1. Tom Smiley BScPhm, PharmD
Current trends and controversies in the diagnosis and treatment of hypertension Focus on the Renin Angiotensin Aldosterone System and Direct Renin Inhibition
Tom Smiley BScPhm, PharmD
CCCEP File L1FT

2. Disclosure
Tom Smiley has previously prepared and delivered pharmacist education sponsored by Novartis Inc.
The Canadian Council on Continuing Education in Pharmacy has accredited this program for 2 CEUs (CCCEP File # L1FT)
Supported by an educational grant from Novartis Canada Inc.

3. Learning Objectives
After successful completion of this workshop pharmacists will be better able to:
Discuss care gaps in current treatment of hypertension
Discuss pathophysiology of RAAS and mechanisms of RAAS inhibition
Discuss efficacy and tolerability of direct renin inhibition on hypertension
Assess and recommend appropriate blood pressure monitoring and hypertension management according to CHEP Guidelines
Discuss the renal outcome evidence for the benefit of RAAS blockade in patients with type 2 diabetes
Discuss alternatives to ACE-I + ARB combination

4. Tom Smiley BScPhm, PharmD
Current trends and controversies in the diagnosis and treatment of hypertension Part 1: A Pharmacist’s Perspective
Tom Smiley BScPhm, PharmD

5. What percent of Canadians have hypertension?
CCHS CMAJ 1992

6. Changes in Management of Hypertension in Canada Large Treatment Gap Still Exists in Diabetes
(DM 9)
BUT ONLY 37% Control in
Pts with Diabetes
The changes in management of hypertension in Canada The data in is from the Canadian Heart Health Survey and Heart and Stroke Foundation of Ontario Survey. Expressed as percent of hypertensives
Joffres, et al. Am J Hyper 2001; 14:

7. Effect of SBP and DBP on Age-Adjusted CAD Mortality: MRFIT
Systolic blood pressure (SBP) and diastolic blood pressure (DBP) have been shown to correlate strongly with coronary artery disease (CAD) mortality. The combined effect of SBP and DBP on age-adjusted CAD mortality is shown on this slide. These data, from a cohort of more than 300,000 men screened for the Multiple Risk Factor Intervention Trial (MRFIT) and followed for an average of 12 years, show that SBP is actually a stronger predictor of death from CAD than DBP, especially in the later years.
Domanski M et al. JAMA 2002;287:

8. Risk of Cardiovascular Event (aged 75-94)
SBP
DBP
Age Adjusted ave Annual Incidence /1000
Blood Pressure
Kannel, Am J Hypertens 2000;13:3S-10S.

9. Lowering BP Reduces Cardiovascular Risk
Small SBP reductions yield significant benefit
Meta-analysis of 61 prospective, observational studies
One million adults, 12.7 million person-years
7% reduction in risk of ischemic heart-disease (IHD) mortality
2 mm Hg decrease in mean SBP
A meta-analysis of 61 prospective, observational studies has shown that a 10 mm Hg lower SBP is associated over the long term with a 40% lower risk of stroke death and a 30% lower risk of death from IHD or other vascular causes.1
Even a small, 2 mm Hg fall in mean SBP was associated with large reductions in premature deaths and disabling strokes.1
There was no evidence of a J-curve (ie, a threshold of reduction beyond which risk begins to increase).1
The reduction in risk associated with a given reduction in mean BP is approximately constant down to at least an SBP of 115 mm Hg and a DBP of 75 mm Hg—well beyond what is normally achieved.1
The reduction in risk holds for all age groups assessed from 40 up to 89 years old.1
Reference:
Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:
10% reduction in risk of stroke mortality
Lewington S, et al. Lancet 2002;360:1903 9

10. Average Number of BP Medications to Achieve Goals
**UKPDS (<85 mm Hg – Diastolic*)
**ABCD (<75 mm Hg – Diastolic*)
MDRD (<92 mm Hg MAP*)
**HOT (<80 mm Hg Diastolic*)
1. Please confirm all those studies are done in diabetic patients. If yes it should appear on the slide.
AASK (<92 mm Hg MAP*)
* Individual Study BP Targets
** Diabetic Patients
Number of BP Meds 1 2 3 4
CHEP 2008: Consider initiating therapy with a combination of first line drugs if BP is 20 mmHg systolic or 10 mmHg diastolic above target
Bakris GL et al. Special Report on DM and HTN
Am J Kidney Dis 2000;36:

11. The Renin Angiotensin Aldosterone System (RAAS)

12. Classic understanding of RAAS
Angiotensinogen
Ang I
Renin
ACE
Ang II
Aldosterone
Activation of the Renin System occurs following release of renin by the kidney. Renin is a proteinase enzyme which catalyzes cleavage of angiotensinogen to form angiotensin I (Ang I). Ang I is itself inactive, but is converted to the biologically active peptide angiotensin II (Ang II) by angiotensin converting enzyme (ACE), which is produced in the lungs and cleaves the Ang I molecule.
Ang II is a vasoconstrictor; it binds with the type 1 Ang II (AT1) receptors in the smooth muscle cells of the peripheral blood vessels causing vasoconstriction and hence increased peripheral vascular resistance and increased blood pressure (BP). Activation of AT1 receptors by Ang II also stimulates release of the mineralocorticoid aldosterone from the adrenal gland, situated superior to the kidney. Aldosterone promotes retention of Na+ and water along the nephron, further increasing BP.
If BP is consistently raised this constitutes hypertension, which in turn can lead to end-organ damage.
Abbreviations
Ang I = angiotensin I
Ang II = angiotensin II
ACE = angiotensin converting enzyme
AT1 = type 1 angiotensin II receptor
BP = blood pressure
Reference
Laragh JH. The renin system and the impact of ACE inhibition for understanding, diagnosis, and treatment of hypertension. In: Sonnenblick EH, Laragh JH, Lesch M, editors. New Frontiers in Cardiovascular Therapy. Excerpta Medica, Princeton, New Jersey, 1989 p.84–116.
AT1 Receptor
Na+/H2O retention
Vasoconstriction
Hypertension
Adapted from: Laragh JH. 1989

13. Consequences in RAS Activation
ACEIs and ARBs cause compensatory rises in Plasma Renin Activity (PRA)
Glomerular vasoconstriction
Inflammation
Fibrosis
KIDNEY
Hypertrophy
Vasoconstriction
HEART
Hyperplasia hypertrophy
Oxidation
VESSELS
BRAIN
Consequences in RAS Activation
Angiotensinogen
Non ACE
pathways
Ang I
Renin
PRA
FEEDBACK LOOP
ACEIs
Ang II
Plasma renin activity (PRA) is a measure of the level of activity in the Renin System (RS) and is an indicator for hypertension. The RS is targeted at different places by existing antihypertensive therapies.
Angiotensin converting enzyme (ACE) inhibitors or ACEIs reduce the production of angiotensin II (Ang II), by inhibiting the conversion of angiotensin I (Ang I) to Ang II by these enzymes. Angiotensin receptor blockers (ARBs) antagonize type 1 Ang II (AT1) receptors and prevent Ang II from binding.
However, ACEIs and ARBs are associated with a feedback loop which increases PRA, as loss of stimulation of AT1 receptors on juxtaglomerular cells in the kidney (i.e. removal of negative feedback) leads to a compensatory increase in renin release. Diuretics also stimulate renin release, to activate the RS in response to a drop in fluid volume. The resulting increase in PRA may limit the organ protection offered by these drugs.
Abbreviations
Ang I = angiotensin
ACE = angiotensin converting enzyme
ACEI = angiotensin converting enzyme inhibitor
ARB = angiotensin receptor blocker
AT1 = type 1 angiotensin II receptor
PRA = plasma renin activity
RS = Renin System
Reference
Müller DN, Luft FC. Direct renin inhibition with aliskiren in hypertension and target organ damage. Clin J Am Soc Nephrol 2006;1:221–8.
AT1 Receptor
ARBs
BIOLOGICAL EFFECTS
Adapted from: Müller DN & Luft FC. 2006

14. New understandings in the cardiovascular continuum: The central role of angiotensin II
Returning to the cardiovascular continuum, we are beginning to see the central role of angiotensin II at all stages of the continuum.
Reference
Dzau V, Braunwald E. Am Heart J. 1991; 121:
Angiotensin II
Adapted from Dzau V, Braunwald E. Am Heart J. 1991;121:

15. Angiotensin II in atherosclerosis
Angiotensin II is a key mediator in the various processes of oxidative stress, inflammation, endothelial dysfunction and tissue remodeling, which all work in concert in the atherosclerosis disease process.

16. Physiologic effects of RAAS activation
Exerts significant effects on cardiovascular and renal function
Many aspects of cardiovascular disease progression can be directly linked to the RAAS system
Vascular inflammation, generation of reactive oxygen species and endothelial dysfunction play a role in atherosclerosis
Activation of the RAAS system is central to these multiple pathways
The renin angiotensin aldosterone system exerts significant effects on cardiovascular and renal function. Many aspects of cardiovascular disease progression can be directly linked to the RAAS system. Mechanisms such as vascular inflammation, generation of reactive oxygen species and alterations of endothelial function are all known to play a role in atherosclerosis. Evidence now indicates that activation of the RAAS system is central to these multiple pathways.

17. Physiologic effects of RAAS inhibition
Reduces systemic vascular resistance
Lowers blood pressure
Vasodilatation occurs, preferentially in the vital organs leading to a redistribution of blood flow
In the kidneys RAAS inhibition increases effective renal blood flow and alters intrarenal hemodynamics
Dilates the efferent more than the afferent arterioles
Intraglomerular pressure drops
Inhibition of the RAAS system leads to blood pressure lowering through a reduction in systemic vascular resistance. Vasodilatation occurs through attenuation of the sympathetic nervous system and through excess bradykinin generation (Ibrahim 2006). Vasodilatation occurs preferentially in the vital organs which leads to a redistribution of blood flow.

19. 19

20. Benefits of RAAS Inhibition beyond BP lowering
End-organ protection: Kidney
Vascular protection: Vessel wall and vascular endothelium
RAAS inhibitors improve carotid intima-media thickness (IMT) (Lonn 2001), vascular remodeling, endothelial function (Schiffrin 2000), and arterial compliance (Asmar 1988)
Regression of left ventricular hypertrophy
Prevention of de novo diabetes mellitus
Several mechanisms have been hypothesized for this including hemodynamic effects and non-hemodynamic effects (Jandeleit-Dahm 2005)
Reduction in risk of stroke, coronary artery disease and heart failure
Beyond blood pressure lowering, blockage of RAAS includes several other key benefits:
End organ protection – kidney: RAAS inhibitors retard the progression of renal damage in hypertensive patients with albuminuria as well as prevent or delay the development of microalbuminuria. They decrease the progression to end stage renal disease or doubling of serum creatinine.
Vascular protection – vessel wall and vascular endothelium: RAAS inhibitors improve carotid IMT (Lonn 2001), improve vascular remodeling and endothelial function (Schiffrin 2000) and improve arterial compliance (Asmar 1988).
Regression of left ventricular hypertrophy.
Prevention of de novo diabetes mellitus. Several mechanisms have been hypothesized for this including hemodynamic effects (improved delivery of insulin and glucose to the peripheral skeletal muscle) and non-hemodynamic effects (direct effects on glucose transport and insulin signalling pathways thereby decreasing insulin resistance) (Jandeleit-Dahm 2005) .
Reduction in risk of stroke.
Reduction in risk of coronary artery disease.
Reduction in risk of heart failure.

21. Risk Reduction for stroke, CAD and HF associated with RAAS Inhibition
Prevention of morbidity and mortality from cardiovascular events is a major treatment goal
ACE inhibitors are known to be vasculo-protective
Outcome trials (HOPE, EUROPA) demonstrated the beneficial role of ACE inhibition
HOPE showed effectiveness of ramipril in preventing major CV events in high-risk patients with and without hypertension
EUROPA showed perindopril reduces CV events in patients with coronary heart disease without apparent heart failure
Prevention of morbidity and mortality from cardiovascular events is a major treatment goal.
Lifestyle changes such as weight reduction, increasing physical activity, a low cholesterol diet and/or stopping smoking can have a CVP effect by reducing risk factors and should be included in the treatment options of all patients with a risk of cardiovascular disease.
The renin–angiotensin–aldosterone (RAS) system has a pivotal role to play in the CV continuum through its principal mediator, angiotensin II. Although the blood pressure-lowering effect of ACE inhibitors and ARBs is equivalent to that of most other antihypertensive agents, these drug classes may have a greater effect on decreasing cardiovascular morbidity and mortality rates in specific patient populations due to their ability to intervene at all stages of the CV continuum.
Cardiovascular benefit from ACE inhibitors is a milestone of evidence-based medicine.
The Heart Outcomes Prevention Evaluation (HOPE) study, which ran between December 1993 and June 1995, was the first outcome trial to show the extent of cardiovascular protection provided by an ACE inhibitor (ramipril) in patients with high risk of a cardiovascular events. Patients (55 years old or more) with evidence of vascular disease or diabetes plus one other risk factor for CVD (not necessarily hypertension) were treated in a double-blind, two-by-two factorial, randomized trial that evaluated ramipril and vitamin E in patients. Patients with known heart failure or reduced ejection fraction were excluded from HOPE. The primary outcome was a composite of myocardial infarction, stroke or death from cardiovascular causes. Ramipril significantly reduced the rate of death, MI and stroke in a broad range of high-risk patients. Other secondary outcomes including revascularisation, cardiac arrest and heart failure; complications related to diabetes and new cases of diabetes were also reduced by ramipril. Treating 1000 patients with ramipril for 4 years prevents about 150 events in approximately 70 patients.
In the EUROPA trial completed in 2003, Fox and colleagues assessed the efficacy of the ACE inhibitor perindopril in reducing cardiovascular risk in a low-risk population with stable coronary heart disease and no apparent heart failure. 12 218 patients were randomly assigned perindopril 8 mg once daily (n=6110), or matching placebo (n=6108). The mean follow-up was 4.2 years, and the primary endpoint was cardiovascular death, myocardial infarction or cardiac arrest. Analysis was by intention to treat.
The authors concluded that amongst patients with stable coronary heart disease without apparent heart failure, perindopril can significantly improve outcomes. About 50 patients need to be treated for a period of 4 years to prevent one major cardiovascular event. And that treatment with perindopril, on top of other preventive medications, should be considered in all patients with coronary heart disease.
References
Kjeldsen S.E. & Julius S., Hypertension mega-trials with cardiovascular end points: effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Am Heart J 2004;148:747–754
Yusuf S., et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. The HOPE Study Investigators, N Engl J Med 2000;342:145–153
Fox K.M., et al. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003;362:782–788
Zimmermann M. & Unger T., Challenges in improving prognosis and therapy: the Ongoing Telmisartan Alone and in Combination with Ramipril Global End point Trial programme. Expert Opin Pharmacother 2004;5:1201–1208

22. Angiotensin II receptor blockers (ARBs)
Clinical trials (e.g., LIFE, REGAAL, CATCH) show that ARBs induce LVH regression
ARBs achieve LVH regression through efficient BP-lowering effects and inhibition of angiotensin II
ARBs inhibit all of the actions of angiotensin II mediated through AT1 receptors
Unlike ACE-Is, which allow some production of angiotensin II via non-ACE pathways
Various clinical trials, such as the Losartan Intervention For Endpoint reduction in hypertension (LIFE) (Devereux), the Losartan LVH Regression (REGAAL) (Dahlof) and the Candesartan Assessment in the Treatment of Cardiac Hypertrophy (CATCH) (Cuspidi) trials, have provided evidence that ARBs reduce LVM in patients with hypertension and LVH.
The effectiveness of ACE-Is and ARBs at reducing LVH suggests that inhibition of the actions of angiotensin II may produce regression through other mechanisms as well as by lowering BP.
ACE-Is do not block the RAAS completely because local tissue production of angiotensin II can occur by enzymatic pathways that do not involve ACE. This results in so-called ACE escape (ie, residual levels of angiotensin and hence, AT1 receptor activation) (Carson).
Because ARBs selectively block AT1 receptors, they inhibit all of the actions of angiotensin II, whether it is produced systemically or in tissues.
References
Devereux RB, Palmieri V, Liu JE, et al. Progressive hypertrophy regression with sustained pressure reduction in hypertension: the Losartan Intervention For Endpoint reduction study. J Hypertens 2002;20:
Dahlöf B, Zanchetti A, Diez J, et al. Effects of losartan and atenolol on left ventricular mass and neurohormonal profile in patients with essential hypertension and left ventricular hypertrophy. J Hypertens 2002;20:
Cuspidi C, Muiesan ML, Valagussa L, et al. Comparative effects of candesartan and enalapril on left ventricular hypertrophy in patients with essential hypertension: the candesartan assessment in the treatment of cardiac hypertrophy (CATCH) study. J Hypertens 2002;20:
Carson PE. Rationale for the use of combination angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker therapy in heart failure. Am Heart J 2000;140:
Carson PE. Am Heart J 2000;140:361
Dahlöf B, et al. Lancet 2002;359:995

23. LIFE results ARB benefits beyond BP-lowering effects
Patients with ECG signs of LVH (13% with diabetes)
The risk of death, MI, or stroke was reduced by 13% with the ARB compared with the β-blocker (P = .02)
This occurred despite similar BP reduction
The difference in risk is primarily explained by a significant (25%) reduction in risk of fatal/non-fatal stroke
The difference was even more significant in diabetic patients
The LIFE study found a significant difference in favour of losartan on the primary endpoint, a composite of death, MI, or stroke (relative risk 0.87, p = 0.02).
However, there was no statistically significant difference between the two treatment arms in the risk of cardiovascular mortality or MI.
Thus, the main reason for the relative improvement in the primary endpoint was due to the large and statistically significant reduction in fatal and nonfatal stroke.
Notably, LVH is significantly associated with the incidence of stroke in the general population.
The difference in risk was even greater for patients with diabetes.
References
Dahlöf B, Devereux RB, Kieldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:
Bots ML, Nikitin Y, Salonen JT, et al. Left ventricular hypertrophy and risk of fatal and non-fatal stroke. EUROSTROKE: a collaborative study among research centres in Europe. J Epidemiol Community Health 2002;56(suppl 1):i8-i13.
Dahlöf B, et al. Lancet 2002;359:995

24. DIRECT RENIN INHIBITORS
The Newest Class Of Anti-Hypertensive Agents
DIRECT RENIN INHIBITORS

25. Aliskiren binds to active site of renin
Aliskiren binds to a pocket in the renin molecule, blocking cleavage of angiotensinogen to angiotensin I
Angiotensinogen
SLIDE SUMMARY: THE BINDING OF THE RENIN INHIBITOR, ALISKIREN, TO THE RENIN MOLECULE PREVENTS CLEAVAGE OF ANGIOTENSINOGEN
The figure shows the crystallized structure of the renin molecule, but with the binding pocket occupied by the renin inhibitor aliskiren. Inhibited renin is no longer available to cleave its substrate, angiotensinogen1,2
Third-generation renin inhibitors, such as aliskiren, have a high binding affinity for renin. This may be explained by the number of interactions with the renin molecule’s active site. These inhibitors appear to bind to both the hydrophobic S1/S3 binding pocket and to a large, distinct, subpocket that extends from the S3 binding site towards the hydrophobic core of the molecule. Compared with a renin molecule not bound by an inhibitor, the bound molecule exhibits a “closed, inhibited” conformation1,2
Ang I
Adapted from Rahuel J et al. J Struct Biol. 1991;107:
Rahuel J, Priestle JP, Grutter MG. The crystal structure of recombinant glycosylated human renin alone and in complex with a transition state analog inhibitor. J Struc Biol. 1991;107:
Stanton A. Potential of renin inhibition in cardiovascular disease. J Renin Angiotensin Aldosterone Syst. 2003;4:6-10.

26. Aliskiren reduces Ang I, Ang II and PRA
Direct renin inhibitor
Angiotensinogen
Non ACE pathways
Ang I
Renin
PRA
ACE
FEEDBACK LOOP
ACEIs
Ang II
ARBs
AT1 Receptor
BIOLOGICAL EFFECTS
Blockade of the Renin System (RS) at any point leads to a compensatory increase in renin release. Angiotensin converting enzyme (ACE) inhibitors or ACEIs and aliskiren cause angiotensin II (Ang II) levels to drop and angiotensin receptor blockers (ARBs) block the action of Ang II on type 1 Ang II (AT1) receptors – both these effects reduce the level of stimulation of AT1 receptors on juxtaglomerular cells in the kidney, leading to increased renin release.
Aliskiren is unique in counteracting the resultant increase in circulating renin concentration by inhibiting its action as an enzyme, i.e. reducing plasma renin activity (PRA). Other classes of drugs acting on the RS, ACEIs and ARBs, are associated with elevation of PRA in parallel with increased renin release. As PRA reflects the capacity of circulating renin to cleave angiotensinogen and form angiotensin I (Ang I), levels of Ang I also increase in the presence of these agents.
ACEIs reduce subsequent conversion of Ang I to Ang II, leading to an overall reduction in Ang II levels, although some Ang II generation continues, mediated by non-ACE pathways, for which substrate (Ang I) is increased. With ARBs, elevated Ang I leads to increased Ang II production. The whole RS is therefore upregulated, although AT1 receptor-mediated effects of the effector molecule Ang II are blocked.
As aliskiren reduces PRA, generation of Ang I decreases. Less substrate is therefore available for conversion to Ang II by ACE or other enzymes. Direct renin inhibition therefore produces effective overall RS suppression.
Abbreviations
Ang I = angiotensin I
Ang II = angiotensin II
ACE = angiotensin converting enzyme
ACEI = angiotensin converting enzyme inhibitor
ARB = angiotensin receptor blocker
AT1 = type 1 angiotensin II receptor
PRA = plasma renin activity
RS = Renin System
Reference
Azizi M, Webb R, Nussberger J, Hollenberg NK. Renin inhibition with aliskiren: where are we now, and where are we going? J Hypertens 2006;24(2):
Ang I
Ang II
Renin
PRA ↑ ↓ ↑ ↑
ACEI ↑ ↑ ↑ ↑
ARB
Aliskiren ↓ ↓ ↑ ↓
Azizi M et al. 2006

27. Introduction to Direct Renin Inhibitors (DRIs)
Newest class of RAAS-active antihypertensives
Aliskiren is the agent with the most comprehensive evidence to date
Inhibit the ability of renin to cleave angiotensinogen to form angiotensin I
Reduce angiotensin II levels
Associated with rise in plasma renin concentration, but no rise in plasma renin activity (PRA)
May also partially inhibit the binding of prorenin to its receptor (Clinical effects unknown)
Direct renin inhibitors (DRIs) represent the newest class of RAS-active antihypertensives. The DRI with the most comprehensive evidence to date is aliskiren, which has proven to be an effective antihypertensive agent alone and in combination. Morbidity and mortality trials are in progress.
DRIs inhibit the ability of renin to cleave angiotensinogen to form angiotensin I; by inhibiting this first, rate-limiting step of the RAS, the production of angiotensin II is also suppressed. Because of the suppression of angiotensin II, there will be a rise in PRC due to the disruption of the short feedback loop. However, unlike with ACE inhibitors and ARBs, this rise in PRC is not correlated with a rise in PRA, due to the presence of the renin inhibitor.
DRIs may also partially inhibit the binding of prorenin to its unique receptor. The degree to which this may be true, and the clinical effects of this inhibition, remain to be elucidated.
Reference:
Danser AH: Novel drugs targeting hypertension: renin inhibitors. J Cardiovasc Pharmacol 2007; 50(2):
Danser AH: J Cardiovasc Pharmacol 2007; 50(2): 27 27 27

28. Direct Renin Inhibitors
HYPERTENSION STUDIES

29. Sustained 24-hour BP Control with the DRI Aliskiren
T/P ratio
Placebo (n=53) –
Aliskiren 150 (n=52)
0.64
Mean ambulatory BP (mmHg)
Aliskiren 300 (n=56)
0.98
Aliskiren 600 (n=55)
0.86
Systolic
160
150
140
130
120
Early morning surge
110
Diastolic
100
Data from a single randomized, placebo-controlled, dose-ranging study with aliskiren were analysed to determine the trough/peak (T/P) ratio for mean ambulatory diastolic blood pressure (DBP) reductions. Patients received 8-weeks’ treatment with once-daily aliskiren 150, 300 or 600 mg, or placebo. Ambulatory blood pressure (BP) monitoring was performed in 216 patients.
The T/P ratios for aliskiren 150, 300 and 600 mg were 0.64, 0.98 and 0.86, respectively. These results indicate that aliskiren provides sustained 24-hour BP control, with up to 98% of the peak BP-lowering effect of aliskiren maintained at trough.
Reference:
Ruilope LM, Anderson DR, Arora V, et al. Aliskiren, a direct renin inhibitor (DRI), provides smooth, sustained 24-h blood pressure control as monotherapy or in combination with valsartan or ramipril in patients with hypertension. Abstract and poster presented at ESC 2007. 90 80 70 60
08:00
12:00
16:00
20:00
00:00
04:00
08:00
Time (hours)
T/P: trough/peak
Adapted from Ruilope LM, et al. Abstract and poster presented at ESC 2007. 29 29

30. Efficacy with DRI Hypertension Trials: Monotherapy
The efficacy of aliskiren has been extensively studied in monotherapy compared to:
Placebo1,2
Active Control:
ARB (irbesartan)2
ACE (ramipril)3
Diuretics (HCTZ)4
The aliskiren hypertension studies have generally been/are being conducted in adult males and females with mild-to-moderate hypertension. Two exceptions are one ongoing study in older hypertensive patients and one in patients with severe hypertension.
With the exception of one study specifically recruiting patients with severe hypertension, diastolic blood pressure ≥110 mmHg and/or systolic blood pressure ≥180 mmHg precluded entry into hypertension studies. The hypertension studies may yield data suitable for sub-analyses of effects in specific patient populations.
References:
1. Oh BH, Mitchell J, Herron JR, et al: Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24-hour blood pressure control in patients with hypertension. J Am Coll Cardiol 2007; 49(11):
2. Gradman AH, Schmieder RE, Lins RL, et al: Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation 2005; 111(8):1012–8.
3. Andersen K, et al: Aliskiren-Based Therapy Lowers Blood Pressure More Effectively Than Ramipril-Based Therapy in Patients With Hypertension: A 6-Month, Randomized, Double Blind Trial. J Am Coll Cardiol 2007; 49(Suppl A):371A [abstract ].
4. Schmieder RE, Philipp T, Guerediaga J, et al: Aliskiren-based therapy lowers blood pressure more effectively than hydrochlorothiazide-based therapy in patients with hypertension. J Clin Hypertens 2007;9(5 suppl A):A1
1. Oh B-H, et al: JACC 2007;49(11):
2. Gradman AH, et al: Circulation. 2005;111:1012–1018.
3. Andersen K, et al: J Am Coll Cardiol 2007;49(Suppl A):371A
4. Schmieder RE, et al: J Clin Hypertens 2007; 9(Suppl A)(5):A182. 30 30

31. Efficacy in DRI Hypertension Trials: Monotherapy
Trial & primary outcome
Regimens
Duration (n)
Conclusions
Oh et al (2007) Change in msBP vs. placebo from BL to wk 8
4 groups:
- Aliskiren 75, 150, 300 mg o.d.
- Placebo
8 weeks
(n = 672)
Aliskiren provides significant antihypertensive efficacy,, with no rebound effects on BP after treatment withdrawal.
Gradman et al (2005) Change in trough msBP from BL to wk 8
5 groups:
- Aliskiren 150, 300, 600 mg o.d.
- Irbesartan 150 mg o.d.
(n = 652)
Aliskiren lowers BP effectively; aliskiren 150 mg is as effective as irbesartan 150 mg.
Safety and tolerability of aliskiren were comparable to irbesartan and placebo.
Andersen K et al (2007) Change in msBP from BL to wk 6
2 groups:
- Aliskiren 150 mg o.d. (option to titrate to 300 mg)
- Ramipril 5 mg o.d. (option to titrate to 10 mg)
12 weeks
(n = 842)
Aliskiren 150 mg provided significantly greater reductions in msSBP compared with ramipril 5 mg. Reductions in MSDBP were similar with aliskiren 150 mg and ramipril 5 mg at Week 6.
Schmieder et al (2007) Change in msBP from BL to wk 26
3 groups:
- Aliskiren 150 mg o.d. (forced titration to 300 mg, then option to add amlodipine)
- HCTZ 12.5 mg o.d (forced titration to 25 mg, then option to add amlodipine)
- Placebo (randomized to one of the above groups at week 6)
52 weeks
(n = 1124)
Aliskiren-based therapy provides greater long-term BP-lowering than HCTZ-based therapy over up to 12 months of treatment.
Aliskiren has been studied in combination with thiazide diuretics (hydrochlorothiazide),1 calcium channel blockers (amlodipine),2 ACE inhibitors
(ramipril—in subjects with diabetes and hypertension)3 and ARBs (valsartan).4 In each case, the combination of the two agents was found to be more efficacious for BP reduction than either monotherapy alone, with no significant additional safety or tolerability concerns.
The data accumulated to date suggest that aliskiren is a useful agent to consider as a component of combination therapy with other commonly used antihypertensives.
References:
1. Oh BH, Mitchell J, Herron JR, et al: Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24-hour blood pressure control in patients with hypertension. J Am Coll Cardiol 2007; 49(11):
2. Gradman AH, Schmieder RE, Lins RL, et al: Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation 2005; 111(8):1012–8.
3. Andersen K, et al: Aliskiren-Based Therapy Lowers Blood Pressure More Effectively Than Ramipril-Based Therapy in Patients With Hypertension: A 6-Month, Randomized, Double Blind Trial. J Am Coll Cardiol 2007; 49(Suppl A):371A [abstract ].
4. Schmieder RE, Philipp T, Guerediaga J, et al: Aliskiren-based therapy lowers blood pressure more effectively than hydrochlorothiazide-based therapy in patients with hypertension. J Clin Hypertens 2007;9(5 suppl A):A1 31 31 31

32. Direct Renin Inhibitors
DUAL RAAS BLOCKADE

33. Stimulation of RAS & SNS
Rationale for ARB/ACEI + DRI combinations
Ang II
production
Peripheral vasoconstriction & hypertension
Complementary
Mechanism
Further lowering of BP and potential end-organ protection
PRA
Compensatory
response mechanism
blocked with DRI
ARBs /
ACEIs BP
Combination therapy has the potential to improve BP control, reduce adverse effects and increase compliance.
The rationale for adding a renin inhibitor to an angiotensin receptor blocker or ARB is that renin inhibitors can block the compensatory response mechanism that we have typically seen in the past when we give an ACE inhibitor or an angiotensin receptor blocker.
That is, these medications can lead to an increase in plasma renin activity and this can be blocked when we give a renin inhibitor.
This can provide further lowering of blood pressure and we think potential end organ protection
Stimulation of RAS & SNS
DRI 33

34. Combination Therapy with DRIs: Efficacy
The efficacy of aliskiren was extensively studied in combination with other antihypertensive agents:
ACE inhibitor (ramipril)1
Diuretic (HCTZ)2
ARB (valsartan)3
CCB (amlodipine)4
Aliskiren has been studied in combination with thiazide diuretics (hydrochlorothiazide),1 calcium channel blockers (amlodipine),2 ACE inhibitors
(ramipril—in subjects with diabetes and hypertension)3 and ARBs (valsartan).4 In each case, the combination of the two agents was found to be more efficacious for BP reduction than either monotherapy alone, with no significant additional safety or tolerability concerns.
The data accumulated to date suggest that aliskiren is a useful agent to consider as a component of combination therapy with other commonly used antihypertensives.
References:
1. Villamil A, Chrysant SG, Calhoun D, et al: Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide. J Hypertens 2007; 25:
2. Drummond W, Munger MA, Rafique Essop M, et al: Antihypertensive efficacy of the oral direct Renin inhibitor aliskiren as add-on therapy in patients not responding to amlodipine monotherapy. J Clin Hypertens (Greenwich) 2007; 9(10):
3. Uresin Y, Taylor AA, Kilo C, et al: Efficacy and safety of the direct renin inhibitor aliskiren and ramipril alone or in combination in patients with diabetes and hypertension. J Renin Angiotensin Aldosterone Syst 2007; 8(4):190-8.
4. Oparil S, Yarows SA, Patel S, et al: Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial. Lancet 2007; 370(9583):221-9.
1. Uresin Y, et al: J Renin Angiotensin Aldosterone Syst 2007; 8(4):190-8.
2. Villamil A, et al: J Hypertens 2007; 25:
3. Oparil S, et al: Lancet 2007; 370(9583):221-9.
4. Drummond W, et al: J Clin Hypertens (Greenwich) 2007; 9(10): 34 34 34

35. Efficacy in DRI Hypertension Trials: Combination Therapy
Trial & primary outcome
Regimens
Duration (n)
Conclusions
Villamil et al (2007) Change in MSBP from BL to wk 8
15 groups:
- 3 HCTZ mono: 6.25, 12.5, 25 mg
- 3 Aliskiren mono: 75, 150, 300 mg
- 8 different HCTZ/aliskiren combinations
- 1 Placebo
8 weeks
(n = 2776)
Aliskiren monotherapy demonstrated significant BP lowering; effect considerably greater combined with HCTZ.
Drummond et al (2007) Change in BP from BL to wk 6
3 groups:
- Amlodipine 5 mg
- Amlodipine 10 mg
- Amlodipine 5 mg + aliskiren 150 mg
6 weeks
(n = 545)
Aliskiren 150 mg + amlodipine 5 mg showed BP-lowering efficacy similar to amlodipine 10 mg and was better tolerated.
Uresin et al (2007) Change in BP from BL to wk 8
- Aliskiren 150 mg → 300 mg
- Ramipril 5 mg → 10 mg
- Aliskiren 150 mg / ramipril 5 mg → 300 / 10 mg
(n = 837)
Combining aliskiren with ramipril
provided a greater reduction in BP than either drug alone in diabetic patients.
Oparil et al (2007) Change in BP from BL to wk 8
4 groups:
- Valsartan 160 mg → 320 mg
- Valsartan 160 mg + aliskiren 150 mg → 320 / 300 mg
- Placebo
(n = 1797)
The combination of aliskiren and valsartan at maximum recommended doses provides significantly greater reductions in BP than either agent alone.
Aliskiren has been studied in combination with thiazide diuretics (hydrochlorothiazide),1 calcium channel blockers (amlodipine),2 ACE inhibitors
(ramipril—in subjects with diabetes and hypertension)3 and ARBs (valsartan).4 In each case, the combination of the two agents was found to be more efficacious for BP reduction than either monotherapy alone, with no significant additional safety or tolerability concerns.
The data accumulated to date suggest that aliskiren is a useful agent to consider as a component of combination therapy with other commonly used antihypertensives.
References:
1. Villamil A, Chrysant SG, Calhoun D, et al: Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide. J Hypertens 2007; 25:
2. Drummond W, Munger MA, Rafique Essop M, et al: Antihypertensive efficacy of the oral direct Renin inhibitor aliskiren as add-on therapy in patients not responding to amlodipine monotherapy. J Clin Hypertens (Greenwich) 2007; 9(10):
3. Uresin Y, Taylor AA, Kilo C, et al: Efficacy and safety of the direct renin inhibitor aliskiren and ramipril alone or in combination in patients with diabetes and hypertension. J Renin Angiotensin Aldosterone Syst 2007; 8(4):190-8.
4. Oparil S, Yarows SA, Patel S, et al: Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial. Lancet 2007; 370(9583):221-9. 35 35 35

36. *p < 0.05; †p < 0.0001 vs respective monotherapies
Aliskiren Provides Additional BP Lowering When Added to Other Antihypertensive Agents
Treatment dose (mg)
Valsartan 160
Ramipril 10
HCTZ 12.5
HCTZ 25
Amlodipine 5
Valsartan 320
n =
275
274 58 60 60 58
188
184
180
175
187
173
177
188 −5
+ aliskiren150
+ aliskiren 300
+ aliskiren 150
+ aliskiren 300
+ aliskiren 150
+ aliskiren 300
+ aliskiren 150
+ aliskiren 300
−5.0
−10
−11.0
−15
−12.0 †
−13.9
Weir et al. (2007) assessed the antihypertensive efficacy and safety of aliskiren in a pooled analysis of data from 7 randomized, multicentre studies (5 placebo-controlled and 2 active-controlled studies). Pooled data were available for patients with mild to moderate hypertension over treatment durations of 6 to 8 weeks.
Combination of aliskiren 150 or 300 mg with ramipril, amlodipine or hydrochlorothiazide provided significant additional BP reductions compared with the respective monotherapies.
Reference:
Weir MR, Bush C, Anderson DR, et al. Antihypertensive efficacy, safety, and tolerability of the oral direct renin inhibitor aliskiren in patients with hypertension: a pooled analysis. Journal of the American Society of Hypertension 2007;1(4):
−14.3
−20
−15.5
−17.6
−16.6
−16.6
−16.5 * †
−19.8
−18.0
−19.5 * *
−25
−21.2 *
Change from baseline in msSBP (mmHg)
*p < 0.05; †p < vs respective monotherapies 36
Adapted from Weir MR, et al: J Am Soc Hypertens 2007; 1(4):264–77. 36

37. Efficacy with DRI Therapy in Hypertension Trials: Different Populations
The efficacy of aliskiren has been extensively studied in the following populations:
Young and elderly1
Obesity2
Diabetes3
Metabolic syndrome4,5
Impaired renal function6
In addition to having been studied in combination with many different antihypertensives, aliskiren has also been investigated in a number of different patient types, including younger and older patients (18 and older), those with obesity and those without, those with diabetes or metabolic syndrome and those with impaired renal function.
References:
1. Dahlöf B, Anderson DR, Arora V, et al: Aliskiren, a direct renin inhibitor, provides antihypertensive efficacy and excellent tolerability independent of age or gender in patients with hypertension. J Clin Hypertens 2007; 9(Suppl. A):A157 [abstract P-376].
2. Prescott MF, Bush C, Arora V, et al: Aliskiren, a direct renin inhibitor, provides effective blood pressure (BP) lowering with placebo-like tolerability in obese patients with hypertension. Int J Obes 2007; 31(Suppl. 1):S99 [abstract T2:PO.88].
3. Taylor AA, Anderson DR, Arora V, et al: Antihypertensive efficacy of the direct renin inhibitor aliskiren in patients with diabetes: a pooled analysis of 10 randomized trials. Diabetes 2007; 56(Suppl. 1):A129 [abstract 483-P].
4. White WB, Anderson DR, Arora V, et al: Antihypertensive effectiveness of the direct renin inhibitor aliskiren in patients with metabolic syndrome: a comparative analysis of 7219 patients from 10 randomized trials. Eur Heart J 2007; 28(Suppl 1):868 [abstract P4845].
5. Weir MR, Bush C, Anderson DR, et al: Antihypertensive efficacy, safety and tolerability of the oral direct renin inhibitor aliskiren in patients with hypertension: a pooled analysis. J Am Soc Hypertens 2007; 1(4):
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): 37 37 37

38. Aliskiren Provides Effective BP-lowering in Patients with Impaired Renal Function: Pooled Analysis
DBP
SBP
eGFR <60
eGFR ≥60
eGFR <60
eGFR ≥60
n=26
n=25
n=740
n=736
n=26
n=25
n=740
n=736 5 10
In this analysis, data from five randomized, placebo-controlled trials with aliskiren monotherapy were pooled. The pooled studies included 5,678 patients with mild-to-moderate hypertension who received treatment with aliskiren monotherapy or placebo for 8 weeks. The effect of aliskiren monotherapy on mean sitting diastolic and systolic BP (DBP and SBP, respectively) in the subgroup of patients with moderate renal impairment (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2) was compared with that in patients with eGFR >60 mL/min/1.73 m2.
After 8 weeks’ treatment, aliskiren 150 and 300 mg provided dose-dependent reductions from baseline in SBP and DBP. There were no noticeable differences in BP-lowering effect between patients with eGFR <60 or ≥60 mL/min/1.73m2.
Furthermore, aliskiren was well tolerated in both subgroups of patients, with a similar incidence of adverse events (AEs) in those patients with eGFR <60 or ≥60 mL/min/1.73m2 (AE incidence: 43.1% and 38.7%, respectively).
These results demonstrate that aliskiren provides antihypertensive efficacy and is well tolerated independent of baseline renal function.
Abbreviations
eGFR = estimated glomerular filtration rate
SBP = systolic blood pressure
DBP = diastolic blood pressure
Reference
Weir MR, Anderson DR, Arora V, et al. Safety and blood pressure-lowering efficacy of the direct renin inhibitor aliskiren in patients with hypertension and impaired renal function. WCN 2007 Book of Abstracts: 384 T-PO-1162.
–9.4
–10.4
–10.1
–11.4
–11.2
–11.5 15
Mean change from baseline in mean sitting BP after 8 weeks (mmHg)
–14.7
–14.9
Aliskiren 150 mg
Aliskiren 300 mg 38
eGFR: estimated glomerular filtration rate (assessed in mL/min/1.73 m2)
Weir MR, et al (Pooled analysis) 38

39. Tolerability of Aliskiren39

40. Aliskiren monotherapy: Tolerability
Placebo
n = 781
Aliskiren
75 mg
n = 478
Aliskiren
150 mg
n = 774
Aliskiren
300 mg
n = 768
All
Aliskiren+
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)
In a pooled analysis of data including 2316 patients who received aliskiren monotherapy, the tolerability profile of aliskiren was similar to placebo. The mean duration of exposure was 54 days (max. 73) for aliskiren monotherapy and 52 days (max. 83) for placebo.
Adverse events (AEs) were reported in 39.8% of aliskiren-treated patients and 40.2% of patients who received placebo. Serious adverse events (SAEs) occurred in 11 patients (0.5%) who received aliskiren compared with 5 patients (0.6%) who received placebo.
AEs that occurred in ≥2% of patients treated with aliskiren monotherapy were headache (5.7% vs 8.7% for placebo), nasopharyngitis (4.4% vs 5.8% for placebo) and diarrhea (2.6% vs 1.2% for placebo). Over 95% of AEs were mild or moderate severity and most were considered not to be related to study medication.
The overall incidence of diarrhoea with aliskiren was higher than placebo due to a significantly higher rate with aliskiren 600 mg (p< vs placebo); at 150 and 300 mg dosages the incidence of diarrhoea was similar to placebo.
Abbreviations
AEs = adverse events
SAEs = serious adverse events
Reference
Weir MR, Bush C, Zhang J, et al. Antihypertensive efficacy and safety of the oral renin inhibitor aliskiren in patients with hypertension: a pooled analysis. Eur Heart J 2006; in press: abstract presented at WCC/ESC 2006.
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)
Weir M, et al. WCC 2006 (Pooled analysis)

41. Aliskiren/ramipril Combination
Ramipril monotherapy* (n=278)
Aliskiren monotherapy* (n=282)
Aliskiren /ramipril combination therapy* (n=277)
Any AE
33.8
32.3
30.0
Serious AEs
2.2
2.8
1.4
Discontinuation due to AEs
4.0
3.9
Treatment-related AEs
11.9
7.4
6.1
Most frequent AEs (³2% in any group)
Headache
3.2
2.9
Cough
4.7
2.1
1.8
Nasopharyngitis
1.1
Diarrhoea
2.5
Adverse events (AEs) occurred in approximately one third of patients across all three treatment groups. Patients in the ramipril group had a higher incidence of cough than other groups, as often occurs with angiotensin converting enzyme inhibitor therapy. Interestingly, the incidence of cough decreases in the combination therapy group. Headache and diarrhoea were also reported more frequently in the ramipril group, while nasopharyngitis was slightly more frequent in the aliskiren group. No AEs occurred in more than 3% of patients in the combination therapy group.
No deaths occurred during the study. Serious AEs were infrequent and evenly distributed among the treatment groups.
Abbreviation
AE = adverse event
Reference
1. Uresin Y, Taylor A, Kilo C, et al. Efficacy and safety of the direct renin inhibitor aliskiren and ramipril alone or in combination in patients with diabetes and hypertension. JRAAS 2007;8(4):
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.
1.Uresin Y, et al (Study 2307)
2. Rasilez® Product Monograph, March 13, 2008 41

42. HCTZ plus Aliskiren or Amlodipine: Incidence of Edema in Patients with Obesity and Hypertension
Irbesartan/
n = 119
Amlodipine/
n = 126
alone
Any AE, n (%)
48 (39.3)
43 (36.1)
57 (45.2)
47 (38.5)
Discontinuations
due to AE, n (%)
2 (1.6)
4 (3.4)
7 (5.6)
4 (3.3)
SAEs, n (%)
3 (2.5)
4 (3.2)
AEs, reported by ≥2% of patients in any treatment group, n (%)
Nasopharyngitis
10 (8.2)
6 (5.0)
5 (4.1)
Headache
9 (7.1)
Dizziness
1 (0.8)
Peripheral oedema
14 (11.1)
Back pain
2 (1.7)
5 (4.0)
This was a double-blind, randomized, active-controlled study in 489 obese patients with mean sitting diastolic blood pressure (MSDBP) ≥90 mmHg despite 4 weeks’ treatment with HCTZ 25 mg once daily (i.e., non-responders).
Patients not responding to 4-week’s HCTZ 25 mg monotherapy were randomized to addition of aliskiren 150 mg, irbesartan 150 mg, amlodipine 5 mg, or placebo, once daily. After 4 weeks, the dosages of aliskiren, irbesartan, and amlodipine were doubled for the final 8 weeks of the double-blind period.
The incidence of adverse events (AEs) was highest in the amlodipine/HCTZ 10/25 mg combination therapy group due to the high incidence of peripheral oedema (11.1%). The incidence of peripheral oedema in the other treatment groups ranged from 0.8% to 1.6%. Combination therapy with aliskiren 300 mg and HCTZ 25 mg was associated with a similar rate of AEs to HCTZ 25 mg monotherapy irrespective of obesity subgroup.
Abbreviations
AE = adverse event
SAE = serious adverse event
HCTZ = hydrochlorothiazide
MSDBP = mean sitting diastolic blood pressure
Reference
Jordan J, Engli S, Boye SW, et al. Direct renin inhibition with aliskiren in obese patients with arterial hypertension. Hypertension 2007;49:1–9.
AE, adverse event; SAE, serious adverse event
Jordan J, et al (Study 2309) 42

43. Aliskiren In Hypertension Clinical Summary
Aliskiren 150–300 mg:
provides dose-dependent reductions in DBP and SBP as monotherapy
BP reductions from baseline greater than HCTZ and ramipril and similar to irbesartan
provides additional BP lowering when combined with other antihypertensives (see next slide)
provides sustained 24-hour BP control with prolonged effect after discontinuation
Rates of adverse effects are similar to placebo
Increases in serum potassium are infrequent in patients with hypertension treated with aliskiren alone. When used in combination with another RAS agent, increases in serum potassium may be more frequent
Abbreviations
BP = blood pressure
DBP = diastolic blood pressure
PRA = plasma renin activity
SBP = systolic blood pressure 43 43

44. Aliskiren In Hypertension Clinical Summary
The combination of aliskiren with other antihypertensive agents, such as ACE inhibitors, ARBs, dihydropyridine CCBs, or thiazide diuretics, is well tolerated
When combined with ramipril, aliskiren appears to reduce the incidence of cough
Long-term combination therapy with aliskiren and valsartan is well tolerated
The combination of aliskiren and amlodipine results in a lower incidence of edema compared with increasing the amlodipine dose
In obese patients who fail to respond adequately to diuretic monotherapy, adding aliskiren results in fewer incidences of peripheral oedema than adding amlodipine 44 44

45. Supporting Appropriate Assessment and Monitoring of Blood Pressure

46. Criteria for the diagnosis of hypertension and recommendations for follow-up
BP: /
Clinic BP
Diagnosis
of HTN
Hypertension visit 3
>160 SBP or >100 DBP
>140 SBP or
>90 DBP
< 140 / 90
Continue to follow-up
<160 / 100
Hypertension visit 4-5
ABPM or HBPM if available or
ABPM (If available)
Diagnosis
of HTN
Awake BP
>135 SBP or
>85 DBP or
24-hour
>130 SBP or
>80 DBP
<135/85
and
<130/80
Continue to follow-up
Home BPM (If available)
>135/85
< 135/85
Diagnosis
of HTN
Continue to follow-up or
Patients with high normal blood pressure (clinic SBP and/or DBP 85-89) should be followed annually.
2008 CHEP Recommendations

47. Criteria for the diagnosis of hypertension and recommendations for follow-up
Non Pharmacological treatment
With or without Pharmacological treatment
Are BP readings below target during 2 consecutive visits?
Yes No
Symptoms, Severe hypertension, Intolerance to anti-hypertensive treatment or Target Organ Damage
Follow-up at 3-6 month intervals *
Yes No
Visits every 1 to 2 months*
More frequent visits *
* Consider Home measurement in hypertension management, to screen for masked hypertension or white coat effect and to enhance adherence.
2008 CHEP Recommendations

48. Assessment of the overall cardiovascular risk
Search for exogenous potentially modifiable factors that can induce/aggravate hypertension
Prescription Drugs:
NSAIDs, including Coxibs
Corticosteroids and anabolic steroids
Oral contraceptive and sex hormones
Vasoconstricting/sympathomimetic decongestants
Calcineurin inhibitors (cyclosporin, tacrolimus)
Erythropoietin and analogues
Monoamine oxidase inhibitors (MAOIs)
Midodrine
Other:
Licorice root
Stimulants including cocaine
Salt
Excessive alcohol use
Sleep apnea
2008 CHEP Recommendations

49. Home measurement of blood pressure
Home BP measurement should be encouraged to increase patient involvement in care
Which patients?
Uncomplicated hypertension
Diabetes mellitus
Chronic kidney disease
Suspected non adherence
Office-induced blood pressure elevation (white coat effect)
Masked hypertension
Average BP equal to or over 135/85 mm Hg should be considered elevated
2008 CHEP Recommendations

50. Potential advantages of home blood pressure measurement
More rapid confirmation of the diagnosis of hypertension
Improved ability to predict cardiovascular prognosis
Improved blood pressure control
Can screen for white coat hypertension (WCH) and masked hypertension
Reduced medication use in some (WCH)
Improved adherence to drug therapy in the non adherent
2008 CHEP Recommendations

51. Not all patients are suited to home measurement
Undue anxiety in response to high blood pressure readings
Physical or mental impairment prevents accurate technique or recording
Arm not suited to blood pressure cuff (e.g. conical shaped arm)
Irregular pulse or arrhythmias prevent accurate readings
Lack of interest
The vast majority of patients can be trained to measure blood pressure
2008 CHEP Recommendations

52. Home blood pressure values should be based on: duplicate measures,
Suggested Protocol for Home Measurement of Blood Pressure for the diagnosis of hypertension
Home blood pressure values should be based on:
duplicate measures,
morning and evening,
for an initial 7-day period.
Singular and first day home BP values should
not be considered.
Daytime average BP equal to or over 135/85
mmHg should be considered elevated.
2008 CHEP Recommendations

53. Home BP Measurement: CHEP Recommendations
Encourage hypertensive patients to use an approved blood pressure measuring device and use proper technique to assess blood pressure at home
Measuring blood pressure at home has a stronger association with cardiovascular prognosis than office-based readings
One of the learning objectives of the 2008 Canadian Hypertension Education Program Recommendations was to emphasize the importance of home BP monitoring for hypertensive patients. The recommendations state that home measurement has a stronger association with positive cardiovascular prognosis than office-based readings.
Reference:
Canadian Hypertension Education Program Recommendations: Part II – Recommendations for Treatment Edition, available at
2008 CHEP Recommendations 53

54. Blood Pressure Assessment: Patient preparation and posture
Standardized technique:
Patient
1. No caffeine in the preceding hour.
2. No smoking or nicotine in the preceding 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.
2008 CHEP Recommendations

55. Blood Pressure Assessment: Patient position
2008 CHEP Recommendations

56. CHEP-recommended Electronic BP Monitors for Home BP Measurement
The Canadian Hypertension Education Program has evaluated the currently available home blood pressure monitors and recommends using one of the following models:
A&D® or LifeSource® monitors: Models 705, 767, 767PAC, 767Plus, 774, 774AC, 779, 787EJ, 787AC, 787W
Omron® monitors: Models HEM-705 PC, HEM-711, HEM-741CINT
Microlife® or Thermor® monitors (also sold as ‘private label brands’): Models: BP 3BTO-A, BP 3AC1-1, BP 3AC1-1 PC, BP 3AC1-2, BP 3AG1, BP 3BTO-1, BP 3BTO-A (2), BP 3BTO-AP, RM 100, BP A100 Plus, BP A 100.
Reference:
Canadian Hypertension Education Program: Approved Home BP Devices , available at
Monitors that have been validated as accurate and available in Canada are listed at
They are also marked with
“Recommended by the Canadian Hypertension Society”
See speaker notes for recommended model numbers
Adapted from Approved Home BP Devices.
2008 CHEP Recommendations 56

57. Use an appropriate size cuff
Arm circumference (cm)
Size of Cuff (cm)
From 18 to 26
9 x 18 (child)
From 26 to 33
12 x 23 (standard adult model)
From 33 to 41
15 x 33 (large, obese)
More than 41
18 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.
2008 CHEP Recommendations

58. Home Measurement of BP: Patient Education
How to?
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
Values over
135 / 85 mm Hg
should be
considered elevated
Home measurement can help to improve patient adherence
AAMI=Association for the Advancement of Medical Instrumentation;
BHS=British Hypertension Society; IP: International Protocol.
2008 CHEP Recommendations

59. Home Measurement of BP: Patient Education
Assist patients select a model with the correct size of cuff
Measure and record the patients mid arm circumference so they can match it to cuff size
Recommend devices listed at 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 high
a lower threshold is appropriate for those with diabetes or chronic kidney disease
Values equal to or over
135 / 85 mm Hg
should be
considered elevated for those without diabetes or chronic kidney disease
Home measurement can help to improve patient adherence
2008 CHEP Recommendations

60. Summary I
Regarding the treatment of hypertension, the recommendations endorse:
ASSESSMENT OF BLOOD PRESSURE AT ALL APPROPRIATE VISITS
Most Canadians will develop hypertension during their lives. Routine assessment of blood pressure is required for early detection and risk management
ENCOURAGE APPROPRIATE PATIENTS TO MONITOR BLOOD PRESSURE AT HOME
Most can assess blood pressure at home. Home measurement can confirm a diagnosis of hypertension, improve adherence to drug treatment, improve control rates and screen for those with white coat hypertension and masked hypertension.
2008 CHEP Recommendations

61. Summary II
Regarding the treatment of hypertension, the recommendations endorse:
INDIVIDUALIZING THERAPY
consider concomitant risk factors and/or concurrent diseases, other patient characteristics and preferences (e.g. age, diabetes, CVD) and other considerations e.g. costs
LIFESTYLE MODIFICATION
To prevent hypertension
In those with hypertension alone if effective to reach the goal value or in combination with pharmacological treatment
2008 CHEP Recommendations

62. Summary III
Regarding the treatment of hypertension, the recommendations endorse:
TREATING TO TARGET BP
treat aggressively using combinations of drugs and lifestyle modification to achieve individualized target
PROMOTING ADHERENCE
a multi-faceted approach should be used to improve adherence with both non pharmacological and pharmacological strategies
2008 CHEP Recommendations