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COMBINATION DRUG THERAPY FOR TREATING HYPERTENSION
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S, provisional application
serial
no. 60/459,563, filed April 1, 2003, and U.S. application serial no.
10/405,076,
filed April 1, 2003, which are incorporated herein by reference in their
entireties.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR
DEVELOPMENT
(0002] This invention was made with U.S. government support under the
National Heart, Lung, and Blood Institute Grant Nos. U01 HL64.924-02 and N01-
HV-68163. The U.S. government has certain rights in this invention.
BACKGROUND
[~003] Cardiovascular disease has become a global burden, manifesting itself
in ever-increasing rates of coronary heart disease (CND), hypertension (HTN),
and stroke. In the United States alone, cost estimates for 2003 cardiovascular
disease-related health-care expenditures exceed $351 .8 billion. The world's
population is aging, and although deaths due to acute myocardial infarction
(MI)
have decreased, the .prevalence of obesity, inactivity, and other risk factors
is
increasing, leading to an epidemic of diabetes and other comorbid conditions.
[0004] Hypertension management in patients has become a complex clinical
challenge, especially in patients with coronary artery disease (CAD) in which
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HTN management requires not only lowering blood pressure (BP), but also
comprehensive therapy focused on the entire vascular system, with the goal of
preserving organ function. Although anti-hypertensive drug therapy may reduce
morbidity and mortality, the optimal choice for initial therapy of HTN is
uncertain, especially in CAD patients who often are excluded from HTN
treatment trials.
[0005] Previous trials documented the benefit of lowering BP primarily by
using thiazide diuretics, (e.g., hydrochlorothiazide), and beta-adrenergic
blockers, but these trials were predominantly done in elderly patients who had
isolated systolic HTN and in an era prior to coronary revascularization, organ
protection, and other contemporary treatments. When newer anti-hypertensive
agents (e.g., dihydropyridine calcium antagonists (DHP CAs), non-
dihydropyridine calcium antagonists (non-DHP CAs), and angiotensin-converting-
enzyme inhibitors (ACEIs)) became available, placebo-controlled trials
d~cumented that these agents may reduce the incidence of adverse events in
hypertensive individuals, while providing equivalent efficacy in reducing
blood
pressure. However, none of these trials were performed and completed using
large populations of high-risk patients,, and as such, limited conclusions
could be
drawn with respect to patients with hypertension and CAD.
[0006] Current trends in hypertension management emphasize multidrug
regimens rather than monotherapy. Combinations of antihypertensive drugs
with complementary actions may minimize adverse effects and reduce clinical
outcomes by improving blood pressure control and organ protection. [3-Blockers
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are effective in hypertension treatment and reduce incidence of death and
reinfarction in patients who have had a myocardial infarction (MI). Along with
diuretics, (3-blockers became the standard of care for hypertensive CAD
patients.
However, (3-blockers may be less effective antihypertensive agents in older
patients, who are also more likely to have CAD. The possibility that other
antihypertensive regimens, particularly those containing calcium antagonists
and/or angiotensin II active agents, might be as or snore effective than ~i-
blocker
and/or diuretic regimens has not been convincingly demonstrated. Previous
trials were performed predominantly in populations with low frequencies of CAD
and used dihydropyridine calcium antagonists. A recent trial in high-risk
hypertensive patients showed that a combination of an angiotensin II-receptor
blocker and a diuretic was more effective than a combination of a ~3-blocker
and
a diuretic.
[0007] Heart rate-reducing nondihydropyridine calcium antagonists, on the
other hand, have rarely been studied in large randomised hypertension trials,
although verapamil appears to reduce the risk of death and reinfarction in
acute
CAD trials. The combination of a nondihydropyridine calcium antagonist and an
angiotensin-converting enzyme (ACE) inhibitor may provide better blood
pressure
control and organ protection than monotherapies. Many recent trials indicate
that drugs influencing the actions of angiotensin II can be beneficial in high-
risk
patients, but no hypertension trial has prospectively used these agents for
CAD
patients with diabetes, renal impairment, or heart failure.
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[0008] As such, a better understanding of how these newer anti-hypertensive
agents may be used to treat hypertension is needed, particularly in patients
with
CAD, diabetes, or those at risk for strokes. Also, a better understanding of
how
these newer anti-hypertensive agents may be used in combination is needed.
Accordingly, we designed a randomized trial, the INternational VErapamil-
E
trandolapril STudy (INVEST), to determine the effects of a CA BP treatment
strategy (CAS) versus a non-CA strategy INCAS) in hypertensive CAD patients.
In particular, INVEST determined the effects when verapamil, (a non-DHP CA),
versus atenolol (a beta-adrenergic blocker), was used in combination with an
ACEI, such as trandolapril, and a diuretic, such as hydrochlorothiazide
(HCTZ).the International Verapamil-Trandolapril Study (INVEST), to compare
outcomes in older hypertensive patients with CAD treated with a calcium
antagonist strategy (CAS; verapamil sustained release [SR]) or a non-calcium
antagonist strategy INCAS; atenolol). Because most older hypertensive patients
require more than 1 agent to adequately control blood pressure, INVEST was
intended to compare multidrug strategies rather than iridividual agents.
SUMMARY
[0009] Described herein is a pharmaceutical composition comprising a
combination of anti-hypertensive agents, such as calcium antagonists (CAs)
(preferably non-dihydropyridine (non-DHP) calcium antagonists), angiotensin-
converting-enzyme inhibitors (ACEIs), and diuretics. Preferably, the CA is
verapamil; the ACEI is trandolapril, and the diuretic is hydrochlorothiazide
(HCTZ). Derivatives of verapamil, trandolapril, and HCTZ, with similar
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therapeutic activities may be used as well. The pharmaceutical composition
also
typically contains one or more pharmaceutical carriers or excipients.
[0010] In one embodiment of the pharmaceutical composition, trandolapril, or
a derivative thereof, may be present in any amount (e.g., between about 0.5 mg
and about 8 mg); verapamil, or a derivative thereof, may be present in any
amount (e.g., between about 40 mg and about 480 mg); HCTZ, or a derivative
thereof, may be present in any amount (e.g., between about 6.25 mg and about
100 mg); with the proviso that if the composition comprises 4 mg trandolapril
or
8 mg trandolapril and the composition comprises 12.5 mg hydrochlorothiazide or
25 mg hydrochlorothiazide, the composition does not comprise 180 mg
verapamil; and with the proviso that if the composition comprises 4 mg
trandolapril and 12.5 mg hydrochlorothiazide, the composition does not
comprise 360 mg verapamil. Preferred amounts of trandolapril are about 0.5
mg, 1 mg, 2 mg, 4 mg, 6 mg, and 8 mg; preferred amounts of verapamil are
about 40 mg, 80 mg, 100 mg, 120 mg, 180 mg, 200 mg, 220 mg, 240 mg,
300 mg, 360 mg, and 480 mg; and preferred amounts of HCTZ are about 6.25
mg, 12.5 mg, 25 mg, 37.5 mg, 50 mg, 75 mg, and 100 mg.
[0011 ] In the aforementioned pharmaceutical compositions, one or more of
trandolapril, verapamil, HCTZ, and/or their derivatives may function as active
ingredients to achieve a therapeutic result. For example, trandolapril
verapamil,
and/or hydrochlorothiazide may function as anti-hypertensive agents to treat
hypertension and to achieve and maintain target blood pressures. As such,
trandolapril, verapamil, and/or hydrochlorothiazide may be present in an
effective
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amount to achieve and maintain target blood pressures when the compositions
are administered to a patient (e.g., a patient with CAD). A preferable target
blood pressure may include a systolic blood pressure (SBP) of no more than
about 150, 145, or 140 mm Hg (or 150-140 mm Hg) and a diastolic blood
pressure (DBP) of no more than about 90 mm Hg. More preferably, a target
blood pressure may include a. systolic blood pressure (SBP) of no more than
about 140 mm Hg and a diastolic blood pressure (DBP) of no more than about
90 mm Hg. In other embodiments, the aforementioned compositions may be
administered to a patient to achieve and maintain other target blood pressures
(e.g., a systolic blood pressure of no more than about 135 mm Hg and a
diastolic blood pressure of no more than about 35 mm Hg, or alternatively, a
systolic blood pressure of no more than about 130 mm Hg and a diastolic blood
pressure of no more than about 30 mm Hg). As such, the active ingredients
may be useful for decreasing SBP and DBP (e.g., by about 10% or more relative
to a baseline measurement.) The above-described target blood pressures may
represent mean blood pressures as determined over a set time period.
(0012] The aforementioned pharmaceutical compositions may be formulated
for controlled release. For example, the pharmaceutical compositions may be
formulated together with a matrix that delays the release of one or more of
the
active ingredients. As such, in one embodiment, the aforementioned
compositions may provide effective blood pressure control or other therapeutic
effects for about 24-30 hours when administered to a patient. ~ In another
embodiment, the aforementioned compositions provide effective blood pressure
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control or other therapeutic effects for days, weeks (e.g., about 7 days),
and/or
months (e.g., about 30 days) when administered to a patient. "Effective blood
pressure control" may mean achieving an maintaining target blood pressures as
described above, (e.g., SBP of no more than about 150, 145, 140, 135, or 130
mm Hg, and DBP of no more than about 90, 85, or 80 mm Hg). "Effective
blood pressure control" may also mean a decrease SBP and DBP (e.g., by at
least about 10% relative to baseline measurements).
[0013] The aforementioned pharmaceutical compositions may be formulated
for any suitable method of administration (e.g., oral, topical, transdermal,
subcutaneous, parenteral, or pulmonary administration, and preferably oral,
transdermal, or parenteral administration). Oral and/or other formulations may
include tablets, capsules, granules, powders, suspensions, liquids, and/or
emulsions.
[0014] Also disclosed herein is a method of treating hypertension in a patient
to achieve and maintain a target blood pressure by administering the above-
described compositions. A preferable target blood pressure may include a SBP
of no more than about 150, 145, or 140 mm Hg and a DPB of no more than
about 90 mm Hg; more preferably a SBP of no more than about 135 mm Hg and
DBP of no more than about 85 mm Hg; and even more preferably a SBP of no
more than about 130 mm Hg and a DBP of no more than about 80 mm Hg. The
method may also be used to decrease SBP and DBP relative to baseline
measurements (e.g., by at least about 10%).
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[0015] The method includes administering a composition that comprises one
or more pharmaceutically suitable carriers or excipients and active
ingredients
including an angiotensin-converting-enzyme inhibitor, a calcium channel
blocker
(preferably a non-DHP CA), and a diuretic. One or more of the active
ingredients
are present in an effect amount to treat hypertension. Any of the
aforementioned pharmaceutical compositions may be administered in the
method. Preferably, the angiotensin-converting-enzyme inhibitor is
trandolapril;
the calcium channel blocker is verapamil; and the diuretic is HCTZ.
Derivatives
of trandolapril, verapamil, and HCTZ with similar therapeutic activities may
be
used as well.
[0016] The method may include administering any of the aforementioned
compositions to a patient, for whom anti-hypertensive treatment is needed or
desirable. In certain embodiments, the patient may have or be at risk for
acquiring one or more of coronary artery disease (CAD), renal disease, or
diabetes. As such, it may be desirable to administer the aforementioned
compositions to treat these diseases or to decrease the likelihood of a
patient
acquiring these diseases.
[0017] In addition to achieving and maintaining a target blood pressure, the
method may also be used to decrease the likelihood of a heart attack, and/or
to
decrease the likelihood of a stroke. Further, the method may be useful in
decreasing mortality (e.g., in patients with CAD).
[0018] It also may be desirable to administer particular pharmaceutical
compositions to a patient based on the patient's age (e.g., an elderly patient
of
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more than about 60 or about 70 years of age), or ancestry (e.g., African or
Hispanic ancestry). A patient's age or ancestry may influence how the patient
will responds to particular amounts of verapamil, tranolapril, and HCTZ, a.nd
as
such, the pharmaceutical composition may be formulated accordingly.
[0019] Also disclosed is a kit for treating hypertension in a patient. The kit
includes an angiotensin-converting-enzyme inhibitor (preferably trandolapril
or a
therapeutic derivative), a calcium antagonist (preferably a non-DHP CA such as
verapamil or a therapeutic derivative), and a diuretic, (preferably HCTZ or a
therapeutic derivative), one or more of which acts as an active ingredient to
treat, prevent, and/or ameliorate hypertension. The kit also typically
includes
one or more pharmaceutically acceptable eaccipients. The kit includes one or
more dosage units, (e.g., up to 35 dosage units), which units may include one
or more of verapamil, trandolapril, HCTZ, or their therapeutic derivatives.
The
dosage units may be formulated as a pharmaceutical composition that includes
the one or more pharmaceutically suitable carriers or ea~cipients.
[~0~0] The kit may include trandolapril, verapamil, HCTZ, or their therapeutic
derivatives, in any of the amounts described in the aforementioned
pharmaceutical compositions as active ingredients. The active ingredients may
be formulated separately in the kit (e.g., separate dosage units), or they may
be
formulated in combination as dosage units (e.g., a dosage unit including
trandolapril, verapamil, and HCTZ or a dosage unit including trandolapril and
verapamil). The dosage units) may include an effective amount of one or more
of the active ingredients to treat hypertension.
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[0021 ] The kit also includes instructions for use to treat, prevent and/or
ameliorate hypertension in a patient in need thereof. For example, the
instructions for use may indicate how to treat, prevent and/or ameliorate
hypertension in a patient in need thereof with regard to the patient's current
condition, (e.g., in a patient with one or more of hypertension and/or CAD,
renal
disease, and diabetes, or at risk for acquiring these diseases.) The
instructions
for use may also indicate how to treat, prevent and/or ameliorate hypertension
in a patient in need thereof with regard to the patient's age or ancestry. The
instructions for use may also include recommended dosage amounts and method
of administration to achieve and maintain target blood pressures (e.g., a SBP
of
no more than about 150, 145, 14.0, 135, or 130 mm Hg and a DBP of no more
than about 90, 35, or 30 mm Hg in the patient). The kit also may include
instruction for reducing SBP and DBP rehative to baseline measurements (e.g.,
by
at least about 10%). The kit also may include one or more implements to
facilitate administering the dosage units.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1 is a schematic representation of the INVEST trial profile and
study protocol.
[0023] FIG. 2 displays the mean systolic and diastolic blood pressure during
the trial.
[0024] FIG. 3 displays the primary outcome of the trial by treatment strategy.
[0025] FIG. 4 displays the 'primary and secondary outcomes of the trial by
treatment strategy.
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[0026] FIG. 5 displays the effects of treatment strategy on primary outcome
in subgroups of patients at baseline.
DETAILED DESCRIPTION
[0027] Unless otherwise specified, "a" or "an" means one or more.
[0028] Described herein is a pharmaceutical composition comprising a
combination of anti-hypertensive agents, such as calcium antagonists (CAs) ,
angiotensin-converting-enzyme inhibitors (ACEIs), and diuretics. Preferably;
the
CA is a non-DHP CA (e.g., verapamil); the ACEI is trandolapril, and the
diuretic
is hydrochlorothiazide (HCTZ). Therapeutic derivatives of verapamil,
trandolapril, and HCTZ may be used as well.
[~029] The term °therapeutic derivative'° is intended to mean
any compound
that has a related structure and achieves a similar therapeutic result.
"Therapeutic derivatives" may include pharmaceutically acceptable or suitable
salts. "Therapeutic derivatives" may also include compounds that differ
structurally from trandolapril, verapamil, and HCT~, prior to being
administered
to a patient, but which are converted to therapeutically similar structures
after
being administered to a patient, (e.g., an oral, acid-activated prodrug of
trandolapril, verapamil, or HCTZ that is hydrolyzed in the stomach to produce
the active drug form.) Angiotensin-converting-enzyme inhibitors, such as
trandolapril or therapeutic derivatives thereof, and/or combinations of ACEI's
with calcium antagonists or diuretics (e.g., TARICA), are described in U.S.
4,933,361; U.S. 5,098,910; U.S. 5,403,856; U.S. 5,500,434; U.S.
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5,684,016; U.S. 5,721,244; U.S. 5,744,496; and U.S. 5,747,504, which are
incorporated herein by reference in their entireties.
[0030] The pharmaceutical composition also typically contains a
pharmaceutical suitable carrier or excipient, which is intended to mean
substances, which are substantially harmless to the individual to which the
dosage unit will be administered. Such an excipient normally fulfills the
requirements given by national drug agencies. Official pharmacopeias such as
the U.S.A. Pharmaco~peia, the British Pharmacopeia, and the European
Pharmacopeia set standards for well-known pharmaceutically acceptable carriers
and excipients.
[0031 ] Suitable carriers and excipients may include all kinds that may be
used
for solid, semi-solid, fluid, or other dosage units. Suitable carriers and
excipients
may include solvents, buffering agents, preservatives, humectants, chelating
agents, antioxidants, stabilizers, emulsifying agents suspending agents, gel-
forming agents, diluents, disintegrating agents, binding agents, lubricants,
coating agents, and wetting agents. Typically, the diluents and disintegrating
agents may be lactose, saccharose, calcium phosphatases, calcium carbonate,
calcium sulfate, mannitol, starches, and cellulose.
[0032] Binding agents may include s.accharose, sorbitol, gum acacia, sodium
alginate, gelatin, 'starches, cellulose, sodium carboxymethylcellulose,
methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, and
polyethyleneglycol.
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(0033] Wetting agents may include by example sodium laurylsulfate and
polysorbate 80. Lubricants may include by example talcum, magnesium
stearate, calcium stearate, silicium oxide, and polyethyleneglycol. Coating
agents may include by example hydroxypropylcellulose,
hydroxypropyl,methylcellulose, polyvinylpropylidone, ethylcellulose, and
polymethylacrylates.
(0034] In one embodiment of the pharmaceutical composition, trandolapril, or
a derivative with a similar therapeutic effect, may be present in an amount
.(e.g.,
between about 0.5 mg and about 8 mg or preferably between about 0.5 mg to
about 2 mg); verapamil, or a derivative with a similar therapeutic effect, may
be
present in an amount (e.g., between about 40 mg and about 480 mg or
preferably about 180 to about 240 mg); and HCTZ, or a derivative with a
similar
therapeutic effect, may be present in an amount (e.g., between about 6.25 mg
and about 100 mg or preferably between about 6.25 mg and 25 mg); with the
proviso that if the composition comprises 4 mg trandolapril or 8 mg
trandolapril
and the composition comprises 12.5 mg hydrochlorothia~ide or 25 mg
hydrochlorothiazide, the composition does not comprise 180 mg verapamil; and
with the proviso that if the composition comprises 4 mg trandolapril and 12.5
mg hydrochlorothiazide, the composition does not comprise 360 mg verapamil.
(0035] In other embodiments, the pharmaceutical composition may include
particular amounts of trandolapril, verapamil, HCTZ, or their therapeutic
derivatives. Non-limiting examples include: (tra,ndolapril: about 0.5, 1, or 2
mg;
verapamil: about 40, 80, 100, 120, 180, 200, 220, 240, 360, or 480 mg;
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HCTZ about 6.25, 12.5, 25, 50, 75, or 100 mg), (trandolapril: about 1 or 2 mg;
verapamil: about 180 or 240 mg; HCTZ: about 6.25, 12.5, 25, 50, 75, or 100
mg), (trandolapril about 2 mg; verapamil: about 180 mg; HCTZ: about 6.25,
12.5, 25, 50, 75 or 100 mg), (trandolapril about 2 mg; verapamil: about 180
mg; HCTZ about 12.5, 25, or 50 mg), (trandolapril: about 2 mg; verapamil:
about 180 mg; HCTZ about 12.5 or 25 mg). As used herein, "about" means
+/- 20%, preferably +/- 10%, and more preferably +/- 5%.
[0036] In the aforementioned pharmaceutical compositions, one or more of
trandolapril, verapamil, HCTZ, and/or their therapeutic derivatives may
function
as active ingredients that exhibit an anti-hypertensive effect in a patient
(e.g., a
patient with CAD). An anti-hypertensive effect may be observed by taking a
sitting cuff blood pressure measurement of systolic and diastolic blood
pressure
before and after the pharmaceutical composition is administered. In one
preferable embodiment, one or more of trandolapril, verapamil, and/or
hydrochlorothia~ide may be present as active ingredients in a dose sufficient
to
achieve and maintain a SBP of no more than about 150-140 mm Hg and a DBP
of no more than about 90 mm Hg; more preferably a SBP of no more than about
135 mm Hg and a DBP of no more than about 85 mm Hg, and even more
preferably SBP of no more than about 130 mm Hg and a DBP of no more than
about 80 mm Hg. The active ingredients may also be present in an effective
amount to reduce SBP and DBP relative to baseline measurements taken prior to
administering the composition. Preferably, the active ingredients are present
in
an effective amount to reduce SBP and DBP by at least about 10% relative to
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baseline measurements. The above-described target blood pressures may
represent mean blood pressures as determined over a set time period.
[0037] The aforementioned compositions may be formulated for oral, topical,
transdermal, subcutaneous, parenteral, or pulmonary (e. g., aerosolized)
administration. Oral, transdermal, and/or parental formulations are
preferable.
Oral and/or other formulations may include tablets, capsules, granules,
powders,
suspensions, liquids, and/or emulsions. Transdermal formulations may include
patches or pads.
[0038] The aforementioned pharmaceutical compositions may be formulated
together with a matrix that controls the release of one or more of the active
ingredients (e.g., a matrix for slow release of the active ingredients). The
matrix
typically is a solid formulation which allows for the controlled, prolonged,
or
extended release of an active ingredient at a rate sufficient to maintain
therapeutic blood levels of the active ingredient over a period of time (e.g.,
24-
30 hours, 1-7 days, 1-30 days or longer). The matrix can represent from about
40% to about 98% of the total weight of a pharmaceutical composition or a
unit dosage form, typically excluding any coatings in the case of tablets.
More
preferably the controlled release matrix will represent from about 50% to
about
95% of the total weight of the inventive compositions. The matrix to active
ingredient ratio can be from about 5 to 1 to about 15 to 1, and compositions
having integer ratios of all possible combinations between these ranges
including
to 1 are considered embodiments of the present invention.
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[0039] The matrix can be any suitable material that provides sustained,
controlled, or slow release of an active ingredient, medicament or drug and
the
like. Pharmaceutically acceptable rate controlling materials which may be used
in the present invention include both synthetic and naturally occurring gums
and/or polymers and other art-known rate controlling substances. Non-limiting
examples include naturally occurring or modified naturally occurring or
synthetic
or semi-synthetic polymers or gums such as, e.g., alginates, carrageenan,
pectin, xanthan gum, locust bean gum, guar gum, modified starch,
alkylcellulose, hydroxypropylmethylcellulose, methylcellulose, and other
cellulosic materials or polymers, such as sodium carboxymethylcellulose and
hydroxypropylcellulose and mixtures of the foregoing. Additional synthetic
and/or semisynthetic polymers include, e.g., cellulose acetate phthalate
(CAP),
polyvinylacetate phthalate (P!./~P), hydroxypropylmethylcellulose phthalate,
and/or acrylic polymers, such as methacrylic acid ester copolymers, zein, and
the like. The matrix can include ingredients such as polysaccharides, cationic
crosslinking agents, inert diluents, alkalizing agents, surfactants, polar
solvents
and other excipients.
[004.0] The controlled release matrix may be formulated to provide effective
blood pressure control or other therapeutic effects for hours (e.g., 24-30
hours),
days (e.g., up to 7), weeks (e.g., up to 4), and/or months (e.g., up to 12),
by
maintaining an effective concentration of one or more of the active
ingredients
(e.g., trandolapril, verapamil, and/or HCT~) in the patient's sera. "Effective
blood pressure control," as defined herein, may mean a SBP of no more than
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about 150, 145, 140, (i.e., 150-140), 135, and 130 mm Hg and a DBP of no
more than about 90, 85, or 80 mm Hg. "Effective blood pressure control," as
defined herein, may also mean a decrease in SBP and DBP by at least about
10% relative to baseline measurements. "Baseline measurements," as defined
herein, may mean SBP arid DBP measurements taken before the composition is
administered.
[0041] The above-described pharmaceutical compositions maybe
administered to a patient to achieve and maintain a target blood pressure.
Methods of administration are well known in the art and may vary based on the
particular formulation, (i.e., oral, transdermal, parenteral, etc.). Methods
of
administration may also vary based on whether the pharmaceutical composition
is formulated for sustained, controlled, or slow release (e.g., by using a
controlled release matrix).
[0042] The method may include administering any of the aforementioned
compositions to any patient, for whom anti-hypertensive treatment is needed or
desirable. The method may be particularly beneficial for patients who may have
coronary artery disease. "Coronary artery disease'° or "CAD,°'
as defined herein,
means remote (>_3 months prior) confirmed MI, coronary angiogram with more
than 50% narrowing of at least 1 major coronary artery, diagnosis of classic
angina pectoris, or concordant abnormalities on 2 different types of signals
(electrocardiograms, echocardiograms, and/or radionuclide scans) from stress
tests provided that 2 different signals showed findings consistent for
ischemia
(e.g., ST-segment depression and/or perfusion defects by radionuclide, and/or
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wall-motion abnormalities by echocardiogram or radionuclide). The method may
also be beneficial for patients with renal disease, or patients with diabetes
or at
risk for acquiring diabetes. For example, the method may be useful to reduce
blood pressure and to decrease the likelihood of a patient acquiring diabetes
or
to delay the onset of diabetes in a patient. In reducing blood pressure, the
method may be beneficial also in reducing mortality, likelihood of a heart
attack
(and/or a myocardial infarction), renal failure, and/or stroke.
[004.3] It may be desirable to administer particular compositions to a patient
based on the patient's age (e.g., an elderly patient older than about 70 years
or
older than about 60 years), or ancestry, such as African or Hispanic ancestry.
For example, because hypertensive patients of African ancestry (i.e., black
hypertensives) may respond differently to certain anti-hypertensive agents in
comparison to caucasian hypertensives, it may be desirable to administer
different compositions to black hypertensives to achieve target blood
pressures.
[0044] The kit for treating, preventing, and/or ameliorating hypertension in a
patient (e.g., a patient with CAD) includes an angiotensin-converting-enzyme
inhibitor, a calcium antagonist (preferably a non-DHP CA), and a diuretic.
Typically, trandolapril, verapamil, HCTZ, or their therapeutic derivatives, as
active ingredients, are present in the kit in any of the amounts described in
the
aforementioned pharmaceutical composition (i.e., trandolapril: 0.5-8 mg;
verapamil: 40-480 mg; and HCTZ: 6.25-100 mg). One or more of the active
ingredients is present in an effective amount to treat hypertension.
Trandolapril,
verapamil, HCTZ, and/or their therapeutic derivatives may be formulated
18
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separately or in combination as dosage units (e.g., trandolapril and verapamil
may be formulated in combination as a dosage unit and/or trandolapril,
verapamil, and HCTZ may be formulated in combination as a dosage unit). As
such, a dosage unit may include one or more of trandolapril, verapamil, and/or
HCTZ, one or more of which acts as an active ingredient to treat, prevent,
and/or ameliorate hypertension.
[0045] The kit includes one or more dosage units, and it may be desirable to
create kits that contain up to 35 dosage units (e.g., where a dosage unit is
to be
administered daily and the kit is designed to last for up to one month).
[0046] The kit also typically includes, one or more pharmaceutically suitable
carriers or excipients, as described above, which may be present in a dosage
unit (e.g., the carrier and/or excipient may be formulated together with one
or
more active ingredient in a dosage unit.)
[0047] The kit may be used to treat or decrease the likelihood of coronary
artery disease, renal failure, stroke, or diabetes. The kit may also be used
to
delay the onset of diabetes, and/or to decrease mortality (e.g., as a result
of
treating any of the aforementioned diseases or conditions).
[004] The kit includes instructions for using the kit for treatment,
prevention
or amelioration of hypertension. As used herein, the phrase "instructions for
use" or "instructions for using" shall mean any FDA-mandated instructions,
package inserts, or labels that relate to the administration of the
aforementioned
compositions or the dosage units in the kit for the purpose of treating
hypertension, or the equivalent instructions, package inserts, or labels
required
19
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by foreign regulatory authorities. For example, instructions for use may
include,
but are not limited to, indications for hypertension, identification of
specific
symptoms of hypertension that can be ameliorated by the aforementioned
compositions or dosage units, and recommended dosage amounts for patients
suffering from hypertension. The instructions for use may indicate that the
kit
may be used to treat or decrease the likelihood of acquiring coronary artery
disease, to decrease mortality, to decrease the likelihood of a heart attack
and/or myocardial infarction, and/or to decrease the likelihood of a stroke.
The
instructions for use may indicate particular dosages for using the kit to
treat,
prevent, and/or ameliorate hypertension by achieving and maintaining target
blood pressures (e.g., a S8P of no more than about 150, 145, 140, 135, Or 130
mm Hg and a D8P of no more than about 90, 85, Or 80 mm Hg). The
instruction may also indicate how to decrease S8P and D8P relative to baseline
measurements (e.g., by at least about 10%).
EXA~IIPLES
(~04.9] The INVEST design and methods have been described in detail
elsewhere. (See, e.g., Pepine CJ, et al,, J Am C~ll ~ardiol 1998; Vol. 32:
1228-
37 and Pepine et al., JAMA (2003), Vol. 290:2805-2816 and E1-E3,
incorporated herein by reference in their entireties). INVEST was an
international, multicenter study with a prospective, randomized, open blinded
end-point evaluation design conducted according to principles of the
Declaration
of Helsinki. The institutional review boards and ethics committees at
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participating sites approved the protocol and patients provided written
informed
consent.
INVEST Design and Patients
[0050] Clinically stable CAD patients with hypertension were randomly
assigned to either a CAS or NCAS for BP treatment at 862 sites in 14 countries
and managed according to the Sixth Report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC
VI) guidelines. (Arch Intern Med 1997; Vol. 157: 2413-46 [Erratum, Arch Intern
Med 1998; Vol 158: 573], incorporated herein by reference in their
entireties).
The primary objective was to evaluate the hypothesis that risk for adverse
outcomes is at least equivalent during treatment initiated with a CAS compared
with an NCAS. The primary outcome was the first occurrence of death (all-
cause), nonfatal MI, or nonfatal stroke.
C~051 ] One objective ~f the study was to test the hypothesis that risk for
adverse outcomes is equivalent to a verapamil SR-based regimen compared with
an atenolol-based regimen. Clinically stable CAD patients with hypertension
were randomly assigned to either verapamil SR or atenolol for blood pressure
treatment according to the sixth report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC
VI) (target: systolic blood pressure [SBP] < 140 and diastolic blood pressure
[DBP] < 90 mm Hg or SBP < 130 mm Hg and DBP < 85 mm Hg when diabetes
or renal impairment is present). Addition of trandolapril and/or
21
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hydrochlorothiazide was recommended when necessary to achieve blood
pressure goals. Trandolapril also was recommended for patients with heart
failure, diabetes, or renal insufficiency. Thus, this was not simply a
comparison
of verapamil SR with atenolol because it was anticipated that few patients
would be treated with only those drugs. Ultimately, it was expected that most
patients would be using the combination of verapamil SR plus trandolapril or
atenolol plus hydrochlorothiazide.
[0052] Patient were eligible for the study if they were aged 50 years or older
and had documented CAD, with essential hypertension as defined by JNC VI
requiring drug therapy. Documented CAD was defined as any of the following:
remote (>_3 months prior to enrollment) confirmed MI, coronary angiogram with
more than 5~% narrowing of at least 1 major coronary artery, diagnosis of
classic angina pectoris, or concordant abnormalities on 2 different types of
signals (electrocardiograms, echocardiograms, and/or radionuclide scans) from
stress tests provided that 2 different signals showed findings consistent for
ischemia (eg, ST-segment depression and/or perfusion defeats by radionuclide,
and/or wall-motion abnormalities by echocardiogram or radionuclide). Patients
with ,heart failure classes I through III were included. Patients taking (3-
blockers
within 2 weeks of randomization or taking (3-blockers for an MI that occurred
in
the previous 12 months were excluded to avoid withdrawal phenomena in
patients randomized to the CAS group.
[0053] Following validity checks of eligibility data, an Internet-based
management system automatically randomized each patient to a treatment
22
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strategy. The randomization scheme used a standard C routine and blocked by
site using randomly permuted block sizes of 4 and 6. The randomization result
was automatically stored in the central database as part of the patient's
record
and was also returned to the site investigator for electronic signature of
strategy
drugs in accordance with the protocol.
Interventions
[0054] The protocol-recommended treatment schedule for each strategy to
achieve JNC VI blood pressure targets is outlined as follows. The blood
pressure target was determined from a mean of 2 sitting cuff blood pressure
measurements as described in JNC VI.
(0055] Patients allocated to the CAS group were given 24~ mg/d of verapamil
SR while patients allocated to the NCAS group were given 50 mg/d of atenolol
(step 1 ). If patients did not achieve target blood pressure, in step 2 the
CAS
group also could receive trandolapril (an ACE inhibitor) and the NCAS group
also
could receive hydrochlorothiazide. The rationale for this was to maximize use
of
the combination of calcium antagonist and ACE inhibitor while minimizing
diuretic use for the CAS group and maximizing use of the combination of ~i-
blocker and diuretic for NCAS group. In step 3, doses were increased in both
groups. In step 4, the CAS group also could receive hydrochlorothiazide and
the
NCAS group also could receive trandolapril. Trandolapril was recommended for
all patients with renal impairment, diabetes, or heart failure. If the dose
was not
well tolerated or the target blood pressure was not achieved, verapamil SR
could
23
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be titrated to between 120 and 480 mg/d and atenolol could be titrated to
between 25 and 200 mg/d. The recommended starting dose for trandolapril
was 2 mg/d and it could be titrated to between 0.5 and 8 mg/d. For patients in
the CAS group, a fixed combination was available for verapamil SR and
trandolapril in doses of 180 mg/d and 2 mg/d, respectively; 240 mg/d and 1
mg/d; and 240 mg/d and 4 mg/d. The recommended starting dose for
hydrochlorothiazide was 25 mg/d and it could be titrated between 12.5 and 100
mg/d. Doses greater than 25 mg of hydrochlorothiazide were provided to limit
the need for nonstudy diuretics in patients with heart failure or edema. If
the
blood pressure goal was not achieved and adverse effects had not occurred,
doses were titrated to those levels as specified in the instant step before a
patient was moved to the next step.
[0~5~] Additional non-study antihypertensive drugs, (except a-blocleers for
CAS patients and calcium antagonists for NCAS patients), could be added when
needed to reach blood pressure targets or minimize adverse effects. Patients
were considered to have crossed over from their randomized treatment strategy
if they received a (3-blocker during the trial and were in the CAS group or
received a calcium antagonist and were in the NCAS group. Standard of care,
non-pharmacological JNC VI guidelines, and secondary prevention according to
the National Cholesterol Education Program were provided online to physicians,
which could be printed and given to patients.
24
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Patient Monitoring and Follow-a
(0057] Protocol visits were scheduled every 6 weeks for the first 6 months
and then biannually until 2 years after the last patient was enrolled.
Patients
were assessed for response to treatment, occurrence of symptoms, treatment
compliance, and adverse effects at each visit and at study close as detailed
elsewhere.
(0058] Patient follow-up was complete when a final assessment form was
received via the online data system or a death report was received. For all
patients not completing the final assessment visit, lost to follow-up, or
withdrawn, data were censored according to last visit date.
Study Outcomes
(0059] The primary outcome was the first occurrence of death (all-cause),
nonfatal MI, or nonfatal stroke by intention-to-treat analysis. TIIe MI and
stroke
definitions are detailed on the IN\/EST Web site. These 3 components
individually were the main secoridary outcomes. Additional outcomes included
time to most serious event (ranked from death as most serious, to MI, to
stroke
as least serious), cardiovascular death (definite or presumed), angina,
cardiovascular hospitalizations, blood pressure control, cancer, Alzheimer
disease, Parkinson disease, and gastrointestinal tract bleeding. Shortly after
the
study started, new information became available on the potential for ACE
inhibitors to prevent or delay the onset of diabetes. Accordingly, at the
CA 02521014 2005-09-29
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recommendation of the independent data safety and monitoring committee, new
diagnosis of diabetes was added as an outcome early in the recruitment phase
of the study.
[0060] Outcomes such as death, MI, stroke, and cardiovascular hospitalization
were reported within 24 hours using the online adverse event reporting system
and then appropriate documentation was gathered. Adverse experiences were
collected from responses to open, active questioning not restricted to those
events known to be associated with the drugs taken. Three members of the
events committee, masked to treatment assignment, confirmed all outcome
events by reviewing documentation and other pertinent patient records. The
data safety and monitoring committee reviewed efficacy and safety data at
regular intervals throughout the trial.
Sample Size
[006] It was decided a priori that a 20°/~ difference in primary
outcome
between the treatment strategies would be clinically relevant using the
intention-
to-treat population. Therefore, the equivalence bound for the risk ratio was a
confidence interval (CI) of 1.20 to 0.83. We assumed an annual primary
outcome rate of no less than 2%, an a, of .05 (2-sided), and 90% power when
estimating the number of patients required. On this basis, a tentative sample
size of 27000 patients was calculated, with an anticipated yearly drop-out
rate
of 5% to 10%. Because the enrollment period was longer than initially planned,
patient-years of follow-up were greater than those used for initial power
26
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estimates. At the recommendation of the INVEST study biostatisticians and the
data safety and monitoring committee, the steering committee reduced the'
sample size to 22000 patients.
Statistical Analysis
[0062] All of the main analyses were completed as specified in the protocol
with the intention-to-treat population, including patients withdrawn or lost
to
follow-up censored at the time of the last visit (unless the patient was known
to
be dead based on death records). One planned interim analysis was performed
in August 2001 and the pre-specified stopping rules were not met:
[006] The final significance level for the primary outcome, adjusted for the
single interim analysis, was ~_ .04806 for a 2-sided test. For the secondary
outcomes of death, nonfatal MI, and nonfatal stroke, a Bonferroni adjustment
was made to the same x'_.04806 significance level (P=.02 for each outcome).
All other analyses are reported at the F< .05 significance level. I<aplan-
Meier
survival analysis was used to assess time to first event for the primary
outcome
and the main secondary outcomes. The primary outcome was analyzed both
unadjusted and adjusted for 5 pre-specified covariates: age, race, sex,
previous
MI, and prior heart failure. Standard relative risk (RR) estimates and 95% Cls
were also calculated.
[0064] x2 Analysis was used to compare CAS with NCAS on percentage
occurrence of different outcomes. Cox proportional hazard models were used to
evaluate potential interactions in the reported pre-specified subgroup
analyses
27
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(by baseline characteristic). All data were captured and stored in database
tables (Version 7.1, Oracle, Redwood Shores, Calif). Data management and
statistical analyses were performed using SAS statistical software (Version
8.2,
SAS Institute Inc, Cary, NC). The database was maintained at the University of
Florida, Division of Biostatistics, Gainesville.
Patient Enrollment
[0065] The pilot phase (30 selected sites) started in September 1997. Full-
scale site recruitment and patient enrollment began in January 1998, and
patient
follow-up was completed on February 14, 2003. A total of 22576 patients at
852 sites in 14 countries provided informed consent, satisfied administrative
requirements, and completed randomisation; 1 1257 were assigned to the CAS
group and 1 1309 to the NCAS group (FIGURE 1 ). A total of 594 patients had
all assigned drugs withdrawn due to an adverse experience. A total of 568
patients failed to return for final assessment and did not appear in death
searches (withdrawals or lost to follow-up). These latter patients were
censored
at the time of their last visit. Mean follow-up was 2.7 years (range, 1 day to
5.4 years) in each strategy. A total of 30829 patient-years were accumulated
in the CAS group and 31006 patient-years in the NCAS group.
Baseline Characteristics
[0066] At baseline, patient characteristics were well-balanced (TABLE 1 ). The
study population included a large proportion of elderly, Hispanic, diabetic,
and
28
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female patients. Blood pressure levels were similar between groups (TABLE 2).
Overall, only 4267 patients (18.9% of all patients) had controlled blood
pressure.
29
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TABLE 1. Patient Characteristics
at Baseline's
Calcium Non-Calcium
Antagonist Antagonist
haracteristic Strategy Strategy
(n = 11 267) (n = 11 309)
Demographic
Age, mean (SD), y 66.0 (9.7) 66.1 (9.8)
> 70 3694 (32.8) 3829 (33.9)
Women 5850 (51.9) 5920 (52.3)
Race/ethnicity
White 5466 (48.5) 5459 (48.3)
Black 1506 (13.4) 1523 (13.5)
Hispanic 4021 (35.7) 4024 (35.6)
Asian 63 (0.6) 86 (0.8)
0ther/multiracial 211 (1.9) 217 (1.9)
BMI, mean (SD), kg/m2 29.1 (6.8) 29.2 (7.4)
Condition
Myocardial infarction 3622 (32.1 ) 3596 (31.8)
Abn~rmal angi~gram 4384 (38.9) 4472 (39.5)
Pri~r MI ~r abnormal angi~gram5932 (52.6) 6025 (53.3)
Concordant stress test 2399 (21.3) 2389 (21 .1 )
abnormalities
Angina pectoris 7463 (66.2) 7582 (67.0)
CABG >_1 month ago 1751 (15.5) 1821 (16.1 )
PCI >_1 month ago 1716 (15.2) 1666 (14.7)
CABG or PCI 3079 (27.3) 3087 (27.3)
Stroke 595 (5.3) 567 (5.0)
Left ventricular hypertrophy2422 (21.5) 2526 (22.3)
Unstable angina >_1 mo 1280 (11.4) 1298 (1 1 .5)
ago
Arrhythmia 802 (7.1 ) 798 (7.1 )
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Heart failure (class I-III) 619 (5.5) 637 (5.6)
Peripheral vascular disease 1345 (11.9) 1354 (12.0)
Smoking
Past 5247 (46.6) 5207 (46.0)
Within last 30 d 1435 (12.7) 1374 (12.2)
Never 6020 (53.4) 6102 (54.0)
Diabetest 3169 (28.1 ) 3231 (28.6)
Hypercholesterolemia t 6300 (55.9) 6293 (55.6)
Renal impairment$ 214 (1.9) 210 (1 .9)
Cancer ~ 389 (3.5) 371 (3.3)
Medication
Aspirin or other antiplatelet agent 6418 (57.0) 6377 (56.4)
Other NSAIDs 1984 (17.6) 2024 (17.9)
Antidiabetic medication ~ ~ 2493 (22.1 ) 2591 (22.9)
Any lipid-lowering agent 4150 (36.8) 4144 (36.6)
Nitrates 3989 (35.4) 4139 (36.6)
Potassium supplement 777 (6.9) 783 (6.9)
Hormone replacement[ 1034 (17.7) 1096 (18.5)
Abbreviations: BMI, body mass index; CA13G, coronary artery~bypass graft;
f~SAIDs,
nonsteroidal anti-inflammatory drugs; PCI, percutaneous coronary
interventions.
Values expressed as number (percentage) unless otherwise indicated.
Percentages
may not equal 100 due to rounding.
t History of or currently taking antidiabetic or lipid-lowering medications.
$ History of or currently have elevated serum creatinine level but less than 4
mg/dL
( < 354 pmol/L).
~ Patients with a history of skin, prostate, and other cancers with long
survival
expectancy were not excluded.
~ ~ Insulin and/or oral hypoglycemics.
~( Data for women only (n = 5850 for calcium antagonist strategy and n = 5920
for
non-calcium antagonist strategy).
31
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TABLE 2. Baseline Blood Pressure
and Antihypertensive Medications
Calcium Non-Calcium
Antagonist Antagonist
Strategy Strategy
Antihypertensive Medication
Use (n = 9791 )
(n = 9758)
Blood pressure, mean (SD), mm
Hg 149.5 (19.7) 149.5 (19.7)
Systolic
Diastolic 86.3 (12.0) 86.3 (11.9)
Heart rate, mean (SD), beats/min75.6 (9.5) 75.5 (9.5)
No.(%) with blood pressure in
control
Systolic 384 (24.4) 359 (24.1 )
Diastolic 5244 (53.7) 531 1 (54.2)
Both 2154 (22.1 ) 21 13 (21.6)
No. of drugs, mean (SD) 1.7 (0.8) 1.7 (0.8)
1 5030 (51 .6) 4978 (50.8)
2 3330 (34.1 ) 3355 (34.3)
3 1110 (11.4) 1172 (12.0)
> 3 288 (3.0) 286 (2.9)
Type of antihypertensive
drug,No.(%)
ACE inhibitor 007 (51 .3) 042 (51.5)
Centrally actingt 516 (5.3) 536 (5.5)
Calcium antagonist 4031 (41.3) 4058 (41.4)
Diuretic 3650 (37.4) 3743 (38.2)
a-Blocker/other vasodilator 828 (8.5) 830 (8.5)
(3-Blocker $ 0 0
Other class 2179 (22.3) 2183 (22.3)
32
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No Antihypertensive Medication Use
(n = 1509) (n = 1518)
Blood pressure, mean (SD), mm Hg
Systolic 159.2 (15.7) 160.1 (15.9)
Diastolic 92.9 (10.1 ) 92.6 (10.6)
Heart rate, mean (SD), beats/min 76.6 (10.0) 76.7 (9.7)
Abbreviations: ACE, angiotensin-converting enzyme; CAS, calcium antagonist
strategy.
According to guidelines from the sixth report of the Joint National Committee
on
Prevention, Detection, Evaluation, and Treatment of High Blood 'Pressure (see
text).
t Included clonidine, methyldopa, and moxonidine.
$ Patients taking (3-blockers within 2 weeks of randomization or taking (3-
blockers for an
MI that occurred in the previous 12 months were excluded to avoid withdrawal
phenomena in patients randomized to the CAS group.
33
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Treatment
[0067] At 24 months, 6391 (81.5%) of CAS patients were taking verapamil
SR and 6083 (77.5%) of NCAS patients were taking atenolol (TABLE 3). As
expected from the recommended order of additional drug treatment by strategy,
usage of trandolapril and hydrochlorothiazide differed significantly (P< .001
).
The distribution of number of study drugs used was similar between strategies
as was the distribution of total antihypertensive medications. At 24 months,
only 2.1 % of patients in each group (CAS, 145; NCAS, 141 ) were taking no
antihypertensive medications. At final assessment, nonstudy antihypertensive
drug use was observed in 5873 patients (43%) in both strategies (TABLE 4).
As expected, calcium antagonist use was more frequent in the CAS group and
~i-blocker use was more frequent in the NCAS group (TABLE 4). Crossover to (3-
blocker use in the CAS group (373 [5.5%]) was less than crossover to calcium
antagonist use in the NCAS group (479 [7.0%]). This difference persisted over
the entire duration of follow-up, (3-blocker use at any time in the CAS group
was
1305 (1 1.6%) of 1 1267 and calcium antagonist use in the NCAS group was
1862 (16.5%) of 11309 (P<.001.). Nonstudy diuretic use was also more
frequent in the NCAS group. The percentage of patients taking antidiabetic
medications was significantly lower in the CAS group (23.2%; n =1574)
compared with the NCAS group (24.7%; n=1682) (P=.04). The frequencies of
other medication use were similar between strategies (TABLE 4).
34
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TABLE 3. Strategy Antihypertensive Medication Use
A. No. (%) of Patients at 12 months
Calcium Non-Calcium
Antagonist Antagonist
Strategy Strategy P Value's
(n = 8639) (n = 8694)
Study drug
Verapamil sustained release 7581 (87.8) N/A
Mean (SD) dose, mg/d 274 (99) N/A
Atenolol N/A 7060 (81 .2)
Mean (SD) dose, mg/d N/A 72 (33) '
Trandolapril 5436 (62.9) 4514 (51 .9) < .001
Mean (SD) dose, mg/d 4 (2) 3 (2)
Hydrochlorothiazide 3515 (40.7) 5168 (59.4) < .001
Mean (SD) dose, mg/d 28 (14) 28 (12)
No, of strategy drugs
~ 715 (8.3) 708 (8.1 )
1 1964 (22.7) 1920 (22.1 ) .73
2 3312 (38.3) 3376 (38.8)
3 2648 (30.7) 2690 (30.9)
Total No. of
antihypertension drugs
(strategy plus nonstrategy)
0 17 ( 1 .4) 26 ( 1 .4)
1 1376 (15.9) 1294 (14.9) .18
2 2941 (34.0) 2931 (33.7)
>-3 4205 (48.7) 4343 (50.0)
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WO 2004/087132 PCT/US2004/010052
B. No. (%) of Patients .
at 24 months
Calcium Non-Calcium
Antagonist Antagonist
Strategy Strategy P Values
(n = 7842) (n = 7850)
Study drug
Verapamil sustained release6391 (81 .5) N/A
Mean (SD) dose, mg/d~ 288 (102) N/A
Atenolol N/A 6083 (77.5)
Mean (SD) dose, mg/d N/A 76 (34)
Trandolapril 4934 (62.9) 41 13 (52.4) < .001
Mean (SD) dose, mg/d 4 (2) 4 (3)
Hydrochlorothiazide 3430 (47.7) 4733 (60.3) < .001
Mean (SD) dose, mg/d 29 (14) 29 (13)
No. of strategy drugs
~, 1096 (14.0) 998 (12.7)
1 . 1363 (17.4) 1424 (18.1 ) .1
1
2 2757 (35.2) 2779 (35.4)
3 2626 (33.5) 2649 (33.8)
Total No. of
antihypertension drugs
(strategy plus nonstrategy)
~ 45 (2.1 )t 41 (2.1 )$
1 1061 (15.6)t 1031 (15.1 )$ .57
2 2123(31.3)t 2089 (30.6)$
3 3464(51 .0)t 3561 (52.2)$
Abbreviation: N/A, not applicable.
Results from x~ test to compare strategies
t Based on reduced sample size of 6793.
$ Based on reduced sample size of 6822.
36
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TABLE 4. Nonstrategy Medication
Frequencies at 24 Months
No. (%) of
Patients
Calcium Non-Calcium
Antagonist Antagonist
Drug Use Strategy Strategy P
(n = 6793) (n = 6822) Value's
Antihypertensive drug
Any nonstudy 2944 (43.3) 2929 (42.9) .64
ACE inhibitor 1300 (19.1) 1310 (19.2) .93
Centrally acting 132 (1.9) 137 (2.0) .79
Calcium antagonist 1133 (16.7) 479 (7.0) <.001
Diuretic 1314 (19.3) 1439 (21 .1 .01
)
a-Blocker/other vasodilator365 (5.4) 365 (5.4) .96
a-Blocker 373 (5.5) 967 (14.2) < .001
Other class 616 (9.1 ) 626 (9.2) .83
Other drug
Aspirin or other 3938 (58.0) 3905 (57.2) .39
antiplatelet agent
Other NSAIDs 1205 (17.7) 121 1 (17.8) .99
Antidiabetic medicationt 1574 (23.2) 1682 (24.7) .04
Any lipid-lowering agent 2836 (41.7) 2822 (41 .4) .66
Nitrates 2024 (29.8) 21 16 (31.0) .13
Potassium supplement 469 (6,9) 507 (7.4) .24
Hormone replacement$ 601 (17.1 599 (16.9) .81
)
Abbreviations: ACE, angiotensin-converting
enzyme; NSAIDs, nonsteroidal
anti-
inflammatory drugs. '
Results from x~ test to
compare strategies.
t Insulin andlor oral hypoglycemics.
$ Data for women only (n or calcium 3554
= 3520 f antagonist for
strategy
and n =
non-calcium antagonist
strategy).
37
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Blood Pressure and Heart Rate
(0068] FIGURE 2 presents SBP and DBP data by treatment strategy over 48
months (error bars in the upward direction represent 1 SD for CAS and bars in
the downward direction represent 1 SD for NCAS). Mean (SD) SBP reduction at
24 months was 18.7 (22.2) mm Hg in the CAS group compared with 19.0
(22.6) mm Hg in the NCAS group (P= .41 ). The mean (SD) DBP reduction at 24
months was 10.0 (12.4) mm Hg in the CAS group compared, with 10.2 (12.4)
mm Hg in the in the NCAS group (P=.26). A reduction of 90% of the
maximum achieved in SBP and 100% in DBP occurred in the first 6 months of
treatment; the reductions were maintained throughout the trial. Mean resting
heart rate at 24 months was significantly lower (P< .001 ) in NCAS patients
(69.2/mm) compared with CAS patients (72.8/min).
Outcomes
[0069] FIGURE 3 presents the primary outcome and FIGURE 4 presents the
patients with events comprising the primary and other outcomes. A total of
2456 events were reported (CAS, 1214; NCAS, 1242) and the events
committee confirmed 2380 of the events (96.9%; CAS, 1 171; NCAS, 1209).
Sites reported that 2333 patients (CAS, 1 153; NCAS, 1 180) experienced an
event in the primary outcome cluster during follow-up and the events committee
confirmed that an event had occurred in 2269 of those patients (97.3%; CAS,
1 1 19; NCAS, 1150). Death (all-cause) occurred in 1766 patients (CAS, 873;
38
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NCAS, 893); 304 were non-fatal Mls (CAS, 151.; NCAS, 153); and 279 were
nonfatal strokes (CAS, 131; NCAS, 148). Of the 1766 confirmed deaths, 862
were classified as definitely or presumed cardiovascular (CAS, 431; NCAS,
431 ); 701 were non-cardiovascular (CAS, 350; NCAS, 351 ); and 203 could not
be classified (CAS, 92; NCAS, 1 1 1 ). Of the 1563 classifiable deaths, 862.
(55.2%) were cardiovascular. The analyses reported herein were performed
only on events confirmed by the events committee, but analyses of site-
investigator reported events yielded similar results (data not shown).
[0070] I<aplan-Meier analysis (unadjusted) of time to first primary outcome
event demonstrated no difference comparing the CAS group with the NCAS
group for a primary outcome (FIGURE 3; RR, 0.98 [95°/~ CI, 0.90-1
.06]). A
sensitivity analysis in which the 568 patients who were lost to follow-up or
witlldrew were all presumed to have died produced an RR of 1 .00 (95% CI,
0.94-1.08). When adjusted for the pre-specified covariates of age, race, sex,
previous MI, and previous heart failure, the CAS and NCAS groups were not
different (hazard ratio [HR] 0.98; 95% CI, 0.91-1 .07; P=.69). Other outcomes
were also similar in frequency between strategies (FIGURE 4). Time to death
(all
cause) did not differ between treatment groups (P= .72), nor did time to
nonfatal MI (P= 95), or time to nonfatal stroke (P= .33). Time to the most
serious event also did riot differ between treatment groups (P= .58). Fatal
and
nonfatal MI occurred in 452 CAS patients (4.01 %) and 441 NCAS patients
(3.90%) (RR, 1 .03; 95% CI, 0.90-1.17). Fatal and nonfatal stroke occurred in
176 CAS patients (1 .56%) and 201 NCAS patients (1 .78%) (RR, 0.88; 95% CI,
39
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0.72-1.07). Subgroup analyses by baseline characteristics showed consistency
for the primary outcome in both high- and low-risk subgroups (FIGURE 5). Of
particular note were the similar event rates for each strategy among patients
with prior MI as well as those with prior coronary revascularization. The
exception was patients with prior heart failure, for which those assigned to
the
NCAS strategy appeared to have fewer events (P=.03 for interaction). Also
important was the marked difference in the event rate of 14.3% (913/6400) for
those with diabetes compared with 8.4% (1356/16176) for those without
diabetes.
[0071 ] The effect of the treatment strategies using an overall SBP control
goal
of less than 140 mm Hg anti DBP control goal of less than 90 mm Hg was
similar. A total of 5625 patients (71 .7%) in the CAS group and 5553 (70.7%)
in the NCAS group achieved overall blood pressure control at 24 months
(P=.18). Based on JNC VI blood pressure goals, SBP control was achieved by
65.0% of CAS patients (n = 5093) c~mpared with 64.0% of NCAS patients
(n = 5025) (P= .23); DBP control was achieved by 88.5 % of CAS patients
(n = 6937) compared with 88.1 % of NCAS patients (n = 6914) (P= .46).
[0072] At baseline, angina was reported in 66.2 % of CAS patients (n = 7463)
compared with 67.0% of NCAS patients (n = 7582). At 24 months, these
percentages decreased to 27.3% in the CAS group (n=2055) and 28.3% in the
NCAS group (n=2136) (P=.18). Angina and unstable angina were infrequently
reported as adverse experiences and rates were similar in both groups (TABLE
5). At baseline (based on the previous 4 weeks), there was a mean (SD) of 1.5
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(2.33) angina episodes/wk in the CAS group and 1.5(2.43) in the NCAS group.
At 24 months, angina episodes decreased in both groups, but the mean (SD)
frequency was lower in the CAS group (0.77 [,1 .31 ] episodes/wk) compared
with the NCAS group (0.88 [1.62] episodes/wk) (P=.02). Revascularization
was required in only 2% of patients in each group (TABLE 5). Nitrate use was
the same in each strategy (TABLE 4).
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TABLE 5. Adverse Experiences'
No. (%) of Patients
Calcium Non-Calcium
Antagonist Antagonist P
dverse Experience Strategy Strategy ~/aluet
(n = 11 267) (n = 11 309)
Angina 261 (2.32) 228 (2.02) .13
I
CABG/PCI 280 (2.49) 275 (2.43) .80
Cancer 192 ( 1.70) 186 ( 1 .64) .73
Constipation 195 (1.73) 15 (0.13) <.001
Cough 201 (1.78) 152 (1.34) .01
Dizziness 154 (1.37) 151 (1.34) .84
Dyspnea 82 (0.73) 1 14 (1 .01 .03
)
Heart failure lclass 189 (1 .68) 173 (1 .53) .38
I-IV)
Lightheadedness ~ 48 (0.43) 70 (0.62) .05
Symptomatic bradycardia74 (0.66) 143 ( 1.26) < .001
Unstable angina 131 (1.16) 122 (1 .08) .55
Wheezing 17 (0.15) 44 (0.39) < .001
~ther$ 1 158 ( 10.28) 1 180 ( 10.43) .70
Abbreviations: CABG, coronary artery bypass graft; PCI, percutaneous coronary
intervention.
Alzheimer disease, gastrointestinal tract bleeding, Parkinson disease,
atrioventricular
block, gout, headache, hyperkalemia, hypokalemia, abnormal liver enzymes,
peripheral
edema, peripheral vascular disease, renal failure, and transient ischemic
attack were
observed in 1 % or fewer of each treatment group; differences between groups
were
nonsignificant (P> .05),
t Results from xa test for categorical measures.
$ Adverse experiences that were not frequently reported and were not
significantly
different between strategies).
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[0073] Analysis of the development of diabetes revealed significant
differences between the treatment strategies. Of the 8098 CAS patients
without diabetes at entry, 569 (7.03%) were diagnosed as having diabetes
during follow-up: Of the 8078 NCAS patients without diabetes at entry, 665
(8.23%) were diagnosed as having diabetes during follow-up (RR, 0.85; 95%
CI, 0.77-0.95). Patients in the CAS group were also less likely to die or
develop
diabetes compared with patients in the NCAS group (1050 [12.97%] vs 1 177
[14.57%]; RR, 0.89; 95% CI, 0.82-0.96) and less likely~to have an event in the
primary outcome cluster or develop diabetes (1 185 [14.63%] vs 1313
[16.25%]; RR, 0.90; 95% CI, 0.84-0.97). To explore possible explanations for
reduced risk of diabetes, we conducted preliminary analyses adjusting for the
5
pre-specified baseline covariates (age, race, sex, prior (VIII, and prior
heart failure)
and included factors for average daily dose of add-on medication (trandolapril
and /or hydrochlorothiazide). In these analyses, trandolapril appeared to
confer
a protective effect in the CAS group. Compared with those in the NCAS group
not taking either trandolapril or hydrochlorothiazide, those in the CAS group
not
taking trandolapril had a HR of developing diabetes of 0.95 (95% CI, 0.82-
1.10). A 2-mg dose of trandolapril was associated with a HR of 0.86 (95% CI,
0.74-1 .00) and a 4-mg dose was associated with a HR of 0.77 (95% CI, 0.62-
0.96). In the NCAS group, a 2-mg dose of trandolapril was associated with a
HR of 0.99 (95% CI, 0.90-1.08) and a 4-mg dose was associated with a HR of
0.98 (95% CI, 0.82-1.18). On the other hand, hydrochlorothiazide appeared to
confer a non-statistically significant increased risk of diabetes. Compared
with
43
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those in the NCAS group not taking either trandolapril or hydrochlorothiazide,
the addition of 12.5 mg of hydrochlorothiazide was associated with a HR of
1.17 (95% CI, 1.09-1.25) and 25 mg of hydrochlorothiazide was associated
with a HR of 1.36 (95% CI, 1.18-1.57). Those in the CAS group not taking
hydrochlorothiazide had a HR of 0.95 (95% CI, 0.82-1 .10); the addition of
12.5mg of hydrochlorothiazide was associated with a HR of 1.1 1 (95% CI,
0.95-1 .29) and 25 mg of hydrochlorothiazide was associated with a HR of 1 .28
(95% CI, 1.05-1.57).
Adverse Experiences
[0074] Both drug combinations were generally well tolerated in each
treatment group. Cancer was reported in 192 patients (1 .70°/~) in the
CAS
group compared with 186 patients (1 .64%) in the NCAS group (P=.73).
Alzheimer disease, gastrointestinal tract bleeding, and Parkinson disease were
reported in 1 % or less of patients in each group and incidence did not differ
between groups. Patients in the CAS group reported constipation and cough
snore frequently than patients in the NCAS group, while NCAS patients had
more dyspnea, lightheadedness, symptomatic bradycardia, and wheezing
(TABLE 5).
Subanalysis
[0075] Subanalysis Design: INVEST afforded an opportunifiy to analyze unique
and specific combinations of antihypertensive drugs due to the data
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accumulated for prescription date, drug, regimen, and dose. One subanalysis
was performed to evaluate the incremental benefit of BP reduction by the
addition of HCTZ to various dose combinations of verapamil SR and trandolapril
in patients randomized to the calcium antagonist strategy. The dose
combinations analyzed included HCTZ added to the following:
Group 1 - Verapamil SR 180 mg / trandolapril 2 mg
Group 2 - Verapamil SR 240 mg / trandolapril 2 mg
Group 3 - Verapamil SR 180 mg / trandolapril 4 mg
(0~76] Patients who received the verapamil SR / trandolapril combination as
their first randomized drug prescription in INVEST, and who received no other
drug prescription or gap in medication until their first HCTZ prescription
added to
the initial verapamil SR / trandolapril combination dose, were selected for
this
subgroup analysis. Because the dosing schedule in the study protocol
recommended starting with verapamil SR as monotherapy, and investigators
were free to vary doses as well as drugs prescribed during the trial, only a
small
proportion of patients satisfied these strict conditions. However, these sub-
populations were selected as the cleanest available subgroup to attempt to
estimate additional blood pressure reduction observed when HCTZ was added.
Summary statistics for change from baseline for SBP and DBP to the last
observation at each dose level for both the verapamil SR / trandolapril dual
combination and the verapamil SR / trandolapril / HCTZ triple combination were
analyzed. In INVEST, patients could have been treated with doses of HCTZ in
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the range of 12.5 - 100 mg. In this subanalysis the incremental effect of HCTZ
on BP reduction was evaluated for any dose of HCTZ.
[0077] Baseline Characteristics: The baseline characteristics of the three
verapamil SR / trandolapril / HCTZ groups are shown in TABLE 6. The groups
were generally comparable with respect to gender and age. Group 1 had the
highest baseline BP and the largest proportion of Blacks. Group 2 had the
largest proportion of Hispanics. Group 3 had the highest weight and body mass
index (BMI) and the largest proportion of Caucasians.
TABLE 6. Subanalysis Baseline Characteristics
Verapamil SR / Trandolapril Group (Dose)
~;r~up 1 ~aroup 2 Group 3
Par~rneter (780/2 rng) (240/2 rig) 240/4 nag
94 21 22
Age, mean (years) 64.5 62.1 64.1
Female (%) 55.3 52.4 45.5
Weight, mean (kg) 74.7 85.2 92.7
BMI, mean (kg/m~) 28.2 31.4 31.8
Race (/~)
Caucasian 45.7 42.9 86.4
Black 19.1 4.8 9.1
Hispanic 35.1 - 52.4 4.5
Systolic BP, mean (mm 164.4 160.3 160.7
Hg)
Diastolic BP, mean (mm 96.2 90.0 84.6
Hg)
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[0078] Subanalysis Results: The results of incremental BP reduction with the
addition of HCTZ to Groups 1, 2, and 3 are shown ~in TABLE 7. BP reductions
after patients were prescribed the initial verapamil SR / trandolapril
combinations
were variable due to differences in the quantity and type of baseline
antihypertensive medication. Because baseline antihypertensive medications
were discontinued at randomization, their impact on the evaluation of HCTZ
additivity was negligible. For each verapamil SR / trandolapril combination
group, clinically significant BP reduction was observed with the addition of
HCTZ. Decreases of mean systolic BP were 7.1, 6.5, and 3.2 mm Hg for
Groups 1, 2, and 3, respectively, after the addition of HCTZ. Decreases of
mean diastolic BP were 1.1, 4.2 and 2.3 mm Hg for Groups 1, 2, and 3,
respectively, with the addition of HCTZ. Thus, the addition of HCTZ to various
dose combinations of verapamil SR / trandolapril conferred further BP
reduction
in hypertensive patients.
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TABLE 7. Changes in Systolic and Diastolic BP
Verapamil SR
Verapamil Trandolapril
SR
Trandolapril HCTZ
BP Parameter Baseline (Dual Therapy)(Triple Therapy)
Mean (SD) last 164.4 / 149.3 / 85.9 142.2 / 84.8
96.2
observation (mm (20.6 / (18.3 / 12.6)(15.0 / 10.3)
Hg) 13.7)
o Mean change (SD) N/A -15.0 / -10.3-22.2 / -11.4
from
baseline (mm Hg)
(22.7 / 12.7)(20.9 / 13.1
)
Mean change (SD) N/A N/A -7.1 / -1.1
from
dual therapy (mm
Hg)
(19.6 / 12.3)
Mean (SD) last 160.3 / 153.6 / 88.4 147.1 / 84.3
90.0
observation (mm (24.3 / (19.7 / 10.1 (13.3 / 10.5)
Hg) 15.3) )
Mean change (SD) N/A -6.7 / -1.5 -13.2 / -5.7
from
baseline (mm Hg)
C'~ (22.8 / 10.9)(23.5 / 14.4)
Mean change (SD) N/A N/A -6.5 / -4.2
from
dual therapy (mm
Hg)
(17.7 / 8.3)
Mean (SD) last 160.7 / 149.9 / 81.7 146.7 / 79.3
84.6
~ observation (mm (17.1 / (15.0 / 10.5)(13.8 / 10.3)
Hg) 11.4)
Mean (SD) change N/A -10.8 / -2.9 -13.9 / -5.3
from
baseline (mm Hg)
C~ (16.1 / 9.6) (19.8 / 8.6)
Mean change (SD) N/a N/A -3.2 / -2.3
from
dual therapy (mm
Hg)
. (16.1 / 8.0)
Group 1 - (Verapamil SR 180 mg / Trandolapril 2 mg) N = 94
Group 2 - (Verapamil SR 240 mg / Trandolapril 2 mg) N=21
Group 3 - (Verapamil SR 240 mg / Trandolapril 4 mg) N=22
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[0079] Subanalysis Conclusion: The results of this subanalysis demonstrate
that HCTZ confers clinically significant, incremental BP reduction in
hypertensive
patients treated with a combination of verapamil SR and trandolapril.
Additional
BP reduction was observed with HCTZ for each of the three verapamil SR /
trandolapril combinations evaluated: 180/2 mg. 240/2 mg, and 240/4 mg.
(TABLE 7, "Mean change (SD) from dual therapy (mm Hg)). Because many
hypertensive patients require more than two agents to achieve BP goals, the
verapamil SR / trandolapril / HCTZ triple combination could be a reasonable
treatment option for moderate to severe hypertension.
[0080] Further, the subanalysis indicates that triple combination therapy with
a 2 mg dose of trandolapril (Groups 1 and 2) decreases blood pressure with
similar efficacy as triple combination therapy with a 4 mg dose of
trandolapril
(Group 3). Interestingly, the mean change from dual therapy was greater for
Groups 1 and 2 (2 mg trandolapril) than it was for Group 3 (4 mg
trandolapril).
(,See mean change from dual therapy for Groups 1, 2, and 3 in Table 7.) These
results demonstrate that it is possible to achieve essentially equivalent
reductions in blood pressure with half the dose of trandolapril in triple
combination therapies, thereby avoiding any needless side-effect's that may be
observed with higher doses.
C'.nnrli icinn
[0081] One objective of the INVEST study was to test the hypothesis that
treatment of hypertensive CAD patients with either a verapamil SR-based
strategy (CAS group) or a [3-blocker-based strategy (atenolol; NCAS group)
49
CA 02521014 2005-09-29
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would result in equivalent clinical outcomes. The findings of the study
demonstrated that these treatment strategies were equivalent in the prevention
of the outcome of all-cause mortality, nonfatal MI, or nonfatal stroke.
Furthermore, similar results were observed comparing the treatment strategies
for all-cause mortality, cardiovascular death, cardiovascular hospitalization,
and
blood pressure control. Significant differences were observed between
strategies that favored the verapamil SR plus trandolapril strategy (CAS
group)
for lower angina frequency and new diagnoses of diabetes. There was a
significant interaction between treatment group and prior heart failure,
suggesting that those randomized to the atenolol plus hydrochlorothiazide
strategy INCAS group) had better outcomes than those randomized to the
verapamil SR plus trandolapril strategy (CAS group). Both strategies were well
tolerated.
[0082] INVEST is the first, to our knowledge, large randomized, prospective
trial to focus on CA~ patients with hypertension and to follow JNC VI
guidelines, whicll recommend use of an ACE inhibitor for special populations
and
lower blood pressure goals than other guidelines. It is important t~ note that
this was not simply a comparison of verapamil SR with atenolol because it was
anticipated that few patients would be treated with only those drugs. At study
end, most were taking the combination of verapamil SR plus trandolapril (CAS
group) or atenolol plus hydrochlorothiazide INCAS group). Also, the study
population included a high percentage of elderly, female, nonwhite, and
diabetic
patients. Thus, the results reported herein should be clinically applicable.
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[0083] Although other trials have investigated use of calcium antagonists in
hypertensive patients, the frequency of CAD in these trials was too low to
reach
any relevant conclusions. For example, the Nordic Diltiazem (NORDIL) study
demonstrated equivalence between diltiazem and diuretics and/or ~i-blockers
for
cardiovascular morbidity and mortality and showed a reduction in incidence of
fatal and nonfatal stroke in the diltiazem group, but only a small proportion
of
those patients (4.5 °/~; n = 496) had coronary heart disease. Results
from several
hypertension trials, including LIFE and ALLHAT, have been confounded by
differences in achieved blood pressure level, which influences outcomes. In
our
study, the reductions and achieved levels for SBP and DBP were similar its
both
treatment groups. 11/lost INVEST patients achieved JNC VI goals for blood
pressure control. These findings in patients with CAD extend those from LIFE
and ALLHAT, demonstrating that even lower blood pressure targets are
achievable with more aggressive management. However, ALLHAT neither
tested a ~3-blocker arm nor used an angiotensin II active agent for organ
protection for patients with diabetes, renal impairment, or heart failure.
Thus,
INVEST results complement ALLHAT by including a [3-blocker-based strategy
plus organ protection in an elderly population with CAD. The INVEST data also
confirm and extend the suggestions of others that monotherapy is not
necessarily sufficient for optimal treatment of hypertension.
[0084] Overall, adverse experiences reported were minimal and similar in
frequency between treatment strategies. Previous articles have suggested that
some calcium antagonists (principally short-acting dihydropyridines) may be
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associated with an increased risk of cancer, gastrointestinal tract bleeding,
and
all-cause mortality. Results of ALLHAT, STOP-2, and INVEST have not
confirmed these suggestions. The difference in crossover rates may reflect the
consequences of adverse 'experiences (dyspnea, lightheadedness, symptomatic
bradycardia, and wheezing) associated with the combination of atenolol plus
hydrochlorothiazide INCAS group) compared with adverse experiences
(constipation and cough) associated with the combination of verapamil SR plus
trandolapril (CAS group). The possibility that the higher crossover rate in
the
atenolol based strategy is related to previous intolerance or physician bias
against [3-blockers cannot be excluded, particularly because patients recently
taking (3-blockers were excluded from the trial. Another possibility is that
the
differing drug components of CAS (verapamil SR plus trandolapril) or NCAS
(atenolol plus hydrochlorothiazide) could have conferred advantages in
addition
to blood pressure control. The combination of verapamil SR plus trandolapril
could result in fewer metabolic complications, as was observed with reduction
of new diagnoses of diabetes. The NCAS might have been expected to have
advantages in patients with a prior MI and prior coronary revascularization;
however, the results observed were similar with both strategies. ~ur outcome
data for patients with prior heart failure, on the other hand, concur with
recent
trials documenting benefits of (3-blockers when added to diuretics and ACE
inhibitors, although not all patients in those trials had hypertension. In
light of
the results reported herein, management of hypertension must focus on the risk
profile of the patient and overall treatment regimen rather than a single
drug.
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[0085] The study used blood pressure goals in accordance with JNC VI;
however, JNC VII and epidemiological data indicate that CHD risk increases
with
SBP levels higher than 1 15 mm Hg, so it could be argued that even lower blood
pressure targets may be reasonable. More than half the patients required 3 or
more antihypertensive drugs to achieve blood pressure control. Better blood
pressure control might have been possible if a fourth drug was included in
each
of the specified treatment strategies. The large sample size resulted in a
statistically significant difference in angina frequency comparing CAS with
NCAS, but this difference may not be clinically significant. The decline in
angina
prevalence and frequency from entry (only 2% underwent revascularization) is
clinically important. This, at least in part, is likely due to the decline in
both SBP
and heart rate. Lastly, although the new. diabetes analysis was not planned
before the trial started, this outcome was added early in the recruitment
phase.
The findings suggest potential clinical implications that require
confirmation.
~ther analyses of INVEST baseline data indicate that Hispanic ethnicity, heart
failure, US residency, hypercholesterolemia, left ventricular hypertrophy,
stroke
and transient ischemic attack, prior coronary revascularization, and body mass
index are linked to risk of developing diabetes. In the preliminary analyses
herein, administration of trandolapril appeared to confer some protection, as
suggested in previous studies of ACE inhibitors. Hydrochlorothiazide was
associated with a non-significantly increased risk of developing diabetes,
which
is also consistent with previous studies (usually a thiazide diuretic with a
(3-
blocker). Further analyses are required to better understand the complex
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CA 02521014 2005-09-29
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interactions among drug, dose, and demographic factors. Patients' potassium
levels were not collected in this study, so the role that hypokalemia may have
played in precipitating hyperglycemia cannot be determined.
[0086] In conclusion, our results indicate that lower targets for blood
pressure
control can be achieved in most hypertensive patients with CAD using a
multidrug strategy that includes administration of ACE inhibitors to patients
with
heart failure, diabetes, or renal impairment. The clinical equivalence of the
CAS
and NCAS groups in prevention of death, MI, or stroke supports the use of
either strategy in clinically stable patients with GAD who require blood
pressure
control. The decision regarding which drug classes to use in specific CAD
patients should be based on additional factors including adverse experiences,
history of heart failure, diabetes risk, and the physician's best judgment.
The
possibility of delaying the emergence of a diabetes diagnosis with a CAS
compared with an NCAS requires further investigation.
[008] All references, patents, and/or applications cited in the specification
are indicative of the level of skill of those skilled in the art to which the
invention pertains, and are incorporated by reference in their entireties,
including
any tables and figures, to the same extent as if each reference had been
incorporated by reference in its entirety individually.
[0088] One skilled in the art would readily appreciate that the present
invention is well adapted to obtain the ends and advantages mentioned, as well
as those inherent therein. The methods, variances, and
compounds/compositions described herein as presently representative of
54
CA 02521014 2005-09-29
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preferred embodiments are exemplary and are not intended as limitations on the
scope of the invention. Changes therein and other uses will occur to those
skilled in the art, which are encompassed within the invention.
[0089] It will be readily apparent to one skilled in the art that varying
substitutions and modifications may be made to the invention disclosed herein
without departing from the scope and spirit of the invention. For example, a
variety of different binding pairs can be utilized, as well as a variety of
different
therapeutic and diagnostic agents. Thus, such additional embodiments are
within the scope of the present invention.
[0090] The invention illustratively described herein suitably may be practiced
in the absence of any element or elements, limitation or limitations which is
not
specifically disclosed herein. Thus, for example, in each instance herein any
of
the terms °°comprising", .'consisting essentially of" and
'°consisting of" may be
replaced with either of the other two terms. The terms and expressions which
have been employed are used as terms of description and not of limitation, and
there is no intention that in the use of such terms and expressions of
excluding
any equivalents of the features shown and described or portions thereof, but
it
is recognized that various modifications are possible within the scope of the
invention. Thus, it should be understood that although the present invention
has been specifically disclosed by preferred embodiments and optional
features,
modification and variation of the concepts herein disclosed may be resorted to
by those skilled in the art, and that such modifications and variations are
considered to be within the scope of this invention.
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[0091] In addition, where features or aspects of the invention are described
in
terms of Markush groups or other grouping of alternatives, those skilled in
the
art will recognize that the invention is also thereby described in terms of
any
individual member or subgroup of members of the Markush group or other
group.
[0092] Also, unless indicated to the contrary, where various numerical values
are provided for embodiments; additional embodiments are described by taking
any 2 different values as the endpoints of a range. Such ranges are also
within
the scope of the described invention.
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CA 02521014 2005-09-29
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REFERENCES
1 . Punzi et al., The Treatment of Severe Hypertension with
Trandolapril, Verapamil, and Hydrochlorothiazide, Journal of Human
Hypertension (1997) 11, 477-481.
2. Skoularigis et al., Once-Daily Fixed Dose Combinations of
Verapamil and Trandolapril in Black Patients with Mild to Moderate
Hypertension: a New Choice for First Line Treatment, International Journal of
Clinical Pharmacology and Therapeutics, Vol. 35, No. 2 (1997), 51-55.
3. Murray et al., Global Mortality, Disability, and the Contribution of
Risk Factors: Global Burden of Disease Study, Lancet 1997; 349: 1436-42.
4. EUROASPIRE II Study Group. Lifestyle and Risk Factor Management
and lJse of Drug Therapies in Coronary Patients From 15 Countries; Principal
Results From EIJROASPIRE II Euro Heart Survey Programme. Eur Heart J 2001;
22: 554-72.
5. Murray et al., Effectiveness and Costs of Interventions to Lower
Systolic Blood Pressure and Cholesterol: a Global and Regional Analysis on
Reduction of Cardiovascular-Disease Risk, Lancet 2003; 361 : 717-25.
6. Dahlof et al.., Morbidity and Mortality in the Swedish Trial in Old
Patients with Hypertension (STOP-Hypertension), Lancet 1991; 338: 1281-5.
7. MRC Working Party. Medical Research Council Trial of Treatment
of Hypertension in Older Adults: Principal Results, Br Med J 1992; 304: 405-
12.
57
CA 02521014 2005-09-29
WO 2004/087132 PCT/US2004/010052
8~ Collins et al., Blood Pressure, Antihypertensive Drug Treatment and
the Risks of Stroke and of Coronary Heart Disease, Br Med Bull 1994; 50: 272-
98.
9. Psaty et al., Health Outcomes Associated with Antihypertensive
Therapies Used as First-Line Agents, JAMA 1997; 277:739-45.
10. Staessen et al., for the Systolic Hypertension in Europe (Syst-Eur)
Trial Investigators. Randomised Double-Blind Comparison of Placebo and Active
Treatment for Older Patients with Isolated Systolic Hypertension, Lancet 1997;
350: 757-64.
1 1 . Pitt, et al., Effect of Amlodipine on the Progression of
Atherosclerosis and the Occurrence of Clinical Events, Girccala~ion 2000; 102:
1503-10
12. HOPE (Heart Outcomes Prevention Evaluation) Study Investigators.
Effects on an Angiotensin-Converting-Enzyme Inhibitor, Ramipril, on
Cardiovascular Events in High-Risk Patients, /V ~r~gl J Med 2000; 342: 145-53.
13. UK Prospective Diabetes Study Group, Tight Blood Pressure Control
and Risk of Macrovascular and Microvascular Complications in Type 2 Diabetes:
UI<PDS 38, BMJ 1998; 317: 703-20.
14. U1< Prospective Diabetes Study Group, Efficacy of Atenolol and
Captopril in Reducing Risk of Macrovascular and Microvascular Complications in
Type 2 Diabetes: UKPDS 39, BMJ 1998; 317: 713-20
58
CA 02521014 2005-09-29
WO 2004/087132 PCT/US2004/010052
15. Zanchetti et al., The Verapamil in Hypertension and Atherosclerosis
Study (VHAS): Results of Long-Term Randomised Treatment with Either
Verapamil or Chlorthalidone on Intima-Media Thickness, J Hyperten 1998; 16:
1667-76.
16. Arauz-Pacheco, et al., The Treatment of Hypertension in Adult
Patients with Diabetes, Diabetes Care 2002; 25: 134-47.
17. Smith, Jr. et al., AHA/ACC Guidelines for Preventing Heart Attack
and Death in Patients with Atherosclerotic Cardiovascular Disease: 2001
update, Circulation 2001; 104: 1577-79.
18. Marks R, et al., Enhancing Clinical Trials on the Internet: Lessons
from INVEST, Clir~ Cardi~l 2001; 24 (1 1 supply: V17-23.
19. Cooper-DeHoff R et al., Electronic Prescribing via the Internet for a
Coronary Artery Disease and Hypertension Megatrial, Clir~ Cardi~l 2001; 24 (1
1
supply: V14-V6.
20. Burt VL et al., Prevalence of Hypertension in the lJS Adult
Population: Results From the Third National Health and Nutrition Examination
Survey, 1988-1991 . Hypertension 1995; 25: 305-13.
21. Sever, PS et al., for the ASCOT Investigators, Rationale, Design,
Methods and Baseline Demography of Participants of the Anglo-Scandinavian
Cardiac Outcomes Trial, J Hypertens 2001; 19: 1 139-47.
22. American Heart Association. Heart Disease and Stroke Statistics-
2003 Update. Dallas, Tex: American Heart Association; 2002.
59
CA 02521014 2005-09-29
WO 2004/087132 PCT/US2004/010052
23. Chalmers J, MacMahon S. Mancia G, et al. Guidelines for the
management of hypertension. Clin Exp. Hypertens. 1999;21:1009-1060.
24. Hansson L, Zanchetti I, Carruthers SC, et al. Effects of intensive
blood-pressure lowering and low-dose aspirin in patents with hypertension.
Lancet. 1998;351:1755-1762.
25. Probstfield JL, for the SHEP Cooperatve Research Group.
Prevention of stroke by antihypertensive drug treatment in older persons with
isolated systolic hypertension. JAMA. 1991 :265:3255-3264.
26. Hansson L, Lindholm LH, Ekbom T, et al. Randomised trial of old
and new antihypertensive drugs in elderly patients. Lancet. 1999;354:1751-
1756.
27. Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality
in patients randomised to double-blind treatment with a long-acting calcium-
channel blocker or diuretic in the International Nifedipine GITS study.
Lancet.
2000;356:366-372.
28. Chobanian AV, Bakris CL, Black HR, et al. The Seventh Report of
the Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure. JAMA. 2003;289:2560-2572.
29. Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-
converting-enzyme inhibition compared with conventional therapy on
cardiovascular morbidity and mortality in hypertension. Lancet 1999;353:611-
616.
CA 02521014 2005-09-29
WO 2004/087132 PCT/US2004/010052
30. The Sixth Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med.
1997;157:2413-2446 [Erratum, Arch. Intern. Med. 1998;158:573].
31 . Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-
converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk
patients. N Engl J. Med. 2000:342:145-153.
32. Hennekens CH, Albert CM, Godfried SL, Gaziano JM, Buring JE.
Adjunctive drug therapy for acute myocardial infarction-evidence from clinical
trials. N Eng J. Med. 1996:335:1660-1667.
33. The Fifth Report of the Joint National Committee on Detection,
Evaluation, and Treatment of High Blood Pressure (JNC V). Arch lnterr~ Med.
1993;153:154-183.
34. Messerli FH, Grossman E, Goldbourt U. Are ~-bloceers efficacious
as first-line therapy for hypertension in the elderly? JAMA. 1998:279:1903-
1907.
35. Dahlof B, Devereux RB, I<jeldsen SE, et al. Cardiovascular morbidity
and mortality in the Losartan Intervention For Endpoint Reduction in
Hypertension study (LIFE): a randomised trial against atenolol. Lancet.
2002:359:995-1003.
36. Neal B, MacMahon S, Chapman N, et al. Effects of ACE inhibitors,
calcium antagonists, and other blood-pressure-lowering drugs. Lancet.
2000:356:1955-1964.
61
CA 02521014 2005-09-29
WO 2004/087132 PCT/US2004/010052
37. 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. JAMA. 2002:288:2981 -2997.
38. Furberg CD, Psaty BM, MeyeriV. Nifedipine. Circulation.
1995:92:1326-1331.
39. Epstein M. The calcium antagonist controversy. Am J. Cardiol.
1997;79(suppl. 10A), 9-19.
40. Pepine CJ. The role of calcium antagonists in ischaemic heart
disease. Eur. Heart J. 1995;16(suppl H):19-24.
41. Pepine CJ, Faich G, Makuch R. Verapamil use in patients with
cardiovascular disease: an overview of randomized trials. Clin. Cardi~l.
1998:21 :633-541.
42. Hansson L, HednerT, Lund-Johansen P, et al. Randomised trial of
effects of calcium antagonists compared with diuretics and ~3-blockers on
cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem
(NORDIL) study. Lancet. 2000;356:359-365.
43. Ruilope LM, de la Sierra A, Moreno E, et al. Prospective comparison
of therapeutical attitudes in hypertensive type 2 diabetic patients
uncontrolled
on monotherapy. a randomized trial: the EDICTA study. J. Hypertens.
1999:17:1917-1923.
44. Karlberg BE, Andrup M, Oden A, for the Swedish TARI<A trialists.
Efficacy and safety of a new long-acting drug combination,
62
CA 02521014 2005-09-29
WO 2004/087132 PCT/US2004/010052
trandolapril/ve,rapamil as compared to monotherapy in primary hypertension.
Blood Press. 2000:9:140-145.
45. PROCOPA Study Group. Dissociation between blood pressure
reduction and fall in proteinuria in primary renal disease. J Hypertens.
2002;20:729-737.
46. Holzgreve H, Nakov R, Beck K, Janka HU. Anti-hypertensive
therapy with verapamil SR plus trandolapril versus atenolol plus
chlorthalidone
on glycemic control. Am J. Hypertens. 2003:16:381-386.
47. Wing LMH, Reid CM, Ryan P, et al. A comparison of outcomes with
angiotensin-converting enzyme inhibitors and diuretics for hypertension in the
elderly. N Engl. J. Med. 2003:348:583-592.
48. Parving HH, Lehnert H, Br~ehner-Mortensen J, et al. TIIe effect of
irbesartan on the development of diabetic nephropathy in patients with type 2
diabetes. N Engl J Med. 2001;345:870-878.
49. Brenner BM, Cooper ME, De ~eeuw D, et al. Effects of losartan on
renal and cardiovascular outcomes in patients with type 2 diabetes and
nephropathy. N Engl. J. Med. 2001:345:861 -869.
50. Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N,
Schrier RW. The effect of nisoldipine as compared with enalapril on
cardiovascular outcomes in patients with non-insulin-dependent diabetes and hy-
pertension. N Engl. J. Med. 1998:338:645-652.
63
CA 02521014 2005-09-29
WO 2004/087132 PCT/US2004/010052
51 . Wright TT Jr. Bakris C, Greene T, et al. Effect of blood pressure
lowering and antihypertensive drug class on progression of hypertensive Kidney
disease: results from the AASK trial. JAMA. 2002:19:2421-2431 .
52. Pepine CJ, Handberg-Thurmond E, Marks RG, et al. Rationale and
design of the International Verapamil SR/Trandolapril Study (INVEST). J Am
Coll
Cardiol. 1998;32:1228-1237.
53. Hansson L, Hedner T, Dahlof B. Prospective Randomized Open
Blinded End-point (PROBE) study. Blood Press. 1992:1 :1 13-1 19.
54. INVEST information pack. Available at:
http://www.medicine.ufl.edu/cardio/research/invest info/invest
definitions.shtml.
Accessed October 4, 2003.
55. Alderman M, Arakawa I<, Beilin L, et al. Effects of calcium
antagonists on the risles of coronary heart disease, cancer and bleeding. J.
Hypertens. 1997:15 :105-1 15 .
56. Bakris GL. Williams M, Dworkin L, et al. Preserving renal functions
in adults with hypertension and diabetes. Am J. l(°idr~ey ~is.
2000:36:646-661 .
57. Psaty BM, Heckbert SR, Koepsell TO, et al. The risk of myocardial
infarction associated with antihypertensive drug therapies. JAMA.
1995:274:620-625.
58. Pahor M, Psaty BM, Alderman MH, et al. Health outcomes
associated with calcium antagonists compared with other first-line
antihypertensive therapies. Lancet. 2000:356:1949-1954.
64
CA 02521014 2005-09-29
WO 2004/087132 PCT/US2004/010052
59. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart
failure. Lancet. 1999:353:2001 -2007.
60. Dargie HJ, Lechat P. The Cardiac Insufficiency Bisoprolol Study II
(CIBIS-II: a randomised trial. Lancet. 1999:353:9-13.
61 . Packer M, Coats AJS, Fowler MB, et al. Effect of carvedilol on
survival in severe chronic heart failure. N Engl J, Med. 2001:344:165.1-1658.
62. Lewington S, Clarke R, QIziIbasH N, Peto R, Collins R. Age-specific
relevance of usual blood pressure to vascular mortality. Lancet.
2002;360:1903-1913.
63. Cooper-DeHoff R, Bakris C, Cohen J, et al. Reduced risk of new
onset diabetes in hypertensive coronary artery disease patients treated with a
calcium antagonist vs a beta blocker regimen: the International
Verapamal/Trandolapril Stxdy. ~irccelati~n. 2003:108:1V-750.
64. Wright J, Davis B, Cutler J, et al. Long-term cardiovascular
consequences of diuretics vs calcium channel bloekers vs angiotensin-
converting
enzyme inhibitors. JAM~I. 2003:289:2067-2069.
65. Bengtsson C, Blohme C, Lapidus L, Lissner L, Lundgren H. Diabetes
incidence in users and non-users of antihypertensive drugs in relation to
serum
insulin, glucose tolerance and degree of adiposity. J, Intern. Med.
1992:231 :583-588.
66. Bakris GL, Weir MR, DeQuattro V, McMahon FG. Effects of an ACE
inhibitor/calcium antagonist combination on proteinuria in diabetic
nephropathy.
Kidney lnt 1998; 54: 1283-9.
CA 02521014 2005-09-29
WO 2004/087132 PCT/US2004/010052
67. Black HR, Elliott WJ, Neaton JD, et al. Baseline characteristics and
early blood pressure control in the CONVINCE trial. Hypertension 2001; 37: 12-
8.
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