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