current trends and controversies in the diagnosis and treatment of hypertension focus on the renin...

Current trends and controversies in the diagnosis Current trends and controversies in the diagnosis and treatment of hypertensionand treatment of hypertension

Focus on the Renin Angiotensin Aldosterone Focus on the Renin Angiotensin Aldosterone System and Direct Renin Inhibition System and Direct Renin Inhibition

Tom Smiley BScPhm, PharmDTom Smiley BScPhm, PharmD

CCCEP File 853-0109L1FT

DisclosureDisclosure

Tom Smiley has previously prepared and Tom Smiley has previously prepared and delivered pharmacist education sponsored delivered pharmacist education sponsored by Novartis Inc. by Novartis Inc.

2

The Canadian Council on Continuing Education in Pharmacy has accredited this program for 2 CEUs (CCCEP File # 853-0109L1FT)

Supported by an educational grant from Novartis Canada Inc.

Learning ObjectivesLearning Objectives

After successful completion of this workshop After successful completion of this workshop pharmacists will be better able to:pharmacists will be better able to:

Discuss care gaps in current treatment of hypertensionDiscuss care gaps in current treatment of hypertension Discuss pathophysiology of RAAS and mechanisms of RAAS Discuss pathophysiology of RAAS and mechanisms of RAAS

inhibition inhibition Discuss efficacy and tolerability of direct renin inhibition on Discuss efficacy and tolerability of direct renin inhibition on

hypertension hypertension Assess and recommend appropriate blood pressure monitoring and Assess and recommend appropriate blood pressure monitoring and

hypertension management according to CHEP Guidelineshypertension management according to CHEP Guidelines Discuss the renal outcome evidence for the benefit of RAAS Discuss the renal outcome evidence for the benefit of RAAS

blockade in patients with type 2 diabetesblockade in patients with type 2 diabetes Discuss alternatives to ACE-I + ARB combination

3

Current trends and Current trends and controversies in the diagnosis controversies in the diagnosis and treatment of hypertension and treatment of hypertension

Part 1: A Pharmacist’s Part 1: A Pharmacist’s PerspectivePerspective

Tom Smiley BScPhm, PharmDTom Smiley BScPhm, PharmD

What percent of Canadians have What percent of Canadians have hypertension?hypertension?

0

10

20

30

40

50

60

18-24 25-34 35-44 44-55 56-65 65-74

age

% o

f C

an

ad

ian

s

CCHS CMAJ 1992

5

Changes in Management of Changes in Management of Hypertension in CanadaHypertension in Canada

Large Treatment Gap Still Exists in Large Treatment Gap Still Exists in DiabetesDiabetes

(DM 9)

BUT ONLY 37% Control in Pts with Diabetes

6Joffres, et al. Am J Hyper 2001; 14: 1099-1105

7

Effect of SBP and DBP onEffect of SBP and DBP onAge-Adjusted CAD Mortality: MRFITAge-Adjusted CAD Mortality: MRFIT

Domanski M et al. JAMA 2002;287:2677-2683

0

20

40

60

80

100

120

140

74-119 120-139 140-159 160-179 180-300

Ag

e A

dju

ste

d a

ve

An

nu

al

Inc

ide

nc

e /

10

00

SBP

0

20

40

60

80

100

120

140

20-74 75-84 85-94 95-104 105-160

MenWomenDBP

Kannel, Am J Hypertens 2000;13:3S-10S.

Blood Pressure

Risk of Cardiovascular Event (aged 75-94)Risk of Cardiovascular Event (aged 75-94)

8

Meta-analysis of 61 prospective, observational studiesOne million adults, 12.7 million person-years

2 mm Hg decrease in mean

SBP10% reduction in risk of stroke mortality

7% reduction in risk of ischemic heart-disease (IHD) mortality

Lewington S, et al. Lancet 2002;360:1903

Small SBP reductions yield significant benefit

Lowering BP Reduces Cardiovascular Lowering BP Reduces Cardiovascular RiskRisk

9

Bakris GL et al. Special Report on DM and HTN Am J Kidney Dis 2000;36:646-661

**ABCD (<75 mm Hg – Diastolic*)

1 2 3 4

**UKPDS (<85 mm Hg – Diastolic*)

MDRD (<92 mm Hg MAP*)

**HOT (<80 mm Hg Diastolic*)

AASK (<92 mm Hg MAP*)

Number of BP Meds* Individual Study BP Targets** Diabetic Patients

Average Number of BP Medications to Achieve Goals

CHEP 2008: Consider initiating therapy with a combination of first line drugs if BP is 20 mmHg systolic or 10 mmHg diastolic above target

10

The Renin Angiotensin The Renin Angiotensin Aldosterone System Aldosterone System

(RAAS)(RAAS)

Adapted from: Laragh JH. 1989

ACE

Na+/H2O retention

Vasoconstriction Hypertension

Aldosterone

Renin

Angiotensinogen

Ang I

AT1 Receptor

Ang II

Classic understanding of RAAS

12

Adapted from: Müller DN & Luft FC. 2006

FEEDBACK LOOP

AT1 Receptor

Renin

BIOLOGICAL EFFECTS

ARBs

ACEIsPRA

Ang II

Ang I

AngiotensinogenNon ACE pathways

ACEIs and ARBs cause compensatory rises in Plasma Renin Activity (PRA)

Consequences in RAS Activation

Glomerularvasoconstriction

Inflammation Fibrosis

KIDNEY

Hypertrophy Fibrosis Vasoconstriction

HEART

Vasoconstriction

Hyperplasia hypertrophy

Inflammation Oxidation Fibrosis

VESSELS

BRAIN

13

New understandings in the New understandings in the cardiovascular continuum: cardiovascular continuum:

The central role of angiotensin IIThe central role of angiotensin II

Adapted from Dzau V, Braunwald E. Am Heart J. 1991;121:1244-1263.

Angiotensin II

14

Angiotensin II in Angiotensin II in atherosclerosisatherosclerosis

15

Physiologic effects of RAAS Physiologic effects of RAAS activationactivation

Exerts significant effects on cardiovascular Exerts significant effects on cardiovascular and renal functionand renal function

Many aspects of cardiovascular disease Many aspects of cardiovascular disease progression can be directly linked to the progression can be directly linked to the RAAS systemRAAS system

Vascular inflammation, generation of Vascular inflammation, generation of reactive oxygen species and endothelial reactive oxygen species and endothelial dysfunction play a role in atherosclerosisdysfunction play a role in atherosclerosis

Activation of the RAAS system is central to Activation of the RAAS system is central to these multiple pathwaysthese multiple pathways

16

Physiologic effects of RAAS Physiologic effects of RAAS inhibitioninhibition

Reduces systemic vascular resistanceReduces systemic vascular resistance Lowers blood pressureLowers blood pressure Vasodilatation occurs, preferentially in the Vasodilatation occurs, preferentially in the

vital organs leading to a redistribution of blood flowvital organs leading to a redistribution of blood flow In the kidneys RAAS inhibition increases effective renal In the kidneys RAAS inhibition increases effective renal

blood flow and alters intrarenal hemodynamics blood flow and alters intrarenal hemodynamics Dilates the efferent more than the afferent arteriolesDilates the efferent more than the afferent arterioles Intraglomerular pressure dropsIntraglomerular pressure drops

17

Benefits of RAAS Inhibition Benefits of RAAS Inhibition beyond BP loweringbeyond BP lowering

End-organ protection: KidneyEnd-organ protection: Kidney Vascular protection: Vessel wall and vascular endotheliumVascular protection: Vessel wall and vascular endothelium

RAAS inhibitors improve carotid intima-media thickness RAAS inhibitors improve carotid intima-media thickness (IMT) (Lonn 2001), vascular remodeling, endothelial (IMT) (Lonn 2001), vascular remodeling, endothelial function (Schiffrin 2000), and arterial compliance function (Schiffrin 2000), and arterial compliance (Asmar 1988) (Asmar 1988)

Regression of left ventricular hypertrophyRegression of left ventricular hypertrophy Prevention of Prevention of de novode novo diabetes mellitus diabetes mellitus

Several mechanisms have been hypothesized for this Several mechanisms have been hypothesized for this including hemodynamic effects and non-hemodynamic including hemodynamic effects and non-hemodynamic effects effects (Jandeleit-Dahm 2005) (Jandeleit-Dahm 2005)

Reduction in risk of stroke, coronary artery disease and Reduction in risk of stroke, coronary artery disease and heart failureheart failure

20

Risk Reduction for stroke, CAD and HF Risk Reduction for stroke, CAD and HF associated with associated with RAAS InhibitionRAAS Inhibition

Prevention of morbidity and mortality from cardiovascular Prevention of morbidity and mortality from cardiovascular events is a major treatment goalevents is a major treatment goal

ACE inhibitors are known to be vasculo-protectiveACE inhibitors are known to be vasculo-protective Outcome trials (HOPE, EUROPA) demonstrated the Outcome trials (HOPE, EUROPA) demonstrated the

beneficial role of ACE inhibitionbeneficial role of ACE inhibition HOPE showed effectiveness of ramipril in preventing HOPE showed effectiveness of ramipril in preventing

major CV events in high-risk patients with and without major CV events in high-risk patients with and without hypertensionhypertension

EUROPA showed perindopril reduces CV events in EUROPA showed perindopril reduces CV events in patients with coronary heart disease without apparent patients with coronary heart disease without apparent heart failureheart failure

21

Angiotensin II receptor blockers (ARBs)Angiotensin II receptor blockers (ARBs)

Clinical trials (e.g., LIFE, REGAAL, CATCH) Clinical trials (e.g., LIFE, REGAAL, CATCH) show that ARBs induce LVH regression show that ARBs induce LVH regression

ARBs achieve LVH regression through ARBs achieve LVH regression through efficient BP-lowering effects and inhibition of efficient BP-lowering effects and inhibition of angiotensin II angiotensin II

ARBs inhibit all of the actions of angiotensin II ARBs inhibit all of the actions of angiotensin II mediated through ATmediated through AT11 receptors receptors Unlike ACE-Is, which allow some production of Unlike ACE-Is, which allow some production of

angiotensin II via non-ACE pathwaysangiotensin II via non-ACE pathways

Carson PE. Am Heart J 2000;140:361Dahlöf B, et al. Lancet 2002;359:995 22

Dahlöf B, et al. Lancet 2002;359:995

LIFE resultsLIFE results

ARB benefits beyond BP-lowering effectsARB benefits beyond BP-lowering effects Patients with ECG signs of LVH (13% with diabetes)Patients with ECG signs of LVH (13% with diabetes) The risk of death, MI, or stroke was reduced by 13% The risk of death, MI, or stroke was reduced by 13%

with the ARB compared with the with the ARB compared with the ββ-blocker (-blocker (PP = .02) = .02) This occurred despite similar BP reductionThis occurred despite similar BP reduction

The difference in risk is primarily explained by a The difference in risk is primarily explained by a significant (25%) reduction in risk of fatal/non-fatal significant (25%) reduction in risk of fatal/non-fatal strokestroke

The difference was even more significant in diabetic The difference was even more significant in diabetic patientspatients

23

DIRECT RENIN DIRECT RENIN INHIBITORSINHIBITORS

The Newest Class Of Anti-Hypertensive AgentsThe Newest Class Of Anti-Hypertensive Agents

24

Angiotensinogen

Ang I

Aliskiren binds to active site of Aliskiren binds to active site of reninrenin

Renin

Aliskiren binds to a pocket in the renin molecule, blocking cleavage of angiotensinogen to angiotensin I

Aliskiren

Adapted from Rahuel J et al. J Struct Biol. 1991;107:227-236. 25

↓↑↓↓Aliskiren

↑↑↑↑ARB

↑↑↓↑ACEI

PRAReninAng IIAng I

Azizi M et al. 2006

FEEDBACK LOOP

AT1 Receptor

Renin

Angiotensinogen

BIOLOGICAL EFFECTS

Non ACE pathways

ACE

Ang II

Ang I

PRA

Direct renin inhibitor

ACEIs

ARBs

Aliskiren reduces Ang I, Ang II and PRA

26

27

Introduction to Direct Renin Introduction to Direct Renin Inhibitors (DRIs)Inhibitors (DRIs)

Newest class of RAAS-active antihypertensivesNewest class of RAAS-active antihypertensives Aliskiren is the agent with the most comprehensive evidence to Aliskiren is the agent with the most comprehensive evidence to

datedate

Inhibit the ability of renin to cleave angiotensinogen to Inhibit the ability of renin to cleave angiotensinogen to form angiotensin Iform angiotensin I

Reduce angiotensin II levelsReduce angiotensin II levels Associated with rise in plasma renin concentration, but Associated with rise in plasma renin concentration, but

no rise in plasma renin activityno rise in plasma renin activity (PRA) (PRA) May also partially inhibit the binding of prorenin to its May also partially inhibit the binding of prorenin to its

receptor (Clinical effects unknown)receptor (Clinical effects unknown)

Danser AH: J Cardiovasc Pharmacol 2007; 50(2):105-11. 27

HYPERTENSION HYPERTENSION STUDIESSTUDIES

Direct Renin InhibitorsDirect Renin Inhibitors

28

29

Sustained 24-hour BP Control Sustained 24-hour BP Control with the DRI Aliskirenwith the DRI Aliskiren

Mean ambulatory BP (mmHg)

160

60

150

130

120

140

90

70

80

100

08:00 12:00 16:00 20:00 00:00 04:00 08:00

110

Systolic

Diastolic

Earlymorning

surge

Placebo (n=53)Aliskiren 150 (n=52)Aliskiren 300 (n=56)Aliskiren 600 (n=55)

–0.640.980.86

T/P ratio

Time (hours)T/P: trough/peakAdapted from Ruilope LM, et al. Abstract and poster presented at ESC 2007. 29

30

Efficacy with DRI Hypertension Efficacy with DRI Hypertension Trials: MonotherapyTrials: Monotherapy

The efficacy of aliskiren has been The efficacy of aliskiren has been extensively studied in monotherapy extensively studied in monotherapy compared to:compared to: PlaceboPlacebo1,21,2

Active Control:Active Control: ARB (irbesartan)ARB (irbesartan)22

ACE (ramipril)ACE (ramipril)33

Diuretics (HCTZ)Diuretics (HCTZ)44

1. Oh B-H, et al: JACC 2007;49(11):1157-63.2. Gradman AH, et al: Circulation. 2005;111:1012–1018. 3. Andersen K, et al: J Am Coll Cardiol 2007;49(Suppl A):371A 1014-1734. Schmieder RE, et al: J Clin Hypertens 2007; 9(Suppl A)(5):A182.

30

31

Efficacy in DRI Hypertension Trials: Efficacy in DRI Hypertension Trials: MonotherapyMonotherapy

Trial & primary Trial & primary outcomeoutcome RegimensRegimens Duration Duration

(n)(n) ConclusionsConclusions

Oh et al (2007)Oh et al (2007)Change in msBP vs. Change in msBP vs. placebo from BL to wk 8placebo from BL to wk 8

4 groups:4 groups:- Aliskiren 75, 150, 300 mg o.d.- Aliskiren 75, 150, 300 mg o.d.- Placebo- Placebo

8 weeks8 weeks(n = 672)(n = 672)

Aliskiren provides significant Aliskiren provides significant antihypertensive efficacy,, with no antihypertensive efficacy,, with no rebound effects on BP after rebound effects on BP after treatment withdrawal.treatment withdrawal.

Gradman et al (2005)Gradman et al (2005)Change in trough msBP Change in trough msBP from BL to wk 8from BL to wk 8

5 groups:5 groups:- Aliskiren 150, 300, 600 mg o.d.- Aliskiren 150, 300, 600 mg o.d.- Irbesartan 150 mg o.d.- Irbesartan 150 mg o.d.- Placebo- Placebo

8 weeks8 weeks(n = 652)(n = 652)

Aliskiren lowers BP effectively; Aliskiren lowers BP effectively; aliskiren 150 mg is as effective as aliskiren 150 mg is as effective as irbesartan 150 mg.irbesartan 150 mg.Safety and tolerability of aliskiren Safety and tolerability of aliskiren were comparable to irbesartan and were comparable to irbesartan and placebo.placebo.

Andersen K et al (2007)Andersen K et al (2007)Change in msBP from Change in msBP from BL to wk 6BL to wk 6

2 groups:2 groups:-- Aliskiren 150 mg o.d. (option to titrate to 300 Aliskiren 150 mg o.d. (option to titrate to 300

mg)mg)-- Ramipril 5 mg o.d. (option to titrate to 10 mg)Ramipril 5 mg o.d. (option to titrate to 10 mg)

12 weeks12 weeks(n = 842)(n = 842)

Aliskiren 150 mg provided Aliskiren 150 mg provided significantly greater reductions in significantly greater reductions in msSBP compared with ramipril 5 msSBP compared with ramipril 5 mg.mg.Reductions in MSDBP were similar Reductions in MSDBP were similar with aliskiren 150 mg and ramipril with aliskiren 150 mg and ramipril 5 mg at Week 6. 5 mg at Week 6.

Schmieder et al (2007)Schmieder et al (2007)CChange in msBP from hange in msBP from BL to wk 26BL to wk 26

3 groups:3 groups:- Aliskiren 150 mg o.d. (forced titration to 300 - Aliskiren 150 mg o.d. (forced titration to 300

mg, then option to add amlodipine)mg, then option to add amlodipine)- HCTZ 12.5 mg o.d (forced titration to 25 mg, - HCTZ 12.5 mg o.d (forced titration to 25 mg,

then option to add amlodipine)then option to add amlodipine)- Placebo (randomized to one of the above - Placebo (randomized to one of the above

groups at week 6)groups at week 6)

52 weeks52 weeks(n = (n =

1124)1124)

Aliskiren-based therapy provides Aliskiren-based therapy provides greater long-term BP-lowering greater long-term BP-lowering than HCTZ-based therapy over up than HCTZ-based therapy over up to 12 months of treatment. to 12 months of treatment.

31

DUAL RAAS DUAL RAAS BLOCKADEBLOCKADE

Direct Renin InhibitorsDirect Renin Inhibitors

32

Rationale for ARB/ACEI + DRI combinations

Peripheral vasoconstriction & hypertension

DRI

ARBs /ACEIs

Stimulation of RAS & SNS

BP

PRA

Ang IIproduction

Compensatoryresponse mechanism blocked with DRI

ComplementaryMechanism

Further lowering of BP and potential end-organ protection

33

34

Combination Therapy with DRIs: Combination Therapy with DRIs: EfficacyEfficacy

The efficacy of aliskiren was extensively The efficacy of aliskiren was extensively studied in combination with other studied in combination with other antihypertensive agents:antihypertensive agents: ACE inhibitor (ramipril)ACE inhibitor (ramipril)11

Diuretic (HCTZ)Diuretic (HCTZ)22

ARB (vARB (valsartan)alsartan)33

CCB (amlodipine)CCB (amlodipine)44

1. Uresin Y, et al: J Renin Angiotensin Aldosterone Syst 2007; 8(4):190-8.2. Villamil A, et al: J Hypertens 2007; 25:217-226. 3. Oparil S, et al: Lancet 2007; 370(9583):221-9. 4. Drummond W, et al: J Clin Hypertens (Greenwich) 2007; 9(10):742-50.

34

35

Efficacy in DRI Hypertension Trials: Efficacy in DRI Hypertension Trials: Combination TherapyCombination Therapy

Trial & primary Trial & primary outcomeoutcome RegimensRegimens Duration Duration

(n)(n) ConclusionsConclusions

Villamil et al Villamil et al (2007)(2007)CChange in hange in MSBP from BL MSBP from BL to wk 8to wk 8

15 groups:15 groups:- 3 HCTZ mono: 6.25, 12.5, 25 mg- 3 HCTZ mono: 6.25, 12.5, 25 mg- 3 Aliskiren mono: 75, 150, 300 mg- 3 Aliskiren mono: 75, 150, 300 mg- 8 different HCTZ/aliskiren combinations - 8 different HCTZ/aliskiren combinations - 1 Placebo- 1 Placebo

8 weeks8 weeks(n = 2776)(n = 2776)

Aliskiren monotherapy Aliskiren monotherapy demonstrated significant BP demonstrated significant BP lowering; effect considerably lowering; effect considerably greater combined with HCTZ.greater combined with HCTZ.

Drummond et Drummond et al (2007)al (2007)Change in BP Change in BP from BL to wk 6from BL to wk 6

3 groups:3 groups:- Amlodipine 5 mg- Amlodipine 5 mg- Amlodipine 10 mg- Amlodipine 10 mg- Amlodipine 5 mg + aliskiren 150 mg- Amlodipine 5 mg + aliskiren 150 mg

6 weeks6 weeks(n = 545)(n = 545)

Aliskiren 150 mg + amlodipine 5 Aliskiren 150 mg + amlodipine 5 mg showed BP-lowering efficacy mg showed BP-lowering efficacy similar to amlodipine 10 mg and similar to amlodipine 10 mg and was better tolerated.was better tolerated.

Uresin et al Uresin et al (2007)(2007)Change in BP Change in BP from BL to wk 8from BL to wk 8

3 groups:3 groups:- Aliskiren 150 mg → 300 mg- Aliskiren 150 mg → 300 mg- Ramipril 5 mg → 10 mg- Ramipril 5 mg → 10 mg- Aliskiren 150 mg / ramipril 5 mg → - Aliskiren 150 mg / ramipril 5 mg → 300 / 10 mg300 / 10 mg

8 weeks8 weeks(n = 837)(n = 837)

Combining aliskiren with ramiprilCombining aliskiren with ramiprilprovided a greater reduction in BP provided a greater reduction in BP than either drug alone in diabetic than either drug alone in diabetic patients.patients.

Oparil et al Oparil et al (2007)(2007)Change in BP Change in BP from BL to wk 8from BL to wk 8

4 groups:4 groups:- Valsartan 160 mg → 320 mg- Valsartan 160 mg → 320 mg- Aliskiren 150 mg → 300 mg- Aliskiren 150 mg → 300 mg- Valsartan 160 mg + aliskiren 150 mg → - Valsartan 160 mg + aliskiren 150 mg →

320 / 300 mg320 / 300 mg- Placebo- Placebo

8 weeks8 weeks(n = 1797)(n = 1797)

The combination of aliskiren and The combination of aliskiren and valsartan at maximum valsartan at maximum recommended doses provides recommended doses provides significantly greater reductions in significantly greater reductions in BP than either agent alone. BP than either agent alone.

35

36

Aliskiren Provides Additional Aliskiren Provides Additional BP Lowering When Added to BP Lowering When Added to

Other Antihypertensive AgentsOther Antihypertensive Agents

*p < 0.05; †p < 0.0001 vs respective monotherapies

Change from baseline in msSBP (mmHg)

−5

−20

−25

−10

−15

Valsartan 320Valsartan 160Ramipril 10 HCTZ 12.5 HCTZ 25 Amlodipine 5

−12.0

−16.6 −15.5−16.6 −16.5

−18.0

−13.9

−17.6

−19.8

−14.3

−19.5

−21.2

−5.0

−11.0

275 58 6060 58 188274 184 175 187 173 177 188180n =

+ aliskiren

150

+ aliskiren 300

+ aliskiren 150

+ aliskiren 300

+ aliskiren

150

+ aliskiren

300

+

aliskiren150

†*

**

*

0

†

Treatment dose (mg)

+ aliskiren 300

Adapted from Weir MR, et al: J Am Soc Hypertens 2007; 1(4):264–77.36

37

The efficacy of aliskiren has been extensively The efficacy of aliskiren has been extensively studied in the following populations:studied in the following populations: Young and elderlyYoung and elderly11

ObesityObesity22

DiabetesDiabetes33

Metabolic syndromeMetabolic syndrome4,54,5

Impaired renal functionImpaired renal function66

Efficacy with DRI Therapy Efficacy with DRI Therapy in Hypertension Trials: in Hypertension Trials: Different PopulationsDifferent Populations

1. Dahlöf B, et al: J Clin Hypertens 2007; 9(Suppl. A):A157 [abstract P-376].2. Prescott MF, et al: Int J Obes 2007; 31(Suppl. 1):S99 [abstract T2:PO.88].3. Taylor AA, et al:. Diabetes 2007; 56(Suppl. 1):A129 [abstract 483-P].4. White WB, et al: Eur Heart J 2007; 28(Suppl 1):868 [abstract P4845].5. Krone W, et al: Presented at AHA 2008; Abstract #4433.6. Weir MR, et al: J Am Soc Hypertens 2007; 1(4):264-277.

37

38

Aliskiren Provides Effective BP-Aliskiren Provides Effective BP-lowering in Patients with Impaired lowering in Patients with Impaired Renal Function: Pooled AnalysisRenal Function: Pooled Analysis

Mean change from baseline in mean sitting BP after 8 weeks (mmHg)

Weir MR, et al. 2007 (Pooled analysis)

Aliskiren 300 mgAliskiren 150 mg

eGFR <60

–14.9

0

5

10

15 –14.7

–10.4–9.4

–11.2–10.1

–11.5

n=25 n=740 n=736n=26 n=25 n=740 n=736 n=26

–11.4

eGFR <60 eGFR ≥60 eGFR ≥60

DBP SBP

eGFR: estimated glomerular filtration rate (assessed in mL/min/1.73 m2)38

39

Tolerability of Tolerability of AliskirenAliskiren

39

Weir M, et al. WCC 2006 (Pooled analysis)

Placebo

n = 781

Aliskiren

75 mg

n = 478

Aliskiren

150 mg

n = 774

Aliskiren

300 mg

n = 768

AllAliskiren+

n = 2316

Any SAE, n (%) 5 (0.6) 3 (0.6) 3 (0.4) 4 (0.5) 11 (0.5)

Any AE, n (%) 314 (40.2) 193 (40.4) 290 (37.5) 309 (40.2) 922 (39.8)

Discontinuations

due to AE, n (%)27 (3.5) 8 (1.7) 12 (1.6) 20 (2.6) 45 (1.9)

Adverse events, reported by ≥2% of patients for aliskiren monotherapy overall, n (%)

Headache 68 (8.7) 31 (6.5) 42 (5.4)* 44 (5.7)* 132 (5.7)**

Nasopharyngitis 45 (5.8) 34 (7.1) 33 (4.3) 29 (3.8) 101 (4.4)

Diarrhoea 9 (1.2) 6 (1.3) 9 (1.2) 18 (2.3) 61 (2.6)*

AE, adverse event; SAE, serious adverse event. *p<0.05; **p<0.01 + = Include data from patients taking 600 mg (n=296)

Aliskiren monotherapy: Tolerability

40

Aliskiren/ramipril CombinationAliskiren/ramipril Combination

Ramipril Ramipril monotherapy* monotherapy*

(n=278)(n=278)

AliskirenAliskirenmonotherapy* monotherapy*

(n=282)(n=282)

AliskirenAliskiren/ramipril /ramipril

combination combination therapy* (n=277)therapy* (n=277)

Any AEAny AE 33.833.8 32.332.3 30.030.0

Serious AEsSerious AEs 2.22.2 2.82.8 1.41.4

Discontinuation due to AEsDiscontinuation due to AEs 4.04.0 3.93.9 2.22.2

Treatment-related AEsTreatment-related AEs 11.911.9 7.47.4 6.16.1

Most frequent AEs (³2% in any group)Most frequent AEs (³2% in any group)

HeadacheHeadache 6.16.1 3.23.2 2.92.9

CoughCough 4.74.7 2.12.1 1.81.8

NasopharyngitisNasopharyngitis 1.81.8 3.23.2 1.11.1

DiarrhoeaDiarrhoea 2.52.5 1.11.1 1.11.1

1.Uresin Y, et al. 2007 (Study 2307)2. Rasilez® Product Monograph, March 13, 2008

*Patients received aliskiren 150 mg, ramipril 5 mg, or aliskiren/ramipril 150/5 mg od. After 4 weeks, patients were titrated to aliskiren 300 mg, ramipril 10 mg or aliskiren/ramipril 300/10 mg for an additional 4 weeks

When aliskiren was combined with an ACE inhibitor in patients with diabetes and hypertension, increases in serum potassium (> 5.5 mmol/L) occurred in 5.5% of the patients2.

41

HCTZ plus Aliskiren or Amlodipine: Incidence of HCTZ plus Aliskiren or Amlodipine: Incidence of Edema in Patients with Obesity and HypertensionEdema in Patients with Obesity and Hypertension

Jordan J, et al. 2007 (Study 2309)

Aliskiren/Aliskiren/

HCTZHCTZ

n = 122n = 122

Irbesartan/Irbesartan/

HCTZHCTZ

n = 119n = 119

Amlodipine/Amlodipine/

HCTZHCTZ

n = 126n = 126

HCTZHCTZ

alonealone

n = 122n = 122

Any AE, n (%) Any AE, n (%) 48 (39.3)48 (39.3) 43 (36.1)43 (36.1) 57 (45.2)57 (45.2) 47 (38.5)47 (38.5)

Discontinuations Discontinuations

due to AE, n (%)due to AE, n (%)2 (1.6)2 (1.6) 4 (3.4)4 (3.4) 7 (5.6)7 (5.6) 4 (3.3)4 (3.3)

SAEs, n (%)SAEs, n (%) 2 (1.6)2 (1.6) 3 (2.5)3 (2.5) 4 (3.2)4 (3.2) 4 (3.3)4 (3.3)

AEs, reported by ≥2% of patients in any treatment group, n (%)AEs, reported by ≥2% of patients in any treatment group, n (%)

NasopharyngitisNasopharyngitis 10 (8.2)10 (8.2) 6 (5.0)6 (5.0) 7 (5.6)7 (5.6) 5 (4.1)5 (4.1)

HeadacheHeadache 5 (4.1)5 (4.1) 3 (2.5)3 (2.5) 9 (7.1)9 (7.1) 4 (3.3)4 (3.3)

DizzinessDizziness 4 (3.3)4 (3.3) 3 (2.5)3 (2.5) 1 (0.8)1 (0.8) 2 (1.6)2 (1.6)

Peripheral oedemaPeripheral oedema 1 (0.8)1 (0.8) 1 (0.8)1 (0.8) 14 (11.1)14 (11.1) 2 (1.6)2 (1.6)

Back painBack pain 1 (0.8)1 (0.8) 2 (1.7)2 (1.7) 5 (4.0)5 (4.0) 5 (4.1)5 (4.1)

AE, adverse event; SAE, serious adverse event42

43

Aliskiren In HypertensionAliskiren In HypertensionClinical SummaryClinical Summary

Aliskiren 150–300 mg:Aliskiren 150–300 mg: provides dose-dependent reductions in DBP and SBP provides dose-dependent reductions in DBP and SBP

as monotherapyas monotherapy BP reductions from baseline greater than HCTZ and ramipril and BP reductions from baseline greater than HCTZ and ramipril and

similar to irbesartansimilar to irbesartan provides additional BP lowering when combined with provides additional BP lowering when combined with

other antihypertensives (see next slide)other antihypertensives (see next slide) provides sustained 24-hour BP control with prolonged provides sustained 24-hour BP control with prolonged

effect after discontinuationeffect after discontinuation Rates of adverse effects are similar to placebo Rates of adverse effects are similar to placebo

Increases in serum potassium are infrequent in patients Increases in serum potassium are infrequent in patients with hypertension treated with aliskiren alone. When used with hypertension treated with aliskiren alone. When used in combination with another RAS agent, increases in serum in combination with another RAS agent, increases in serum potassium may be more frequentpotassium may be more frequent

43

44

Aliskiren In HypertensionAliskiren In HypertensionClinical SummaryClinical Summary

The combination of aliskiren with other antihypertensive The combination of aliskiren with other antihypertensive agents, such as ACE inhibitors, ARBs, dihydropyridine agents, such as ACE inhibitors, ARBs, dihydropyridine CCBs, or thiazide diuretics, is well toleratedCCBs, or thiazide diuretics, is well tolerated

When combined with ramipril, aliskiren appears to When combined with ramipril, aliskiren appears to reduce the incidence of coughreduce the incidence of cough

Long-term combination therapy with aliskiren and Long-term combination therapy with aliskiren and valsartan is well toleratedvalsartan is well tolerated

The combination of aliskiren and amlodipine results in a The combination of aliskiren and amlodipine results in a lower incidence of edema compared with increasing the lower incidence of edema compared with increasing the amlodipine doseamlodipine dose

In obese patients who fail to respond adequately to In obese patients who fail to respond adequately to diuretic monotherapy, adding aliskiren results in fewer diuretic monotherapy, adding aliskiren results in fewer incidences of peripheral oedema than adding incidences of peripheral oedema than adding amlodipineamlodipine

44

Supporting Appropriate Assessment Supporting Appropriate Assessment and Monitoring of Blood Pressure and Monitoring of Blood Pressure

45

Criteria for the diagnosis of hypertension and Criteria for the diagnosis of hypertension and recommendations for follow-uprecommendations for follow-up

BP: 140-179 / 90-109BP: 140-179 / 90-109

ABPM (If available)ABPM (If available)

Diagnosisof HTN

Awake BP>135 SBP or

>85 DBP or 24-hour

>130 SBP or

>80 DBP

Awake BP>135 SBP or

>85 DBP or 24-hour

>130 SBP or

>80 DBP

Awake BP<135/85and24-hour<130/80

Awake BP<135/85and24-hour<130/80

Continue to follow-up

Clinic BPClinic BP

Diagnosisof HTN

Hypertension visit 3

>160 SBP or

>100 DBP

>140 SBP or

>90 DBP

< 140 / 90

Diagnosisof HTN


<160 / 100

Hypertension visit 4-5

ABPM or HBPM if available

or

Home BPM (If available)Home BPM (If available)

>135/85>135/85 < 135/85 < 135/85

Diagnosisof HTN


or

Patients with high normal blood pressure (clinic SBP 130-139 and/or DBP 85-89) should be followed annually.

462008 CHEP Recommendations

Symptoms, Severe hypertension, Intolerance to anti-hypertensive treatment or Target Organ Damage

Criteria for the diagnosis of hypertension and Criteria for the diagnosis of hypertension and recommendations for follow-uprecommendations for follow-up

Are BP readings below target during 2 consecutive visits?

Non Pharmacological treatmentWith or without Pharmacological treatment

Diagnosis of hypertension

Follow-up at 3-6 month intervals *

NoYes

Yes

More frequentvisits *

Visits every 1 to 2 months*

* Consider Home measurement in hypertension management, to screen for masked hypertension or white coat effect and to enhance adherence.

No


Search for exogenous potentially modifiable factors that Search for exogenous potentially modifiable factors that can induce/aggravate hypertensioncan induce/aggravate hypertension

Prescription Drugs:Prescription Drugs: NSAIDs, including CoxibsNSAIDs, including Coxibs Corticosteroids and anabolic steroidsCorticosteroids and anabolic steroids Oral contraceptive and sex hormonesOral contraceptive and sex hormones Vasoconstricting/sympathomimetic decongestantsVasoconstricting/sympathomimetic decongestants Calcineurin inhibitors (cyclosporin, tacrolimus)Calcineurin inhibitors (cyclosporin, tacrolimus) Erythropoietin and analoguesErythropoietin and analogues Monoamine oxidase inhibitors (MAOIs)Monoamine oxidase inhibitors (MAOIs) MidodrineMidodrine

Other:Other: Licorice rootLicorice root Stimulants including cocaineStimulants including cocaine SaltSalt Excessive alcohol useExcessive alcohol use Sleep apneaSleep apnea

Assessment of the overall cardiovascular riskAssessment of the overall cardiovascular risk


Home measurement of blood pressureHome measurement of blood pressure

• Uncomplicated hypertension• Diabetes mellitus• Chronic kidney disease• Suspected non adherence• Office-induced blood pressure elevation (white coat effect)• Masked hypertension

Which patients?

Average BP equal to or over 135/85 mm Hg should be considered elevated

Home BP measurement should be encouraged to increase patient involvement in care


Potential advantages of home blood Potential advantages of home blood pressure measurementpressure measurement

More rapid confirmation of the diagnosis of More rapid confirmation of the diagnosis of hypertensionhypertension

Improved ability to predict cardiovascular Improved ability to predict cardiovascular prognosisprognosis

Improved blood pressure controlImproved blood pressure control Can screen for white coat hypertension (WCH) Can screen for white coat hypertension (WCH)

and masked hypertensionand masked hypertension Reduced medication use in some (WCH)Reduced medication use in some (WCH) Improved adherence to drug therapy in the non Improved adherence to drug therapy in the non

adherentadherent


Not all patients are suited to home Not all patients are suited to home measurementmeasurement

Undue anxiety in response to high blood pressure Undue anxiety in response to high blood pressure readingsreadings

Physical or mental impairment prevents accurate Physical or mental impairment prevents accurate technique or recordingtechnique or recording

Arm not suited to blood pressure cuff (e.g. conical Arm not suited to blood pressure cuff (e.g. conical shaped arm)shaped arm)

Irregular pulse or arrhythmias prevent accurate Irregular pulse or arrhythmias prevent accurate readingsreadings

Lack of interestLack of interest

The vast majority of patients can be trained to measure blood pressure


Suggested Protocol for Home Measurement Suggested Protocol for Home Measurement of Blood Pressure for the diagnosis of of Blood Pressure for the diagnosis of

hypertensionhypertension

Home blood pressure values should be based on:Home blood pressure values should be based on:- duplicate measures,duplicate measures,- morning and evening,morning and evening,- for an initial 7-day period. for an initial 7-day period.

Singular and first day home BP values shouldSingular and first day home BP values shouldnot be considered.not be considered.

Daytime average BP equal to or over 135/85Daytime average BP equal to or over 135/85mmHg should be considered elevated.mmHg should be considered elevated.


Home BP Measurement: Home BP Measurement: CHEP Recommendations CHEP Recommendations

Encourage hypertensive patients to use an Encourage hypertensive patients to use an approved blood pressure measuring approved blood pressure measuring device and use proper technique to device and use proper technique to assess blood pressure at homeassess blood pressure at home

Measuring blood pressure at home has a Measuring blood pressure at home has a stronger association with cardiovascular stronger association with cardiovascular prognosis than office-based readings prognosis than office-based readings


Blood Pressure Assessment:Blood Pressure Assessment:Patient preparation and posturePatient preparation and posture

Standardized technique:

Patient1. No caffeine in the preceding hour.2. No smoking or nicotine in the preceding 15-30

minutes.3. No use of substances containing adrenergic

stimulants such as phenylephrine or pseudoephedrine (may be present in nasal decongestants or ophthalmic drops).

4. Bladder and bowel comfortable.5. Quiet environment. Comfortable room

temperature for 5 minutes.6. No tight clothing on arm or forearm.7. No acute anxiety, stress or pain.8. Patient should stay silent prior and during the

procedure.


Blood Pressure Blood Pressure Assessment:Assessment:

Patient positionPatient position


CHEP-recommended Electronic BP CHEP-recommended Electronic BP Monitors for Home BP MeasurementMonitors for Home BP MeasurementCHEP-recommended Electronic BP CHEP-recommended Electronic BP Monitors for Home BP MeasurementMonitors for Home BP Measurement

See speaker notes for recommended model numbersAdapted from Approved Home BP Devices. www.hypertension.ca

Monitors that have been validated as accurate and available in Canada are listed at www.hypertension.ca/chs.

They are also marked with .

56

“Recommended by the Canadian Hypertension Society”


Use an appropriate size cuff Use an appropriate size cuff

Arm circumference (cm) Size of Cuff (cm)

From 18 to 26 9 x 18 (child)

From 26 to 3312 x 23 (standard adult model)

From 33 to 41 15 x 33 (large, obese)

More than 4118 x 36 (extra large, obese)

For automated devices, follow the manufacturer’s directions.

For manual readings using a stethoscope and sphygmomanometer, use the table as a guide.


Home Measurement of BP:Home Measurement of BP:Patient EducationPatient Education

AAMI=Association for the Advancement of Medical Instrumentation;BHS=British Hypertension Society; IP: International Protocol.

Use devices:• appropriate for the individual • appropriate cuff size• have met the criteria of the AAMI

and or the BHS and or IP

Adequate patient training in:• measuring their BP• interpreting these readings

Regular verifications• accuracy of the device• measuring techniques

How to?

Home measurement can help to improve patient adherence

Values over135 / 85 mm Hgshould beconsidered elevated


Home Measurement of BP: Patient EducationHome Measurement of BP: Patient Education

Assist patients select a model with the correct size of cuffMeasure and record the patients mid arm circumference so they can match it to cuff size

Recommend devices listed at www.hypertension.ca or marked with this symbol

Ask patients to carefully follow the instructions with device and to record only those blood pressure where they have followed recommended procedure

Check the device accuracy on the patient after purchase and periodically thereafter (e.g. annually)

Advise patients that average readings equal to or over 135/85 mmHg are higha lower threshold is appropriate for those with diabetes or chronic kidney disease

Home measurement can help to improve patient adherence

Values equal to or over135 / 85 mm Hgshould beconsidered elevated for those without diabetes or chronic kidney disease


Summary ISummary I Regarding the treatment of hypertension, the recommendations Regarding the treatment of hypertension, the recommendations

endorse: endorse: • ASSESSMENT OF BLOOD PRESSURE AT ALL ASSESSMENT OF BLOOD PRESSURE AT ALL

APPROPRIATE VISITSAPPROPRIATE VISITS• Most Canadians will develop hypertension during their Most Canadians will develop hypertension during their

lives. Routine assessment of blood pressure is required lives. Routine assessment of blood pressure is required for early detection and risk managementfor early detection and risk management

• ENCOURAGE APPROPRIATE PATIENTS TO MONITOR ENCOURAGE APPROPRIATE PATIENTS TO MONITOR BLOOD PRESSURE AT HOMEBLOOD PRESSURE AT HOME

• Most can assess blood pressure at home. Home Most can assess blood pressure at home. Home measurement can confirm a diagnosis of hypertension, measurement can confirm a diagnosis of hypertension, improve adherence to drug treatment, improve control improve adherence to drug treatment, improve control rates and screen for those with white coat hypertension rates and screen for those with white coat hypertension and masked hypertension.and masked hypertension.


Summary IISummary II Regarding the treatment of hypertension, the Regarding the treatment of hypertension, the

recommendations endorse:recommendations endorse: INDIVIDUALIZING THERAPYINDIVIDUALIZING THERAPY

consider concomitant risk factors and/or concurrent consider concomitant risk factors and/or concurrent diseases, other patient characteristics and preferences diseases, other patient characteristics and preferences (e.g. age, diabetes, CVD) and other considerations e.g. (e.g. age, diabetes, CVD) and other considerations e.g. costs costs

LIFESTYLE MODIFICATIONLIFESTYLE MODIFICATION To prevent hypertensionTo prevent hypertension In those with hypertension alone if effective to reach the In those with hypertension alone if effective to reach the

goal value or in combination with pharmacological goal value or in combination with pharmacological treatmenttreatment


Summary IIISummary IIIRegarding the treatment of hypertension, the Regarding the treatment of hypertension, the

recommendations endorse:recommendations endorse:

TREATING TO TARGET BPTREATING TO TARGET BP treat aggressively using combinations of drugs and treat aggressively using combinations of drugs and

lifestyle modification to achieve individualized lifestyle modification to achieve individualized targettarget

PROMOTING ADHERENCEPROMOTING ADHERENCE a multi-faceted approach should be used to a multi-faceted approach should be used to

improve adherence with both non pharmacological improve adherence with both non pharmacological and pharmacological strategiesand pharmacological strategies


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