5.2 BP Variability Single Pill Combination - Dr. Budi Bakti Sp.jp(1)

8/18/2019 5.2 BP Variability Single Pill Combination - Dr. Budi Bakti Sp.jp(1)

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Telmisartan + Amlodipine Clinical Studies

Single Pill Combination Concept & Why ARB + CCB

Summary

Introduction & Background

Agenda


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Summary


Agenda


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Krishnan A. Regional Health Forum. Vol 17, Number 1;2013;7-11

WHO Age-standardized Estimates of the Prevalence of

Hypertension in Sout East Asia Region

Estimates of age-standardized prevalence (%) of raised blood pressure in adults aged 25+

years in countries of the SEA Region, 2008

Country Men Women Both

Myanmar44.3

(37.7-50.5)

39.8

(33.1-46.5)

42.0

(37.2-46.8)

Indonesia 42.7(35.3-49.9)

39.2(32.5-46.0)

41.0(35.9-45.8)

India36

(29.7-41.8)

34.2

(28.6-39.9)

35.2

(30.9-35.2)

Thailand37.0

(31.3-42.5)

31.6

(26.0-37.1)

34.2

(30.0-38.1)

Asia Tenggara37.6

(32.6-42.4)

35.4

(30.9-39.8)

36.6

(33.1-39.8)

Global40.8

(37.7-43.7)

36.0

(33.3-38.6)

38.4

(36.3-40.5)


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Chobanian A et al. JAMA 2003. 289:2560-72

Classification of Blood Pressure (JNC 7)

BP categorySBP

(mmHg)

DBP

(mmHg)

Normal


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James P et al. JAMA. 2013;289: E1-E14

2014 Hypertension Guideline Management Algorithm (JNC

8)


7/31James P et al. JAMA. 2013;289: E1-E14

2014 Hypertension Guideline Management Algorithm (JNC

8)


8/31Chobanian A et al. JAMA 2003. 289:2560-72

The Relationship Between BP

and Risk of CVD events

*Individuals aged 40-70 years, from BP

115/75 mm Hg to 185/115 mmHg.

Benefits of Lowering BP

35-40%

Stroke

Incidence20-25 %

MI

50 %

HF


9/31Chobanian A.. NEJM 2009. 361:878-87

Rate of Controlled Patients

28% ---------------------------------

Unaware of their

hypertension

39% ---------------------------------

Not Receiving therapy

65% ---------------------------------

Do not have their BPcontrolled to levels below

140/90 mmHg


10/31Barkas F, et al. Hellenic Journal of Atherosclerosis 1 (1):18-25

Poor Compliance with Antihypertensive Treatment

24-51%

Non-

compliant

29-58%

Non-

persistent

- 1/3 – 1/2 patients in US & Canada

with inadequately BP control

- 40-66% with concurrent

hypertension & diabetes

- In Euro : > 2/3 of treated patients

with inadequately BP control

Consequences of poor adherence &

compliance

- Encompasses a higher risk of CVD,

hospitalization and increased

health care utilization cost- Nonpersistence

↑ 15% AMI, ↑ 28% Stroke


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Guidelines worldwide Acknowledge That Most Patients

Need Combination Therapy

to Achieve BP Goals

1. James P et al. JAMA. 2013;289: E1-E142. Mancia et al. Jounal of Hypertension 2013. 31:1281-13573. Weber M et al. The Journal of Clinical Hypertension. 2013. 1-13

• Initiate therapy with ≥ 2 drugs simultaneously

– If SBP is > 20 mmHg above goal and/or DBP is > 10 mmHg

above goal

• Combination of two antihypertensive drugs at fixed doses in a

single tablet may be recommended and favored, because

reducing the number of daily pills improves adherence, which is

low in patients with hypertension.

• If the untreated blood pressure is at least 20/10 mmHg above the

target blood pressure, consider starting treatment immediately

with 2 drugs

JNC 8; 20141

ESH/ESC 20132

ASH/ISH Hypertension Guidelines 20133


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2013 ESH-ESC Guidelines for Arterial Hypertension:

Choice of antihypertensive drugs

Mancia et al. Jounal of Hypertension 2013. 31:1281-1357

ARB+CCB is one of the preffered

antihypertensive combination


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Summary


Agenda


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Monotherapy

1. Monotherapy can effectively reduce BP in only a limited number of hypertensive patients1

Combination Therapy

1. The most patients require the combination of at least two drugs to achieve BP control1

2. The advantage of initiating with combination therapy is potentially beneficial in high-risk

patients1

3. A greater probability of achieving the target BP in patients with higher BP values and a lower

probability of discouraging patient adherence with many treatment changes1

4. Lower drop-out rate than patients given any monotherapy1

5. Fewer side effects and provide larger benefits than those offered by a single agent. (e.g :

RAAS + CCB reduces oedema) 16. Convenient once-daily administration of a single tablet, with potential compliance benefits2

7. Effectively lowers BP in patients with an inadequate response to monotherapy2

Pros and cons of

Monotherapy and combination therapy

Mancia et al. Jounal of Hypertension 2013. 31:1281-1357Drugs The Perspect 2011;Vol.27. No. 5


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Loose Combination or

Single-pill Combination ?

Mancia et al. Jounal of Hypertension 2013. 31:1281-1357Suarez C. Drugs 2011. 71(17):2295-2305Drugs The Perspect 2011;Vol.27. No. 5

Single-pill combination (SPC)1. Reducing the number of pills to be taken daily improves

adherence/patient compliance (Simplify treatment regimens) 1,2,3

2. Provide superior BP-lowering Efficacy2

3. Increases the rate of BP control1

4. Enhanced patient adherence2

5. Reducing healthcare costs3

6. Improved tolerability profile2


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Benefits of Single Pill Combination Concept

Mancia et al. Jounal of Hypertension 2013. 31:1281-1357Suarez C. Drugs 2011. 71(17):2295-2305Drugs The Perspect 2011;Vol.27. No. 5

Single Pill Combination

Good levels of compliance

More rapid and sustained BP control

Reduce cardiovascular morbidity & mortality


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Fixed-dose Combinations Provide a Strong Armamentarium

in Chronic Disease Management

Bangalore S et al. The American Journal of Medicine (2007) 120, 713-719

Effect of fixed-dose combination vs free-drug combination on the risk of

medication non-compliance in cohort with hypertension

Non-compliance

to medication

regimens is

reduced by24-26%

with fixed-dose

combinations

regimens


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Why ARB + CCB ???

Suarez C. Drugs 2011. 71(17):2295-2305

The advantages of ARB+CCB :

1. Synergistic mechanism of action

2. Vascular protective effects due to the improvement in endothelial dysfunction

3. A neutral metabolic profile4. Nephroprotective effect due to its capacity to dilate the renal arterioles

5. Reduced incidence of oedema secondary to the use of CCBs

6. Greater capacity to reduce morbidity/mortality rates in high-risk hypertensive patients than the

RASI-diuretic combination

Natriuresis

Vasodilation

CCB ARB RAS inhibition

↓RAS ↓SNS

Attenuates peripheral oedema

↑RAS ↑SNS

Peripheral Oedema

ArterialArterial +

Venous


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Effects of CCB & RAS

on Capillary Pressure and Oedema Formation

Sierra. Journal of Human Hypertension 2009. 23:503-511

CCB monotherapy

• Selective vasodilation of the

arteriolar side of the circulation

• Increased pressure within the

capillary bed, leading to fluidtransudation and oedema

formation

ARB + CCB (Telmisartan+Amlodipine)

• Cause both arteriolar and venous

vasodilation• Reduces the pressure within the

capillary bed, thereby ameliorating

the oedema

Increased

capillary

pressure

Capillarypressure

lower than

in A

a

b

CCB monotherapy

Arteriolar vasodilationVenous resistance

unchanged

Arteriolar vasodilation Venous vasodilation

RAS inhibitor + CCB

Oedema formation

Oedema formation

reduced


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Telmisartan has Unique Pharmacology among ARBs


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Telmisartan : No Posology Adjustment is Required for

Patients with Renal Impairment,

including those on Haemodialysis

DrugElimination

(feces/urine)

Telmisartan >98% fecal

Losartan 60/35

Valsartan 83/13

Irbesartan 80/20

Candesartan 67/33

Eprosartan 90/10

Olmesartan 35-49% urinary recovery rate*

1. Local Product Information of Micardis, 20142. Adapted from Verdecchia., et al. Expert Rev. Clin. Pharmacol. 4(2). 151-161 (2011)

*For Intravenous olmesartan


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Amlodipine – The longest Half-life in Class

Abernethy et al. The new England Journal of Medicine 1999. 341(9):1447-57

P l a s m a e l i m i n

a t i o n h a l f - l i f e ( h )

2 2

8

12

16

50

0

5

10

15

20

25

30

35

Nifedipine Nimodipine Nicardipine Nisoldipine Felodipine Amlodipine


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Summary


Agenda


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Telmisartan + Amlodipine: Provides consistent BP

Reductions across hypertension severities1,2


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Telmisartan + Amlodipine: Consistently High BP reductions

in added-risk Hypertensive Patients1


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Telmisartan + Amlodipine: Provides Significant Greater BP

Reductions Compared to Amlodipine monotherapy after 1

week

Neutel et al. The Journal of Clinical Hypertension 2012; 14:206-215


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Telmisartan + Amlodipine

Provides 80% of its Maximum Effect After Just 2 Weeks of

Treatment

Neutel J et al. The Journal of Clinical Hypertension. April 2012

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

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

end of study (Week 8)

M e a n S B P ( m m H g )

Mean SBP reduction (mmHg)

185.4

137.9Week 8

80%*

Week 2147.5

Baseline

–47.5 mmHg

T80/A10(n =379)


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Twynsta®: The BP reductions needed

to get hypertensive patients to goal1


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Incidence of peripheral oedema in hypertensive patients

treated for 8 weeks


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Summary


Agenda


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Summary

• Hypertension is the single most important risk factor for mortality in South-East Asia (SEA) region1

• Guidelines on hypertension have consistently recommended early diagnosis and treatment ofhypertension in order to reduce cardiovascular morbidity and mortality2,3,4

• Single Pill Combination simplify treatment regimen, enhanced patient adherence and provide

superior BP-lowering efficacy and improved tolerability profile5

Why Telmisartan + Amlodipine, because:

• Telmisartan has the longest plasma half-life, and long duration of action, higher binding affinity

and longer blockade AT1 receptor, high lipophilicity and large volume distribution6

• Amlodipine has the longest half life in class7

• Twynsta reduces incidence of peripheral oedema in hypertensive patients up to 90%8

• Telmisartan + Amlodipine are well tolerated and provide the combined benefits of powerful BP

reduction and CV protection for difficult-to-manage patients with additional risk factors6

1. Krishnan A. Regional Health Forum. Vol 17, Number 1;2013;7-112. James P et al. JAMA. 2013;289: E1-E143. Mancia et al. Jounal of Hypertension 2013. 31:1281-13574. Weber M et al. The Journal of Clinical Hypertension. 2013. 1-13

5. Suarez C. Drugs 2011. 71(17):2295-23056. Adapted from Verdecchia., et al. Expert Rev. Clin. Pharmacol. 4(2). 151-161 (2011)

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5.2 BP Variability Single Pill Combination - Dr. Budi Bakti Sp.jp(1)