and elderly with isolated systolic hypertension.

PRoFESS (Prevention Regimen For Effectively avoiding Second Strokes)

The world’s largest secondary stroke prevention trial

► 15,000 patients with recent ischaemic stroke

– 32 countries, 600 study centres
► Two primary analyses:
– Telmisartan added to standard antiplatelet therapy versus standard
antiplatelet therapy alone
– ER-DP + ASA compared with Clopidogrel
► Treatment period up to 4 years
► Primary outcome is time to recurrent stroke
(target is 2,280 strokes)

ONTARGET/TRANSCEND

(ONgoing Telmisartan Alone and in combination with Ramipril Global

Endpoint Trial / Telmisartan Randomized Assessment study in ACE-I
Intolerant subjects with cardiovascular disease)

Largest ARB cardiovascular protection trial ever undertaken

► 31000 patients (aged ≥55 years) over 5.5 years

► Compares telmisartan, ramipril and the combination
► Parallel TRANSCEND trial(5000 patients) compares telmisartan with
placebo in ACE-inhibitor intolerant patients
► Patients at high risk of cardiovascular events, with history of
– coronary artery disease
– peripheral vascular disease
– stroke or recent ischaemic attack
 – diabetes mellitus type 1 or 2 with target-organ damage
► Primary endpoint is a composite of cardiovascular death, stroke, acute
myocardial infarction and hospitalization for congestive heart failure

References:

1.Trends in hypertension epidemiology in India.J Hum Hypertens. 2004;

18(2):73-8.

2.Hypertension in diabetes.Diabetes and cardiovascular disease review;issue2:1-

4

3.2003 WHO/International society of hypertension(ISH) statement on

management of hypertension.Journal of Hypertension 2003;21:1983-1992.

4.hypertension and cardiovascular disease.cardiovascular MedicineII.2004 1 (6):

217-56.

5.Morning surge in blood pressure as a predictor of silent and clinical

cerebrovscular disease in elderly hypertensives:a prospective
study.circulation;107:1401-1406.
6. Morning surge and variability in blood pressure.a new therapeutic target?
Hypertension 2005; 45:485-486.

7.AngiotensinI I receptor blockers. BUMC proceedings 2003;16:123-126..Morning

surge and variability in blood pressure.a new therapeutic target? Hypertension
2005; 45:485-486.
8. Telmisartan,its potential therapeutic implications in cardiometabolic
disorders.Recent patents on cardiovascular Drug discovery, 2006;1:79-83.

9.Identification of telmisartan as a unique Angiotensin II receptor antagonist

with selective PPAR-γ modulating activity.Hypertension.2004;43:993-1002.

10.Angiotensin II receptor antagonist telmisartan in isolated systolic

hypertension(ARAMIS) study:efficacy and safety of telmisartan 20, 40, or 80 mg
versus hydrochlorothiazide 12.5 mg or placebo.J Hypertension.2004
May;22(5):1033-7.
11. The effect of telmisartan and ramipril on early morning blood pressure surge
: a pooled analysis of two randomized clinical trials.Blood Press Monit.2007
Jun;12(3):141-147.

12. Efficacy and safety of telmisartan vs. losartan in control of mild to moderate
hypertension : a multi centre, randomized, double blind study.Int J Clin Pract
Suppl.2004 Dec;(145):46-9.

13. ABPM comparison of the antihypertensive profiles of the selective

angiotensin II receptor antagonists telmisartan and losartan in patients with mild
to moderate hypertension.Journal of Human Hypertension ( 1999) 13. 657-664.

14. Comparison of telmisartan versus losartan : meta-analysis of titration to

response studies.Blood Pressure Monitoring.2003;8(3):111-117.

15. Impact of telmisartan versus ramipril on renal endothelial function in patients

with hypertension and type 2 diabetes.Diabetes Care.2007;30: 1351-1356.

16. The differential effects of angiotensinII type 1 receptor blockers on

microalbuminuria in relation to low grade inflammation in metabolic hypertensive
patients.Am J Hypertens.2007 ;20(5):565-72.

17. Three-dimensional echocardiographic and magnetic resonance assessment of

the effect of telmisartan compared with carvedilol on left ventricular mass a
multicenter, randomized, longitudinal study.Am J Hypertens.2005:18:1563-9.

18. Metabolic effect of telmisartan and losartan in hypertensive patients with

metabolic syndrome.Cardiovascular diabetology 2005;4:6

19. Comparison of a Fixed-Dose Combination of 40 mg Telmisartan Plus 12.5

mg Hydrochlorothiazide With 40 mg Telmisartan in the Control of Mild to
Moderate Hypertension.American Journal of Therapeutics.2002.9(2):111-117.

20. Telmisartan/Hydrochlorothiazide in Comparison with

Losartan/Hydrochlorothiazide in Managing Patients with Mild-to-Moderate
Hypertension.Hpertens Res 2005; 28: 555-563.

21. Efficacy and tolerability of a fixed-dose combination of telmisartan plus

hydrochlorothiazide in patients uncontrolled with telmisartan
monotherapy.2001.15;763-770.
22. J Hypertens Suppl. 2006 Apr;24(2):S31-5.