1 1 ALLHAT Role of Diuretics in 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 :
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 personyears during was 564 for men and 327 for women, age 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) 2
3 3 ALLHAT Hypertension Control and 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 betablockers (BB) were equally effective in preventing HF events (Psaty, JAMA, 1997).
4 4 ALLHAT Hypertension Control and Heart Failure A meta analysis of active comparator trials found no significant difference between ACEinhibitors and diuretics for preventing HF; ACEinhibitors 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 5 ALLHAT 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.
6 Randomized Design of ALLHAT Hypertension Trial 6 42,418 high-risk hypertensive patients 90% previously treated 10% untreated STEP 1 AGENTS Chlorthalidone mg Amlodipine mg Lisinopril mg Doxazosin 1-8 mg N=15,255 N=9,048 N=9,054 N=9,061 Atenolol 28.0% STEP 2 AND 3 AGENTS (5 years) Clonidine 10.6% Reserpine 4.3% Hydralazine 10.9% Other AHT Drugs
7 7 ALLHAT Decision to Stop Doxazosin 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).
8 8 ALLHAT 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
9 9 ALLHAT Category A ALLHAT Criteria for HF Evaluation* Must have one from each category: Category B Paroxysmal nocturnal dyspnea Dyspnea at rest NYHA Classification III Orthopnea Rales 2+ ankle edema Tachycardia Cardiomegaly by CXR CXR characteristic of CHF S 3 gallop Jugular venous distention *ALLHAT Manual of Operations, 5.3.4; adopted from the SHEP trial
10 Validity of HF Outcome Verified 10 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
11 Heart Failure Validation Study 11 Criteria % Agreement ALLHAT 71% Framingham Heart Study 80% Reviewers judgement 84%
12 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
13 Step 1 Treatment Protocol 13 Step 1 Agent Initial Dose* Dose 1* Dose 2* Dose 3* Chlorthalidone Amlodipine Lisinopril Doxazosin * mg/day Step 2/3 drugs atenolol, reserpine, clonidine, hydralazine Non-study drugs all other antihypertensive medications
14 Baseline Characteristics Hospitalized/Fatal HF During Trial Yes No Difference p N 1,773 31,584 Age (mean) <0.001 Men, % 55.2% 53.0% +2.2% Pre-RZ Treatment, % 93.1% 90.0% +3.1% SBP (mean mm Hg) <0.001 DBP (mean mm Hg) <0.001 Pulse (mean bpm) <0.001 Cigarette smoking, % 18.3% 22.1% -3.8 <0.001 Diabetes, % % <0.001 LVH by ECG, % 18.4% 16.3% +2.1% <0.001 History of CHD, % 37.6% 24.7% <0.001 BMI (mean) <
15 Hospitalized/ Fatal Heart Failure by ALLHAT Treatment Group 15 Cumulative Event Rate RR 95% CI A-C L-C A-L Chlorthalidone Amlodipine Lisinopril Years
16 16 ALLHAT 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.
17 Hospitalized/ Fatal Heart Failure by ALLHAT Treatment Group Within 1 Year and >1 Year 17 Baseline to Year 1 > Year 1 RR 95% CI RR 95% CI A-C A-C L-C L-C Cumulative Hosp/Fatal HF Rate A-L Chlorthalidone Amlodipine Lisinopril A-L Years to Hosp/Fatal HF Years to Hosp/Fatal HF
18 Hospitalized/fatal HF in Subgroups - Amlodipine / Chlorthalidone Relative Risks from Baseline to 1 Year of Follow-up 18 Relative Risk (95% CI) Favors Amlodipine Favors Chlorthalidone Total Age < 65 Age 65 Non-Black Black Men Women Diabetic Non-Diabetic 2.22 ( ) 2.89 ( ) 2.06 ( ) 2.12 ( ) 2.37 ( ) 2.27 ( ) 2.17 ( ) 2.71 ( ) 1.83 ( )
19 Hospitalized/fatal HF in Subgroups - Amlodipine / Chlorthalidone Relative Risks After 1 Year of Follow-up 19 Relative Risk (95% CI) Favors Amlodipine Favors Chlorthalidone Total Age < 65 Age 65 Non-Black Black Men Women Diabetic Non-Diabetic 1.22 ( ) 1.38 ( ) 1.17 ( ) 1.20 ( ) 1.28 ( ) 1.28 ( ) 1.16 ( ) 1.23 ( ) 1.21 ( )
20 Hospitalized/fatal HF in Subgroups - Lisinopril / Chlorthalidone Relative Risks from Baseline to 1 Year of Follow-up 20 Relative Risk (95% CI) Favors Lisinopril Favors Chlorthalidone Total Age < 65 Age 65 Non-Black Black Men Women Diabetic Non-Diabetic 2.08 ( ) 2.53 ( ) 1.98 ( ) 2.04 ( ) 2.15 ( ) 1.80 ( ) 2.40 ( ) 1.99 ( ) 2.16 ( )
21 Hospitalized/fatal HF in Subgroups - Lisinopril / Chlorthalidone Relative Risks After 1 Year of Follow-up 21 Relative Risk (95% CI) Favors Lisinopril Favors Chlorthalidone Total Age < 65 Age 65 Non-Black Black Men Women Diabetic Non-Diabetic 0.96 ( ) 0.95 ( ) 0.97 ( ) 0.90 ( ) 1.10 ( ) 1.02 ( ) 0.89 ( ) 1.01 ( ) 0.93 ( )
22 HF Development and Relation to Other Outcomes 22 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
23 Why are hazard ratios not constant throughout? Hypotheses? 23 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
24 Prior Use of Antihypertensive Agents 24 Prior medication use associated with HF risk, especially during first year RR 1.42 ( ) Relative benefits of chlorthalidone consistent with or without prior antihypertensive medication use
25 Specific Prior Antihypertensive Agents 25 Data not collected within ALLHAT Available for 1115 / 1773 HF cases CCB s 47% ACEI 37% Diuretics 39% 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
26 Immediate vs Delayed Effects 26 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
27 27 ALLHAT Use of Step-up BP Meds Addition of Step 2 and Step 3 meds could have contributed to lessening or cessation of divergence of HF curves after 1 year.
28 Open-Label ACEI and Atenolol Use 28 Percent Year 3 Years 5 Years Chlor - AC Amlod - AC Lisin - AC Chlor - AT Amlod - AT Lisin - AT
29 30.0 Open-Label Diuretic and CCB Use Percent Year 3 Years 5 Years Chlor - D Amlod - D Lisin - D Chlor - CCB Amlod - CCB Lisin - CCB
30 Percent Diuretic, ACEI, or Atenol Use 1 Year 3 Years 30 Chlor Amlod Lisin
31 BP Results by Treatment Group 31 Chlorthalidone Amlodipine Lisinopril mm Hg BP 140 mm Hg BP Years Years 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 32 ALLHAT BP Differences Adjustment for follow-up SBP as timedependent covariates in a Cox regression model only slightly modified the relative risks Amlodipine/chlorthalidone first year, after 1 year Lisinopril/chlorthalidone first year, after 1 year
33 33 ALLHAT All-Cause Mortality Cumulative Event Rate Chlorthalidone Amlodipine Lisinopril Years from Hospitalized HF to Death
34 34 ALLHAT 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.
35 Heart Failure and Total Mortality 35 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).
36 36 ALLHAT 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
37 37 ALLHAT 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
38 38 ALLHAT 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.
39 Extra Slides 39
40 40 ALLHAT 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.
41 41 ALLHAT Active-Controlled Trials VALUE STOP Hypertension-2 ANBP2 INVEST CONVINCE CCB or diuretic/β-blocker BP reduced similarly, HF 30% more with CCB
42 42 ALLHAT 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
43 Randomized Design of ALLHAT 43 High-risk hypertensive patients 55 years Consent / Randomize (42,418) Amlodipine Chlorthalidone Doxazosin Lisinopril Eligible for lipidlowering 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).
44 Event Reduction in SHEP, Syst-Eur Eur, and HOPE 44 0 Stroke CHD CHF CVD Death Risk Reduction, % SHEP Syst-Eur HOPE SHEP: Systolic Hypertension in the Elderly, n=4,736; chlorthalidone Syst-Eur Eur: : Systolic Hypertension in Europe, n=4,695; nitrendipine HOPE: Heart Outcomes Prevention Evaluation Study, n=9,297; ramipril