Did Type of Prior Antihypertensive Therapy Influence the Heart Failure

Results in ALLHAT?

Richard Grimm, Barry Davis, Linda Piller, Karen Margolis, Joshua Barzilay, Richard Dart, James Graumlich, Robert Murden, Otelio Randall, Katrina Sawyer, for the ALLHAT Collaborative Research Group

ALLHAT

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

Secondary Outcomes

• All-cause mortality

• Stroke

• Combined CHD – nonfatal MI, CHD death, coronary revascularization, hospitalized angina

• Combined CVD – combined CHD, stroke, lower extremity revascularization, treated angina, fatal / hospitalized / treated CHF

• All components of CVD – prespecified

ALLHAT

ALLHAT Criteria for HF Evaluation*

Must have one from each category:

Category “A” Category “B”Paroxysmal nocturnal dyspnea Rales

Dyspnea at rest 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

ALLHAT

Heart Failure Data Collection

• Hospitalized nonfatal – discharge summary

• Hospitalized fatal – death certificate, discharge summary

• Nonhospitalized fatal – death certificate

• Nonhospitalized nonfatal (treated) – checkbox

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

ALLHAT

--Queries to clinics if diagnosis questionable

Background: Hospitalized and Fatal Heart Failure

HR P value 95% CI

A vs. C* 1.35 < 0.001 1.21-1.50

L vs. C* 1.10 0.11 0.98-1.23

D vs. C† 1.66 < 0.001 1.46-1.89

ALLHAT

*JAMA 2002;288:2981-2997 †Hypertension 2003;42:239-246

Cumulative Event Rates for Hospitalized/Fatal Heart Failure by

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 1.10 0.98-1.23

ChlorthalidoneAmlodipineLisinopril

ALLHAT

Cumulative Event Rates for Hospitalized/ Fatal Heart Failure by Treatment Group

RR (95% CI) p value

D/C 1.66 (1.46-1.89) <0.001

ALLHATC

um

ula

tive

Fat

al+

Ho

sp H

F E

ven

t R

ate

Years to Fatal or Hosp HF

0 1 2 3 4 5

0

.03

.06

.09

.12

Chlorthalidone

Doxazosin

ALLHAT Question to be Addressed by these Analyses

Kaplan-Meier curves for the HF outcome show an early divergence of the curves for chlorthalidone vs. amlodipine, lisinopril, or doxazosin.

Question: Can the heart failure findings in part be explained by discontinuing antihypertensive medications such as diuretics and ACE-inhibitors upon entry into ALLHAT?

HF Validation Study – BP Meds at Entry

• 2091 pts w/ 3032 hosp/fatal HF cases centrally reviewed

• Criteria – ALLHAT, Framingham, reviewer judgment

• 70-84% confirmed on central review (similar across Rx groups; Rx group effects larger in confirmed cases)

• Requested information about pts’ BP drug use at trial entry just before end of study

• Received information for 1418 pts (~ 2/3 total) population for this study

ALLHAT

ALLHAT

ID Label

ALLHAT BLOOD PRESSURE MEDICATION AT STUDY ENTRY

ReceivedALLHAT

Baseline Characteristics

HF Ppts with BP Med Data

Total HF Ppts

Number 1418 2091

Age, mean, yr 70.3 70.1

Female, % 43.9 43.3

Ethnicity

White, % 62.4 61.1

Black, % 33.2 34.8

RX at baseline, % 93.6 93.5

BP, mean, mg Hg 148.5 / 82.0 148.5 / 81.9

ALLHAT

Baseline CharacteristicsALLHAT

HF Ppts with BP Med Data

Total HF Ppts

Hx of CHD, % 38.4 37.2

Hx of coro. revasc., % 23.1 21.5

Hx of diabetes, % 47.5 49.4

Cigarette smoker,% 15.3 19.1

LVH on ECG, % 18.0 18.8

T-chol, mean, mg/dL 217.8 216.9

Fast. trig., mean, mg/dL 181.4 182.2

Source of Entry Drug Information

Source of information Distribution

ALLHAT RZ records 66.2%

Other medical chart 53.7%

Asked patient 1.6%

Other 4.1%

ALLHAT

Note: More than one source was used for some patients.

Heart Failure During ALLHAT: Percent of Patients on Prior BP Meds

Prior BP Med C A L D Total

Diuretics 36 41 37 42 39

CCB 46 47 45 49 47

ACE-I 38 39 35 34 37

Beta Blockers 17 14 22 16 17

Total # of ppts*† 460 369 285 304 1418

*Participants may have been on one, multiple, or no prior BP meds.†Refers to participants with HF during ALLHAT and for whom prior medication data is available.

ALLHAT

Heart Failure Within the First Year Following Randomization: Percent

of Patients on Prior BP Meds

ALLHAT

Prior BP Med C A L D Total

Diuretics 45 47 52 49 48

CCB 35 44 51 46 45

ACE-I 43 42 36 40 40

Beta Blockers 10 11 24 10 14

Total # of ppts*† 49 79 75 99 302

*Participants may have been on one, multiple, or no prior BP meds. †Refers to participants with HF during first year following randomization and for whom prior medication data is available.

Cumulative Event Rates for Heart Failure by Prior Meds Status

ALLHAT

RR (95% CI) p value

Y/N 1.48 (1.25-1.75) <.001

C

um

ula

tive

HF

Rat

e

Years to HF

0 1 2 3 4 5 6 70

.03

.06

.09

No Prior Meds

Prior Meds

Case-Only Analyses

• Cannot do analyses on entire population since pre-ALLHAT BP meds data was only collected for HF cases.

• A technique know as case-only analyses will allow us to examine if there was interaction.

• Do “full” analyses and case-only analyses provide comparable results?

ALLHAT

Interactions of Step 1 Treatment and Use of ANY Prior BP Meds for

Occurrence of HF*

Full logistic Case-only

Year 1 OR P OR P

A vs C 1.81+ 0.29 1.83 0.28

L vs C 3.52 0.07 3.49 0.07

D vs C 1.70 0.30 1.69 0.30

ALLHAT

* All hospitalized/fatal heart failure cases

+ OR (A vs. C) = 2.32 (1.75, 3.08) for those on meds; 1.28 (.44, 3.71) for those not on meds

Interaction of Treatment (L vs. C) and Specific Prior BP Meds

for Occurrence of HF

Univariate Multivariate*

Prior BP Meds OR 95% CI OR 95% CI

Diuretic 1.33 0.65-2.74 1.57 0.73-3.38

ACE-I 0.75 0.36-1.57 1.03 0.47-2.29

CCB 1.93 0.92-4.06 2.51 1.13-5.60

Beta blocker 2.78 0.96-8.07 3.30 1.08-10.07

ALLHAT

* Controlled for use of other classes of BP drugs

Interaction of Treatment (A vs. C) and Specific Prior BP Meds

for Occurrence of HFALLHAT

Univariate Multivariate*

Prior BP Meds OR 95% CI OR 95% CI

Diuretic 1.08 0.53-2.21 1.17 0.55-2.47

ACE-I 0.96 0.47-1.97 1.06 0.49-2.28

CCB 1.50 0.72-3.13 1.68 0.77-3.68

Beta blocker 1.13 0.36-3.60 1.42 0.43-4.72

* Controlled for use of other classes of BP drugs

Potential Confounders

• Confounders by indication: why was the patient placed on a specific class of drug prior to participation in the study?

• Use of additional meds during the study: what conditions developed that caused the patient to be placed on additional meds?

• Possibility of misclassification of drugs used prior to study entry

• Missing data: approximately one third of heart failure cases lacked information on specific drugs used prior to entry into ALLHAT

ALLHAT

Conclusions

• Among the HF cases, CCB’s were the most used BP drug prior to entry into ALLHAT, followed by diuretics and ACE inhibitors.

• Pts on any prior BP med (vs. none) were at higher risk of developing HF.

• These findings are noteworthy for those on CCB’s and BB’s at entry (confounding by indication?).

• These findings suggest that the type of BP drug at entry is not a major determinant of the HF results.

ALLHAT