A1256656546GZSqC

1
Update on the Management of Hypertension New
Studies and the JNC 7
2
Relative Risk for Cardiovascular Disease of
Elevated Systolic and Diastolic Blood Pressures
Adjusted Relative Risk

• SBP lt110 110-119 120-129 130-135 135-139 140-149
  150-159 160
• DBP lt70 70-74 75-79 80-84 85-89 90-94 95-100 100

Data from Multiple Risk Factor Intervention
Trial Research group, JAMA. 19902631795-1801.
3
What were the results of the diuretic/
B-blocker controlled long-term hypertension
treatment trials?
4
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
5
100 90 80 70 60 50 40
7 6 5 4 3 2 1 0
Rate of events (per 100 patient-years)
Probability of event-free survival ()
0 100 200 300 400 500
Time to event (wk)

• Reversal of cardiac hypertrophy in hypertensive
  patients with initial LVH treated by
  antihypertensive drug therapy.
• Non regressors (solid line and bar) (N52)
• Regressors (hashed line and bar) (N50)
• Verdecchia, Circ. 19989748

6
Is It Blood Pressure Alone That Makes The
Difference or Specific Drugs?
7
Studies where Blood Pressure Lowering and Not
Specific Medications determined outcome
8
Results of the Verapamil in Hypertension and
Atherosclerosis Study (VHAS)

• Varapamil compared to Chlorthalidone
• No difference in percentage of adverse events
• No difference in fatal or non fatal events
• No difference in changes in total cholesterol or
  glucose levels
• Rosei EA, et al. J of Hypertension 199415
  (11)1338-1344

9
Results of Different Levels of Blood Pressure
Control in Hypertensive Patients with Type 2
Diabetes

• Beta Blocker compared to ACE-I Based Treatment
  Program
• Better control of BP compared to less aggressive
  treatment in 8.4 year follow-up of 1148 subjects
• Endpoint 144/82 compared to 154/87 mm HG
• Reduces Risk of
• Stroke 44
• Death related to diabetes 32
• Heart Failure 56
• Microvascular disease 37
• MI and sudden death 21 (NS)
• No difference in outcome between a
  captopril-based and an atenolol-based treatment
  program
• BMJ 1998317703-713

10
15 10 5 0
Proportion of patients who reached primary
endpoint ()
0 1 2 3 4 5 6
Time since randomisation (years)

• Proportion of patients in each group who reached
  primary endpoint
• Swedish Trial in Old Patients with Hypertension-2
  
• Lancet 19993541751

11
Comparative Trials Where Different Outcomes
Were Noted with Different Medications
12
Results of Therapy with Doxazosin Compared to
Chlorthalidone

• Chlorthalidone decreased SBP more than doxazosin
• In the doxazosin (D) compared to the
  chlorthalidone (C) group there was
• A 10 increase in CHD events
• A 19 increase in strokes
• A 16 increase in angina
• A 104 increase in CHF
• Combined cardiovascular disease events increased
  by 25 DC
  ALLHAT trial at
  3.3 yrs (C-15,268 patients) (D-9067 patients)
• JAMA 2000283(15)1967-1973

13
Relative Risk of Cardiovascular Mortality and
Morbidity for ACEIs vs Calcium Antagonists
(STOP-2 Study)

• Significant difference.
• Hansson L et al. Lancet. 19993541751-1756

14
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.
15
Results of An ARB-Based (Losartan Compared to a
B-Blocker Based (Atenolol) Treatment Program in
Hypertensive Patients with LVH (LIFE Study)

• Losartan Atenolol
  Goal BPs
• Achieved BP (mm Hg) 144/82
  145/82 45-50 SBP lt140
• 89 DBP lt90

• Difference Losartan vs Atenolol
• Primary endpoint P Value
• (CV death, MI, Stroke) -13 .02
• Stroke -25 .001
• MI 07 NS
• CV mortality -11 NS
• Total mortality -10 NS
• New onset diabetes -25 .001
• Lancet 20023591004 Statistically significant

16
Percentage of Type 2 Diabetic Patients with
End-Stage Renal Disease in the RENAAL Study
30 20 10 0
Placebo
End-Stage Renal Disease ()
Losartan
0 12 24 36 48
Months of Study

• Losartan therapy with ARB plus other
  medications placebo therapy with medications
  other than an ARB or ACE inhibitor. (Risk
  reduction, 28 P 0.002)
• Brenner BM, et al. N Engl J Med 2001345865

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Heart Outcomes Preventions Evaluation
(HOPE) Study
Events
ACE-1 (Ramipril)
Regimen that did not include an ACE-1
No. Randomized 4645 4652
Reduction in Risk - RamiprilOther therapy
MI, Stroke, CVD 22 CV death 25 MI 20 Stroke
31 Non-CV death 3
(NS) All cause mortality 16
10 mg/day - 62.5 remained on Rx at 4.5 years
New Engl J Med 11/10/99
18
Comparisons of ACE Inhibitor-based with Diuretic
or B-Blocker-Based Therapy in Hypertensive
Patients
6 4 2 0 -2 -4 -6 -8 -10

• Difference in Overall Risk

Stroke CHD Heart CV Deaths Total
Failure Mortality
No siginificant differences Studies included
STOP-2, UKPDS and CAPPP Total No. patients
16,161 Lancet 20003561955-1964
19
Comparisons of ACE Inhibitor-Based with Calcium
Blocker-Based Therapy in Hypertensive Patients
5 0 -5 -10 -15 -20
Difference in Risk
Stroke CHD Heart Major CV Total Failure
CV events Deaths Mortality
Statistically significant Major CV events 1178
deaths from all causes 774 Studies include ABCD
and STOP-2 Total No. patients 4871 Lancet
20003561955-1964
20
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.

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
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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
2003
The Antihypertensive and Lipid Lowering
Treatment to Prevent Heart Attack Trial
(ALLHAT),
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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

26
Step 1Treatment Protocol
27
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.
28
Cumulative Event Rates for the Primary Outcome
(Fatal CHD or Nonfatal MI) by ALLHAT Treatment
Group
Chlorthalidone Amlodipine Lisinopril
29
Cumulative Event Rates for Stroke by
ALLHAT Treatment Group
Chlorthalidone Amlodipine Lisinopril
30
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
31
The ALLHAT results indicate that there was no
difference in fatal or non fatal MIs or death
with a thiazide diuretic compared to an ACE or
CCB based treatment regimen
BUT

• There were fewer incidents of hospitalized/fatal
  episodes of heart failure with a diuretic than
  with a CCB
• There were fewer strokes with a thiazide than
  with an ACE-1 based treatment regimen

32
Biochemical Changes
Chlorthalidone Amlodipine
Lisinopril
Serum cholesterol Baseline 216.1 216.5
215.6 (mg/dL) 4 Years 197.2 195.6
195.0 Serum potassium Baseline 4.3
4.3 4.4 (mol/L) 4 Years 4.1
4.4 4.5 Glucose (mg/dL) Baseline 123.5 123
.1 122.9 4 Years 126.3 123.7 121.
5 Diabetes Incidence 4 Years 11.6 9.8
8.1 (fasting glucose gt 126 mg/dL)
plt.05 compared to chlorthalidone
33
Effect of Antihypertensive Therapy on New Onset
Diabetes
No. of BP Study Subjects
Ages (mm Hg)
Comment LIFE 8000 55-85 174/98
Losartan (ARB) Atenolol (B-blocker)
(HCTZ added) 4.5 fewer cases/1000
Pt Yrs HOPE 9200
55 139/99 ACE inhibitor (ramipril)
-1.8 lower incidence other
medications
SCOPE 4964
70-89 166/90 Candesartan (ARB) based
therapy (76) trend to
fewer new onset diabetics
other medications
ALLHAT
33,000 67 146/84
3.5 fewer cases of diabetes with
lisinopril than with chlorthalidone
INVEST gt16,000
1.1 fewer new onset diabetes in
CCB/ACE compared with B-
blocker/diuretic INSIGHT 1.3 higher
with diureticsCCB

34
Many clinical trial results demonstrate that

• Fewer cases of new onset diabetes occur if an ACE
  or an ARB is included in therapy
• Diabetic patients, especially those with
  proteinuria, have a better outcome if an ACE or
  an ARB rather than a CCB is included in therapy

IDNT, RENAAL, HOPE, CAPPP, AASK
35
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

36
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
37
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
38
7th Joint National Committee Report on
Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure
39
JNC 7 Blood Pressure Classification
40
Pre hypertension (120/80 - 140/90 mm Hg) - Is
It a Risk Factor for T.O.D.?
1) LV mass greater in pre hypertensives than in
normotensives (Strong Heart Study) 2)
Pre hypertension does not increase stroke
risk. (Presented at Stroke Conference,
Feb. 2004, San Diego) 3) CRP as a marker of
inflammation may be increased
41
Laboratory Tests

• Routine Tests in the Evaluation of a Hypertensive
  Patient (JNC 7)
• Electrocardiogram
• Urinalysis
• Blood glucose and hematocrit
• Serum potassium, creatinine, or the corresponding
  estimated GFR, and calcium
• Lipid profile (fasting)
• Optional Tests
• Measurement of urinary albumin excretion or
  albumin/creatinine ratio

42
Lifestyle Modifications
43
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
44
Specific or Compelling Indications for Different
Medications
45
Specific or Compelling Indications for Different
Medications
46
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

47
Trends in Awareness, Treatment, and Control of
High Blood Pressure in Adults Ages 1874
Sources Unpublished data for 19992000 computed
by M. Wolz, National Heart, Lung, and Blood
Institute JNC 6.
48
QUESTIONS TO BE ADDRESSED
THE FUTURE
2. Do we need newer medications with
different actions to control more patients
or can we accomplish goal BPs with present
medications?
49
(No Transcript)
50
Hypertension in Women

• Oral contraceptives may increase BP, HRT does not
  raise BP
• ACEIs and ARBs are contraindicated in pregnancy

51
Lifestyle Interventions in the Management of
Hypertension
Intervention
Possible BP Effect
5-10 mm Hg (gt30 min gt3x/wk)
Exercise Weight reduction Alcohol intake
reduction Sodium intake reduction
1-2 mm Hg/Kg
1 mm Hg/drink/d
1-3 mm Hg/40 mmol/d
52
Time of Day of 1 End Point
76 of events had known time
COER-v Standard of Care
No significant difference in time of day of event
53

• Black patients demonstrate a reduced BP response
  to monotherapy with BBs, ACEIs, or ARBs compared
  to diuretics or CCBs
• These differences are usually eliminated by the
  addition of a diuretic