Transcript Document

1
The JNC 7 recommendations for
initial or combination drug therapy
are based on sound scientific evidence.
2
7th Joint National Committee Report on
Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure
3
Algorithm for Drug Treatment of
Hypertension
Initial Drug Choices
Without Specific or Compelling Indications
Stage 1 Hypertension
(SBP 140–159 or DBP 90–99 mmHg)
Thiazide-type diuretics for most.
May consider ACEI, ARB, BB, CCB,
or combination.
Stage 2 Hypertension*
(SBP >160 or DBP >100 mmHg)
2-drug combination for most
(usually thiazide-type diuretic and
ACEI, or ARB, or BB, or CCB)
*Combination therapy may also be appropriate initial therapy in
patients with diabetes or renal disease
4
Most of the trials upon which the JNC 7
recommendations were based were
multiple drug trials. Specific
recommendations for monotherapy for
specific patient groups may be difficult
to justify.
5
What were the results of the diuretic/
B-blocker controlled long-term
hypertension treatment trials?
6
Results of Therapy
% Reduction
in Events **
Effect of Antihypertensive Drug
Treatment on Cardiovascular Events
CHF
Strokes
Fatal/Non-fatal
LVH
CVD CHD events
Deaths Fatal/Non-fatal
*Combined results from 17 randomized placebo controlled treatment
trials (48.000 subjects) Diuretic or Beta-blocker based
**All differences are statistically significant
J Am Coll Cardiol. 1996;27:1214-1218; Arch Intern Med 1993;S76-S71
7
A diuretic or diuretic-based treatment
regimen has
• lowered blood pressure
• reduced cerebro and cardiovascular events
• been as well tolerated as any treatment
program based on other antihypertensive
regimens
8
Specific or Compelling
Indications for Different
Medications
Indication
Initial Therapy
Diabetes
Thiazide diuretic, BB, ACEI, ARB, CCB
Chronic kidney
disease
ACEI, ARB
Recurrent stroke
prevention
Thiazide diuretic, ACEI
9
Specific or Compelling
Indications for Different
Medications
Indication
Initial Therapy
Heart failure
Thiazide diuretic, BB, ACEI, ARB,
aldosterone antagonist
Post-myocardial
infarction
BB, ACEI, aldosterone antagonist
High CAD risk
Thiazide diuretic, BB, ACEI, CCB
10
JNC 7 Key Messages
Thiazide-type diuretics should be initial
drug therapy for most hypertensive
patients, alone or combined with other
medications
If BP is >160/100 mmHg, therapy should
probably started with two medications,
one of which should be a thiazide-type
diuretic
11
ALLHAT
Antihypertensive
Trial Design
• Randomized, double-blind, multi-center
clinical trial
• Determine whether occurrence of fatal CHD or
nonfatal MI is lower for high-risk hypertensive
patients treated with newer agents (CCB, ACEI,
alpha-blocker) compared with a diuretic
• 42,418 high-risk hypertensive patients
12
ALLHAT
Step 1 Agent
Step 1
Treatment Protocol
Initial Dose*
Dose 1*
Dose 2*
Dose 3*
Chlorthalidone
12.5
12.5
12.5
25
Amlodipine
2.5
2.5
5
10
Lisinopril
10
10
20
40
Doxazosin
1
2
4
8
* mg/day
13
Percent of Patients Who Received a
Step -2 or Step-3 Medication in the ALLHAT
Study
100
80
1 Year
60
3 Years
40
5 Years
20
0
Chlor
Aml
*JAMA 2000;283(15):1967-1973
Lis
14
ALLHAT Trial
Results indicate that in hypertensive patients
(mean age of 67 years) >90% can be controlled
with a DBP <90 mm Hg; >60% with a SBP <140
mm Hg and >60% with BPs <140/90 mm Hg –
with a less than ideal regimen.
15
Blood Pressure Differences in the
ALLHAT Trial: Diuretic compared to
ACE-I
SBP 4 mm Hg less in Blacks
3 mm Hg less in >65
16
Cumulative Event Rates for the Primary Outcome
(Fatal CHD or Nonfatal MI) by ALLHAT Treatment
Group
Cumulative CHD Event Rate
.2
.16
RR (95% CI)
p value
A/C
0.98 (0.90-1.07)
0.65
L/C
0.99 (0.91-1.08)
0.81
Chlorthalidone
Amlodipine
Lisinopril
.12
.08
.04
0
Number at Risk:
Chlorthalidone
Amlodipine
Lisinopril
0
1
2
15,255
9,048
9,054
14,477
8,576
8,535
13,820
8,218
8,123
3
4
5
Years to CHD Event
13,102
7,843
7,711
11,362
6,824
6,662
6,340
3,870
3,832
6
2,956
1,878
1,770
7
209
215
195
17
Cumulative Event Rates for Heart
Failure by ALLHAT Treatment Group
Cumulative CHF Rate
.15
HR (95% CI)
p value
A/C
1.38 (1.25-1.52)
<.001
L/C
1.19 (1.07-1.31)
<.001
.12
Chlorthalidone
Amlodipine
Lisinopril
.09
.06
.03
0
0
1
2
3
4
Years to HF
5
6
7
18
Significant Differences in Outcomes
in the Clinical Trials
Heart Failure: Other Rx Compared to Diuretics/B-Blockers
LA Nifedipine
Amlodipine
2x
INSIGHT
1.4x
ALLHAT
Verapamil (high risk) 1.3x
CONVINCE
19
Monotherapy
Antihypertensive monotherapy is
effective in only about 40-60% of
hypertensive patients, irrespective of the
category of the agent that is used.
Therefore, there is frequently a need for
the use of two medications with different
mechanisms of action.
BP Control Rates with Low-dose
Beta-blocker /Diuretic Combination
Compared to Monotherapy with Other Agents
Patients with DBP <90
mmHg (%)
20
80
70
60
50
40
30
20
10
0
Placebo
N=78
Bisoprolol/
HCTZ
N=77
Amlodipine
N=82
Enalapril
N=84
† P=.0001 vs Placebo ‡ P=.075 vs Amlodipine *P=.0001 vs Enalapril
Cardiovascular Rev Rep. 1996;17:1-9.
21
ACE Inhibitor/Diuretic Combination Therapy:
Racial Differences in Response
D mm Hg
(n=66) (n=110)
0
-5
-10
-15
-20
-25
(n=97) (n=92)
(n=41)(n=49)
- 6.8
-11.8
-14.3
-14.6
Black
Nonblack
Enalapril
10mg BID
-21
-21.7
HCTZ
Enalapril/HCTZ
25 mg BID 10/25 mg BID
Vidt. J Hypertens. 1984;2(suppl 2):81-88
22
Percent Response
Percentage Response (SBP <140 mm Hg; DBP
<90 mm Hg) on Combination Therapy with 2
Drugs that Either Do or Do Not Include
Hydrochlorothiazide*
With HCTZ
Without HCTZ
100
80
60
77
69
51
46
40
20
0
30/39
29/63
Systolic BP
27/39
32/63
Diastolic BP
*Example, captopril + diltiazem, or captopril +diuretic
From Materson, et al. J Human Hypertension
1995;9:791-796
23
Proportion with Event
Stroke Risk Reduction ACE/diuretic
Treated Patients Compared to Patients
on Other Medications
0.20
0.15
0.10
0.05
0.00
0
1
2
Lancet 2001:358:1033-41 – PROGRESS Study
3
4 (Years)
24
In several trials in high-risk patients
(HOPE, IRMA, IDNT, RENAAL, and LIFE),
the use of an ACE-I (or an ARB) usually with
a diuretic) reduced CV events more than a
regimen that did not include these medications.
25
ALLHAT
•
Conclusions
Among non diabetics, incidence of fasting
glucose 126 mg/dL at 4 years was 1.8%
higher in chlorthalidone vs amlodipine, and
3.5% higher in chlorthalidone vs lisinopril.
•
Overall, metabolic differences did not
translate into more adverse cardiovascular
events, or into higher all-cause mortality,
with chlorthalidone.
26
• Are JNC goal levels based on good data?
27
Cardiovascular Events in Diabetics in the
Hypertension Optimal Treatment Study
CV Events/1000 Patient-Years
<90 mm Hg (n=501
<80 mm Hg (n= 501)
25
20
15
10
5
0
Major CV
Events
Myocardial
Infarctions
CV Mortality
CV events were reduced to a greater degree in diabetics who achieved
the lowest levels of diastolic blood pressure Hansson L, et al. Lancet 1998;351:1755-1762
28
Cardiovascular Event Free Survival
1.00
0.95
Female
0.90
0.85
0.80
0.75
Male
ACEI
DIURETIC
0.70
0.00
0
Adjusted for age
1
2
3
Years Since Randomization
4
5
ANBP2
29
Oftentimes, all of the is cannot
be dotted or the Ts crossed in
finalizing recommendations.
These are based on judgement
and interpretation of outcome data.
30
31
32
Results of Different Levels of Blood Pressure Control in
Hypertensive Patients with Type 2 Diabetes: B-Blocker
compared with ACE Inhibitor-Based Treatment Program
• Better control of blood pressure compared with less aggressive
treatment in 8.4-year follow-up of 1148 subjects (achieved blood
pressure of 144/82 mm Hg compared with 154/87 mm Hg)
• Reduced risk of:
–
–
–
–
–
Stroke (44%)
Fatal strokes (58%)
Death related to diabetes (32%)
Heart failure (56%)
Fatal and nonfatal coronary heart disease events (21%)
(trend but not significant)
• No difference in outcome between a captopril-based and an atenololbased treatment program
UKPDS . BMJ 1998;317:703-713
33
Suggested Approaches for Initiation of Pharmacologic
Therapy
Low Risk
•Male <55 years of age
•Female <65 years of age
•Stage 1 hypertension (140-159/90-99 mm Hg)
with no other risk factors*
Lifestyle modifications for 3 to 4 months
If BP >140/90 mm Hg, begin medicaton
*Risk factors include: male >55, female >65,
diabetes, smoking history, hyperlipidemia, target
organ involvement, or obesity
34
Suggested Approaches for Initiation
of Pharmacologic Therapy
Medium Risk
Stage 1 hypertension with one other risk factor*
Lifestyle modifications for 2 to 3 months
If BP >140/90 mm Hg, begin medication
*Risk factors include: male >55, female >65, diabetes,
smoking history, hyperlipidemia, target organ involvement,
or obesity
35
Suggested Approaches for Initiation
of Pharmacologic Therapy
High Risk
•BP >140/90 mm Hg with evidence of CVdisease
and/or diabetes, with/without other risk factors*
•Stage 2 hypertension
•Stage 1 or 2 hypertension with at least three other risk factors*
Lifestyle modifications and medication
*Risk
factors include: male >55, female >65, diabetes,
smoking history, hyperlipidemia, target organ involvement,
or obesity
36
2003
The Antihypertensive and Lipid
Lowering Treatment to Prevent Heart
Attack Trial (ALLHAT)
37
Cumulative 5-Year Rates (1000 Patient Years) of Cardiovascular
Events in the Systolic Hypertension in the Elderly program
Diabetic
Active
Therapy
Placebo
Non Diabetic
Active
Therapy
Placebo
Major CHD events
9.2
16
6.9
7.6
Nonfatal MI or fatal CHD
7.7
13.1
5.1
5.7
Nonfatal and fatal strokes
9.7
14.4
4.4
7.5
21.4
31.5
13.3
10.4
Major cerebrovascular
disease events
Placebo-treated diabetic patients had about 2-3 times the risk of a
cardiovascular event as placebo-treated nondiabetics
38
ALLHAT
AHT Age 65+
Amlodipine/Chlorthalidone
Relative Risk and 95% Confidence Intervals
Nonfatal MI + CHD Death
0.97 (0.88 - 1.08)
All-Cause Mortality
0.96 (0.88 - 1.03)
Combined CHD
1.04 (0.96 - 1.12)
Combined CVD
1.05 (0.99 - 1.12)
Stroke
0.93 (0.81 - 1.08)
Heart Failure
1.33 (1.18 - 1.49)
End Stage Renal Disease
1.12 (0.85 - 1.48)
0.50
05/15/03
Favors Amlodipine
1
2
Favors Chlorthalidone
39
AHT Age 65+
ALLHAT
Lisinopril/Chlorthalidone
Relative Risk and 95% Confidence Intervals
Nonfatal MI + CHD Death
1.01 (0.91 - 1.12)
All-Cause Mortality
1.03 (0.95 - 1.12)
Combined CHD
1.11 (1.03 - 1.20)
Combined CVD
1.13 (1.06 - 1.20)
Stroke
1.13 (0.98 - 1.30)
Heart Failure
1.20 (1.06 - 1.35)
End Stage Renal Disease
1.01 (0.76 - 1.36)
0.50
05/15/03
Favors Lisinopril
1
2
Favors Chlorthalidone
40
ALLHAT
AHT Age 75+
Lisinopril/Chlorthalidone
Relative Risk and 95% Confidence Intervals
Nonfatal MI + CHD Death
1.06 (0.89 - 1.26)
All-Cause Mortality
1.00 (0.89 - 1.13)
Combined Coronary Heart Disease
1.06 (0.92 - 1.23)
Combined Cardiovascular Disease
1.12 (1.01 - 1.24)
Stroke
1.10 (0.88 - 1.37)
Heart Failure
1.20 (1.00 - 1.45)
End Stage Renal Disease
1.39 (0.84 - 2.31)
0.50
05/11/03
Favors Lisinopril
1
2
Favors Chlorthalidone
41
ALLHAT
AHT Age 75+
Amlodipine/Chlorthalidone
Relative Risk and 95% Confidence Intervals
Nonfatal MI + CHD Death
0.95 (0.79 - 1.13)
All-Cause Mortality
0.91 (0.81 - 1.03)
Combined Coronary Heart Disease
1.02 (0.88 - 1.18)
Combined Cardiovascular Disease
1.03 (0.92 - 1.14)
Stroke
0.86 (0.68 - 1.09)
Heart Failure
1.22 (1.01 - 1.46)
End Stage Renal Disease
0.50
05/11/03
Favors Amlodipine
0.98 (0.56 - 1.72)
1
2
Favors Chlorthalidone
42
3-5 Year Studies Directly Comparing a Diuretic-Based
Treatment Regimen to other Therapies
Diuretic vs B-blocker
MRC Elderly
Diuretic vs ACE inhibitor
ALLHAT Double blind
ANBP-2
Open
STOP-2
Open
CAPPP (B-blocker or diuretic)
Open
43
Systolic and Diastolic Blood Pressure after
Randomization
6083
170
ACEI
Systolic
160
Diuretic
6035
150
5585
5487
4323
1183
140
130
95
6083
90
Diastolic
85
6035
5583
5487
4320
2
3
4
80
1183
75
0
0
1
5
N Engl J Med. 2003;348(7):583-592.
Second Australian National Blood
Pressure Study (ANBP 2)
• To determine in hypertensive patients aged
65-84 years whether there is any difference
in total cardiovascular events (fatal and nonfatal) over a 5 year treatment period between
treatment with either a diuretic-based
regimen or an ACE inhibitor-based regimen
ANBP2
45
ANBP 2
Conclusion
Initiation of antihypertensive treatment
in older patients with an ACE inhibitor in
males has an advantage over a diuretic.
46
Primary Result
ACEI better
0.2
Hazard Ratio (95% CI)
Diuretic better
1.0
5.0
p
All CV Events or Any Death
0.89 (0.79,1.00)
0.05
First CV Event or Any Death
0.89 (0.79,1.01)
0.06
Any Death
0.90 (0.75,1.09)
0.27
ANBP2
47
JNC 7 Key Messages
• For persons over age 50, SBP is more important
than DBP as CVD risk factor
• Normotensive individuals at age 55 have a 90%
lifetime risk for developing hypertension
• Those with SBP 120-139 mm Hg or DBP 80-90
mm Hg should be considered prehypertensive;
they may require lifestyle modifications to
prevent CVD
48
“Intensive control of blood pressure reduces
cardiovascular morbidity and mortality in
diabetic patients regardless of whether lowdose diuretics, B-blockers, angiotensinconverting enzyme inhibitors, or calcium
antagonists are used as first-line treatment.”
Grossman, Messerli…Arch Intern Med 2000;?60;2447-2452
49
Primary Result - Females
ACEI better
0.2
Hazard Ratio (95% CI)
1.0
5.0
p
All CV Events or Any Death
1.00 (0.83,1.21)
0.98
First CV Event or Any Death
1.00 (0.83,1.20)
0.98
Any Death
1.01 (0.76,1.35)
0.94
All events
Diuretic better
ANBP2
50
Cumulative 5-Year Rates (1000 Patient Years) of Cardiovascular
Events in the Systolic Hypertension in the Elderly program
Diabetic
Active
Therapy
Placebo
Non Diabetic
Active
Therapy
Placebo
Major CHD events
9.2
16
6.9
7.6
Nonfatal MI or fatal CHD
7.7
13.1
5.1
5.7
Nonfatal and fatal strokes
9.7
14.4
4.4
7.5
21.4
31.5
13.3
10.4
Major cerebrovascular
disease events
Placebo-treated diabetic patients had about 2-3 times the risk of a
cardiovascular event as placebo-treated nondiabetics
51
3-5 Year Studies Directly Comparing a Diuretic-Based
Treatment Regimen to other Therapies
Diuretic vs CCB
INSIGHT
Double-blind
NORDIL (BB or D)
Open
SHELL
Open
STOP-2
Open
VHAS
Open
52
Results of Tight Blood Pressure Control
Compared with Less-Tight BP Control in the
UKPDS Study
Risk Reduction (%)
60
56
50
47
44
40
37
32
34
30
24
20
10
0
Any diabetes
related endpoint
Diabetes
related
death
BMJ 1998;317:703-713
Stroke
Micro
vascular
endpoints
Retinopathy
progression
Deterioration of
vision
Heart
failure