Resistant Hypertensionevaluation and management

Resistant HTN-definition
BP > 140/90 inspite of three concurrent

antihypertensive drugs which also

includes a diuretic in routine patients and

In diabetics and patient with CKD a BP >

130/80 is considered as resistant HTN

Resistant HTN-evaluation
Compliance
Analgesics, appetite suppressants,

erythropoetin

Renal artery stenosis

Hyperaldosteronism
Pheochromocytoma
Thyroid disease
Steroid intake
Salt intake,smoking

Resistant HTN-evaluation
Alchohol binge
Nasal decongestants
Cold and cough medications
Indigenous drugs
Obesity-hypoventilation
Renal parenchymal disease
Polycystic kidney
Primary aldosteronism

Resistant HTN-evaluation
Cushings disease
Pregnancy induced hypertension
Coarctation of aorta

Resistant hypertension-pseudoresistance
High office blood pressure

Adequately controlled home blood

pressure

Role of ambulatory BP monitoring

Cardiovascular Disease Burden

Indian perspective

25% of total deaths in India are related to

cardiovascular diseases (2.3 million deaths)

It has been predicted that by 2020, there would

be a 111% increase in cardiovascular deaths in

India

This increase is much more than 77% for China

Gupta R. Journal of Human Hypertension (2004) 18, 7378.

Cardiovascular Disease Burden

..rising trend in IHD!

Park K. Cardiovascular diseases: Parks Textbook of PSM, 19th Ed, 2007:303

Cardiovascular Disease Burden

Hypertension shares Consistent relationship with CVD risk!

Mortality

16 million

Drop in SBP & DBP by

10- and 5 mm Hg respectively
reduces risk of mortality
from IHD by 30%

7-8 million

4-3 million

2-3 million

Lewington 2002

Population
All cardiovascular
High blood pressure
High cholesterol
Overweight and obesity
Norman M Kaplan, Lionel H Opie Lancet 2006;367:168-76

Hypertension in India
Control remains suboptimal..
Kerala
One third
AWARE

Total

One fourth
TREATED

One tenth
CONTROLLED

Zachariah et al. Ind Heart J 2003; 55:245-51

Hypertension in India
Control remains suboptimal..

% of
uncontrolled
hypertensive
patients

An Indian survey conducted in hypertensive patients (n=3402)

receiving antihypertensive medications showed prevalence of
Uncontrolled HT
Hathial M. J Indian Med Assoc. 2007; 105 (7): 401-2, 404, 410.

Despite the best of treatment care

and drugs available,
Hypertension largely remains
Uncontrolled!

Uncontrolled Hypertension
Complications..
Oxidative Stress /
Endothelial
Dysfunction

Target Organ
Damage
Tissue Injury
(IHD, Stroke)

Vascular Disease
Vascular
Dysfunction

Risk Factors:
Diabetes
Hypertension

Pathological
Remodeling
Target Organ
Dysfunction (HF, Renal)

End-stage
Organ Failure

MI: Myocardial
infarction
HF: Heart failure

Death
Adapted from Dzau et al. Circulation. 2006;114:2850-2870.

Uncontrolled Hypertension
Contributing factors..

1. Monotherapy of drugs controls only 25% of patients

2. Concomitant risk factors Type 2 Diabetes
3. Multi-Pill regimen leading to poor compliance
4. Side effects of conventional agents on higher doses
5. Stringent BP goals to be achieved

Uncontrolled Hypertension
1. Monotherapy with drugs

Counter-regulatory mechanisms with monotherapy

Vasodilatation due to
CCB or Diuretic
RAAS
Activation

BP
RAAS blockade is the foundation
of modern combination therapy

Combination with ARBs counters this mechanism

Uncontrolled Hypertension In India

1. Monotherapy or Combination therapy

Review of 42 trials shows combination of different

classes results in 5 times greater BP reduction
thereby reducing cardiovascular risk*
%

ALLHAT

shows
need for 3
drugs
when
continued
on longterm basis
Chrysant 2011

*Wald DS. Am J Med 2009;122(3):290-300 ; Calhoun DA. Hypertension 2009: 54(1):32-39

Avoiding Cardiovascular events through

COMbination
therapy in Patients LIving with Systolic
Hypertension

ACCOMPLISH
N ENGL J MED 359;23, DEC 2008

Uncontrolled Hypertension

1. Triple Drug Combination required..

Patients often require several anti-hypertensives

%
%
% pts

ACCOMPLISH: Avoiding Cardiovascular Events through COMmbination therapy in Patients Living wIth Systolic Hypertension

Chrysant SG. Postgraduate Medicine 2011;123(6):21-31

Uncontrolled Hypertension
2. Concomitant risk factors ..

Uncontrolled Hypertension
2. Concomitant risk factors..

Diabetes
Diabetes

Hypertension
Hypertension

HTN vs No HTN

2.4x in DM

DM vs No DM

2.0x in HTN

Resistant Hypertension

2. High incidence in Diabetics..

% of
uncontrolled
hypertensive
patients

An Indian survey conducted in hypertensive patients (n=3402) showed that

amongst Diabetics (n=1435 patients), >80% pts had Uncontrolled BP

Guidelines recommend Target Goals of <130/80 mm Hg

Hathial M. J Indian Med Assoc. 2007; 105 (7): 401-2, 404, 410.

Action to Control Cardiovascular

Disease in Diabetes (ACCORD)
10,000 subjects with type 2 diabetes
Double 22 design

Intensive

Standard

HbA1c goal

<6%

<7.5%

Systolic BP

<120

<130

Anti-hypertensive therapy to achieve Target Goals in

Intensive or Standard arms
NHLBI and ACCORD Study Web Site: http://www.nhlbi.nih.gov/new/press/03-02-20.htm. Accessed 10/22/04.

ACCORD

Hypertension controlled by Combination

therapy of antihypertensives
%

% pts

ACCORD: Action to Control Cardiovascular Disease in Diabetes

The ACCORD Study Group . N Engl J Med 2010;362:1575-85

Resistant Hypertension

3. Poor patient compliance..

Multi-drug regimen required to control HT & other risk factors
Fixed drug combination tablets reduces pill burden to improve

patient adherence

%
%

Fung V. Clin Ther 2007;29(5):972-984

Resistant Hypertension

4. Dose dependent side effects

Edema

Edema

Peripheral edema with CCBs

Hypokalemia with Diuretics

Resistant Hypertension In India

4. ARBs ..ideal for Triple Drug therapy

Diuretics

1.83

1.64

-blockers

1.23

CCBs

1.08

ACE-Is

1.00

ARBs

0.92
0.5

1.0

2.0

Cause-specific HR (95% CI) for discontinuation*

* Relative to ACE-I after 1 y of treatment

ARBs are safe & avoid Dose dependant Peripheral edema

Corrrao et al. J Hypertens. 2008;26:819824.
or Hypokalemia with
CCBs or Diuretics

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

29

Mistry et al. Expert Opin Pharmacother. 2006;7:575581;

Sica. Drugs. 2002;62:443462; Quan et al. Am J Cardiovasc Drugs. 2006;6:103113.

CCB
RAS activation
No renal or CHF
benefits

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

30

BP

Synergistic
BP reduction
Complementary
clinical benefits

Mistry et al. Expert Opin Pharmacother. 2006;7:575581; Sica. Drugs. 2002;62:443462;

Quan et al. Am J Cardiovasc Drugs. 2006;6:103113.

ARB
RAS blockade
CHF and renal
benefits

CCB
RAS activation
No renal or CHF
benefits

Telmisartan Plus Amlodipine

as Initial Therapy

31

Telmisartan Plus Amlodipine Provides Consistent

BP Reductions Across HTN Severities
Moderate HTN
Baseline SBP =

160 < 1701 170 < 1801

Mean SBP reductions from

baseline (mmHg)

(n = 31)

32

(n = 13)

Severe HTN
180 < 1902

190 < 2002

(n = 305)

(n = 71)

T80/A10 (n = 1361; n = 3792)

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

Telmisartan Plus Amlodipine Provides BP Reductions of 50

mmHg in Almost 50% of Patients With Severe HTN*

T80/A10

Patients (%)

A10

(n = 65)

(n = 183)

50 mmHg

(n = 37)

(n = 117)

55 mmHg

(n = 20)

60 mmHg

Mean SBP reductions from baseline*

* Mean baseline BP = 185.4/103.2 mmHg
33 Neutel et al. J Clin Hypertens. 2010: In press; ASH 2010 poster presentation (LB-PO-10).

(n = 61)

Telmisartan Plus Amlodipine Provides Consistently High BP

Reductions in Hypertensive at-Risk Patients
Obese
Metabolic Elderly
Diabetic1 BMI 30kg/m1 syndrome1* 65 y1
(n = 175)

Mean SBP reductions from

baseline (mmHg)

(n = 62)

(n = 36)

(n = 100)

T80/A10

Mean baseline BP = 185.4/103.2 mmHg

* Diabetes, obesity (BMI 30kg/m2), and HTN
34

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).

Black

(n = 30)

Severe HTN
180/95 mmHg2
(n = 379)

Telmisartan/Amlodipine Provides 80% of its Maximum Effect

After Just 2 Weeks of Treatment
Mean SBP reduction (mmHg)

Mean SBP (mmHg)

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

* Percentage of effect achieved after 2 weeks of treatment compared with

end of study (Week 8)
A5 and T80/A5 for the first 2 weeks, then forced-titration to A10 and T80/A10, respectively;
baseline BP = 185.4/103.2 mmHg
35 Neutel et al. J Clin Hypertens. 2010: In press; ASH 2010 poster presentation (LB-PO-10).

Telmisartan Plus Amlodipine

24-h ABPM

36

Telmisartan Plus Amlodipine Provides Superior 24-h ABPM

Goal Rate Achievement (< 130/80 mmHg*) in > 82% of Patients

Patients achieving 24-h

ABPM goal* (%)

p < 0.0001

A10
(n = 58)

* AHA criteria for 24-h BP goal

37 Littlejohn et al. J Hypertens. 2008;26(suppl 1):S494; White et al. Blood Press Monit. 2010: In press.

T80/A10
(n = 52)

Telmisartan Plus Amlodipine

Safety and Tolerability

38

Patients with
AEs > 1% incidence (%)

Telmisartan Plus Amlodipine Has a Safety and

Tolerability Profile Similar to Placebo

Placebo (n = 46)

Fatigue Oedema Sinusitis

39 Littlejohn et al. J Clin Hypertens. 2009;11:207213.

A mono (n = 319)

NasoUpper Influenza
pharyn- respiratory
gitis
tract
infection

T/A (n = 789)

Back
pain

Dizziness

Headache Peripheral
oedema

Venous Fluid Leakage Induced by CCBs

Fluid leakage

Arterial
dilation
(CCBs)

No
venous
dilation

Fluid leakage
Capillary bed

40

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.

Telmisartan significantly reduces peripheral oedema

associated with Amlodipine
Incidence of peripheral oedema (%)

* p <0.05; p <0.0001
Littlejohn TW et al. J Clin Hypertension. 2009;11(4):207-213

Telmisartan Plus Amlodipine is Associated With Less

Peripheral Oedema Compared With Amlodipine 10 mg
p < 0.0001

Patients with peripheral

oedema (%)

p < 0.0001

90%

A10
(n = 124)

T4080+A5A10
T4080+A5
(n = 264)

42 Littlejohn et al. J Clin Hypertens. 2009;11:207213.

71%

(n = 543)

Telmisartan + Amlodipine Data

Fast and superior BP reductions of > 31 mmHg (SBP) already after 1 week of
treatment1
Up to 80% of maximum effect already after 2 weeks of treatment 1
Consistent and strong BP reductions of up to 49.5 mmHg (SBP) across
hypertension severities and a wide range of hypertensive at-risk (complex)
patients1
SBP reduction of 50 mmHg in almost 50% of patients with baseline
SBP 180 mmHg1
High BP response rates of up to 99.7% of patients1
Superior and dose dependent 24-h ABPM reductions
Superior 24-h ABPM goal rate achievement (< 130/80 mmHg) of > 82% 2,3
Superior efficacy and safety in patients not at goal with amlodipine 4
A safety and tolerability profile similar to placebo, with up to 90% lower
oedema rates compared with A10 monotherapy5

43

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.

4. ARBs ..ideal for Combination therapy

8-wk, randomized, double-blind clinical trial involving singlet or doublet
therapy for Hypertension

Significant reduction in AEs with

combination at starting dosages
Julian Segura. Integrated Blood Pressure Control 2011:4 2734

Resistant Hypertension

5. Triple Drug therapy for Stringent BP Goals

JNC - 7
< 140 / < 90 mm Hg in pts
with h/o of CVD

130/80 mmHg in pts with

h/o of CVD

< 130 /< 80 mm Hg for

diabetics, CKD

130 /< 80 mm Hg for

diabetics

International Guidelines and Clinical trials recommend

BP levels of 130/80 mm Hg in most pts
JNC 7 guidelines 2003; ESH guidelines 2009; AHA Council statement 2007

Resistant Hypertension

..Role of Triple Drug therapy

1. Monotherapy of drugs controls only 25% of patients

ALLHAT, SCOPE, ACCOMPLISH 3 antihypertensives often

required

2. Concomitant risk factors Type 2 Diabetes

ACCORD, IDNT benefits of combination therapy

3. Multi-Pill regimen leading to poor compliance

FDC tablets increase patient adherence

4. Side effects of conventional agents on higher doses

COACH side effects avoided with combination therapy

5. Stringent BP goals to be achieved

ESH (2009) and AHA council (2007) guidelines for High-risk

patients

Need of Triple drug combination

especially for..
Resistant HTN in Primary hypertensives
or
High-risk patients

Ideal Triple drug therapy option for

Resistant Hypertension

Telmisartan + Amlodipine + HCTZ

Telmisartan+ Amlodipine+ HCTZ

For Hypertension
12 Weeks Randomized, single blind study in patients with
SBP 140 - 200 mmHg and DBP 90 - 120 mmHg (n= 220)
Telmisartan (40 mg) + Amlodipine
(5 mg) + HCT (12.5 mg) OD

Telmisartan (40 mg) +

HCT (12.5 mg) OD

Group A

Group B

Efficacy Parameter:
1.Effect on both SBP and DBP in sitting and supine position
2.Quality of Life (QOL) questioner
3.Safety parameters
Follow-up: on week 1, 2, 4, 6, 8 and 10 for periodic efficacy and
safety evaluations.
Manish Maladkar et al.
Open Journal of Internal Medicine, 2012, 2, 67-71

Telmisartan+ Amlodipine+ HCTZ

RESULTS
The Effect of Triple Drug Combination on SBP and DBP

Telmisartan+ Amlodipine+ HCTZ

RESULTS
Effect on Quality of Life (QOL): Both the treatments were
associated with improved QOL.
Safety Evaluations: Both the treatments were tolerated well with
few reports of adverse events.
All the reported adverse events were of mild to moderate inten- sity
and did not require any active management.
Conclusion:
Telmisartan when combined with amlodipine and HCT showed better control
of both SBP and DBP.
Thus this combination may serve a potential role in achieving desired BP
goals, in patients with essential hypertension, which are otherwise poorly
managed by either mono- therapy or dual drug therapy.
At the same time studied triple drug combination exhibits comparable
tolerability profile to that of dual drug combination .

Triple drug therapy

..for Earlycontrol in Diabetics

Diabetic subgroup analysed

Treatment goal for BP was <130/80 mm Hg
Patients on Dual therapy shifted to Triple

drug therapy after 4 weeks

Results for Triple drug combination

Greater change in BP (p<0.05)

More patients achieved treatment goals (p<0.05)
Most treatment-emergent adverse events were
mild to moderate in severity

Chrysant SG. J Am Soc Hypertens 2012 Mar;6(2):132-41

Telmisartan Amlodipine HCTZ

rationale
Telmisartan

Amlodipine

HCTZ

ARB
Potent vasodilator

Ca Channel blocker
Potent vasodilator

Long half-life of
24 h
Insurmountable
antagonism for 24 h
BP control
vasculoprotection
[NO]

Long half-life of
36-48 h
Excellent
antianginal agent.
vasculoprotection
[NO]
Diuretic property

Thiazide diuretic
Medium potency
diuretics acting by
inhibiting the
Na+/Clsymporter in the
DCT
Long half life of
upto 12 h

Dosage for HTN

Dosage for HTN

40 to 80 mg

2.5 to 5 mg

Dosage for HTN

12.5 to 25 mg

Telmisartan Amlodipine HCTZ

rationale
Telmisartan

Amlodipine

HCTZ

Negligible side effects

Dose dependent
rise in side effects

Safe coprescription
profile
Counters Renin rise due
to Diuretic properties of
HCTZ & Amlodipine
Counteracts
hypokalemia of HCTZ
by preventing
aldosterone release
Potential to diminish
peripheral oedema by
providing both arterial
& venous
vasodilatation.
Lipid neutral

Peripheral edema
, incidence
doubles or triples
with dosages of 5
to 10 mg
Lipid neutral

Dose dependent rise

in side effects
Diabetogenic
effects with 25 mg
Hyperlipidemia
Hypokalemia

Resistant HTN-emerging Rx

Renal denervation therapy

Resistant Hypertension-Summary
Resistant HTN is common
Detailed evaluation and investigation may

be required

Proper management results in significant

reduction in morbidity and mortality