All concepts, explanations, trials, and studies have been
re-written in plain English and may contain errors. I am
not a doctor
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Source: Rev Med Liege 1999 Dec;54(12):952-4
Title: Clinical study of the month. The ATLAS study.
Author: Kulbertus H.

INTRODUCTION:
The Atlas Study compared the effectiveness and safety of
low doses versus high doses of the ACE inhibitor
lisinopril on risk of death and hospitalization in
chronic heart failure.

3,164 class 2-4 CHF patients with an ejection fraction
less than 30% participated. They took either low doses of
2.5 to 5mg daily, 1,596 patients) or high doses (32.5 to
35 mg daily, 1,568 patients) of lisinopril for 39 to 58
months. They were all also taking other standard CHF drug
therapy.

FINDINGS:
Patients in the high dose group had an 8% lower risk of
death, a 12% lower risk of all-cause death or
hospitalization, and 24% fewer hospitalizations for
heart failure. Side-effects such as dizziness and kidney
failure were more frequent in the high dose group, but
the same number of patients quit the drug in both groups.

CONCLUSIONS:
These findings suggest that CHF patients should be on
high doses of the drug if it is tolerated. They may
benefit more if they take higher doses.

PMID: 10686803
=========================================================

Source: Arch Intern Med 2001 Jan 22;161(2):165-71
Title: Toleration of high doses of angiotensin-converting
       enzyme inhibitors in patients with chronic heart
       failure: results from the ATLAS trial.
Authors: Massie BM, Armstrong PW, Cleland JG, Horowitz JD,
         Packer M, Poole-Wilson PA, Ryden L.

INTRODUCTION:
ACE inhibitors reduce mortality and symptoms in patients
with chronic heart failure. However, most patients are
taking doses lower than those used in trials. This study
examines the safety and tolerability of high dose therapy
versus low-dose therapy withlisinopril in CHF.

ATLAS was a randomized, double-blind trial. Patients not
taking an ACE inhibitor were stabilized with medium-dose
lisinopril (12.5 to 15mg daily) for 2 to 4 weeks. They
were then given either high-dose (32.5 to 35mg daily) or
low-dose (2.5 to 5mg daily) lisinopril.

Class 2-4 patients with ejection fractions less than 31%
(3,164 patients) were followed up for an average of 46
months. We studied adverse events and need for stopping
the drug or reducing its dose, with a focus on low blood
pressure and kidney failure.

FINDINGS:
Only 4% of patients could make it to the beginning
"medium" drug dose due to low blood pressure, kidney
dysfunction or too-high potassium level. More than 90%
of patients reached target dose. More low-dose patients
(31%) stopped the drug than high-dose patients (27%).
Patients with low blood pressure to start with, who were
over 70 years old, or who had diabetes tolerated the
drug at high dose well.

CONCLUSIONS:
ACE inhibitor therapy in most CHF patients can be
successfully raised to high doses and higher dose are
advised.

PMID: 11176729
=========================================================
 
Source: Eur Heart J 2000 Dec;21(23):1967-78
Comment in: Eur Heart J. 2000 Dec;21(23):1902-3
Title: Efficacy and safety of high-dose lisinopril in
       chronic heart failure patients at high
       cardiovascular risk, including those with
       diabetes mellitus. Results from the ATLAS trial.
Authors: Ryden L, Armstrong PW, Cleland JG, Horowitz JD,
         Massie BM, Packer M, Poole-Wilson PA.

INTRODUCTION:
We studied whether high-risk CHF patients get the same
benefit from high-dose lisinopril as others in the ATLAS
trial did.

We analyzed ATLAS info on high-risk heart failure
patients (3,164 patients) taking either high-dose (32.5
to 35mg daily) or low-dose (2.5 to 5mg daily) lisinopril
for 46 months. These high-risk patients were those with
low blood pressure, low potassium, kidney problems, the
elderly and diabetics.

FINDINGS:
In ATLAS trial, high-dose lisinopril reduced all-cause
mortality and all-cause mortality plus hospitalization.
There were no differences based on age, sodium level,
creatinine level, or potassium level. Diabetics got the
same benefit from high-dose therapy as non-diabetics.
The higher mortality and complication rate in diabetics
with heart failure means that high-dose lisinopril may
have a very good impact in these patients.

CONCLUSION:
Long-term high-dose lisinopril was as effective and
well tolerated in high-risk patients as anyone else,
including diabetics.

PMID: 11071803
=========================================================

Source: J Card Fail 2000 Jun;6(2):165-8
Title: What does ATLAS really tell us about "high" dose
       angiotensin-converting enzyme inhibition in heart
       failure?
Authors: Nicklas JM, Cohn JN, Pitt B.

INTRODUCTION:
ATLAS trial results have been widely used to promote
using "high" dose ACE inhibitors to treat heart failure.
In ATLAS, however, the relative benefits of "high" versus
"low" dose ACE inhibition were small.

FINDINGS:
Intermediate doses of ACE inhibitors proven effective in
previous placebo-controlled trials give benefit that may
be as good as benefit from "high" doses.

CONCLUSIONS:
We recommend that doctors continue prescribing ACE
inhibitors at the doses used in placebo-controlled
trials and not at the high" dose target used in ATLAS.

PMID: 10908091
=========================================================

Source: Drugs 2000 May;59(5):1149-67
Title: Lisinopril: a review of its use in congestive
       heart failure.
Authors: Simpson K, Jarvis B.

INTRODUCTION:
The ACE inhibitor lisinopril is a derivative of
enalaprilat, which is active part of enalapril (Vasotec).
In heart failure patients, maximum drug effects are seen
6 to 8 hours after taking lisinopril. Drug effects last
for 12 to 24 hours.

High doses (32.5 to 35mg daily) of lisinopril in the
ATLAS trial showed important advantages over low doses
of 2.5 to 5mg daily. High doses more effectively
reduced risk of major events in CHF patients treated
for 39 to 58 months.

FINDINGS:
Compared to patients taking low doses, those taking
high doses had an 8% lower risk of all-cause mortality,
a 12% lower risk of all-cause death or hospitalisation,
and 24% fewer hospitalisations for heart failure.

In short-term (roughly 12 week long) trials, lisinopril
was much more effective than placebo and was at least
as effective as captopril, enalapril, digoxin and
irbesartan at improving symptoms and heart function in
heart failure patients. Lisinopril is usually well
tolerated. The most common adverse events were
dizziness, headache, low blood pressure, and diarrhea.
Adverse events were about the same for high and low
dose patients. Generally, changing drug dose solved
these problems.

CONCLUSIONS:
Lisinopril (when added to diuretics and/or digoxin)
gives symptom relief to heart failure patients. ATLAS
showed that high doses reduced risk of mortality and
complications compared to low doses. The drug was well
tolerated at high doses. Lisinopril is at least as
effective and well tolerated as other ACE inhibitors.

PMID: 10852646
=========================================================

Source: Circulation 2000 Feb 29;101(8):844-6
Title: Maximally recommended doses of
       angiotensin-converting enzyme (ACE) inhibitors do
       not completely prevent ACE-mediated formation of
       angiotensin II in chronic heart failure.
Authors: Jorde UP, Ennezat PV, Lisker J, Suryadevara V,
         Infeld J, Cukon S, Hammer A, Sonnenblick EH,
         Le Jemtel TH.

INTRODUCTION:
The added benefits of ARBs (angiotensin II type I
receptor blockers) to ACE inhibitors suggests that
trial doses of ACE inhibitors only partly stop ACE in
CHF.

Forty-two patients with CHF taking 40mg daily of a
long-acting ACE inhibitor or 150mg of captopril were
studied. Radial artery systolic pressure was monitored.
Response to rising doses of angiotensin I was measured
before and after adding the ARB valsartan. This was also
done afte doubling the ACE inhibitor dose for one week.

FINDINGS:
Pressure went up with rising angiootensin I doses
despite ACE inhibitor therapy. Valsartan greatly blunted
the response. After the ACE inhibitor dose was doubled,
the pressor response to angiotensin I was equal to when
valsartan had been added.

CONCLUSIONS:
Recommended doses of ACE inhibitors do not fully inhibit
ACE in CHF. Greater ACE inhibition is achieved at twice
the recommended dose.

PMID: 10694521
=========================================================

Source: Br J Clin Pharmacol 2000 Jan;49(1):23-31
Title: Comparison of the pharmacokinetics of fosinoprilat
       with enalaprilat and lisinopril in patients with
       congestive heart failure and chronic renal
       insufficiency.
Authors: Greenbaum R, Zucchelli P, Caspi A, Nouriel H,
         Paz R, Sclarovsky S, O'Grady P, Yee KF, Liao WC,
         Mangold B.

INTRODUCTION:
Class 2-4 heart failure patients with chronic kidney failure
(creatinine clearance less than 30ml min-1) took either
fosinopril, enalapril or lisinopril in 2 parallel studies.

In the first study, 12 patients took 10mg fosinopril and 12
patients took 2.5mg enalapril every morning for 10 days. In
the second study 16 patients took 10mg fosinopril and 15
patients took 5mg lisinopril every morning for 10 days.
Blood tests were done.

FINDINGS:
All 3 ACE inhibitors completely inhibited blood ACE levels
for 24 hours. All were well tolerated. There were
differences in how much drug accumulated in the body.

CONCLUSIONS:
Fosinoprilat did not accumulate nearly as much as
enalaprilat or lisinopril in CHF patients with kidney
dysfunction. This may be because fosinoprilat is processed
by both the kidney and liver. Increased processing by the
liver with fosinoprilat may be easier on patients with
kidney problems.

PMID: 10606834
=========================================================

Source: Int J Clin Pract 1999 Mar;53(2):99-103
Title: The incidence of cough: a comparison of
       lisinopril, placebo and telmisartan, a novel
       angiotensin II antagonist.
Author: Lacourciere Y.

INTRODUCTION:
Dry cough is a side effect of ACE inhibitors. We studied
the rate of dry cough with use of 2 such drugs: the ARB
telmisartan and the ACE inhibitor lisinopril. this was a
randomised, parallel-group, double-blind, placebo-controlled,
8 week study of 88 patients with high blood pressure. All
had suffered ACE inhibitor cough before.

FINDINGS:
Patients took either 80mg telmisartan, 20mg lisinopril, or
placebo daily. Cough happened more often with lisinopril
(60%) than with telmisartan (16%) or placebo (10%).

CONCLUSIONS:
Incidence of cough with 80mg telmisartan is much less than
with 20mg lisinopril.

PMID: 10344043