EP1610775A2 - Combination drug therapy for treating hypertension - Google Patents

Abstract

Disclosed are compositions and methods for treating, preventing, and ameliorating hypertension, especially in patients with coronary artery disease, patients at risk for strokes, patients with renal disease, and patients with diabetes or at risk for diabetes. The compositions and methods relate to a combination therapy using three classes of anti-hypertension drugs, including calcium antagonists, angiotensin-converting-enzyme inhibitors, and diuretics. The preferred drugs in the compositions and methods are verapamil, trandolapril, and hydrochlorothiazide.

Description

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 HL64924-02 and N01 -

HV-681 63. The U.S. government has certain rights in this invention.

BACKGROUND

[0003] Cardiovascular disease has become a global burden, manifesting itself

in ever-increasing rates of coronary heart disease (CHD), 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 (Ml)

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 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

documented 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. β-Blockers are effective in hypertension treatment and reduce incidence of death and

reinfarction in patients who have had a myocardial infarction (Ml) . Along with

diuretics, β-blockers became the standard of care for hypertensive CAD patients.

However, β-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 β-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 ll-receptor

blocker and a diuretic was more effective than a combination of a β-blocker and

a diuretic.

[0007] Heart rate-reducing nondihydropyridine calcium antagonists, on the

other hand, have rarely been studied in large randomized 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. [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-

trandolapril STudy (INVEST), to determine the effects of a CA BP treatment

strategy (CAS) versus a non-CA strategy (NCAS) 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 (NCAS; 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 individual 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 therapeutic activities may be used as well. The pharmaceutical composition also

typicajly 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

1 00 mg); with the proviso that if the composition comprises 4 mg trandolapril or

8 mg trandolapril and the composition comprises 1 2.5 mg hydrochlorothiazide or

25 mg hydrochlorothiazide, the composition does not comprise 1 80 mg

verapamil; and with the proviso that if the composition comprises 4 mg

trandolapril and 1 2.5 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, 1 00 mg, 1 20 mg, 1 80 mg, 200 mg, 220 mg, 240 mg,

300 mg, 360 mg, and 480 mg; and preferred amounts of HCTZ are about 6.25

mg, 1 2.5 mg, 25 mg, 37.5 mg, 50 mg, 75 mg, and 1 00 mg.

[001 1 ] 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 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 1 50, 1 45, or 140 mm Hg (or 1 50-140 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 1 40 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 1 35 mm Hg and a

diastolic blood pressure of no more than about 85 mm Hg, or alternatively, a

systolic blood pressure of no more than about 1 30 mm Hg and a diastolic blood

pressure of no more than about 80 mm Hg) . As such, the active ingredients

may be useful for decreasing SBP and DBP (e.g. , by about 1 0% 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 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 1 50, 145, 140, 1 35, or 1 30

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 1 0% 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 1 50, 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 1 35 mm Hg and

DBP of no more than about 85 mm Hg; and even more preferably a SBP of no

more than about 1 30 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%) . [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 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, and 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 excipients. 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 excipients.

[0020] 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 unit(s) may include an effective amount of one or more

of the active ingredients to treat hypertension. [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 1 50, 145, 140, 1 35, or 1 30 mm Hg and a DBP of no more

than about 90, 85, or 80 mm Hg in the patient) . The kit also may include

instruction for reducing SBP and DBP relative to baseline measurements (e.g. , by

at least about 1 0%) . 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. [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.

[0029] 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 HCTZ, 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. , TARKA), are described in U.S.

4,933,361 ; U.S. 5,098,91 0; U.S. 5,403,856; U.S. 5,500,434; U.S. 5,684,01 6; 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. Pharmacopeia, 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 saccharose, sorbitol, gum acacia, sodium

alginate, gelatin, starches, cellulose, sodium carboxymethylcellulose,

methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, and

polyethyleneglycol. [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,

hydroxypropylmethylcellulose, 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 1 80 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 1 2.5 mg hydrochlorothiazide or 25 mg

hydrochlorothiazide, the composition does not comprise 1 80 mg verapamil; and

with the proviso that if the composition comprises 4 mg trandolapril and 1 2.5

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: (trandolapril: about 0.5, 1 , or 2 mg;

verapamil: about 40, 80, 1 00, 1 20, 1 80, 200, 220, 240, 360, or 480 mg; HCTZ about 6.25, 1 2.5, 25, 50, 75, or 100 mg), (trandolapril: about 1 or 2 mg;

verapamil: about 1 80 or 240 mg; HCTZ: about 6.25, 1 2.5, 25, 50, 75, or 1 00

mg), (trandolapril about 2 mg; verapamil: about 1 80 mg; HCTZ: about 6.25,

1 2.5, 25, 50, 75 or 100 mg), (trandolapril about 2 mg; verapamil: about 1 80

mg; HCTZ about 1 2.5, 25, or 50 mg), (trandolapril: about 2 mg; verapamil:

about 1 80 mg; HCTZ about 1 2.5 or 25 mg). As used herein, "about" means

+ /- 20%o, preferably + /- 1 0%, 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

hydrochlorothiazide may be present as active ingredients in a dose sufficient to

achieve and maintain a SBP of no more than about 1 50-1 40 mm Hg and a DBP

of no more than about 90 mm Hg; more preferably a SBP of no more than about

1 35 mm Hg and a DBP of no more than about 85 mm Hg, and even more

preferably SBP of no more than about 1 30 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 1 0% relative to 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 1 5 to 1 , and compositions

having integer ratios of all possible combinations between these ranges including

1 0 to 1 are considered embodiments of the present invention. [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 (PVAP), 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.

[0040] 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 1 2), by

maintaining an effective concentration of one or more of the active ingredients

(e.g. , trandolapril, verapamil, and/or HCTZ) in the patient's sera. "Effective

blood pressure control," as defined herein, may mean a SBP of no more than about 1 50, 145, 140, (i.e. , 1 50-140), 1 35, and 1 30 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

1 0% relative to baseline measurements. "Baseline measurements," as defined

herein, may mean SBP and DBP measurements taken before the composition is

administered.

[0041] The above-described pharmaceutical compositions may be

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 Ml, 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 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.

[0043] 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: 6.25-1 00 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 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) .

[0048] 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 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 SBP of no more than about 1 50, 145, 140, 1 35, Or 1 30

mm Hg and a DBP of no more than about 90, 85, Or 80 mm Hg) . The

instruction may also indicate how to decrease SBP and DBP relative to baseline

measurements (e.g. , by at least about 10%) .

EXAMPLES

[0049] The INVEST design and methods have been described in detail

elsewhere. (See, e.g., Pepine CJ, et a/. , J Am Coll Cardiol 1 998; Vol. 32: 1 228-

37 and Pepine et a/. , JAMA (2003), Vol. 290:2805-281 6 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 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 1 997; Vol. 1 57: 241 3-46 [Erratum, Arch Intern

Med 1 998; Vol 1 58: 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 Ml, or nonfatal stroke.

[0051 ] One objective of 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 < 1 30 mm Hg and DBP < 85 mm Hg when diabetes

or renal impairment is present) . Addition of trandolapril and/or 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 Ml, 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 (eg, ST-segment depression and/or perfusion defects by radionuclide,

and/or wall-motion abnormalities by echocardiogram or radionuclide) . Patients

with heart failure classes I through III were included. Patients taking β-blockers

within 2 weeks of randomization or taking β-blockers for an Ml that occurred in

the previous 1 2 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 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 240 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 β-

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 be titrated to between 1 20 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 1 80 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 1 2.5 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.

[0056] Additional non-study antihypertensive drugs, (except β-blockers 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 β-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. Patient Monitoring and Follow-up

[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 Ml, or nonfatal stroke by intention-to-treat analysis. The Ml and stroke

definitions are detailed on the INVEST Web site. These 3 components

individually were the main secondary outcomes. Additional outcomes included

time to most serious event (ranked from death as most serious, to Ml, 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 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, Ml, 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

⁾61 ] 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 (Cl) of 1 .20 to 0.83. We assumed an annual primary

outcome rate of no less than 2%, an α 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 1 0%. Because the enrollment period was longer than initially planned,

patient-years of follow-up were greater than those used for initial power 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.^'

[0063] The final significance level for the primary outcome, adjusted for the

single interim analysis, was P= .04806 for a 2-sided test. For the secondary

outcomes of death, nonfatal Ml, and nonfatal stroke, a Bonferroni adjustment

was made to the same P= .04806 significance level (P= . 2 for each outcome) .

All other analyses are reported at the P< .05 significance level . Kaplan-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

Ml, and prior heart failure. Standard relative risk (RR) estimates and 95% Cls

were also calculated.

[0064] χ2 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 (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 1 997. Full-

scale site recruitment and patient enrollment began in January 1 998, and patient

follow-up was completed on February 14, 2003. A total of 22576 patients at

862 sites in 1 4 countries provided informed consent, satisfied administrative

requirements, and completed randomization; 1 1 267 were assigned to the CAS

group and 1 1 309 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 female patients. Blood pressure levels were similar between groups (TABLE 2).

Overall, only 4267 patients (18.9% of all patients) had controlled blood

pressure.

TABLE 1. Patient Characteristics at Baseline*

Calcium Non-Calcium

Antagonist Antagonist

Strategy Strategy

Characteristic

(n = 11 267) (n = 11309)

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)

Other/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)

Abnormal angiogram 4384 (38.9) 4472 (39.5)

Prior Ml or abnormal angiogram 5932 (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 hypertrophy 2422 (21.5) 2526 (22.3)

Unstable angina >1 mo ago 1280 (11.4) 1298 (11.5)

Arrhythmia 802 (7.1) 798 (7.1) Heart failure (class l-l 61 9 (5.5) 637 (5.6)

Peripheral vascular disease 1 345 (1 1 .9) 1 354 (1 2.0)

Smoking Past 5247 (46.6) 5207 (46.0)

Within last 30 d 1435 (1 2.7) 1 374 (1 2.2)

Never 6020 (53.4) 6102 (54.0)

Diabetesf 31 69 (28.1 ) 3231 (28.6)

Hypercholesterolemia f 6300 (55.9) 6293 (55.6)

Renal impairment^ 21 4 (1 .9) 210 (1 .9)

Cancer§ 389 (3.5) 371 (3.3)

Medication

Aspirin or other antiplatelet agent 641 8 (57.0) 6377 (56.4

Other NSAIDs 1 984 (1 7.6) 2024 (1 7

Antidiabetic medication § : 2493 (22.1 ) 2591 (22

Any lipid-lowering agent 41 50 (36.8) 41 44 (36 6

Nitrates 3989 (35.4) 41 39 (36 6

Potassium supplement 777 (6.9) 783 (6.9)

Hormone replacement! 1034 (1 7.7) 1096 (1 8.5)

Abbreviations: BMI, body mass index; CABG, coronary artery. bypass graft; NSAIDs, 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 μmol/L). § Patients with a history of skin, prostate, and other cancers with long survival expectancy were not excluded. § § Insulin and/or oral hypoglycemics. f Data for women only (n = 5850 for calcium antagonist strategy and n = 5920 for non-calcium antagonist strategy). TABLE 2. Baseline Blood Pressure and Antihypertensive Medications

Calcium Non-Calcium

Antagonist Antagonist

Strategy Strategy

Antihypertensive Medication Use

(n = 9758) (n = 9791)

Blood pressure, mean (SD), mm Hg Systolic 149.5 (19.7) 149.5 (19.7)

Diastolic 86.3 (12.0) 86.3 (11.9)

Heart rate, mean (SD), beats/min 75.6 (9.5) 75.5 (9.5)

No.(%) with blood pressure in control* Systolic 2384 (24.4) 2359 (24.1)

Diastolic 5244 (53.7) 5311 (54.2)

Both 2154 (22.1) 2113 (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 5007 (51.3) 5042 (51.5)

Centrally acting! 516 (5.3) 536 (5.5)

Calcium antagonist 4031 (41.3) 4058 (41.4)

Diuretic 3650 (37.4) 3743 (38.2) α-Blocker/other vasodilator 828 (8.5) 830 (8.5) β-Blocker φ 0 0

Other class 2179 (22.3) 2183 (22.3) No Antihypertensive Medication Use

(n = 1509) (n = 1518)

Blood pressure, mean (SD), mm Hg Systolic 1 59.2 (1 5.7) 1 60.1 (1 5.9)

Diastolic 92.9 (1 0.1 ) 92.6 (1 0.6)

Heart rate, mean (SD), beats/min 76.6 (1 0.0) 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. t Patients taking β-blockers within 2 weeks of randomization or taking β-blockers for an

Ml that occurred in the previous 1 2 months were excluded to avoid withdrawal phenomena in patients randomized to the CAS group.

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 (/°< .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, 1 41 ) 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

β-blocker use was more frequent in the NCAS group (TABLE 4) . Crossover to β-

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, β-blocker use at any time in the CAS group was

1 305 (1 1 .6%) of 1 1 267 and calcium antagonist use in the NCAS group was

1 862 (1 6.5%) of 1 1 309 (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 = 1 574)

compared with the NCAS group (24.7%; n = 1 682) (P= .04). The frequencies of

other medication use were similar between strategies (TABLE 4). TABLE 3. Strategy Antihypertensive Medication Use

A. No. (%) of Patients at 12 months

Calcium Non-Calcium Antagonist Antagonist

Strategy Strategy P Value* (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 0 715 (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)

0 117 (1.4) 126 (1.4)

1 1376 (15.9) 1294 (14.9) .18

2 2941 (34.0) 2931 (33.7)

>3 4205 (48.7) 4343 (50.0) B. No. (%) of Patients at 24 months

Calcium Non-Calcium Antagonist Antagonist

Strategy Strategy P Value* (n = 7842) (n = 7850)

Study drug

Verapamil sustained release 6391 (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) 4113 (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 0 1096 (14.0) 998 (12.7)

1 1363 (17.4) 1424 (18.1) .11

2 2757 (35.2) 2779 (35.4)

3 2626 (33.5) 2649 (33.8)

Total No. of antihypertension drugs (strategy plus nonstrategy) 0 145 (2.1)f 141 (2.1)4:

1 1061(15.6)t 1031 (15. Dφ .57

2123(31.3)f 2089 (30.6)φ

>3 3464(51.0)f 3561 (52.2)φ

Abbreviation: N/A, not applicable. * Results from χ² test to compare strategies, t Based on reduced sample size of 6793. Based on reduced sample size of 6822. TABLE 4. Nonstrategy Medication Frequencies at 24 Months

No. (%) of Patients

Calcium Non-Calcium Antagonist Antagonist

Strategy Strategy P

Drug Use (n = 6793) (n = 6822) Value*

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 -Blocker/other vasodilator 365 (5.4) 365 (5.4) .9.6 β-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) ■ 3 antiplatelet agent

Other NSAIDs 1205 (17.7 1211 (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 2116 (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 χ² test to compare strategies, t Insulin and/or oral hypoglycemics. t Data for women only (n = 3520 for calcium antagonist strategy and n 3554 for non-calcium antagonist strategy). 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 1 8.7 (22.2) mm Hg in the CAS group compared with 1 9.0

(22.6) mm Hg in the NCAS group (P= .41 ) . The mean (SD) DBP reduction at 24

months was 1 0.0 (1 2.4) mm Hg in the CAS group compared with 10.2 (1 2.4)

mm Hg in the in the NCAS group (P= .26). A reduction of 90% of the

maximum achieved in SBP and 1 00% 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, 1 214; NCAS, 1 242) and the events

committee confirmed 2380 of the events (96.9%; CAS, 1 1 71 ; NCAS, 1 209).

Sites reported that 2333 patients (CAS, 1 1 53; NCAS, 1 1 80) 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 1 9; NCAS, 1 1 50). Death (all-cause) occurred in 1 766 patients (CAS, 873; NCAS, 893); 304 were non-fatal Mis (CAS, 1 51 .; NCAS, 1 53); and 279 were

nonfatal strokes (CAS, 1 31 ; NCAS, 148). Of the 1 766 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 1 563 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] Kaplan-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 % Cl, 0.90-1 .06]). A

sensitivity analysis in which the 568 patients who were lost to follow-up or

withdrew were all presumed to have died produced an RR of 1 .00 (95% Cl,

0.94-1 .08). When adjusted for the pre-specified covariates of age, race, sex,

previous Ml, and previous heart failure, the CAS and NCAS groups were not

different (hazard ratio [HR] 0.98; 95 % Cl, 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 Ml (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 Ml occurred in 452 CAS patients (4.01 %) and 441 NCAS patients

(3.90%) (RR, 1 .03; 95 % Cl, 0.90-1 .1 7). Fatal and nonfatal stroke occurred in

1 76 CAS patients (1 .56%) and 201 NCAS patients (1 .78%) (RR, 0.88; 95 % Cl, 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 Ml 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 1 4.3% (91 3/6400) for

those with diabetes compared with 8.4% (1 356/1 61 76) for those without

diabetes.

[0071 ] The effect of the treatment strategies using an overall SBP control goal

of less than 1 40 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= .1 8) . Based on JNC VI blood pressure goals, SBP control was achieved by

65.0% of CAS patients (n = 5093) compared 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 = 691 4) (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 = 21 36) (P= .1 8) . 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 (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) .

TABLE 5. Adverse Experiences'

No. (%) of Patients

Calcium Non-Calcium

Antagonist Antagonist P

Strategy Strategy

Adverse Experience Value⁷

(n = 11 267) (n = 11 309)

Angina 261 (2.32) 228 (2.02) .13

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) 114 (1.01) .03

Heart failure (class l-IV) 189 (1.68) 173 (1.53) .38

Lightheadedness 48 (0.43) 70 (0.62) .05

Symptomatic bradycardia 74 (0.66) 143 (1.26) < 001

Unstable ang ina 131 (1.16) 122 (1.08) .55

Wheezing 17 (0.15) 44 (0.39) <.001

Other* 1158 (10.28) 1180 (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). f Results from χ² test for categorical measures.

X Adverse experiences that were not frequently reported and were not significantly different between strategies). [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 %

Cl, 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 (1 050 [1 2.97%] vs 1 1 77

[1 4.57%]; RR, 0.89; 95 % Cl, 0.82-0.96) and less likely to have an event in the

primary outcome cluster or develop diabetes (1 1 85 [1 4.63%] vs 1 31 3

[1 6.25 %]; RR, 0.90; 95% Cl, 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 Ml, 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% Cl, 0.82-

1 .10) . A 2-mg dose of trandolapril was associated with a HR of 0.86 (95% Cl,

0.74-1 .00) and a 4-mg dose was associated with a HR of 0.77 (95% Cl, 0.62-

0.96) . In the NCAS group, a 2-mg dose of trandolapril was associated with a

HR of 0.99 (95% Cl, 0.90-1 .08) and a 4-mg dose was associated with a HR of

0.98 (95% Cl, 0.82-1 .1 8). On the other hand, hydrochlorothiazide appeared to

confer a non-statistically significant increased risk of diabetes. Compared with those in the NCAS group not taking either trandolapril or hydrochlorothiazide,

the addition of 1 2.5 mg of hydrochlorothiazide was associated with a HR of

1 .1 7 (95% Cl, 1 .09-1 .25) and 25 mg of hydrochlorothiazide was associated

with a HR of 1 .36 (95 % Cl, 1 .1 8-1 .57). Those in the CAS group not taking

hydrochlorothiazide had a HR of 0.95 (95 % Cl, 0.82-1 .1 0); the addition of

1 2.5mg of hydrochlorothiazide was associated with a HR of 1 .1 1 (95% Cl,

0.95-1 .29) and 25 mg of hydrochlorothiazide was associated with a HR of 1 .28

(95% Cl, 1 .05-1 .57) .

Adverse Experiences

[0074] Both drug combinations were generally well tolerated in each

treatment group. Cancer was reported in 1 92 patients (1 .70%) in the CAS

group compared with 1 86 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 opportunity to analyze unique

and specific combinations of antihypertensive drugs due to the data 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 1 80 mg / trandolapril 2 mg Group 2 - Verapamil SR 240 mg / trandolapril 2 mg Group 3 - Verapamil SR 1 80 mg / trandolapril 4 mg

[0076] 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 the range of 1 2.5 - 1 00 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)

Group 1 Group 2 Group 3

Parameter (180/2 mg) (240/2 mg) 240/4 mg

[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.

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 [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: 1 80/2 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-effects that may be

observed with higher doses.

Conclusion

[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 β-blocker-based strategy (atenolol; NCAS group) 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 Ml, 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 (NCAS 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 CAD patients with hypertension and to follow JNC VI

guidelines, which recommend use of an ACE inhibitor for special populations and

lower blood pressure goals than other guidelines. It is important to 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 (NCAS 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. [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 β-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. Most 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 β-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 β-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 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 (NCAS 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 β-blockers cannot be excluded, particularly because patients recently

taking β-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 Ml and prior coronary revascularization;

however, the results observed were similar with both strategies. Our outcome

data for patients with prior heart failure, on the other hand, concur with recent

trials documenting benefits of β-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. [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 1 5 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.

Other 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 β-

blocker) . Further analyses are required to better understand the complex 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, Ml, 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.

[0087] 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 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 o 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. [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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8.

Claims

WHAT IS CLAIMED IS:

1 . A pharmaceutical composition comprising:

between about 0.5 mg and about 2 mg trandolapril or a therapeutic

derivative thereof;

verapamil or a therapeutic derivative thereof;

hydrochlorothiazide or a therapeutic derivative thereof; and

one or more pharmaceutically suitable carriers or excipients.

2. The composition of claim 1 , wherein the composition comprises

about 2 mg trandolapril or a therapeutic derivative thereof.

3. The composition of claim 1 , wherein the composition comprises

about 1 mg trandolapril or a therapeutic derivative thereof.

4. The composition of claim 1 , wherein the composition comprises

between about 40 mg and about 360 mg verapamil or a therapeutic derivative

thereof.

5. The composition of claim 4, wherein the composition comprises

between about 1 80 mg and about 240 mg verapamil or a therapeutic derivative

thereof.

6. The composition of claim 5, wherein the composition comprises

about 240 mg verapamil or a therapeutic derivative thereof.

7. The composition of claim 5, wherein the composition comprises

about 1 80 mg verapamil or a therapeutic derivative thereof.

8. The composition of claim 1 , wherein the composition comprises

between about 6.25 mg and about 1 00 mg hydrochlorothiazide or a therapeutic

derivative thereof.

9. The composition of claim 8, wherein the composition comprises

between about 6.25 mg and about 25 mg hydrochlorothiazide or a therapeutic

derivative thereof.

1 0. The composition of claim 1 , wherein the composition comprises:

about 40, 80, 1 00, 1 20, 1 80, 200, 220, 240, 300, or 360 mg verapamil

or a therapeutic derivative thereof;

about 0.5, 1 , or 2 mg trandolapril or a therapeutic derivative thereof; and

about 6.25, 1 2.5, 25, 50, 75, or 1 00 mg hydrochlorothiazide or a

therapeutic derivative thereof.

1 1 . The composition of claim 1 0, wherein the composition comprises

about 2 mg trandolapril or a therapeutic derivative thereof.

1 2. The composition of claim 1 0, wherein the composition comprises

about 1 mg trandolapril or a therapeutic derivative thereof.

1 3. The composition of claim 1 0, wherein the composition comprises

about 240 mg verapamil or a therapeutic derivative thereof.

1 4. The composition of claim 1 0, wherein the composition comprises

about 1 80 mg verapamil or a therapeutic derivative thereof.

1 5. The composition of claim 1 0, wherein the composition comprises

about 6.25, 1 2.5, or 25 mg hydrochlorothiazide or a therapeutic derivative

thereof.

1 6. The composition of claim 1 0, wherein the composition comprises:

about 2 mg trandolapril or a therapeutic derivative thereof; and

about 240 mg verapamil or a therapeutic derivative thereof.

1 7. The composition of claim 1 6, wherein the composition comprises

about 6.25, 1 2.5, or 25 mg hydrochlorothiazide or a therapeutic derivative

thereof.

1 8. The composition of claim 1 0, wherein the composition comprises:

about 2 mg trandolapril or a therapeutic derivative thereof; and

about 1 80 mg verapamil or a therapeutic derivative thereof.

1 9. The composition of claim 1 8, wherein the composition comprises

about 6.25, 1 2.5, or 25 mg hydrochlorothiazide or a therapeutic derivative

thereof.

20. The composition of claim 1 , wherein verapamil, trandolapril, and

hydrochlorothiazide or their therapeutic derivatives are present as active

ingredients for treating hypertension.

21 . The composition of claim 20, further comprising a matrix

formulated for controlled release of one or more of the active ingredients after

the composition is administered to a patient.

22. The composition of claim 21 , wherein one or more of the active

ingredients provide effective blood pressure control for about 24-30 hours when

administered to a patient.

23. The composition of claim 22, wherein the composition releases

effective amounts of one or more of the active ingredients for about 24-30

hours to achieve a systolic blood pressure of no more than about 1 50-1 40 mm

Hg and a diastolic blood pressure of no more than about 90 mm Hg in the

patient.

24. The composition of claim 22, wherein the composition releases

effective amounts of one or more of the active ingredients to achieve a decrease

in systolic blood pressure and diastolic blood pressure of at least about 1 0% in

the patient relative to baseline measurements.

25. The composition of claim 21 , wherein the composition provides

effective blood pressure control for about 1 to 30 days when administered to a

patient.

26. The composition of claim 25, wherein the composition provides

effective blood pressure control for about 7 days when administered to a

patient.

27. The composition of claim 1 , wherein the composition is formulated

for oral, topical, transdermal, subcutaneous, parenteral, or pulmonary

administration.

28. The composition of claim 27, wherein the composition is

formulated for oral, transdermal, or parenteral administration.

29. The composition of claim 1 , wherein the composition is formulated

as one or more tablets, capsules, granules, powders, liquids, suspensions, or

emulsions.

30. A pharmaceutical composition for treating hypertension, comprising

one or more pharmaceutically suitable carriers or excipients and active

ingredients including:

trandolapril or a therapeutic derivative thereof, present in an amount

between about 0.5 mg and about 2 mg;

verapamil or a therapeutic derivative thereof; and

hydrochlorothiazide or a therapeutic derivative thereof;

wherein one or more of the active ingredients are present in an amount to

achieve effective blood pressure control in a patient to which the composition is

administered.

31 . The composition of claim 30, wherein the composition comprises

about 2 mg trandolapril or a therapeutic derivative thereof.

32. The composition of claim 30, wherein the composition comprises

about 1 mg trandolapril or a therapeutic derivative thereof.

33. The composition of claim 30, wherein verapamil or a therapeutic

derivative thereof is present in an amount between about 40 mg and about 360

mg.

34. The composition of claim 33, wherein verapamil or a therapeutic

derivative thereof is present in an amount between about 1 80 mg and about

240 mg.

35. The composition of claim 34, wherein the composition comprises

about 240 mg verapamil.

36. The composition of claim 35, wherein the composition comprises

about 1 80 mg verapamil.

37. The composition of claim 30, wherein one or more of the active

ingredients are present in an amount to achieve a systolic blood pressure of no

more than about 1 50-140 mm Hg and a diastolic blood pressure of no more

than about 90 mm Hg in a patient to which the composition is administered.

38. The composition of claim 30, wherein one or more of the active

ingredients are present in an amount to achieve a systolic blood pressure of no

more than about 1 35 mm Hg and a diastolic blood pressure of no more than

about 85 mm Hg in a patient to which the composition is administered.

39. The composition of claim 30, wherein one or more of the active

ingredients are present in an amount to achieve a systolic blood pressure of no

more than about 1 30 mm Hg and a diastolic blood pressure of no more than

about 80 mm Hg in a patient to which the composition is administered.

40. The composition of claim 30, wherein one or more of the active

ingredients are present in an amount to achieve a decrease in systolic blood

pressure and diastolic blood pressure of at least about 1 0% relative to baseline

measurements in a patient to which the composition is administered.

41 . The composition of claim 30, wherein the patient has coronary

artery disease.

42. The composition of claim 30, wherein the patient has renal disease.

43. The composition of claim 30, wherein the patient has diabetes or is

at risk for acquiring diabetes.

44. The composition of claim 30, wherein the patient is about 60 years

of age or older.

45. The composition of claim 44, wherein the patient is about 70 years

of age or older.

46. Use of a composition comprising one or more pharmaceutically

suitable carriers or excipients and active ingredients including:

a calcium channel blocker;

an angiotensin-converting-enzyme inhibitor;

a diuretic; and

for the preparation of a medicament for achieving and maintaining

effective blood pressure control in a patient with coronary artery disease,

wherein one or more of the active ingredients are present in an effective amount

for treating hypertension in the patient.

47. Use of the composition of claim 46 for achieving and maintaining a

systolic blood pressure of no more than about 1 50-1 40 mm Hg and a diastolic

blood pressure of no more than about 90 mm Hg in the patient.

48. Use of the composition of claim 46 for achieving and maintaining a

systolic blood pressure of no more than about 1 35 mm Hg and a diastolic blood

pressure of no more than about 85 mm Hg in the patient.

49. Use of the composition of claim 48 for achieving and maintaining a

systolic blood pressure of no more than about 1 30 mm Hg and a diastolic blood

pressure of no more than about 80 mm Hg in the patient.

50. Use of the composition of claim 46 for achieving and maintaining a

decrease in systolic blood pressure and diastolic blood pressure of at least about

1 0% relative to baseline measurements in the patient.

51 . Use of the composition of claim 46, wherein the angiotensin-

converting-enzyme inhibitor is trandolapril; the calcium channel blocker is

verapamil or a therapeutic derivative thereof; and the diuretic is

hydrochlorothiazide or a therapeutic derivative thereof.

52. Use of the composition of claim 51 , wherein the composition

comprises between about 0.5 mg and about 2 mg trandolapril.

53. Use of the composition of claim 52, wherein the composition

comprises about 2 mg trandolapril.

54. Use of the composition of claim 52, wherein the composition

comprises about 1 mg trandolapril.

55. Use of the composition of claim 52, wherein the composition

comprises between about 40 mg and about 240 mg of verapamil; and between

about 6.25 mg and about 1 00 mg of hydrochlorothiazide.

56. Use of the composition of claim 55, wherein the composition

comprises about 240 mg of verapamil.

57. Use of the composition of claim 55, wherein the composition

comprises about 1 280 mg of verapamil.

58. Use of the composition of claim 46, wherein the patient has ,

diabetes..

59. Use of the composition of claim 46, wherein the patient has renal

disease.

60. Use of the composition of claim 46, wherein the patient is about

60 years of age or older.

61 . Use of the composition of claim 60, wherein the patient is about

70 years of age or older.

62. Use of a composition comprising one or more pharmaceutically

suitable carriers or excipients and active ingredients including:

a calcium channel blocker;

an angiotensin-converting-enzyme inhibitor;

a diuretic; and

for the preparation of a medicament for decreasing mortality in a patient

by achieving and maintaining effective blood pressure control in the patient.

63. Use of a composition comprising one or more pharmaceutically

suitable carriers or excipients and active ingredients including:

a calcium channel blocker;

an angiotensin-converting-enzyme inhibitor;

a diuretic; and

for the preparation of a medicament for decreasing the likelihood of a

heart attack and/or a myocardial infarction in a patient by achieving and

maintaining effective blood pressure control in the patient.

64. Use of a composition comprising one or more pharmaceutically

suitable carriers or excipients and active ingredients including:

a calcium channel blocker;

an angiotensin-converting-enzyme inhibitor;

a diuretic; and

for the preparation of a medicament for decreasing the likelihood of a

stroke in a patient comprising by achieving and maintaining effective blood

pressure control in the patient.

65. Use of a composition comprising one or more pharmaceutically

suitable carriers or excipients and active ingredients including:

a calcium channel blocker;

an angiotensin-converting-enzyme inhibitor;

a diuretic; and

for the preparation of a medicament for decreasing the likelihood of a

patient acquiring diabetes or delaying the onset of diabetes in a patient by

achieving and maintaining effective blood pressure control in the patient.

66. A kit for treating hypertension in a patient with coronary artery

disease comprising: (a) one or more dosage units, wherein a dosage unit

comprises one or more pharmaceutically acceptable excipients and active

ingredients including an angiotensin-converting-enzyme inhibitor, a calcium

antagonist, and a diuretic; and one or more of the active ingredients are present

in an effective amount to treat hypertension, and (b) instructions for using the

kit to treat, prevent, and/or ameliorate hypertension by achieving and

maintaining effective blood pressure control in the patient.

67. The kit of claim 66, wherein the kit is used to achieve and maintain

a systolic blood pressure of no more than about 1 50-1 40 mm Hg and a diastolic

blood pressure of no more than about 90 mm Hg in the patient.

68. The kit of claim 66, wherein the kit is used to achieve and maintain

a decrease in systolic blood pressure and diastolic blood pressure of at least

about 1 0% relative to baseline measurements in the patient.

69. The kit of claim 66, wherein the angiotensin-converting-enzyme

inhibitor is trandolapril or a therapeutic derivative thereof; the calcium antagonist

is verapamil or a therapeutic derivative thereof; and the diuretic is

hydrochlorothiazide or a therapeutic derivative thereof.

70. The kit of claim 69, wherein the dosage unit comprises between

about 0.5 mg and about 2 mg trandolapril.

71 . The kit of claim 70, wherein the dosage unit comprises about 2 mg

trandolapril.

72. The kit of claim 70, wherein the dosage unit comprises about 1 mg

trandolapril.

73. The kit of claim 70, wherein the dosage unit comprises between

about 40 mg and about 360 mg verapamil; and between about 6.25 mg and

about 1 00 mg hydrochlorothiazide.

74. The kit of claim 73, wherein the dosage unit comprises about 240

mg verapamil.

75. The kit of claim 73, wherein the dosage unit comprises about 1 80

mg verapamil.

76. The kit of claim 66, wherein the kit comprises up to about 35

dosage units.

77. The kit of claim 66, further comprising instructions for using the kit

to treat coronary artery disease, to decrease mortality, to decrease the likelihood

of a heart attack and/or myocardial infarction, to decrease the likelihood of

acquiring diabetes, and/or to decrease the likelihood of a stroke.

78. A kit for treating hypertension in a patient with coronary artery

disease comprising:

(a) active ingredients formulated as:

(i) one or more dosage units comprising an angiotensin-converting-

enzyme inhibitor and one. or more pharmaceutically suitable carriers or

excipients;

(ii) one or more dosage units comprising a calcium antagonist and

one or more pharmaceutically suitable carriers or excipients; and

(iii) one or more dosage units comprising a diuretic and one or more

pharmaceutically suitable carriers or excipients;

wherein one or more the active ingredients are present in an

effective amount to treat hypertension in the patient; and

(b) instructions, for using the kit to treat, prevent, and/or ameliorate

hypertension by achieving and maintaining effective blood pressure control in

the patient.

79. The kit of claim 78, wherein the kit is used to achieve and maintain

a systolic blood pressure of no more than about 1 50-1 40 mm Hg and a diastolic

blood pressure of no more than about 90 mm Hg in the patient.

80. The kit of claim 78, wherein the kit is used to achieve and maintain

a decrease in systolic blood pressure and diastolic blood pressure of at least

about 1 0% relative to baseline measurements in the patient.

81 . The kit of claim 78, wherein the angiotensin-converting-enzyme

inhibitor is trandolapril or a therapeutic derivative thereof; the calcium antagonist

is verapamil or a therapeutic derivative thereof; and the diuretic is

hydrochlorothiazide or a therapeutic derivative thereof.

82. The kit of claim 81 , wherein the trandolapril dosage unit comprises

between about 0.5 mg and about 2 mg trandolapril.

83. The kit of claim 82, wherein the trandolapril dosage unit comprises

about 2 mg trandolapril.

84. The kit of claim 83, wherein the trandolapril dosage unit comprises

about 1 mg trandolapril.

85. The kit of claim 82, wherein the verapamil dosage unit comprises

between about 40 mg and about 360 mg verapamil; and the hydrochlorothiazide

dosage unit comprises between about 6.25 mg and about 1 00 mg

hydrochlorothiazide.

86. The kit of claim 85, wherein the verapamil dosage unit comprises

about 240 mg verapamil.

87. The kit of claim 85, wherein the verapamil dosage unit comprises

about 1 80 mg verapamil.

88. The kit of claim 78, further comprising instructions for using the kit

to treat coronary artery disease, to decrease mortality, to decrease the likelihood

of a heart attack and/or myocardial infarction, to decrease the likelihood of

acquiring diabetes, and/or to decrease the likelihood of a stroke.