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The JNC 7 recommendations for initial or combination drug therapy are based on sound scientific evidence. 7 th Joint National Committee Report on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Algorithm for Drug Treatment of Hypertension. Initial Drug Choices.

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The jnc 7 recommendations for initial or combination drug therapy

The JNC 7 recommendations for

initial or combination drug therapy

are based on sound scientific evidence.


The jnc 7 recommendations for initial or combination drug therapy

7th Joint National Committee Report on

Prevention, Detection, Evaluation, and

Treatment of High Blood Pressure


Algorithm for drug treatment of hypertension

Algorithm for Drug Treatment of Hypertension

Initial Drug Choices

Without Specific or Compelling Indications

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)

Stage 1 Hypertension

(SBP 140–159 or DBP 90–99 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


The jnc 7 recommendations for initial or combination drug therapy

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.


The jnc 7 recommendations for initial or combination drug therapy

What were the results of the diuretic/

B-blocker controlled long-term

hypertension treatment trials?


Results of therapy

Results of Therapy

Effect of Antihypertensive Drug

Treatment on Cardiovascular Events

% Reduction in Events **

CHFStrokesLVHCVDCHD events

Fatal/Non-fatalDeathsFatal/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


The jnc 7 recommendations for initial or combination drug therapy

  • 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


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

Specific or Compelling Indications for Different Medications


Specific or compelling indications for different medications1

Indication

Initial Therapy

Thiazide diuretic, BB, ACEI, ARB, aldosterone antagonist

Heart failure

Post-myocardialinfarction

BB, ACEI, aldosterone antagonist

Thiazide diuretic, BB, ACEI, CCB

High CAD risk

Specific or Compelling Indications for Different Medications


Jnc 7 key messages

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


Antihypertensive trial design

ALLHAT

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


Step 1 treatment protocol

ALLHAT

Step 1 Agent

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

Step 1Treatment Protocol


Percent of patients who received a step 2 or step 3 medication in the allhat study

Percent of Patients Who Received a Step -2 or Step-3 Medication in the ALLHAT Study

Percent

*JAMA 2000;283(15):1967-1973


The jnc 7 recommendations for initial or combination drug therapy

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.


The jnc 7 recommendations for initial or combination drug therapy

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


The jnc 7 recommendations for initial or combination drug therapy

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

.2

.16

.12

Cumulative CHD Event Rate

.08

.04

0

0

1

2

3

4

5

6

7

Years to CHD Event

Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group

Chlorthalidone

Amlodipine

Lisinopril


The jnc 7 recommendations for initial or combination drug therapy

HR (95% CI)

p value

A/C

1.38 (1.25-1.52)

<.001

L/C

1.19 (1.07-1.31)

<.001

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


The jnc 7 recommendations for initial or combination drug therapy

Significant Differences in Outcomes

in the Clinical Trials

Heart Failure: Other Rx Compared to Diuretics/B-Blockers

LA Nifedipine 2xINSIGHT

Amlodipine 1.4xALLHAT

Verapamil (high risk) 1.3xCONVINCE


Monotherapy

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.


The jnc 7 recommendations for initial or combination drug therapy

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

PlaceboBisoprolol/AmlodipineEnalapril

N=78 HCTZ N=82N=84

N=77

  • Patients with DBP <90 mmHg (%)

  • † P=.0001 vs Placebo‡ P=.075 vs Amlodipine*P=.0001 vs Enalapril

  • Cardiovascular Rev Rep. 1996;17:1-9.


Ace inhibitor diuretic combination therapy racial differences in response

ACE Inhibitor/Diuretic Combination Therapy: Racial Differences in Response

(n=66)(n=110)(n=97)(n=92)(n=41)(n=49)

D mm Hg

0

-5

-10

-15

-20

-25

- 6.8

-11.8

-14.3

-14.6

Black

Nonblack

-21

-21.7

EnalaprilHCTZEnalapril/HCTZ

10mg BID25 mg BID10/25 mg BID

Vidt. J Hypertens. 1984;2(suppl 2):81-88


The jnc 7 recommendations for initial or combination drug therapy

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

With HCTZ

Without HCTZ

77

69

Percent Response

51

46

30/3929/6327/3932/63

Systolic BPDiastolic BP

*Example, captopril + diltiazem, or captopril +diuretic

From Materson, et al. J Human Hypertension 1995;9:791-796


Stroke risk reduction ace diuretic treated patients compared to patients on other medications

Stroke Risk Reduction ACE/diuretic Treated Patients Compared to Patients on Other Medications

0.20

0.15

0.10

0.05

0.00

Lancet 2001:358:1033-41 – PROGRESS Study

Proportion with Event

01234

(Years)


The jnc 7 recommendations for initial or combination drug therapy

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.


Conclusions

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.


The jnc 7 recommendations for initial or combination drug therapy

  • Are JNC goal levels based on good data?


Cardiovascular events in diabetics in the hypertension optimal treatment study

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 1998;351:1755-1762


Cardiovascular event free survival

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


The jnc 7 recommendations for initial or combination drug therapy

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.


The jnc 7 recommendations for initial or combination drug therapy

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


The jnc 7 recommendations for initial or combination drug therapy

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


The jnc 7 recommendations for initial or combination drug therapy

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


The jnc 7 recommendations for initial or combination drug therapy

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


The jnc 7 recommendations for initial or combination drug therapy

2003

The Antihypertensive and Lipid

Lowering Treatment to Prevent Heart

Attack Trial (ALLHAT)


The jnc 7 recommendations for initial or combination drug therapy

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 events21.4 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


The jnc 7 recommendations for initial or combination drug therapy

ALLHAT

AHT Age 65+

Amlodipine/Chlorthalidone

Relative Risk and 95% Confidence Intervals

0.50 1 2

Favors Amlodipine Favors Chlorthalidone

05/15/03


The jnc 7 recommendations for initial or combination drug therapy

ALLHAT

AHT Age 65+

Lisinopril/Chlorthalidone

Relative Risk and 95% Confidence Intervals

0.50 1 2

Favors Lisinopril Favors Chlorthalidone

05/15/03


The jnc 7 recommendations for initial or combination drug therapy

AHT Age 75+

ALLHAT

Lisinopril/Chlorthalidone

Relative Risk and 95% Confidence Intervals

0.50 1 2

Favors Lisinopril Favors Chlorthalidone

05/11/03


The jnc 7 recommendations for initial or combination drug therapy

AHT Age 75+

ALLHAT

Amlodipine/Chlorthalidone

Relative Risk and 95% Confidence Intervals

0.50 1 2

Favors Amlodipine Favors Chlorthalidone

05/11/03


The jnc 7 recommendations for initial or combination drug therapy

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-2Open

STOP-2Open

CAPPP (B-blocker or diuretic) Open


Systolic and diastolic blood pressure after randomization

ACEI

Diuretic

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. 2003;348(7):583-592.


Second australian national blood pressure study anbp 2

ANBP2

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


The jnc 7 recommendations for initial or combination drug therapy

ANBP 2

Conclusion

Initiation of antihypertensive treatment

in older patients with an ACE inhibitor in

males has an advantage over a diuretic.


Primary result

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


Jnc 7 key messages1

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


The jnc 7 recommendations for initial or combination drug therapy

“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


Primary result females

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


The jnc 7 recommendations for initial or combination drug therapy

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 events21.4 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


The jnc 7 recommendations for initial or combination drug therapy

3-5 Year Studies Directly Comparing a Diuretic-Based

Treatment Regimen to other Therapies

Diuretic vs CCBINSIGHT Double-blind

NORDIL (BB or D)Open

SHELL Open

STOP-2 Open

VHAS Open


Results of tight blood pressure control compared with less tight bp control in the ukpds study

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 1998;317:703-713


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