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
7th Joint National Committee Report on
Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure
3
JNC 7 Blood Pressure Classification
4
European Guidelines - 2003

• Do not support the term pre hypertension
• Definition of high normal may be
• hypertension in people with other risk
• factors or normal or acceptable in people
• without other risk factors

5
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) CRP
as a marker of inflammation may be
increased 3) Pre hypertension does not increase
stroke risk. 4) CHD mortality not
increased with pre hypertension
6
WHAT REALLY MATTERS IN DECIDING ON THERAPY?

• CONFLICTING TRIAL RESULTS
• Is it blood pressure alone that
• makes the difference
• or specific medications?

7

• Some comparative trials where
• blood pressure levels were the
• determining factors in outcome

8

• 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.

9
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
10
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
11
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.
12
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.
13
2003
The Antihypertensive and Lipid Lowering
Treatment to Prevent Heart Attack Trial
(ALLHAT),
14
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

15
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.
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

• ALLHAT results.
• Diuretic based therapy resulted in fewer CHD
  events than an ACEI or CCB regimen?
• Fewer CVD events occurred in Diabetics treated
  with ACEIs?
• Strokes were more frequent in CCB treated
  subjects.?

18
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?
19
Cumulative Event Rates for the Primary Outcome
(Fatal CHD or Nonfatal MI) by ALLHAT Treatment
Group
Chlorthalidone Amlodipine Lisinopril
20
Cumulative Event Rates for Stroke by
ALLHAT Treatment Group
Chlorthalidone Amlodipine Lisinopril
21
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
22
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
23
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

24
Comments on the ALLHAT Conclusions

• Conclusions were based solely on
  analyses of secondary endpoints.
• We should remember as we were told by the
  ALLHAT investigators that secondary endpoints
  are soft data that should not form a basis for
  main conclusions or lead to a labeling of a drug
  class as preferred
• Messerli

25
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
26
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

27
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

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
ANBP-2 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

30
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
BP differences1 month - (A) -4.0 / -2.0 6
months - (A) -2.1/ -1.6
1 year - (A) -1.5/ -1.3 mm Hg lower than
with (V)
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)
31
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.
32
Primary Composite Endpointsin Value Study
33

• 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?

34
Valsartan Antihypertension Long-Term
Use Evaluation Trial (VALUE)
Early control of BP appears to make
a difference in outcome
35
ASCOT Trial Baseline 1
9,339 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
36
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
37
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
Perindopril 4-8 mg
Bendroflumethiazide-K 1.25 - 2.5 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
38

• ASCOT Trial
• CCB/ACEI therapy resulted in fewer CHD events
  than therapy with a B/BL /diuretic?

39

• ASCOT Trial
• No significant difference in primary outcome
  (fatal non fatal MI) but CCB/ACE-I
  significantly reduced secondary endpoints, i.e.,
  total CHD and CV events including strokes
• 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
40
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
41
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?
42
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?
43

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

VALUE - ASCOT Statistical manipulations to
demonstrate that BP differences did not explain
different results

• ASCOT
• Wrong comparator medications?
• Secondary analyses for conclusions?
• Are these generalizable results?

44

• The combination of an ACEI and a CCB is effective
  and a reasonable choice for therapy for many
  hypertensives. At present, however, there is no
  strong evidence that this is a better combination
  than other available agents

45

• THE MESSAGE IS CLEAR. 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.

46
Is the Development of new onset diabetes as a
result of antihypertensive therapy of clinical
significance.?
47
Recommendations for a change in
treatment approaches should be made based on
consistent evidence from well controlled
clinical trials. At present data on new onset
diabetes do not satisfy these criteria.
48
Therefore----The concerns about new onset
diabetes with various antihypertensive
medications should not be a major determining
factor in the choice of initial therapy.
49
While data indicate that NOD is increased by
about 1 with diuretics compared to CCBs and
1-3.5 compared to ACEIs, long-term CV outcomes
are not affected
50
Incidence of New Onset Diabetes with Various
Medications. How significant is it?
51
Risk of Hyperglycemia with Use of
Antihypertensive Drugs

Thiazide Central antiadrenergic agents
Peripheral antiadrenergic agents
ACE inhibitors
B-Blockers Calcium
channel blockers
Vasodilators gt1 Agent without
thiazide gt1 Agent with thiazide
0.5 1 1.5 2 2.5 3
Decreased Risk
Increased Risk
GurwitzJH. Arch Intern Med 1993118273-278
Adjusted ORs and 95CI
52
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
53
Conclusions Concern about the risk of
diabetes should not discourage physicians from
prescribing thiazide diuretics to nondiabetic
adults who have hypertension. The use of
B-blockers appears to increase the risk of
diabetes, but this adverse effect must be weighed
against the proven benefits of B-blockers in
reducing the risk of cardiovascular events.
Gress, et al. NEJM 2000342905-12
54
Effects of High-Dose Diuretic Therapy Compared
To Control or Placebo on Glucose Metabolism
Study Yrs Hyperglycemia or
Diabetes Oslo 5 No
data EWPHE MRC
3-4 Excess of 6 new cases/1000 pt
yrs HAPPY HDFP 5 1.6
(57/3,563) SHEP 1 No diff new onset
diabetes Rx/C

Moser,M. Cleve Clin J Med 19936027-37
55
Incidence of New Onset Diabetes in the 3-8 Year
Hypertension Treatment Trials

Years Absolute
Difference Trial Duration
New Onset Diabetes
I. ACE-I compared to conventional Rx
ACE / D/B-BL
CAPPP 6.1
-1.0 STOP-2 6
-0.2 ANBP-2
4
-2.1 ALLHAT
4.9 - 3.5 II.
CCB compared to conventional Rx CCB /
D/B-BL NORDIL 4.5
- 0.6 ALLHAT 4.9
- 1.8 INVEST 4.0
- 1.1 INSIGHT 3.5
- 1.6 STOP-2
6 - 0.1
Approximate overall difference ACEI vs D/B-BL
2.0 CCB vs D/B-B/L 1.5
56
Incidence of New Onset Diabetes in the 3-8 Year
Hypertension Treatment Trials
Years Absolute Difference
Trial Duration New Onset
Diabetes

• III. ARB vs other Rx ARB /
  Other Rx
• VALUE 4.2
  - 3.3
• LIFE 4.8
  - 2.0
• SCOPE 5
  - 1.0
• CHARM 3
  - 1.4
• IV. ACE-I vs CCB ACE / CCB
• ALLHAT 4.9
  -1.7

Approximate overall difference ARB vs D/B-BL
2.0 ACE/CCB 2.0
57

• Conflicting data on the

significance of new
onset diabetes
58
CV RISK WITH NEW ONSET DIABETES

• New Onset Diabetes as a result of
• various medications has the same
• prognosis as preexisting diabetes ?

59
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
60
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)
61
Plasma glucose levels at entry and
diuretic treatment on follow-up were
independent predictors of new diabetes but"
while the occurrence of new diabetes was an
independent predictor of cardiovascular risk, the
use of diuretics, albeit predictive of new
diabetes, did not show any independent relation
with the subsequent cardiovascular events.
Verdecchia, Hypertens 200443963-968
62
SHEP STUDY FOLLOW UP

• NEW ONSET DIABETES AS A RESULT
• Of THE USE OF VARIOUS MEDICATIONS
• DOES NOT HAVE THE SAME PROGNOSIS
• AS PREEXISTING DIABETES

63
SHEP Follow-Up - New Onset Diabetes

• To assess the long term (14.3 years) mortality
  of Systolic
• Hypertension in Elderly Program (SHEP)
  participants by
• diabetes status
• No diabetes
• Diabetes at Baseline
• New onset diabetes (during SHEP)

From Kostis, et al
64
Results-6 CV death ()
SHEP-X
14.3 Year Follow-up
30
50
27
20
40

22

30
18
18
PLACEBO
20

10
ACTIVE
0
B-L DM
F-U DM
NO DM
From Kostis et al
65
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
66
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
67
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
68
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
69
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 based regimen usually with a diuretic
  is given rather than a CCB

IDNT, RENAAL, LIFE, HOPE, CAPPP, AASK, VALUE,
ALLHAT
70
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
71
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72
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73
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
74
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
75
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
76
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
77
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.
78
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
79
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
80
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
81
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
82
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?

83
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
84
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 More than 3
medications necessary to attain goal BP
85
Causes of Resistance to Antihypertensive Drug
Therapy
Drug-related causes

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

86
CV Events in Treated Hypertensive Diabetics
Does Specific Therapy Make A Difference?
87
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
88
There are physiologic, psychologic and practical
reasons for the use of combination therapy in
hypertensive patients.
89
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
90

• 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

91
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.
92
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
93
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
94
Combination Therapy

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

95
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.
96
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
97
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
98
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

99
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
100
Why not use 2 different Medications instead
of A one-pill combination?
101
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
102
Lower Blood Pressure Goals
Lower Treatment Goals Reduces the Success of
Monotherapy
Hansson et al. Lancet 1998 3511755-1762
103
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
104
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

105
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
106
Is it Ever Too Late to Lower Blood
pressure?
107
Trial of Non Pharmacologic Interventions in the
Elderly (TONE)
Reduction () in Incidence of Hypertension or CV
Event
-31
-30
-53
JAMA 1998279839-846
108
Benefits of Lowering BP by
Average Percent Reduction Stroke incidence
3540 Myocardial infarction 2025
Heart failure 50
109
Blood Pressure (mm Hg) in SHEP and Syst-Eur
Trials
SHEP
Syst-Eur
Entry Goal (SBP) Baseline Achieved Rx Achieved
Placebo
160-219/lt90 160-219/lt95 lt160 lt150
170/77 174/86 143/68 151/79
155/72 161/84
110
The Difficulty in Reducing SBP STOP-2
Conventional ACEI based Calcium antagonist based
SBP Goal
? BP(mm Hg)
DBP Goal
1
0
6
12
24
36
48
54
Months
Hansson L, et al. Lancet. 19993541751-1756.
111
REDUCTION OF STROKES WITH BP LOWERING - SHEP TRIAL
No. of Patients 4736
Follow-up 4.5 years
37 in ischemic strokes 47 in lacunar
infarcts 54 in hemorrhagic strokes
Lower BPs - fewer strokes
Am J Hypertension 200013724-733
112
Public Health Implications of SHEP Study
Reduction in Events on Active Treatment (per
1000 patients/5 years)
CVA 30 CAD 16 CHD 55
Annually in USA 24,000 fewer strokes
44,000 fewer major CV events 84,000 fewer
hospital admissions
113
In the SHEP study the beneficial effect on
cardiovascular events was attenuated in
patients with potassium levels below 3.5 mmol
d/L but were no greater than placebo
114
Diuretics or B-Blockers as Initial Therapy in 8
Randomized Controlled Hypertension Treatment
Trials in Older Persons
Risk Reduction ()
All reductions significant (p lt.05) except CHD
and death with B-blockers
Cutler JA, et al. In Laragh JH, Brenner BM, eds,
Hypertension 1995
115
ISH META-ANALYSIS OF OUTCOME TRIALS
n15,6933.8-yr follow-up
1000
Nonfatal events Fatal events Treatment Control
835
800
734
T
656
647
600
C
Total individuals affected (n)
387
373
400
342
327
293
279
100
329
200
244
193
136
100
0
T
C
T
C
T
C
T
C
T
C
Totalmortality130.002
AllCV events 26lt0.001
Non-CVmortality
CHD23lt0.001
Stroke30lt0.0001
odds reduction
2P value
Adapted from Staessen et al. Lancet 2000355865
116
Meta-analysis of Hypertension Treatment Trials in
People gt 80 Years of Age
6
pns
-22
pns
-34
-39
p.014
p.01
Lancet 1999353793-796
117
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
118
Isolated Systolic Hypertension
Definition gt140 lt90 mm
Hg Etiology Age related decrease in aortic
compliance (increase in
vascular stiffness)
Decrease in elastic tissue In rigid
aorta Increase in collagen deposition
Intimal thickening
Diastolic pressure remains constant or
decreases. In rigid aorta elastic recoil that
helps maintain DBP is decreased.
119

• Algorithm for Management of the Elderly -
• Primarily Systolic Hypertension
• 1) Lifestyle changes
• Low dose diuretic (12.5 mg HCTZ)
• CCB B-Blocker
  ACE or ARB
• 3) Stop, Look Listen before dosages
• Let the Baroreceptors reset
• 4) Rx until goal achieved

120
Status of BP Control Among 800 Elderly Men in a
2-year Study

• More than 40 percent of subjects had BPs gt 160/90
  mm Hg
• Patient visits average 5-6/year
• Medication was increased only 26 of the time in
  patients with BPs gt 155/90 mm Hg
• Medication was increased only 22 of the time in
  patients with BPs lt90 but gt 165 mm Hg

N Engl J Med. 19983391957.
121
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
122
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
123
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
124

• In the ASCOT Trial
• 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
• Mean trial differences 2.9/1.8 mm Hg between
• therapies
• Did the differences in BP or specific treatments
  determine the outcome?