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Rationale for combination therapy in hypertension management: focus on angiotensin receptor blockers and thiazide diuretics.



Abstract: Despite recognition that hypertension is a major risk factor for cardiovascular events and mortality, blood pressure control rates remain low in the US population. Reflecting clinical trial results, hypertension management guidelines assert the clinical benefit of achieving current blood pressure goals and indicate that most patients will require 2 or more drugs to reach goal. Well-designed drug combinations counter hypertension via complementary mechanisms that increase antihypertensive antihypertensive /an·ti·hy·per·ten·sive/ (-ten´siv) counteracting high blood pressure, or an agent that does this.

an·ti·hy·per·ten·sive
adj.
Reducing high blood pressure.

n.
 efficacy, potentially with lower rates of adverse events than higher dose monotherapy regimens. Lower adverse event rates, in turn, may contribute to greater adherence with treatment. The combination of a low-dose diuretic diuretic (dī'yərĕt`ĭk), drug used to increase urine formation and output. Diuretics are prescribed for the treatment of edema (the accumulation of excess fluids in the tissues of the body), which is often the result of underlying  with agents that block the effects of the renin-angiotensin system For an autonomous region of Nicaragua, see .

The renin-angiotensin system (RAS) or the renin-angiotensin-aldosterone system (RAAS) is a hormone system that helps regulate long-term blood pressure and extracellular volume in the body.
 (RAS (1) See network access server.

(2) (Remote Access Service) A Windows NT/2000 Server feature that allows remote users access to the network from their Windows laptops or desktops via modem. See RRAS and network access server.
), such as angiotensin receptor The angiotensin receptors are a class of G protein-coupled receptors with angiotensins as ligands. They are important in the renin-angiotensin system: they are responsible for the signal transduction of the main effector hormone.  blockers, has been found in numerous clinical trials to be highly effective for lowering blood pressure in patients with uncomplicated as well as high-risk hypertension, with a comparable favorable side effect profile compared with monotherapy. Moreover, agents that block the RAS are associated with a lower risk of new-onset diabetes mellitus diabetes mellitus

Disorder of insufficient production of or reduced sensitivity to insulin. Insulin, synthesized in the islets of Langerhans (see Langerhans, islets of), is necessary to metabolize glucose. In diabetes, blood sugar levels increase (hyperglycemia).
 than other antihypertensive classes. Complementary combinations of antihypertensive agents provide an efficient and effective approach to hypertension management.

Key Words: angiotensin receptor blockers, cardiovascular disease Cardiovascular disease
Disease that affects the heart and blood vessels.

Mentioned in: Lipoproteins Test

cardiovascular disease 
, combination therapy, hypertension, thiazide diuretics, renin-angiotensin system

**********

More than 50 years ago, Franklin Roosevelt and Joseph Stalin, two powerful men with unlimited resources, died due to intracerebral hemorrhage Intracerebral hemorrhage
A cause of some strokes in which vessels within the brain begin bleeding.

Mentioned in: Stroke

Intracerebral hemorrhage 
 as a direct result of uncontrolled hypertension. (1,2) An estimated 65 million Americans currently have hypertension, (3) and despite the availability of more than 100 antihypertensive agents, only 34% of all persons with hypertension and 56% of those treated reach the blood pressure (BP) goal of <140/90 mm Hg. (4) This holds true even for hypertensive hypertensive /hy·per·ten·sive/ (-ten´siv)
1. characterized by increased tension or pressure.

2. an agent that causes hypertension.

3. a person with hypertension.
 patients with access to healthcare; in the third National Health and Nutrition Examination Survey (NHANES III NHANES III Third National Health & Nutrition Examination Survey Public health A population-based survey conducted by the National Center for Health Statistics, designed to assess the health and nutritional status of the noninstitutionalized Americans ), the vast majority of persons with uncontrolled hypertension had health insurance, reported a usual source of care, and visited their physician more than once in the prior year. (5) The problem of poor BP control is magnified by new definitions of hypertension (>140/90 mm Hg or > 130/80 mm Hg for patients with diabetes mellitus or chronic renal disease Renal disease
Kidney disease.

Mentioned in: Glycogen Storage Diseases

hypertension High blood pressure Cardiovascular disease An abnormal ↑ systemic arterial pressure, corresponding to a systolic BP of > 160 mm Hg
) and prehypertension (120-139/80-89 mm Hg), by increasing rates of overweight and obesity, and by an aging population. (6) Two thirds of Americans with hypertension are [greater than or equal to]60 years of age, (4) and by age [greater than or equal to]65 years, approximately 88% of persons with inadequate BP control have isolated systolic hypertension Systolic hypertension is defined as an elevated systolic blood pressure with a normal diastolic blood pressure. Systolic hypertension may be due to reduced compliance of the aorta with increasing age[1].  (7); this reflects both the age-related increase in systolic Systolic
The phase of blood circulation in which the heart's pumping chambers (ventricles) are actively pumping blood. The ventricles are squeezing (contracting) forcefully, and the pressure against the walls of the arteries is at its highest.
 BP and the difficulty in treating systolic hypertension.

The clinical benefits of BP lowering are well established by numerous studies that show reductions in cardiovascular morbidity and mortality Morbidity and Mortality can refer to:
  • Morbidity & Mortality, a term used in medicine
  • Morbidity and Mortality Weekly Report, a medical publication
See also
  • Morbidity, a medical term
  • Mortality, a medical term
 across a wide range of patient populations. (6) Meta-analyses of studies evaluating the effects of antihypertensive therapy on cardiovascular outcomes suggest that BP lowering largely drives the reduction in cardiovascular events across different classes of antihypertensive agents. (8,9) It is also evident based on clinical trial results that most persons with hypertension require therapy with a combination of 2 or more antihypertensive agents to achieve currently recommended BP targets. (6) Thus, the immediate focus of antihypertensive therapy should be reaching target BP with the ultimate aim of reducing cardiovascular morbidity and mortality. Because the pathophysiology pathophysiology /patho·phys·i·ol·o·gy/ (-fiz?e-ol´ah-je) the physiology of disordered function.

path·o·phys·i·ol·o·gy
n.
1.
 of hypertension is multifactorial multifactorial /mul·ti·fac·to·ri·al/ (mul?te-fak-tor´e-al)
1. of or pertaining to, or arising through the action of many factors.

2.
, well-designed combination regimens that target complementary BP-lowering mechanisms and associated compensatory responses provide an effective approach to achieving BP goals. (10) Whereas past guidelines identified specific BP thresholds above which treatment should be considered, (6) current recommendations focus on an individual patient's absolute or global risk as the basis for treatment decision making. (11) Rather than staging hypertension severity on the basis of BP values alone, more recently developed algorithms take into account a patient's BP level, cardiovascular risk factors, early disease markers, and clinical evidence of target organ target organ
n.
A tissue or organ that is affected by a specific hormone.


target organ,
n the organ or body part whose activity levels demonstrate change in the course of biofeedback.
 damage. Thus, clinicians must be alert to a patient's overall cardiovascular risk and consider antihypertensive therapy even among normotensive normotensive /nor·mo·ten·sive/ (-ten´siv)
1. characterized by normal tone, tension, or pressure, as by normal blood pressure.

2. a person with normal blood pressure.
 patients at high risk.

Despite the clarity offered by treatment guidelines, which are based on clinical trial results achieved under optimal conditions, attaining and maintaining BP control is problematic in real-world settings, as evidenced by poor control rates and diminishing adherence with antihypertensive therapy over time. (12,13) Two issues fundamental to achieving BP control are sufficient therapy and patient adherence with therapy. Fixed-dose combinations of antihypertensive drugs Antihypertensive Drugs Definition

Antihypertensive drugs are medicines that help lower blood pressure.
Purpose

The overall class of antihypertensive agents lowers blood pressure, although the mechanisms of action vary greatly.
 with complementary mechanisms of action provide for greater efficacy often using lower doses of component agents than monotherapy, (14) a strategy which has the potential to reduce the risk of adverse events, increase adherence by simplifying the therapeutic regimen, and ultimately improve outcomes. (6) Several such combinations are available including: angiotensin-converting enzyme angiotensin-converting enzyme /an·gio·ten·sin-con·vert·ing en·zyme/ (-ten´sin kon-vert´ing en´zim) see peptidyl-dipeptidase A.

angiotensin-converting enzyme
n.
 (ACE) inhibitor plus calcium channel blocker calcium channel blocker
n.
Any of a class of drugs that inhibit movement of calcium ions across a cell membrane, used in the treatment of cardiovascular disorders.
 (CCB CCB Calcium channel blocker, see there ) or diuretic; beta blocker Beta blocker
A drug that can be used to reduce blood pressure.

Mentioned in: Mitral Valve Stenosis

beta blocker Beta-adrenergic blocking agent Pharmacology Any of a class of agents that blocks β1
 plus diuretic; or angiotensin receptor blocker (ARB) plus diuretic.

Combinations consisting of a low-dose thiazide diuretic with an ARB provide several advantages for the treatment of uncomplicated as well as high-risk hypertension. ARBs demonstrate BP-lowering efficacy comparable to ACE inhibitors and other antihypertensive drug classes, with an overall risk of adverse events comparable to placebo. (15) Treatment with ARBs is associated with a lower incidence of troublesome events commonly reported with other antihypertensive classes, such as cough with ACE inhibitors (16-18) and peripheral edema Peripheral edema is the swelling of tissues, usually in the lower limbs, due the accumulation of fluids.

The condition is commonly associated with ageing, but can be caused by many other conditions, including congestive heart failure, trauma, pregnancy, hypertension or
 with CCBs. (19,20) In addition, ARBs have been shown to reduce the risk of cardiovascular events in a range of patients at high risk, (19) including those with prior myocardial infarction myocardial infarction: see under infarction. , (18) left ventricular dysfunction ventricular dysfunction,
n an abnormality in contraction and wall motion within the ventricles.
, (21) and heart failure. (22-24)

This review addresses current clinical guidelines for the use of combination antihypertensive therapy; the rationale for combining an ARB with a thiazide diuretic; clinical trial evidence supporting the ARB/diuretic combination in terms of BP-lowering efficacy and tolerability; and observational data regarding rates of adherence with different antihypertensive classes. To review clinical trials of ARB/diuretic combinations, a MEDLINE The online medical database of the U.S. National Library of Medicine (NLM) whose parent is the National Institutes of Health, Bethesda, MD. MEDLINE contains millions of articles from thousands of medical journals and publications. The consumer section of the site (http://medlineplus.  search was conducted using the terms "angiotensin receptor blocker," "angiotensin receptor antagonist," "diuretic," and "hydrochlorothiazide hydrochlorothiazide /hy·dro·chlo·ro·thi·a·zide/ (-klor?o-thi´ah-zid) a thiazide diuretic, used for treatment of hypertension and edema.

hy·dro·chlo·ro·thi·a·zide
n. Abbr.
" with the limits of "clinical trial" and "randomized controlled trial A randomized controlled trial (RCT) is a scientific procedure most commonly used in testing medicines or medical procedures. RCTs are considered the most reliable form of scientific evidence because it eliminates all forms of spurious causality. ." The terms "adherence," "compliance," and "persistence" were combined with "antihypertensive therapy" to retrieve studies on medication adherence.

Sufficient Therapy: Combination Regimens

Clinical Guidelines for the Use of Combination Therapy

Lifestyle modifications, including weight reduction, physical activity, and adopting Dietary Approaches to Stop Hypertension Dietary Approaches to Stop Hypertension or the DASH diet is a diet promoted by the National Heart, Lung, and Blood Institute (part of the NIH) to control hypertension.  (DASH), remain the cornerstone of hypertension management, regardless of whether patients ultimately require pharmacologic therapy. (6) In a substantial proportion of patients, however, combination therapy will likely be necessary particularly for those at high risk for cardiovascular or renal disease in whom lower BP goals necessitate a more aggressive treatment plan (Fig. 1). (25) According to according to
prep.
1. As stated or indicated by; on the authority of: according to historians.

2. In keeping with: according to instructions.

3.
 the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC JNC Joint National Committee
JNC Japan Nuclear Cycle Development Institute
JNC Judicial Nominating Commission
JNC Jet Navigation Chart
JNC Journal of Nuclear Cardiology
JNC JNet Consultancy (Netherlands) 
 7), starting therapy with 2 drugs, separately or as fixed-dose combinations, may be considered when systolic BP is >20 mm Hg or diastolic Diastolic
The phase of blood circulation in which the heart's pumping chambers (ventricles) are being filled with blood. During this phase, the ventricles are at their most relaxed, and the pressure against the walls of the arteries is at its lowest.
 BP is >10 mm Hg above the desired goal for the individual patient. (6) In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT ALLHAT Cardiology An ongoing randomized, open label, multicenter trial evaluating whether antihypertensive therapy reduces M&M in CAD, and to determine whether lipid-lowering pravastatin therapy in moderately hypercholesteremic Pts reduces heart-related M&M. ), which included patients with difficult-to-treat hypertension, 66% of patients reached BP goal by 5 years, with 63% of patients taking 2 or more medications. (26) JNC 7 recommends that physicians follow up monthly after initiating antihypertensive therapy to adjust medications until the BP goal is reached. (6) Once at goal, patients can be checked every 3 to 6 months.

[FIGURE 1 OMITTED]

In general, diuretics Diuretics Definition

Diuretics are medicines that help reduce the amount of water in the body.
Purpose

Diuretics are used to treat the buildup of excess fluid in the body that occurs with some medical conditions such as congestive heart
 are recommended as one element of combination therapy to achieve BP control. (6) However, in high-risk patients, treatment with specific classes of antihypertensive agents has been shown to improve disease outcomes. (6,18) For example, RAS blockade is an important component of treatment for patients with diabetes and hypertension according to the JNC 7 guidelines, (6) a position that is in agreement with recommendations of the American Diabetes Association The American Diabetes Association, or the ADA, is an American health organization providing diabetes research, information and advocacy. Founded in 1940, the American Diabetes Association conducts programs in all 50 states and the District of Columbia, reaching hundreds of  (ADA Ada, city, United States
Ada (ā`ə), city (1990 pop. 15,820), seat of Pontotoc co., S central Okla.; inc. 1904. It is a large cattle market and the center of a rich oil and ranch area.
). (27) The ADA guidelines assert that all patients with diabetes and hypertension should be treated with an ACE inhibitor or ARB. If further BP reduction is needed, a diuretic should be added to the regimen. The ADA notes that in clinical trials of antihypertensive therapy for preventing vascular complications, many patients with diabetes needed 3 or more drugs to achieve the more stringent blood pressure targets. (27)

Additive effects of antihypertensive agents should be considered in other populations at high risk. The prevalence of hypertension among African Americans is substantially higher than in other racial/ethnic groups (41% versus 28% among white Americans), (28) as are rates of diabetes, heart failure, and end-stage renal disease End-stage renal disease (ESRD)
Total kidney failure; chronic kidney failure is diagnosed as ESRD when kidney function falls to 5-10% of capacity.

Mentioned in: Chronic Kidney Failure

end-stage renal disease 
, (29) which are all compelling indications for RAS blockade. (6) Guidelines from the Hypertension in African Americans Working Group of the International Society of Hypertension in Blacks (ISHIB ISHIB International Society on Hypertension in Blacks ) state that most African-American patients require at least 2 drugs to reach BP goals; in contrast to JNC 7, ISHIB suggests initiating combination therapy in African-American patients with BP [greater than or equal to]15/10 mm Hg above goal. (30) The ISHIB guidelines recommend 4 combination regimens for treatment of hypertension in African-American patients: a diuretic plus an ACE inhibitor, a diuretic plus an ARB, a diuretic plus a [beta]-blocker, or an ACE inhibitor plus a CCB. A summary of JNC-7, ADA, and ISHIB guidelines is shown in Table 1.

Rationale for Combining an ARB with Thiazide Diuretics

The mechanisms of action of agents that block the effects of the RAS augment the BP-lowering efficacy of diuretics. Thiazide diuretics lower BP through natriuresis natriuresis /na·tri·ure·sis/ (na?tre-ur-e´sis) excretion of sodium in the urine, particularly in excessive amounts.

pressure natriuresis
 (ie, sodium excretion), resulting in volume depletion volume depletion Internal medicine A state of vascular instability characterized by ↓ sodium in the extracellular space–intravascular and interstitial fluid after GI hemorrhage, vomiting, diarrhea, diuresis Management 0.9% saline ASAP.  and reduction of peripheral vascular resistance vascular resistance,
n the degree to which the blood vessels impede the flow of blood. High resistance causes an increase in blood pressure, which increases the workload of the heart.
 over time. (31,32) However, sodium depletion may result in RAS activation, increasing renin renin /re·nin/ (re´nin) a proteolytic enzyme synthesized, stored, and secreted by the juxtaglomerular cells of the kidney; it plays a role in regulation of blood pressure by catalyzing the conversion of angiotensinogen to angiotensin I.  release and formation of angiotensin II angiotensin II
n.
An octapeptide that is a potent vasopressor and a powerful stimulus for production and release of aldosterone from the adrenal cortex.
, and potentially limiting the effect of the diuretic (Fig. 2). (32) Angiotensin II causes vasoconstriction vasoconstriction /vaso·con·stric·tion/ (-kon-strik´shun) decrease in the caliber of blood vessels.vasoconstric´tive

va·so·con·stric·tion
n.
, sodium retention, activation of the sympathetic nervous system, and other deleterious effects on the heart, kidney, and vasculature vasculature /vas·cu·la·ture/ (vas´ku-lah-chur)
1. circulatory system.

2. any part of the circulatory system.


vas·cu·la·ture
n.
. Combining an ARB with a diuretic reduces sodium retention and vasoconstriction mediated by angiotensin II, at the same time reducing volume and enhancing the efficacy of both antihypertensive components. Several fixed-dose combinations of an ACE inhibitor or ARB plus hydrochlorothiazide (HCTZ HCTZ
abbr.
hydrochlorothiazide
) are currently available. (6)

[FIGURE 2 OMITTED]

In general, combination therapy may help patients attain BP control in a more timely manner and allow for lower doses of the component agents with fewer adverse events than higher-dose monotherapy. (14) An advantage of including an ARB in combination regimens is the low rate of adverse events associated with this class compared with other antihypertensive agents. (14,15) For example, ARBs have demonstrated greater tolerability than ACE inhibitors, as evidenced by a lower incidence of cough and angioedema. (33) ARB/HCTZ combinations are associated with a low rate of adverse events and treatment discontinuations comparable to that observed with ARB monotherapy. (34-37) Moreover, increasing the dose of diuretic in combination with an ARB only modestly increases the incidence of adverse events (statistical significance not reported). (35-37)

Clinical Trials of ARB/HCTZ Combination Therapy

Clinical trials evaluating ARB/HCTZ therapy consistently show significantly greater BP reductions with the combination versus component monotherapy in patients with mild-to-moderate hypertension, (36,37) stage 2 hypertension, (34,35,38) and systolic hypertension. (39) In addition, combination ARB/HCTZ therapy produced significant BP reductions in patients with uncomplicated hypertension who failed to respond to ARB monotherapy. (36,37) In two separate trials of valsartan (160 mg/d) (36) and eprosartan (600 mg/d), (37) patients with mild-to-moderate hypertension not controlled after 3 to 4 weeks on monotherapy were randomly assigned to 8 weeks of continued monotherapy or the addition of HCTZ. In both studies, the combination achieved a significantly greater reduction in diastolic BP, and significantly higher responder rates (percentage with <90 mm Hg or [greater than or equal to]10 mm Hg decrease) than monotherapy. (36,37) In the study of valsartan, systolic and diastolic BP reductions, as well as responder rates, were significantly (P [less than or equal to] 0.01) greater with a higher-versus lower-dose combination. (36)

ARB/HCTZ combination therapy also demonstrates BP-lowering efficacy comparable to amlodipine monotherapy, including in studies using 24-hour ambulatory BP monitoring. (40-44) In these studies, the ARB/HCTZ combination was associated with a lower rate of treatment discontinuations (ARB/HCTZ 2.5%-10.1%; amlodipine 11.3%-24.5%) and a lower incidence of peripheral edema (ARB/HCTZ 1.2%-8.9%; amlodipine 5.8%-44.6%). In a study of African Americans with mild-to-moderate hypertension, ARB/HCTZ combination therapy produced reductions in mean 24-hour BP similar to CCB monotherapy; however, peripheral edema and joint swelling were more common with the CCB than ARB/HCTZ, whereas rates of other adverse events were similar and low in both groups. (40) In a recent study, treatment of elderly patients with systolic hypertension with combination ARB/HCTZ resulted in greater reductions in 24-hour BP than CCB/HCTZ therapy, with lower rates of adverse events and treatment discontinuations in the ARB/HCTZ group (primarily due to a lower incidence of peripheral edema). (41)

A dose-dependent effect of ARB/HCTZ on BP reductions and control rates has been observed through the approved ARB dose range with losartan (up to 100 mg), valsartan (up to 320 mg), and olmesartan (up to 40 mg) in combination with HCTZ 12.5 to 25 mg. (38,39,45,46) A low incidence of adverse events with ARBs allows the use of these agents at higher doses, which may be advantageous for both lowering BP and improving clinical outcomes. Evidence from several clinical endpoint In a research trial, a clinical endpoint refers to a disease, symptom, or sign that constitutes one of the target outcomes of the trial. The results of a clinical trial generally indicate the number of people enrolled who reached the pre-determined clinical endpoint during the  trials suggests that maximal ARB dosing produces the greatest reductions in cardiovascular and renal disease events (reviewed in Weir (47)). For example, in patients with type 2 diabetes type 2 diabetes
n.
See diabetes mellitus.
 and microalbuminuria, irbesartan 300 mg reduced the progression to nephropathy nephropathy /ne·phrop·a·thy/ (ne-frop´ah-the) disease of the kidneys.nephropath´ic

analgesic nephropathy
 (relative risk 0.32; P < 0.001 versus placebo) to a greater degree than the 150 mg dose (0.56; P = 0.05 versus placebo). (48)

Diabetes and the RAS

RAS blockade is established therapy for patients with diabetes, who are at high risk for renal disease. (6,27) Treatment with ARBs has been shown to slow the progression of renal disease in patients with type 2 diabetes and microalbuminuria or nephropathy, the benefit of which appears to be maintained with combination ARB/HCTZ treatment. (20,48-50) Importantly, accumulated evidence indicates that RAS blockade also decreases the risk of new-onset diabetes among patients receiving antihypertensive therapy. A meta-analysis of hypertension trials involving approximately 116,000 patients, two thirds of whom did not have diabetes at baseline, found an overall 25% reduction (27% for ACE inhibitors; 23% for ARBs) in new-onset diabetes compared with other antihypertensive classes or placebo (Table 2). (51)

ALLHAT demonstrated a significantly higher risk of new-onset diabetes in those treated with a thiazide diuretic compared with a CCB or ACE inhibitor. (52) However, in the Losartan Intervention For Endpoint reduction in hypertension study, the ARB was associated with a 25% lower incidence of new-onset diabetes than [beta]-blocker therapy, even though the majority of patients in both groups were treated with a diuretic; this suggests a potentially mitigating effect of RAS blockade. (53) Supporting these findings, the Valsartan Antihypertensive Long-term Use Evaluation showed a 23% reduction in new-onset diabetes with valsartan-based versus amlodipine-based therapy that included HCTZ. (19) A potential mechanism for the protective effect is suggested by a recent analysis of hypertension trials indicating that RAS blockade improves insulin sensitivity insulin sensitivity The systemic responsiveness to glucose, which can be measured by 1. The insulin sensitivity index–measures the ability of endogenous insulin to ↓ glucose in extracellular fluids by inhibiting glucose release from the liver and  and glucose metabolism glucose metabolism,
n the process by which simple sugars found in many foods are processed and used to produce energy in the form of ATP. Once consumed, glucose is absorbed by the intestines and into the blood.
. (54) Decreasing the risk of diabetes represents a crucial treatment advantage beyond BP reduction, as new-onset diabetes increases vascular risk comparably to preexisting pre·ex·ist or pre-ex·ist  
v. pre·ex·ist·ed, pre·ex·ist·ing, pre·ex·ists

v.tr.
To exist before (something); precede: Dinosaurs preexisted humans.

v.intr.
 diabetes and is associated with considerable morbidity and costs. (55,56)

Persistent Therapy

Clinical trial data demonstrate that effective antihypertensive regimens are available; however, no drug can be effective if the patient does not take it as prescribed. The choice of antihypertensive agent strongly determines patient persistence with therapy. (14) Treatment with ARBs has been associated with higher rates of adherence with therapy than other antihypertensive drug classes. (13,57-62) Although these studies used different designs, precluding comparison among them, the general order of antihypertensive drugs from most to least favorable long-term adherence was ARB > ACE inhibitor [greater than or equal to] CCB > diuretic. A study of adherence with antihypertensive therapy in usual-care settings analyzed a pharmacy claims database for new prescriptions of a CCB, an ACE inhibitor, and an ARB. (61) After 12 months, 63% of patients were still taking the ARB, 53% were still taking the CCB, and 50% were still on the ACE inhibitor (P < 0.001 for ARB versus both comparators).

Similarly, another clinic-based survey of more than 14,000 new users of antihypertensive agents found that patients initially prescribed an ARB had higher persistence rates than those prescribed agents from other classes. (62) Patients prescribed ACE inhibitors, CCBs, or diuretics discontinued therapy at rates that were higher by approximately 39%, 66%, and 85%, respectively, compared with ARBs (P < 0.0001). Moreover, switching, adding, or dropping a drug relative to the initial regimen also predicted low persistence: fewer than 10% of patients persisted with regimens that did not include the initial drug prescribed. (62) If patients are more likely to continue treatment with the first medication prescribed, tolerability and efficacy should figure heavily in that choice.

A Shifting Paradigm

Although physicians and patients have been concerned about the potential for adverse events due to rapid BP reduction, negative metabolic effects, and overall safety, these concerns have been allayed by the efficacy and tolerability profile of newer combination antihypertensive regimens. (63) In addition, the evidence that risk due to elevated BP is continuous and graded, with no lower threshold at least down to 115/75 mm Hg, (64) should give clinicians a sense of urgency to assess individual patients' absolute risk and treat to recommended targets. (6) Treatment of hypertension has come a long way in the past 50 years, yet much remains to be done. New and lower definitions of hypertension increase the difficulty of helping patients achieve BP control. Because a substantial proportion of patients require 2 or more antihypertensive medications to reach their BP goal, combinations of agents with complementary mechanisms offer the potential for greater efficacy without an increase in adverse events. Fixed-dose combination therapy offers an effective, well-tolerated, and convenient option for initiating therapy in a range of hypertensive patients who require greater BP reductions or those at higher risk. Combination therapy may help patients reach goal sooner and continue therapy longer. With the use of more effective and efficient treatment regimens, we can begin to relegate rel·e·gate  
tr.v. rel·e·gat·ed, rel·e·gat·ing, rel·e·gates
1. To assign to an obscure place, position, or condition.

2. To assign to a particular class or category; classify. See Synonyms at commit.
 the risks of undertreated hypertension to history.

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16. Dickstein K, Kjekshus J, and the OPTIMAAL Steering Committee steer·ing committee
n.
A committee that sets agendas and schedules of business, as for a legislative body or other assemblage.


steering committee
Noun
 of the OPTIMAAL Study Group. Effects of losartan and captopril captopril /cap·to·pril/ (kap´to-pril) an angiotensin-converting enzyme inhibitor used in the treatment of hypertension, congestive heart failure, and post–myocardial infarction left ventricular dysfunction.  on mortality and morbidity in high-risk patients after acute myocardial infarction acute myocardial infarction (·kyōōtˑ mī·ō·karˑ·dē· : the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet 2002;360:752-760.

17. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial: the Losartan Heart Failure Survival Study ELITE II. Lancet 2000;355:1582-1587.

18. Pfeffer MA, McMurray JJ, Velazquez EJ, et al, for the Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-1906.

19. Julius S, Kjeldsen SE, Weber M, et al, for the VALUE Trial Group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004;363:2022-2031.

20. Viberti G, Wheeldon NM, MicroAlbuminuria Reduction With VALsartan (MARVAL) Study Investigators. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus Type 2 diabetes mellitus
One of the two major types of diabetes mellitus, characterized by late age of onset (30 years or older), insulin resistance, high levels of blood sugar, and little or no need for supple-mental insulin.
: a blood pressure-independent effect. Circulation 2002;106:672-678.

21. Dahlof B, Devereux RB, Kjeldsen SE, et al, for the LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol atenolol /aten·o·lol/ (ah-ten´ah-lol) a cardioselective ß used in the treatment of hypertension and chronic angina pectoris and the prophylaxis and treatment of myocardial infarction and cardiac arrhythmias. . Lancet 2002;359:995-1003.

22. Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators. A randomized ran·dom·ize  
tr.v. ran·dom·ized, ran·dom·iz·ing, ran·dom·iz·es
To make random in arrangement, especially in order to control the variables in an experiment.
 trial of the angiotensin-receptor blocker angiotensin-receptor blocker: see under ACE inhibitor.  valsartan in chronic heart failure. N Engl J Med 2001;345:1667-1675.

23. Granger CB, McMurray JJ, Yusuf S, et al, for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003;362:772-776.

24. McMurray JJ, Ostergren J, Swedberg K, et al, for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003;362:767-771.

25. Bakris GL, Williams M, Dworkin L, et al, for the National Kidney Foundation Not to be confused with American Kidney Fund.

The National Kidney Foundation, Inc. (NKF) is a major voluntary health organization in the United States. Its mission is to prevent kidney and urinary tract diseases, improve the health and well-being of individuals and
 Hypertension and Diabetes Executive Committees Working Group. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis 2000;36:646-661.

26. Cushman WC, Ford CE, Cutler JA, et al. Success and predictors of blood pressure control in diverse North American North American

named after North America.


North American blastomycosis
see North American blastomycosis.

North American cattle tick
see boophilusannulatus.
 settings: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens (Greenwich) 2002;4:393-404.

27. Arauz-Pacheco C, Parrott MA, Raskin P, et al, American Diabetes Association. Hypertension management in adults with diabetes. Diabetes Care 2004;27 (Suppl 1):S65-S67.

28. Hertz RP, Unger AN, Cornell JA, et al. Racial disparities in hypertension prevalence, awareness, and management. Arch Intern Med 2005;165:2098-2104.

29. American Heart Association American Heart Association (AHA),
n.pr a national voluntary health agency that has the goal of increasing public and medical awareness of cardiovascular diseases and stroke, and thereby reducing the number of associated deaths and disabilities.
. Heart Disease and Stroke Statistics: 2004 Update. Dallas: American Heart Association; 2004.

30. Douglas JG, Bakris GL, Epstein M, et al. Management of high blood pressure in African Americans: consensus statement of the Hypertension in African Americans Working Group of the International Society on Hypertension in Blacks. Arch Intern Med 2003;163:525-541.

31. Waeber B. Very-low-dose combination: a first-line choice for the treatment of hypertension? J Hypertens Suppl 2003;21(Suppl 3):S3-S10.

32. Waeber B. Combination therapy with ACE inhibitors/angiotensin II receptor antagonists and diuretics in hypertension. Expert Rev Cardiovasc Ther 2003;1:43-50.

33. Elliott WJ. Therapeutic trials comparing angiotensin converting enzyme Noun 1. angiotensin converting enzyme - proteolytic enzyme that converts angiotensin I into angiotensin II
angiotensin-converting enzyme, ACE

peptidase, protease, proteinase, proteolytic enzyme - any enzyme that catalyzes the splitting of proteins into
 inhibitors and angiotensin II receptor blockers. Curr Hypertens Rep 2000;2:402-411.

34. Salerno CM, Demopoulos L, Mukherjee R, et al. Combination angiotensin receptor blocker/hydrochlorothiazide as initial therapy in the treatment of patients with severe hypertension. J Clin Hypertens (Greenwich) 2004;6:614-620.

35. Lacourciere Y, Poirier L, Hebert D, et al. Antihypertensive efficacy and tolerability of two fixed-dose combinations of valsartan and hydrochlorothiazide compared with valsartan monotherapy in patients with stage 2 or 3 systolic hypertension: an 8-week, randomized, double-blind, parallel-group trial. Clin Ther 2005;27:1013-1021.

36. Mallion JM, Carretta R, Trenkwalder P, et al. Valsartan/hydrochlorothiazide is effective in hypertensive patients inadequately controlled by valsartan monotherapy. Blood Press Suppl 2003;1:36-43.

37. Sachse A, Verboom CN, Jager B. Efficacy of eprosartan in combination with HCTZ in patients with essential hypertension essential hypertension
n.
Hypertension without known cause or preexisting renal disease.


essential hypertension 
. J Hum Hypertens 2002;16:169-176.

38. Chrysant SG, Weber MA, Wang AC, et al. Evaluation of antihypertensive therapy with the combination of olmesartan medoxomil olmesartan medoxomil

Benicar, Olmetec (UK)

Pharmacologic class: Angiotensin II type 1-receptor antagonist

Therapeutic class: Antihypertensive

Pregnancy risk category C (first trimester), D
 and hydrochlorothiazide. Am J Hypertens 2004;17:252-259.

39. Lacourciere Y, Poirier L. Antihypertensive effects of two fixed-dose combinations of losartan and hydrochlorothiazide versus hydrochlorothiazide monotherapy in subjects with ambulatory systolic hypertension. Am J Hypertens 2003;16:1036-1042.

40. Weir MR, Ferdinand KC, Flack JM, et al. A noninferiority comparison of valsartan/hydrochlorothiazide combination versus amlodipine in black hypertensives. Hypertension 2005;46:508-513.

41. Neldam S, Edwards C, ATHOS Study Group. Telmisartan plus HCTZ vs amlodipine plus HCTZ in older patients with systolic hypertension: results from a large ambulatory blood pressure monitoring ambulatory blood pressure monitoring,
n measurement of a patient's blood pressure at regular intervals while the patient carries out daily activities.
 study. Am J Geriatr Cardiol 2006;15:151-160.

42. Franco RJ, Goldflus S, McQuitty M, et al. Efficacy and tolerability of the combination valsartan/hydrochlorothiazide compared with amlodipine in a mild-to-moderately hypertensive Brazilian population. Blood Press Suppl 2003;2:41-47.

43. Ruilope LM, Malacco E, Khder Y, et al. Efficacy and tolerability of combination therapy with valsartan plus hydrochlorothiazide compared with amlodipine monotherapy in hypertensive patients with other cardiovascular risk factors: the VAST study. Clin Ther 2005;27:578-587.

44. Ruilope LM, Heintz D, Brandao AA, et al. Twenty-four-hour ambulatory blood-pressure effects of valsartan and hydrochlorothiazide combinations compared with amlodipine in hypertensive patients at increased cardiovascular risk: a VAST sub-study. Blood Press Monit 2005;10:85-91.

45. de Pablos-Velasco PL, Pazos Toral F, Esmatjes JE, et al. Losartan titration titration (tītrā`shən), gradual addition of an acidic solution to a basic solution or vice versa (see acids and bases); titrations are used to determine the concentration of acids or bases in solution.  versus diuretic combination in type 2 diabetic patients. J Hypertens 2002;20:715-719.

46. Pool J Glazer R, Weinberger M, et al. Treatment with valsartan and hydrochlorothiazide alone and in combination at doses up to 320/25 mg provides effective blood pressure control in hypertensive patients. Presented at the 21st annual meeting of the American Society of Hypertension; New York New York, state, United States
New York, Middle Atlantic state of the United States. It is bordered by Vermont, Massachusetts, Connecticut, and the Atlantic Ocean (E), New Jersey and Pennsylvania (S), Lakes Erie and Ontario and the Canadian province of
; May 16-20, 2006.

47. Weir MR. Angiotensin II receptor blockers: the importance of dose in cardiovascular and renal risk reduction. J Clin Hypertens (Greenwich) 2004;6:315-323.

48. Parving HH, Lehnert H, Brochner-Mortensen J, et al, for the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy diabetic nephropathy (nfro´p  in patients with type 2 diabetes. N Engl J Med 2001;345:870-878.

49. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-869.

50. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851-860.

51. Abuissa H, Jones PG, Marso SP, et al. Angiotensin-converting enzyme inhibitors Angiotensin-Converting Enzyme Inhibitors Definition

Angiotensin-converting enzyme inhibitors (also called ACE inhibitors) are medicines that block the conversion of the chemical angiotensin I to a substance that increases salt and water retention in the
 or angiotensin receptor blockers for prevention of type 2 diabetes: a meta-analysis of randomized clinical trials randomized clinical trial,
n a clinical study where volunteer participants with comparable characteristics are randomly assigned to different test groups to compare the efficacy of therapies.
. J Am Coll Cardiol 2005;46:821-826.

52. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor angiotensin-converting enzyme inhibitor: see ACE inhibitor.  or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA JAMA
abbr.
Journal of the American Medical Association
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54. Pepine CJ, Cooper-Dehoff RM. Cardiovascular therapies and risk for development of diabetes. J Am Coll Cardiol 2004;44:509-512.

55. Verdecchia P, Reboldi G, Angeli F, et al. Adverse prognostic significance of new diabetes in treated hypertensive subjects. Hypertension 2004;43:963-969.

56. Aguilar D, Solomon SD, Kober L, et al. Newly diagnosed and previously known diabetes mellitus and 1-year outcomes of acute myocardial infarction: the Valsartan in Acute Myocardial Infarction (VALIANT) Trial. Circulation 2004;110:1572-1578.

57. Degli Esposti E, Sturani A, Di Martino M, et al. Long-term persistence with antihypertensive drugs in new patients. J Hum Hypertens 2002;16:439-444.

58. Bloom BS. Continuation of initial antihypertensive medication after 1 year of therapy. Clin Ther 1998;20:671-681.

59. Marentette MA, Gerth WC, Billings DK, et al. Antihypertensive persistence and drug class. Can J Cardiol 2002;18:649-656.

60. Hasford J, Mimran A, Simons WR. A population-based European cohort study of persistence in newly diagnosed hypertensive patients. J Hum Hypertens 2002;16:569-575.

61. Wogen J, Kreilick CA, Livornese RC, et al. Patient adherence with amlodipine, lisinopril, or valsartan therapy in a usual-care setting. J Manag Care Pharm 2003;9:424-429.

62. Degli Esposti L, Di Martino M, Saragoni S, et al. Pharmacoeconomics of antihypertensive drug treatment: an analysis of how long patients remain on various antihypertensive therapies. J Clin Hypertens (Greenwich) 2004;6:76-84.

63. Neutel JM, Smith DH. Improving patient compliance: a major goal in the management of hypertension. J Clin Hypertens (Greenwich) 2003;5:127-132.

64. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for 1 million adults in 61 prospective studies. Lancet 2002;360:1903-1913.

David T. Nash, MD

From State University of New York Upstate Medical University The State University of New York Upstate Medical University is a State University of New York university of health sciences in the University Hill district of Syracuse, New York, USA. , Syracuse Preventive Cardiology Center, Syracuse, NY.

Reprint requests to Dr. David T. Nash, Syracuse Preventive Cardiology, 600 East Genesee Street, Suite 204, Syracuse, NY 13202. E-mail: davidtnash@aol.com

Accepted November 29, 2006.

RELATED ARTICLE: Key Points

* Results of large-scale clinical trials indicate that most patients, particularly those at high risk for cardiovascular events require 2 or more antihypertensive agents to reach blood pressure goals recommended by current clinical guidelines.

* Because the pathophysiology of hypertension is multifactorial, well-designed combination regimens that target complementary blood pressure-lowering mechanisms provide an effective approach to achieving goals.

* The combination of an angiotensin receptor blocker with a thiazide diuretic provides several advantages for treating essential hypertension as well as patients at high risk for cardiovascular or renal disease events, based on their additive efficacy and lower rate of adverse effects and treatment discontinuations compared with higher dose component monotherapy or other antihypertensive regimens.

* Rates of patient adherence to antihypertensive therapy are higher with angiotensin receptor blockers than other antihypertensive classes in several observational studies observational studies,
n.pl an investigational method involving description of the associations be-tween interventions and outcomes. Outcomes research and practice audits are examples of this investigational method.
.

* Agents that block the renin-angiotensin system also are associated with a lower incidence of new-onset diabetes than other antihypertensive classes or placebo.
Table 1. Clinical guidelines for hypertension management (6,26,29)

                        JNC-7

Goals
Initiate drug therapy
  Monotherapy           <20/10 mm Hg above goal
  Combination therapy   [greater than or equal to]20/10 mm Hg above goal
Special considerations  Treat with RAS blockade for patients with
                          compelling indications (a)

                        ADA

Goals                   Uncomplicated hypertension: 140/90 mm Hg
                        Diabetes/renal disease: 130/80 mm Hg
Initiate drug therapy
  Monotherapy           [greater than or equal to]10/10 mm Hg above goal
  Combination therapy   Generally required to reach goal
Special considerations  Treat all patients with diabetes and
                          hypertension with RAS blockade; if greater BP
                          reduction is needed, add a thiazide diuretic

                        ISHIB

Goals
Initiate drug therapy
  Monotherapy           <15/10 mm Hg above goal
  Combination therapy   [greater than or equal to]15/10 mm Hg above goal
Special considerations  Treat with RAS blockade for all patients with
                          diabetes or renal disease

(a) Heart failure, postmyocardial infarction, high coronary disease
risk, diabetes, chronic kidney disease, recurrent stroke prevention. (6)
JNC, Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure; ADA, American Diabetes Association;
ISHIB, International Society of Hypertension in Blacks; RAS,
renin-angiotensin system.

Table 2. Prevention of new-onset type 2 diabetes in clinical trials

        No.                               Risk Ratio
Trial   patients  Drugs                   (95% CI)

HOPE     9,297    ACE vs placebo          0.66 (0.51-0.85)
SOLVD    4,228    ACE vs placebo          0.26 (0.13-0.53)
PEACE    8,290    ACE vs placebo          0.83 (0.72-0.96)
CAPPP   10,985    ACE vs diuretic/BB      0.79 (0.67-0.94)
STOP-2   6,614    ACE vs diuretic/BB      0.96 (0.72-1.27)
ALLHAT  33,357    ACE vs diuretic         0.70 (0.56-0.86)
ANBP2    6,083    ACE vs diuretic         0.66 (0.54 0.85)
SCOPE    4,937    ARB vs placebo          0.81 (0.61-1.02)
CHARM    7,599    ARB vs placebo          0.78 (0.64-0.96)
LIFE     9,193    ARB vs BB               0.75 (0.63-0.88)
VALUE   15,245    ARB vs CCB              0.77 (0.69-0.86)
ALPINE     392    ARB [+ or -] CCB vs     0.13 (0.03-0.99)
                    BB [+ or -] diuretic

ACE, angiotensin-converting enzyme inhibitor; ALLHAT, Antihypertensive
and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ALPINE,
Antihypertensive Treatment and Lipid Profile in a North of Sweden
Efficacy Evaluation; ANBP2, The second Australian National Blood
Pressure study; ARB, angiotensin receptor blocker; BB, beta blocker;
CAPPP, Captopril Prevention Project; CCB, calcium channel blocker;
CHARM, Candesartan in Heart Failure Assessment of Reduction in Mortality
and Morbidity; HOPE, Heart Outcomes Prevention Evaluation; LIFE,
Losartan Intervention For Endpoint Reduction in hypertension study;
PEACE, Prevention of Events with Angiotensin Converting Enzyme
Inhibition Trial; SCOPE, The Study on Cognition and Prognosis in the
Elderly; SOLVD. Studies Of Left Ventricular Dysfunction; STOP-2, Second
Swedish Trial in Old Patients with hypertension; VALUE, Valsartan
Antihypertensive Long-term Use Evaluation.
Adapted from Abuissa H et al. J Am Coll Cardiol 2005;46:821-826.
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Title Annotation:Review Article
Author:Nash, David T.
Publication:Southern Medical Journal
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Date:Apr 1, 2007
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