CONFUSING MESSAGES FROM GUIDELINES AND THE HYPERTENSION TREATMENT TRIALS

1
CONFUSING MESSAGES FROM GUIDELINES AND THE
HYPERTENSION TREATMENT TRIALS

• What and whom shall we believe?

2
WHAT REALLY MATTERS IN DECIDING ON THERAPY?

• CONFLICTING TRIAL RESULTS

3
Is It Blood Pressure Alone That Makes The
Difference or Specific Drugs?
4

• In the
• Verapamil in Hypertension and Atherosclerosis
  Study
• (VHAS)
• Controlled Onset Verapamil Investigation of CV
• Endpoints (CONVINCE) and
• United Kingdom Prospective Diabetes Study
  (UKPDS),
• There were no differences in primary endpoints
  with
• different medications with similar BP
  outcomes.

5
Results of Different Levels of Blood Pressure
Control in Hypertensive Patients with Type 2
Diabetes B-Blocker compared with ACE
Inhibitor-Based Treatment Program

• 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
6
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.
7
CV Events in Swedish Trial in Old Persons
(Stop-2)
Conventional Rx (diuretics and B-blockers) compare
d to ACE-Is and CCBs No difference in BP
outcomes No overall difference in EVENTS
Lancet 1999354751
8
Some Comparative Trials Where Different
Outcomes Were Noted with Different Medications
9
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

10
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

11
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
12
Relative Risk of Cardiovascular Mortality and
Morbidity for ACEIs vs Calcium Antagonists
(STOP-2 Study)

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

13
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.
14
2003
The Antihypertensive and Lipid Lowering
Treatment to Prevent Heart Attack Trial
(ALLHAT),
15
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

16
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
17
Cumulative Event Rates for the Primary Outcome
(Fatal CHD or Nonfatal MI) by ALLHAT Treatment
Group
Chlorthalidone Amlodipine Lisinopril
18
Cumulative Event Rates for Stroke by
ALLHAT Treatment Group
Chlorthalidone Amlodipine Lisinopril
19
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
20
ALLHAT results - No difference in fatal or non
fatal MIs or death with a thiazide diuretic
compared to an ACE or CCB based treatment regimen
BUT

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

(BP differences or medication?)
21
Implications of ALLHAT

• Diuretics should be the drug of choice for first
• step therapy of hypertension in most
  patients
• Most hypertensive patients require more than one
  drug. Diuretics should generally be part of the
  antihypertensive regimen.
• BP levels were lower in diuretic treated
  patients

22
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

23
ANBP 2 Protocol

• ACE Inhibitor Group
• Step 1. ACE Inhibitor
• Step 2. Beta or alpha blocker or calcium
  antagonist
• Step 3. Drug from class not used in Step 2 or
  diuretic
• Step 4. Drug from class not used in step 2 or 3
• Diuretic Group
• Step 1. Thiazide type diuretic
• Step 2. Beta or alpha blocker or calcium
  antagonist
• Step 3. Drug from class not used in Step 2
• Step 4. Drug from class not used in step 2 or 3

24
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
25
ASBP2 CONCLUSIONS

• ACEI BASED TREATMENT IS MORE EFFECTIVE IN
  REDUCING C.V. EVENTS IN MALES THAN A DIURETIC
  BASED TREATMENT REGIMEN.
• No difference in BP between groups

26
Valsartan Antihypertension Long-Term
Use Evaluation Trial (VALUE)
Valsartan (V) Compared to Amlodipine (A) Based
Regimen
No. 15,245 high risk - 4.2 years Rx V -
80-160 mg/qd HCTZ A - 5-10 mg HCTZ
Results CARDIAC ENDPOINTS - NO DIFFERENCE MI
25.8 lower with (A)
(S) Heart failure 12.7 greater with
(A) (NS) Stroke 17.1 lower
with (A) (NS)
27
VALUE Systolic Blood Pressure in Study
Sitting SBP by Time and Treatment Group
155
Valsartan (N 7649)
Amlodipine (N 7596)
150
mmHg
145
140
135
1
24
48
2
3
4
6
12
18
30
36
42
54
60
66
Baseline
Months
(or final visit)
Difference in SBP Between Valsartan and Amlodipine
5.0
4.0
3.0
2.0
mmHg
1.0
0
1
24
48
2
3
4
6
12
18
30
36
42
54
60
66
1.0
Months
(or final visit)
Julius S et al. Lancet. June 2004363.
28
Primary Composite Endpointsin Value Study
29

• In the VALUE trial
• MIs were lower in amlodipine compared to
• Valsartan-based treatment groups
• BP control better with Amlodipine
• Differences in BP 4/2 mm Hg at 6 mos.
• 1.5/1.3 mm Hg at 1
  year
• Did the differences in BP or specific treatments
• determine the outcome?

30
Serial matching BPs

• Statistical maneuvers to demonstrate that the BP
  differences did not account for the difference in
  outcome

VALUE study
31
Valsartan Antihypertension Long-Term
Use Evaluation Trial (VALUE)
1) Early control of BP appears to make a
difference in outcome 2) New onset
diabetes is less common with an ARB than a
CCB-based treatment regimen (13.1 compared
to 16.4)
32
ASCOT Trial Baseline 19
,339 patients - 77 men 95 white - age 63 yrs
- 27 diabetics BP 164/94 mm Hg 3 other
risk factors 80 on 1 or 2 medications prior to
study
Anglo-Scandinavian Cardiac Outcomes Trial,
Lancet 2005366895
33
ASCOT Trial
BP Targets lt140/90 m Hg or lt130/80 mm Hg in
Patients with Diabetes
Unblinded - Probe Design
Amlodipine 5-10 mg
Atenolol 50-100 mg
add
add
Bendroflumethiazide-K 1.25 - 2.5 mg
Perindopril 4-8 mg
add
Doxazosin 4-8 mg
Other medications
More than 50 in each group were on 2 or
more medications 26 crossed over to other
study drugs 40 used Rx not prescribed by
investigators
Anglo-Scandinavian Cardiac Outcomes Trial,
Lancet 2005366895
34
ASCOT Trial
Primary Objectives
To compare the effect on non-fatal myocardial
infarction (MI) and fatal CHD of an
antihypertensive regimen based on a B-blocker /-
diuretic with a regime based on a CCB /- an ACE
inhibitor
Anglo-Scandinavian Cardiac Outcomes Trial,
Lancet 2005366895
35

• In the ASCOT Trial No difference in primary
  outcome BUT
• A CCB/ACE-I regimen reduced mortality, MIs and
• strokes more than a B-blocker/diuretic based
• regimen
• BP control better with CCB/ACE-I, especially 1st
• few months 5.9/2.1 mm Hg at 3 mos.
• Mean trial differences 2.9/1.8 mm Hg
• Did the differences in BP or specific treatments
• determine the outcome?

36
ASCOT Trial
Conclusions Benefits seem to be somewhat
greater than might be anticipated from the
observed difference in BP. Cost analyses -
fairly small absolute benefits associated with
A/P regimen Findings are generalizable to
most hypertensive patients?
Are these consistent with the data?
Anglo-Scandinavian Cardiac Outcomes Trial,
Lancet 2005366895
37
Should conclusions of a clinical trial be based
on results of primary or secondary
outcomes? How much statistical manipulation is
acceptable to prove a point?
38
ASCOT Trial
Report failed to reference or mention ALLHAT,
SHEP or STOP-2 studies where results were
somewhat different
Anglo-Scandinavian Cardiac Outcomes Trial,
Lancet 2005366895
39
Conflicting Data
1. ALLHAT (favors a diuretic) 2. ASNBP-2 (favors
an ACE-I) 3. STOP-2 (equal outcomes B-BL/D vs
CCB or ACE-I) 4. ASCOT (different outcomes
CCB/ACE-I vs B-BL/D) 5.VALUE (CCB reduces MI
events more than an ARB)
Are there explanations for these differences?
40

• ALLHAT Critics
• Wrong add-on drugs
• Demographics favored diuretics
• Should have adhered to primary outcome results
• BP differences accounted for difference in outcome

ASCOT Wrong comparator medications? Secondary
analyses for conclusions? Are these
generalizable results?
VALUE - ASCOT Statistical manipulations to
demonstrate that BP differences did not explain
different results
41
BP-Lowering Treatment Trialists
Stroke
CHD
1.50
1.25
1.00
RR of Outcome Event
RR of Outcome Event
0.75
0.50
0.25
Systolic BP Difference Between Randomized Groups
(mm Hg)
Systolic BP Difference Between Randomized Groups
(mm Hg)
Blood Pressure Lowering Treatment Trialists
Collaboration. Lancet. 20033621527-1535.
42
THE BOTTOM LINE

• WHILE THERE MAY BE DIFFERENT INTERPRETATIONS OF
  THE RESULTS OF THE TRIALS, THE OVERRIDING MESSAGE
  IS TO GET THE BP TO GOAL.
• THIS USUALLY REQUIRES MORE THAN ONE MEDICATION!

43

• . WHILE THERE MAY BE REASONS TO USE SPECIFIC
  DRUGS, MOST OF THE BENEFIT REPORTED IN THE
  CLINICAL TRIALS RESULTED FROM BP LOWERING. TRIAL
  RESULTS ARE,THEREFORE, NOT REALLY CONFUSING.

44
Monotherapy

• Antihypertensive monotherapy is effective in only
  about 40-60 of hypertensive patients,
  irrespective of the category of the agent that is
  used. Most of the responders are Stage I
  hypertensives. Therefore, there is frequently a
  need for the use of two medications with
  different mechanisms of action.Should therapy be
  started with two drugs or a combination?

45
The concept of combination therapy is not new.
Every major hypertension treatment trial has
been a study of multiple drug therapy. This was
necessary to achieve goal BP
46
Multiple Drug Therapy in the Clinical Trials
SHEP - only 46 on diuretic alone LIFE
gt 85 on multiple drugs UKPDS - 29 in tight
BP group on 3 or more drugs
compared to 11 in less tight BP group MDRD, -
ABCD, - AASK, - IDNT, - HOT, ASCOT 2-3
medications necessary to attain goal BP
47
Causes of Resistance to Antihypertensive Drug
Therapy
Drug-related causes

• Doses too low
• Therapy does not include a diuretic
• Inappropriate combinations
• Drug interactions

48
Drug-related Causes of Resistance
Drug Interaction 1
5
6
9
Suboptimal
54
Drug-related
5
Medication
58
Regimen
1
94
3
16
Objective Medication Intolerance
49
There are physiologic, psychologic and practical
reasons for the use of combination therapy in
hypertensive patients.
50
Physiologic Reasons for Combination Drug
Therapy
1) Different pathways that control BP are
affected 2) Each compound may potentially
neutralize mechanisms activated by the other
51
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.
52
Effect of Losartan or Losartan/HCTZ on Blood
Pressure in African American Patients
SiSBP SiDBP
P 0.01 vs placebo P 0.01 vs losartan
Clin Ther. 2001231193-1208.
53
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

-21
-21.7
Black Nonblack
Enalapril HCTZ Enalapril/HCTZ 10mg BID 25 mg
BID 10/25 mg BID
Vidt. J Hypertens. 19842(suppl 2)81-88
54
ACE Inhibitor/Ca-Blocker Combination
Benazepril 10 mg/ Amlodipine 2.5 mg Amlodipine
2.5 mg Benazepril 10 mg Placebo
62
41
38
19
0
50
100
Response Rate ()
Supine DBP lt90 mm Hg or 10 mm Hg decrease
Frishman WH et al. J Clin Pharmacol 1995351060-6
55
Stroke Risk ReductionACE/diuretic treated
patients compared to patients on other
medications
28 risk reduction
0.20 0.15 0.10 0.05 0.00
P lt0.0001
Medications other than ACE/diuretic
ACE-I
ACE/diuretic
Proportion with event

Mean BP difference -9.0 mm Hg (active vs placebo
-4.0
(Years)
0
1
2
3
4
Lancet 2001 358 1033-41 - PROGRESS Study
56
Lower Blood Pressure Goals
Lower Treatment Goals Reduces the Success of
Monotherapy
Hansson et al. Lancet 1998 3511755-1762
57
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
Stage 1 Hypertension (SBP 140159 or DBP 9099
mmHg) Thiazide-type diuretics for most -May
consider other medications or combination.
Combination therapy may also be appropriate
initial therapy in patients with diabetes or
renal disease
JNC 7
58
Why not use 2 different Medications instead
of A one-pill combination?
59

• In Stage II or potentially resistant or
  difficult-to-treat
• hypertensives, a fixed dose combination rather
  than 2
• individual medications will help to
• achieve goal BP faster than sequential or add-on
  
• monotherapy
• reduce the number of pills necessary
• change the patients perception of their illness
• possibly reduce cost - fewer visits for titration

60
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61
Conclusion Until more consistent and definitive
data on the significance of new onset diabetes
(NOD) are available, achieving goal blood
pressures should be the overriding objective of
treatment NOD should be a secondary concern
62
JNC 7 Key Messages

• If BP is gt160/100 mmHg, therapy should probably
  be started with two medications, one of which
  should be a thiazide-type diuretic

63
Message to Health Care Providers
Recent data suggest that therapy with
combinations of 2 different medications in
lower doses is more effective than higher dose
monotherapy A further decrease in
hypertension-related morbidity and mortality will
be achieved if more patients are treated to BP
levels lt140/90 mm Hg
64
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65
Risk of Diabetes among 3804 Hypertensive
Patients with Various Antihypertensive
Medications
Rx Hazard Ratio None 1.0 ACEI 0.
9 B-Blocker 1.25 CCB 1.17 Thiazides
0.95
adjusted for age, race, BMI, CV risk factors,
etc. significant difference
Gress, et al. NEJM 2000342905-12
66
Cardiovascular Events inTreated Hypertensive
Subjects
4.70
3.90
Rate of events (per 100 patient years)
.97
Total number of CV events - 63
Verdecchia, Hypertens 200443963-968
67
Prognostic Significance of New Diabetes in
Treated Hypertensive Subjects

• At entry and at 3 year follow-up
  non
• diabetic patients who developed diabetes
  had
• higher SBP and DBP
• more LVH
• higher glucose levels
• 42 vs 6 who developed NOD had IFG

Greater baseline risk more diabetes
more events
Verdeccia, Hypertens 200443963-968
(observational cohort study)
68
SHEP Study Follow-Up
Diuretic Rx in patients with diabetes - lower
long-term CV mortality than placebo patients
Subjects who had diabetes associated with
chlorthalidone did not have a significant
increase in CV mortality and had a better
prognosis than did those who had preexisting
diabetes.
Kostis, et al. Am J Card 20059529-35
69
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
70
Morbidity and Mortality in Diabetic and
Nondiabetic Subjects in the Systolic Hypertension
in the Elderly Program
Reduction in risk () in treated compared with
placebo groups
Diabetics (283)
Nondiabetics (2080)
80
70
60
50
40
30
20
10
0
Fatal or nonfatal MI, SCD, CABG, or angioplasty
All-cause mortality
Nonfatal and fatal MI
Therapy low-dose diuretic with B-blocker added
if necessary n 4736 subjects gt60 years of age
Curb KD. et al. JAMA 19962761886-1892
71
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
72
ALLHAT
Changes in serum glucose did not translate into
more CV events in chlorthalidone group Patients
on doxazosin lower levels of serum glucose
than chlorthalidone more CV events
73
CV Events in Treated Hypertensive Diabetics
Does Specific Therapy Make A Difference?
74
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, LIFE, HOPE, CAPPP, AASK, VALUE,
ALLHAT
75
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76
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77
Combination versus Monotherapy
Risk Reduction ( 95CI )
Favors active
Favors placebo

• Stroke
• Combination 43
• Single Drug
  5 (-19 to 23)
• Total Stroke 28

0.4
1.0
2.0
Hazard Ratio
PROGESS Study
78
Combination Therapy

• In the LIFE trial treatment to goal was
  aggressively pursued
• 90 of patients required multiple medications

79
Options to Treat A Patient Not at Goal with
Monotherapy

• Increase the starting dose
• Possibly Increase dose-related adverse events
• Substitute another medication
• Increases time to get patient to goal
• Use a combination of 2 medications
• Complementary mechanism of action
• Lower doses of each medication
• May lessen dose-dependent side effects

Shorten time to goal BPs - Increase response
rates
Moser M, Black H. Am J Hypertens 19981173S-78S
80
Benefits of Lowering BP by
Average Percent Reduction Stroke incidence
3540 Myocardial infarction 2025
Heart failure 50
81
Options to Treat A Patient Not at Goal with
Monotherapy

• Increase the starting dose
• Substitute another medication
• Use a combination of 2 medications

Moser M, Black H. Am J Hypertens 19981173S-78S
82
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83
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
84
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85
Blood Pressure Control Reduces Cardiovascular End
Points in Diabetic Subgroup of HOT
51 RR
P 0.005
Hansson L, et al. Lancet. 19983511755-1762
86
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
87
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
88
Significant Clinical Outcomes in the ALLHAT

Amlodipine vs Chlorthalidone Lisinopril vs
Chlorthalidone RR P
Value RR P Value Primary Outcome 0.98 NS
0.99 0.81 CHD NS
NS Secondary Outcomes Combined CVD NS
NS ESRD NS NS All-cause
mortality NS
NS Stroke NS
1.15 0.02 Combined CVD
1.00 0.04 1.10 lt0.001 Heart
failure 1.36
lt0.001 1.19 lt0.001 Hospitalized
/ fatal heart failure 1.35
lt0.001 NS Angina (hospitalized
or treated) NS 1.11
0.01
Significant difference
89
Possible Advantages of Low-Dose Combination
Therapy Compared to High-Dose Monotherapy

• Blood pressure response is greater
• Percentage of responders is higher
• Side effects may be less
• Titration to effective dose is simplified- Goal
  BP achieved sooner
• Adherence is improved

90
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
91
Swedish Trial in Old Persons (STOP-2)

• 46 were on more than one medication
• 62 remained on conventional Rx (Diuretics
  and B-blockers)
• 61 were on ACE
• 66 were on CCBs

Lancet 1999354751
92
LIFE Study 1195 Diabetics
24
25 Risk Reduction p0031

• of patients
• with 1st event
• MI
• stroke
• death

12
0
0
12
24
36
48
60
Study Month
L Lindholm et al. Lancet, March 23, 2002.
93
VALUE Analysis of Results Based on BP Control
at 6 Months
Pooled Treatment Groups
Odds Ratio

Fatal/Non-fatal cardiac events
0.75 (0.670.83)

Fatal/Non-fatal stroke
0.55 (0.460.64)

All-cause death
0.79 (0.710.88)
Myocardial infarction
0.86 (0.731.01)

Heart failure hospitalizations
0.64 (0.550.74)
0.4
0.6
0.8
1.0
1.2
1.4
Controlled patients (n 10755)
Non-controlled patients (n 4490)
Hazard Ratio 95 CI
SBP lt 140 mmHg at 6 months.
P lt 0.01.
Weber MA et al. Lancet. 2004363204749.
94
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
95
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
96
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
97
ALLHAT

• Thiazide diuretics - associated with increase
• in serum glucose of approximately 3-5 mg/dL
• For diabetic patients there was no advantage
• to the use of lisinopril and no detrimental
• effect of amlodipine on CVD outcome or end
• stage renal disease compared to chlorthalidone

Annals Intern Med 2004141
98
ASCOT Trial
Assumption Although lowering of blood pressure
with diuretics B-blockers was associated with
a significant decrease in CHD events, these were
less than expected from prospective 10-15 year
observational studies.
Long-term follow-up data from HDFP and SHEP
are not consistent with this assumption
Anglo-Scandinavian Cardiac Outcomes Trial,
Lancet 2005366895
99

• ASCOT Trial
• No significant difference in primary outcome
  (fatal non fatal
• non fatal MI) between groups but CCB/ACE-I
  significantly reduced secondary endpoints, i.e.,
  total CHD and CV events including strokes
  compared to BBL/D
• BP control better with CCB/ACE-I, especially 1st
  few months (differences 5.9/2.1 mm Hg
  at 3 months)
• Mean trial differences 2.7/1.9 mm Hg between
  therapies
• Did the differences in BP or specific treatments
  determine the outcome?

Anglo-Scandinavian Cardiac Outcomes Trial,
Lancet 2005366895