Role of Diuretics in the Prevention of Heart Failure The Antihypertensive and LipidLowering Treatmen

1
Role of Diureticsin the Prevention of Heart
Failure -The Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial
Davis BR, Piller LB, Cutler JA, et al.
Circulation 2006.1132201-2210.
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)

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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).

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Hypertension Controland Heart Failure

• A metaanalysis 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).

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.

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Randomized Design of ALLHAT Hypertension Trial
42,418 high-risk hypertensive patients
90 previously treated 10 untreated
STEP 1 AGENTS
Chlorthalidone 12.5-25 mg
Lisinopril 10-40 mg
Doxazosin 1-8 mg
Amlodipine 2.5-10 mg
N9,061
N9,054
N9,048
N15,255
Other AHT Drugs
STEP 2 AND 3 AGENTS (5 years)
Atenolol 28.0
Clonidine 10.6
Reserpine 4.3
Hydralazine 10.9
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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).

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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

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ALLHAT Criteria for HF Evaluation
ALLHAT Manual of Operations, 5.3.4 adopted from
the SHEP trial
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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

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Heart FailureValidation Study
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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 ? 2 mg/dL, require diuretics, CCB, ACEI, or ABs
  for non-BP indication

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Step 1Treatment Protocol
Step 2/3 drugs atenolol, reserpine, clonidine,
hydralazine Non-study drugs all other
antihypertensive medications
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Baseline Characteristics
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Hospitalized/ Fatal Heart Failure by ALLHAT
Treatment Group



.1
.08
Chlorthalidone Amlodipine Lisinopril
.06
Cumulative Event Rate
.04
.02
0
0
1
2
3
4
5
6
7
Years
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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) was utilized.

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Hospitalized/ Fatal Heart Failure by ALLHAT
Treatment Group Within 1 Year and 1 Year
.1
.02
.08
.06
Cumulative Hosp/Fatal HF Rate
.01
.04
.02
0
0
0
1
2
3
4
5
6
7
0
.5
1

Years to Hosp/Fatal HF
Years to Hosp/Fatal HF

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Hospitalized/fatal HF in Subgroups - Amlodipine /
Chlorthalidone Relative Risks from Baseline to 1
Year of Follow-up
Favors Amlodipine
Favors Chlorthalidone
Relative Risk (95 CI)
2.22 (1.69 - 2.91)
Total
2.89 (1.62 - 5.17)
Age 2.06 (1.51 - 2.80)
Age 65
2.12 (1.49 - 3.01)
Non-Black
2.37 (1.55 - 3.63)
Black
2.27 (1.56 - 3.30)
Men
2.17 (1.46 - 3.21)
Women
2.71 (1.83 - 4.02)
Diabetic
1.83 (1.25 - 2.67)
Non-Diabetic
0.50
1
2
3
4
5
6
19
Hospitalized/fatal HF in Subgroups - Amlodipine /
Chlorthalidone Relative Risks After 1 Year of
Follow-up
Favors Amlodipine
Favors Chlorthalidone
Relative Risk (95 CI)

1.22 (1.08 - 1.38)
Total
1.38 (1.10 - 1.73)
Age 1.17 (1.02 - 1.35)
Age 65
1.20 (1.04 - 1.39)
Non-Black
1.28 (1.03 - 1.58)
Black
1.28 (1.09 - 1.50)
Men
1.16 (0.97 - 1.39)
Women
1.23 (1.04 - 1.46)
Diabetic
1.21 (1.02 - 1.43)
Non-Diabetic
0.50
1
2
3
4
5
6
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Hospitalized/fatal HF in Subgroups - Lisinopril /
Chlorthalidone Relative Risks from Baseline to 1
Year of Follow-up
Relative Risk (95 CI)
Favors Lisinopril
Favors Chlorthalidone
2.08 (1.58 - 2.74)
Total
2.53 (1.39 - 4.59)
Age 1.98 (1.45 - 2.70)
Age 65
2.04 (1.43 - 2.90)
Non-Black
2.15 (1.39 - 3.33)
Black
1.80 (1.22 - 2.67)
Men
2.40 (1.63 - 3.54)
Women
1.99 (1.31 - 3.05)
Diabetic
2.16 (1.50 - 3.10)
Non-Diabetic
0.50
1
2
3
4
5
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Hospitalized/fatal HF in Subgroups - Lisinopril /
Chlorthalidone Relative Risks After 1 Year of
Follow-up
Relative Risk (95 CI)
Favors Lisinopril
Favors Chlorthalidone
0.50
1
2
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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

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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

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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

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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

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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

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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.

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Open-Label ACEI and Atenolol Use
29
Open-Label Diuretic and CCB Use
30
Diuretic, ACEI,or Atenol Use
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).
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

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All-Cause Mortality
Chlorthalidone Amlodipine Lisinopril
.6
.5
.4
Cumulative Event Rate
.3
.2
.1
0
0
1
2
3
4
5
6
7
Years from Hospitalized HF to Death
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.

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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
  (n1314).
• 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 (n1256).

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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

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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

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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.

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Extra Slides
40
Placebo-Controlled Trials

• Most placebo-controlled trial have used diuretics
  and/or ß-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.

41
Active-Controlled Trials

• VALUE
• STOP Hypertension-2
• ANBP2
• INVEST
• CONVINCE CCB or diuretic/ß-blocker
• BP reduced similarly, HF 30 more with CCB

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BPLTTC Meta-Analyses

• CCB-based therapies
• NS 20 increase in HF incidence compared with
  placebo
• 33 higher risk of HF compared with
  diuretic/ß-blocker
• ACEI-based therapies
• 18 fewer HF events than with CCB or placebo
• 7 NS higher risk than with diuretic/ ß-blocker
• CCBs less effective in preventing HF than other
  regimens
• ACEI no more effective in preventing HF than
  diuretic/ ß-blocker

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Randomized Designof ALLHAT
Amlodipine Chlorthalidone Doxazosin Lisinopril
High-risk hypertensive patients 55 years
Consent / Randomize (42,418)
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).
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Event Reduction in SHEP, Syst-Eur, and HOPE
SHEP Systolic Hypertension in the Elderly,
n4,736 chlorthalidone Syst-Eur Systolic
Hypertension in Europe, n4,695
nitrendipine HOPE Heart Outcomes Prevention
Evaluation Study, n9,297 ramipril