The Importance of Hypertension…

  Hypertension is a powerful risk factor for cardiovascular morbidity and mortality, including:

  Ischemic heart disease

  Ischemic and hemorrhagic stroke

  Heart failure

  Chronic kidney disease, and

  Cognitive decline.

  Hypertension is also a potentially preventable cause of premature morbidity and mortality.

Hypertension contributes significantly to the global burden of disease and global mortality

16 million

7–8 million

4–3 million

2–3 million

Global mortality

128 million

59 million

39 million

30 million

Global burden of disease

All cardiovascular High BP High cholesterol Overweight and obesity

Ezzati et al. PloS Med 2005;2:e133

According to the 2010 data from the Institute for Health Metrics

and Evaluation, hypertension is the biggest contributor to the

global burden of disease (GBD) and to global mortality

Hypertensive Patients Are at Increased Risk for Cardiovascular Events

Framingham Heart Study - Risk of Cardiovascular Events by Hypertensive Status in Patients Aged 35-64 Years; 36-Year Follow-Up

Kannel WB JAMA 1996;275(24):1571-1576.

Risk Ratio 2.0 2.2 3.8 2.6 2.0 3.7 4.0 3.0 Excess Risk 22.7 11.8 9.1 3.8 4.9 5.3 10.4 4.2

Bie

nnia

l Age

-Adj

uste

d R

ate

per

1000

0 10 20

30 40 50 Coronary Disease

9.5

45.4

21.3 22.7

Men Women

Peripheral Artery Disease

5 2

9.9 7.3

Men Women

Cardiac Failure

3.5 2.1

13.9 6.3

Men Women

Stroke

3.3 2.4

12.4 6.2

Men Women

Normotensive Hypertensive

Managing the Patient with Hypertension...

How do I control my Blood Pressure?

What should my Blood Pressure be?

What should my Patient’s Blood Pressure

Target be?

What therapeutic intervention should I

advise to achieve this?

Is my Blood Pressure too high?

At what Blood Pressure should I consider

treating my patient?

At what Blood Pressure should treatment be started?

What is the Target Blood Pressure (for the patient under consideration)?

Which Drug should I prescribe to get to that target?

3 Important Clinical Questions to Answer...

An Overview of Hypertension Guidelines

Guidelines… Why do we need them?

  Guidelines provide a useful and practical framework with which medical practitioners can deliver optimal healthcare for their patients.

  Guidelines give physicians and healthcare providers assurance that their treatment is aligned with that of fellow professionals from other countries, both regionally and internationally.

  Guidelines provide patients with the confidence and assurance that their medical practitioners are up-to-date with current therapies and treatment regimes that conform to an internationally accepted standard and quality of care.

  Guidelines are now published based on extensive clinical trial evidence in millions of diverse patient populations worldwide.

Blood Pressure Goals of New Hypertension Guidelines

Guidelines Population BP target Recommended drugs BHS/NICE (2011) General <80 <140/<90 ARB/ACE-I for <55

General >80 <150/<90 CCB for >55 or AA-Blacks

KDIGO (2012) CKD no/mild proteinuria <140/<90 No specific recommendation CKD +proteinuria <130/<80 ARB or ACE-I

ESH/ESC (2013) General non-elderly <140/<90 All General elderly <80 140-150/<90 All (<140 if tolerated) General elderly >80 140-150/<90 All Diabetics <140/<85 All, but RAS blockers preferred if proteinuria present CKD <140/<90 RAS blockers preferred, no Aldo CKD with proteinuria <130/<90 RAS blockers preferred, no Aldo

Blood Pressure Goals of New Hypertension Guidelines

Guidelines Population BP target Recommended drugs

JNC 8 (2013) General >60 <150/<90 Non-black: Diuretic, ACE-I, General <60 <140/<90 ARB, CCB; Black: Diuretic, CCB

Diabetics <140/<90 Diuretic, ACE-I, ARB or CCB CKD <140/<90 ACE-I or ARB

ASH-ISH (2013) General <80 <140/<90 Non-black <60: ARB or ACE-I General >80 <150/<90 Non-black >60: CCB or diuretic

Black: CCB or diuretic Diabetics <140/<90 ARB or ACE-I

Diabetics+albuminuria, CKD <130/<80 ARB or ACE-I

ADA (2013) Diabetics <140/<80 Regimen should include ACE-I or ARB

Risk Stratification

No other RF

Blood pressure (mm Hg)

The 2013 ESH/ESC Guidelines for the Management of Arterial Hypertension

High normal Grade 1 HT Grade 2 HT Grade 3 HT SBP 130-139 SBP 140-159 SBP 160-179 SBP >180 or DBP 85-89 or DBP 90-99 or DBP 100-109 or DBP >110

Other risk factors, asymptomatic organ damage or disease

1-2 RF

>3 RF

OD, CKD stage 3 or diabetes

Low risk Moderate risk High risk

Low risk Moderate risk

Low to moderate risk

Moderate to high risk High risk

High risk

Symtomatic CVD, CKD stage >4 or diabetes with OD/RFs

Moderate to high risk

Moderate to high risk

High risk

High risk High risk High to very high risk

Very high risk Very high risk Very high risk Very high risk

To Summarize: Your patients’ BP target...

  If your patient has diabetes:   Aim for a SBP target of <140 mm Hg (ESH/ESC, JNC 8, ASH,

ADA)

  Aim for a DBP target of 80-90 mm Hg (ESH/ESC, JNC 8, ASH)

  The ADA and CHEP recommend a DBP target of < 80 mm Hg

  If your patient has CKD:   Aim for a BP target of <140/<90 mm Hg (All)

  If your patient has proteinuria (CKD and/or diabetes):   Aim for a SBP target of <130 mm Hg (KDIGO, ESH/ESC, ASH)

  Aim for a DBP target of <80 mm Hg (KDIGO, ASH) (<90 mm Hg for ESH/ESC)

To Summarize: Your patients’ BP target...

  For your patient without diabetes, CKD or proteinuria:   Aim for a BP target of <140/<90 mm Hg (All guidelines)

  When your patient reaches the age of 80:   Continue to maintain the BP target of <140/<90 mm Hg if

tolerated (ESH/ESC), OR

  Aim for a higher SBP target of <150 mm Hg (BHS/NICE, ASH, CHEP)

(JNC 8 suggests a target of <150/<90 mm for patients >60)

Anti-Hypertensive Therapy

Initiation of Lifestyle Changes and Antihypertensive drug treatment

No other RF

Blood pressure (mm Hg)

The 2013 ESH-ESC Guidelines for the Management of Arterial Hypertension

High normal Grade 1 HT Grade 2 HT Grade 3 HT SBP 130-139 SBP 140-159 SBP 160-179 SBP >180 or DBP 85-89 or DBP 90-99 or DBP 100-109 or DBP >110

Other risk factors, asymptomatic organ damage or disease

1-2 RF

>3 RF

OD, CKD stage 3 or diabetes

No BP intervention •  Lifestyle changes

for several months •  Add BP drugs

targeting <140/<90

•  Lifestyle changes for several weeks

•  Then add BP drugs targeting <140/<90

•  Lifestyle changes •  Immediate BP drugs targeting <140/<90

•  Lifestyle changes •  No BP intervention

•  Lifestyle changes for several weeks

•  Then add BP drugs targeting <140/<90

•  Lifestyle changes •  No BP intervention

•  Lifestyle changes for several weeks

•  Then add BP drugs targeting <140/<90

•  Lifestyle changes •  Immediate BP drugs targeting <140/<90

•  Lifestyle changes •  Immediate BP drugs targeting <140/<90

Symptomatic CVD, CKD stage >4 or diabetes with OD/RFs

•  Lifestyle changes for several weeks

•  Then add BP drugs targeting <140/<90

•  Lifestyle changes •  No BP intervention

•  Lifestyle changes •  BP drugs

targeting <140/<90

•  Lifestyle changes •  BP drugs

targeting <140/<90

•  Lifestyle changes •  BP drugs

targeting <140/<90

•  Lifestyle changes •  Immediate BP drugs targeting <140/<90

•  Lifestyle changes •  Immediate BP drugs targeting <140/<90

•  Lifestyle changes •  No BP intervention

•  Lifestyle changes •  BP drugs

targeting <140/<90

•  Lifestyle changes •  BP drugs

targeting <140/<90

Choice of Anti-hypertensive Therapy

  The current ESH/ESC guidelines confirm that diuretics, beta-blockers, calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers are all suitable for the initiation and maintenance of antihypertensive treatment, either as monotherapy or in some combinations.

  In the general nonblack population, including those with diabetes, initial antihypertensive treatment should include a thiazide-type diuretic, calcium channel blocker (CCB), angiotensin-converting enzyme inhibitor (ACEI), or angiotensin receptor blocker (ARB). (JNC 8)

  The American Society of Hypertension (ASH), Canadian Hypertension Education Program (CHEP) and the National Institute for Health and Clinical Excellence (NICE) guidelines recommend initial therapy based on age and ethnicity.

All guidelines agree that the choice of drugs to be considered would

depend on whether there are any compelling indications that would

necessitate the preferential use of a group of drugs over another.

To Summarize: Your Choice of Anti-hypertensive Drug...

  If your patient has diabetes:   ARB and ACE-I recommended, especially if there is proteinuria (ASH/ISH)

  Regimen should include a RAS blocker (ADA)

  All groups of drugs but RAS blockers preferred if proteinuria is present (ESH-ESC)

  All groups of drugs (JNC 8, CHEP)

  If your patient has CKD:   ARB or ACE-I recommended (ASH/ISH, JNC 8)

  RAS blockers preferred, no Aldosterone (ESH-ESC)

  ARB or ACE-I in CKD with proteinuria, no specific recommendation in CKD without proteinuria (KDIGO)

To Summarize: Your Choice of Anti-hypertensive Drug...

  For your general hypertensive patient:   All groups of drugs (ESH-ESC)

  All groups of drugs in the non-black population (JNC 8)

  ARB or ACE-I in “younger” non-black patients (<55 in BHS/NICE, <60 in ASH/ISH)

  CCB or Diuretic in “older” non-black patients (>60 in ASH/ISH)

  CCB in “older” non-black patients (>55 in BHS/NICE)

  For your “high-risk” patient (CHEP):   ARB or ACE-I

Multiple antihypertensive agents are required to reach BP goal, particularly in patients with co-morbidities

Average no. of antihypertensive medications 1 2 3 4

Trial (SBP achieved)

ALLHAT (138 mmHg)

RENAAL (141 mmHg)

UKPDS (144 mmHg)

ABCD (132 mmHg)

MDRD (132 mmHg)

HOT (138 mmHg)

AASK (128 mmHg)

ACCOMPLISH (132 mmHg) Initial 2-drug combination therapy

Bakris et al. Am J Med 2004;116(5A):30S–8; Dahlöf et al. Lancet 2005;366:895–906 Jamerson et al. Blood Press 2007;16:80-6; Jamerson et al. N Engl J Med 2008;359:2417-28

IDNT (138 mmHg)

ASCOT-BPLA (136.9 mmHg)

~1/3 normalized with 1 drug ~1/3 normalized with 2 drugs

~1/3 normalized with >3 drugs

Rationale for Combination Therapy

  Combines drugs acting on different physiological systems in a situation where the phenotype is not known and where a pharmacological ‘attack’ on two (or more) systems will have a greater impact on blood pressure reduction than blind monotherapy.

  Blocks counter-regulatory responses that are activated by the perturbation of the blood pressure regulatory mechanisms when a physiological system is blocked with single-drug therapy.

  Reduces blood pressure variability.

  More and more patients, particularly the elderly and those with multiple risk factors, require two or more drugs for adequate blood pressure control.

Modified from Sever PS, Messerli F. Eur Heart J, (2011) 32 (20): 2499-2506

Guidelines Recommendations on Combination Therapy

  Initiation of antihypertensive therapy with a two-drug combination may be considered in patients with markedly high baseline BP or at high CV risk.1

  The guidelines favour the use of combinations of two antihypertensive drugs at fixed doses in a single tablet, because reducing the number of pills to be taken daily improves adherence... and increases the rate of BP control.1

  In no less than 15–20% of hypertensive patients, BP control cannot be achieved by a two-drug combination. When three drugs are required, the most rational combination appears to be a blocker of the renin–angiotensin system, a calcium antagonist & a diuretic at effective doses.2

1Mancia G, et al. Journal of Hypertension 2013, 31:1281–1357. 2Mancia G, Laurent S, Agabiti–Rosei E et al. Journal of Hypertension 2009, 27:2121–2158

Treatment of Adults with Systolic/Diastolic Hypertension without Other Compelling Indications

TARGET <140/90 mmHg INITIAL TREATMENT AND MONOTHERAPY

•  BBs are not indicated as first line therapy for age 60 and above

Beta- blocker*

Long-acting CCB Thiazide ACEI " ARB"

Lifestyle modification therapy

ACEI, ARB and direct renin inhibitors are contraindicated in pregnancy and caution is required in prescribing to women of child bearing potential

A combination of 2 first line drugs may be considered as initial therapy if the blood pressure is >20 mmHg systolic or >10 mmHg diastolic above target

2013 ESH-ESC Guidelines for Arterial Hypertension: Choice of antihypertensive drugs

Angiotensin-receptor blockers

Calcium antagonists

ACE inhibitors

Other antihypertensives

Beta-blockers

Thiazide diuretics

Preferred 2-drug combinations

Acceptable 2-drug combinations

Unacceptable 2-drug combinations

•  ACE inhibitor/diuretic •  ARB/diuretic •  ACE inhibitor/CCB •  ARB/CCB

•  Beta-blocker/diuretic* •  CCB/diuretic •  Renin inhibitor/diuretic •  Thiazide diuretic/potassium- sparing diuretic

•  ACE inhibitor/ARB •  ACE inhibitor/beta blocker •  ARB/beta blocker •  CCB (non-dihydropyridine)/ beta blocker

•  Centrally acting agent/beta blocker

Sever PS, Messerli F. Eur Heart J, (2011) 32 (20): 2499-2506

•  Beta-blocker/diuretic •  CCB/diuretic •  CCB (di-hydropyridine)/ beta blocker

•  Renin inhibitor/diuretic •  Renin inhibitor/CCB •  Dihydropyridine CCB/non- dihydropyridine CCB

•  ACE inhibitor/ARB •  Renin inhibitor/ARB •  Renin inhibitor/ACE inhibitor •  RAS inhibitor/beta blocker •  CCB (non-dihydropyridine)/ beta blocker

•  Centrally acting agent/beta blocker

CCB=calcium-channel blocker ARB=angiotensin-receptor blocker

Hypertension management 2011: optimal combination therapy

Preferred 2-drug combinations

Acceptable 2-drug combinations

Unacceptable 2-drug combinations

•  ACE inhibitor/diuretic* •  ARB/diuretic* •  ACE inhibitor/CCB* •  ARB/CCB*

•  Beta-blocker/diuretic* •  CCB/diuretic •  Renin inhibitor/diuretic •  Thiazide diuretic/potassium- sparing diuretic

•  ACE inhibitor/ARB •  ACE inhibitor/beta blocker •  ARB/beta blocker •  CCB (non-dihydropyridine)/ beta blocker

•  Centrally acting agent/beta blocker

*Single-pill combinations available in the US CCB=calcium-channel blocker ARB=angiotensin-receptor blocker

Gradman AH et al. J Am Soc Hypertens 2010, 4:42-50., 90-98.

Drug combinations in hypertension: Recommendations of ASH

Australian Heart Foundation: Combination Therapy

ACE inhibitor or Angiotensin II receptor antagonist

plus Calcium channel blocker

Based on the best available evidence, the most effective combination is:

Other effective combinations include: ACE inhibitor or Angiotensin II receptor antagonist

plus Thiazide diuretic

ACE inhibitor or Angiotensin II receptor antagonist

plus Beta-blocker

Beta-blocker

plus

plus

plus

Di-hydropyridine calcium channel blocker

Thiazide diuretic Calcium channel blocker Thiazide diuretic Beta-blocker (not recommended in people with glucose intolerance,

metabolic syndrome or established diabetes)

(particular role in the presence of coronary heart disease)

(recommended post myocardial infarction or in people with heart failure)

(particular role in the presence of heart failure or post stroke)

(particular role in the presence of diabetes or lipid abnormalities)

Properties of Telmisartan compared to other ARBs

Telmisartan Losartan Irbesartan Candesartan

Cilexetil Olmesartan medoxomil Eprosartan Valsartan

Active metabolite No EXP3174 No Candesartan Olmesartan No No

Bioavailability (%) 30–60 29–43 60–80 15–42 26–29 13–15 10–43

Volume of distribution (L) 500 28–47 53–93 9 17 13 17

Terminal t½ (h) 24 6–9 11–15 3–11 10–15 5–7 9

Hepatic: renal elimination

98:2 no CYP450

65:35 CYP450

80:20 CYP450

67:33 no CYP450

60:40 no CYP450

90:10 no CYP450

80:20 no CYP450

Protein binding (%) 99.5 98.7 90.0 99.5 99.0 98.0 95.0

t½= elimination half-life; Table adapted from: Brunner HR. J Hum Hypertens 2002;16(Suppl. 2):S13–6. Burnier M, Brunner HR. Lancet 2000;355:637–45; Barreras A, Gurk-Turner C. BUMC Proceedings 2003; 16:123–6; Israili ZH. J Hum Hypertens 2000;14(Suppl. 1):S73–S86. Whittaker A. Br J Cardiol 2005;12:125–9

Compared to other ARBs, telmisartan has a

high oral bioavailability and a longer half-life

Amlodipine has Shown CV Protective Efficacy in Landmark Studies

1. Pitt et al. Circulation. 2000;102:1503–1510; 2. Nissen et al. JAMA. 2004;292:2217–2226; 3. Dahlof et al. Lancet. 2005;366:895–906; 4. Williams et al. Circulation. 2006;113:1213 –1225; 5. Leenen et al. Hypertension.2006;48:374–384.

PREVENT1 825 CAD patients (≥ 30%); multicentre, randomized, placebo-controlled

Primary outcome: no difference in mean 3-y coronary angiographic changes vs placebo 35% ↓hospitalization for heart failure + angina 33% ↓revascularization procedures

CAMELOT2 1,991 CAD patients (≥ 20%); double-blind, randomized study vs placebo and enalapril 20 mg

Primary outcome: 30%↓in CV events vs placebo 41% ↓hospitalization for angina 27% ↓coronary revascularization

ASCOT-BPLA/CAFE3,4 19,257 HTN patients; multicentre, randomized, prospective study vs atenolol

Primary outcome: 10%↓in non-fatal MI and fatal CHD 16% ↓total CV events and procedures 30% ↓new-onset diabetes 27% ↓stroke 11% ↓all-cause mortality 4.3 mmHg ↓central aortic pressure

ALLHAT5 18,102 HTN patients; multicentre, randomized, prospective study vs lisinopril

Primary outcome: no difference in composite of fatal CHD and non-fatal MI vs lisinopril 6% ↓combined CVD 23% ↓stroke

33

Telmisartan is the Most Studied Amongst ARBs in Mortality and Morbidity Endpoint Trials

Num

ber o

f pat

ient

s 44,264

51,878

19,335

12,565

1,405

1. Schrader et al. Stroke. 2005;36:1218–1226; 2. http://www.roadmapstudy.org/resident.aspx; 3. Parving et al. N Engl J Med. 2001;345:870–878; 4. Lewis et al. N Engl J Med. 2001;345:851–860; 5. Carson et al. J Card Fail. 2005;11:576–585; 6. Papademetriou et al. J Am Coll Cardiol. 2004;44:1175–1180; 7. www.atacand.com; 8. Brenner et al. N Engl J Med. 2001;345:861–869; 9. Pitt et al. Lancet. 2000;355:1582–1587; 10. Dickstein et al. Lancet. 2002;360:752–760; 11. Dahlof et al. Lancet.

2002;359:955–1003; 12. Cohn et al. N Engl J Med. 2001;345:1667–1675; 13. www.novartis.com; 14. Pfeffer et al. N Engl J Med. 2003;349:1893–1906; 15. Julius et al. Lancet. 2004;363:2022–2031; 15. www.ontarget-micardis.com.

6,405 4,449

Val-HeFT12 IRMA II3

LIFE11

ONTARGET®16

TRANSCEND®16

PRoFESS®16 NAVIGATOR13

VALIANT14

VALUE15

OPTIMAAL10

ELITE II9

RENAAL8 SCOPE6

CHARM7

MOSES1

IDNT4

I-Preserve5

ROADMAP2

Epro- sartan

Lo- sartan

Val- sartan

Cande- sartan

Irbe- sartan

Telmi- sartan

Olme-sartan

* 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

Mea

n ch

ange

from

bas

elin

e (m

mH

g)

A5–A10* (n = 195)

-5

-10

-15

-20

Week

p = 0.0301

p = 0.0089

p = 0.0001 p =

0.0002 p =

0.0006

0 2 4 6 8

DBP

T80/A5–A10* (n = 379)

Mea

n ch

ange

from

bas

elin

e (m

mH

g)

-10

-20

-30

-40

-50

0 2 4 6 8

Week

p = 0.0077

p = 0.0001

p = 0.0001 p =

0.0001 p =

0.0002

SBP

Telmisartan/Amlodipine Provides Significant BP Reductions (> 31 mmHg SBP) After Only 1 Week of Treatment

Neutel et al. J Clin Hypertens. 2010: In press; ASH 2010 poster presentation (LB-PO-10).

Telmisartan Plus Amlodipine (80/10) Provides Consistent BP Reductions Across HTN Severities

-33.7 -36.9

-47.5 -48.9

- 6 0

- 5 0

- 4 0

- 3 0

- 2 0

- 1 0

0 160 – < 1701 190 – < 2002 170 – < 1801 180 – < 1902

1. Littlejohn et al. J Clin Hypertens. 2009;11:207–213; 2. Neutel et al. J Clin Hypertens. 2010; ASH 2010 poster presentation (LB-PO-10) & data on file

Moderate HTN Severe HTN Baseline SBP =

(n = 31) (n = 71) (n = 13) (n = 305)

Mea

n SB

P re

duct

ions

from

ba

selin

e (m

mH

g)

Obese BMI ≥ 301

(n = 175)

-43.2

- 6 0 - 5 0

- 4 0 - 3 0

- 2 0 - 1 0

0 Diabetic1

(n = 62)

Metabolic syndrome1*

(n = 36)

Severe HTN ≥ 180/95 mmHg2

(n = 379) (n = 100)

Elderly ≥ 65 y1

(n = 30) Black1

Mea

n SB

P re

duct

ions

from

ba

selin

e (m

mH

g)

Mean baseline BP = 185.4/103.2 mmHg * Diabetes, obesity (BMI ≥ 30kg/m2), and HTN

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).

Telmisartan Plus Amlodipine Provides Consistently High BP Reductions in Hypertensive at-Risk Patients

-46.8 -46.6 -46.1 -47.5 -44.2

Telmisartan (mg)

0

5

10

15

20 25

0 40 80 0

5 10

Telmisartan (mg)

0 2 4 6 8

10 12 14 16

0 40 80 0

5 10

24-h mean SBP reduction (mmHg)

24-h mean DBP reduction (mmHg)

** p < 0.001; *** p < 0.0001 vs Telmisartan alone; ††† p < 0.0001 vs Amlodipine alone; n = 562

***††† ***†††

***††† ***†††

***†††

**†††

***†††

***†††

Telmisartan Plus Amlodipine Provides Consistent 24-h ABPM Dose Response

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

Conclusions

  Hypertension remains a powerful and important risk factor for cardiovascular disease.

  As we review the various available guidelines, it is essential that we determine how they may be applicable to our daily clinical practice.

  In managing our patients with hypertension, we need to:

  Assess their overall cardiovascular risk

  Determine the patient’s appropriate blood pressure

  Advise non-pharmacological lifestyle measures

  Select an appropriate anti-hypertensive agent/agents

  The ARB/CCB combination of Telmisartan and Amlodipine has been shown to provide excellent blood pressure control in a range of hypertension severities and in a variety of difficult-to-treat and high-risk hypertensives.

Thank you!

Striving towards a blood pressure goal...

  Categorization of blood pressure

  Risk stratification of hypertensive patients

  Decision on target blood pressure

  Choice of treatment