Blood Pressure, Blood Pressure Agents and Blood Pressure Guidelines

1

• Blood Pressure, Blood Pressure Agents and Blood
  Pressure Guidelines
• Ty J. Gluckman, Andrew P. DeFilippis, James Mudd,
  Catherine Campbell, Gregg Fonarow,
• Roger S. Blumenthal

2
JNC VII Guidelines for Measurement of BP
BPBlood pressure, CVDCardiovascular disease,
HTNHypertension, RxTreatment
Chobanian AV et al. JAMA 20032892560-2572
3
JNC VII Causes of Secondary Hypertension
NSAIDSNon-steroidal anti-inflammatory drugs
Chobanian AV et al. JAMA 20032892560-2572
4
Blood Pressure Risk in U.S. Adults
National Health and Nutrition Examination Survey
(NHANES)
45
40
35
30
25
Prevalence of Hypertension
20
15
10
5
0
All
Hypertension defined as blood pressure gt140/90
mmHg or treatment
FFemale, MMale
Fields LE et al. Hypertension 200444398-404
5
Blood Pressure Risk Increases with Age
National Health and Nutrition Examination Survey
(NHANES) III
72
66
51
38
Hypertension Prevalence ()
18
9
3
18-29
30-39
40-49
60-69
70-79
80
50-59
Age
Hypertension defined as blood pressure gt140/90
mmHg or treatment
JNC-VI. Arch Intern Med 19971572413-2446
6
Blood Pressure Lower is Better
Ischemic Heart Disease Mortality and Blood
Pressure
Age at Risk (Y)
Age at Risk (Y)
80-89
80-89
70-79
70-79
60-69
60-69
50-59
50-59
Ischemic Heart Disease Mortality (Floating
absolute risk)
Ischemic Heart Disease Mortality (Floating
absolute risk)
40-49
40-49
Usual Diastolic BP (mm Hg)
Usual Systolic BP (mm Hg)
BPBlood pressure
Prospective Studies Collaboration. Lancet
20023601903-1913
7
Blood Pressure Risk of CHD with Active Treatment
0.79 (0.69 to 0.90)
0
0.5
1.0
1.5
2.0
Worse than placebo
Better than placebo
CHDCoronary heart disease
He J et al. Am Heart J 1999138211-219
8
Blood Pressure Number of Medications Needed
Trial (SBP Achieved)
UKPDS (144 mm Hg)
ABCD (127 mm Hg)
MDRD (132 mm Hg)
HOT (138 mm Hg)
AASK (127 mm Hg)
1
1.5
2
2.5
3
3.5
4
Number of BP Meds
UKPDSUK Prospective Diabetes Study
ABCDAppropriate Blood Pressure Control in
Diabetes MDRDModification of Dietary Protein in
Renal Disease HOTHypertension Optimal
Treatment AASKAfrican American Study of Kidney
Disease and Hypertension
Abbott K et al. J Clin Pharmacology
200444431-438
9
Blood Pressure Evidence Primary Prevention
Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial (ALLHAT)
33,357 patients with HTN and gt1 CHD risk factor
randomized to chlorthalidone, amlodipine, or
lisinopril for 5 years There is similar
efficacy among BP lowering agents
Chlorthalidone Amlodipine Lisinopril
Rate of MI or fatal CHD
Years to CHD Event
BPBlood pressure, CHDCoronary heart disease,
HTNHypertension, MIMyocardial infarction
ALLHAT Investigators. JAMA 20022882981-97
10
Blood Pressure Evidence Primary Prevention
Losartan Intervention for Endpoint (LIFE)
Reduction in Hypertension Study
9,193 high-risk hypertensive patients with LVH
randomized to losartan (100 mg) or atenolol (100
mg) for 5 years An ARB provides greater
efficacy in patients with LVH
16
Atenolol Losartan
12
Proportion with CV death, MI, or stroke ()
8
4
13 RRR, P0.021
0
0
6
12
18
24
30
36
42
48
54
60
66
Study Month
ARBAngiotensin receptor blocker,
CVCardiovascular, DBPDiastolic blood pressure,
LVHLeft ventricular hypertrophy, MIMyocardial
infarction, SBPSystolic blood pressure
Defined by SBP160-200 mmHg or DBP95-115 mmHg
Dahlöf B et al. Lancet 2002359995-1003
11
Blood Pressure Evidence Primary Prevention
Anglo-Scandinavian Cardiac Outcomes TrialBlood
Pressure Lowering Arm (ASCOT-BPLA)
19,342 high-risk hypertensive patients with 3
additional CV risk factors randomized to
amlodipine (10 mg) perindopril (8 mg) or
atenolol (100 mg) bendroflumethiazide (2.5 mg)
for 5.5 years There is similar efficacy
with both BP lowering regimens
6
Atenolol-based regimen
Amlodipine-based regimen
4
Nonfatal MI and fatal CHD ()
2
RRR 10, P 0.1052
0
0
1
2
3
4
5
6
Time since randomization (years)
BPBlood pressure, CVCardiovascular,
CHDCoronary heart disease, MIMyocardial
infarction
Dahlöf B et al. Lancet 2005366895-906
12
Blood Pressure Evidence Secondary Prevention
International Verapamil-Trandolapril Study
(INVEST)
22,576 patients with HTN and CAD randomized to a
BP lowering strategy with verapamil SR (240 mg)
or atenolol (50 mg) for 2.7 years There
is comparable efficacy with a CAS or NCAS
Calcium antagonist strategy (CAS) Non-calcium
antagonist strategy (NCAS)
Incidence of death, MI, or stroke
RR0.98, P0.57
Months
BPBlood pressure, DMDiabetes mellitus,
HTNHypertension, MIMyocardial infarction
Trandolapril (up to 4 mg) was added in those
with DM, chronic kidney disease, or heart
failure.
Pepine CJ et al. JAMA 20032902805-2816
13
Blood Pressure Evidence Secondary Prevention
Valsartan Antihypertensive Long-Term Use
Evaluation (VALUE) Trial
15,245 patients with untreated HTN and high CV
risk randomized to a BP lowering strategy with
valsartan (160 mg) or amlodipine (10 mg) for 4.2
years There is similar efficacy with an
ARB and CCB
Primary cardiac composite endpoint Cardiac
mortality Cardiac morbidity All myocardial
infarction All congestive heart failure All
stroke All-cause death New-onset diabetes
0.5
1
2
Favors valsartan
Favors amlodipine
ARBSAngiotensin receptor blocker, CCBCalcium
channel blocker, CVCardiovascular
Julius S et al. Lancet 20043632022-2031
14
Blood Pressure Evidence Secondary Prevention
Comparison of Amlodipine vs Enalapril to Limit
Occurrences of Thrombosis (CAMELOT) Trial
1,991 patients with CAD and a DBP lt100 mmHg
randomized to amlodipine (10 mg), enalapril (20
mg), or placebo for 2 years A BP lt130/80
mmHg is associated with fewer CV events
130/78
0.25
Placebo
Follow-up BP (mmHg)
124/77
Enalapril
0.20
125/77
Amlodipine
0.15
CV event rate
0.10
0.05
0
6
12
18
24
0
Months
Includes CV death, myocardial infarction,
cardiac arrest, coronary revascularization,
hospitalization for heart failure or angina
pectoris, stroke, transient ischemic attack,
development of peripheral arterial disease
BPBlood pressure, CADCoronary artery disease,
CVCardiovascular, DBPDiastolic BP
Nissen S et al. JAMA 20042922217-26
15
JNC VII Guidelines for Management and Treatment
and
or
or
or
ACE-IAngiotensin converting enzyme inhibitor,
ARBAngiotensin receptor blocker, BBb-blocker,
BPBlood pressure, CCBCalcium channel blocker,
DBPDiastolic blood pressure, SBPSystolic blood
pressure
Treatment determined by highest blood pressure
category Initial combined therapy should be used
cautiously in those at risk for
orthostatic hypotension Treat patients with
chronic kidney disease or diabetes mellitus
to blood pressure goal of lt130/80 mmHg
Chobanian AV et al. JAMA 20032892560-2572
16
JNC VII Lifestyle Modifications for BP Control
BMIBody mass index, SBPSystolic blood pressure
Chobanian AV et al. JAMA 20032892560-2572
17
JNC VII Compelling Indications for Drug Classes
NKF-ADA Guideline,UKPDS, ALLHAT
Diuretic, BB, ACE-I,ARB, CCB
Diabetes Mellitus
NKF Guidelines, Captopril Trial, RENAAL, IDNT,
REIN, AASK
ACE-I, ARB
Chronic Kidney Disease
Recurrent Stroke Prevention
PROGRESS
Diuretic, ACE-I
ACE-IAngiotensin converting enzyme inhibitor,
Aldo ANTAldosterone antagonist, ARBAngiotensin
receptor blocker, BBb-blocker, CADCoronary
artery disease, CCBCalcium channel blocker,
MIMyocardial infarction
Chobanian AV et al. JAMA 20032892560-2572
18
JNC VII Blood Pressure Treatment Algorithm
Lifestyle modifications
Not at goal BP (lt140/90 mm Hg)(lt130/80 mm Hg for
those with diabetes mellitusor chronic kidney
disease)
Initial drug choices
WITH compelling indications
WITHOUT compelling indications
Stage 1 hypertension (SBP 140159 mm Hg or DBP
9099 mm Hg) Thiazide-type diuretic for
most. May consider ACEI, ARB, BB, CCB, or combo.
Stage 2 hypertension(SBP ³160 or DBP ³100 mm
Hg) Two-drug combination for most (usually
thiazide-type diuretic and ACEI or ARB or BB or
CCB).
Drugs for compelling indications Other
antihypertensive drugs (diuretic, ACEI, ARB, BB,
CCB)as needed.
Not at goal BP
Optimize dosages or add additional drugs until
goal BP is achieved. Consider consultation with
hypertension specialist.
BPBlood pressure, DBPDiastolic blood pressure,
SBPSystolic blood pressure
Chobanian AV et al. JAMA 20032892560-2572
19
Blood Pressure Recommendations
Initiation or maintenance of lifestyle
modification in those with BP gt120/80 mmHg. A
target BP of lt130/80mmHg for individuals with any
of the following DM, chronic renal disease, CAD
or CAD risk equivalents, carotid artery disease,
peripheral artery disease, abdominal aortic
aneurysm, those with a Framingham risk score gt10
and a goal of lt140/90mmHg for individuals with
none of the above.
A BP gt130/80 mmHg should be used for individuals
with CKD or DM
20
Blood Pressure Recommendations
ACE-I, ARB, CCB or thiazide diuretic as first
line therapy, supplement with a second agent if
BP goal is not achieved with monotherapy. A beta
blocker is a more appropriate choice for post-MI
or angina pectoris patients.
ACEAngiotensin converting enzyme, BPBlood
pressure, CKDChronic kidney disease, DMDiabetes
mellitus
A BP gt130/80 mmHg should be used for individuals
with CKD or DM
21

• Angiotensin Converting Enzyme Inhibitor Evidence
  and Guidelines

22
ACE Inhibitor Mechanism of Action
Vasoconstriction
Vasodilation
Aldosterone
Prostaglandins
Vasopressin
tPA
Kininogen
Sympathetic
Kallikrein
Angiotensinogen
Renin
Bradykinin
Angiotensin I
Kininase II
Inhibitor
ACE
Angiotensin II
Inactive Fragments
ACEAngiotensin converting enzyme
23
ACE Inhibitor Evidence Secondary Prevention
Heart Outcomes Prevention and Evaluation (HOPE)
Study
9,297 patients with DM or vascular disease plus
an additional CV risk factor, but without HF or
known LVSD randomized to ramipril (10 mg) or
placebo for 5 years ACE-I reduce CV
events in high-risk individuals
0.20
Ramipril
0.15
Placebo
CV death, MI, or stroke ()
0.10
0.05
22 RRR, Plt0.001
0.00
0
500
1000
1500
Days of Follow-Up
ACE-IAngiotensin converting enzyme inhibitors,
DMDiabetes mellitus, CVCardiovascular, HFHeart
failure, LVSDLeft ventricular systolic
dysfunction, MIMyocardial infarction
HOPE Investigators. NEJM 2000342145-153
24
ACE Inhibitor Evidence Secondary Prevention
European Trial on Reduction of Cardiac Events
with Perindopril in Stable Coronary Artery
Disease (EUROPA)
12,218 patients with CAD and presumed normal LV
function randomized to perindopril (8 mg) or
placebo for 4 years ACE-I reduce CV
events in intermediate-risk individuals
Cardiovascular death (0.86 0.72-1.03)
Non-fatal MI (0.78 0.20-0.90)
Cardiac arrest (0.54 0.20-1.47)
Combined endpoint (0.80 0.71-0.91)
Favors Perindopril
Favors Placebo
ACE-IAngiotensin converting enzyme inhibitors,
CADCoronary artery disease, CVCardiovascular,
MIMyocardial infarction
EUROPA Investigators. Lancet 2003362782-788
25
ACE Inhibitor Evidence Secondary Prevention
Prevention of Events with Angiotensin Converting
Enzyme Inhibition (PEACE) Trial
8,290 patients with stable CAD and normal LV
function randomized to trandolapril (4 mg) or
placebo for 5 years ACE-I do not reduce
CV events in lower-risk individuals
30 25 20 15 10 5 0
Placebo Trandolapril
Primary End Point ()
0 1 2 3 4 5
6
Years After Randomization
Includes death from cardiovascular causes,
myocardial infarction, or coronary
revascularization
The PEACE Trial Investigators. NEJM
20043512058-68
26
ACE Inhibitor Evidence Secondary Prevention
Comparison between the HOPE and PEACE trials
MI, Cardiac death, or Stroke ()
Years
Patients enrolled in the PEACE trial were at
lower risk
Reflects better blood pressure control,
revascularization, and use of other risk-reducing
medications (i.e., antiplatelet therapy,
b-blocker, lipid-lowering medication)
CHDCoronary heart disease, MIMyocardial
infarction
The PEACE Trial Investigators. NEJM
20043512058-68
27
ACE Inhibitor Evidence Secondary Prevention
Meta-Analysis of the HOPE, EUROPA, and PEACE
Trials
Clinical Trial
N
Deaths
RR of Mortality
HOPE 9,297 1051

HR0.84 P0.005
EUROPA 12,218 795
HR0.89 P0.10
HR0.89 P0.13
PEACE 8,290 633
HR0.86 Plt0.001
All Trials 33,960 gt3000
0.4 0.6 0.8
1.0
1.2 1.4 1.6
ACE-I Better
Placebo Better
7 RCTs, 33,960 randomized patients, and 4.4
years of mean follow-up. Other findings include
a CVD HR0.81, MI HR0.82, and stroke HR0.77
ACE-IAngiotensin converting enzyme inhihbitors,
CVDCardiovascular disease, MIMyocardial
infarction
Danchin N et al. Arch Intern Med 2006166787-796
28
ACE Inhibitor Evidence Secondary Prevention
SAVERadionuclideEF lt40
AIREClinical and/or radiographic signs of HF
TRACEEchocardiogramEF lt35
Probability of Event
0.1
OR 0.74 (0.660.83)
Years
ACE-I provide substantial benefit in post-MI LVSD
ACE-IAngiotensin converting enzyme inhibitors,
EFEjection fraction, LVSDLeft ventricular
systolic dysfunction, MIMyocardial infarction,
OROdds ratio
Flather MD et al. Lancet 200035515751581
29
ACE Inhibitor Recommendations
Secondary Prevention
An ACE inhibitor in those following a MI,
regardless of EF or in those with CAD along with
hypertension (SBP gt120 mmHg), LVSD (EF lt0.40),
heart failure, DM, or CKD Optional use of an ACE
inhibitor in those with low risk CAD, well
controlled risk factors, normal EF, and
successful revascularization
ACEAngiotensin converting enzyme, CADCoronary
artery disease, CKDChronic kidney disease,
CVCardiovascular, DMDiabetes mellitus,
EFEjection fraction, LVSDLeft ventricular
systolic dysfunction, MIMyocardial infarction,
SBPSystolic blood pressure
Defined by previous MI or angiographically
significant CAD
30

• Angiotensin Receptor Blocker Evidence and
  Guidelines

31
Angiotensin Receptor Blocker Mechanism of Action
Renin
Angiotensinogen
Angiotensin I
ACE
AT II Receptor Blocker
Other Pathways
Angiotensin II
AT I Receptor Blocker
Receptors
ATII
ATI
Antiproliferative Action
Vasodilation
Proliferative Action
Vasoconstriction
32
ARB Evidence Secondary Prevention
Candesartan in Heart Failure Assessment of
Reduction in Mortality and Morbidity (CHARM)
Alternative Trial
2,028 patients with symptomatic HF, LVSD (EF
lt40), and intolerance to ACE-I randomized to
candesartan (32 mg) or placebo for 34
months ARB reduce CV events in those
intolerant of ACE-I
50
Placebo
40
Candesartan
CV Death or Hospitalization for HF
30
20
10
HR 0.77 p0.0004
0
0
1
2
3
Years
ACE-IAngiotensin converting enzyme inhibitors,
ARBAngiotensin receptor blockers, EFEjection
fraction, HFHeart failure, LVSDLeft ventricular
systolic dysfunction
Granger CB et al. Lancet 2003362772-777
33
ARB Evidence Secondary Prevention
Valsartan in Acute Myocardial Infarction Trial
(VALIANT)
14,703 patients with post-MI HF or LVSD (EF
lt0.40) randomized to captopril (50 mg tid),
valsartan (160 mg bid), or captopril (50 mg tid)
plus valsartan (80 mg bid) for 2
years ARB provide similar efficacy to
ACE-I in Post-MI LVSD
0.4
Captopril
Valsartan
0.3
Valsartan and Captopril
0.2
All Cause Mortality
0.1
Valsartan vs. Captopril HR 1.00 P 0.982
Valsartan Captopril vs. Captopril HR 0.98 P
0.726
0.0
0
6
12
18
24
30
36
Months
ACE-IAngiotensin converting enzyme inhibitors,
ARBAngiotensin receptor blockers, EFEjection
fraction, LVSDLeft ventricular systolic
dysfunction
Pfeffer M et al. NEJM 20033491893-1906
34
ARB Evidence Secondary Prevention
Candesartan in Heart Failure Assessment of
Reduction in Mortality and Morbidity (CHARM)
Added Trial
2,548 patients with symptomatic HF and LVSD (EF
lt40) randomized to candesartan (32 mg) or
placebo in addition to an ACE-I for 34
months Chronic dual RAS blockade provides
additional benefit
50
Placebo
40
Candesartan
30
CV Death or Hospitalization for HF
20
10
HR 0.85, p0.011
0
0
1
2
3
Years
ACE-IAngiotensin converting enzyme inhibitors,
ARBAngiotensin receptor blockers, EFEjection
fraction, HFHeart failure, LVSDLeft ventricular
systolic dysfunction, RASRenin angiotensin system
McMurray JJ et al. Lancet 2003362767-71
35
Angiotensin Receptor Blocker Recommendations
Secondary Prevention
An ARB in those with asymptomatic LVSD (EF
lt0.40) or DM following a MI who can (Class IIa,
Level B) or cannot (Class I, Level B) tolerate an
ACE-I An ARB in those with symptomatic LVSD (EF
lt0.40) and intolerance of an ACE-I Addition of
an ARB to an ACE-I in those with symptomatic HF
or LVSD (EF lt0.40)
ACE-IAngiotensin converting enzyme inhibitor,
ARBAngiotensin receptor blocker, EFEjection
fraction, HFHeart failure, LVSDLeft ventricular
systolic dysfunction, MIMyocardial infarction
36

• b-blocker Evidence and Guidelines

37
b-blocker Targets and Receptor Selectivity
Heart
Blood Vessel
a2
a2
_
_
b1
a2
Vasoconstriction Vasoconstriction Vasodilation Vas
odilation

Inotropy Chronotropy Dromotropy

a1
b2
NE
NE
NE
_


_
a1
b2
M2
b2
M2
M2
Sympathetic Nerve Terminal
b1 selective blocker
b non-selective blocker
ACh
b non-selective blocker with a1 blocking activity
Parasympathetic Nerve Terminal
Sympathetic Cholinergic Nerve Terminal
aAlpha receptor, AchAcetylcholine, bBeta
receptor, MMuscarinic receptor,
NENorepinephrine Klabunde, RE (ed)
Cardiovascular Physiology Concepts LWW 2001
38
b-blocker Evidence Secondary Prevention
Placebo-Controlled Post-MI Trials Using Oral
?-Blockers
MIMyocardial infarction, NANot applicable,
NSNot significant
Includes the largest trials performed to
date Patients received IV followed by oral
metoprolol
39
b-blocker Evidence Benefit in HF and/or LVSD
HFHeart failure, LVSDLeft ventricular systolic
dysfunction, NSNot significant, TXTransplant
Not an approved indication Not a planned end
point. Not approved for severe HF or mortality
reduction alone
40
b-blocker Evidence Secondary Prevention
Summary of Secondary Prevention Trials of
b-blocker Therapy
Phase of Treatment
Total Patients
RR (95 CI)
Acute treatment
28,970
0.87 (0.77-0.98)
Secondary prevention
24,298
0.77 (0.70-0.84)
Overall
53,268
0.81 (0.75-0.87)
0.5
1.0
2.0
RR of death
b-blocker better
Placebo better
CIConfidence interval, RRRelative risk
Antman E, Braunwald E. Acute Myocardial
Infarction. In Braunwald E, Zipes DP, Libby P,
eds. Heart Disease A textbook of Cardiovascular
Medicine, 6th ed., Philadelphia, PA W.B.
Sanders, 2001, 1168.
41
b-blocker Recommendations
Secondary Prevention
b-blocker in all patients following MI or
ACS b-blocker in all patients with
LVSD b-blocker in those with other forms of CV
disease or DM, unless contraindicated
ACSAcute coronary syndrome, CVCardiovascular,
DMDiabetes mellitus, LVSDLeft ventricular
systolic dysfunction, MIMyocardial infarction
Relative contraindications include asthma,
chronic obstructive pulmonary disease, insulin
dependent diabetes mellitus, severe peripheral
arterial disease, and a PR interval gt0.24 seconds