Robert A. Phillips, M.D., Ph.D., F.A.C.C., F.A.H.A. Chairman Department of Medicine Lenox Hill Hospital Professor of Medicine NYU School of Medicine President, Eastern Chapter, American Society of Hypertension
From clinical trials to JNC 7: Evidence That Will Change Practice
Recent Clinical Trials in “Uncomplicated Hypertension” that Inform JNC7
HOT - Hansson et al., Lancet 1998:351:1755
Optimal BP <140/90 mm Hg
Felodipine based trial
HOT Study: Risk of a Major CV Event Reduced by 30% (DBP)
100
95
90
80
85
Achieved DBP (mm Hg)
Optimal DBP reduction
Hansson L et al. Lancet. 1998;351:1755-1762
Percent
risk
reduction in
major CV
events*
*Fatal and nonfatal MI, stroke, all other CV deaths.
HOT Study: Risk of a Major CV Event Reduced by 30% (DBP)
170
160
150
130
140
Achieved SBP (mm Hg)
Hansson L et al. Lancet. 1998;351:1755-1762
*Fatal and nonfatal MI, stroke, all other CV deaths.
Percent
risk
reduction
in major
CV events*
Optimal SBP reduction
HOT Study Results: Lower is Marginally Better for Non-Diabetic Hypertensives and ASA is Good
Those assigned to < 80 mm Hg group had few myocardial infarctions than those assigned to <90 mm Hg group
2.6 vs. 3.6 events per 1000 patient years (p=0.05)
ASA group (one-half of the patients) had 15% few CV events (p=0.05)
Hansson et al., Lancet 1998:351:1755
Recent Clinical Trials in “Uncomplicated Hypertension”
STOP-2 - Hansson et al., Lancet, 1999; 354:1751–56
Compared “old” (diuretics and ?-blockers) vs. “new” (calcium channel blockers and ACE inhibitors) in overall CV outcomes
All had equal ability to prevent CV morbidity or mortality in elderly patients with hypertension.
ACE inhibitors prevented more MI and CHF than CCBs
INSIGHT - Brown et al., Lancet, 2000;356:366-72
Nifedipine-GITS vs diuretic-based therapy.
Equally effective in reducing stroke and total cardiovascular events,
Greater incidence of MI and CHF in CCB group.
Recent Clinical Trials in “Uncomplicated Hypertension”
NORDIL - Hansson et al., Lancet, 2000;356:359-65
Diltiazem as effective as diuretic and ?-blocker therapy in preventing the combined primary endpoint of all stroke, myocardial infarction, and other cardiovascular death
CCB was more effective in reducing stroke.
2nd Australian National BP Study, NEJM, 2003;348:583-592
Low risk elderly population
ACE better than diuretic
Summary:
BP reduction in the patient with uncomplicated hypertension is the critical factor
Which drug is better may be a nuance
CCB monotherapy appears to be related to more CHF
Combinations are usually required
Recent Clinical Trials in “Complicated” Hypertension that Inform JNC7
HOT - Hansson et al., Lancet 1998:351:1755
HOPE - NEJM,2000;342:145-153; Lancet 2000;355:253-259
ALLHAT- JAMA 2000 Apr 19;283(15):1967-75
RENAAL - Brenner BM, et al. N Engl J Med. 2001;345:861-869.
IDNT - Lewis EJ, et al. N Engl J Med. 2001;345:851-860.
AASK – AASK Study Group, JAMA, 2002;
ALLHAT – 2002, JAMA, 2002;288:2981-2997
Clinical Summary:
In renal disease, blockade of the renin-angiotensin-aldosterone system is beneficial
If multiple risk factors, including diabetes, blood pressure lowering may be most important, diuretics should be part of therapy if possible
HOT Study Results: Lower is Definitely Better in Patients with Diabetes and Hypertension
50% reduction in major CV events in those diabetic hypertensives assigned to < 80 mm Hg compared to <90 mm Hg group
Impressive, since only 4 mm Hg difference between groups at end of study
Hansson et al., Lancet 1998:351:1755
Impact of Randomized Drug Class on Outcomes in AASK
AASK Study Group, JAMA. 2002;288:2421-2431
Follow-up BP by Drug Group
(Mean ? SD)
Summaries include visits after three months and exclude GFR visits
* Significant difference between amlodipine and metoprolol groups (p < 0.05)
AASK Study Group, JAMA. 2002;288:2421-2431
Main Clinical Composite Outcome
Declining GFR Event, ESRD, or Death
%
w
i
t
h
E
v
e
n
t
s
Metoprolol vs. Amlodipine:
RR= 20%, p=0.17
Ramipril vs. Amlodipine:
RR= 38%, p=0.004
Metoprolol
Ramipril
Amlodipine
0
5
10
15
20
25
30
35
40
Follow-up Month
0
6
12
18
24
30
36
42
48
54
60
Ramipril vs. Metoprolol
RR = 22%, p = 0.042
RR = Risk Reduction, Adjusting for Baseline Covariates
AASK Study Group, JAMA. 2002;288:2421-2431
Hard Clinical Endpoint Composite
Of ESRD or Death
RR = Risk Reduction, Adjusting for Baseline Covariates
AASK Study Group, JAMA. 2002;288:2421-2431
% of Patients Reached Urine Protein >300 mg/24 hrs
During Follow-up by Drug Group
Ramipril vs. Metoprolol: p=0.014
Amlodipine vs. Metoprolol: p=0.009
Ramipril vs. Amlodipine: p<0.001
%
w
i
t
h
E
v
e
n
t
s
0
10
20
30
40
50
60
Follow-up Month
0
6
12
18
24
30
36
42
48
54
60
Analysis of patients with UP/Cr < 0.22 at baseline
Metoprolol
Ramipril
Amlodipine
AASK Study Group, JAMA. 2002;288:2421-2431
ALLHAT: Chlorthalidone Group had Lowest Average Systolic BP
ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.
Medication Use and BP Control in ALLHAT
Cushman et al. J Clin Hypertens. 2002;4:393-404.
Baseline
6 mo
1 y
3 y
5 y
1 Drug
2 Drugs
?3 Drugs
% Controlled <140/90 mm Hg
% Patients
ALLHAT Primary Endpoint: CHD Death and Nonfatal MI
ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.
ALLHAT: Secondary Endpoints: Stroke
ALLHAT: Stroke (Lisinopril vs Chlorthalidone) Subgroups
ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.
ALLHAT: Secondary Endpoints: Combined CVD
ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.
Favors Lisinopril
ALLHAT: Combined CVD (Lisinopril vs Chlorthalidone) Subgroups
ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.
ALLHAT: Components of Secondary Endpoints*: Heart Failure
*Heart failure is a component of combined CVD.
ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.
ALLHAT: Heart Failure (Amlodipine vs Chlorthalidone) Subgroups
ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.
ALLHAT: Heart Failure (Lisinopril vs Chlorthalidone) Subgroups
ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.
ALLHAT Summary and Conclusions
The ALLHAT trial addressed the most typical patient -- i.e. the 55 y.o. with another risk factor for CAD, many of whom had prior CVD
It brings therapeutics back to 30 years ago, but with a twist -- the chlorthalidone dose was 12.5 mg compared to higher doses used in the 1970s and 1980s
Avoids the diuretic-related hypokalemia issues of the 70s and 80s
Patients treated with diuretics had lower risk of stroke, heart failure and CHD compared to patients taking lisinopril
ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)
For persons over age 50, SBP is a more important than DBP as CVD risk factor.
Starting at 115/75 mmHg, CVD risk doub