Note: Descriptions are shown in the official language in which they were submitted.
CA 02488370 2000-08-30
Use of Inhibitors of the Renin-Angiotensin System in the Prevention of
Cardiovascular Events
FIELD OF THE INVENTION
The present invention relates to the use of an inhibitor of the renin-
angiotensin
system or a phamlaceuticafly acceptable derivative thereof, optionally
together with
an other antihypertensive, a cholesterol lowering agent, a diuretic or
aspirin, in the
manufacture of a medicament for the prevention of cardiovascular events; to a
method of preventing cardiovascular events comprising administering to a
patient in
need of such prevention an effective amount of an inhibitor of the renin
angiotensin
system or a pharmaceutically acceptable derivative thereof, optionally
together with
an other antihypertensive, a cholesterol lowering agent, a diuretic or
aspirin; or to a
combination product containing an an inhibitor of the renin-angiotensin system
or a
phamzaceutically acceptable derivative thereof and a cholesterol Powering
agent.
BACKGROUND OF THE INVENTION
The renin-angiotensin system (RAS) can be inferred with by inhibition of the
enzymes synthesizing angiotensins or by blocking the corresponding receptors
at
the effector sites. There are many marketed or investigation-stage agents
which
inhibit RAS activity, and many fall into two broad classes: the inhibitors of
angiotensin-converting enzyme (ACE), whose approved names generally end in "-
pril" or in the case of active metabolites "-prilat°, and antagonists
at angiotensin
receptors (more specifically, currently, the AT1 receptor) (Angiotensin 11
Antagonists), whose approved names generally end in "-sartan". Also
potentially of
increasing importance may be a class of drugs known as neutral endopeptidase
(NEP) inhibitors which will also have an ACE-inhibitory effect or the
potential to
reduce RAS activity and are therefore also known as NEP/ACE-inhibitors.
ACE inhibitors are well known in the art for their activity in inhibiting
angiotensin
converting enzyme, thereby blocking conversion of the decapeptide angiotensin
I to
angiotensin ll. The principal pharmacological and clinical effects of ACE
inhibitors
CONFIR~lATI0l~1 COPY
CA 02488370 2000-08-30
z
arise from suppression of synthesis of angiotensin II. Angiotensin II is a
patent
pressor substance and, therefore, blood pressure lowering can result from
inhibition
of its biosynthesis, especially in animals and humans whose hypertension is
angiotensin II related. ACE inhibitors are effective antihypertensive agents
in a
variety of animal models and are clinically useful for the treatment of
hypertension in
humans.
ACE inhibitors are also employed for the treatment of heart conditions such as
hypertension and heart failure. It is known that at least some ACE inhibitors
can
improve (i.e., decrease) morbidity and mortality in patient populations with
heart
conditions, ie. patients with low ejection fraction (EF) or heart failure
(HF), but their
role in a broader population of high risk patients without ventricular
dysfunction or HF
is unknown.
'15 SUMMARY OF THE INVENT10N
The present invention generally relates to the use of an inhibitor of the
renin-
angiotensin system or a pharmaceutically acceptable derivative thereof in the
manufacture of a medicament for the prevention of cardiovascular events.
The present inventions further relates to the use of an inhibitor of the renin-
angiotensin system or a pharmaceutically acceptable derivative thereof in the
manufacture of a medicament for the prevention of myocardial infarction (M!),
worsening of angina and cardiac arrest.
Furthermore, the present inventions relates the use of an ,inhibitor of the
renin-
angiotensin system or a pharmaceutically acceptable derivative thereof ~ in
the
manufacture of a medicament for the prevention of cardiovascular events such
as for
example myocardial infarction (MI), worsening of angina or cardiac arrest in a
patient
with an increased cardiovascular risk, for example due to a manifest coronory
heart
disease, a history of transient ischaemic attacks or stroke, or a history of
peripheral
vascular disease.
CA 02488370 2000-08-30
3
More generally, the present inventions relates the use of an inhibitor of the
renin-
angiotensin system or a pharmaceutically acceptable derivative thereof in the
manufacture of a medicament for the prevention of cardiovascular events in
patients
with no evidence of left ventricular dysfunction or heart failure.
The present invention further relates the use of an inhibitor of the renin-
angiotensin
system or a pharmaceutically acceptable derivative thereof in the manufacture
of a
medicament for the prevention ~f myocardial infarction (MI), stroke,
cardiovascular
death or overt nephropathie in a diabetic patient.
Another embodiment of the present invention is the use of an inhibitor of the
renin-
angiotensin system or a pham~aceutically acceptable derivative thereof
together with
an other antihypertensive, a cholesterol lowering agent, a diuretic or aspirin
in the
manufacture of a medicament for the prevention of cardiovascular events, for
example stroke, congestive heart failure, cardiovascular death, myocardial
infarction,
worsening of angina, cardiac arrest, or revascularisation procedures.
Yet another embodiment of the present invention is the use of an inhibitor of
the
renin-angiotensin system or a pharmaceutically acceptable derivative thereof
together with an other antihypertensive, a cholesterol lowering agent, a
diuretic or
aspirin in the manufacture of a medicament for the prevention of diabetes or
diabetic
complications.
A further embodiment of the present invention is the use of an inhibitor of
the renin-
angiotensin system or a pharmaceutically acceptable derivative thereof
together with
an other antihypertensive, a cholesterol lowering agent, a diuretic or aspirin
in the
manufacture of a medicament for the prevention of congestive heart failure
(CHF) in
a patient not previously having congestive heart failure.
Another embodiment of the present invention is a combination product
containing an
inhibitor of the renin-angiotensin system or a pharmaceutically acceptable
derivative
thereof and an other antihypertensive, a cholesterol lowering agent, a
diuretic or
aspirin for the use in the prevention of cardiovascular events.
CA 02488370 2000-08-30
4
Yet another embodiment of the present invention is a combination product
containing an inhibitor of the resin-angiotensin system or a pharmaceutically
acceptable derivative thereof and a cholesterol lowering agent.
A further embodiment of the present invention is a method of preventing
cardiovascular events, for example myocardial infarction, worsening of angina
and
cardiac arrest, comprising administering to a patient in need of such
prevention an
effective amount of an inhibitor of the resin-angiotensin system or a
pharmaceutically
acceptable derivative thereof, and particular in patients having an increased
cardioavascular risk.
An other embodiment of the present invention is a method of preventing
myocardial
infarction, stroke, cardiovascular death or overt nephropathie in a diabetic
patient,
comprising administering to said patient an effective amount of an inhibitor
of the
resin-angiotensin system or a pharmaceutically acceptable derivative thereof.
A further embodiment of the present invention is a method of preventing
cardiovascular events, for example stroke, congestive heart failure,
cardiovascular
death, myocardial infarction, worsening of angina, cardiac arrest, or
revascularisation
procedures, or diabetes or diabetic complications comprising administering to
a
patient in need of such prevention an effective amount of an inhibitor of the
renin-
angiotensin system or a pharmaceutically acceptable derivative thereof
together with
f..,.~
an effective amount of an other antihypertensive, a cholesterol lowering
agent, a -
diuretic or aspirin (combination therapy).
Yet another embodiment of the present invention is a method of preventing
congestive heart failure in a patient not previously having congestive heart
failure,
comprising administering to said patient an effective amount of an inhibitor
of the
resin-angiotensin system or a pharmaceutically acceptable derivative thereof
together with an effective amount of an other antihypertensive, a cholesterol
towering
agent, a diuretic or aspirin (combination therapy).
CA 02488370 2000-08-30
S
DETAILED DESCRIPTION OF THE INVENTfON
It has been surprisingly found that cardiovascular events such as stroke,
congestive
heart failure, cardiovascular death, myocardial infarction, worsening of
angina,
cardiac arrest, or revascularisation procedures such as coronary atery bypass
graft
surgery (CABG), PTCA, Peripheral Angioplasty Surgery, Amputation, Cariotid
Endarterectomy) and metabolic disorders such as diabetis or diabetic
complications
such as overt nephropathy, renal dialysis or laser therapy, or new
rnicroalbuminuria
can be prevented in a broad population of high risk patients with no evidence
of left
venticular dysfunction or heart failure, by use of an inhibitor of the RAS
system.
Furthermore and very surprisingly, the prevention of such cardiovascular
events is
also observed in a very broad range of high risk patients in addition to other
effective
therapies with for example antihypertensives (other than inhibitors of the RAS
system), diuretics, cholesterol lowering agents or aspirin.
Thus the present invention describes a new method to prevent cardiovascular
events, comprising administering to a patient in need of such prevention an
effective
amount of an inhibitor of the renin angiotensin system or a pharmaceutically
acceptable derivative thereof, optionally together with an other
antihypertensive, a
cholesterol lowering agent, a diuretic or aspirin.
High risk patients are for instance those patients which are at risk having an
cardiovascular event due to a manifest coronary heart disease, a history of
transient
ischaemic attacks or stroke, or a history of peripheral vascular disease.
Another group of high risk patients inctude those patients with diabetis.
-,
The phrase "diabetis' as used herein includes both type I diabetis, also known
as
insulin -dependent, diabetis mellitus (IDMM), and type II diabetis, also known
as
non-insulin-dependent diabetis mellitus (NIDDM).
The phrase "diabetic complications" as used herein includes overt
nephropathy, new microalbuminuria or the need for laser therapy or dialysis.
CA 02488370 2000-08-30
6
The phrase "inhibitor of the renin-angiotensin system (RAS) or a
pharmaceutically
accetable derivative thereof' as used herein includes any compound which by
itself
or upon administration blocks the negative effects of angiotensin II on the
vasculature either by reducing the synthesis of angiotensin II or blocking its
effect at
the receptor.
Inhibitors of the RAS include ACE inhibitors, Angiotensin Il antagonist and
renin
inhibitors and the pharmaceutically accetable derivatives thereof including
prodrugs
and metabolites.
The phrase "angiotensin converting enzyme inhibitor" ("ACE inhibitor") is
intended to
embrace an agent or compound, or a combination of two or more agents or
compounds, having the ability to block, partially or completely, the rapid
enzymatic
conversion of the physiologically inactive decapeptide form of angiotensin
("Angiotensin I") to the vasoconstrictive octapeptide form of angiotensin
("Angiotensin ll"). The phrase "ACE inhibitor" also embraces so-called NEP/ACE
inhibitors (also referred to as selective or dual acting neutral endopeptidase
inhibitors) which possess neutral endopeptidase (NEP) inhibitory activity and
angiotensin converting enzyme (ACE) inhibitory activity.
Example of ACE inhibitors suitable for use herein are for instance the
following
compounds: AB-103, ancovenin, benazeprilat, BRL-36378, BW-A575C, CGS-
13928C, CL242817, CV-5975, Equaten, EU-4865, EU-4867, EU-5476,
foroxymithine, FPL 66564, FR-900456, Hoe-065, 1582, indolapril,
ketomethylureas,
KRI-1177, KRI-1230, L681176, libenzapril, MCD, MDL-27088, MDL-27467A,
moveltiprii, MS-41, nicotianamine, pentopril, phenacein, pivopril, rentiaprii,
RG-5975,
RG-6134, RG-6207, RGH0399, ROO-911, RS-10085-197,'RS-2039, RS 5139, RS
86127, RU-44403, S-8308, SA-291, spiraprilat, SQ26900, SQ-28084, SQ-28370,
SQ-28940, SQ-31440, Synecor, utibapril, WF-10129, Wy-44221, Wy-44655, Y-
23785, Yissum, P-0154, zabicipril, Asahi Brewery AB-47, alatriopril, BMS
182657,
Asahi Chemical C-111, Asahi Chemical C-112, Dainippon DU-1777, mixanpril,
Prentyl, zofenoprilat, 1
(- (1-carboxy-6- (4-piperidinyl) hexyl) amino) -1-oxopropyl octahydro-1H-
indole-2-
carboxylic acid, Bioproject BP1.137, Chiesi CHF 1514, Fisons FPL-66564,
idrapril,
CA 02488370 2000-08-30
perindoprilat and Servier S-5590, alacepril, benazepril, captopril,
cilazapril, delapril,
enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, fisinopril,
perindopril, quinapril,
rarnipril, ramiprilat, saralasin acetate, temocapril, trandoiapril,
trandolaprilat,
ceranapril, moexiprii, quinaprilat and spirapril.
A group of ACE inhibitors of high interest are alacepril, benazepril,
captoprii,
cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat,
imidapril, lisinopril,
perindopril, quinapril, ramipril, ramiprilat, saralasin acetate, temocapril,
trandolapril,
trandolaprilat, ceranapril, moexipril, qerinaprilat and spirapril.
Many of these ACE inhibitors are commercially available, especially those
listed in
. the above group. For example, a highly preferred ACE inhibitor ramipril
(known from
EP 79022) is sold by Aventis, e.g. under the trademark Delix~ or Altacec9.
Enalapril
or Enalapril Maleate, and Lisinopril are two more highly preferred ACE
inhibitors sold
by Merck 8~ Co. Enalapril is sold under the trademark Vasotec~. Lisinopril is
sold
under the trademark Prinivil~.
Examples of NEPIACE inhibitors suitable for use herein inciose those disclosed
in
U.S. Patents Nos. 5,508,272, 5,362,727, 5,36fi,973, 5,225,401, 4,722,810,
5223,516, 5,552,397, 4,749,688, 5,504,080, 5,612,359, 5,525,723, 5,430,145,
and
5,679,671, and European Patent Applications 0481522, 0534263, 0534396,
0534492 and 0671172.
Preferred are those NEPIACE inhibitors which are designated as preferred in
the
above U.S. patents and European Patent Applications. Especially preferred
is the NEPIACE inhibitor omapatrilat (disclosed In U.S. Patent No. 5,508,272,
or MDL100240 (disclosed in U.S. Patent No. 5,430,145)).
The phrase "angiotensin II antagonist" is intended to embrace an agent or
compound, or a combination of two or more agents or compounds, having the
ability
to block, partially or completely the binding of angiotensin II at angiotensin
receptors,
spec~cally at the ATE receptor.
CA 02488370 2000-08-30
g
Example of Angiotensin I1 Antagonists suitable for use herein are for instance
the
following compounds:
Saralasin acetate, candesartan cilexetif, CGP-63170, EMD-66397, KT3-671, LR-
Bl081, valsartan, A-81282, BiBR-363, BIBS-222, BMS-184698, candesartan, CV-
11194, EXP-3174, KW-3433, L-161177, L-162154, LR-B/057, LY-235656, PD-
150304, U-96849, U-97018, UP-275-22, WAY-126227, WK-1492.2K, YM-31472,
losartan potassium, E-4177, EMD-73495, eprosartan, HN-65021, irbesartan,
L-159282, ME-3221, SL-91.0102, Tasosartan, Telmisartan, UP-269-6, YM-358,
CGP-49870, GA-0056, L-159689, L-162234, L-162441, L-163007, PD-123177, A-
81988, BMS-180560, CGP-38560A, CGP-48369, DA-2079, DE-3489, DuP-167,
EXP-063, EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, HR-720, !CI-
D6888, ICI-D7155, ICI-D8731, isoteoline, KRI-1177, L-158809, L-158978, L-
159874,
LR B087, LY-285434, LY-302289, LY-315995, RG-13647, RWJ-38970,
RWJ-46458, S-8307, S-8308, saprisartan, saralasin, Sarmesin, WK-1360, X-6803,
ZD-6888, ZD-7155, ZD-8731, BIBS39, CI-996, DMP-811, DuP-532, EXP-929, L-
163017, LY-301875, XH-148, XR-510, zolasartan and PD-123319.
A group of Angiotensin 11 Antagonists of high interest are saralasin acetate,
candesartan ciiexetil, valsartan, candesartan, losartan potassium, eprosartan,
irbesartan, tasosartan, or telmisartan.
Examples of renin inhibitors suitable for use herein are for instance the
following
compounds: enalkrein; RO 42-5892; A 65317; CP 80794; ES 1005; ES 8891; SQ
34017; CGP 29287; CGP 38560; SR 43845; U-71038; A 62198; A 64662, A-69729,
FK 906 and FK 744.
Pharmaceutically acceptable derivatives of RAS inhibitors are understood to
include
physiologically tolerable salts of RAS inhibitors, such physiologically
tolerable salts
are understood as meaning both their organic and inorganic salts, such as are
described in Remington's Pharmaceutical Sciences (17th Edition, page 1418
(1985}). On account of the physical and chemical stability and the solubility,
for
acidic groups, inter alia, sodium, potassium, calcium and ammonium salts are
preferred; for basic groups, inter alia, salts of hydrochloric acid, sulfuric
acid,
CA 02488370 2000-08-30
9
phosphoric acid or of carboxylic acids or sulfonic acids, such as, for
example, acetic
acid, citric acid, benzoic acid, malefic acid, fumaric acid, tartaric acid and
p-
toluenesulfonic acid are preferred.
The RAS inhibitors suitable for use herein or their pharmaceutically
acceptable
derivatives can be used in animals, preferably in mammals, and in particular
in
human, as pharmaceuticals per se, in mixtures with one another or in the form
of
pharmaceutical preparations.
The present invention also relates to pharmaceutical formulations comprising
as
active ingredient at feast one RAS inhibitor andlor an pharmaceutically
acceptable
derivative thereof in addition to customary pharmaceutically innocuous
excipients
and auxiliaries and their use in the prevention of cardiac events and the
production
of medicaments therefor. The pharmaceutical preparations normally contain 0.7
to
99 percent by weight, preferably 0.5 to 95 percent by weight, of the RAS
inhibitor
and/or an pharmaceutically acceptable derivative thereof. The pharmaceutics!
preparations can be prepared in a manner known per se. To this end, the RAS
inhibitor andlor an pharmaceutically acceptable derivative thereof are
brought,
together with one or more solid or liquid pharmaceutical excipients and/or
auxiliaries
and, if desired, in combination with other pharmaceutical active compounds
into a
suitable administration form or dose form, which can then be used as a
pharmaceutical in human medicine or veterinary medicine.
Pharmaceuticals which contain a RAS inhibitor and/or an pharmaceutically
acceptable derivative thereof can be administered orally, parenterally,
intravenously,
rectally or by inhalation, the preferred administration being dependent on the
particular symptoms of the disorder. The RAS inhibitors andlor an
pharmaceutically
acceptable derivative thereof can be used here on their own or together with
pharmaceutical auxiliaries, namely both in veterinary and in human medicine.
The person skilled in the art is familiar on the basis of his expert knowledge
with the
auxiliaries which are suitable for the desired pharmaceutical formulation. In
addition
to solvents, gel-forming agents, suppository bases, tablet auxiliaries and
other active
CA 02488370 2000-08-30
~1 O
compound excipients, it is possible to use, for example, antioxidants,
dispersants,
emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers or
colorants.
For an oral administration form, the active compounds are mixed with the
additives
suitable therefor, such as excipients, stabilizers or inert diluents and are
brought by
means of the customary methods into the suitable administration forms, such as
tablets, coated tablets, hard capsules, aqueous, alcoholic or oily solutions.
Inert
excipients which can be used are, for example, gum arabic, magnesia, magnesium
carbonate, potassium phosphate, lactose, glucose or starch, in particular corn
starch. Preparation can take place here both as dry and as moist granules.
Possible
oily excipients or solvents are, for example, vegetable or animal oils, such
as
sunflower oil or codliver oil.
.... ,
.,....
~. v
For subcutaneous or intravenous administration, the active compounds are
brought
into solution, suspension or emulsion, if desired with the substances
customary
therefor such as solubilizers, emuls~ers or other auxiliaries. Suitable
solvents, for
example, are: water, physiological saline solution or alcohols, e.g. ethanol,
propanol,
glycerol, and additionally also sugar solutions such as glucose or mannitol
solutions,
or alternatively a mixture of the various solvents mentioned.
Pharmaceutical formulations suitable for administration in the form of
aerosols or
sprays are, for example, solutions, suspensions or emulsions of the active
compound of the formula I in a pharmaceutically acceptable solvent, such as,
in . ,
T.. ...
particular, ethanol or water, or a mixture of such solvents.
If required, the formulation can also contain other pharmaceutical auxiliaries
such as
surfactants, emulsifiers and stabilizers, and also a propellant. Such a
preparation
customarily contains the active compound in a concentration from approximately
0.1
to 10, in particular from approximately 0.3 to 3, % by weight.
The dose of the active compound to be administered and the frequency of
administration will depend on the potency and duration of action of the
compounds
used; additionally also on the nature of the indication and on the sex, age,
weight
and individual responsiveness of the mammal to be treated.
CA 02488370 2000-08-30
On average, the daily dose in a patient weighing approximately 75 kg is at
least
0.001 rng/kg, preferably 0.01 mg/kg, to about 20 mglkg, preferably 1 mg/kg, of
body
weight.
The RAS inhibitors and/or an pharmaceutically acceptable derivative thereof
can
also be used to achieve an advantageous theraupeutic action together with
other
pharmacologicaily active compounds for the prevention of the abovementioned
syndromes.
The present invention furthemlore relates to a combination product containing
an
inhibitor of the renin-angiotensin system or a pharmaceutically acceptable
derivative
thereof and an other antihypertensive, a cholesterol lowering agent, a
diuretic or
aspirin for the use in the prevention of cardiovascular events.
The invention additionally relates very generally to the combination of a RAS
inhibitor
and/or an pharmaceutically acceptable derivative thereof with a cholosterol
lowering
agent.
In addition to administration as a fixed combination, the invention also
relates to the
simultaneous, separate or sequential administration of an RAS inhibitor and/or
an
pharmaceutically acceptable derivative thereof with an other antihypertensive,
a
cholesterol lowering agent, a diuretic or aspirin.
The invention additionally relates to a pharmaceutical preparation comprising
an
RAS inhibitor and/or an pham~aceutically acceptable derivative thereof and a
cholesterol lowering agent (combination product).
The pharmaceutical preparations of the combination product according to the
invention can be prepared, for example, by either intensively mixing the
individual
components as a powder, or by dissolving the individual components in the
suitable
solvent such as, for example, a lower alcohol and then removing the solvent.
CA 02488370 2000-08-30
t1
The weight ratio of the RAS inhibitor andlor an pharmaceutically acceptable
derivative thereof and the cholesterol lowering agent in the novel
combinations and
preparations lies in the range from 1:0.01 to 1:100, preferably 1:0.1 to 1:10.
The novel combinations and preparations in total may contain 0.5-99.5% by
weight,
in particular 4-99% by weight, of these active compounds.
When used according to the invention in mammals, preferably in human, the
doses
of the various active compound components, for example, vary in the range from
0.001 to 100 mg/kg/day.
Typically, the individual daily dosages for these combinations can range from
about =
one-fifth of the minimally recommended clinical dosages to the maximum
recommended levels for the entities when they are given singly.
By means of combined administration, the effect of one combination component
can
be potentiated by the other respective component, i.e. the action and/or
duration of
action of a novel combination or preparation is stronger or longer lasting
than the
action and/or duration of action of the respective individual components
(synergistic
effect). This leads on combined administration to a reduction of the dose of
the
respective combination component, compared with individual administration. The
novel combinations and preparations accordingly have the advantage that the
amounts of active compound to be administered can be significantly reduced and
undesired side effects can be eliminated or greatly reduced.
A preferred combination product would contain for instance as a RAS inhibitors
alacepril, benazepril, captopril, cilazapril, delapril, enalapril,
enalaprilat, fosinopril,
fosinoprifat, imidapril, lisinopril, perindopril, quinapril, ramipril,
ramiprilat, saralasin
acetate, temocapril, trandolapril, trandolaprilat, ceranapril, moexipril,
quinaprilat or ,
spirapril, most preferably ramiprii and as a cholosterol lowering agent
lovastatin,
pravastatin, simvastatin or fluvastatin.
The phrase "combination therapy", in defining use of an inhibitor of the RAS
system
together with an other antihypertensive, a cholosterol lowering agent, a
diuretic or
CA 02488370 2000-08-30
~3
aspirin is intended to embrace administration of each agent in a sequential
manner
in a regimen that will provide beneficial effects of the drug combination, and
is
intended as well to embrace co-administration of these agents in a
substantially
simultaneous manner, such as by oral ingestion of a single capsule having a
fixed
ratio of these active agents or ingestion of multiple, separate capsules for
each
agent.
"Combination therapy" will also include simultaneous or sequential
administration by
intravenous, intramuscular or other parenteral routes into the body, including
direct
absorption through mucuous membrane tissues, as found in the sinus passages.
Sequential administration also includes drug combination where the individual
elements may be administered at different times andlor by different routes but
which
act in combination to provide a beneficial effect.
The phrase "effective amount "is intended to qualify the amount of each agent
for
use in the combination therapy which will achieve the goal of preventing
cardiac
events while avoiding adverse side effects typically associated with each
agent.
Examples of classes of other antihypertensives for use in the combination
product
or useful in the combination therapy are for example calcium channel blockers
(or
calcium antagonists) and beta-blockers.
.. Useful beta-blockers include timolol, atenolol, metoprolol, propanolol,
nadolol and
pindololpropanolol.
Useful calicum channel blockers include diltiazem, felodipine, nifedipine,
amlodipine,
nimodipine, isradipine, nitrendipine and verapamil.
Useful diuretics include methyclothiazide, hydrochlorothiazide, torsemide,
metolazone, furosemide, chlorthalidone, N-(5-sulfamoyl-1,3,4-thiadiazol-2-
yl)acetamide, triamterene, chlorothiazide, indapamide, bumetanide, amiloride,
spironolactone, bendroflumethiazide, benzthiazide, cyclothiazide,
quinethazone,
hydrofiumethiazide, polythiazide, trichlormethiazide, and ethacrynic acid.
CA 02488370 2000-08-30
!4
An example for useful cholesterol lowering agents are statins.
The conversion of 3-hydroxy-Omethylglutaryl-coenzyme A (HMGCoA) to mevalonate
is an early and rate-limiting step in the cholesterol biosynthetic pathway.
This step is
catalyzed by the enzyme HMOCoA reductase. Statins inhibit HMGCoA reductase
from catalyzing this conversion. As such, statins are collectively potent
cholesterol
towering agents.
Statins include such compounds as simvastatin, disclosed in U.S. 4,444,784,
pravastatin, disclosed in U.S. 4,346,227, cerivastatin, disclosed in U.S.
5,502,199
mevastatin, disclosed in U.S. 3,983,140, velostatin, disclosed in U.S.
4,448,784
and U.S. 4,450,171; fluvastatin, disclosed in U.S. 4,739,073, compactin,
disclosed in .-:..
,,.~;..
U.S. 4,804,770; lovastatin, disclosed in U.S. 4,231,938; dalvastatin,
disclosed in EP-
A 738510, fluindostatin, disclosed in EP-A 363934; atorvastatin, disclosed in
U.S.
4,681,893, atorvastatin calcium, disclosed in U.S. 5,273,995; and
dihydrocompactin,
disclosed in U.S. 4,450,171.
Preferred statins include lovastatin, pravastatin, simvastatin and
fluvastatin.
Aspirin irreversibly inactivates platelet cyclooxygenase by acetyiating this
enzyme at
the active site. fn addition to reducing mortality, aspirin also reduces
strokes and
myocardial infarction. The excact mechanisms of the benefit of aspirin is not
known.
EXAMPLES
The examples as set forth herein are meant to exemplify the various aspects of
carrying out the present invention and are not intended to limit the invention
in any
way.
A large-scale clinical trial (HOPE (Heart Outcomes Prevention Evaluation)
Study)
was designed to examine the effect of the ACE inhibitor ramipril versus
placebo in
reducing cardiovascular events. 9,297 high risk patients (>_ 55 yrs with
evidence of
vascular disease or diabetes plus one additional risk factor), without known
low EF
CA 02488370 2000-08-30
or HF were randomized to receive Ramipril (2.5mg to 10mg/day) or matching
placebo for a mean duration of 5 years. The primary outcome was the first
occurrence of the composite of cardiovascular (CV) mortality, myocardial
infarction
or stroke. The study was stopped at 4.5 years by the independent Data and
Safety
Monitoring Board because of convincing evidence of benefit.
646 (13.9%) patients allocated to Ramipril and 816 (17.5%) placebo patients
experienced a primary outcome (Relative risk, RR of 0.78, 95% confidence
interval
of 0.70-0.86; Portable=0.000002). There were clear and significant reductions
separately in CV deaths (6.0% v. 8.0%, RR of 0.75, Portable=0.0002),
myocardial
infarction (9.8% v. 12.0%, RR of 0.68, Portable=0.0002). Secondary outcomes
such
as total mortality (10.3% v. 12.2%, RR of 0.00035), revascularization
procedures
(16.0% v: 18.4%, RR of 0.85, Portable=0.0013), cardiac arrests (0.8% v. 1.2%,
RR
of 0.63; Portable=0.03), heart failure (7.4% v. 9.4%, RR of 0.78;
Portable=0.0005),
and diabetic complications (6.4% v. 7.7%, RR 0.85; Portable=0.017), were also
significantly reduced. Other outcomes included worsening or new angina, or new
heart failure (irrespective of hospitalization).
Ramipril signficantiy reduces mortality, myocardial infarction, stroke,
revascularization procedures, and heart failure and prevents diabetic
complications
in a broad range of high risk patients without low EF or heart failure.
The protocols and results are set forth in the Examples presented hereinbelow.
Example 1
Study Design
fn a double blind, 2x2 factorial, randomized trial, HOPE evaluated Ramiprii or
vitamin
E in 9541 patients. A substudy of 244 patients tested a low dose (2.5 mg/day)
versus
the full dose (10 mg/day) of Ramipril. The primary outcome in these 244
patients is
reported as a footnote to Table 3. Therefore the main results report is on
9,297
patients randomized to receive l0mg Ramipril or equivalent placebo. The
effects of
vitamin E are reported separately. The design of HOPE has been published (Can
J
Cardiology 1996; 12(2); 127-137), a brief summary follows below:
CA 02488370 2000-08-30
16
Patient inclusion/exclusion
Men an women were eligible if aged 55 years and older, with prior coronary
artery
disease, stroke, peripheral vascular disease or diabetes plus at least one
other risk
factor (current or previous hypertension, elevated total cholesterol, low HDL
cholesterol, current cigarette smoking, known microalbuminuria or previous
vascular
disease). Patents who had HF, were known to have low EF, those on ACE-I or
vitamin E, those with uncontrolled hypertension or avert nephropathy, or
recent MI
(<4 weeks) were excluded. In this large, simple trial it was impractical to
measure left
ventricular function in all patients (none of whom had heart failure or were
considered to need an ACE-I). Instead, echocardiograms Were done in all
patients
(n=496) from 3 centres who entered a substudy. 2.6% were found to have an -
.~,,
~;:'.,,
~.~ .
EF<0.40. Additionally, an audit of charts identified that in 5285 patients a
prerandomization and evaluation of ventricular function had been conducted.
Only
409 (7.7%) were documented to have low EF and none had heart failure prior to
randomization. A separate analysis of those documented to have a preserved EF
(n=4876) is provided. After obtaining written informed consent, all eligible
patients
entered a run in phase where they received 2.5mg Ramipril OD for 7-10 days
followed by matching placebo for 10-14 days. Patients who were non compliant
(<80% of pills taken), who experienced side effects, developed abnormal
creatinine
or potassium levels or those who withdrew consent were excluded. 9,541 were
included ; 9,297 were randomized to receive Ramipril at l0mg/day or matching
placebo, with 244 randomized to tow dose (2.5mg/day) of Ramipril. ,
At randomization, patients were allocated to receive Ramipril at 2.5mg OD for
one
week, then 5mg OD for another 3 weeks, followed by l0mg once daily, or
matching
placebo. Additionally, all patients were randomized to vitamin E 400 iU/day or
matching placebo. Follow-up visits occurred at 1 month, 6 months and then at 6
month intervals. At each visit, data were collected on events, compliance, and
side
effects leading to alteration of study medications. Alf primary and secondary
events
were documented on additional forms and were centrally adjudicated using
standardized definitions.
CA 02488370 2000-08-30
Study organization: Patients were recruited over an 18 month period (Dec 1993
to
June 1995) from centres in Canada (129), the USA (27), 14 Western European
countries (76), Argentina and Brazil (30), and Mexico (5). Each institution's
review
board approved the protocol. The study was organized and coordinated by the
Canadian Cardiovascular Collaboration Project Office located at the Preventive
Cardiology and Therapeutics Research Program, Hamilton Health Sciences
Corporation Research Centre, McMaster University, Hamilton, Canada. Adjunct
project offices were located in London, England; Sao Paulo, Brazil and
Rosario,
Argentina. The responsibility for the overall study was undertaken by the
Steering
Committee.
Statistical Analyses: The study was originally designed to follow participants
for a
mean of 3.5 years. However, before the end of this period, the Steering
Committee
(blinded to any results) postulated a possible lag before treatment would have
its full
effects and recommended extension of follow up to 5 years. Assuming an event
rate
of 4% per year for 5 years, with 9,000 patients there would be 90% power to
detect a
13.5% relative risk reduction utilizing a 2 sided alpha of 0.05, analyzed on
an
intention to treat basis. Survival curves were estimated using the Kaplan-
Meier
procedure and compared treatments utilizing a log-rank test. Because of the
factorial
design, all analyses were stratified for the randomization to vitamin E or
control.
Subground analyses were conducted utilizing tests for interaction in the Cox
regression model. This model was also used for treatment effect estimates
adjusted
for any imbalances in key prognostic factors. The adjusted and unadjusted
analyses
provided virtually identical results, so only the unadjusted estimates are
provided.
Interim analysis, data monitoring and early termination: An independent Data
and
Safety Monitoring Board (DSMB) monitored the progress of all aspects of the
study.
Four formal interim analyses were planned. The statistical monitoring boundary
for
benefit required crossing four standard deviations for the first half of the
trial and
three standard deviations in the second half. For harm the respective
boundaries
were three and two standard deviations respectively. The decision to stop or
continue the trial would depend on a number of additional factors including
consistency of results across key subgroups. On March 22nd 1999, the
independent
CA 02488370 2000-08-30
f$
DSMB recommended termination of the trial because of clear and persistent
evidence of benefit of Ramipril which had consistently and clearly crossed the
monitoring boundaries on two consecutive looks. (20% relative risk reduction
in the
primary outcome with 95% CI of 12% to 28%, Z of -4.5; p=0.00001 ). The results
of
the trial were disclosed to the investigators at two meetings held on April
i7th and
April 24th. A cut off for all events for the main analysis was set for April
15th 1999. ,
Close our visits commenced on April 19th and were scheduled to be completed by
June 30th, 199g.
Example 2
i . .
Patient characteristics: t~'
Table 1 provides the baseline characteristics of patients entering the trial.
Of note
there were 2480 women (26.7%), 5128 individuals>_65 years (55.2%), 8160 with
vascular disease (87.8%), 4355 with a history of hypertension (46.8%) and 3578
with
diabetes (38.5%). This makes HOPE the largest trial of ACE-I in women, the
elderly
and among diabetics and with a sizeable number of high risk hypertensives.
Table 1: Baseline Characteristics of the HOPE Study Patients
Ramipril Placebo
n (%) N (%)
No. Randomized N = 4645 N = 4652 w
Mean Age 66 (7} 66 (7)
No. Women 27.5 25.8
History of Coronary artery disease 3691 (79.5) 3784 (81.3)
Myocardial infarction 2410 (51.9) 2482 (53.4)
<_ 1 year 1 452 (9.7) 445 (9.6)
> 1 year 1985 (42.7) 2070 (44.5)
~
Stable angina pectoris 2538 (54.6) 2609 (56.1
I )
Unstable angina pectoris 117g (25.4) 1188 (25.5}
CABG surgery 1192 (25.7) 1207 (25.9}
CA 02488370 2000-08-30
t9
~CA I 853 (18.4) 806 (17.3)
I
~ Stroke or Transient ischemic attacks f 500 (10.8) 513 (11.0
Peripheral Vascular disease 1963 (42.3) 2083 (44.8)
Hypertension I 2212 (47.6) 2143 (46.1
)
~ Diabetes
1808 (38.9) 1770 (38.0)
Known elovated total cholesterol 3036 (65.4) 3089 (66.4)
Known low LDL 842 (18.1) 882 (19.0)
Current cigarette smoking ~ 645 (13.9) 674 (14.5)
Drugs at Baseline:
Beta Blockers 1820 (39.2) 1853 (39.8)
Aspirin/ other antiplatelets 3497 (75.3) 3577 (76.9)
Lipid lowering agent 1318 (28.4) 1340 (28.8)
Diuretics 713 (15.3) 706 (15.2)
Calcium channel blockers 2152 (46.3) 2228 (47.9)
ECG left ventricular hypertrophy 378 (8.1) 405 (8.7)
No. With microalbuminuria 955 (20.6) 1008 (21.7)
Blood Pressure 139179 139/79
Heart Rate 69 69
Body Mass Index 26 28
CABG = Coronary artery bypass graft surgery, PTCA = Percutaneous transhuminal
coronary angioplasty, No. = number, LDL = Low density Lipoprotein. Peripheral
vascular disease includes ciaudication, history of peripheral arterial disease
or ankle-
arm BP ratio of <0.90.
Example 3
Compliance
Among those allocated to the Ramiprii group, the proportion taking study or
open
label ACE-I was 87.4% at 1 year, 85.2% at 2 years, 82.2% at 3 years, 75.5% at
4
years and 78.3% at the final visit. 82.9% were receiving 10mg of Ramipril at 1
year,
74.8% at 2 years, 71.0% at 3 years, 62.8% at 4 years and 64.6% at last visit.
Among
those allocated to placebo, the proportion on open label ACE-1 was 3.4%, 6.0%,
8.1 %, 10.7% and 12.7% respectively. At the end of the study 1.6% of Ramipril
CA 02488370 2000-08-30
patients and 1.9% of placebo patients were receiving an angiotensin-2 receptor
antagonist. The most common reasons for discontinuing blinded medication ace
outlined in Table 2. More patients in the Ramipril group stopped medications
for
cough (7.2% v 1.7%) or hypertension (1.8% v 1.4%). By contrast, more placebo
5 patients stopped blinded medication for uncontrolled hypertension (0.3% v
0.6%) or
for a clinical event (1.9% v 2.4%). The proportions of patients receiving non-
study
ACE-I for heart failure was 3.3% in the active group and 4.5% in the placebo
group,
for proteinuria was 1.4% v 1.6%, and for control of hypertension 4.4% v 6.2%.
The
use of open label A-2 receptor antagonists in both groups was low (1.6% v
1.9%) but
10 the reasons reflect a pattern similar to the use of ACE-inhibitors (heart
failure 0.6% v
0.8%, hypertension 1.1 % v 1.3%).
Table 2: Reasons for discontinuing blinded medication
E-::.:~:
~_r
Ramipri! Placebo
No. Randomized 4645 4652
No. Stopping at any time' 1370 (33.0) 1247 (30.7)
No. Permanently discontinuing* 1207 (29.1 1087 (26.7)
)
Reasons for stopping
Cough 335 (7.2 %) 81 (1.7 %)
Hypotensionldizziness 82 (1.8 %) 65 (1.4 ~)
Angioedema 16 (0.3 %) 12 (0.3 %)
Uncontrolled Hypertension 16 (0.3 %) 30 (0.6 %)
Clinical Events 9C (1.9 %) 113 (2.4 %) dry
Non-study ACE-I 124 (2.7 %) 187 (4.0 %)
Reasons for using open label ACE-l:
Heart Failure 231 (5.0 %) 320 (6.9 %)
Proteinuria 63 (1.4) 73 (1.6 %)
Hypertension 205 (4.4 %) 289 (6.2 %)
15 ' % of alive
Example 4
Blood Pressure
CA 02488370 2000-08-30
2!
The BP at entry was 139179 in both groups. This decreased to 133176 in the
active
group and 137178 in the control group at 1 month, 135r16 and 138/78 at 2 years
and
136/76 and 139/77 at the end of the study.
Example 5
Primary Outcomes and total mortality (Table 3)
There were 646 patients in the Ramipril group (13.9%) who suffered CV death,
MI or
stroke compared to 816 (17.5%) in the placebo group (RR of 0.78, 95% Ci of
0.70-
0.86; p=0.000002). In addition there were highly significant reductions
separately in
CV mortality (278 v 371, RR of 0.75, 95% CI of 0.64-0.87; p=0.0002), MI (453 v
559,
RR of 0.80, 95% Ci of 0.71-0.91; p=0.0005) and stroke (155 v 225, RR of 0.68,
95°!°
w .. CL of 0.56-0.84; p=0.0001). All cause mortality was also significantly
reduced (476 v
567, RR of 0.83, 95% CI of 0.74-0.94; p=0.0035).
Table 3: Primary Outcome and its Components in the HOPE Study
Ramipril Placebo RRR (95 % CI) Z Log
rank p
No. Randomized4645 4652
CV death, MI, 646 (13.9 816 (17.5 0.78 (0.70-0.86)-4.75 0.000002
Stroke* %) %)
CV death 278 (6.0 371 (8.0 0.75 (0.64-0.87)-3.72 0.0002
%) %)
MI 453 (9.8 559 (12.0 0.80 (0.71-0.91)-3.49 0.0005
%) %)
Strokes 155 (3.3 225 (4.8 0.68 (0.56-0.84)-3.70 0.0002
%) %)
Total mortality476 (10.3 567 (12.2 0.83 (0.74-0.94)-2.92 0.0035
%) %)
*There were an additional 34/24.4 events with low dose Ramipril. Inclusion of
these
events leads to 13.9 % primary events with Ramipril v .7.5 % with placebo (RRR
of
0.78, 95 % CI of 0.70-0.86). Note that patients could have experienced more
than
one event.
Example 6
Secondary and other outcomes (Table 4)
CA 02488370 2000-08-30
2L
There was a signifcant reduction in the number of patients undergoing
revascularization procedures (742 v 854, RR of 0.85, 95% CE of 0.77-0.94;
p=0.0013), and a trend to fewer HF hospitalizations (150 v 176; RR of 0.84,
95% CI
of 0.68 to 1.05; p=0.13). However, there was no impact on hospitalizations for
unstable angina. There were also significant reductions in the number of
patients
with cardiac arrests (37 v 58, RR=0.63, pØ03) worsening angina (1104 v 1220,
RR=0.88, p=0.003), new heart failure (343 v 435, RR=0.78, p=0.0005), new
diagnosis of diabetes (108 v 157, RR=0.69, p=0.003), or those experiencing
diabetic
complications (319 v 378, RR=0.85, p=0.018).
Table 4: Secondary and other Outcomes in the HOPE Study
Ramipril Placebo RRR (95 % Cl) Z Log
rank
p
No. Randomized 4.645 4652
Secondary Outcomes
Revascularization*742 (16.0 854 (18.4 0.85 (0.77-0.94)-3.220.0013
%) %)
Unstable angina 564 (12.1 573 (12.3 0.98 (0.87-1.10) n.s.
hospitafization* %) %)
Diabetic 298 (6.4 357 (7.7 0.83 (0.71-0.97)-2.390.017
Complications %) lo)
+*
Heart Failure 150 (3.2 176 (3.8 0.84 (0.68-1.05)-1.530.13
Hospitalizations*%) %)
Other Outcomes
All Heart Failure**3.43 (7.4 435 (9.4 0.78 (0.67-0.90)-3.570.0005
%) %)
Cardiac Arrests 37 (0.8 58 (1.2 lo) 0.63 (0.42-0.96)-2.190.03
%) ~
Worsening angina**1104 (23.8 1220 (26.2 0.88 (0.81-0.96)-2.980.0029
%) %)
New diagnosis 108 (3,8 157 (5.5 0.69 (0.54-0.88)-3.010.0026
of %) %)
diabetes
UA with ECG 179 (3.4 185 (4.0 0.96 (0.78-1.18) n.s.
changes %) %)
CA 02488370 2000-08-30
23
Centrally adjudicated events, ** includes cases irrespective of
hospitalization.
+ Diabetic complications include diabetic nephropathy, renal dialysis and
laser
therapy for diabetic retinopathy.
Example 7
Subgroup analysis (Table 5)
The beneficial impact on the primary outcome was consistently observed among
diabetic and nondiabetic patients; females and males, those with and without
evidence of vascular disease, those under and over 65 years, those with and
without
hypertension at baseline and those with and without microalbuminuria at
baseline. In
addition, there was a clear benefit among both groups of patients entering the
study
with or without evidence of coronary artery disease, with and without an MI
and
among those (n=4676) with a documented EF >_0.40 (317/2339 v 427/2337, RR of
0.73, 95% CI of 0.63-0.84, p=0.00002).
Table 5: impact of Ramipril compared to Placebo in Various Subgroups: Note the
consistency of results and that the upper 95 % CI is less than 1 in most
instances.
No. of Placebo Primary Composite
Patients Rate Outcome
RRR (95 % C1)
A) Prespecified Subgroups
CVD + - - 8160 18.5 078 (0.71 - 0.87)
... CVD - 1137 10.1 0.81 (0.56 -
. 1.20)
Diabetes+ 3578 19.6 0.76 (0.65 -
0.89)
Diabetes- 5719 16.3 0.79 (0.69 -
0.91 )
B) Other Subgroups
Age <65 4169 , 14.0 0.82 (0.70 -
0.98)
Age 65+ 5128 I 20.5 0.75 (0.66 -
0.85)
Male 6817 18.5 I 0.79 (0.70 -
0.89)
---~
Female I 2480 ~ 14.7 ' )
1 0.76 (0.61 -
0.95
Hypertension + 4355 19.0 0.75 (0.65 -
0.87)
Hypertension - 4942 16.3 ~ 0.81 (0.70 -
0.93)
CAD+ i 7475 18.4 0.80 (0.71 -
0.89)
CA 02488370 2000-08-30
2.~
~D- 1822 - '-- ~ 13.g - ~ 0.71 (0.54 -
~- 0.93)
~
.
~ 4892 ~ 20.7 I 0.79 (0.69 -
P 0.90)
or MI+
n
'Prio Mi- 4405 i 14.0 ~ 0.77 (0.65 -
0.91)
Cerebro VD+ 1013 25.5 ~ 0.73 (0.56 -
0.95)
Cerebro VD- 8284 16.6 0.79 (0.71 - 0.88)
PVD+ 4046 21.8 ~ 0.74 (0.64 - 0.86)
PVD- 5251 14.1 0.84 (0.72 - 0.98)
'MA+ 1963 26.1 0.71 (0.59 - 0.86)
MA- 7334 15.2 0.82 (0.72 - 0.92)
GVU = Cardiovascular disease, GAD = Coronary artery disease,
MA = Microalbuminuria, PVD = Peripheral vascular disease
;;T4
Example 8
Time Course of Benefit
The reduction in the primary outcome was evident within 1 year after
randomization
(167 v 197, RR of 0.85; 95% CI of 0.69 to 1.04), and became statistically
significant
at 2 years (323 v 396; RR of 0.81; 95% CI of 0.70 to 0.94. Conditioned on
survival up
to the prior year, the relative risk in the second year was 0.78, in the third
0.74, and
0.73 in the fourth year.
DISCUSSION
The HOPE trial conclusively proves that Ramipril, an ACE-I, is beneficial in a
broad
range of patients without evidence of LV systolic dysfunction or HF who are at
high ~,~.;
risk of future cardiovascular events. There are clear reductions in each of
mortality,
M1 and strokes. Coronary revascularizations, cardiac arrests and development
of
heart failure are also clearly reduced. Ramipril also reduces the risk of
diabetic
complications; and the development of diabetes among non-diabetics.
Benefits of ACE-I Now Extend More Widely
These data substantially expand the population who would benefit from ACE-I
and
ace complementary to previous studies in patients with low EF or HF and acute
MI.
The underlying rationale for the HOPE study was that ACE inhibition would
prevent
the events that related to ischemia and atherosclerosis, in addition to the
heart
failure and left ventricular dysfunction. To avoid potential confusion in the
CA 02488370 2000-08-30
i5
interpretation of the results of this study, we deliberately confined our
trial to those
without HF and excluded those with a known low EF. The study did include,
however, the large number of individuals at risk of outcomes related to the
progression of atherosclerosis and thrombotic vascular occlusion. Thus a broad
range of patients with any manifestation of coronary artery disease (eg
unstable
angina, stable angina or previous revascularization), previous history of
cerebrovascular disease or peripheral arterial disease were included. As a
result, we
have been able to demonstrate the value of ACE-I in a broad spectrum of
patients
with a range of clinical manifestations of atherosclerosis that increased the
risk of CV
death, Ml or stroke. This approach is neither primary or secondary prevention,
but is
rather a high risk prevention strategy, which includes individuals with a high
likelihood of a future event, rather than including patients solely by the
presence of a
speck risk factor or occurrence of a speck cardiovascular event. The present
results attest to the success of this approach in identifying a high-risk
population with
a signifecant rate of CV endpoints who are likely to benefit from a therapy
which
prevents the progression of atherosclerosis or its complications. These
findings
along with those from previous trials are of major clinical importance and
indicate
that documentation of low EF on HF should not be a criterion to using ACE-!
long
term in patients who are at high risk of CV events, due to other clinical
criteria.
There were 3578 diabetic patients entering our study, of whom 1100 had no
clinical
manifestations of CVD, and their risk of CV outcomes was lower by about half.
Despite this, the RRR we observed was consistent with the overall benefit in
the trial
and among such diabetics the composite outcome of CV death, MI, stroke, heart
failure, revascularization and diabetic complications was significantly
reduced.
Benefits of ACE-i Similar to Other Preventive Strategies
The magnitude of benefit of ACE-I is at least as large as that observed with
other
proven secondary prevention measures such as betablockers (Yusuf S et aL, Prog
Cardiovasc Dis 1985; 27(5): 335-371), aspirin (BMJ 1994; 308(6921): 81-106)
and
lipid lowering (Law M. Lipids and cardiovascular disease. Chpt 13 In: Yusuf S,
Cairns
JA, Camm AJ, Fallen EL, Gersh BJ. (Eds), Evidence Based Cardiology. London:
BMJ Books, 1998. Pg. 191-205) over a 4 year treatment period. Given the broad
population in HOPE and previous trials of ACE-l, the very clear evidence of
beneft in
CA 02488370 2000-08-30
addition to other effective therapies and high tolerance, ACE-I have a major
role in
CV prevention and treatment. The relative risk reduction in the first year of
the trial
was about 11 °!°, increasing to 22% (conditional RRR) in the 2nd
year, 26% in the 3rd
year and 27% in the 4th year. These data indicate a very rapid emergence of
benefit
with increasing divergence in the second year which is at least maintained and
perhaps increased in future years. This suggests that the benefits of ACE-i
are likely
to be sustained and perhaps enhanced on longer term treatment.
Benefits are Additional to Concomitant Proven Medications
The benefits of Ramipril were observed among patients receiving a number of
effective treatments such as aspirin, betablockers and lipid lowering agents
indicating that ACE inhibition offers an additional approach to prevent
atherothrombotic complications. Only a small part of the reductions in CV
mortality,
Mt and strokes could be attributed to BP reduction as the majority of patients
entering the study were not hypertensive (hy conventional definitions) and the
difference in BP reduction was extremely modest {-3 systolic /-2 mmHg
diastolic). A
2mm reduction in diastolic BP reduction might at best explain about half in
the
reduction in stroke and about one-quarter of the reduction in myocardial
infarction
(Collins R. et al., Lancet 1990; 335(8693): 827-838). However, recent trials
such as
the Hypertension Optimum Treatment (Hansson L. et al., Lancet 1998; 351 (91 t
8):
1755-1762} have suggested that for high risk patients, eg diabetics, it may be
beneficial to lower BP even within the "normal" range. Moreover, a recent
reanalysis
of the Framingham Heart Study based on 20 year BP data (Clarke R. et al., Am
,! w'v;
Epidemiology 1999; 150(4): (In press) suggests that the degree of benefit
expected
from a lower BP may have been underestimated. Despite these considerations, it
is
possible that additional direct mechanisms of ACE-1 on the heart or the
vasculaturs
is of importance. This includes antagonizing the direct effects of angiotensin-
11 on
vasconstriction, vascular smooth muscle proliferation (Lonn EM et a1.
Circulation
1994; 90(4): 2056-2069) and plaque rupture (Schieffer B. et al., Circulation
(in
press}); improvement in vascular endothelial function, reduction of LV
hypertrophy
and enhanced fibrinolysis (Loan EM et al. Circulation 1994; 90(4): 2056-2069).
CA 02488370 2000-08-30
z~
Also a reduction in the number of patients developing or being hospitalized
for heart
failure was observed in patients with no evidence of impairment of LV systolic
function. These data complement the SOLVD Prevention Trial in patients with
low
EF, and the SAVE trials (low EF early post-MI) which demonstrated that ACE-I
prevent the development of heart failure; and the trials in patients with
documented
low EF and HF which indicated a reduction in hospitalization for heart
failure. HOPE
and these studies indicate that ACE-I are likely to be of value among patients
who
are at high risk of developing heart failure irrespective of the degree of
left ventricular
systolic dysfunction. One issue that should be considered is the extent to
which the
results may have been affected by inclusion of individuals with undiagnosed
low EF.
This is likely to be very low because a) a large substudy in 3 centres
involving 468
consecutive patients indicated that only 2.6% had an EF below .40, b) an
extensive
chart audit ident~ed only <5% of patients with a low EF prior to
randomization; and
c) clear benefit (RR of 0.73, 95% CI of 0.63 to 0.84; p=0.00002) was seen in
the
subgroup of patients (n = 4676) with documented preserved ventricular function
and
also in those without previous Ml. (RR of 0.79, 95% CI of 0.69 to 0.90;
p=0.0004)
Possible Mechanisms of Benefit in Diabetes
A marked reduction in the number of patients developing diabetic complications
and
the number being newly diagnosed as having diabetes was observed. These
effects
may be mediated through improved insulin sensitivity or a decrease in hepatic
clearance of insulin. The results are also consistent with the results of the
recent
Captopril Prevention Project trial (Hansson L. et al., Lancet 1999; 353(9153):
611-
616), which indicated a reduction in newly diagnosed diabetes in patients
randomized to captopril compared to a diuretic or beta blocker, and other
trials
indicating that the progression of diabetic nephropathy among type I!
diabetics
treated with an ACE-inhibitor is reduced (Ruggenenti P. et a1. Lancet 1999;
354
(9176): 359-364).
Safety and Tolerability
The ACE-inhibitor Ramiprii, was generally well tolerated in the trial. Apart
from an
increase in the number of patients stopping Ramipril for cough (excess of 5%),
no
other side effect was significantly more frequent. There was a small
nonsignificant
CA 02488370 2000-08-30
28
increase in the number of patients stopping medication for
dizzinesslhypotension
(0.3%). The majority of patients (approximately 80%) remained on an ACE-i over
the
4_2 year duration of the trial.
Conclusion
The HOPE study clearly demonstrates that Ramipril, a long acting ACE-
inhibitor,
reduces mortality, M1, strokes, revascularization rates, cardiac arrests, new
heart '
failure and diabetic complications in a broad spectrum of high risk patients.
Treating
1000 patients with ACE-inhibitors for 4 years prevents 160 patients from
experiencing any one of the above events.
As various changes can be made in the above-described subject matter without
departing from the scope and spirit of the invention, it is intended that all
subject ~_
matter contained in the above description, shown in the accompanying drawings,
or
defined in the appended claims, be interpreted as descriptive and
illustrative, and not
in a limiting sense. Many modifications and variations of the present
invention are
possible in fight of the above teachings. It is therefore to be understood
that within
the scope of the appended claims, the invention may be practiced othervvise
than as
spec~calfy described.
