advances in antihypertensive combination therapy: benefits of low-dose thiazide diuretics in...

VOL. III NO. V SEPTEMBER/OCTOBER 2001 THE JOURNAL OF CLINICAL HYPERTENSION 307

The preferred initial agents for the treatment ofhigh blood pressure are low-dose thiazide diuretics, β blockers, calcium antagonists, and an-giotensin-converting enzyme (ACE) inhibitors. Inhigh-risk patients, including those with diabetes,renal insufficiency, left ventricular dysfunction,and atherosclerosis, ACE inhibitors may have spe-cific benefit in reducing cardiovascular morbidityand mortality. Omapatrilat, the prototypical va-sopeptidase inhibitor, inhibits not only ACE butalso neutral endopeptidase. Like conventionalACE inhibitors, omapatrilat causes extracellularvolume reduction and vasodilatation; moreover, itincreases levels of atrial and brain natriuretic pep-tides and bradykinin. Effective blood pressurecontrol, especially in the high-risk patient, usuallynecessitates combination therapy. A recent studyrandomized 274 subjects with mild to severe hy-pertension (stages 1–3 diastolic blood pressure ele-vation) and confirmed the benefits of omapatrilatcombined with hydrochlorothiazide in patientsnot controlled on hydrochlorothiazide alone. Thefrequencies of adverse events, serious adverseevents, and discontinuation attributed to adverseevents were similar for omapatrilat and placebo.Furthermore, there were no clinically significantchanges in serum creatinine, potassium, or otherlaboratory parameters. Adding omapatrilat to the

background of hydrochlorothiazide treatment pro-duced statistically significant additional reductionsin trough diastolic and systolic blood pressures at weeks 4 and 8.(J Clin Hypertens. 2001;3:307–312). ©2001 Le Jacq Communications, Inc.

Of the approximately 50 million Americans whohave hypertension, fewer than 50% respond

adequately to monotherapy and only approximately25% have blood pressures controlled to <140/90mm Hg.1 As the United States population continuesto age, the burden of uncontrolled hypertension willincreasingly contribute to unnecessary morbidityand mortality from stroke and other complicationsof cardiovascular disease. There is evidence that thepreferred initial agents for the treatment of highblood pressure are low-dose thiazide diuretics, βblockers, and angiotensin-converting enzyme (ACE)inhibitors.2,3 Dihydropyridine calcium channelblockers are alternative agents to the preferred low-dose diuretics in isolated systolic hypertension inolder persons.2 The recent Heart Outcomes Preven-tion Evaluation (HOPE) randomized trial4 andother data5–9 suggest that ACE inhibitors may havespecific benefit in reducing cardiovascular morbidityand mortality in high-risk settings, including dia-betes, renal insufficiency, left ventricular dysfunc-tion, and atherosclerosis. The pharmacologictreatment of hypertension is an important ap-proach to improving the cardiovascular health ofthe United States population.

The sixth report of the Joint National Commit-tee on the Prevention, Detection, Evaluation, andTreatment of High Blood Pressure (JNC-VI)2 andtwo recent National Heart, Lung, and Blood Insti-tute clinical advisory statements10,11 have con-

Advances in Antihypertensive Combination Therapy: Benefits of Low-Dose Thiazide Diuretics in Conjunction With Omapatrilat, a Vasopeptidase Inhibitor

Keith C. Ferdinand, MD

From the Department of Clinical Pharmacology,Xavier University College of Pharmacy, and Heartbeats Life Center, New Orleans, LAAddress for correspondence/reprint requests:Keith C. Ferdinand, MD, Heartbeats Life Center, 1201 Poland Avenue, New Orleans, LA 70117Manuscript received January 8, 2001;accepted January 17, 2001

THE JOURNAL OF CLINICAL HYPERTENSION VOL. III NO. V SEPTEMBER/OCTOBER 2001308

firmed the importance of aggressive, specific med-ical treatment of elevated blood pressure in pa-tients with other cardiovascular risk factors, inolder Americans, and in patients with hyperten-sion and diabetes (Table I). In diabetics, the goalblood pressure is <130/85 mm Hg, as suggested byJNC VI2 and the recent clinical advisory, or<130/80 mm Hg, as recommended by the 2000National Kidney Foundation guidelines.12 Forrenal insufficiency with proteinuria of >1 g/24hours, the goal blood pressure is <125/75 mmHg.2,13 World Health Organization guidelines3

support the JNC VI position on intensive bloodpressure lowering and the use of thiazide diureticsas first-line therapy. These lower blood pressuregoals can usually be achieved only with the appro-priate use of a combination of agents.

Omapatrilat is the prototype of a new class ofagents, the vasopeptidase inhibitors,14,15 and iscurrently in clinical development for treatment ofhypertension, heart failure, and other cardiac andvascular conditions.14,15 The safety and effective-ness of omapatrilat, when given in conjunctionwith hydrochlorothiazide (HCTZ), has beendemonstrated in hypertensive patients who arenonresponsive to HCTZ alone.16 Coadministra-tion of omapatrilat with HCTZ, compared toHCTZ alone, results in better blood pressure con-trol and a high level of acceptability by patients.16

African Americans are at increased risk for hy-pertensive complications, including end-stagerenal disease.17 Whereas ACE inhibitors as mono-therapy are less effective for blood pressure lower-ing in many African Americans, the addition ofthiazide diuretics blunts any ethnic differences inresponse.2,18

THE BENEFITS OF LOW-DOSE DIURETIC THERAPYIncreasingly, data have supported the preference oflow-dose thiazide diuretic therapy as the initial ap-proach in most patients with hypertension. This includes patients who have uncomplicated hyperten-sion, diabetes, or renal insufficiency, and older hypertensives. A systematic review of 23 trials repre-senting 50,853 patients in both drug/drug anddrug/no treatment comparison trials confirms thatlow-dose diuretic therapy is significantly more effec-tive in reducing systolic blood pressure (SBP) thanother classes of agents, including β blockers, calciumchannel blockers, and even ACE inhibitors.19

Generally, there are few unexpected side effectsfrom thiazide diuretic therapy. Although a potentialincrease in the risk of renal carcinoma has beensuggested by some authors,20 this association doesnot appear definitive. More importantly, in terms of usual clinical practice, diuretic-associated hy-pokalemia has the potential of blunting some of thebenefits of therapy, specifically in patients with isolated systolic hypertension.21 Therefore, hypo-kalemia should be avoided by use of a potassium-sparing diuretic and early initiation of supplementalpotassium, or perhaps use of combination therapywith modulators of the renin-angiotensin system,including ACE inhibitors, angiotensin receptorblockers (ARBs), and possibly the vasopeptidase in-hibitor omapatrilat.

One unrecognized benefit of HCTZ therapy maybe reduction of cortical bone loss in postmenopausalwomen. An intention-to-treat analysis of a recentrandomized, controlled trial22 of 185 women treatedwith HCTZ for over 2 years showed significant ben-efits on total bone density. HCTZ may act directly

Table I. Risk Stratification and Treatment2

Blood Pressure Risk Group A Risk Group B Risk Group C Stage (mm Hg) (no risk factors; (≥1 risk factor, (TOD/CCD

no TOD/CCD) not including diabetes; and/or diabetes;no TOD/CCD) with or without other

risk factors)

High-normal Lifestyle Lifestyle Drug therapy(130–139/85–89) modification modification

Stage 1 Lifestyle Lifestyle Drug therapy(140–159/90–99) modification modification

(up to 12 mo) (up to 6 mo)

Stages 2 and 3 Drug therapy Drug therapy Drug therapy(≥160/≥100)

TOD=target organ disease; CCD=clinical cardiovascular disease


on bone, affect renal calcium absorption, and protectagainst postmenopausal bone loss.22

VASOPEPTIDASE INHIBITORSVasopeptidase inhibitors have now been synthe-sized and are being tested in humans. The proto-type omapatrilat inhibits not only ACE but alsoneutral endopeptidase (NEP).23 Both NEP andACE are cell surface metalloproteases with similarstructures at their active sites.23 Omapatrilat ap-pears to cause extracellular volume reduction andvasodilatation by blocking the effects of an-giotensin II, a mechanism similar to that of con-ventional ACE inhibition; in addition, omapatrilatincreases levels of atrial and brain natriuretic pep-tides and bradykinin via NEP inhibition (Figure).Preliminary data have suggested that omapatrilatis effective regardless of low or high renin statusor ethnicity.14,15 Like ACE inhibitors, omapatrilatmay induce high levels of angioedema in AfricanAmericans, relative to Caucasians, especially whendoses are started at ≥20 mg.15

ACE inhibitors and omapatrilat not only bluntthe conversion of angiotensin I to angiotensin IIbut also stimulate bradykinin, a powerful va-sodilator that increases prostacyclin and nitric

oxide. Omapatrilat decreases degradation ofbradykinin by blocking ACE and NEP. Experi-mental studies have suggested that the vasodilat-ing effects of bradykinin may provide additionalprotection in terms of reducing left ventricular hy-pertrophy and blood pressure. Especially inAfrican Americans, the blood pressure lowering of ACE inhibitors may be partially negated bybradykinin antagonism, such as occurs with theadministration of a specific bradykinin receptorantagonist, icatibant acetate (HOE 140).

Unfortunately, angioedema, a rare but potentiallylife-threatening complication of conventional ACEinhibitors and omapatrilat, may be more common inAfrican Americans, perhaps due to a greater sensitiv-ity to the effects of bradykinin.24 This does not con-traindicate the use of these agents in a high-riskpopulation such as African Americans, but suggeststhe need for appropriate patient education and grad-ual initiation of omapatrilat in this population. TheHOPE trial4 was a large, multicenter, placebo-con-trolled trial that confirmed the benefits of the ACEinhibitor ramipril. Although it was not specificallydesigned as an antihypertensive trial, 46.5% of thepatients had elevated blood pressure (>140/90 mmHg), and the reduction was greatest with SBP (>125

Figure. Mechanism of action of omapatrilat.16 This compound not only blocks the generation of angiotensin II and increasesthe availability of bradykinin by inhibiting its breakdown (ACE I effect), but also increases the activity of natriuretic pep-tides by inhibiting the breakdown of these substances (NEP effect). ANP=atrial natriuretic peptide; BNP=brain natriureticpeptide; AT=angiotensin; VPI=vasopeptidase inhibitor; ACE=angiotensin-converting enzyme; NEP=neutral endopeptidase


mm Hg).5 Therefore, there is increasing interest inagents that modulate the renin-angiotensin system, interms of not only blood pressure control but also re-duction of cardiovascular morbidity and mortality.

HEART FAILURE AND ACE AND NEP INHIBITIONOmapatrilat may be an important new agent for im-proving the prognosis and well-being of patients withheart failure. A recent comparison16 of the effects ofomapatrilat and lisinopril on exercise tolerance andmorbidity in patients with heart failure suggested thatomapatrilat may have advantages over lisinopril in thetreatment of congestive heart failure. In the IMPRESStrial,25 (Inhibition of Metaloprotease by Omapatrilatin a Randomized Exercise and Symptoms Study ofHeart Failure) omapatrilat was more effective thanlisinopril in improving the New York Heart Associa-tion class in patients of classes III and IV (p= 0.035).The two drugs were equally well tolerated. Althoughthere was no statistically significant improvement inthe combined end point of death and hospital admis-sion for worsening heart failure, there was a trend to-ward fewer cardiovascular adverse events in theomapatrilat group.

BENEFITS OF COMBINATION THERAPY To achieve optimal blood pressure lowering, once-daily agents with >24-hour efficacy and at least50% of peak effect remaining at the end of dosingshould be utilized.2 Short-acting agents should beavoided for several reasons, including poor adher-ence, the need for multiple tablets, and intermit-tent blood pressure control.2 Newer formulationsof low-dose combination agents of two classesmay have the benefit of minimizing dose-depen-dent adverse effects, requiring fewer tablets, and

conferring additional blood pressure lowering.26

Inadequate management of blood pressure re-mains an area of concern. An examination of 800hypertensive men at five Veterans Affairs sites27

suggested that poor blood pressure control was pri-marily due to lack of intensive medical therapy onthe part of physicians, and was not simply the re-sult of nonadherence by patients.27 Effective bloodpressure control, therefore, especially in high-riskpatients with diabetes, renal insufficiency, or leftventricular dysfunction, will probably necessitatecombination therapy. While low-dose thiazide di-uretics, β blockers, and ACE inhibitors are themainstays of initial pharmacotherapy, combinationtherapy provides more effective blood pressure con-trol. Combinations of β blockers/diuretics, ACE in-hibitors/diuretics and ARBs/diuretics have provedto be effective and well tolerated in a high percent-age of hypertensive individuals.

OMAPATRILAT AND HCTZ IN COMBINATIONIn the future, pharmacologic therapy with a combina-tion of omapatrilat and low-dose diuretics may beadded to clinicians’ antihypertensive armamentarium.A recent study16 randomized 274 subjects with mildto severe hypertension (stages 1–3 diastolic elevation)and confirmed the benefit of omapatrilat combinedwith HCTZ. The baseline seated diastolic blood pres-sure (SeDBP) was 95–120 mm Hg after a 2-weekplacebo lead-in period and a 4-week period duringwhich HCTZ was utilized alone.16 Subjects whomaintained an SeDBP of 93–100 mm Hg on HCTZalone were randomized to receive omapatrilat at 10or 20 mg, titrated to 20 or 40 mg, respectively, or toreceive a matching placebo at week 4 if SeDBP was≥90 mm Hg. Both omapatrilat and placebo were

Table II. Changes in Seated Diastolic and Systolic Blood Pressure with Omapatrilat/HCTZ and Placebo/HCTZ16

MEAN VALUE (SE) IN MM HG

PLACEBO OMA 10/20 MG OMA 20/40 MG

+ HCTZ + HCTZ + HCTZ

SeDBPBaseline 99.8 (4.7) 99.9 (4.9) 100.9 (4.9)Week 8 -7.5 (0.9) -11.9 (0.9)* -12.8 (0.9)*

SeSBPBaseline 151.0 (14.8) 146.7 (14.5) 154.2 (13.4)Week 8 -8.0 (1.3) -14.4 (1.3)* -17.9 (1.3)*

OMA=omapatrilat; HCTZ=hydrochlorothiazide; SeDBP=seated diastolic blood pressure; SeSBP=seated systolicblood pressure; *p<0.001 vs. placebo + HCTZ


given in addition to HCTZ 25 mg as backgroundtherapy. The primary outcome measure was thechange in baseline SeDBP at week 8.

At weeks 4 and 8, additional reductions inSeDBP were significant, as were changes in SeSBP,with the omapatrilat/HCTZ regimen compared to the placebo/HCTZ combination (Table II). The frequency of adverse events, serious adverseevents, and discontinuation attributed to adverseevents was similar in all groups. Furthermore,there were no clinically relevant changes in serumcreatinine, potassium, or any other laboratory pa-rameters. In this study, omapatrilat produced sig-nificant additional blood pressure reduction5

when added to HCTZ 25 mg in patients withblood pressure not controlled by HCTZ alone.The omapatrilat/HCTZ combination was well tol-erated; the frequency of adverse events with oma-patrilat/HCTZ was slightly, but not significantly,greater than that with placebo/HCTZ (Table III).

CONCLUSIONBlood pressure is influenced by a variety of factors,including volume status, sodium intake, obesity, ac-tivity level, and psychosocial stress. The vasoactivepeptides, including vasodilator and vasoconstrictingpeptides, appear to be important in the regulation ofhypertension and cardiovascular disease, includingheart failure. Omapatrilat inhibits both NEP andACE and also stimulates bradykinin. An increase invasoactive peptides with vasodilator and antiprolif-erative activity may be beneficial in the future, ifstudies confirm the safety and efficacy of this agent.The addition of omapatrilat to HCTZ enhances theblood pressure response and is well tolerated. Thisapproach to therapy may prove beneficial in high-risk patients, including African Americans and pa-tients with diabetes, renal insufficiency, and leftventricular dysfunction. Further studies are neces-sary to compare outcomes with this combinationand other diuretic/antihypertensive formulations.

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Table III. Adverse Events With Omapatrilat/HCTZ vs. Placebo/HCTZ16

HCTZ 25 mg HCTZ 25 mg HCTZ 25 mg + Placebo + Omapatrilat + Omapatrilat

10/20 mg 20/40 mg

(n=91) (n=93) (n=90)

Adverse events, total patients (%) 53 (58.2) 58 (62.4) 60 (66.7)

HCTZ=hydrochlorothiazide


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26 Prisant LM, Nuetel JM, Ferdinand KC, et al. Low-dose com-bination therapy as first-line hypertension treatment for blacksand nonblacks. J Natl Med Assoc. 1999;91:40–48.

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advances in antihypertensive combination therapy: benefits of low-dose thiazide diuretics in...

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