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Pharmacologic properties of combination therapies
NIl-APRIL 1996-VOL. 9, NO.4, PART 2
204A ASH XI ABSTRACfS
Wednesday, May 15, Mercury Ballroom, 4:00 pm Recent Data on the Safety and Efficacy of Newer Therapies for the Management of Hypertension
Wednesday, May 15, Mercury Ballroom, 4:00 pm Recent Data on the Safety and Efficacy of Newer Therapies for the Management of Hypertension
PHARMACOLOGIC PROPERTIES OF COMBINAnON THERAPIES D.R. Abernethy, Division of Clinical Pharmacology, Georgetown University Medical Center, Washington, D.C.
Rnub 01 TnatlDellt 01 Hyperteulolo w1t1a II-BIoc:......Dluntlc Comblaatloa.. Foc.... Ve..,. Ltnr-Dooe Approacll William H. Frislunan MD, Albert Einstein College oCMedicine, Bronx. New York.
Single Drug therapy for the treatment of hypertensiOll has traditionally been a standard of practice. More recently combination therapy as first-line treatment has gained acceptance both by the medical practice community and the FDA. Advantages of combinations may be synergistic or additive antihypertensive effect, metabolic, or both. Combination of a thiazide-type diuretic and a potassiumsparing diuretic has been quite useful in the past to prevent the need for potassium supplementation. Combination of beta adrenoceptor blockade and a thiazide diuretic results in an additive antihypertensive effect which pennits the effective use of very low thiazide doses. Mechanism of antihypertensive effects of each member of the combination are complimentary, with increased sympathetic outflow and renin-angiotensin axis activation induced by the diuretic being blunted by beta-I adrenergic blockade. Combinations not used as first line therapy, such as angiotensin converting enzyme inhibitiors or angiotensin receptor blockade and a thiazide diuretic have complimentary antihypertensive mechanisms and have been useful to treat patient groups who do not respond well to converting enzyme inhibitor monotherapy. Combination of a calcium antagonist with diuretic therapy has an additive antihypertensive effect as well, however, the complimentary mechanisms are less obvious. Finally combination of angiotensin converting enzyme inhibition and calcium antagonist therapy has been useful in selected patients, but again the complimentary mechanisms are less obvious. As first-line therapy, combinations of diuretics and beta-l receptor blockade and a thiazide diuretic have been useful to achieve increased antihypertensive effect with decreased adverse drug effect.
The purpose ofusing single-agent combination (combo) thenpies for IOI'Ig periods of time to treat syslemic hypcrtensioo (lITN) bas been to improve patient complillllCC by taking I tablet or capsule other than 2 Combos a1110 could allow smaller doses of indiVIdual drugs to be used and occasionally the properties of t treatment could counteract the side effects of mocha Most of the diureticJP-adrenergic blocker combos used ClJIlvenbonal doses oCeach agent in a single formulation and were nol recommended u first·line therapy We had the opportunity to study a very low-dose diuretic regimen, hydrochlorotlu8Zlde (HCTZ) 6.25 mg, WIth a very Iow-dose II,-ilelecbve adrenergic blocker, bisoprolol (Bis), m 2 large placebo-controlled trials Both HCTZ and II blocken bave dooo-dc:pendent Ilde effects, therefOR SIde effects (metabolic and physical) should be reduced with lower doses Using • factorial design in the f1J'Sl study that allowed \IS to use placebo, HCTZ 6.25 and 25 mg, Bis2.5, 10 and 40 mg, and lhelrcomboa, It wu found that doses ofHCTZ 6.25 mg and Bis 2.5 mg bad modest 8Ilb-HTN actions and that the 2.5 mg Bis/6 25 mg HCTZ dose wu u effecltve u high-dose diuretic·p blocker treatment used u monother-apies The very Iow-dose combo wu shown to bave a side effect profile Identical to placebo In a second study using a double-blind, parallel, placebo-controlled destgn. placebo, Bis 5 mg, Bis 5mgIHCTZ 6.25 mg, and HCTZ 25 mg were compared. The combo wu more effective than placebo and Bis 5 mg alone, and just u good u HCTZ 25 mg. Based 01\ these studies. HCTZlBia wu approved u f1J'Sl-line treatmenl for HTN baving demonstrated addtbVlty from each drug component and a favorable side effect profile. Betaxolol and chlor1halidone, in • very low-dose combo, is also approved u f1J'Sl·line treatment for HTN There are also no published experiences evaluating morbidity and mortality with the very Iow-dose combos In companlive studies, the low-dose dlllreticlJl blocker combos bave been shown to be u effective u amlodipine and all ACE mhib,ton m the treatment oCHTN
KeyWords:
low-dose combination therapy, diuretICS. p block....
Key Words: Antihypertensive, Combination
Wednesday, May 15, Trianon Ballroom, 4:00 pm The Cost-Effective Management of Hypertension: Evaluation, Treatment and Appropriate Referral Pharmacoeconomic Considerations of Hypertension in a Managed Care Environment Robert P. Navarro, PharrnD, Emron, Inc. The complications and treatment of hypertension present a significant economic burden on any health delivery system, including managed care organizations (MCOs). While the economic benefits of effectively treating hypertension are well known, MCOs are attempting to more efficiently detect and treat hypertension to maximize the quality of care while at the same time minimizing the cost of diagnosis and treatment. The correlation between reduced complications and the reduction in diastolic blood pressure can be quantified, although confounding variables include patient compliance, blood pressure fluctuation, concomitant disease, and the individual course of the disease. The desire to demonstrate clinical and economic value of various antihypertensives has also been attempted by pharmaceutical manufacturers. Naturalistic observations based upon data obtained from MCOs has been helpful in quantifying patient compliance, the incidence of adverse drug events, the use of adjunctive therapy, dosage titration and other events that influence the effectiveness of an antihypertensive agent. MeOs are beginning to effectively use pharmacoeconomic data to make more rational drug formulary decisions based upon the ability of an agent to effectively reduce blood pressure, and presumably complications due to ineffectively treated hypertension.
Wednesday, May 15, Trianon Ballroom, 4:00 pm The Cost-Effective Management of Hypertension: Evaluation, Treatment and Appropriate Referral DEFINING OUTCOMES OF HYPERTENSION
TREATMENT
Michael A. Weber, MD The Brookdale VDlnnky Hospital ud Medical CeDIer
There are several vabd approacbes to derUJing and cl..sifying !be OII_S of antlbypencDlive therapy Fint. they caD be divided on a chronological basis iuo sbon~rm (clinical and ocher linding. during the rlnt weeks or mooths of eslablisbtng lte8l11lentl. Intermediate (observauons after the Ii'" several mooths of treatment). and long~nn (major endpoint flJldings lyplCBlly aller yean of lte8UDent). Within eacb of these time periods 0IIIC0IDes can be fwtber divided tnlo functional categortel. For eumple. clinical observaUODl (e.g blood pressure. blood cbenuslries. mcBIures of cardl8C and reoal structure and (unction); quality of life mdices (e g treatmem Itde
e!Tects. palients' sense of general well-being;. indices of ..lufaction by palients. families. and phySICians). and ecODOllllC (e g COIl of professional services. _. drogs. ocher health resoun:es lIll1Wuon. lime IOSI fnxn work) Fill8l1y. all of these auriblJles can be classuoed from the point of view of the major panlClp8nlJ In the hypencrulOn lreatment proceSI: patients. fanulJes: physlClaru. employen. health plans. msuraocc ccmparucs. and governmell agencies The IUD of this preseDLIllon II to try and construct a lOgICal framework for
consldenng lIus cOlllplex undenakutg so that cnllC8l cluucal and other cOlIChuions of interest 10 tbese palUClpaOO caD be more conveniently summarized and used in the process of decISIon making
KeyWords'
204A ASH XI ABSTRACfS
Wednesday, May 15, Mercury Ballroom, 4:00 pm Recent Data on the Safety and Efficacy of Newer Therapies for the Management of Hypertension
Wednesday, May 15, Mercury Ballroom, 4:00 pm Recent Data on the Safety and Efficacy of Newer Therapies for the Management of Hypertension
PHARMACOLOGIC PROPERTIES OF COMBINAnON THERAPIES D.R. Abernethy, Division of Clinical Pharmacology, Georgetown University Medical Center, Washington, D.C.
Rnub 01 TnatlDellt 01 Hyperteulolo w1t1a II-BIoc:......Dluntlc Comblaatloa.. Foc.... Ve..,. Ltnr-Dooe Approacll William H. Frislunan MD, Albert Einstein College oCMedicine, Bronx. New York.
Single Drug therapy for the treatment of hypertensiOll has traditionally been a standard of practice. More recently combination therapy as first-line treatment has gained acceptance both by the medical practice community and the FDA. Advantages of combinations may be synergistic or additive antihypertensive effect, metabolic, or both. Combination of a thiazide-type diuretic and a potassiumsparing diuretic has been quite useful in the past to prevent the need for potassium supplementation. Combination of beta adrenoceptor blockade and a thiazide diuretic results in an additive antihypertensive effect which pennits the effective use of very low thiazide doses. Mechanism of antihypertensive effects of each member of the combination are complimentary, with increased sympathetic outflow and renin-angiotensin axis activation induced by the diuretic being blunted by beta-I adrenergic blockade. Combinations not used as first line therapy, such as angiotensin converting enzyme inhibitiors or angiotensin receptor blockade and a thiazide diuretic have complimentary antihypertensive mechanisms and have been useful to treat patient groups who do not respond well to converting enzyme inhibitor monotherapy. Combination of a calcium antagonist with diuretic therapy has an additive antihypertensive effect as well, however, the complimentary mechanisms are less obvious. Finally combination of angiotensin converting enzyme inhibition and calcium antagonist therapy has been useful in selected patients, but again the complimentary mechanisms are less obvious. As first-line therapy, combinations of diuretics and beta-l receptor blockade and a thiazide diuretic have been useful to achieve increased antihypertensive effect with decreased adverse drug effect.
The purpose ofusing single-agent combination (combo) thenpies for IOI'Ig periods of time to treat syslemic hypcrtensioo (lITN) bas been to improve patient complillllCC by taking I tablet or capsule other than 2 Combos a1110 could allow smaller doses of indiVIdual drugs to be used and occasionally the properties of t treatment could counteract the side effects of mocha Most of the diureticJP-adrenergic blocker combos used ClJIlvenbonal doses oCeach agent in a single formulation and were nol recommended u first·line therapy We had the opportunity to study a very low-dose diuretic regimen, hydrochlorotlu8Zlde (HCTZ) 6.25 mg, WIth a very Iow-dose II,-ilelecbve adrenergic blocker, bisoprolol (Bis), m 2 large placebo-controlled trials Both HCTZ and II blocken bave dooo-dc:pendent Ilde effects, therefOR SIde effects (metabolic and physical) should be reduced with lower doses Using • factorial design in the f1J'Sl study that allowed \IS to use placebo, HCTZ 6.25 and 25 mg, Bis2.5, 10 and 40 mg, and lhelrcomboa, It wu found that doses ofHCTZ 6.25 mg and Bis 2.5 mg bad modest 8Ilb-HTN actions and that the 2.5 mg Bis/6 25 mg HCTZ dose wu u effecltve u high-dose diuretic·p blocker treatment used u monother-apies The very Iow-dose combo wu shown to bave a side effect profile Identical to placebo In a second study using a double-blind, parallel, placebo-controlled destgn. placebo, Bis 5 mg, Bis 5mgIHCTZ 6.25 mg, and HCTZ 25 mg were compared. The combo wu more effective than placebo and Bis 5 mg alone, and just u good u HCTZ 25 mg. Based 01\ these studies. HCTZlBia wu approved u f1J'Sl-line treatmenl for HTN baving demonstrated addtbVlty from each drug component and a favorable side effect profile. Betaxolol and chlor1halidone, in • very low-dose combo, is also approved u f1J'Sl·line treatment for HTN There are also no published experiences evaluating morbidity and mortality with the very Iow-dose combos In companlive studies, the low-dose dlllreticlJl blocker combos bave been shown to be u effective u amlodipine and all ACE mhib,ton m the treatment oCHTN
KeyWords:
low-dose combination therapy, diuretICS. p block....
Key Words: Antihypertensive, Combination
Wednesday, May 15, Trianon Ballroom, 4:00 pm The Cost-Effective Management of Hypertension: Evaluation, Treatment and Appropriate Referral Pharmacoeconomic Considerations of Hypertension in a Managed Care Environment Robert P. Navarro, PharrnD, Emron, Inc. The complications and treatment of hypertension present a significant economic burden on any health delivery system, including managed care organizations (MCOs). While the economic benefits of effectively treating hypertension are well known, MCOs are attempting to more efficiently detect and treat hypertension to maximize the quality of care while at the same time minimizing the cost of diagnosis and treatment. The correlation between reduced complications and the reduction in diastolic blood pressure can be quantified, although confounding variables include patient compliance, blood pressure fluctuation, concomitant disease, and the individual course of the disease. The desire to demonstrate clinical and economic value of various antihypertensives has also been attempted by pharmaceutical manufacturers. Naturalistic observations based upon data obtained from MCOs has been helpful in quantifying patient compliance, the incidence of adverse drug events, the use of adjunctive therapy, dosage titration and other events that influence the effectiveness of an antihypertensive agent. MeOs are beginning to effectively use pharmacoeconomic data to make more rational drug formulary decisions based upon the ability of an agent to effectively reduce blood pressure, and presumably complications due to ineffectively treated hypertension.
Wednesday, May 15, Trianon Ballroom, 4:00 pm The Cost-Effective Management of Hypertension: Evaluation, Treatment and Appropriate Referral DEFINING OUTCOMES OF HYPERTENSION
TREATMENT
Michael A. Weber, MD The Brookdale VDlnnky Hospital ud Medical CeDIer
There are several vabd approacbes to derUJing and cl..sifying !be OII_S of antlbypencDlive therapy Fint. they caD be divided on a chronological basis iuo sbon~rm (clinical and ocher linding. during the rlnt weeks or mooths of eslablisbtng lte8l11lentl. Intermediate (observauons after the Ii'" several mooths of treatment). and long~nn (major endpoint flJldings lyplCBlly aller yean of lte8UDent). Within eacb of these time periods 0IIIC0IDes can be fwtber divided tnlo functional categortel. For eumple. clinical observaUODl (e.g blood pressure. blood cbenuslries. mcBIures of cardl8C and reoal structure and (unction); quality of life mdices (e g treatmem Itde
e!Tects. palients' sense of general well-being;. indices of ..lufaction by palients. families. and phySICians). and ecODOllllC (e g COIl of professional services. _. drogs. ocher health resoun:es lIll1Wuon. lime IOSI fnxn work) Fill8l1y. all of these auriblJles can be classuoed from the point of view of the major panlClp8nlJ In the hypencrulOn lreatment proceSI: patients. fanulJes: physlClaru. employen. health plans. msuraocc ccmparucs. and governmell agencies The IUD of this preseDLIllon II to try and construct a lOgICal framework for
consldenng lIus cOlllplex undenakutg so that cnllC8l cluucal and other cOlIChuions of interest 10 tbese palUClpaOO caD be more conveniently summarized and used in the process of decISIon making
KeyWords'