1 the jnc 7 recommendations for initial or combination drug therapy are based on sound scientific...
TRANSCRIPT
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
Effect of Antihypertensive DrugTreatment on Cardiovascular Events
*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
% R
edu
cti
on
in
Ev
en
ts *
*
CHF Strokes LVH CVD CHD eventsFatal/Non-fatal Deaths Fatal/Non-fatal
7
A diuretic or diuretic-based treatmentregimen 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
Initial TherapyIndication
Thiazide diuretic, ACEI
ACEI, ARB
Thiazide diuretic, BB, ACEI, ARB, CCB
Recurrent stroke prevention
Chronic kidney disease
Diabetes
9
Specific or Compelling Indications for Different
Medications
Initial TherapyIndication
Thiazide diuretic, BB, ACEI, CCB
BB, ACEI, aldosterone antagonist
Thiazide diuretic, BB, ACEI, ARB, aldosterone antagonist
High CAD risk
Post-myocardialinfarction
Heart failure
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
AntihypertensiveTrial 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
ALLHAT
12
Step 1Treatment Protocol
8421Doxazosin
* mg/day
40201010Lisinopril
1052.52.5Amlodipine
2512.512.512.5Chlorthalidone
Dose 3*Dose 2*Dose 1*Initial Dose*Step 1 Agent
ALLHAT
13
Percent of Patients Who Received a Step -2 or Step-3 Medication in the ALLHAT
Study
0
20
40
60
80
100
Chlor Aml Lis
1 Year
3 Years
5 Years
Per
cent
*JAMA 2000;283(15):1967-1973
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
Years to CHD Event0 1 2 3 4 5 6 7
Cu
mul
ativ
e C
HD
Eve
nt R
ate
0
.04
.08
.12
.16
.2
Number at Risk: Chlorthalidone 15,255 14,477 13,820 13,102 11,362 6,340 2,956 209 Amlodipine 9,048 8,576 8,218 7,843 6,824 3,870 1,878 215 Lisinopril 9,054 8,535 8,123 7,711 6,662 3,832 1,770 195
Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group
0.810.99 (0.91-1.08)L/C
0.650.98 (0.90-1.07)A/C
p valueRR (95% CI)
ChlorthalidoneAmlodipineLisinopril
17
Cu
mu
lati
ve C
HF
Rat
e
Years to HF
0 1 2 3 4 5 6 70
.03
.06
.09
.12
.15
Cumulative Event Rates for Heart Failure by ALLHAT Treatment Group
<.0011.19 (1.07-1.31)L/C
<.0011.38 (1.25-1.52)A/C
p valueHR (95% CI)
ChlorthalidoneAmlodipineLisinopril
18
Significant Differences in Outcomes in the Clinical Trials
Heart Failure: Other Rx Compared to Diuretics/B-Blockers
LA Nifedipine 2x INSIGHT
Amlodipine 1.4x ALLHAT
Verapamil (high risk) 1.3x CONVINCE
19
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.
Monotherapy
20BP Control Rates with Low-dose
Beta-blocker /Diuretic Combination Compared to Monotherapy with Other Agents
Placebo Bisoprolol/ Amlodipine EnalaprilN=78 HCTZ N=82 N=84
N=77
† P=.0001 vs Placebo ‡ P=.075 vs Amlodipine*P=.0001 vs Enalapril
Cardiovascular Rev Rep. 1996;17:1-9.
Pat
ien
ts w
ith
DB
P <
90
mm
Hg
(%
)
80
70
60
50
40
30
20
10
0
21
ACE Inhibitor/Diuretic Combination Therapy: Racial Differences in Response
m
m H
g
0
-5
-10
-15
-20
-25
Vidt. J Hypertens. 1984;2(suppl 2):81-88
Enalapril HCTZ Enalapril/HCTZ10mg BID 25 mg BID 10/25 mg BID
(n=66) (n=110) (n=97) (n=92) (n=41)(n=49)
BlackNonblack
- 6.8
-14.3 -14.6-11.8
-21 -21.7
22
Percentage Response (SBP <140 mm Hg; DBP <90 mm Hg) on Combination Therapy with 2
Drugs that Either Do or Do Not Include Hydrochlorothiazide*
100
80
60
40
20
0
30/39 29/63 27/39 32/63
Systolic BP Diastolic BP
*Example, captopril + diltiazem, or captopril +diuretic
From Materson, et al. J Human Hypertension 1995;9:791-796
Pe
rce
nt
Re
spo
ns
e With HCTZWithout HCTZ
77
46 51
69
23
Stroke Risk Reduction ACE/diuretic Treated Patients Compared to Patients
on Other Medications
Lancet 2001:358:1033-41 – PROGRESS Study
(Years)
Pro
po
rtio
n w
ith
Ev
en
t 0.20
0.15
0.10
0.05
0.000 1 2 3 4
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
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.
ALLHAT
26
• Are JNC goal levels based on good data?
27
Cardiovascular Events in Diabetics in the Hypertension Optimal Treatment Study
0
5
10
15
20
25
<90 mm Hg (n=501 <80 mm Hg (n= 501)
CV Events/1000 Patient-Years
Major CVEvents
MyocardialInfarctions
CV Mortality
CV events were reduced to a greater degree in diabetics who achievedthe lowest levels of diastolic blood pressure Hansson L, et al. Lancet 1998;351:1755-1762
28
Cardiovascular Event Free Survival
Adjusted for age ANBP2
Female
MaleACEI
DIURETIC||
0.00
0.70
0.75
0.80
0.85
0.90
0.95
1.00
Years Since Randomization
0 1 2 3 4 5
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 atenolol- based treatment program
UKPDS . BMJ 1998;317:703-713
33
Suggested Approaches for Initiation of Pharmacologic Therapy
*Risk factors include: male >55, female >65, diabetes, smoking history, hyperlipidemia, target organ involvement, or obesity
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
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
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
Suggested Approaches for Initiation of Pharmacologic Therapy
*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
Active Active Therapy Placebo Therapy Placebo
Major CHD events 9.2 16 6.9 7.6Nonfatal MI or fatal CHD 7.7 13.1 5.1 5.7
Nonfatal and fatal strokes 9.7 14.4 4.4 7.5
Major cerebrovascular disease events 21.4 31.5 13.3 10.4
Placebo-treated diabetic patients had about 2-3 times the risk of acardiovascular event as placebo-treated nondiabetics
Diabetic Non Diabetic
38
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)
AHT Age 65+Amlodipine/Chlorthalidone
Relative Risk and 95% Confidence Intervals
Favors Amlodipine Favors Chlorthalidone
0.50 1 2
ALLHAT
05/15/03
39
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)
AHT Age 65+Lisinopril/Chlorthalidone
Relative Risk and 95% Confidence Intervals
Favors Lisinopril Favors Chlorthalidone
0.50 1 2
ALLHAT
05/15/03
40
05/11/03
ALLHAT
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 1 2
Favors Lisinopril Favors Chlorthalidone
Relative Risk and 95% Confidence Intervals
Lisinopril/Chlorthalidone
AHT Age 75+
41
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 0.98 (0.56 - 1.72)
0.50 1 2
05/11/03
ALLHAT
Favors Amlodipine Favors Chlorthalidone
Relative Risk and 95% Confidence Intervals
Amlodipine/ChlorthalidoneAHT Age 75+
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
N Engl J Med. 2003;348(7):583-592.
Diastolic
6083
6035 5583 5487 4320 1183
Systolic
6083
6035 5585 5487 4323 1183
ACEI
Diuretic
0
75
80
85
90
95
130
140
150
160
170
0 1 2 3 4 5
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 non-
fatal) 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
ANBP2
Hazard Ratio (95% CI) p
ACEI better Diuretic better
0.2 1.0 5.0
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
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 low-
dose diuretics, B-blockers, angiotensin-
converting enzyme inhibitors, or calcium
antagonists are used as first-line treatment.”
Grossman, Messerli…Arch Intern Med 2000;?60;2447-2452
49
Primary Result - Females
ANBP2All events
Hazard Ratio (95% CI) p
ACEI better Diuretic better
0.2 1.0 5.0
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
50
Cumulative 5-Year Rates (1000 Patient Years) of Cardiovascular
Events in the Systolic Hypertension in the Elderly program
Active Active Therapy Placebo Therapy Placebo
Major CHD events 9.2 16 6.9 7.6Nonfatal MI or fatal CHD 7.7 13.1 5.1 5.7
Nonfatal and fatal strokes 9.7 14.4 4.4 7.5
Major cerebrovascular disease events 21.4 31.5 13.3 10.4
Placebo-treated diabetic patients had about 2-3 times the risk of acardiovascular event as placebo-treated nondiabetics
Diabetic Non Diabetic
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
24
32
44
3734
47
56
0
10
20
30
40
50
60
Risk Reduction (%)
Any diabetesrelated end-point
Diabetesrelateddeath
Stroke Microvascularendpoints
Retinopathyprogression
Deterior-ation ofvision
Heartfailure
BMJ 1998;317:703-713