Download ALLHAT

Understanding the Neuronal Hormonal
Mechanisms and End-Organ Protection
JEAN-BERNARD DURAND, M.D., FCCP, FACC
ASSOCIATE PROFESSOR OF MEDICINE
MEDICAL DIRECTOR CARDIOMYOPATHY SERVICES
UNIVERSITY OF TEXAS
M. D. ANDERSON CANCER CENTER
HOUSTON, TEXAS
Jean-Bernard Durand, M.D.
Presenter Disclosure Information
I will not discuss off label use and/or investigational
use in my presentation.
I have the following financial relationships to
disclose:
Employee of: University of Texas M. D. Anderson
Cancer Center
Overview
• The renin –angiotensin system
• Defining effective RAS blockade
• Strategies for RAS blockade
• End-organ Protection provided by RAS blockade
Development of Antihypertensive Therapies
ANGIOTENSIN CONVERTING
ENZYME INHIBITORS (ACEIs)
• MOA: Block conversion of angiotensin I (AG I ) to
angiotensin II ( AG II )
– AG II is a potent vasoconstrictor, and causes aldosterone
secretion
– Cause peripheral vasodilation   TPR   BP
ACEIs
• 1st LINE IN PATIENTS WITH CHF OR
DIABETES per JNC VI
–  Proteinuria in DM pts
– May stabilize renal function
• Also 1st Line Agents for CHF
ACEIs
Agents
• Captopril ( Capoten )
• Enalapril ( Vasotec )
• Fosinopril ( Monopril )
• Lisinopril ( Prinivil,
Zestril )
Side Effects
• DRY COUGH: 80-90%
• 1st dose hypotension ( seen
more with captopril)
• Hyperkalemia
• Quinapril ( Accupril )
• Angioedema (rare)
• Ramipril ( Altace )
• Renal dysfunction
ACEIs
Dosage Range
(mg/day)
Common
Dose
Captopril
Enalapril
Fosinopril
Lisinopril
Quinapril
Ramipril
25 – 150 mg
5 – 40 mg
10 – 40 mg
5 – 40 mg
5 – 80 mg
5 – 20 mg
25 mg BID-TID
10 mg BID
10-20 mg QD
10-20 mg QD
20-40 mg QD
5 mg QD
4 – 32 mg
150 – 300 mg
25 – 100 mg
20 – 80 mg
80 – 320 mg
8 mg QD
150 mg QD
50 mg QD-BID
40 mg QD
160 mg QD
ARBS
Candesartan
Irbesartan
Losartan
Telmisartan
Valsartan
ACEIs
Drug Interactions
• K+ sparing diuretics
• K+ supplements
•  ACEI effect:
– ASA / NSAIDs
– Sympathomimmetics
Contraindications
• Bilateral Renal artery
stenosis
• Pregnancy
Precautions
• Renal Insufficiency
ACEIs
Monitoring Parameters
Special Considerations
• BP
• Post MI
• Scr
• K+
• Prevent progression of
proteinuria in DM pts
• Angioedema
• Improve insulin sensitivity
• Tolerance of dry cough
• No change in lipids
• No sexual dysfunction
ACEIs Counseling
• We are treating HTN to prevent MI and stroke!
• Stress adherence
• Side effects:
– DRY COUGH: will occur, usually  with time
– May do some blood work to make sure kidneys working
properly
Physiology and Pathophysiology of the
Renin Angiotensin System
Hypertension Is Associated With Vascular
Damage Along the Entire CV Continuum
Transmural MI
Ventricular
Remodeling
Atherosclerosis
Ventricular
Dilatation
Heart Failure (HF)
Endothelial
Dysfunction
Hypertension
Oxidative
Stress
Angiotensin II
Vascular
Damage
Adapted from Dzau V et al. Am Heart J. 1991;121:1244–1263.
End Stage
CVD
The Renin-Angiotensin System
Alternate Pathway
Circulating
Local
(Liver)
(Tissue)
Renin inhibitors
Angiotensinogen
Renin
Non-renin pathways
• t-PA
• Cathepsin G
• Tonin
Angiotensin I
ACE inhibitor
Converting enzyme
Angiotensin II
A-II receptor blockers
Angiotensin
receptors
Non-ACE pathways
• Chymase
• CAGE
• Cathepsin G
Ang II Plays a Central Role in Organ
Damage
Angiotensin I
Angiotensinogen
Liver
Blood Vessel
Renin
ACE
Lungs
Heart
Angiotensin II
Vasoconstriction
SMC hypertrophy
Superoxide generation
Endothelin secretion
Monocyte activation
Inflammatory cytokines
Brain
Reduced fibrinolysis
Vasopressin secretion
Sympathetic activation
Kidney
Sodium and water
retention
Efferent arteriolar
vasoconstriction
Glomerular and
intenstitial fibrosis
Adapted with permission from Givertz MM. Circulation. 2001;104:E14–E18.
Cellular hypertrophy
Myocyte apoptosis
Myocardial fibrosis
Inflammatory
cytokines
Coronary
vasoconstriction
Positive inotropy
Proarrhythmia
Adrenal Gland
Aldosterone secretion
The Definition of “Uncontrolled Hypertension”
varies in clinical practice
JNC 7 Blood Pressure Classification
(mmHg)
Blood Pressure Classification
Systolic Blood Pressure
Normal
Prehypertension
Stage 1 hypertension
Stage 2 hypertension
<120
120-139
140-159
≥160
Clin J Onco Nursing;2005:9(4);407-11
(mmHg)
Diastolic Blood Pressure
<80
80-90
90-99
≥ 100
RAS and SNS Pathophysiology in
Cardiac Disease Progression
Hypertension
MI/CAD
CHEMOTHERAPY
Injury to the Heart
Renin-angiotensin
system (RAS) activation
Sympathetic nervous system
(SNS) activation
Angiotensin I
ACE
inhibition
Norepinephrine
1-Receptors
2-Receptors
Arrhythmia,
myocyte cell death,
hypertrophy, LVD
Arrhythmia, sudden death,
potassium loss
1-Receptors
Arrhythmia, sudden death,
vascular resistance,
adverse lipid effects,
impaired renal blood flow,
myocyte cell death,
hypertrophy, Na retention
Selective -blockade
Angiotensin II
Nonselective -blockade
ARB
Mortality and
disease progression
ARB=angiotensin II receptor blocker; CAD=coronary artery disease; MI=myocardial infarction.
Reaven GM et al. N Engl J Med. 1996;334:374–381. Packer M. Prog Cardiovasc Dis. 1998;41:39–52.
Nonselective -blockade with
1-blockade
ACC/AHA Staging System for Heart Failure
Stage
A
B
C
C
D
High risk for developing heart
failure (HF)
Patient Description
•
•
•
•
•
Hypertension
Coronary artery disease
Diabetes mellitus
Family history of cardiomyopathy
Cardiotoxic chemotherapy
Asymptomatic HF
• Previous myocardial infarction
• Left ventricular systolic dysfunction
• Asymptomatic valvular disease
Symptomatic HF
• Known structural heart disease
• Shortness of breath and fatigue
• Reduced exercise tolerance
Refractory end-stage HF
Hunt SA, et al. Circulation 2000; 104:2996-3007.
• Marked symptoms at rest despite maximal
medical therapy (eg, those who are recurrently
hospitalized or cannot be safely discharged from
the hospital without specialized interventions)
ACC/AHA Guidelines for the Evaluation and the
Management of Chronic Heart Failure in the Adult
ACE Inhibitor Therapy
A
Stage
High risk for developing
heart failure (HF)
Guideline Recommendation
ACE inhibition in patients with history of
atherosclerotic vascular disease, diabetes mellitus,
or hypertension and associated risk factors
B
Asymptomatic HF
C
Symptomatic HF
ACE inhibition in patients with recent or remote
history of myocardial infarction regardless of
ejection fraction
ACE inhibition in patients with reduced ejection
fraction, whether or not they have experienced a
myocardial infarction
ACE inhibition in all patients, unless
contraindicated
D
Refractory end-stage HF
Hunt SA et al. J Am Coll Cardiol. 2001; 38:2101–2113.
Includes all the above listed
ACC/AHA Guidelines for the Evaluation and
Management of Chronic Heart Failure in the Adult
-Blockade Therapy
Stage
Patient Description
A
High risk for developing
heart failure (HF)
For patients that are on combination therapy for
hypertension (HTN), drugs that treat HTN and HF
(eg, diuretics, ACE inhibitors, and
-blockers) are preferred
B
Asymptomatic HF
Patients with a recent myocardial infarction,
regardless of ejection fraction
Patients with a reduced ejection fraction, whether or
not they have experienced a myocardial infarction
C
Symptomatic HF
In all stable patients, unless contraindicated. Patients
should have no or minimal evidence of fluid retention
and should not have required treatment recently with
a intravenous positive inotropic agent
D
Refractory end-stage HF
Includes all the above listed
Hunt SA et al. J Am Coll Cardiol. 2001; 38:2101–2113.
JNC 7: Antihypertensive Drug Classes
for High-Risk Hypertensive Conditions
Recommended Drugs
High-Risk Condition
With Compelling
Indication
HF
ThiazideType
Diuretic
•
-Blocker
•
•
Post-MI
ACEI
•
•
•
•
Diabetes
•
•
•
Recurrent Stroke
Prevention
•
•
CCB
•
•
High Coronary
Disease Risk
Chronic Kidney
Disease
ARB
•
•
•
Aldosterone
Antagonist
Clinical Trial Basis
•
ACC/AHA HF
Guidelines, MERIT-HF,
COPERNICUS, CIBIS,
SOLVD, AIRE,
TRACE, Val-HeFT,
RALES
•
ACA/AHA Post-MI
Guidelines, BHAT,
SAVE, CAPRICORN*,
EPHESUS
•
ALLHAT, HOPE,
ANBP2, LIFE,
CONVINCE
•
NKF-ADA Guidelines,
UKPDS, ALLHAT
NKF Guidelines,
Captopril Trial,
RENAAL, IDNT,
REIN, AASK
PROGRESS
Effect of Ramipril on Cardiovascular Events in
Diabetic Patients: MICRO-HOPE
Primary Outcome*
0.25
Placebo
Kaplan-Meier Rates
0.20
All-Cause Mortality
0.16
Ramipril
0.12
0.15
0.08
0.10
0.04
0.05
0
0
0
200
400
600
800 1,000 1,200
MI
0.16
1,400
1,600 1,800
0
200
400
Stroke
0.08
0.06
0.09
0.08
0.04
0.06
0.04
0.02
0.03
500
1,000
1,500
2,000
1,400
1,600
1,800
0
0
0
1,000 1,200
Cardiovascular Mortality
0. 12
0.12
0
800
600
0
500
1,000
1,500
2,000
Duration of Follow-up (days)
*Primary outcome defined as development of MI, stroke, or CV death.
Kaplan-Meier survival curves for 3,577 participants with diabetes.
HOPE Study Investigators. Lancet. 2000;355:253-259.
0
500
1,000
1,500
2,000
Angiotensin II Plays a
Central Role in Organ Damage
Atherosclerosis*
Stroke
Vasoconstriction
Vascular hypertrophy
Endothelial dysfunction Hypertension
A II
AT1
Receptor
LV hypertrophy
Fibrosis
Remodeling
Apoptosis
GFR
Proteinuria
Aldosterone release
Glomerular sclerosis
Heart Failure
MI
Death
Renal Failure
*Preclinical data.
LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate.
Adapted from Willenheimer R, et al. Eur Heart J . 1999;20:997–1008; Dahlöf B. J Hum Hypertens. 1995;9(suppl 5):S37–S44;
Daugherty A, et al. J Clin Invest. 2000;105:1605–1612; Fyhrquist F, et al. J Hum Hypertens. 1995;9(suppl 5):S19–S24;
Booz GW, Baker KM. Heart Fail Rev. 1998;3:125–130; Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy.
17th ed. Whitehouse Station, NJ: Merck Research Laboratories. 1999:1682–1704; Anderson S. Exp Nephrol . 1996;4(suppl 1):34–40;
Fogo AB. Am J Kidney Dis. 2000;35:179–188.
Plasma ACE,
nmol/mL/min
Angiotensin II Escape With Long-term
ACEI Therapy
100
80
60
40
20
0
Plasma A II levels increase with time,
although plasma angiotensin-converting
enzyme activity remained suppressed
*
*
*
*
*
*
*
*
24h
1
2
3
4
Months
5
6
Plasma A II,
pg/mL
30
20
10
*
0
Placebo 4h
Hospital
*P < 0.001 vs placebo.
Adapted with permission from Biollaz J, et al. J Cardiovasc Pharmacol. 1982;4:966–972.
ALLHAT Trial Design
 Antihypertensive and Lipidlowering Treatment to Prevent
Heart Attack Trial (ALLHAT)
 33,357 participants aged 55 years or
older with HTN and at least 1 other
CHD risk factor
 Antihypertensive component:
randomized, double-blind (no ARB
studied)
 Lipid-lowering component is
unblinded
 Assessment ALLHAT.
of MI JAMA.
will rely
on
2002;288:2981-2997.
ALLHAT Study Endpoints
Antihypertensive Component
• Primary endpoints:
 CHD, non-fatal MI
• Secondary endpoints:
 All-cause mortality
 Combined CHD (CHD, revascularization,
hospitalized angina)
 Stroke
 LVH by ECG
 Renal disease
• Slope and reciprocal of serum creatinine
• ESRD
• QOL, major costs of medical care
ALLHAT. JAMA. 2002;288:2981-2997.
ALLHAT Primary Outcome*
No significant differences among the 3 treatment groups
Cumulative Event
Rate, %
20
Chlorthalidone
Amlodipine
Lisinopril
16
12
8
4
0
No. at Risk
Chlorthalidone
Amlodipine
Lisinopril
15255
9048
9054
1
2
3
4
5
Time to Event, years
14477
8576
8535
13820
8218
8123
13102
7843
7711
11362
6824
6662
6340
3870
3832
6
7
2956
1878
1770
209
215
195
* Fatal coronary heart disease event or non-fatal myocardial infarction.
ALLHAT. JAMA. 2002;288:2981-2997.
ALLHAT Study Results
Primary Endpoint:
• ALLHAT found no difference between the three treatment groups on the
primary endpoint of combined fatal coronary heart disease and non-fatal
myocardial infarction.
Secondary Endpoints:
• Secondary outcomes were similar for clorthalidone, and amlodipine,
except that a 38% higher for HF with a 6-year absolute risk difference of
2.5% was seen with amlodipine
• Secondary outcomes were also similar for chorthalidone and lisinopril,
except that a 15% higher risk for stroke and a 10% higher risk for
combined CVD was seen with lisinopril.
Author’s Conclusion:
• Thiazide-type diuretics are superior in preventing 1 or more major forms
of CVD and are less expensive. They should be preferred for first-step
ALLHAT. JAMA. 2002;288:2981-2997.
antihypertensive therapy.
ALLHAT Key Messages
• More aggressive treatment of blood pressure is needed
today. According to JNC VI, only 27% of hypertensive
patients are treated to goal. In ALLHAT, despite the use
of multiple medications, only 66% of patients were
controlled to <140/90 mmHg.
• Multiple agents are required to achieve BP targets.
Regardless of which agent was used, Initially, only 30%
of patients in ALLHAT were controlled on monotherapy.
Six-Year Rate of Clinical Outcomes by
High-Risk Treatment Group
Chlorthalidone
Amlodipine
CHD*
11.5%
11.3%
Heart Failure
7.7
10.2
Revascularization
ALLHAT
9.2
Lisinopril
11.4%
8.7
10.0
10.2
Cancer
9.7
10.0
9.9
Stroke
5.6
5.4
6.3
GI Bleeding
8.8
8.0
9.6
17.3
16.8
17.2
All-cause mortality
•Primary outcome, consisting of 64-66 percent of nonfatal MI’s
Source: ALLTHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to
angiotensin-converting enzyme inhibitor or calcium-channel blocker vs diuretic.
JAMA 288:2981, 2002
Benefits of Lowering BP
Average Percent
Reduction
Stroke incidence
35–40%
Myocardial infarction
20–25%
Heart failure
50%