The JNC 7 recommendations for

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 2 Hypertension (SBP gt160 or DBP gt100
mmHg) 2-drug combination for most (usually
thiazide-type diuretic and ACEI, or ARB, or BB,
or CCB)
Stage 1 Hypertension (SBP 140159 or DBP 9099
mmHg) Thiazide-type diuretics for most. May
consider ACEI, ARB, BB, CCB, or combination.
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 Drug
• Treatment on Cardiovascular Events

Reduction in Events
CHF Strokes LVH CVD CHD events Fatal/Non-fatal D
eaths 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. 1996271214-1218 Arch Intern Med
1993S76-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
9
Specific or Compelling Indications for Different
Medications
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 gt160/100 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

12
Step 1Treatment Protocol
13
Percent of Patients Who Received a Step -2 or
Step-3 Medication in the ALLHAT Study
Percent
JAMA 2000283(15)1967-1973
14
ALLHAT Trial
Results indicate that in hypertensive patients
(mean age of 67 years) gt90 can be controlled
with a DBP lt90 mm Hg gt60 with a SBP lt140 mm
Hg and gt60 with BPs lt140/90 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 gt65
16
Cumulative Event Rates for the Primary Outcome
(Fatal CHD or Nonfatal MI) by ALLHAT Treatment
Group
Chlorthalidone Amlodipine Lisinopril
17
Cumulative Event Rates for Heart Failure by
ALLHAT Treatment Group
.15
.12
Chlorthalidone Amlodipine Lisinopril
.09
Cumulative CHF Rate
.06
.03
0
0
1
2
3
4
5
6
7
Years to HF
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
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.

20
BP Control Rates with Low-dose Beta-blocker
/Diuretic Combination Compared to Monotherapy
with Other Agents
80 70 60 50 40 30 20 10 0
Patients with DBP lt90 mmHg ()

• Placebo Bisoprolol/ Amlodipine Enalapril
• N78 HCTZ N82 N84
• N77

P.0001 vs Placebo P.075 vs
Amlodipine P.0001 vs Enalapril Cardiovascular
Rev Rep. 1996171-9.
21
ACE Inhibitor/Diuretic Combination Therapy
Racial Differences in Response
(n66) (n110) (n97) (n92) (n41) (n49)
0 -5 -10 -15 -20 -25
- 6.8
-11.8
-14.3
-14.6

• D mm Hg

Black Nonblack
-21
-21.7
Enalapril HCTZ Enalapril/HCTZ 10mg BID 25 mg
BID 10/25 mg BID
Vidt. J Hypertens. 19842(suppl 2)81-88
22
Percentage Response (SBP lt140 mm Hg DBP lt90 mm
Hg) on Combination Therapy with 2 Drugs that
Either Do or Do Not Include Hydrochlorothiazide

• 100
• 80
• 60
• 40
• 20
• 0

With HCTZ Without HCTZ
77
69
Percent Response
51
46
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 19959791-796
23
Stroke Risk Reduction ACE/diuretic Treated
Patients Compared to Patients on Other Medications
0.20 0.15 0.10 0.05 0.00
Proportion with Event
0 1 2 3 4
(Years)

• Lancet 20013581033-41 PROGRESS Study

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.

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
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 19983511755-1762
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
1
2
3
4
5
Years Since Randomization
ANBP2
Adjusted for age
29
Oftentimes, all of the is cannot be dotted or
the Ts crossed in finalizing recommendations. Th
ese are based on judgement and interpretation of
outcome data.
30
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31
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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 1998317703-713
33
Suggested Approaches for Initiation of
Pharmacologic Therapy
Low Risk

• Male lt55 years of age
• Female lt65 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 gt140/90 mm Hg, begin medicaton
Risk factors include male gt55, female gt65,
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 gt140/90 mm Hg, begin medication
Risk factors include male gt55, female gt65,
diabetes, smoking history, hyperlipidemia,
target organ involvement, or obesity
35
Suggested Approaches for Initiation of
Pharmacologic Therapy
High Risk

• BP gt140/90 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 gt55, female gt65,
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
Non Diabetic
Active Active Therapy
Placebo 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 Major
cerebrovascular disease events 21.4
31.5 13.3 10.4
Placebo-treated diabetic patients had about 2-3
times the risk of a cardiovascular event as
placebo-treated nondiabetics
38
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 1 2
Favors Amlodipine Favors
Chlorthalidone
05/15/03
39
AHT Age 65
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 1 2
Favors Lisinopril Favors
Chlorthalidone
05/15/03
40
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 1 2
05/11/03
Favors Lisinopril Favors
Chlorthalidone
41
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 0.98 (0.56 - 1.72)
0.50 1 2
05/11/03
Favors Amlodipine
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
Systolic
160
6035
5585
5487
150
4323
1183
140
130
95
6083
90
Diastolic
85
6035
5583
5487
4320
1183
80
75
0
0
1
2
3
4
5
N Engl J Med. 2003348(7)583-592.
44
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

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
Diuretic better
0.2
1.0
5.0
Hazard Ratio (95 CI) 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 low-
dose diuretics, B-blockers, angiotensin-
converting enzyme inhibitors, or calcium
antagonists are used as first-line treatment.
Grossman, MesserliArch Intern Med
2000?602447-2452
49
Primary Result - Females
ACEI better
Diuretic better
0.2
1.0
5.0
Hazard Ratio (95 CI) 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
ANBP2
All events
50
Cumulative 5-Year Rates (1000 Patient Years) of
Cardiovascular Events in the Systolic
Hypertension in the Elderly program
Diabetic
Non Diabetic
Active Active Therapy
Placebo 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 Major
cerebrovascular disease events 21.4
31.5 13.3 10.4
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 N
ORDIL (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 ()
Any diabetes related end- point
Diabetes related death
Stroke
Micro vascular endpoints
Retinopathy progression
Deterior- ation of vision
Heart failure
BMJ 1998317703-713