Setting the Record Straight by HC12100509625

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									ALLHAT



    Setting the Record
          Straight


                         1
ALLHAT                Major ALLHAT Findings

• CHD risk not improved for any of the 3 newer agents
  compared with chlorthalidone
• Total mortality was similar for the 4 groups
• Diuretic superior in preventing one or more major
  forms of CVD, including stroke and heart failure
• Subgroups consistent except stroke, combined CVD
   – Heterogeneity in L / C comparison by ethnicity – greater
     reductions in Blacks

• Diuretics drug of choice for initial therapy of HTN
  and should be included in multidrug regimens
                                                                2
ALLHAT     Setting the Record Straight –
                   Study Design


  How could ALLHAT test first-step
     therapy, given the study’s
   inclusion criteria and lack of a
          washout period?




                                      3
ALLHAT       Testing First-Step Therapy –
                    The Ideal Trial

 • Include all hypertensive patients
   – Low and high risk
   – Treated (with washout) and untreated

 BUT
 • Require more patients
 • More complex
 • Unaffordable
                                            4
ALLHAT       Testing First-Step Therapy –
                       ALLHAT

 • Practice-based trial mirrors community
   treatment of hypertension
 • Obtained sufficient patients
 • Captures diversity of patients
 • High risk patients assure adequate
   numbers of outcome events
 • No washout, except for β-blockers
                                            5
ALLHAT    Setting the Record Straight –
                  Study Design


  Why were diuretics and calcium-
   channel blockers avoided as
       second-step drugs?




                                     6
ALLHAT               Second-Line Drugs


 • Second- and third-line drugs available for BP
   control
 • Discouraged step-up from same class as any of
   the first-step agents unless compelling
   indications
 • Odd that β-blocker a step-up agent for ACEI?
 • Reserpine, clonidine, hydralazine also provided
   as step-up therapy in addition to β-blocker –
   different mechanisms of action than first-step

                                                     7
                Second-Line Drugs &
ALLHAT
                    BP Control

 • BP control with ALLHAT regimen more
   than twice that at entry
 • Exceeded that observed in 3rd NHANES




                                          8
ALLHAT     Setting the Record Straight –
                  Study Conduct


      Doesn’t the attrition rate
  necessarily bias the conclusions?




                                      9
                   Study Conduct –
ALLHAT
                       Attrition

 • Mean length of follow-up 4.9 years
 • 99% of expected person-years were
   observed
 • 97.1% of participants had known vital
   status during closeout period
 • Sensitivity analyses consistent with trial’s
   published conclusions

                                              10
ALLHAT    Setting the Record Straight –
                 Study Conduct


        Wasn’t the outcome
   ascertainment process flawed
     since end points were not
    systematically reviewed by a
         panel of experts?
  Aren’t the secondary outcomes
         “soft end points”?
                                     11
                 Study Conduct –
ALLHAT
              Endpoint Ascertainment

 • Not feasible to systematically verify all
   endpoints
   – 11,000 CVD end points during follow-up

 • AHT double-blind  no bias for or against
   any treatment when reporting and
   classifying endpoints
 • LLT not double-blind  potential bias for
   all nonfatal outcomes  secondary
   endpoints for LLT “soft data”               12
                  Study Conduct –
ALLHAT
               Endpoint Ascertainment

• Investigators trained per definitions detailed
  in Manual of Operations
• Review of all end points at ALLHAT Clinical
  Trials Center by medical reviewers.
  – Verified investigator-assigned diagnoses using
    death certificates & discharge summaries




                                                     13
                 Study Conduct –
ALLHAT
              Endpoint Ascertainment

• Random 10% subset of CHD & stroke – more
  detailed information collected; reviewed by
  Endpoint Subcommittee
  – 90% agreement for primary outcome (CHD)
  – 84% agreement for stroke
• Smaller one-time sample of HF cases
  – 85% agreement
• Rates of agreement similar across treatment
  groups.
                                              14
ALLHAT    Setting the Record Straight –
          Conclusions and Interpretations



   Why do the authors emphasize
  the secondary outcome results?




                                      15
ALLHAT Conclusions & Interpretations –
            Primary vs Secondary Outcomes

• Identification of primary outcome assures
  statistical power to test question related to
  that end point
  – Primary outcome essentially identical in all
    treatment groups.

• Other important predefined clinical outcomes
  – Public health viewpoint, all major clinical
    outcomes are worth examining
  – E.g., Total mortality
                                                   16
ALLHAT      Setting the Record Straight –
             Conclusions and Interpretations



    Are the heart failure findings real?
    Can’t all or most of the heart failure
    findings be explained by the use of
  antihypertensive medications, such as
   diuretics and CCBs, before entry into
                  ALLHAT?


                                             17
ALLHAT Conclusions & Interpretations –
                       Heart Failure Validity

 • First validity sample - 85% agreement in 39 cases
 • All HF hospitalizations and deaths – 3031 cases
   in 2091 patients
    – All relevant materials collected, 2 reviewers per case
      (blinded to treatment group)
    – ALLHAT and Framingham criteria, reviewer’s judgment
    – Confirmed 70-84% of cases in each treatment group,
      depending on criteria used
    – Analysis using only confirmed cases confirmed original
      ALLHAT findings regarding HF
                                                               18
ALLHAT Conclusions & Interpretations –
           Early Divergence of HF Differences


 • Divergence continued after 1 year for
   doxazosin & amlodipine vs chlorthalidone
 • For lisinopril vs chlorthalidone, curves
   converged between 6-7 years




                                              19
           Conclusions & Interpretations –
ALLHAT     Suggested Reasons for Divergence
                     of HF Curves

 • Precipitation of edema with amlodipine?
 • Unmasking of edema upon withdrawal of
   diuretics at entry?
 • Central review algorithm for HF
   disallowing peripheral edema
   – Did not alter HF confirmation rate
   – Did not alter treatment group differences


                                                 20
ALLHAT Conclusions & Interpretations –
             HF Findings vs Meds at Entry

 • IMS data 1994-1998 (ALLHAT recruitment)
   – U.S. hypertensives taking diuretics decreased
     from 30% to just over 20%

 • Central review of HF cases
   – No interaction of study treatment with pre-
     entry diuretic use




                                                   21
ALLHAT      Conclusions & Interpretations –
              HF vs 2nd and 3rd line drugs

 • Addition of 2nd and 3rd line drugs probably
   contributed to lessening of the divergence
   6-12 months after randomization
   – Open-label diuretics, β-blockers, ACEI
   – Excess risk with doxazosin as monotherapy
     reduced but not eliminated after 1 year
   – Greatest differential in participants with
     controlled BP – difference not explained by BP
     differential
                                                  22
ALLHAT        Conclusions & Interpretations –
                  HF vs Total Mortality

 • Δ HF  Δ total mortality?
   – 9 excess cases of fatal HF for lisinopril
      • <1% of all deaths

   – 39 fatal HF for amlodipine, 3% of deaths
   – Differences unlikely to be detected




                                                 23
ALLHAT    Setting the Record Straight –
          Conclusions and Interpretations


  Can’t all or most of the outcome
       findings (especially the
   differential ethnicity subgroup
  findings for stoke) be explained
  by the observed blood pressure
  differences among the treatment
               groups?

                                        24
ALLHAT Conclusions & Interpretations –
               Blood Pressure Differences

• Goal – achieve equivalent BP control in all
  4 groups
   – Mean decrease in BP not a declared outcome

• Chlorthalidone-based regimen the most
  effective in reducing clinical outcomes
  and, to a small degree, in lowering BP



                                                  25
ALLHAT Conclusions & Interpretations –
            Blood Pressure Differences

    If a given agent is less effective in
   reducing clinical events unless it is
    combined with another agent like
chlorthalidone to lower BP, not clear why
treatment would be started with anything
             other than diuretic


                                      26
ALLHAT Conclusions & Interpretations –
                Blood Pressure Differences

• Δ achieved SBP  Δ in CV findings?
• Meta-regressions of BP differences on
  trial results
   – True to some extent, except for HF




                                          27
ALLHAT Conclusions & Interpretations –
                Blood Pressure Differences

• Δ BP for amlodipine vs chlorthalidone,
  and for lisinopril vs chlorthalidone in non-
  Black participants  1 mm Hg
   – Expect no / negligible effect on CV events
   – HF higher with amlodipine (38%) and with
     lisinopril (15%) than with chlorthalidone
• Larger differences in Black participants
   – 4 mm Hg SBP in lisinopril vs chlorthalidone
   – Explains < ½ of observed higher risk for stroke
     (40%) and HF (32%)                            28
ALLHAT     Setting the Record Straight –
           Conclusions and Interpretations



   Doesn’t the increased incidence
         of new diabetes in the
    chlorthalidone group portend
  greater long-term cardiovascular
  risk for patients taking this drug?



                                         29
ALLHAT         Conclusions & Interpretations –
                     Incident Diabetes

• Incident diabetes not a pre-specified outcome
• Thiazide diuretics  small increase in serum
  glucose (3-4 mg/dL) in short term
  – Consistent with other literatuve

• Results for major outcomes consistent by
  baseline diabetes status


                                             30
ALLHAT         Conclusions & Interpretations –
                     Incident Diabetes

• ↑ in serum glucose did not lead to ↑ CV events
  or ↑ total mortality during the trial
• Patients in doxazosin group had ↓ mean
  glucose compared to chlorthalidone
  – Did not translate in better CV reduction for
    doxazosin




                                                   31
ALLHAT         Conclusions & Interpretations –
                     Incident Diabetes

• Thiazide-induced diabetes can probably be
  prevented or reversed:
  – Maintenance of potassium balance
  – Adequate weight control
  – Increased physical activity
  – Caution when using β-blockers in combination
    therapy


                                                   32
ALLHAT          Conclusions & Interpretations –
                      Incident Diabetes

• Long follow-up for ALLHAT, avg. 4.9 years
  – Cannot predict outcomes beyond trial’s duration
  – Applies to any clinical trial
  – Lack of evidence that a result will hold up decades
    after trial ends does not prove that a different
    outcome will result

• Does thiazide-induced diabetes carry same
  prognosis as naturally-occurring diabetes?
                                                      33
ALLHAT    Setting the Record Straight –
          Conclusions and Interpretations



   Diuretics themselves may be
   cheaper, but does the cost of
    management with diuretics
   translate into less expensive
              therapy?



                                       34
ALLHAT         Conclusions & Interpretations –
                 Cost of Antihypertensive Management


• Cost subordinate to safety & efficacy
• Still should be considered in selection of
  antihypertensive agents
• Could have major impact on health care
  expenditures in U.S.
  – Diuretic use declined from 56% of prescriptions in
    1982 to 27% of prescriptions in 1992
  – $3.1 billion in savings on drugs costs if diuretic use
    had remained at 1982 levels
                                                      35
ALLHAT       Conclusions & Interpretations –
               Cost of Antihypertensive Management


• Cost effectiveness analyses for ALLHAT are
  underway
• Preliminary analyses suggest costs driven by
  drug acquisition
• Cost for monitoring K+ and glucose not
  proven to be more than that required during
  treatment with ACEI or in routine care of
  patients with risk factors.

                                                36
ALLHAT   Setting the Record Straight –
          Conclusions and Interpretations



  Can the findings be extrapolated
       to drugs within class?




                                        37
ALLHAT         Conclusions & Interpretations –
                Extrapolation to Drug Classes

• For α-blockers, ACE inhibitors, &
  dihydropyridine CCBs, extrapolation seems
  reasonable
• Chlorthalidone  thiazide diuretics  HCTZ?
• MRFIT mortality trends less favorable at clinics
  where HCTZ favored over chlorthalidone
  – Based on post hoc subgroup analysis
  – Based on group identifier (clinic) rather than patients
    – results did not hold up at patient level
                                                      38
ALLHAT        Conclusions & Interpretations –
               Extrapolation to Drug Classes

• Data from other studies (except MRFIT) using
  various thiazide-type diuretics suggest similar
  benefit in CVD prevention
  – Chlorthalidone
  – HCTZ
  – Indapamide
  – Bendrofluazide


                                              39
ALLHAT   Setting the Record Straight –
         Conclusions and Interpretations



    Why do the findings from
     ALLHAT and the Second
    Australian National Blood
    Pressure Study seemingly
             conflict?



                                       40
ALLHAT        Conclusions & Interpretations –
                   ALLHAT vs ANBP2

Second Australian National Blood Pressure Study
• Practice-based open-label trial
• Diuretic-based vs ACEI-based treatment
  – Recommended – HCTZ, enalapril

• 6083 participants, 65-84 years of age
• Followed for a mean of 4.1 years


                                           41
ALLHAT         Conclusions & Interpretations –
                    ALLHAT vs ANBP2

• Primary endpoint - composite of all CV events
  (initial & recurrent) plus all-cause mortality
• Results marginally favored ACEI
  – RR 0.89 (0.79 – 1.00, p=0.05)

• First CV event or death, p=0.06
• First CV event, p=0.07


                                              42
ALLHAT         Conclusions & Interpretations –
                    ALLHAT vs ANBP2

• Frohlich NEJM. 2003;5:192-5 - samples studied,
  specific drugs used
• 2X CV events in ALLHAT as participants in
  ANBP2
• ALLHAT double-blind vs ANBP2 PROBE design
  – increased potential for bias in ANBP2
• Results consistent if upper confidence limit for
  relative risks in ANBP2 compared with
  estimates in ALLHAT
                                               43
ALLHAT                Limitations & Expectations

• New drugs have been or will soon be released
   – Angiotensin-receptor blockers, selective aldosterone
     antagonists

• Equivalent BP control not fully achieved
• Step-up agents  somewhat artificial regimen for ACE
  group  high BP in ACE group?
   – Mean BP well below 140/90 mm Hg in all groups

• Did not include low-risk individuals nor a wash-out
  period
• Information on previous AHT meds not collected            44
ALLHAT                     Conclusions


• As 1st-step agents, ACEI, CCB, and α-blockers
  add no value over and above diuretics in
  preventing CHD or other major forms of CVD
  – Less effective in preventing HF
  – More expensive than diuretics




                                             45
ALLHAT                   Conclusions


• Lowering high BP is of fundamental importance
  in reducing CVD risk
• How BP is lowered does matter
• Diuretics should remain the preferred 1st step
  drugs for treatment of hypertension
• Diuretics should be a cornerstone in the
  arsenal for care of hypertensive patients.

                                               46
ALLHAT                   Other Remarks

• Surprising ALLHAT findings
  – ACEI not the best in preventing CV events
  – CCB not the worst in terms of CHD and deaths

• Expectations derived from preclinical studies,
  extrapolation from surrogate outcomes, and
  case-control and other observational studies
• Results from randomized, double-blind, clinical
  endpoint trials needed whenever possible as
  basis for therapeutic decisions
                                                   47

								
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