Hypertension

1
Hypertension
gjgibson 2001/09
2
First reliable and effective antihypertensive
agents ganglionic blockers (ca. 1950)
3
Unbearable side effects extreme orthostatic
hypotension, incapacitating intestinal
immobility, and severe sexual dysfunction (viz.
only in life-threatening hypertension)
4
First large-scale efficacy trial reserpine/
reserpine combined with hydralazine/ and
ganglionic blocking agents were compared,
followed by a study of chlorothiazide (1960s)
5
1930s Veratrum Alkalois
Pyrogens 1940s Thiocyanates Ganglion blocking
agents Catecholamine depletors (Rauwolfia
deriatives) 1950s Vasodilators (Hydralazine) Peri
pheral sympathetic inibitors (guanethidine) Monoa
mine oxidase inhibitors Diuretics 1960s Central
alpha2-agonists (sympathetic nervous system
inhibitors) beta-Adrenergic inhibitors 1970s alph
a-Adrenergic inhibitors alpha-beta-blockers 1980s
/calcium channel blockers 1990s Angiotensin II
(ATI) receptor antagonists 2000s ? Gene therapy
6
why we treat(1st Vet Admin Study)

• 1964
• 73 volunteers
• dBP 115-129
• thiaside/hydralizine/reserpine
• lowering of fatal incidents by 2190 in 18/12

7
Outcome studies (whether blood pressure
lowering improves a patients cardiovascular
prognosis)...
8
Special populations most found a significant
decreased in mortality and morbidity, but results
were much less robust that in previous trials.
9

• Currently 16 ongoing acronym trials
• AASK (African American Study of Kidney disease
  and hypertension)
• ALLHAT (Antihypertensive and Lipid Lowering
  treatment to prevent Heart Attack Trial)
• ANBP2 (Australian National Blood Pressure
  trial-2)
• ASCOT (AngloScandinavian Cardiac Outcomes Trial)
• CONVINCE (Controlled Onset Verapamil
  Investigation for Cardiovascular Endpoints)
• CSGTEI (Collaborative Study Group Trial on Effect
  of Irbesartan)
• Diab-Hycar, ELSA (European Lacidipine Study on
  Atherosclerosis)

10

• HYVET (Hypertension in the Very Elderly Trial)
• INSIGHT (International Nifepidine-GITS Study
  Intervention as a Goal in Treatment)
• LIFE (Losartan Intervention For Endpoint
  reduction)
• NORDIL (NORdic DILtiazem Study)
• PROGRESS (Perindorpil pROtection aGainst
  Recurrent Stroke Study)
• SCOPE (Systolic Hpyertension in the Elderly
  Longterm Lacipidine trial)
• VALUE (Valsartan Antihypertensive Longfunksies
  -term Use Evaluation trial

11
ULTIMATE GOAL OF ANTIHYPERTENSIVE THERAPY
BLOOD PRESSURE REDUCTION
PREVENTIONOF COMPLICATIONS
PROLONGED SURVIVAL
12
PROFILE OF AN IDEAL ANTIHYPERTENSIVE

• SCIENTIFIC RATIONALE AND SELECTIVE MECHANISM OF
  ACTION
• SIMPLE PHARMACOKINETIC PROFILE
• CONSISTENT BLOOD PRESSURE REDUCTION
• OUTSTANDING SAFETY AND TOLERABILITY
• SUPERIOR TO EXISTING THERAPIES
• EASY TO USE IN SPECIAL POPULATIONS
• EFFECTS BEYOND BLOOD PRESSURE REDUCTION

13
SCIENTIFIC RATIONALE
ANGIOTENSIN II PLAYS A KEY ROLE IN
CARDIOVASCULAR HOMEOSTASIS
ALDOSTERONESECRETION
NA RETENTION
VASCULARTONE
SYMPATHETICTONE
SMOOTH MUSCLECELL PROLIFERATION
CARDIAC MYOCYTEPROLIFERATION
ANGIOTENSIN II
ENDOTHELINRELEASE
TXA2/PGPRODUCTION
VASOPRESSINRELEASE
APOPTOSIS
14
MECHANISM OF ACTION
ANGIOTENSINOGEN (LIVER)
RENIN INHIBITOR
ANGIOTENSIN I
BRADYKININ
ACE INHIBITOR
PEPTIDES
ANGIOTENSIN II
AT1 RECEPTOR BLOCKER
15
SELECTIVE MECHANISM OF ACTION
ANGIOTENSINOGEN (LIVER)
CHYMASE
RENIN INHIBITOR
ANGIOTENSIN I
BRADYKININ
ACE INHIBITOR
PEPTIDES
ANGIOTENSIN II
AT1 RECEPTOR BLOCKER
16
ANGIOTENSIN II
VIA AT1 RECEPTOR
DIABETICNEPHROPATHY
VASOCONSTRICTION NA RETENTION ALDOSTERONE
SECRETION VASCULAR PROLIFERATION CARDIAC
MYOCYTEPROLIFERATION
REMODELING(LOCALLY PRODUCED ANG II)
WORSENING OF RENAL HEMODYNAMICS ALBUMINURIA
VASOCONSTRICTION FLUID OVERLOAD SYMPATHETIC
STIMULATION REMODELING
17
Treatment failures hypertension treatment trials
Patients not achieving goal on active treatment
()
Study
Blood pressure goal (mm Hg)
Reference
lt90 (DBP) lt90 (DBP)lt160/90 (SBP/DBP) lt90
(DBP) lt95 (DBP)
2337 36.1 2232 34.6 23 2835
HDFP, 1979 ANBP, 1980 Amery et al, 1991 IPPSH,
1985 Wilhelmsen et al, 1987 SHEP, 1991
HDFP Australian Trial EWPHE IPPSH HAPPHY SHE
P
18
Blood pressure and target organ damage
Current evidence suggests that

• Measures of 24-h blood pressure more closely
  predict target organ damage than do clinic or
  casual measurements
• There is a higher incidence of cardiovascular
  complications when night-time blood pressure
  remains elevated
• Blood pressure variability is an additional
  and independent determinant of target organ
  damage
• The highest incidence of cardiovascular events
  occurs in the morning at (approximately) 24 h
  post dose

Sokolow et al, 1966 Devereux et al, 1983
Devereux et al, 1987 Parati et al,1987 Mancia,
1990
19
Weighted Average Changes in SBP at Trough
2359
1455
582
268
2217
855
567
593
1605
94
124
61
N
-2
Can 8 mg
Los 50 mg
Val 80 mg
-4
Irb 150 mg
Can 8 - 16 mg
Los 50 - 100 mg
Val 80 - 160 mg
Irb 150 - 300 mg
-6
Can 8 Hctz 12.5 mg
Los 50 Hctz 12.5 mg
Val 80 Hctz 12.5 mg
Irb 150 Hctz 12.5 mg
-8
-10
-12
-14
-16
Losartan Valsartan Irbesartan Candesartan
-18
-20
-22
Weighted Avg for the group
-24
-26
-16.5
-16.1
-19.7
-14.7
-10.4
-13.8
-10.9
-11.2
-11.8
-20.6
-13.1
-12.4
20
Weighted Average Changes in DBP at Trough
2359
1455
582
336
2217
855
610
593
1605
190
181
298
N
-2
Can 8 mg
Los 50 mg
Val 80 mg
Irb 150 mg
Can 8 - 16 mg
Val 80 - 160 mg
Los 50 - 100 mg
Irb 150 - 300 mg
-4
Can 8 Hctz 12.5 mg
Val 80 Hctz 12.5 mg
Los 50 Hctz 12.5 mg
Irb 150 Hctz 12.5 mg
-6
-8
-10
Losartan Valsartan Irbesartan Candesartan
-12
-14
Weighted Avg for the group
-16
-12.0
-12.4
-13.6
-9.5
-8.2
-10.4
-8.8
-8.7
-8.9
-9.9
-10.0
-9.6
mmHg
21
Weighted Average Responders Rates ()(DBP lt 90
mmHg or reduced by 10 mmHg)
Weighted Avg for the group
Losartan Valsartan Irbesartan Candesartan
80
70
70.4
66.3
66.0
60
63.2
56.0
55.7
56.4
54.8
50
53.3
53.2
49.2
48.0
40
30
Irb 150 Hctz 12.5 mg
Los 50 Hctz 12.5 mg
Val 80 Hctz 12.5 mg
Can 8 Hctz 12.5 mg
Irb 150 - 300 mg
Los 50 - 100 mg
Val 80 - 160 mg
20
Can 8 - 16 mg
Irb 150 mg
Val 80 mg
Los 50 mg
Can 8 mg
10
1711
1455
582
199
1795
855
531
191
843
190
181
61
N
22
Conclusions
Comparable efficacy of AT1 antagonists at initial
doses DBP reduction 8.5 mmHg SBP
reduction 10.7 mmHg Responders 50
Doubling the dose of these agents produces small
additional BP reduction DBP reduction 1.5
mmHg SBP reduction 2.5 mmHg Responders 7
more responders
Addition of 12.5mg Hydrochlorthiazide to the
initial dose produces 40-60 more BP lowering
produces 40 more responders
23
The Rule of Halves
Proportions of the General Population Who Have
Undiagnosed Hypertension (gt160/95 mmHg) or Who
Are Untreated or Inadequately Treated (Scotland,
1984-1986)
24
Efficacy Tolerability Product

• As effective in monotherapy as other classes
• of antihypertensive therapy
• In placebo-controlled randomised clinical
  trials,
• lower adverse event rate than other classes of
• antihypertensive therapy (Adverse event rate
  placebo)
• Very High efficacy Tolerability Product

25

• Drug-related causes
• Doses too low
• Inappropriate combinations (e.g. two centrally
  acting adrenergic inhibitors)
• Rapid inactivation (e.g. hydralazine, oral
  clonidine, captopril, short-acting calcium
  channel blockers)
• Drug interactions
• Glucocorticoids
• Mineralocorticoids
• NSAIDs
• Appetite suppressants
• Oral contraceptives
• Antidepressants
• Adrenal steroids
• Nasal decongestants
• Erytropoetin

26

• Associated conditions
• Obesity
• Alcohol intake greater than 1 oz of ethanol per
  day
• Sedentary lifestyle
• Sleep apnea

27

• COMPONENTS OF RISK STRATIFICATIONS IN PATIENTS
  WITH HYPERTENSION
• MAJOR RISK FACTORS
• Smoking
• Dyslipidaemia
• Diabetes mellitus
• Age gt 60 years
• Sex (men and postmenopausal women)
• Family history of cardiovascular disease women
  lt 65 years or men lt 55 years
• TARGET ORGAN DAMAGE/CLINICAL CARDIOVASCULAR
  DISEASE
• Heart diseases
• Left ventricular hypertrophy / Angina or prior
  myocardial infarction / Prior
• coronary revascularisation / Heart failure
• Stroke or transient ischaemic attack
• Nephropathy
• Peripheral arterial disease
• Retinopathy

28
Combinations
(i) Diuretic and ß-blocker ii) Diuretic and ACE
inhibitor (or AII receptor blocker) iii) CCB
(dihydropyridine) and ß-blocker iv) CCB and ACE
inhibitor and v) ð-blocker and ß-blocker
29
ANTIHYPERTENSIVE AGENTS IN WHITE AND BLACK
COMMUNITIES AGENT WHITE BLACK Thiazide
Rauwolfia ß-blockers - ð- and
ß-blockers Methyldopa Vasodilators
ACE inhibitors - ACE inhibitors
thiazides Calcium channel
blockers Angiotensin II antagonists -
30
GUIDELINES FOR SELECTING DRUG TREATMENT FOR
HYPERTENSION CLASS OF DRUG COMPELLING POSSIBLE
COMPELLING POSSIBLE INDICATIONS INDICATIONS
CONTRAINDICATIONS CONTRAINDICATIONS Diuretic He
art Failure Diabetes Gout Dyslipidaemia Elder
ly patients Sexually active males Systolic
hypertension ß-blockers Angina Heart
Failure Asthma and COPD Dyslipidaemia After
myocardial Pregnancy Heart block Athletes and
physically infarct Diabetes active
patients Tachyarrhythmias Peripheral
vascular disease ACE inhibitors Heart
Failure Pregnancy Left ventricular Hyperka
laemia dysfunction Bilateral renal
artery After myocardial infarct stenosis Dia
betes nephropathy Calcium Angina Peripheral
vascular Heart block Congestive heart
failure antagonists Elderly patients disease S
ystolic hypertension ð-blockers Prostatic
hypertrophy Glucose intolerance Orthostatic
hypotension Dyslipidaemia Angiotensin II ACE
inhibitor cough Heart failure Pregnancy antagonis
t Bilateral renal artery stenosis
Hyperkalaemia
31
Management of High Risk patients with
Hypertension and Type 2 diabetes

• Program for Irbesartan Mortality and Morbidity
  Evaluations

• IDNT
• IRMA II

32
32
Worldwide Rates of Hypertension
Germany
Australia
Scotland
Egypt
Finland
Taiwan
Spain
Canada
US
India
China
Hypertension prevalence ()
Adapted from Marques-Vidal P and Tuomilehto J. J
Hum Hypertens. 199711213220.
33
Worldwide Rates of Diabetes MellitusPredictions
Year
1995
2000
2025
Estimated prevalence (millions)
World Health Organization. The World Health
Report 1997.
34
The Natural Associations With High Risk
Hypertensive
HYPERTENSION
Diabetes type II

• Cardiac problems
• MI
• CHD
• Atherosclerosis
• Stroke
• Family History (card.)

• Extent of BP
• mixed definitions
• uncontrolled
• persistently elevated

Hyper- cholesterolaemia
35
Coexistence of Hypertension in Diabetes
The bad companions...
hypertension is associated with a doubling of
the presence of
LVH, left ventricle hypertrophy ECG,
electrocardiogram MI, myocardial ischemia, CV,
cardiovascular.
Kaplan NM. In Ellenberg and Rifkins Diabetes
Mellitus Theory and Practice, 5th ed. 1997.
36
Effect of ACE Inhibition on Diabetic Nephropathy
in Patients with Type 1 Diabetes
Captopril
Placebo
Progressing to death, dialysis or
transplant ()

Follow-up (y)
p 0.006 vs placebo.
Adapted from Lewis EJ et al. N Engl J Med.
19933291456-1462.
37
IDNT Pilot Study Effect of Irbesartan onRenal
Function in Type 2 Diabetic Nephropathy
Irbesartan 300 mg (n 24)
Amlodipine 10 mg (n 23)
Creatinine Clearance
Urine Protein Excretion
Adjusted change from baseline at week 12 ()
Adjusted change from baselineat week
12(mL/min/1.73 m2)
Pohl M et al. Am J Hypertens. 199710105A.
Abstract.
Collaborative Study Group
38
Scope of the PRIME program in relation to the
time-course of type 2 diabetes
ESRD
Microalbuminuria
Proteinuria
IRMA II
IDNT
Cardiovascular complications
39
Irbesartan DiabeticNephropathy Trial (IDNT)
Objective

• Comparative trial of the effects of irbesartan,
  amlodipine, and placebo on renal function, total
  mortality, and cardiovascular morbidity in
  patients with hypertension and type 2 diabetic
  nephropathy
• Primary comparison of irbesartan with placebo
• Secondary comparison of irbesartan with
  amlodipine
• Independent, unblinded Data Safety Monitoring
  Committee reviewing safety and efficacy data
  every 6 months

40
Irbesartan Diabetic NephropathyTrial (IDNT)
Study Design

• Multicenter, randomized, double-blind comparison
  of irbesartan vs placebo vs amlodipine (N 1,715)

Double-blind Treatment
Irbesartan
Screening/Enrollment
Placebo
Amlodipine
Up to 5 weeks
Minimum follow-up approximately 2 years
(average 3 years)
Adjunctive antihypertensive therapies
(excluding ACE inhibitors, angiotensin II
receptor antagonists, and calcium channel
blockers) added to each arm to achieve equal
blood pressure reduction.
Rodby RA et al. Nephrol Dial. In press.
41
Irbesartan Diabetic NephropathyTrial (IDNT)
Clinical Outcome Measures

• Primary outcome is time to a composite endpoint
  consisting of
• Doubling of baseline serum creatinine level
• End-stage renal disease
• Death (all-cause mortality)
• Secondary outcome is time to a composite endpoint
  of fatal or nonfatal cardiovascular events

Rodby RA et al. Nephrol Dial. In press.
42
Irbesartan in Patients with Type 2 Diabetes and
Microalbuminuria (IRMA II) Study Objectives

• To study patients at an early stage of diabetic
  nephropathy (normal renal function and
  microalbuminuria)
• To determine whether irbesartan can slow the
  progression from microalbuminuria to overt
  proteinuria
• To evaluate renal hemodynamics (substudy)

43
IRMA II Design

• Population 610 patients with type 2 diabetes,
  microalbuminuria (albumin excretion rate 20200
  µg/min), normal renal function, and hypertension

Double-blind Treatment
Screening/Enrollment
Placebo
Irbesartan 150 mg
Irbesartan 300 mg
Up to 5 weeks
Follow-up 2 years
44
Irbesartan Microalbuminuria (IRMA II) Trial in
Hypertensive Patients With Type 2 Diabetes
Clinical Outcome Measures

• Primary outcome time to occurrence of clinical
  proteinuria
• Secondary outcomes
• Incidence at 2 years of clinical proteinuria with
  each treatment
• Change in overnight urinary albumin excretion
  rate at each timepoint
• After 1 and 2 years, change in 24-hour creatinine
  clearance, clotting factors, and lipid profile
• After 3 months and 2 years, change in renal
  function

45
Positive features to highlight...

• First trial to address the unanswered question of
  treatment of DN in type 2 patients
• Definite design helping to address the on-going
  CCB controversy
• Similar efficacy to ACEI with improved
  tolerability
• Superior within-class efficacy
• Improved compliance vs all other classes

46
The New Therapeutic Window in Hypertension
Freedom fromside effects()
Ideal
Traditional
Efficacy()
Dose
Man int Veld AJ. J Hypertens. 199715(suppl
7)S27-S33.
47
Persistence With Antihypertensive Treatment in
the UK
49
50
45
41
41
40
30
Patients continuing treatment at 6 months ()
20
10
0
Beta blocker (n3615)
ACE inhibitor (n2710)
CCB (n3244)
Diuretic (n5171)
Jones JK et al. BMJ. 1995311293-295.
48
Persistence Rates by Antihypertensive Class
64
58
Patients remaining on therapy at 1 year()
50
43
38
AIIRAs
ACEinhibitors
CCBs
Betablockers
Diuretic
Plt0.01 for AIIRAs vs ACE inhibitors. Bloom S.
Clin Ther. 199820671-681.
49
Persistence With AIIRAs vs Other Antihypertensive
Agents
AIIRAs ACE inhibitors CCBs Beta
blockers Diuretics Combination Other
Patients persistent with therapy ()
6
12
18
24
Time (months)
Database from Saskatchewan, Canada. Regimen is
initially prescribed class filled between 1/1/95
and 1/9/98. Plt0.001 AIIRAs vs all other classes
combined at all time points. Chaput AJ. Can J
Cardiol. 200016(suppl F)194F.
50
Reasons for Changing AntihypertensiveTherapy
Regimen
48.4
30.1
of patients
20.0
16.8
4.9
Adverseevents
Patientdissatisfaction
Non-compliance
Cost
InadequateBPcontrol
N1603 treated hypertensive patients in
Germany. Düsing R et al. Blood Pressure.
19987313-315.
51
Factors Thought to Influence Persistence
Good tolerability
Confidence
Good BP control
Persistence
Simple drug regimen
52
Persistence, BP Control, and Events

• Preliminary data from a hypertension clinic shows
  that people who drop out of treatment have
• A 63 higher chance of death or first
  cardiovascular hospitalization
• A 74 increase in charges in annual medical care
• Patients who stop taking their medications end up
  with higher blood pressures and the attendant
  higher risk of cardiovascular events

Elliott W. J Hypertens. 200018(suppl 4)S169.
53
THE SELECTION OF INITIAL DRUG IN HYPERTENSION
Monotherapy from any of the classes of
antihypertensives will control around 50 of
patients with mild hypertension, though
individual responses in respect of the various
drugs do occur. The choice of initial
antihypertensive agent may follow a

• Partially restrictive approach
• Based on evidence
• Based on economic considerations
• Unrestrictive

54
Irbesartan Dose Response and Tolerability
(n216)
(n357)
Total responders
(n277)
(n539)
(n516)
(n282)
(n641)
(n297)
Placebo- subtracted adverse events ( patients)
Irbesartan (mg/d)
Pooled results from placebo-controlled
trials.SeDBP lt 90 mm Hg or ?10 mm Hg reduction
from baseline. Man int Veld AJ. J Hypertens.
199715(suppl 7)S27-S33.
55
Long-Term Efficacy of Irbesartan
22normalized oncombination therapy
110
105
100
9notnormalized
95
SeDBP(mm Hg)
90
85
80
75
70
Baseline(n171)
2(n165)
6(n161)
12(n152)
69normalized on monotherapy
Month
Pouleur HG. Am J Hypertens. 199710(part
2)318S-324S.
56
Adverse Drug Events in Placebo-Controlled Trials
10
Placebo (n641) Irbesartan (n1965)
8
6
Patients
4
2
0
Headache
Dizziness
Fatigue
Edema
Cough
Sexual dysfunction
Depression
Insomnia
Pooled data from 9 placebo-controlled
studies. Pouleur HG. Am J Hypertens. 199710(part
2)318S-324S.
57
AIIRAs Pharmacologic Comparisons
Compound (active metabolite)
Volume of distribution
Half-life, hours
Bioavailability,
Food effect
Irbesartan
53-93 L
11-15
None
60-80
Losartan (EXP 3174)
2 (6-9)
34 L (12 L)
33
Minimal
17 L
??40-50
Valsartan
6
25
None
Candesartan
9
0.13 L/kg
15
500 L
Minimal ? 6
Telmisartan
24
42-58
? 25
Eprosartan
5-9
NA
13
Avapro (irbesartan) US PI, 1999. Cozaar
(losartan potassium) US PI, 1999. Diovan
(valsartan) US PI, 1999. Atacand (candesartan
cilexetil) US PI, 1999. Micardis (telmisartan)
US PI, 1999. Teveten (eprosartan mesylate) US
PI, 1999.
58
Superior Antagonism of Ang II With Irbesartan
Irbesartan 150 mg
Valsartan 80 mg
Losartan 50 mg
In vivoDR-1(DBP)at Day 8
n18
Time (h)
Belz GG et al. Clin Pharmacol Ther.
199966367-373. plt0.05 Irbesartan vs Valsartan
at 24h, Irbesartan vs Losartan at 4h, 24h, 47h,
on Day 1 plt0.05 Irbesartan vs Valsartan at 36h,
Irbesartan vs Losartan at 4h, 24h, 36h, 47h, on
Day 8. Belz et al, 1999.
59
Superior Inhibition of SBP to Exogenous Ang
IIWith Irbesartan
Values are mean SEM. plt0.01 plt0.05 vs
placebo plt0.05 vs other antagonists,
n12. Mazzolai L et al. Hypertension.
199933850-855. plt0.05 Irbesartan vs Valsartan
at 24h, Irbesartan vs Losartan at 4h, 24h, 47h,
on Day 1 plt0.05 Irbesartan vs Valsartan at 36h,
Irbesartan vs Losartan at 4h, 24h, 36h, 47h, on
Day 8. Belz et al, 1999.
60
Dose Response With Irbesartan/HCTZ Combination
Therapy and Components
Results at 8 weeks
Results at 12 weeks
0
0
-2
-2
-4
-4
-3.5
-6
-6
-5.1
-6.2
? SeDBP (mm Hg)
-8
-8
-8.2
-10
-10
-9.7
-10.2
-12
-12
-12.0
-14
-14
-15.0
-16
-16
Study duration 12 weeks Weber M et al. J
Hypertens. 199816(suppl 2)S129.
Study duration 8 weeks Kochar M et al. Am J
Hypertens. 199912797-805.
61
Long-Term Therapeutic Response With
Irbesartan/HCTZ-Based Regimens
100
91
90
90
85
83
81
Normalized Responder
80
75
70
60
50
Patients()
40
30
20
10
0
2
6
12
Month
N1098. Trough SeDBP lt90 mm Hg Normalized or
reduction from baseline of ?10 mm Hg. Raskin P et
al. J Hum Hypertens. 199913683-687.
62
Long-Term Therapeutic Response With Irbesartan-
and Irbesartan/HCTZ-Based Regimens
Normalized Responder
100
90
87
87
90
83
80
81
80
70
60
Patients()
50
40
30
20
10
0
6
24
12
Month
N1006. Trough SeDBP lt90 mm Hg Normalized or
reduction from baseline of ?10 mm Hg. Littlejohn
T III et al. Clin Exp Hypertens.
1999211273-1295.
63
ICE Discontinuations at One Year

22.9
16.6
Proportionof patients discontinuing antihypertens
ive therapy ()
14.2
Irbesartan
Losartan
All otherantihypertensives
Univariate analysis. Includes ACE inhibitors,
beta blockers, CCBs, diuretics, AIIRAs (excluding
irbesartan). P0.01 vs irbesartan. Data on file,
Bristol-Myers Squibb and Sanofi-Synthelabo.
64
ICE Conclusions

• The initial choice of antihypertensive agent has
  a major impact on persistence
• Patients started on irbesartan had significantly
  better persistence than all other
  antihypertensive classes, including other AIIRAs
• Persistence previously has been shown to be a
  major determinant of long-term blood pressure
  control

Data on file, Bristol-Myers Squibb and
Sanofi-Synthelabo.
65
ACE Inhibitors vs AIIRAs

• ACE inhibitors improve survival in heart failure,
  but morbidity and mortality remain high
• Disadvantages of ACE inhibitors
• Incomplete inhibition of angiotensin II
• Significant incidence of cough
• Potential advantages of angiotensin II receptor
  antagonists
• Complete blockade of the renin angiotensin system
  at the receptor level
• Well tolerated

66
Addition of Irbesartan to ACE Inhibitor in Heart
Failure Conclusions

• In patients with mild-to-moderate heart failure,
  irbesartan added to conventional therapy,
  including ACE inhibitor, for 12 weeks
• Tended to improve ETT, LVEF and heart size
• Reduced blood pressure without reflex tachycardia
• Reduced the need for supplemental diuretic
• Was well tolerated

Note Irbesartan is only indicated for the
treatment of hypertension.
Tonkon M et al. Int J Clin Pract. 20005411-18.
67
Management of High-Risk Patients With
Hypertension and Type 2 Diabetes Conclusions

• Hypertensive patients with type 2 diabetes and
  renal disease at very high risk for renal and CV
  complications
• Diabetic patients require lower thresholds for
  initiation of antihypertensive therapy and lower
  BP targets
• Various antihypertensive regimens shown to reduce
  CV events and slow the decline in renal function
  in hypertensive patients with diabetes
• Agents blocking the RAS may be most beneficial,
  although definitive proof lacking
• PRIME will demonstrate the CV and renal benefits
  of irbesartan in high-risk hypertensive patients
  with type 2 diabetes
• Relative importance of BP reduction vs unique
  benefits of AT1 blockade with irbesartan will be
  evaluated

68
Defining the problem

• HRT is one of the most prevalent and powerful
  contributors to cardiovascular disease (affects
  about 20 of adults)
• theres no evidence of a decline in the
  prevalence of HRT
• HRT clusters with dyslipidemia, insulin
  resistance, glucose intolerance, and obesity (in
  isolation in less than 20)
• Kannel WB JAMA
  27524 May 1996

69
Antihypertensive treatment for the future

• Duration of action which is appropriate for
  once-daily administration
• High troughpeak ratio which is consistent over
  the recommended dosage range
• Maintenance of control of blood pressure fully
  and consistently throughout 24 h
• Maintenance of control of blood pressure beyond
  24 h despite poor compliance with treatment
• No increases in blood pressure variability

70
Antihypertensive treatment for the future

• Additional benefit may be offered by a profile of
  pharmacological activity which can augment the
  benefits of blood pressure reduction
• interference with the early stages of the
  atherosclerotic process
• protection against renal damage