Transcript ALLHAT - Coordinating Center for Clinical Trials

ALLHAT
Setting the Record
Straight
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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
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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?
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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
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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
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ALLHAT
Setting the Record Straight –
Study Design
Why were diuretics and calciumchannel blockers avoided as
second-step drugs?
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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
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ALLHAT
Second-Line Drugs &
BP Control
• BP control with ALLHAT regimen more
than twice that at entry
• Exceeded that observed in 3rd NHANES
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ALLHAT
Setting the Record Straight –
Study Conduct
Doesn’t the attrition rate
necessarily bias the conclusions?
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ALLHAT
Study Conduct –
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
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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”?
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ALLHAT
Study Conduct –
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”
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ALLHAT
Study Conduct –
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
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ALLHAT
Study Conduct –
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.
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ALLHAT
Setting the Record Straight –
Conclusions and Interpretations
Why do the authors emphasize
the secondary outcome results?
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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
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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?
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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
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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
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ALLHAT
Conclusions & Interpretations –
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
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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 preentry diuretic use
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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
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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
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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?
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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
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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
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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
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ALLHAT Conclusions & Interpretations –
Blood Pressure Differences
• Δ BP for amlodipine vs chlorthalidone,
and for lisinopril vs chlorthalidone in nonBlack 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%)
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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?
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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
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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
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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
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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?
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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?
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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
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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.
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ALLHAT
Setting the Record Straight –
Conclusions and Interpretations
Can the findings be extrapolated
to drugs within class?
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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
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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
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ALLHAT
Setting the Record Straight –
Conclusions and Interpretations
Why do the findings from ALLHAT
and the Second Australian
National Blood Pressure Study
seemingly conflict?
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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
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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
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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
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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
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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
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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.
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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
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