disclosure of relationships for william c. cushman, md, over the past 12 months
DESCRIPTION
Is It the Achieved Blood Pressure or Specific Medications that Make a Difference in Outcome, or Is the Question Moot?. William C. Cushman, MD Professor, Preventive Medicine and Medicine University of Tennessee College of Medicine Chief, Preventive Medicine VA Medical Center, Memphis, Tennessee. - PowerPoint PPT PresentationTRANSCRIPT
Is It the Achieved Blood Pressure or Specific Medications
that Make a Difference in Outcome,
or Is the Question Moot?William C. Cushman, MD
Professor, Preventive Medicine and MedicineUniversity of Tennessee College of Medicine
Chief, Preventive MedicineVA Medical Center, Memphis, Tennessee
3
DISCLOSURE OF RELATIONSHIPS for William C. Cushman, MD, Over the Past 12
Months Type of RelationshipType of Relationship Name of CompanyName of Company
Grant/Research SupportGrant/Research Support Astra-Zeneca, Abbott, Novartis,Astra-Zeneca, Abbott, Novartis,Aventis, King PharmaceuticalsAventis, King Pharmaceuticals
ConsultantConsultant Sanofi-Aventis, Bristol-Myers Squibb, Sanofi-Aventis, Bristol-Myers Squibb, Novartis, Pfizer, Sankyo, Forest, Novartis, Pfizer, Sankyo, Forest, MyogenMyogen
Speakers BureauSpeakers Bureau nonenone
Major Stock ShareholderMajor Stock Shareholder nonenone
Other Support, Other Support, Tangible or IntangibleTangible or Intangible
nonenone
VA Cooperative Morbidity Trial VA Cooperative Morbidity Trial in Hypertensionin Hypertension
39
55
1.4
18
0
15
30
45
60
75
115-129 90-114
Entry Diastolic BP, mm Hg
CV
Ev
en
ts (
%)
Placebo Active
Stopped afterStopped after1.5 years1.5 years
Stopped afterStopped after3.3 yrs3.3 yrs
96% RR96% RR
67% RR67% RR
Blood pressure (BP) goal: DBP <90 mm Hg.Blood pressure (BP) goal: DBP <90 mm Hg.
Therapy: HCTZ + reserpine + hydralazine.Therapy: HCTZ + reserpine + hydralazine.
NNT = 2.7 for both.NNT = 2.7 for both.
RR = risk reduction.RR = risk reduction.
JAMA.JAMA. 1967;202(11):1028-1034. 1967;202(11):1028-1034.
JAMA.JAMA. 1970;213(7): 1143-1152. 1970;213(7): 1143-1152.
(N = 143) (N = 380)
Blood Pressure Levels* and Event Blood Pressure Levels* and Event Reduction Reduction
in Selected Clinical Trialsin Selected Clinical TrialsTrialTrial Baseline BPBaseline BP Treated BPTreated BP Event Event ↓↓
ActiveActive ControlControl
HDFPHDFP 159/101 159/101 131/86131/86 142/91142/91 17% - mortality17% - mortality
SHEPSHEP 170/77170/77 144/68144/68 155/73155/73 36% - stroke36% - stroke
Syst-EURSyst-EUR 174/86174/86 151/79151/79 161/84161/84 42% - stroke42% - stroke
PROGRESSPROGRESS 147/86147/86 134/78134/78 143/82143/82 28% - stroke28% - stroke
PROGRESS - HTNPROGRESS - HTN 159/93159/93 138/81138/81 146/84146/84 32% - stroke32% - stroke
HOPEHOPE 139/79139/79 135/76135/76 138/78138/78 22% - 22% - CVDCVD
* mm HgHypertension Detection and Follow-up Program (HDFP). JAMA. 1979;242(23):2562-2571. Systolic
Hypertension in the Elderly Program (SHEP) Cooperative Research Group. JAMA. 1991;265(24):3255-3264. Systolic Hypertension in Europe Trial (Syst-EUR) Investigators. Lancet. 1997;350:757-764.
Perindopril Protection Against Recurrent Stroke Study (PROGRESS) Collaborative Group. Lancet. 2001;358(9287):1033-1041. Heart Outcomes Prevention Valuation Study (HOPE) Investigators. N Engl J
Med. 2000;342:145-153.
Low-dose Diuretics versus PlaceboLow-dose Diuretics versus Placebo
CHDCHD 0.790.79 0.69-0.920.69-0.92 0.0020.002
Heart failureHeart failure 0.510.51 0.42-0.620.42-0.62 <0.001<0.001
StrokeStroke 0.710.71 0.63-0.810.63-0.81 <0.001<0.001
CVD eventsCVD events 0.760.76 0.69-0.830.69-0.83 <0.001<0.001
CVD mortalityCVD mortality 0.810.81 0.73-0.920.73-0.92 0.0010.001
Total mortalityTotal mortality 0.900.90 0.84-0.960.84-0.96 0.0020.002
OutcomeOutcome RRRR 95% CI95% CI PP
0.400.40 0.650.65 0.900.90 1.151.15 1.401.40
Low-dose diuretics better Low-dose diuretics worseLow-dose diuretics better Low-dose diuretics worse
Network Meta-analysis Network Meta-analysis of Antihypertensive Drugsof Antihypertensive Drugs
Psaty BM et al. JAMA. 2003;289:2534-2544.
Systolic blood pressure difference between randomised groups (mmHg).
Rel
ativ
e ri
sk o
f st
roke
Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet. 2003;362:1527-1535.
Rel
ativ
e ri
sk o
f C
VD
0.25
0.50
0.75
1.00
1.25
1.50
Rel
ativ
e ri
sk o
f h
ear t
fa
ilure
0.25
0.50
0.75
1.00
1.25
1.50
-10 -8 -6 -4 -2 0 2 4
BP Reduction and Major Cardiovascular BP Reduction and Major Cardiovascular OutcomesOutcomes
-10 -8 -6 -4 -2 0 2 4
Rel
ativ
e ri
sk o
f C
HD
StrokeStroke
CHDCHDHeart FailureHeart Failure
CVDCVD
MRC in the Elderly:MRC in the Elderly:Mean Level of BP by Sex and Mean Level of BP by Sex and
TreatmentTreatment
140
150
160
170
180
190
140
150
160
170
180
190
70
75
80
85
90
95
70
75
80
85
90
95
Mea
n sy
stol
ic B
PM
ean
dias
tolic
BP
Men Women
Placebo-blockerDiuretic
MRC Working Party. BMJ. 1992;304:405-412.
Interval from entry (months)Interval from entry (months)
MRC in the Elderly: MRC in the Elderly: Effects of Treatment on Stroke Effects of Treatment on Stroke
IncidenceIncidence
0
1
2
3
4
5
6
7
8
0 1 2 3 4 5 6 7
Cu
mu
lati
ve %
eve
nts
Interval from entry (years)
Treatment vs Placebo, Treatment vs Placebo, PP = 0.04 (RR = 25%) = 0.04 (RR = 25%)
N = 4396 N = 4396
MRC Working Party. BMJ. 1992;304:405-412.
Diuretic vs Diuretic vs ββ-blocker,-blocker,PP = 0.33 = 0.33
Placebo-blockerDiuretic
MRC in the Elderly: MRC in the Elderly: Effects of Treatment on Coronary Effects of Treatment on Coronary
EventsEvents
0
2
4
6
8
10
0 1 2 3 4 5 6 7
Cu
mu
lati
ve %
eve
nts
Interval from entry (years)
Treatment vs Placebo, Treatment vs Placebo, PP = 0.08 (RR = 19%) = 0.08 (RR = 19%)
Diuretic vs Diuretic vs ββ-blocker,-blocker,PP = 0.006 = 0.006
N = 4396 N = 4396
Placebo-blockerDiuretic
MRC Working Party. BMJ. 1992;304:405-412.
25.2 24.6
17.4
0
5
10
15
20
25
30
Placebo Atenolol HCTZ/amiloride
Randomized Group
CV
D E
ve
nts
/1,0
00
pt-
yrs
MRC in the Elderly: Effects of MRC in the Elderly: Effects of Treatment on Cardiovascular EventsTreatment on Cardiovascular Events
Diuretic vs Diuretic vs ββ-blocker,-blocker,PP = 0.007 = 0.007
N = 4396 N = 4396
MRC Working Party. BMJ. 1992;304:405-412.
12
90% previously treated10% untreated
42,418 high-riskhypertensive patients
Chlorthalidone12.5-25 mg
Amlodipine2.5-10 mg
Lisinopril10-40 mg
Doxazosin1-8 mg
N=15,255 N=9,048 N=9,054 N=9,061
Atenolol28.0%
Clonidine10.6%
Reserpine4.3%
Hydralazine10.9%
Hypertension TrialHypertension TrialALLHAT
STEP 2 AND 3 AGENTSSTEP 2 AND 3 AGENTS
STEP 1 AGENTS (Double-blind)STEP 1 AGENTS (Double-blind)
13
ALLHAT: Doxazosin vs ALLHAT: Doxazosin vs ChlorthalidoneChlorthalidone
SBP Results by Treatment GroupSBP Results by Treatment Group
130
135
140
145
150
0 6 12 18 24 30 36 42 48
Months
mm
Hg
Chlorthalidone Doxazosin
There were no There were no differences in DBP.differences in DBP.
ALLHAT Collaborative Research group. JAMA. 2000;283:1967-1975
BLBL 6M6M 1Y1Y 2Y2Y 4Y4Y
DOXDOX 146.3146.3 141.1141.1 140.1140.1 138.2138.2 137.4137.4
CTDCTD 146.2146.2 138.2138.2 136.9136.9 135.9135.9 135.3135.3
1414
Relative Risk and 95% Confidence IntervalsRelative Risk and 95% Confidence Intervals
Final Outcomes Final Outcomes ResultsResults
Doxazosin vs. Chlorthalidone
Favors Doxazosin Favors ChlorthalidoneFavors Doxazosin Favors Chlorthalidone0.500.50 11 22 33
CHD
All-Cause Mortality
Combined CHD
Stroke, p=0.001
Heart Failure, p<0.001
Combined CVD, p<0.001 1.20 (1.13 - 1.27)
1.80 (1.61 - 2.02)
1.26 (1.10 - 1.46)
1.07 (0.99 - 1.16)
1.03 (0.94 - 1.13)
1.03 (0.92 - 1.15)
ALLHAT Collaborative Research group. Hypertension. 2003;42:239-246.
ALLHATALLHAT
15
Estimated BP Effect on RR Estimated BP Effect on RR DifferencesDifferences
• A 3 mm Hg higher SBP in the doxazosin group could explain a 10% to 20% difference in HF* but not an 80% difference in risk.
• 3 mm Hg could account for 15-20% increase in stroke risk**—26% was observed.
• Thus, the observed BP differential may explain much of the stroke, but not HF, differences observed between chlorthalidone and doxazosin in ALLHAT.
* Based on SHEP and Syst-EUR.** Based on meta-analysis of all diuretic/-blocker trials.
ALLHAT Collaborative Research group. JAMA. 2000; 283:1967-1975; Hypertension. 2003;42:239-246.
16
Doxazosin vs Doxazosin vs Chlorthalidone:Chlorthalidone:
Heart Failure, Adjusting* for BPALLHAT
ALL HFALL HF
RR (95% CI)RR (95% CI)
Hosp./Fatal HFHosp./Fatal HF
RR (95% CI)RR (95% CI)
As randomizedAs randomized2.042.04††
(1.79, 2.32)(1.79, 2.32)
1.831.83††
(1.58, 2.13)(1.58, 2.13)
AdjustedAdjusted2.002.00††
(1.72, 2.32)(1.72, 2.32)
1.801.80††
(1.51, 2.13)(1.51, 2.13)
*Adjusted for BL SBP/DBP and FU SBP/DBP
Davis BR et al. Ann Intern Med. 2002;137:313-320.
†† PP < 0.001 < 0.001
17
0
0.5
1
1.5
2
140/90 mm Hg <140/90 mm Hg
Rat
e /1
00p
t-yr
s
Chlorthalidone Doxazosin
Doxazosin vs Chlorthalidone:Doxazosin vs Chlorthalidone:Heart Failure Beyond 1 Yr Heart Failure Beyond 1 Yr
by BP Level at 1 Yrby BP Level at 1 Yr
RR=1.17RR=1.17RR=1.63*RR=1.63*
Davis BR et al. Ann Intern Med. 2002;137:313-320.
RR = hazard ratio (doxazosin/chlorthalidone)RR = hazard ratio (doxazosin/chlorthalidone)*CI = 1.20-2.05*CI = 1.20-2.05
≥≥
18 BP Levels by Treatment Group BP Levels by Treatment Group for Chlorthalidone, Amlodipine, and for Chlorthalidone, Amlodipine, and
LisinoprilLisinopril
BP <140/90 mm Hg at 5 yrs: Chlorthalidone 68% Amlodipine 66% Lisinopril 61%
ALLHAT Collaborative Research group JAMA. 2002;288:2981-2997.
~2 mm Hg lower in2 mm Hg lower inchlorthalidone vs chlorthalidone vs lisinopril grouplisinopril group
~1 mm Hg lower in amlodipine group
19
Major OutcomesMajor OutcomesRelative Risks and 95% Confidence Intervals
Amlodipine/Chlorthalidone
0.50 1 2
ESRD 1.12 (0.89-1.40)
Heart Failure 1.38 (1.25-1.52)
Combined CVD 1.04 (0.99-1.09)
Stroke 0.93 (0.82-1.06)
All-Cause Mortality 0.96 (0.89-1.02)
CHD 0.98 (0.90-1.07)
Favors FavorsAmlodipine Chlorthalidone
Lisinopril/ChlorthalidoneLisinopril/Chlorthalidone
0.500.50 11 22
1.11 (0.88-1.38)1.11 (0.88-1.38)
1.19 (1.07-1.31)1.19 (1.07-1.31)
1.10 (1.05-1.16)1.10 (1.05-1.16)
1.15 (1.02-1.30)1.15 (1.02-1.30)
1.00 (0.94-1.08)1.00 (0.94-1.08)
0.99 (0.91-1.08)0.99 (0.91-1.08)
Favors FavorsLisinopril Chlorthalidone
ALLHAT
ALLHAT Collaborative Research group JAMA. 2002; 288: 2981-2997.
1.29 (0.94 - 1.75)1.29 (0.94 - 1.75)ESRDESRD
1.32 (1.11 - 1.58)1.32 (1.11 - 1.58)Heart FailureHeart Failure
1.40 (1.17 - 1.68)1.40 (1.17 - 1.68)Stroke*Stroke*
1.19 (1.09 - 1.30)1.19 (1.09 - 1.30)Combined CVD*Combined CVD*
1.06 (0.95 - 1.18)1.06 (0.95 - 1.18)All-Cause MortalityAll-Cause Mortality
1.10 (0.94 - 1.28)1.10 (0.94 - 1.28)CHDCHD
Favors FavorsFavors FavorsLisinopril ChlorthalidoneLisinopril Chlorthalidone
0.500.50 11 22
0.93 (0.67 - 1.30)0.93 (0.67 - 1.30)
1.15 (1.01 - 1.30)1.15 (1.01 - 1.30)
1.00 (0.85 - 1.17)1.00 (0.85 - 1.17)
1.06 (1.00 - 1.13)1.06 (1.00 - 1.13)
0.97 (0.89 - 1.06)0.97 (0.89 - 1.06)
0.94 (0.85 - 1.05)0.94 (0.85 - 1.05)
0.50 1 2 0.50 1 2
Only Subgroup Differences:Only Subgroup Differences:Lisinopril vs Chlorthalidone in Lisinopril vs Chlorthalidone in Blacks/Non-Blacks for CVD & Blacks/Non-Blacks for CVD &
Stroke Stroke BlacksBlacks Non-BlacksNon-Blacks
ALLHATALLHAT
Favors FavorsFavors FavorsLisinopril ChlorthalidoneLisinopril Chlorthalidone
Wright JT et al. JAMA. 2005; 293: 1595-1608. * Significant interaction* Significant interaction
21
Cumulative Event Rates for Heart Cumulative Event Rates for Heart Failure Failure by ALLHAT Treatment Group for by ALLHAT Treatment Group for Year 1Year 1
ALLHATALLHAT
Cu
mu
lati
ve H
F R
ate
Cu
mu
lati
ve H
F R
ate
Years to HFYears to HF
00 .5.5 1100
.01.01
..0202
ChlorthalidoneChlorthalidone
AmlodipineAmlodipine
LisinoprilLisinopril
RR (95% CI)RR (95% CI) PP value value
A/CA/C 2.32 (1.83-2.94)2.32 (1.83-2.94) <.001<.001
L/CL/C 2.22 (1.75-2.82)2.22 (1.75-2.82) <.001<.001
Davis, et al. Circulation. 2006;113:2201-2210.
22
0
2
4
6
8
Chlorthalidone Amlodipine Lisinopril
5 Y
r E
ven
t R
ate/
100
140/90 mm Hg <140/90 mm Hg
Heart Failure Beyond 1 Yr by BP Level at 1 Heart Failure Beyond 1 Yr by BP Level at 1 Yr in Chlorthalidone, Amlodipine and Yr in Chlorthalidone, Amlodipine and
Lisinopril GroupsLisinopril Groups
RR U/C RR U/C = 1.41*= 1.41*
ALLHAT. Unpublished data. 2006.
≥≥
RR U/C = hazard ratio uncontrolled/controlledRR U/C = hazard ratio uncontrolled/controlled*p<0.001, **p=0.017, *p<0.001, **p=0.017, ††p=0.023p=0.023
RR U/CRR U/C= 1.29= 1.29††
RR U/C RR U/C = 1.27**= 1.27**
23
0
2
4
6
8
140/90 mm Hg <140/90 mm Hg
5 Y
r E
ven
t R
ate/
100
Chlorthalidone Amlodipine Lisinopril
Amlodipine and Lisinopril vs Amlodipine and Lisinopril vs Chlorthalidone:Chlorthalidone:
Heart Failure Beyond 1 Yr by BP Level at Heart Failure Beyond 1 Yr by BP Level at 1 Yr1 Yr
RR A/C RR A/C = 1.16= 1.16
RR A/CRR A/C= 1.30*= 1.30*
ALLHAT. Unpublished data. 2006.
≥≥
RR = hazard ratioRR = hazard ratio *p<0.01*p<0.01
RR L/CRR L/C= 0.92= 0.92
RR L/CRR L/C= 1.01= 1.01
24 BP Differences: BP Differences: Lisinopril versus Lisinopril versus ChlorthalidoneChlorthalidone
Mean follow-up SBP for L versus CMean follow-up SBP for L versus C 2 mm Hg higher2 mm Hg higher——all participantsall participants 4 mm Hg higher4 mm Hg higher——Black participantsBlack participants
Adjustment for follow-up SBP/DBP as time-Adjustment for follow-up SBP/DBP as time-dependent covariates in a Cox regression model dependent covariates in a Cox regression model slightly reduced the relative risks, but they slightly reduced the relative risks, but they remained statistically significant.remained statistically significant. Stroke (1.15 Stroke (1.15 →→ 1.12) & HF (1.20 1.12) & HF (1.20 →→ 1.17), overall 1.17), overall Stroke (1.40 Stroke (1.40 →→ 1.35) & HF (1.32 1.35) & HF (1.32 →→ 1.26), for 1.26), for
BlacksBlacks
ALLHAT
ALLHAT Collaborative Research group JAMA. 2002; 288: 2981-2997.
25
Prospective observational studies predict that 2 Prospective observational studies predict that 2 mm Hg difference mm Hg difference →→ 9% higher stroke mortality 9% higher stroke mortality and 6% higher HF mortality, versus 15 and 19% and 6% higher HF mortality, versus 15 and 19% higher risk (fatal + nonfatal events) observed in higher risk (fatal + nonfatal events) observed in ALLHAT.ALLHAT.
Based on same data, 4 mm Hg difference in Based on same data, 4 mm Hg difference in blacks would predict 19% higher stroke mortality blacks would predict 19% higher stroke mortality and 14% higher HF mortality, versus 40% and and 14% higher HF mortality, versus 40% and 32% higher risk (fatal + nonfatal events) 32% higher risk (fatal + nonfatal events) observed in ALLHAT.observed in ALLHAT.
BP Differences: BP Differences: Lisinopril versus Lisinopril versus ChlorthalidoneChlorthalidone
(continued)(continued)
ALLHAT
ALLHAT Collaborative Research group JAMA. 2002; 288: 2981-2997.
26
0.5 0.5 1.0 1.0 2.02.0
Cardiovascular Events and Total Cardiovascular Events and Total Mortality in SCOPE and LIFEMortality in SCOPE and LIFE
Lithel H et al.Lithel H et al. J Hypertens J Hypertens. 2003;21:875–886.. 2003;21:875–886.
Relative riskRelative risk
Major CV event Major CV event SCOPESCOPELIFELIFE
CV death CV death SCOPESCOPELIFELIFE
Fatal/non-fatal stroke Fatal/non-fatal stroke SCOPESCOPELIFELIFE
Fatal/non-fatal MI Fatal/non-fatal MI SCOPESCOPELIFELIFE
Total Mortality Total Mortality SCOPESCOPELIFELIFE
Favors ATFavors AT11 blockade blockade Favors controlFavors control
There was little BP There was little BP difference in LIFE and difference in LIFE and 3.2/1.6 mm Hg lower BP 3.2/1.6 mm Hg lower BP in the candesartan in the candesartan group in SCOPE, but group in SCOPE, but event RRs were similarevent RRs were similar
LIFE (n=9193): losartan vs atenololLIFE (n=9193): losartan vs atenololSCOPE (n=4964): candesartan vs placeboSCOPE (n=4964): candesartan vs placebo
2727
Initial Combinations of Initial Combinations of Medications Medications
for Management of Hypertension*for Management of Hypertension*
Initial Combinations of Initial Combinations of Medications Medications
for Management of Hypertension*for Management of Hypertension*DiureticsDiuretics
ACE inhibitorsACE inhibitorsoror
ARBsARBs
CalciumCalciumantagonistsantagonists
* Compelling indications may modify this.
Achieved Blood Pressure Achieved Blood Pressure Versus Specific Medications: Effects on Versus Specific Medications: Effects on
OutcomesOutcomes
Achieved Blood Pressure Achieved Blood Pressure Versus Specific Medications: Effects on Versus Specific Medications: Effects on
OutcomesOutcomes
Drugs with very different physiologic effects may
logically have different effects on organs/events
independent of BP.
In ALLHAT and other trials, adjustment of clinical
event rates based on observational analyses of BP
differences are limited by variability of BP
measurement and absence of non-clinic BPs.
Outcome differences in many studies are not fully
explained by clinically detectable BP differences.
BP control IS of paramount importance, but it
DOES also matter which drugs we use.
Achieved Blood Pressure Achieved Blood Pressure Versus Specific Medications: Effects on Versus Specific Medications: Effects on
OutcomesOutcomes(continued)(continued)
Achieved Blood Pressure Achieved Blood Pressure Versus Specific Medications: Effects on Versus Specific Medications: Effects on
OutcomesOutcomes(continued)(continued)