1

Role of Diureticsin the Prevention of Heart Failure -

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart

Attack Trial

ALLHAT

Davis BR, Piller LB, Cutler JA, et al. Circulation 2006.113:2201-2210.

2

Introduction and Background Heart failure is a major public health problem,

especially in persons 65 years of age and older (= number one reason for hospitalizations in this age group).

Age-adjusted incidence per 100,000 person-years during 1990-1999 was 564 for men and 327 for women, age 65-74 years (NEJM, 2002, Framingham)

Five-year age-adjusted survival rate was only 59% among men and 45% for women.

In 91% of HF cases, hypertension is an antecedent (Framingham, JAMA, 1996)

ALLHATALLHAT

3

Hypertension Controland Heart Failure

• In a meta-analysis of 12 trials of patients with hypertension it was found that, compared to placebo, drug therapy for hypertension prevents over 50% of HF events (Moser, JACC, 1996).

• In another meta-analysis, diuretics and beta-blockers (BB) were equally effective in preventing HF events (Psaty, JAMA, 1997).

ALLHAT

4

Hypertension Controland Heart Failure

• A meta–analysis of active comparator trials found no significant difference between ACE-inhibitors and diuretics for preventing HF; ACE-inhibitors were more efficacious than CCBs (BPLTT Collaboration, Lancet, 2002).

• The INSIGHT trial found that a long-acting nifedipine regimen was associated with a > 2x higher incidence of HF events compared to a diuretic combination (HCTZ/amiolride) (Brown, Lancet, 2000).

ALLHAT

5

Objectives

• Characterize HF in ALLHAT by its antecedent risk factors and underlying conditions.

• Examine occurrence of HF by treatment group overall, in subgroups, and over time.

• Explore relation of initial occurrence of HF to pre-randomization type of BP medication used.

• Explore follow-up BP and use of additional drugs as mediating/modifying factors.

• Examine post-HF mortality overall and by treatment group.

ALLHAT

6

42,418 high-riskhypertensive patients

90% previously treated10% untreated

STEP 1 AGENTSSTEP 1 AGENTS

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

STEP 2 AND 3 AGENTS (5 years)STEP 2 AND 3 AGENTS (5 years)

Atenolol28.0%

Clonidine10.6%

Reserpine4.3%

Hydralazine10.9%

Randomized Design of ALLHAT Hypertension Trial

ALLHAT

Other AHT Drugs

7

Decision to StopDoxazosin Arm

• NHLBI Director accepted recommendation of independent review group to terminate doxazosin arm (early in year 2000), due to:

– Futility of finding a significant difference for primary outcome

– Statistically significant 25 percent higher rate of major secondary endpoint, combined CVD outcomes, along with twofold higher rate of HF

• Detailed HF analyses published (Davis et al. Ann Intern Med 2002).

ALLHAT

8

Heart Failure Data Collection

• Hospitalized nonfatal – discharge summary

• Hospitalized fatal – death certificate, discharge summary

• Nonhospitalized fatal – death certificate

• Nonhospitalized nonfatal (treated) – clinician report

• 100% review of discharge summaries and death certificates by CTC Medical Reviewers

– Queries to clinics if diagnosis questionable

ALLHAT

9

ALLHAT Criteria for HF Evaluation*

Must have one from each category:

Category “A” Category “B”

Paroxysmal nocturnal dyspnea Rales

Dyspnea at rest 2+ ankle edema

NYHA Classification III Tachycardia

Orthopnea Cardiomegaly by CXR

CXR characteristic of CHF

S3 gallop

Jugular venous distention

*ALLHAT Manual of Operations, 5.3.4; adopted from the SHEP trial

ALLHAT

10

Validity of HFOutcome Verified

• Traditional risk factors in agreement with previous studies, e.g., Framingham

• HF Validation Study confirmed original observed treatment differences

– Independent central review using both ALLHAT and Framingham criteria

ALLHAT

11

Heart FailureValidation Study

Criteria % Agreement

ALLHAT 71%

Framingham Heart Study 80%

Reviewers’ judgement 84%

ALLHAT

12

Inclusion/Exclusion Criteria for Antihypertensive Trial

• Men and women > 55 years old

• If untreated: 140/90, 180/110 mm Hg (2 visits)

• If treated: ≤ 160/100 mm Hg (visit 1), ≤ 180/110 mm Hg (visit 2)

–No washout required

• At least one additional cardiovascular risk factor

• Exclude if symptomatic HF or EF < 35%, creatinine 2 mg/dL, require diuretics, CCB, ACEI, or AB’s for non-BP indication

ALLHAT

13

Step 1Treatment Protocol

Step 1 Agent Initial Dose*

Dose 1* Dose 2*

Dose 3*

Chlorthalidone 12.5 12.5 12.5 25

Amlodipine 2.5 2.5 5 10

Lisinopril 10 10 20 40

Doxazosin 1 2 4 8

* mg/day

ALLHAT

Step 2/3 drugs –– atenolol, reserpine, clonidine, hydralazine

“Non-study” drugs –– all other antihypertensive medications

14

Baseline CharacteristicsALLHATHospitalized/Fatal HF During Trial

Yes No Difference p

N 1,773 31,584

Age (mean) 70.3 66.7 +3.6 <0.001

Men, % 55.2% 53.0% +2.2% 0.008

Pre-RZ Treatment, % 93.1% 90.0% +3.1% 0.004

SBP (mean mm Hg) 148.2 146.2 +2.0 <0.001

DBP (mean mm Hg) 81.8 84.1 -2.3 <0.001

Pulse (mean bpm) 74.6 73.5 +1.1 <0.001

Cigarette smoking, % 18.3% 22.1% -3.8 <0.001

Diabetes, % 49.4 35.4 +14.0% <0.001

LVH by ECG, % 18.4% 16.3% +2.1% <0.001

History of CHD, % 37.6% 24.7% +12.9 <0.001

BMI (mean) 30.3 29.7 +0.6 <0.001

15

Hospitalized/ Fatal Heart Failure by ALLHAT Treatment Group

Cu

mu

lati

ve E

ven

t R

ate

Years0 1 2 3 4 5 6 7

0

.02

.04

.06

.08

.1

RR 95% CI

A-C 1.35 1.21-1.50

L-C 1.11 0.99-1.24

A-L 1.23 1.09 – 1.38

ChlorthalidoneAmlodipineLisinopril

ALLHAT

16

Heart Failure Before and After 1 Year

• Observed HF differences were larger earlier in the follow-up.

• The lisinopril group had a lower HF rate than the amlodipine group, but event curves did not separate until later.

• A test of the proportional hazards assumption for Cox regression revealed that RRs were not constant over time. Therefore, a Cox regression that used a time-dependent indicator variable (<=1 year versus >1 year) was utilized.

ALLHAT

17

1 2 3 4 5 6 7

.02

.04

.06

.08

.1

0

Cu

mu

lati

ve H

osp

/Fat

al H

F R

ate

0 .5 1

0

.01

.02

Years to Hosp/Fatal HF

ChlorthalidoneAmlodipineLisinopril

Years to Hosp/Fatal HF

0

Baseline to Year 1

RR 95% CI

A-C 2.22 1.69 – 2.91

L-C 2.08 1.58 – 2.74

A-L 1.07 0.82 – 1.38

> Year 1

RR 95% CI

A-C 1.22 1.08 – 1.38

L-C 0.96 0.85 – 1.10

A-L 1.27 1.10 – 1.46

Hospitalized/ Fatal Heart Failure by ALLHAT Treatment Group Within 1 Year and >1 YearALLHAT

18

1.83 (1.25 - 2.67)Non-Diabetic

2.71 (1.83 - 4.02)Diabetic

2.17 (1.46 - 3.21)Women

2.27 (1.56 - 3.30)Men

2.37 (1.55 - 3.63)Black

2.12 (1.49 - 3.01)Non-Black

2.06 (1.51 - 2.80)Age ≥ 65

2.89 (1.62 - 5.17)Age < 65

2.22 (1.69 - 2.91)Total

0.50 1 2 3 4 5 6

FavorsAmlodipine

FavorsChlorthalidone

Relative Risk(95% CI)

Hospitalized/fatal HF in Subgroups -Amlodipine / Chlorthalidone Relative Risks

from Baseline to 1 Year of Follow-up ALLHAT

19Hospitalized/fatal HF in Subgroups -

Amlodipine / Chlorthalidone Relative Risks After 1 Year of Follow-up

0.50 1 2 3 4 5 6

FavorsAmlodipine

FavorsChlorthalidone

Relative Risk(95% CI)

1.21 (1.02 - 1.43)Non-Diabetic

1.23 (1.04 - 1.46)Diabetic

1.16 (0.97 - 1.39)Women

1.28 (1.09 - 1.50)Men

1.28 (1.03 - 1.58)Black

1.20 (1.04 - 1.39)Non-Black

1.17 (1.02 - 1.35)Age ≥ 65

1.38 (1.10 - 1.73)Age < 65

1.22 (1.08 - 1.38)Total

ALLHAT

20Hospitalized/fatal HF in Subgroups -

Lisinopril / Chlorthalidone Relative Risks from Baseline to 1 Year of Follow-up

2.16 (1.50 - 3.10)

1.99 (1.31 - 3.05)

2.40 (1.63 - 3.54)

1.80 (1.22 - 2.67)

2.15 (1.39 - 3.33)

2.04 (1.43 - 2.90)

1.98 (1.45 - 2.70)

2.53 (1.39 - 4.59)

2.08 (1.58 - 2.74)

0.50 1 2 3 4 5

Relative Risk(95% CI)

FavorsLisinopril

FavorsChlorthalidone

Non-Diabetic

Diabetic

Women

Men

Black

Non-Black

Age ≥ 65

Age < 65

Total

ALLHAT

21

Non-Diabetic

Diabetic

Women

Men

Black

Non-Black

Age ≥ 65

Age < 65

Total

0.93 (0.77 - 1.12)

1.01 (0.84 - 1.22)

0.89 (0.73 - 1.09)

1.02 (0.86 - 1.21)

1.10 (0.88 - 1.37)

0.90 (0.77 - 1.06)

0.97 (0.84 - 1.13)

0.95 (0.74 - 1.23)

0.96 (0.85 - 1.10)

0.50 1 2

Relative Risk(95% CI)

FavorsLisinopril

FavorsChlorthalidone

Hospitalized/fatal HF in Subgroups -Lisinopril / Chlorthalidone Relative Risks

After 1 Year of Follow-upALLHAT

22

HF Development and Relation to Other Outcomes

• HF development associated with:

– 6.6-fold increase in death rate

– 11.7-fold increase in CV death rate

• Previous MI → 5.7-fold increased HF risk

• Of participants with hospitalized HF:

– 72% hospitalized once

– 23.3% hospitalized 2-3 times

– 4.7% hospitalized 4+ times

ALLHAT

23

Why are hazard ratios not constant throughout?

Hypotheses?

• Withdrawal from BP meds used prior to enrollment

• Time course for effect of first-step (primary) drug– Diuretic – immediate?

– ACEI – delayed?

• Addition of step-up meds (esp. anti-HF meds)

• Differences in BP

ALLHAT

24

Prior Use ofAntihypertensive Agents

• Prior medication use associated with HF risk, especially during first year

– RR 1.42 (1.18 – 1.71)

• Relative benefits of chlorthalidone consistent with or without prior antihypertensive medication use

ALLHAT

25

Specific PriorAntihypertensive Agents

• Data not collected within ALLHAT

– Available for 1115 / 1773 HF cases

• Case-only analysis

– No evidence for any statistically significant interaction between prior drug type (e.g., diuretic) and treatment effect for HF, overall or during the first year

ALLHAT

CCB’s 47%

ACEI 37%

Diuretics 39%

26

Immediate vsDelayed Effects

• Do diuretics have a more immediate effect on HF prevention than ACEI or ARB?

– Effect of diuretics begins at trial onset

– Several ACEI vs placebo studies suggest that ACEI effect is not immediate

– VALUE trial – valsartan vs amlodipine – HF similar in first 2 years, strong trend afterward favoring valsartan

ALLHAT

27

Use of Step-upBP Meds

Addition of Step 2 and Step 3 meds

could have contributed to lessening or

cessation of divergence of HF curves

after 1 year.

ALLHAT

28

0.0

5.0

10.0

15.0

20.0

25.0

30.0

Per

cen

t

Chlor - AC 4.8 10.1 14.3

Amlod - AC 5.2 10.6 15.2

Lisin - AC 5.9 11.8 16.0

Chlor - AT 17.3 24.4 28.5

Amlod - AT 16.6 23.5 27.9

Lisin - AT 19.7 24.5 27.9

1 Year 3 Years 5 Years

Open-Label ACEI and Atenolol UseALLHAT

29

0.0

5.0

10.0

15.0

20.0

25.0

30.0

Per

cen

t

Chlor - D 6.0 11.1 16.4

Amlod - D 9.5 16.1 23.5

Lisin - D 9.3 17.1 24.3

Chlor - CCB 4.7 8.8 11.2

Amlod - CCB 4.7 7.9 10.3

Lisin - CCB 7.3 11.8 16.0

1 Year 3 Years 5 Years

Open-Label Diuretic and CCB UseALLHAT

30

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

90.0

100.0

Per

cen

t

Chlor 91.4 89.3

Amlod 27.7 41.7

Lisin 88.9 86.7

1 Year 3 Years

Diuretic, ACEI,or Atenol UseALLHAT

31

BP Results by Treatment Group

Compared to chlorthalidone:

SBP significantly higher in the amlodipine group (~1 mm Hg) and the lisinopril group (~2 mm Hg).

Compared to chlorthalidone:

DBP significantly lower in the amlodipine group (~1 mm Hg).

ALLHAT

32

BP Differences

Adjustment for follow-up SBP as time-dependent covariates in a Cox regression model only slightly modified the relative risks

Amlodipine/chlorthalidone 2.22 2.16 first year, 1.22 1.18 after 1 year

Lisinopril/chlorthalidone 2.08 2.01 first year, 0.96 0.93 after 1 year

ALLHAT

33

Cu

mu

lati

ve E

ven

t R

ate

Years from Hospitalized HF to Death 0 1 2 3 4 5 6 7

0

.1

.2

.3

.4

.5

.6

ChlorthalidoneAmlodipineLisinopril

All-Cause MortalityALLHAT

34

Post-HF Mortality

• Mortality rates after hospitalized HF high relative to those seen in ALLHAT overall

– 25% vs 5% at 2.5 years, respectively

• No significant treatment group differences for post-HF mortality

• The reason that the treatment difference for hospitalized HF did not translate into an effect on total mortality is that only 5.6% of all deaths were attributed to HF.

ALLHAT

35

Heart Failureand Total Mortality

• Lisinopril-chlorthalidone absolute difference in hospitalized HF over 6 years was 0.4%.

– The excess of cases in the lisinopril group = 36 patients.

– Case-fatality rate over average follow-up of 2.5 years = 25%.

– Thus, 9 excess cases of fatal HF would be expected in the lisinopril group. This is fewer than 1% of all deaths in the lisinopril group (n=1314).

• Similar calculations for the amlodipine group:

– 154 excess cases of hospitalized HF

– Estimated number of fatal HF cases was 39, 3% of the amlodipine deaths (n=1256).

ALLHAT

36

Effect on Total Mortality

• HF differences in the trial would not have affected differences in total mortality

– Also noted in the BPLTTC analyses

– Absolute HF risk low

– Increase in RR outweighed by even small reduction in higher absolute risks for stroke and CHD

– Differences in # of HF events during trial result in only very small differences in # of deaths

– ALLHAT post-trial mortality surveillance to examine this further

ALLHAT

37

Conclusions 1

• Chlorthalidone superior to amlodipine in both time periods

• Chlorthalidone superior to lisinopril during the first year

• True for subgroups – age, race, sex, diabetes history

• Other factors could not individually account for all of the observed treatment differences

– Prior antihypertensive meds

– Other open-label BP meds

– Follow-up BP differences

ALLHAT

38

Conclusions 2

• Developing HF is associated with a high mortality rate (~50% at 5 years)

• It may take time for HF differences to translate into detectable mortality differences between treatments

• Diuretics are clearly preferred over CCBs overall and over ACE inhibitors, at least in the short term, in preventing HF.

ALLHAT

39

Extra Slides

40

Placebo-Controlled Trials

• Most placebo-controlled trial have used diuretics and/or β-blockers as active regimens

• Diuretics & ACEI shown to prevent HF in patients with hypertension

– SHEP, HOPE

• CCB vs placebo trials less conclusive

– Syst-Eur

• Meta-analyses – active therapy of hypertension can prevent >40% of HF events

– Psaty, Smith, Siscovick, et al.

ALLHAT

41

Active-Controlled Trials

• VALUE

• STOP Hypertension-2

• ANBP2

• INVEST

• CONVINCE – CCB or diuretic/β-blocker

– BP reduced similarly, HF 30% more with CCB

ALLHAT

42

BPLTTC Meta-Analyses

• CCB-based therapies

– NS 20% increase in HF incidence compared with placebo

– 33% higher risk of HF compared with diuretic/β-blocker

• ACEI-based therapies

– 18% fewer HF events than with CCB or placebo

– 7% NS higher risk than with diuretic/ β-blocker

• CCBs less effective in preventing HF than other regimens

• ACEI no more effective in preventing HF than diuretic/ β-blocker

ALLHAT

43

Randomized Designof ALLHAT

High-risk hypertensive patients ≥ 55 years

Consent / Randomize

(42,418)

Amlodipine

Chlorthalidone

Doxazosin

Lisinopril

Eligible for lipid-lowering

Not eligible for lipid-lowering

Consent / Randomize (10,355)

Pravastatin Usual care

Follow for CHD and other outcomes until death or end of study (up to 8 yr).

ALLHAT

44

Event Reduction in SHEP, Syst-Eur, Event Reduction in SHEP, Syst-Eur, and HOPEand HOPE

-36

-27

-49

-32

-42

-31-32

-20-23 -22

-16-13-14

-29-30

-60

-40

-20

0

Stroke CHD CHF CVD Death

Ris

k R

edu

ctio

n, %

SHEP Syst-Eur HOPE

SHEP: Systolic Hypertension in the Elderly, n=4,736;SHEP: Systolic Hypertension in the Elderly, n=4,736; chlorthalidonechlorthalidoneSyst-Eur: Systolic Hypertension in Europe, n=4,695;Syst-Eur: Systolic Hypertension in Europe, n=4,695; nitrendipinenitrendipineHOPE: Heart Outcomes Prevention Evaluation Study, n=9,297;HOPE: Heart Outcomes Prevention Evaluation Study, n=9,297; ramiprilramipril