E-drug: Hypertension: the ALLHAT study
---------------------------------------------
Dear E-druggers,
The final results of a large study on drug treatment of hypertension,
ALLHAT, was published in JAMA 18 December. Both the article and the
editiorial is available free on the links below, however, because of the
importance of the findings, I have copied the abstract and the full
editorial below. The study found that the thiazide diuretic chlorthalidone
was better than the ACE-inhibitor lisinopril and the calcium antagonist
amlodipine as first line treatment of hypertension. Preliminary results were
published in JAMA in 2000 (The ALLHAT Officers and Coordinators for the
ALLHAT Collaborative Research Group: major cardiovascular events in
hypertensive patients randomized to doxazosin vs chlorthalidone. JAMA 2000;
283: 1967-75) when the doxazosin arm of the study was stopped because
doxazosin came out significantly worse than chlorthalidone. Needless to say,
the current study has received little publicity although CNN and NY Times
have mentioned it. Norwegian media have kept silent as has the regulatory
authority - and of course the multinationals.
The thiazide being used, chlorthalidone (a thiazide-related compound), may
not be widely available, but the results are applicable to any thiazide and
thiazide related compound. Unfortunately also many other thiazides have been
withdrawn by the innovator brand manufacturers which are more
interested in selling new drugs or combination pills. Hopefully the
generic manufacturers will see a market here, but unfortunately they
spend less on marketing, making a case for independent sources and
educational institutions to come forward and bring the results to the
prescribers.
Lastly, in the current debate on scope of diseases to be covered by
compulsory licensing: here is one example of cheap old drugs being more
essential than new patented drugs!
Copied as fair use.
http://jama.ama-assn.org/issues/v288n23/rfull/joc21962.html
The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research
Group. 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 (18 December)
Context: Antihypertensive therapy is well established to reduce
hypertension-related morbidity and mortality, but the optimal first-step
therapy is unknown.
Objective: To determine whether treatment with a calcium channel blocker or
an angiotensin-converting enzyme inhibitor lowers the incidence of coronary
heart disease (CHD) or other cardiovascular disease (CVD) events vs
treatment with a diuretic.
Design: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart
Attack Trial (ALLHAT), a randomized, double-blind, active-controlled
clinical trial conducted from February 1994 through March 2002.
Setting and Participants: A total of 33 357 participants aged 55 years or
older with hypertension and at least 1 other CHD risk factor from 623 North
American centers.
Interventions: Participants were randomly assigned to receive
chlorthalidone, 12.5 to 25 mg/d (n = 15 255); amlodipine, 2.5 to 10
mg/d (n = 9048); or lisinopril, 10 to 40 mg/d (n = 9054) for planned
follow-up of approximately 4 to 8 years.
Main Outcome Measures: The primary outcome was combined fatal CHD or
nonfatal myocardial infarction, analyzed by intent-to-treat. Secondary
outcomes were all-cause mortality, stroke, combined CHD (primary outcome,
coronary revascularization, or angina with hospitalization), and combined
CVD (combined CHD, stroke, treated angina without hospitalization, heart
failure [HF], and peripheral arterial disease).
Results: Mean follow-up was 4.9 years. The primary outcome occurred
in 2956 participants, with no difference between treatments. Compared
with
chlorthalidone (6-year rate, 11.5%), the relative risks (RRs) were
0.98 (95% CI, 0.90-1.07) for amlodipine (6-year rate, 11.3%) and 0.99
(95% CI, 0.91-1.08) for lisinopril (6-year rate, 11.4%). Likewise,
all-cause
mortality did not differ between groups. Five-year systolic blood pressures
were significantly higher in the amlodipine (0.8 mm Hg, P = .03) and
lisinopril (2 mm Hg, P<.001) groups compared with chlorthalidone, and
5-year diastolic blood pressure was significantly lower with
amlodipine (0.8 mm Hg, P<.001). For amlodipine vs chlorthalidone,
secondary outcomes were similar except for a higher 6-year rate of HF
with amlodipine (10.2% vs 7.7%; RR, 1.38; 95% CI, 1.25-1.52). For
lisinopril vs chlorthalidone, lisinopril had higher 6-year rates of
combined CVD (33.3% vs 30.9%; RR, 1.10; 95% CI, 1.05-1.16); stroke
(6.3% vs 5.6%; RR, 1.15; 95% CI, 1.02-1.30); and HF (8.7% vs 7.7%;
RR, 1.19; 95% CI, 1.07-1.31).
Conclusion: Thiazide-type diuretics are superior in preventing 1 or more
major forms of CVD and are less expensive. They should be preferred for
first-step antihypertensive therapy.
Editorial
"The ALLHAT results provide compelling evidence that thiazide diuretics
should be the initial drug of choice for patients with hypertension,
especially compared with those agents that were directly tested in this
trial."
http://jama.ama-assn.org/issues/v288n23/ffull/jed20075.html
Lawrence J. Appel, MD, MPH. The Verdict From ALLHAT Thiazide Diuretics Are
the Preferred Initial Therapy for Hypertension. JAMA 2002; 288:
3039-42 (18 December)
Quite simply, the Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial (ALLHAT) is one of the most important trials of
antihypertensive therapy. For decades, experts have passionately debated
which class of drugs should be initial therapy for hypertension. Resolution
of this issue, which has enormous clinical, public health, and economic
implications, comes at a time of intense pressure to reduce health care
costs while improving clinical outcomes. In this setting, the ALLHAT
results, reported in this issue of THE JOURNAL, are particularly noteworthy,
because there is no cost-quality tradeoff; the most effective therapy was
also the least expensive.(1)
The magnitude of the hypertension epidemic is enormous. For individuals aged
55 to 65 years, the lifetime probability of developing hypertension is
90%.(2) Across the United States, more than 40 million adults aged 25 years
and older have hypertension.(3) Of these, 21.9 million are treated with
medication. Each year, an estimated 2 million persons develop
hypertension.(4) The ALLHAT results are of direct relevance to these
patients with newly diagnosed hypertension and to medication-treated
patients not receiving a thiazide diuretic.
Previous trials of antihypertensive therapy have consistently documented
that diuretic-based drug regimens substantially reduce the risk of
stroke.(5) However, the benefits of diuretic therapy on coronary heart
disease, although evident in quantitative overviews, were less than
expected.(5,6) Hypertension specialists postulated that diuretic-induced
metabolic effects (ie, hypokalemia, dyslipidemia, and insulin resistance)
might have mitigated the otherwise beneficial effects of blood pressure (BP)
reduction. Such speculation led in part to a progressive shift from thiazide
diuretic therapy to nondiuretic therapies, particularly
angiotensin-converting enzyme (ACE) inhibitors and calcium channel
blockers (CCBs).(7) Because these nondiuretic therapies reduce BP
without apparently adverse metabolic consequences, many specialists
concluded that such drugs would likely be superior to diuretics as a
means to prevent coronary heart disease. Virtually no one thought
that such therapies might be harmful.
Several years ago, the case-control study by Psaty et al(8) stunned the
hypertension community by providing strong, albeit nondefinitive, evidence
that certain CCBs when used as drug therapy for hypertension were associated
with an increased risk of myocardial infarction. This provocative report
spawned numerous trials that tested the effects of newer antihypertensive
therapies on clinical cardiovascular outcomes. However, none of these trials
tested more than one alternate therapy, and several had design limitations
including inadequate power. ALLHAT, which had been initiated prior to the
publication of this case-control study,(8) gained in importance because it
simultaneously compared 3 classes of antihypertensive drug therapies with
conventional thiazide therapy. Clinical researchers and practicing
physicians have eagerly awaited the results of this trial.
ALLHAT compared 3 distinct medications: amlodipine (representing
dihydropyridine CCBs [DHP-CCBs]), lisinopril (representing ACE
inhibitors), and doxazosin (representing -blockers) with
chlorthalidone (representing conventional thiazide therapy). In
contrast to hundreds of trials with surrogate outcomes, the major
outcomes in ALLHAT were clinically relevant cardiovascular events.
The primary outcome was fatal coronary heart disease or nonfatal
myocardial infarction. Secondary outcomes were all-cause
mortality, fatal and nonfatal stroke, combined coronary heart disease, and
combined cardiovascular disease. The planned follow-up was long (4-8
years). A previous report from ALLHAT documented that chlorthalidone
was superior to doxazosin in preventing cardiovascular events,
especially heart failure.(9)
Each of the medications substantially reduced BP, although the extent of BP
reduction was not equivalent. Blood pressure reductions from chlorthalidone
were somewhat greater than corresponding reductions from lisinopril.
Amlodipine reduced diastolic BP to a slightly greater extent and systolic BP
to a slightly lesser extent than chlorthalidone. By the fifth year of
follow-up, control of hypertension (defined as a systolic BP <140 mm
Hg and diastolic BP <90 mm Hg) was achieved in approximately two
thirds of participants (61% lisinopril, 66% amlodipine, and 68%
chlorthalidone); these hypertension control rates greatly exceed
corresponding rates in the general population (approximately 44%).(3)
Follow-up was excellent and the number of
dropins and dropouts from the assigned groups was relatively small. Hence,
the trial has high internal validity.
The major finding of ALLHAT was a striking and unequivocal null result,
namely, that the occurrence of coronary heart disease death and nonfatal
myocardial infarction was virtually identical in the amlodipine,
lisinopril, and chlorthalidone groups. The data effectively rule out
a 10% or more
difference between chlorthalidone and each of the other therapies. However,
for certain secondary outcomes, there were apparent differences, some of
which were anticipated. Chlorthalidone was superior to amlodipine in
preventing heart failure. This finding is consistent with trends observed in
other trials.(10,11) In contrast with the study of Psaty et al,(8) there was
no excess of coronary heart disease in the amlodipine group.
Less expected were the results of the lisinopril group. Among the many
researchers who tried to predict the results of ALLHAT, many had anticipated
that lisinopril would be similar in efficacy, if not superior to
chlorthalidone. Previous trials documented that ACE inhibitors were
beneficial in heart failure,(12) type 1 diabetic kidney disease,(13)
and nondiabetic kidney disease.(14,15) Furthermore, there was a
strong biological basis to anticipate a beneficial effect of an ACE
inhibitor, which blocks the renin-angiotensin system, compared with
diuretic therapy, which stimulates the renin-angiotensin system.
Despite these considerations, chlorthalidone was superior to
lisinopril as a means to lower BP and prevent stroke, combined
cardiovascular disease, and perhaps heart failure. The increased risk
of heart failure (statistically significant for total heart failure
but nonsignificant for the more restrictive outcome of hospitalized
for or death from heart failure) is surprising and difficult to
reconcile in view of the well-documented benefits of ACE inhibitors
in the treatment of heart failure.(12) This phenomenon (ie, an
interaction in which ACE inhibitors might increase the risk of
developing heart failure, yet improve health outcomes in persons with
prevalent heart failure) is uncommon.
Even the best designed and executed trials raise critical interpretive
issues. First and foremost is whether differences in achieved BP between
groups might account for the observed differences in clinical outcomes. Not
so for amlodipine. The BP differences between amlodipine and chlorthalidone
were small (<1 mm Hg) and balanced (lower systolic BP in chlorthalidone but
lower diastolic BP for amlodipine). Hence, the increased risk of heart
failure associated with amlodipine most certainly represents a drug-specific
effect rather than a difference in achieved BP. Findings are less clear for
lisinopril, in which absolute BP levels were higher, hypertension control
rates lower, and use of add-on drug therapy more common. Even though
differences in clinical outcomes between lisinopril and chlorthalidone
persisted after adjustment for follow-up BP, the possibility that the
increased risk of stroke and cardiovascular disease resulted primarily from
less BP reduction cannot be ruled out.
A second issue is the type of medication used as add-on therapy in ALLHAT.
In contrast with the drug treatment algorithm used in ALLHAT, physicians
commonly add a thiazide diuretic if BP reduction from an ACE inhibitor alone
is unsatisfactory. Occasionally, physicians begin treatment with an ACE
inhibitor/diuretic combination agent, particularly in black patients. Still,
in light of ALLHAT results, it is unclear why physicians should implement an
ACE inhibitor�based strategy that commonly leads to use of 2 drugs (ACE
inhibitor and diuretic) when monotherapy with a thiazide diuretic can
effectively reduce BP and prevent BP-related cardiovascular outcomes.
A third issue commonly raised by trials of drug therapies is whether results
can be extrapolated from the specific drug tested to other drugs of the same
class. For ACE inhibitors, there is no compelling reason to believe that any
one ACE inhibitor is superior. Hence, physicians might be willing to
extrapolate the results of ALLHAT to other ACE inhibitors. In contrast,
differences in structure and function of the CCBs lead most physicians to
consider DHP-CCBs as distinct from non�DHP-CCBs. Hence, it seems
reasonable to extrapolate ALLHAT results to other DHP-CCBs but not to
non�DHP-CCBs. As for the "winner," chlorthalidone is a thiazide
diuretic commonly used in large trials(1,16) but infrequently used in
clinical practice in the United States. Although thiazide-type
diuretics are reasonably similar and ALLHAT results might be
extrapolated to hydrochlorothiazide, purists might argue that
chlorthalidone should be used in view of its well-documented efficacy
in trials.
The metabolic effects and adverse effect profile of the drugs were
anticipated. Instances of angioedema were rare but still occurred more
frequently in the lisinopril group compared with the other groups.
Hypokalemia, hypercholesterolemia, and evidence of insulin resistance were
more evident among those assigned to chlorthalidone. Specifically, levels of
fasting blood glucose were increased in the chlorthalidone group, and
patients without diabetes had an increased risk of developing a fasting
glucose of more than 125 mg/dL (>7 mmol/L). Despite these trends, it is
important to emphasize that there was no excess of cardiovascular events or
mortality from chlorthalidone in the entire population or among patients
with diabetes. Such findings reaffirm the importance of relying on hard
clinical outcomes rather than surrogate markers for clinical decision
making.
The results of ALLHAT are robust, unambiguous, and generalizable, especially
to the broad population of patients with stage 1 or 2 hypertension.
Approximately 50% of participants were women and 35% were black. To
enhance statistical power, the trial focused on high-risk patients
with
hypertension, defined by the presence of another risk factor for
cardiovascular disease. Still, there is little reason to believe that the
results should differ qualitatively in lower risk patients. The authors
report no apparent differences in subgroups for the comparison of amlodipine
and chlorthalidone. The only notable subgroup differences were an increased
risk of stroke and combined cardiovascular disease in the ACE inhibitor
group in black but not in nonblack patients. These findings may have
resulted from the fact that among black patients, follow-up BP was
substantially higher in the ACE inhibitor group than in the chlorthalidone
group. Otherwise, among prespecified subgroups of interest defined by age,
sex, race, and diabetes, results were remarkably consistent. Short of
another large trial of similar design, the demographic heterogeneity of
study participants and the consistency of subgroup findings suggest that
ALLHAT results are generalizable.
The ALLHAT results provide compelling evidence that thiazide diuretics
should be the initial drug of choice for patients with hypertension,
especially compared with those agents that were directly tested in this
trial. Although -blocker therapy was not one of the first-line therapies
studied in ALLHAT, available data indicate that -blocker therapy is
certainly no more effective and quite possibly may be less effective than
thiazide-diuretic therapy.(17) In this setting, an appropriate next question
is what type of medication should be second-line therapy? In ALLHAT, the
average number of medications used to control BP progressively increased
from approximately 1.5 in first year of follow-up to 2.0 in the fifth year.
While physicians may be tempted to use an on-patent CCB or ACE inhibitor,
there is an impressive armamentarium of low-cost, off-patent drugs that can
be used as add-on therapy after diuretics. These medications include a CCB
(verapamil), 3 ACE inhibitors (captopril, enalapril, and lisinopril),
several -blockers, low-dose reserpine, and a direct vasodilator
(hydralazine). A logical strategy that incorporates these low-cost agents
may differ from those that are more popular, but contemporary
strategies may be somewhat artificial because of the heavy influence
of marketing that
preferentially leads to use of expensive medications. In short, physicians
have the means to effectively control BP with inexpensive medications, even
among patients who require multiple drugs.
While the challenges of designing and implementing ALLHAT were daunting, the
subsequent tasks of disseminating results and changing physician
prescription habits may be an even greater challenge. An important next step
is to update policy documents(18) to emphasize the unambiguous role of
thiazide diuretics as initial therapy. Concomitantly, a concerted effort
should be made to educate physicians, medical residents, and other health
care professionals, as well as those who develop guidelines for provider
networks and health maintenance organizations. Leading this effort will be
the National High Blood Pressure Education Program and the ALLHAT
investigators themselves. Is a massive shift in aggregate prescription
patterns likely? The results of ALLHAT, if disseminated and implemented,
will likely have their greatest impact on patients with newly diagnosed
hypertension. Hence, a large immediate shift in aggregate prescription
patterns is unlikely.
Finally, it is important to emphasize that treatment of hypertension is just
one component of an overall strategy to prevent BP-related cardiovascular
disease. Results from ALLHAT provide definitive data on one important aspect
of hypertension managementselecting the best initial therapy. Attention must
now return to other critical issues, specifically, controlling BP among
patients with hypertension (3,19,20) and preventing hypertension in the
first place.(21)
Author Affiliation: Welch Center for Prevention, Epidemiology and Clinical
Research, Johns Hopkins University, Baltimore, Md.
Corresponding Author and Reprints: Lawrence J. Appel, MD, MPH, Johns Hopkins
University, 2024 E Monument St, Suite 2-600, Baltimore, MD 21205-2223
(e-mail: lappel@jhmi.edu).
Editorials represent the opinions of the authors and THE JOURNAL and not
those of the American Medical Association.
Acknowledgment: I thank Jean Marie Ricketts for her insightful comments on
earlier versions of this editorial.
Financial Disclosure: Dr Appel currently receives a research grant from King
Pharmaceutical.
REFERENCES
1. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative
Research Group. 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.
2. Vasan RS, Beiser A, Seshadri S, et al. Residual lifetime risk for
developing hypertension in middle-aged women and men: the Framingham
Heart Study. JAMA 2002;287:1003-1010.
3. Hyman DJ, Pavlik VN. Characteristics of patients with uncontrolled
hypertension in the United States. N Engl J Med 2001;345:479-486.
4. Whelton PK, Adams-Campbell LL, Appel LJ, et al. National High Blood
Pressure Education Program Working Group report on primary prevention of
hypertension. Arch Intern Med 1993;153:186-208.
5. Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and
coronary heart disease, part 2: short-term reductions in blood pressure:
overview of randomised drug trials in their epidemiological context. Lancet
1990;335:827-838.
6. MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary
heart disease, part 1: prolonged differences in blood pressure: prospective
observational studies corrected for the regression dilution bias. Lancet
1990;335:765-774.
7. Manolio TA, Cutler JA, Furberg CD, et al. Trends in pharmacologic
management of hypertension in the United States. Arch Intern Med
1995;155:829-837.
8. Psaty BM, Heckbert SR, Koepsell TD, et al. The risk of myocardial
infarction associated with antihypertensive drug therapies. JAMA
1995;274:620-625.
9. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative
Research Group. Major cardiovascular events in hypertensive patients
randomized to doxazosin vs chlorthalidone: the Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA
2000;283:1967-1975.
10. Pahor M, Psaty BM, Alderman MH, et al. Health outcomes associated with
calcium channel antagonists compared with other first-line antihypertensive
therapies: a meta-analysis of randomised controlled trials. Lancet
2000;356:1949-1954.
11. Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of
ACE inhibitors, calcium antagonists, and other blood-pressure-lowering
drugs: results of prospectively designed overviews of randomised trials.
Lancet 2000;355:1955-1964.
12. The SOLVD Investigators. Effect of enalapril on mortality and the
development of heart failure in asymptomatic patients with reduced left
ventricular ejection fractions. N Engl J Med 1992;327:685-691.
13. The ACE Inhibitors in Diabetic Nephropathy Trialist Group. Should all
patients with type 1 diabetes mellitus and microalbuminuria receive
angiotensin-converting enzyme inhibitors? a meta-analysis of individual
patient data. Ann Intern Med 2001;134:370-379.
14. Jafar TH, Schmid CH, Landa M, et al, for the ACE Inhibition in
Progressive Renal Disease Study Group. Review: Angiotensin-converting
enzyme inhibitors reduce the progression of nondiabetic renal
disease. Ann Intern Med 2001;135:73-87.
15. Wright JW, Bakris G, Greene T, et al, for the AASK Collaborative
Research Group. Effect of blood pressure lowering and antihypertensive class
on progression of hypertensive kidney disease: results from the AASK trial.
JAMA 2002;288:2421-2431.
16. SHEP Cooperative Research Group. Prevention of stroke by
antihypertensive drug treatment in older persons with isolated systolic
hypertension: final results of the Systolic Hypertension in the Elderly
Program (SHEP). JAMA 1991;265:3255-3264.
17. Psaty BM, Smith NL, Siscovick DS, et al. Health outcomes associated with
antihypertensive therapies used as first-line agents: a systematic review
and meta-analysis. JAMA1997;277:739-745.
18. Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure. The sixth report of the Joint National
Committee on the prevention, detection, evaluation, and treatment of high
blood pressure. Arch Intern Med 1997;157:2413-2446.
19. Berlowitz DR, Ash AS, Hickey EC, et al. Inadequate management of blood
pressure in a hypertensive population. N Engl J Med 1998;339:1957-1963.
20. Chobanian AV. Control of hypertension: an important national priority. N
Engl J Med 2001;345:534-535.
21. Whelton PK, He J, Appel LJ, et al. Primary prevention of hypertension:
clinical and public health advisory from the National High Blood Pressure
Education Program. JAMA 2002;288:1882-1888.
----------------------------------------------------
Kirsten Myhr, MScPharm, MPH
Head, RELIS Ost Drug Information Centre
Ulleval University Hospital
0407 OSLO, Norway
Tel: +47 23 01 64 11 Fax: +47 23 01 64 10
kirsten.myhr@relis.ulleval.no (w)
www.relis.no
--
To send a message to E-Drug, write to: e-drug@usa.healthnet.org
To subscribe or unsubscribe, write to: majordomo@usa.healthnet.org
in the body of the message type: subscribe e-drug OR unsubscribe e-drug
To contact a person, send a message to: e-drug-help@usa.healthnet.org
Information and archives: http://www.essentialdrugs.org/edrug