Download Relative risk of cardiovascular events or death

Recent Developments in the
Treatment of Hypertension
The Value of Facts
1999
Objectives
• To review recent clinical trial evidence of efficacy
for antihypertensive agents
• To present new data on the treatment of
hypertensive patients with type 2 diabetes
• To discuss the emerging evidence for use of
ACE inhibitors in diabetes
• To review recent safety data on antihypertensive
agents
Documentation of Drug
Safety and Efficacy
• Patients, clinicians and the health-care
establishment expect adequate documentation
• A week-long treatment for an acute condition
requires randomized trials that follow patients for
> 1 week
• Lifelong treatments are ideally evaluated in lifelong
trials, but evaluations in large populations over 4 to
5 years are typically accepted.
Antihypertensive Drugs: Documentation
By the Time of Regulatory Approval
Known
• BP lowering potential (N = 200-500 patients)
• Common side effects (symptoms)
• Any common early drug complications (events)
• Major changes in blood chemistry
• Major animal toxicity
Antihypertensive Drugs: Documentation
By the Time of Regulatory Approval
Unknown
• Effect on major CVD mortality/morbidity
• Optimal dose (risk-benefit balance)
• Uncommon early side effects or clinical
•
•
•
•
complications
ADRs and complications of long-term drug use
Efficacy or safety in various subgroups
Effect on pregnancy
Drug interactions
Aim of Antihypertensive
Therapy
To prevent the cardiovascular complications of
hypertension -- stroke, acute myocardial infarction,
congestive heart failure -- not just to lower an
elevated blood pressure.
Eligibility criteria for meta-analysis
• Randomized placebo controlled trials
• Treatment duration of > 1 year
• Assessment of major disease endpoints
• Unconfounded by other therapies
Psaty et al., JAMA 1997
Definition of Treatment Strategies
• Multiple agents used in most trials
• Trials classified by first-line strategy
•
-- High-dose diuretic therapy
-- Low-dose diuretic therapy
-- Beta-blocker therapy
No eligible trials evaluating CCBs or
ACE inhibitors
Psaty et al., JAMA 1997
Summary of Eligible Trials (n = 18)
Therapy
Trial
Intervention
Control
Low-dose diuretics
4
4,305
5,116
High-dose diuretics
11
7,768
12,075
Beta-blockers
4
6,736
12,147
HDFP
1
5,484
5,455
Psaty et al., JAMA 1997
Meta-analysis: Antihypertensives
High-dose diuretics
Event
RR
95% CI
Stroke
0.49
0.39-0.62
CHF
0.17
0.07-0.41
CHD
0.99
0.83-1.18
Total mortality
0.88
0.75-1.03
Psaty et al., JAMA 1997
Meta-analysis: Antihypertensives
Low-dose diuretics
Event
RR
95% CI
Stroke
0.66
0.55-0.78
CHF
0.58
0.44-0.76
CHD
0.72
0.61-0.85
Total mortality
0.90
0.81-0.99
Psaty et al., JAMA 1997
Meta-analysis: Antihypertensives
Beta-blockers
Event
RR
95% CI
Stroke
0.71
0.59-0.85
CHF
0.58
0.40-0.84
CHD
0.93
0.80-1.09
Total mortality
0.95
0.84-1.07
Psaty et al., JAMA 1997
Summary of Major Findings
• High-dose diuretic and ß-blocker therapies
reduced the incidence of CHF and stroke
• Low-dose diuretic therapy reduced the
incidence not only of CHF and stroke but also
of CHD and total mortality
• High-dose versus low-dose diuretic comparison
was confounded by patient age
Psaty et al., JAMA 1997
Syst-Eur -- Nitrendipine in ISH
•
•
•
•
•
•
Randomized, placebo-controlled, 2N = 4,695
Baseline, mean age 70 yrs, BP 174/85 mm Hg
Median FU of 2 yrs, BP 10/5 mm Hg
Step-up drugs: enalapril (33%), HCTZ (20%)
237 randomized patients lost-to-follow-up
Reduction in stroke: RR 0.58, 95% CI 0.40 - 0.83
CHF: RR 0.71, 95% CI 0.47 - 1.10
Staessen et al., Lancet 1997
Concerns About Syst-Eur
SHEP
# randomized
# primary events (stroke)
# lost-to-follow-up
Case-fatality, stroke (%)
Case-fatality, CHF (%)
Syst-Eur
4,736
262
10
vs
vs
vs
4,695
124
237
8.9
6.4
vs
vs
27.3
20.4
Questions in Syst-Eur: incomplete ascertainment?
level of medical care?
generalizable findings?
Pahor et al., Lancet 1998
Captopril Prevention Project (CAPPP)
Design
Population
Intervention
Follow-up
Randomized, open
10,985 hypertensives, aged 2566 years, with DBP > 100 mm Hg
Captopril (50-100 mg) vs clinician’s
choice of a diuretic or a ß-blocker;
diuretic or the other class as step-up
Average of 6.1 years
Hansson et al., Lancet 1999
Captopril Prevention Project - CAPPP
Outcome
Captopril
better
Conventional
treatm. better
Stroke, MI, CV death
Stroke
MI
Death
Diabetes
0.33
0.5
1
2
Relative Risk
Hansson et al., Lancet 1999
Limitations of CAPPP
• Captopril only given once or twice per day
• Flawed randomization process (envelopes)
• Baseline difference on BP unlikely explained
•
by chance
Potential differential evaluation of incident
diabetes in the 2 groups due to lack of blinding
Cutler, Lancet 1999
Antihypertensive Treatment
in Type 2 Diabetes
1.
Active treatment vs control (placebo)
2.
More tight vs less tight BP control
3.
Comparisons of active treatments
SHEP - CV Event Rate in ISH
by Diabetes Status
7
6
5
Annual
cardiovascular
event rate
(%)
Placebo
Active treatment
RR .66, 95%CI .46-.94
RR .66, 95%CI .55-.79
4
3
2
1
0
No diabetes
Diabetes
Curb et al., JAMA 1996
Syst-Eur -- Diabetic Cohort
Mortality
30
26
NS
No. of
Events
25
Stroke
Cardiac Events
p=0.02
NS
20
16
15
15
15
10
5
5
7
0
Placebo
Nitrendipine
Tuomilento et al., NEJM 1999
UK Prospective Diabetes Study
150/85 vs 180/105 mmHg BP Target
Endpoint
RR
95% CI
Any endpoint
0.76
0.62-0.92
Diabetes death
0.68
0.49-0.94
Any death
0.82
0.63-1.08
MI
0.79
0.59-1.07
Stroke
0.56
0.35-0.89
PAD
0.51
0.19-1.37
Microvascular dis.
0.63
0.44-0.89
n = 758 vs 390
UKPDS Group, BMJ 1998
HOT - Rate of Major CV Events
According to Randomized Groups
p for trend
0.005
Rate/1000 person-years
30
25
20
15
BP goal
mmHg
<90
<85
<80
p for trend 0.5
10
5
0
All n=18790
Diabetic n=1501
Hansson et al., Lancet 1998
Comparative Trials in Hypertensives
with Type 2 Diabetes or Impaired
Glucose Metabolism
FACET
ABCD
UKPDS
CAPPP
MIDAS
FACET - Fosinopril versus Amlodipine
Cardiovascular Events Trial
Design
Patients
Sample size
Intervention
Outcomes
Follow-up
Prospective randomized trial
Hypertension and type 2 diabetes
380 patients
Fosinopril / amlodipine open label
- Primary: serum lipids
- Secondary: CV events, BP
2.5 to 3.5 years
Tatti et al., Diabetes Care 1998
Cardiovascular Events in FACET
Amlodipine n=191
Fosinopril n=189
5
4
Rate
3
per 100
person-years 2
1
0
The figures at top
of the bars indicate
the number of events
p=.03
27
14
13
10
10
4
4
Stroke
AMI
0
Hospit. Any major
Angina CV event
Tatti et al., Diabetes Care 1998
ABCD Trial
Design
Double-blind randomized trial
Enalapril vs nisoldipine
Intensive vs moderate BP control
Patients
Type 2 diabetes, a normotensive
and a hypertensive group
Outcomes
- Primary: renal function
- Secondary: CV events, BP
Follow-up
5 years
Estacio et al., NEJM 1998
ABCD Trial
Risk of Myocardial Infarction Intensive and Moderate Groups
P= 0.03
Number of Patients
14
12
12
P= 0.002
13
10
8
6
4
4
1
2
0
Intensive
Nisoldipine
Moderate
Enalapril
Estacio et al., NEJM 1998
ABCD Trial
Cardiovascular Disease
Number of Patients
P= 0.002
43
45
40
35
30
25
20
15
10
5
0
P= 0.001
25
22
20
5
Non-Fatal MI's
Nisoldipine
P= 0.001
Enalapril
5
All MI's
All CV Events
Estacio et al., NEJM 1998
ABCD Trial
• The independent Data Safety Monitoring
Committee recommended early termination of
the hypertensive arm because of the 5-fold
increase in risk of fatal and non-fatal AMI in the
nisoldipine group compared to the enalapril
group
• Those receiving the calcium antagonist were
reassigned to the ACE inhibitor
Estacio et al., NEJM 1998
UK Prospective Diabetes Study
Design
Randomized trial comparing (a) less
tight vs tight BP control and (b) two
forms of tight control
Patients
Hypertensives with type 2 diabetes
Intervention Furosemide-based vs captopril- or
atenolol-based
Outcomes
Fatal and nonfatal CV events
Follow-up
8.4 years
UKPDS Group, BMJ 1998
UK Prospective Diabetes Study
Captopril vs Atenolol (reference group)
Endpoint
RR
95% CI
Any endpoint
1.10
0.86-1.41
Diabetes death
1.27
0.82-1.97
Any death
1.14
0.81-1.61
MI
1.20
0.82-1.76
Stroke
1.12
0.59-2.12
PAD
1.48
0.35-6.19
Microvascular dis.
1.29
0.80-2.10
n = 400 vs 358
UKPDS Group, BMJ 1998
CAPPP - patients with diabetes
Outcome
Captopril
better
Conventional
treatm. better
Stroke, MI, CV death
Stroke
MI
Death
0.33
0.5
1
2
Relative Risk
Hansson et al., Lancet 1999
MIDAS Trial
• 883 hypertensive patients randomized to
isradipine or HCTZ and followed for 3 years
• No difference in carotid intimal medial thickness,
the primary outcome
• Increased risk of major CV events by 78%
(p=0.07) and all CV events and procedures by
63% (p=0.02) in the isradipine group
Borhani et al., JAMA 1996
MIDAS Trial - Relative Risk of CV
Events for Isradipine versus HCTZ
4
3.22*
2.71*
3
RR
2
*p<.05
1.81
1.16
1.25
<6.7 6.7+
<9.8 9.8+
1
0
All
HbA1c %
Serum insulin U/ml
Byington et al., Diabetes Care 1998
Blood Pressure Changes in FACET
180


Systolic


160


*
140
mmHg




Fosinopril
Amlodipine
120
100


Diastolic






1
2
3
80
60
Baseline
Follow-up time (years)
*p .05 amlodipine vs fosinopril.
Tatti et al., Diabetes Care 1998
The Appropriate Blood Pressure
Control in Diabetes (ABCD) Trial
Blood Pressure
(mm Hg)
Intensive-Treatment Group
150
Nisoldipine
Enalapril
Systolic
130
110
Diastolic
90
70
0
6
12
18 24
30 36
42 48 54 60
Month
No. of patients
237
189
199
176
166
137
Adapted from Estacio RO et al., NEJM 1998
Systolic Blood Pressure Reduction
and Cardiovascular Events in FACET
0
Fosinopril
Amlodipine
-5
mm Hg
-10
-15
No events
-20
Events
-25
-20
-20
-23
-30
-32
p<.05
-35
p<.01
Pahor et al., J Cardiovasc Pharmacol 1998
One-year Diastolic BP Reduction and
Cardiovascular Events in MIDAS
0
HCTZ
Isradipine
mm Hg
-5
No events
-10
Events
-15
p=.03
-20
p=.01
Byington et al., Diabetes Care 1998
Comparative Trials of
Antihypertensive Agents in Diabetes
Demonstrate that:
• Blood pressure alone is not a sufficient marker of
•
•
•
drug efficacy
Pronounced reductions may be harmful in diabetics
Health benefits may differ among antihypertensive
agents
ACE inhibitors appear to be most beneficial;
calcium antagonists least beneficial
Other Benefits of ACE
Inhibitors in Diabetes
BRILLIANT
Urinary albumin excretion
(microg/min)
Urinary Albumin Excretion
70
*
60
50
*p=0.0006
40
30
20
10
Lisinopril (10-20mg o.d)
Nifedipine (20-40 mg b.d)
0
Baseline
6 months
12 months
Agardh et al., J Human Hypertens 1996
ACE Inhibitors and Microvascular
Disease in Diabetic Patients
• ACEIs delay the development and progression of
diabetic nephropathy*
• ACEIs markedly slow progression of retinopathy**
• ACEIs appear to improve peripheral neuropathy***
* Ahmad et al., Diabetes Care 1997
* Maschio et al., NEJM 1996
** Chaturvedi et al., Lancet 1998
*** Malik et al., Lancet 1998
Short-term mortality benefit of ACE
Inhibitors in Diabetic Patients with
Acute MI
%
of pts
p <0.05
21.1
25
20
p <0.05
15
10.6
10
11.8
8
5
0
Lisinopril
Control
Lisinopril
Control
NIDD
IDD
Zuanetti & Latini, J Diabetes Complications 1997
Safety Documentation
• More than 100,000 person-years desired
• Safety problems common across indications
• Extensive safety documentation for diuretics,
beta-blockers and ACE inhibitors
• Inadequate documentation of long-term safety
for calcium antagonists, alpha-blockers,
angiotension II blockers
Safety Documentation for Slow-Release
CAs in Hypertension
Drugs
Person-years
Active
Control
Adalat CC
Procardia XL
Plendil
Norvasc
Cardene
Cardizem SR
Dilacor XR
Isoptin
Verelan
31
56
39
269
53
138
24
1
5
10
36
14
158
22
115
7
1
2
Total
616 (x = 68)
365 (x = 41)
Risk of Primary Cardiac Arrest
Therapy
ß-blocker
Thiazide, 100 mg
Thiazide, 50 mg
Thiazide, 25 mg
Thiazide, 50 mg
Thiazide, 25 mg
K-sparing
RR
95% CI
No
No
No
Yes
Yes
1.0
2.4
1.1
0.7
0.5
0.3
reference
0.7-8.8
0.5-2.5
0.2-2.5
0.1-2.2
0.1-1.0
Siscovick et al., N Engl J Med 1994
CCBs in Hypertension
Potential Serious Adverse Events
•
•
•
•
•
Coronary events
Bleeding (GI and surgical)
Cancer (blocking apoptosis)
Cerebral white matter lesions (MRI)
Others
• Strong association to drug dose and duration
of exposure support causation
CAs safety - Non Randomized
Studies and Meta-analysis
12
increase risk
neutral
CAs
10
Number of reports
10
reduce risk
8
6
5
6
5
4
4
2
2
1
0
0
0
CVD, death
Bleeding
Cancer
Pahor et al., (to be published)
Hypertensive Emergencies
• IR nifedipine widely used in hypertensive
emergencies and even moderately elevated BP in
asymptomatic patients
• Never approved by the FDA for this indication;
complete lack of outcome data
• Unpredictable BP fall associated with stroke,
acute MI, severe hypotension and death
• “Routine use of IR nifedipine in hypertensive
emergencies and pseudoemergencies should be
abandoned”
Grossman et al., JAMA 1996
Hypertension Optimal
Treatment Trial (HOT)
 18,790 hypertensives randomized to three DBP
goals: < 90, < 85 and < 80 mm Hg.
 Achieved mean DBP: 85.2, 83.2 and 81.1 mm Hg.
 No difference in incidence of major CV events:
9.9, 10.0 and 9.3/1,000 pt. years.
 Post-hoc analysis suggested benefit of lower DBP
among diabetics. Offset by increase in events
among non-diabetics.
Hansson et al., Lancet 1998
Interpretation of HOT Results
MRFIT 5.8 mm Hg lower DBP associated with lower stroke
(44%) and CHD (25%) risks
HDFP Mean 5.4 mm Hg reduction in DBP translated into
17% mortality and 35% stroke benefit
HOT
Mean 4.0 mm Hg reduction in DBP between < 90
and < 80 target groups translated into a 7% lower
CV event rate (N.S.)
Explanations (1) Null hypothesis true (unlikely)
(2) Higher doses of felodipine
increased CV event offsetting
benefit of BP lowering itself (likely)
(3) Insufficient power
Antihypertensive and Lipid
Lowering Treatment to Prevent
Heart Attack Trial (ALLHAT)
Design
Patients
Intervention
Endpoints
Follow-up
Randomized, double-blind clinical
trial
42,451 hypertensives; 15,290 diabetics
Lisinopril, amlodipine and doxazosin
compared to chlorthalidone
Same BP goal -- 140/90 mm Hg
Fatal and nonfatal CV events
Approximately 6 years
Conclusions
• ACEIs appear to convey similar antihypertensive
benefits as the established first-line agents low-dose
diuretics and beta-blockers
• ACEIs are the antihypertensive drugs of choice in
hypertensives with type 2 diabetes
• ACEIs are recommended in diabetic patients with
nephropathy and myocardial infarction
• CCBs should be 4th-line agents in diabetics
Ordering of Slide Set
If you wish to order an electronic copy
of this slide set, “Recent Developments in
the Treatment of Hypertension,” please
contact Ms. Sarah Hutchens, Wake Forest
University School of Medicine at:
[email protected]
The slide set is in PowerPoint Version 4.0.