Major Outcomes in HighRisk Hypertensive Patients Randomized to AngiotensinConverting Enzyme Inhibito

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Major Outcomes in High-Risk Hypertensive Patients
Randomized to Angiotensin-Converting Enzyme
Inhibitor or Calcium Channel Blocker vs Diuretic
The Antihypertensive and Lipid-Lowering Treatment
to Prevent Heart Attack Trial (ALLHAT)

• JAMA. 2002 288 2981-2997
• EBM Journal Club
• Allegra Melillo, MD
• April 16, 2003

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Patient-Case

• 58 yo Latino Male, with PMH significant for HTN,
  prior history of CVA in 1999, and currently
  smoking..
• Had been seen by Neurology 2 weeks ago who
  started him on Enalapril for his HTN, ASA, and a
  statin and was referred to me to be his PMD.
• BP 180/90, HgBA1c 6.1, FBS 88, Tchol 230, LDL
  198, Cr 1.0

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PICO

• Population high-risk hypertensive patients
• Intervention treatment with ACE-Inhibitors
• Comparison thiazides
• Outcomes decrease morbidity and mortality,
  particularly CHD, CVD
• Question In high-risk hypertensive patients,
  does treatment with an ACE-I lower the incidence
  of CHD or CVD events compared to treatment with a
  diuretic?

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Background

• 50-60 million people in US with hypertension
• Rx and complications are costly 37 billion/yr
• Rx reduces HTN-related MM
• B-blockers and thiazides proven beneficial
• Unclear how newer, more costly drugs (CCB,
  ACE-Is) compare to older drugs
• Optimal first-line therapy is uncertain

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Importance of Trial

• Very recent, large clinical trial
• Examines relative benefits of various agents in
  high-risk hypertensives and diverse population
• Classes of drugs compared in the study are widely
  used
• Outcomes evaluated are clinically relevant CHD,
  CVD
• Results may change practice and reduce costs

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Objective of the ALLHAT Trial

• To determine whether treatment of hypertension in
  high-risk patients with a calcium channel blocker
  (amlodipine), an angiotensin-converting enzyme
  inhibitor (lisinopril), or an alpha-blocker
  (doxazosin) lowers the incidence of coronary
  heart disease (CHD) or other cardiovascular
  disease (CVD) events compared with diuretic
  treatment (chlorthalidone).

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Design

• Randomized, double-blind, active-controlled
  clinical trial conducted from February 1994
  through March 2002
• The doxazosin arm was terminated in 2000 because
  of a high incidence of congestive heart failure.

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Setting and Participants

• N 33,357 participants
• Age gt 55 yrs
• Included white, hispanic, and black subgroups
• Equal female male
• Recruited at 623 centers in North America

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Participants

• All had hypertension and at least 1 other CHD
  risk factor
• previous (gt6 mos) MI or stroke
• LVH, type II DM, current cigarette smoking, HDL lt
  35 mg/dl, documentation of other atherosclerotic
  CVD
• Exclusion criteria history of hospitalized or
  treated symptomatic heart failure (HF) and/or
  known LV EF lt35

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Interventions

• Participants were randomly assigned to
• chlorthalidone, 12.5-25 mg/d, (n 15,255)
• amlodipine, 10- 40 mg/d, (n 9048)
• lisinopril, 10-40 mg/d,.(n9054)
• Step 2 Rx atenolol, reserpine, clonidine
• Step 3 Rx hydralazine
• Low doses of open-label step 1 drug classes, were
  permitted if clinically indicated
• Planned follow- up of approximately 4 to 8 yrs

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Outcomes

• Primary fatal CHD or nonfatal myocardial
  infarction combined
• Secondary
• all-cause mortality
• fatal and nonfatal stroke,
• combined CHD (including, coronary
  revascularization, hospitalized angina)
• combined CVD (combined CHD, stroke, HF, PVD,
  other Rxd angina)

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Summary of Major Results

• Average follow-up of 5 yrs
• no significant differences among groups in the
  primary outcome (fatal CHD or nonfatal MI) or in
  all-cause mortality
• Amlodipine group compared to chlorthalidone had a
  significantly higher 6-yr cumulative incidence of
  heart failure (10.2 vs. 7.7 RR, 1.38 95 CI,
  1.25-1.52)

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Summary of Major Results

• Lisinopril group compared to chlorthalidone group
  had higher 6-year incidences of
• combined CVD (33.3 vs 30.9 RR, 1.10 95 CI,
  1.05-1.16)
• heart failure (8.7 vs 7.7 RR 1.19, 95 CI,
  1.07-1.31 ),
• stroke ( 6.3 vs 5.6 RR, 1.15, 95 CI,
  1.02-1.30)

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Are the results valid? Did experimental and
control groups begin the study with a similar
prognosis?

• Patients were randomized and blinded
• Patients were analyzed in the groups to which
  they were randomized (intention to treat) (Fig.
  1)
• Patients in the treatment and control groups were
  similar with respect to known prognostic factors
  (see Table 1)

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Are the Results Valid?Did experimental and
control groups retain a similar prognosis after
the study started?

• Patients were not aware of group allocation
• Clinicians may have been made aware of group
  allocation since in certain instances it was
  permitted to use open-label step 1 drugs of other
  classes
• Outcome assessors may have been aware of group
  allocation since they noted early on the high
  incidence of HF in the doxazosin arm

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Are the Results Valid?Did experimental and
control groups retain a similar prognosis after
the study started?

• See Table 2
• Visit adherence decreased over time from about
  92 at 1 yr to 84 to 87 at 5 years in all three
  treatment arms
• 2 lost-to- follow-up in all arms

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What are the Results?

• See Table 5
• Fig 3-6

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What are the results?6 Year Rate of Heart
Failure with Amlodipine
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What are the Results?6 yr rate of Outcomes with
Lisinopril Compared to Chlorthalidone
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What are the Results? Risks of Biochemical
Changes between Chlorthalidone and Amlodipine
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What are the Results? Risks of Biochemical
Changes between Chlorthalidone and Lisinopril
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Limitations

• Is chlorthalidone equivalent to the more widely
  used hydrochlorothiazide?
• How do B-blockers compare to these newer classes
  of antihypertension therapy?
• Some of the step II/III drugs are not typically
  used as second and third-line agents
• Partial and full crossovers lead to more
  conservative results gt there may be a
  significant difference in outcomes.

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Comparison Trial

• A Comparison of Outcomes with Angiotensin-Converti
  ng Enzyme Inhibitors and Diuretics for
  Hypertension in the Elderly. NEJM
  2003348583-92
• Open-label, randomized trial in Australia
• 6083 hypertensive patients received either a
  diuretic or an ACE inhibitor as initial therapy
  (no mandatory specific drug)

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Comparison Trial

• Additional drugs were given when monotherapy was
  inadequate.
• Age range was 65-84
• Predominantly white,
• Few with diabetes or known CHD

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Comparison Trial

• During 4 year follow-up, the frequency of the
  primary outcome -- all cardiovascular events or
  all-cause mortality (P0.05)
• 56 per 1000 pt yrs in the ACE I group
• 60 per 1000 pt yrs in the diuretic group
• ACE I grouop had a lower rate of first-event MI
  with a hazard ratio of 0.68 95 CI (0.47-0.98)
• No decrease rate of stroke or overall mortality

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Can I apply the ALLHAT results to patient care?

• Patient population diverse, similar to FHC
• High-risk hypertensive patients
• Multiple important clinical outcomes were
  considered CHD, CVD, all-cause mortality
• With thiazide, increased long-term risk of
  raising cholesterol, new diabetes and hypokalemia
  gt Rx and lifestyle changes
• Overall no increase in new cardiovascular events
  or into higher all-cause mortality

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Return to Patient Case

• 58 yo Latino male smoker w/ HTN and h/o CVA,
  recently started on Enalapril
• If we can generalize that thiazides compared to
  ACE inhibitors have a lower risk of stroke, HF
  and combined CVD
• Would have started him on a thiazide first!
• Remember to monitor chol, FBS, and K
• May reduce morbidity and health care costs!

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Summary and Conclusions

• The ALLHAT trial is overall robust and
  generalizable to a diverse, high risk population
• No differences in fatal coronary disease or
  nonfatal MI among three groups
• Compared to chlorthalidone, lisinopril had a
  increased 6 year incidence of heart failure,
  stroke and combined CVD
• Compared to chlorthalidone, amlodipine had a
  increased 6 year incidence of HF

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Summary and Conclusions

• Cautious about higher risk of elevated
  cholesterol, new-onset diabetes, and hypokalemia
  with thiazide
• Unfortunately no comparison to Beta-blockers in
  study
• ? Generalizability to all thiazides,
  ACE-inhibitors and CCBs
• ALLHAT more relevant to CHN population than
  Australian trial

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Clinical Bottom-Line

• Thiazides should be considered initial treatment
  choice for most hypertensive patients.