update in pharmacologic treatment of hypertension

DRUG THERAPY IN CARDIOVASCULAR DISEASE 0733-8651/01 $15.00 + .OO

UPDATE IN PHARMACOLOGIC TREATMENT OF HYPERTENSION

Keith C. Ferdinand, MD

Approximately 50 million Americans have hypertension.* As the population of the United States increases in age, the burden of uncontrolled hypertension will continue to contribute to unnecessary morbidity and mortality including complications of stroke and other forms of cardiovascular disease. Increasing data have demonstrated that high- risk populations benefit from rigorous blood- pressure control; systolic blood pressure (SBP) and, perhaps even more importantly, elevated pulse pressure in adults age 55 and beyond are the strongest predictors for cardiovascular risk, and that there may be benefits and potential harm in the use of various classes of antihypertensive agents in selected patients.37

In the year 2000, the Sixth Report of the Joint National Committee on the Prevention, Detection, and Evaluation and Treatment of High Blood Pressure (JNC-VI) was supplemented by two clinical advisory statements from the National High Blood Pressure Edu- cation Program (NHBPEP) Coordinating Committee on the importance of SBP in older Americans and treatment of hypertension and diabetes.35, 63 Furthermore, the National

Portions of this article appeared in Cardiology Clinics: Annual of Drug Therapy, Vol. 3, 1999.

Heart, Lung, and Blood Institute (NHLBI) in January 2000 stopped one arm of the Antihy- pertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) because of excess cardiovascular events including congestive heart failure (CHF) and strokes in patients using the a-adrenergic blocker, doxazosin, versus the diuretic, chlorthalidone, as the primary randomized antihypertensive medication.'

There is evidence that the preferred initial agents for the treatment of high blood pressure are low-dose diuretics, P-blockers, and angiotensin converting enzyme (ACE) inhibi- t o r ~ . ~ ~ , 77 Moreover, in high-risk patients, including patients with diabetes mellitus, renal insufficiency, left ventricular systolic dysfunction, and atherosclerosis, ACE inhibitors may have distinct outcome benefits.77 The recent Heart Outcomes Prevention Evaluation (HOPE) Investigators demonstrated in a large, randomized clinical trial of 9297 people at high risk for cardiovascular events that the ACE inhibitor ramipril (10 mg/d) reduced the composite primary outcome of cardiovascular death, stroke, or myocardial infarction (MI) over 4.7 years compared with placebo.33 Although not an antihypertensive trial per se, HOPE data suggest benefit in the use of ACE

From the Department of Clinical Pharmacology, Xavier University College of Pharmacy; and the Heartbeats Life Center, New Orleans, Louisiana

CARDIOLOGY CLINICS

VOLUME 19 - NUMBER 2 MAY 2001 279

280 FERDINAND

inhibitors in patients with elevated blood pressure and of those at high risk with and without hyperten~ion.~~ The use of long-acting calcium channel blockers (CCBs), however, is of less definite benefit in certain high- risk populations, including those with renal insufficiency, CHF, and perhaps type 2 diabetes. Recent studies have confirmed that CCBs, when used as components of appropriate blood pressure lowering, are protective for the risk for stroke and overall cardiovascular disease.

The pharmacologic treatment of hypertension remains an important means of improving the overall cardiovascular health of the US population. Nationwide initiatives are needed to improve blood-pressure control rates, especially for SBP, and promote the wider use of ACE inhibitors in high-risk patients.44

INITIATION OF PHARMACOLOGIC THERAPY AND RISK

DOSE DIURETICS STRATIFICATION: FOCUS ON LOW-

The decision to use pharmacologic therapy for hypertension must include an assessment of risk stratification. The JNC-VI reporP has suggested that, along with various levels of blood pressure, components of cardiovascular risk help define levels for initiation of drug therapy (Tables 1-2 Box l).36 Low-dose diuretic therapy is a preferred initial approach for most patients with hypertension, including patients with uncomplicated hypertension, diabetes, renal insufficiency, and hypertension in older persons. Loop diuretics may be needed with moderate or severer renal insufficiency serum creatinine level greater than 2.5 mg/dL. p-blockers and ACE inhibitors are also acceptable initial agents in many patients. Low-dose thiazide diuretics can be prescribed as initial pharmacologic therapy with confidence that in the general hypertensive population there will be a reduction in the risk for overall mortality, CHF, coronary artery disease (CAD), and stroke.n A systematic review of 23 trials representing 50,853 patients suggested that in the drug-drug and drug-no treatment comparison trials, low- dose thiazide therapy was significantly better

Table 1. CLASSIFICATION OF BLOOD PRESSURE FOR ADULTS AGE 18 AND OLDER

Systolic Category (mm Hg)

Optimal <120 and < 80 Normal <130 and < 85 High-normal 130-139 or 85-89 Hypertension

Stage I 14&159 or 90-99 Stage I1 160-179 or 100-109 Stage I11 2180 or 2110

From Joint National Committee, National High Blood Pressure Education Program: The Sixth Report of the Joint National Com- mittee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI): NIH Publication No. 984080. Bethesda, National Heart, Lung, and Blood Institute, National Institutes of Health, 1997; with permission.

at reducing SBP then other drug classes, with risk reduction not as clearly demonstrated for high-dose thiazide therapy, p-blockers, CCBs, or even ACE inhibit01-s.~~

Box 1. Components of Cardiovascular Risk

Stratification in Patients with Hypertension

Major Risk Factors Smoking Dyslipidemia Diabetes mellitus Age older than 60 years Sex (men and postmenopausal women) Family history of cardiovascular disease:

women younger than 65 years of age or men younger than 55 years of age

Target Organ Damage or Clinical Cardio- vascular Disease

Heart diseases Left ventricular hypertrophy Angina or previous myocardial infarction Previous coronary revascularization Heart failure

Stroke or transient ischemic attack Nep h rology Peripheral arterial disease Retino pathy

From Joint National Committee, National High Blood Pressure Education Program: The Sixth Re- port of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI): NIH Publication No. 98- 4080. Bethesda, National Heart, Lung, and Blood Institute, National Institutes of Health, 1997; with permission.

UPDATE IN PHARMACOLOGIC TREATMENT OF HYPERTENSION 281

Table 2. RISK STRATIFICATION AND TREATMENT

Course of Action Blood Pressure Stages (mm Hg) Risk Group A* Risk Group B t Risk Group C#

High-normal Lifestyle modification Lifestyle modification Drug therapy

Stage 1 Lifestyle modification Lifestyle modification Drug therapy

Stages 2 and 3 Drug therapy Drug therapy Drug therapy

(13&139/85-89)

(140-159/90-99) (up to 12 mo) (up to 6 mo)

(?160/?100)

*No risk factors; mo target organ disease/clinical cardiovascular disease (TOD/CCD). tAt least one risk factor, not including diabetes; No TOD/CCD. $TOD/CCD or diabetes with or without other risk factors. From Joint National Committee, National High Blood Pressure Education Program: The Sixth Report of the Joint National Committee

on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI): NIH Publication No. 98-4080. Bethesda, National Heart, Lung, and Blood Institute, National Institutes of Health, 1997, with permission.

Generally, few concerns have been raised regarding unexpected side effects from thiazide therapy. Nevertheless, the potential for an increased risk for renal cell carcinoma in women was recently suggested by an examination of nine case-control studies and three cohort studies." The hypothesis of the association of diuretics and renal cell carcinoma deserves further study but does not, at this time, seem to be a definitive relationship.

Clinically, a more important area of concern is diuretic-associated hypokalemia, potentially blunting the benefits of therapy specifically in isolated systolic hypertension (ISH). A secondary analysis of the Systolic Hyper- tension in the Elderly Program (SHEP)18 demonstrated more frequent hypokalemia in patients randomly assigned to diuretic therapy (7.2% with a serum potassium <3.5 mEq/dL compared with 1% on placebo). After adjustment for known risk factors and the dose of the study drug, the active treatment patients who were hypokalemic after 1 year had a risk for CAD, stroke, and any cardiovascular event similar to that of patients on placebo.18 Therefore, being hypokalemic did not allow for the favorable reduction in cardiovascular events previously reported in the SHEP study. Clinicians should consider using a potassium sparing diuretic or initiating early supple- mental potassium therapy to avoid hypokalemia, which may blunt the benefits of this first line approach to blood pressure control.

Hydrochlorothiazide, however, has the potential benefit of reducing loss of cortical bone

in normal postmenopausal women. A randomized controlled trial of 185 women over 2 years in an intention-to-treat analysis demonstrated significant benefits with hydrochlorothiazide on total bone density.59 Hydrochlo- rothiazide may directly act on bone and renal calcium reabsorption, suggesting an additional benefit of thiazides in the prevention of postmenopausal bone loss, a favorable effect listed in the JNC-VI for individualizing antihypertensive therapy.

OPTIMAL BLOOD PRESSURE

Intensive control of blood pressure has been confirmed as beneficial using evidence based medicine in large trials including the Hypertensive Optimal Treatment (HOT) trialz8 and the United Kingdom Prospective Diabetes Study (UKPDS).70 This intensive approach to blood pressure lowering recently has been endorsed by the National Kidney Foundation (NKF).2 While the JNC-VI recommends a blood pressure goal of less than 130/ 85 mm Hg with renal insufficiency and diabetes mellitus, the NKF recommends blood pressure be lowered to a goal in diabetic patients of less than 130/80 mm Hg2 JNC-VI and the NKF report suggest lower blood pressure goal less than 125/75 mm Hg with proteinuria greater than 1 g/d and renal insufficiency regardless of causes.2, 36, 40 Optimal blood pressure in the JNC-VI report and in

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the 1999 World Health Organization/Interna- tional Society of Hypertension guidelines for adults age 18 and older is less than 120/80 mm Hg with respect to cardiovascular risk reduction.z7* 36

THE IMPORTANCE OF SYSTOLIC BLOOD PRESSURE

Systolic Blood Pressure and Cardiovascular Risks

A new clinical advisory from the NHBPEP3 advanced and clarified the recommendations of the JNC-VI regarding the relationship of SBP and cardiovascular risk. Pathophysiolog- ically, there is a strong association among aging, increased stiffness of large arteries, increased SBP, increased pulse pressure, and the prevalence of cardiac and vascular disease.2n Epidemiologic data suggest that ISH is the commonest form of hypertension and present in approximately two-thirds of hypertensive individuals older than 60 years of age.zn

A recent report from the National Institute on Agingzn analyzed data after an average follow-up of 10.6 years among survivors of 9431 participants aged 65 to 102 years who had blood pressure measured along with other determinations of disability and function. The lowest overall death rate occurred among those with SBP less than 130 mm Hg and diastolic pressure (DBP) 80 to 89 mm Hg. The highest death rate occurred in those with SBP greater than or equal to 160 mm Hg and diastolic pressure less than 70 mm Hg (relative risk, 1.9; cofidence interval [CI] =

95% confidence interval [CI], 1.4-2.46).2n Low diastolic pressure and elevated SBP were in- dependently predictive of cardiovascular (P < .001) and total (P < .001) mortality.zn Pulse pressure was a strong predictor of cardiovascular and total mortality and explains the discrepant result of low DBP and increased mortality in other population studies.zn Diag- nostically, classifying and staging hypertension is more precise when systolic rather than DBP is used as the principle criterion.

Benefits of Treating Systolic Hypertension: Focus on Older Persons

Compelling data from clinical trials confirm the benefit of treating ISH. The SHEP trial with thiazide based therapy in 4,736 individuals older than age 60 with ISH documented marked reductions of MI (-27%), CHF (- 55%0), and stroke ( - 37%) and improvement in depression and dementia scores.66 Also, the large randomized Systolic Hyper- tension in Europe (Syst-Eur) trial in 4695 patients using a dihydropyridine CCB (nitrendipine) demonstrated similar reductions in SBP and decreases in cardiovascular risk." Recently, the results of Syst-Eur with nitrendipine were replicated in 2394 patients in systolic Hypertension in China (Sy~t-China).~~ SHEP, Syst-Eur, and Syst-China demonstrate that lowering SBP to less than 160 mm Hg is markedly beneficial, although no trial has confirmed additional benefit of lowering SBP to the target of less than 140 mm Hg, which is the goal in the JNC-IV report.

Another unanswered question regarding antihypertensive therapy in older persons remains the potential superiority of specific agents for risk reduction versus others. A recent large unblinded randomized, trial of 6614 people aged 70 to 84 years, the Swedish Trial in Old People with Hypertension-2 (STOP-2), was conducted with stage 3 hypertension (pretreatment and posttreatment blood pressure values approximately 190/ 100 and 160/80 mm Hg, respecti~ely).~~ Although it was not an ISH trial per se, there seemed to be similar benefit claimed with "newer drugs," such as low-dose ACE inhibitors and CCBs when compared with standard therapy of diuretics or p- blockers. STOP-2 found no significant difference in blood pressure control or cardiovascular mortality or morbidity among the classes although there was superiority of ACE inhibitors versus CCBs for MI protection (P = 0.018) and new onset CHF (P = 0.025).29

Antihypertensive drug therapy in very old people (280 y) in randomized controlled trials has shown benefit. Although inconclusive for overall mortality, a meta-analysis of data from 1670 participants noted a 34% reduction


of strokes with major cardiovascular events, and CHF significantly decreased by 22% and 39y0.'~ There was a lack of treatment benefit for cardiovascular death and a nonsignificant 6% relative excess of death from all causes."j An additional meta-analysis of eight trials, 15 693 patients with ISH followed for 3.8 years, confirms prevention of stroke more effectively then that for coronary events but overall reduction of total mortality by 13% ( P = 0.02%).65 Drug treatment seems justified in very old patients (2 80 y) and may give abso- lute benefit for reduction in cardiovascular disease and stroke.

ALLHAT UPDATE

ALLHAT recently terminated the a-adrenergic blocker, doxazosin, cohort because it was found to be less effective then chlorthalidone in reducing cardiovascular disease. ALLHAT involved 42,448 patients enrolled through 623 clinics and centers across the United States, Canada, Puerto Rico, and the US Virgin Islands.' Approximately 7000 US Veterans were included through 69 Depart- ment of Veterans Affairs clinics. ALLHAT participants are age 55 years and older and diverse: 47% women, 49% White, 35% Afri- can-American, 16% Hispanic, and 36% with diabetes.'

The ALLHAT study,l which began in 1994, continues and is scheduled to end in 2002. In the ALLHAT arm recently stopped, a total of 24,335 with hypertension and at least one other CAD risk factor were randomly assigned to receive chlorthalidone 1.25 to 25 mg/d (N = 15,268) or doxazosin, 2 to 8 mg/ d (N = 9067).' Following independent data reviews, on January 6 and January 21, 2000, the director of the NHLBI accepted a recom- mendation to discontinue the doxazosin treatment arm in the blood pressure component of the trial. Users of doxazosin had 25% more cardiovascular events and were twice as likely to be hospitalized for CHF as users of chlortha1idone.l Nevertheless, the drug regimens were equally effective in preventing MI and reducing the primary endpoint of fatal CAD and nonfatal MI. Confounding the ALL- HAT data, is the fact that the doxazosin co-

hort had slightly higher SBP, although DBP was the same. The 3 mm Hg higher SBP could explain 10% to 20% increase in CHF but not doubling the risk as described in ALLHAT.l The apparent benefit of a-blockers in terms of dyslipidemia and insulin resistance did not lead to cardiovascular benefits, specifically for CHF and CAD death and nonfatal MI.

The use of doxazosin as an add-on to multidrug regimens for treating hypertension or with lower-risk hypertensive patients with symptoms of benign prostatic hypertrophy was not tested in the trial. Furthermore, because this was not a placebo-controlled trial, but rather a comparison trial, the study does not allow an assessment whether doxazosin is better than placebo. ALLHAT continues with patients randomized to amlodipine, lisinopril, and chlorthalidone.

The findings might extent to other a-blockers and at the present time, this class should not be considered first-line (initial) therapy to lower blood pressure in older hypertensive patients, especially those with CAD risk factors. While it can not be concluded that doxazosin precipitates CHF, the possible overdi- agnosis of CHF based on clinical assessment of edema and fluid retention with doxazosin could not fully explain the significantly higher rate of combined hospitalized and fatal CHF.l

CALCIUM CHANNEL BLOCKER THERAPY POTENTIAL BENEFITS AND HARM

The first major trial to demonstrate outcome benefit with CCBs was the Syst-Eur trial. Although using nitrendipine, which is not available in the United States, this randomized study suggested that the use of a long-acting dihydropyridine CCBs may reduce fatal and nonfatal strokes and trend to- wards CAD mortality pr~tec t ion .~~ Based primarily on Syst-Eur, the JNC-VI listed long- acting dihydropyridine CCBs as alternatives to the preferred low-dose thiazide diuretics for ISH in older persons.3'j Furthermore, the Hypertension Optimal Trial (HOT)28 demonstrated in a felodipine-based therapy robust outcome benefits especially in the 1501 dia-

284 FERDINAND

betic patients randomized to a target group less than or equal to 80 mm Hg.

The Verapamil and Antihypertensive and Atherosclerosis study (VAHS), demonstrated, in 1414 patients, no differences in nonfatal or fatal events in patients randomized to sus- tained released verapamil versus chlorthalidone in a double-blind fashion over 6 months.61

Most recently, a large randomized trial, the Nordic Diltiazem (NORDIL) Study, reported in July, 2000 the effects of diltiazem compared with diuretics and p-blockers on cardiovascular morbidity and mortality in 10,881 patients aged 50 to 70 years at health centers in Nor- way and Sweden who had DBP greater than or equal to 100 mm Hgm As a prospective, randomized, open-blinded endpoint study (PROBE), diltiazem was effective as blood pressure lowering based on diuretics, p- blockers, or both and in preventing the combined primary endpoint of all strokes, MI, and other cardiovascular deaths. The PROBE design of the study is suggested to be similar to clinical practice. The diltiazem regimen was significantly more effective in lowering the rate of all strokes ( P = 0.04).30 There was a nonsignificant trend of nonfatal and fatal MI in the diltiazem group ( P = 0.17).30

A 4-year prospective, double-blind trial conducted in Europe and Israel, the Interna- tional Nifedipine once-daily Study: Interven- tion as a Goal in Hypertension Treatment (IN- SIGHT), also published in July, 2000, randomized 6321 patients aged 55 to 80 with blood pressure greater than 150/95 mm Hg or SBP greater than 160 mm Hg and at least one additional cardiovascular risk f a~ to r .~ Pa- tients were randomized to the CCB nifedipine (30 mg of the long-acting formulation daily) or a diuretic combination of 25 mg hydrochlorothiazide plus 2.5 mg amil~ride.~ The primary endpoints (composite cardiovascular death, MI, CHF, and stroke) occurred in 6.3% of the nifedipine group and 5.8% of the diuretic potassium-sparing agent group, a nonsignificant differen~e.~ There were more fatal MI (P = 0.017) and nonfatal CHF (P = 0.028) in the nifedipine cohort.

These newer data combined with the results of Syst-Eur, Syst-China, and the STOP-2 confirm the stroke and overall cardiovascular

benefit of blood pressure lowering using long-acting CCBs with perhaps a trend to- wards less protection from CAD mortality and CHF.

Calcium Channel Blockers and Renal Disease

One area where CCBs appear to have less benefit than other agents, specifically ACE inhibitors, may be the prevention of progression of renal insufficiency. ACE inhibitors slow progression of renal disease, decrease proteinuria and appear to be superior for protection against deterioration of renal function in both diabetic and nondiabetic patient^.'^, 41, 45 Diltiazem, verapamil, and perhaps long- acting dihydropyridine CCBs may reduce uri- nary albumin excretion and slow the decline of glomerular infiltration with effective blood-pressure lowering but data appear less conclusive. There was recently reported an extension of the prospective, randomized, blinded Appropriate Blood Pressure Control in Diabetes (ABCD) trial,16 comparing intensive versus moderate blood pressure control over 5.3 years in 470 patients with hypertension. Blood pressure control with either nisoldipine, a long-acting dihydropyridine CCB, or enalapril, an ACE inhibitor, as initial antihypertensive therapy appeared to equally sta- bilize renal function in hypertensive type 2 diabetics without overt albuminuria over a 5 year period.16 The more intensive blood pressure control improved all-cause mortality, confirming the benefit of tight blood pressure control regardless of agent used.16

Nevertheless, recent report from the Na- tional Institute of Diabetes and Digestive and Kidney Disease Study, the African-American study of Kidney Disease and Hypertension (AASK) noted that in a double-blinded regimen with amlodipine as a first step versus ramipril or metoprolol, there was faster deterioration of renal function in the amlodipine subgroup with proteinuria at baseline greater than 1 g/24 h.14 AASK has enrolled 1094 Afri- can-Americans at 21 centers.14 Although Afri- can-Americans represent 12.6% of the US population, they are 29.8% of people treated for end stage renal disease (ESRD).71 Hardest


hit are African-Americans age 25 to 4.4 who are 20 times more vunerable to hypertensive- related ESRD.3s, 71 Because CCBs are often used as first-step agents in African-Ameri- cans, the AASK trial indicates that clinicians should avoid underutilization of ACE inhibitors in this pop~ la t ion .~~ AASK will continue to compare the ACE inhibitor and p-blocker arms to test whether lowering blood pressure to a target of 125/75 mm Hg is more protective of the kidneys then 140/90 mm Hg.14 CCBs may be used as secondary treatment to reach blood pressure goals in AASK but not as a primary means of therapy in patients with proteinuria and renal insufficiency.

Calcium Channel Blockers and Atherosclerosis and Heart Failure

The original Prospective, Randomized Am- lodipine Survival Evaluation (PRAISE-1)49 suggested benefit of amlodipine in patients with nonischemic left ventricular systolic dysfunction and CHF.49 The second and larger trial (PRAISE-2) with 1652 subjects did not confirm mortality benefit in patients with nonischemic cardiomyopathy treated with aml0dipine.4~ The effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events in 825 patients with angiographically documented CAD suggested no treatment benefit with amlodipine in terms of all-cause mortality or major cardiovascular events in a multicenter randomized placebo-controlled trial but potential fewer cases of unstable angina and coronary revasc~larization.~~

Overall, it seems, versus therapy with diuretics, p-blockers, and ACE inhibitors, that CCBs are as protective against stroke, but may be less protective of CAD mortality, CHF and renal insufficiency progression and proteinuria, especially versus ACE inhibitors. Suggested associations of the use of CCBs and the risk for hospitalized gastrointestinal bleeding and cancer have not been conclusively demonstrated.62

Nevertheless, CCBs comprise a heteroge- neous class of medications. Diltiazem or verapamil have deleterious effects in patients with left ventricular systolic dysfunction, whereas

amlodipine and felodipine have neutral effects in this population. Diltiazem and verapamil, however, may be more effective than dihydropyridine CCBs in preventing progression of proteinuria and deterioration of renal function in patients with renal insufficiency.

The ALLHAT trial continues to examine the potential benefits and harms of amlodipine versus chlorthalidone and lisinopril in patients with hypertension and at least one coronary heart disease risk factor. Despite regular unblinded scrutiny of morbidity and mortality data by the Data and Safety Moni- toring Board of ALLHAT, the amlodipine arm continues.

HYPERTENSION AND DIABETES

Hypertension occurs in 60% to 70% of diabetics and is twice as prevalent among diabetic patients at any age versus the general p0pu1ation.l~ The development of type 2 diabetes is almost 2.5 times more likely in hypertensive versus normotensive patients suggesting a potential interaction of insulin resistance, type 2 diabetes, and elevated blood pressure.23 Elevated blood pressure is a major risk factor for cardiovascular disease and causes a 7.2-fold increase in mortality in diabetic patients and a 37-fold rise in mortality in diabetic patients with diabetic nephropathy.13 While hyperglycemia with a 1% increase in Hb A1C increases the risk for developing CHF by 15%, tight blood pressure control reduces the development of CHF by 56Y0.~~ Pharmacologic therapy for lowering blood pressure in diabetics is perhaps even more important for decreasing cardiovascular and diabetic risks and outcomes than glucose control alone.70

Antihypertensive Pharmacological Therapy and New Onset Diabetes Mellitus

Antihypertensive therapy has been suggested to potentially increase the risk for type 2 diabetes, specifically diuretics on p-blockers.& The Atherosclerosis Rsk in Communi- ties (ARIC) prospectively studied

286 FERDINAND

12,550 adults without diabetes to examine the independent relationship between the use of antihypertensive medicines and the risk for the subsequent development of type 2 diabetes. After appropriate adjustment for potential confounders, patients with hypertension who were taking thiazide diuretics, ACE inhibitors, or CCBs were not found to be at greater risk for subsequent diabetes than patients not receiving antihypertensive ther- apyZ3 Hypertensive patients who were taking P-blockers, however, had a 28% higher risk for diabetes than those on no medication^.^^ Any risk for developing type 2 diabetes on P- blocker therapy must be weighed against the proven benefits of P-blockers in reducing cardiovascular events, including in diabetic hypertensive patients.

Although not demonstrated in the ARK study, ACE inhibitors may have a protective effect on the development of diabetes. The HOPE trial demonstrated a 30% decrease in new onset diabetes with r a m i ~ r i l . ~ ~ Poten- tially ACE inhibitors may exert beneficial effects by improving blood flow through micro- circulation in the skeletal muscle tissue and improving insulin action in mediating glucose transport at the cellular level, improved insulin sensitivity, decreased hepatic clear- ance of insulin, an anti-inflammatory effect, improved blood flow to the pancreas, or an effect on abdominal fat.32

NHLBI Clinical Advisory Treatment of Hypertension and Diabetes

Recently, the NHLBI released a clinical advisory confirming the benefit of therapy in patients with hypertension and diabetes, including weight reduction, increased physical activity, moderation of salt and alcohol intake, and the appropriate use of antihypertensive therapy to reach a goal blood pressure of less than 130/85 mm Hg.63 Based on clinical trial data, four classes of drugs were noted to be effective as first-line therapy: (1) low-dose thiazide diuretics, (2) P-blockers, (3) CCBs, and (4) ACE inhibitors (Fig. 1).42, 63 Most diabetic patients, however, will require the use of more than one agent to achieve a therapeutic goal of less than 130/85 mm Hg. Considering that diabetics and albuminuria and proteinuria are associated with cardiovascular dis-

ease risk and renal disease, ACE inhibitors are preferred and appear to afford unique benefits.63 Overall, the benefit of antihypertensive treatment with diabetes seems to be even greater than that in the general hypertensive population. Recognizing the potential harm of a-blockers as first-line agents, they are no longer considered appropriate as initial antihypertensive medications for diabetic patients.

Randomized Clinical Trials in Diabetics

The original Appropriate Blood Pressure Control in Diabetes (ABCD) triaP5 and the Fosinopril Amlodipine Cardiovascular Events Trial (FACET)67 suggested cardioprotective effect of ACE inhibitors versus CCBs. The United Kingdom Prospective Diabetes Study (UKPDS) Group70 noted that blood pressure lowering was effective using a captopril- based or P-blocker-based regimen in reducing diabetic complications (microvascular and macrovascular). Multiple drugs were required in UKPDS to achieve tight control of 144/82 mm Hg versus less tight control of 154/87 mm Hg70 The use of aggressive blood pressure reduction in diabetic hypertensives decreased 24% diabetes endpoints, 32% deaths related to diabetes, 44% strokes, and 37% in microvascular endpoints predominately diabetic retin~pathy.~~ The Captopril Prevention Proj- ect (CAPPP)31 also demonstrated equal benefits for blood pressure reduction in terms of primary outcome with captopril or the diuretic- and P-blocker-based regimens. The SHEP trial showed benefit using low-dose chlorthalidone with addition of atenolol and other agents if needed for reducing stroke and CAD in patients with and without diabetes.

Nevertheless, a substantial reduction of the risk of cardiovascular disease and stroke was noted using CCBs in hypertensive type 2 diabetes in the HOT trial and a recent subana- lysis of the diabetic cohort in the Syst-Eur

The Syst-Eur risk reduction in mortality from CVD was 13% for nondiabetics and 76% for diabetic hypertensive patients.69 The HOT trial also confirms that multiple drug regimens are required to reach goal for most hypertensive diabetes.


TREATMENT GOAL < 130/85 MM HG

J

Initiate Pharmacologic Selection plus Lifestyle Modification

ACE inhibitors, p-blockers, calcium antagonists, and diuretics in low dose are preferred because of clinical trial data

(ACE inhibitors are drugs of choice in patients with albuminuridproteinuria.)

I

I .I, 1

Inadequate Response

Increase drug dose Add a second agent from a different class (e.g., a diuretic, if not selected initially)

I I

Inadequate Response

Add a second or third agent, one of which should he a diuretic, if not already prescribed

Figure 1. Hypertension and diabetes. (From Sowers JR, Reed J: 1999 Clinical Advisory: Treatment of Hypertension and Diabetes. Journal of Clinical Hyperten- sion 2(2):132-133, 2000; with permission.)

Systematic Review of Hypertension and Diabetic Risk Reduction

A recent meta-analysis of blood pressure lowering in diabetes reviewed multiple prospective randomized studies of more than 12 months duration on the effect of drug treatment on morbidity and mortality in diabetic hypertensive patient^.^ This analysis concluded that antihypertensive treatment to less than 130/85 mm Hg reduces the risk for cardiovascular events. Furthermore, in this meta-analysis, all four drug classes, including diuretics, P-blockers, ACE inhibitors, and CCBs, were effective in reducing morbidity and m~rtality.~ Overall, however, diabetic hypertensives will require combination therapy. More than 60% of diabetic hypertensive patients will require more than one drug to control blood pressure, and the combination of multiple drugs may actually be more beneficial than monotherapy with any individual agent or class.2

Optimal treatment of type 2 diabetes is a multifactorial intervention using intensive antihypertensive therapy, control of lipids, and

blood glucose.25 The risk for improvement suggested in UKPDS, however, was greatest with tight control of elevated blood pressure versus tight glucose control alone.

HEART OUTCOME PREVENTION EVALUATION TRIAL: FINDINGS AND IMPLICATIONS

The Heart Outcome Prevention Evaluation (HOPE) trial33 was initiated in December 1993 and reported in 2000. Patients eligible for HOPE included high-risk men and women 55 years of age or older, 80.6% with CAD, 52.8% with previous MI, and 38.3% with diabete~?~ This large multicenter placebo-controlled trial randomized 4645 patients to an ACE inhibitor, ramipril (10 mg/d), versus 4652 to pla- ~ e b o . ~ ~ The Food and Drug Administration of the US Department of Health and Human Services recently approved the use of ramipril for reduction of MI, strokes, and deaths in patients who are at increased risk for these diseases based on the HOPE study. Diabetics were eligible if they had at least one other

288 FERDINAND

cardiovascular risk factor, including hypertension, elevated total cholesterol, cigarette smoking, low high density lipoprotein (HDL) levels, or microalb~minuria.~~ The patients did not need to be hypertensive to be enrolled, and those with hypertension had their blood pressures controlled on other drugs. Clinical CHF or cardiac systolic dysfunction patients were excluded. The HOPE study was initiated after randomized clinical trials and systematic reviews consistently demonstrated a reduction in MI and other ischemic events with ACE-inhibitor therapy.5l. 56, 58

Although not specifically designed as an antihypertensive trial, 46.5% of the patients had elevated blood pressure greater than 140/90 mm Hg, and the benefit was greatest with SBP greater than 125 mm Hg.33 There was a 3.3 mm Hg reduction in SBP in the ramipril group. Ramipril demonstrated a reduction in primary events with robust statisti- cal benefit. In the ramipril group, 653 patients (14.1%) died of cardiovascular causes or had an MI or stroke compared with 824 patients (17.7%) in the placebo group ( P < O.OOl).” At each of the outcomes analyzed separately, including MI, stroke, cardiovascular death, and all-cause mortality, ramipril had benefit.33 Fortunately, there was no difference between ramipril and placebo in noncardiovascular death.33 The ramipril reduction of cardiovascular morbidity and mortality was observed by 1 year of therapy increased over 4 years of the study. Ramipril demonstrated 16% reduction in the need for revascularization, a 22% reduction in new CHF and also significantly reduced the risk for cardiac arrest and worsening angina.33

NEW APPROACHES TO THE RENlN ANGIOTENSIN ALDOSTERONE KlNlN SYSTEM.

Angiotensin to Receptor Blockers

The latest major group of approved agents for hypertension are the angiotensin receptor blockers (ARBs). There are now six orally active potent selective nonpeptide ARBs released for clinical use: (1) eprosartan mesy- late, (2) irbesartan, (3) candesartan, (4) losartan, (5) valsartan, and (6) telmisartan. ARBS different in pharmacologic half-life, absorption effected by food, bioavailability, pro-

drug status, and metabolism.12 These pharmacologic properties, however, have not been shown to conclusively demonstrate any significant differences in antihypertensive therapy. Losartan’s minimal uric acid lower effect appears unique but has not been shown to have definite proven clinical benefit.

ARBs provide effective blockade of angiotensin I1 (AT 11) at the subtype of angiotensin I1 receptor l2 Although ACE inhibitors block the formation of AT I1 from AT I, AT I1 also may be formed by enzymes other than ACE, such as chymase. Important characteristics of ARBs are a relatively high-binding effect and a slow dissociation from the AT, receptor.12 The AT, receptor appears to play the key role in the regulation of blood pressure versus the AT, re~eptor.~ Although in terms of blood pressure lowering, ARBs are similar to ACE inhibitors and other agents, the side-effect profile of this class is at least comparable and probably superior to other many widely used agents with the potential benefit of increasing compliance.

As the class of AT I1 receptor blocker ex- pands, the relevancy of differences between various agents of the class must be evaluated. A recent analysis of 25 randomized clinical trials that compared ARBs demonstrated equivalent antihypertensive efficacy at recom- mended doses.ll Data pooled from 51 clinical trials showed comparable weighted average DBP reduction (not placebo-controlled cor- rected) for monotherapy with losartan, Val- sartan, irbesartan, candesartan, and telmisartan.l’ Reductions in SBP also seemed to be similar among the various ARBS.” Overall, there seems to be few clinical significant differences in blood pressure efficacy among the six marketed ARBs in the treatment of hypertension at this time (Table 3).11

THE ROLE OF BRADYKlNlN IN ANGIOTENSIN CONVERTING ENZYME INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS

A significant difference between ARBs versus ACE inhibitors is the ability to avoid potential deleterious (or protective) effects of brad~kinin.~ Bradykinin is a potent vasodila- tor that acts to stimulate the release of prosta-


Table 3. COMPARATIVE PHARMACOLOGY OF SOME ANGIOTENSIN II RECEPTOR BLOCKERS

Parameter Eprosartan lrbesartan Candesartan Losartan Valsartan Telmisartan

Indication Hypertension Hypertension Hypertension Hypertension Hypertension Hypertension Inhibition of 100 100 90 85 80 90

angiotensin I1 pressor effect peak (%)*

Half-life (h) 5-9 11-15 9 &9 6 24 Bioavailabiiity (YO) 13 60-80 15 33 25 42 (40 mg)

Usual starting dose 600 150 16 50 80 40 58 (160 mg)

(md/d)

(mg)

Dosing range 400-800 150-300 8-32 25-100 80-320 20-80 Available strengths 400/600 75/150/300 4/8/16/32 25/50/100 80/160 40/80

Absorption No No No Yes Yes Yes

CYP450 No Yes (2C9) No Yes No No affected by food

metabolism

*The dosages required to achieve the above levels of inhibition were: eprosartan 350 mg, irbesartan 150 mg, candesartan 8 mg,

Datafrom Physicians' Desk Reference, 55th ed. Montvale, NJ, Medical Economic, 2001, pp 564, 996, 1902, 2166, 979, 3225. losartan 100 mg, valsartan 80 mg, and telmisartan 80 mg.

cyclin and nitric oxide. ACE inhibitors decrease the degradation of bradykinin by blocking ACE, which is also, kininase II.4 One clinical relevance to this is limited or little cough associated with ARBs versus an often clinically significant 10% to 15% cough rate with ACE inhibitor^.^^ Experimental studies suggest some benefit with the vasodilating effects of bradykinin and some of the effects of ACE inhibitor therapy on preventing left ventricular hypertrophy (LVH) and blood pressure lowering may be negated by bradykinin antagonism, such as the coadministra- tion of a specific bradykinin receptor antagonist, icatibant acetate (HOE 140).

Although the randomized trial of losartan versus captopril in patients over 65 with heart failure (ELITE I) reported in 1997 suggested potential survival benefit with captopril, a follow-up study, ELITE 11, which was more definitive, failed to confirm the initial observa- tion when based on over 10 times as many deaths.54 At this time, ARBs are not confirmed as effective as ACE inhibitors for reducing renal progression, clinical events, or mortality from heart failure.

PRECAUTIONS WITH ANGIOTENSIN CONVERTING ENZYME INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS

ACE inhibitors have been associated with angioedema, a potentially life-threatening

complication, which, although rare, appears to be common & in African-Americans, perhaps because of greater sensitivity to bradykinin effect.'j Thirteen case reports of angioedema associated with the use of losartan in the Netherlands have been reviewed. It may not be advisable to prescribe ARBs to patients with history of angioedema (of whatever ori-

Therapy with ARBs does not affect glucose homeostasis, lipid profile, or other chemis- tries." No significant drug interactions have been reported with ARBs and other com- monly used cardiovascular drugs, including oral hypoglycemics, calcium antagonists, di- goxin, warfarin, hydrochlorothiazide, or oral contraceptive^.^^

ARBs and ACE inhibitors should be avoided with pregnant women because of morbidity and mortality consequences in the fetus when used in the second and third tri- m e s t e r ~ . ~ ~ ACE inhibitors and potentially ARBs, in patients with unilateral and bilateral renal artery stenosis may cause significant increases in serum creatinine or blood urea ni- trogen (or both) with acute renal failure.47

An analysis of 20,902 Medicare beneficiar- ies treated for documented left ventricular dysfunction showed that ACE inhibitors are underused especially with comorbid reduction in renal f~nction. '~ After adjusting for patient characteristics, comorbidity, and se- verity of illness, including left ventricular

gin) .72

290 FERDINAND

ejection fraction, the receipt of ACE inhibitor was associated with a 37% (16%-52%) lower mortality for patients who had poor renal function (serum creatinine >3 mg/dL) and a 16% (8%-23%) lower mortality for patients who had better renal function.17 Use of aspirin appeared to attenuate somewhat the benefit of ACE inhibitors in patients with poor renal f~nc t ion . '~ Moderate renal insufficiency should not be considered a contraindication to the use of ACE inhibitors in patients with other compelling indications.

ANGIOTENSIN II RECEPTOR BLOCKERS AND CLINICAL OUTCOMES

Overall, AT I1 receptor blockers have not, as of yet, demonstrated reduction in morbidity and mortality as noted in multiple large trials with ACE 68 The failure of ELITE I1 confirms that at the present time, ACE inhibitors remain compelling with patients with heart failure and left ventricular dysfunction with ARBs as an alternative only for disabling side effects to ACE inhibitors. Recently, the Valsartan Heart Failure Trial (Val-HeFT) suggested some benefit of the addition of ARBs to ACE inhibitors in patients with heart failure.'O Val-HeFT included 5010 patients, aged 62.7 years (+ 11.2 y), with a mean ejection fraction of 26.7 (k 7.2). This was not an antihypertensive trial with average blood pressure at baseline 123.8/75.5 with 92.6% of patients on diuretics.1° When randomized to the addition of valsartan at 40 mg twice daily titrated to 160 mg twice daily, there was no difference in all-cause mortality versus placebo in patients receiving standard care including ACE inhibitors, diuretics, di- goxin, and P-blockers.lo Hospitalizations because of heart failure were reduced by 27.5% (P < .001). In addition, quality of life measured by the Minnesota Living With Heart Failure Questionnairelo was improved (P = .005). Patients in the valsartan group also had an improvement in functional capacity. Val- HeFT suggests a potential benefit of combination therapy in patients with hypertension and a history of heart failure or left ventricular systolic dysfunction, although this was not the population actually studied.

A recent trial suggested that ARBs alone or in combination with thiazide diuretics may be effective in blood pressure control in African- Americans with a sodium supplemented diet.74 Nevertheless, effective blood pressure lowering with ARBs in low renin populations, such as African-Americans, obese patients, and persons with type 2 diabetes mellitus, is best achieved not by increasing the dose but by adding a low dose of hydrochlorothia- ~ i d e . ~ ~

ADVANCES IN ADHERENCE, CONTROL, AND QUALITY OF LIFE

Antihypertensive Dosing and Combination Therapy

To achieve optimal blood pressure lowering, once-daily dosing with agents having 24-hour efficacy, with at least 50% of the peak effect remaining at the end of 24 hours, should be Short-acting agents should be avoided for several reasons, including increased adherence with once-daily dosing, fewer tablets with potentially lower cost, smooth rather than intermittent BP control, and perhaps beneficial protection against the risk for sudden death, -heart attack, and stroke during the abrupt increase in blood pressure during the early-morning surge.36 Twice-daily dosing may be an alternative, especially in patients who are high risk.

New formulations that combine low doses of two agents of different classes often give the benefit of minimizing dose-dependent ad- verse effects and using fewer tablets while giving additional antihypertensive therapy.55 Multidrug therapy was also needed to inten- sively treat hypertensive patients effectively in the HOT, UKPDS, and AASK trials.

Inadequate management of blood pressure remains a cause of concern. Examination of 800 hypertensive men at five Veterans Affairs sites over 2 years confirms that in a selected population, blood pressure was poorly controlled, perhaps primarily because of a lack of intensive medical therapy and that many physicians may not be aggressive enough in their approach to hyperten~ion.~


Quality of Life Improvement With Pharmacologic Therapy

The cost of care, including medication and quality of life considerations, is an important adherence factor in a disease that is chronic and, in many instances, asymptomatic. Im- pairment of sexual function by antihypertensive medications can affect compliance. In the Treatment of Mild Hypertension Study (TOMHS),22 patients reported a higher inci- dence of erectile dysfunction over 24 months with chlorthalidone versus placebo. Men randomized to other agents did not differ significantly from the placebo group, however."

Newer studies have suggested that quality of life may actually improve with intensive blood pressure management, and even stage I hypertension may be associated with insidi- ous, disturbing clinical symptoms. Effective blood pressure lowering with drugs versus lifestyle alone in TOMHS was associated with an improvement in quality of life and a decrease in certain symptoms, such as headache, fatigue, and palpitations.21 In a HOT sub- study of 922 patients, lowering blood pressure improved quality of life and general psy- chological well-being after only 6 months of treatment.76 Patients in the lowest target group of less than or equal to 80 mm Hg demonstrated statistically significant improvement in quality of life scores and decreased anxiety.76 Furthermore, effective pharmacologic therapy may avoid disabling but often undetected cerebrovascular disease causing cognitive dysfunction.34

Recent data have confirmed that antihypertensive medications, including ACE inhibitors, P-blockers, and CCBs, are associated with significant protection from cognitive im- pairment in older patients.60 Nevertheless, one class of antihypertensive agents, centrally acting sympatholytic agents (methyldopa and others) may be associated with increased risks.60 In Indianapolis, Indiana with a random sample of 2212 African-Americans patients aged 65 and older, noted that antihypertensive agents excluding centrally acting drugs, were associated with a significant reduction in the diagnosis of cognitive impair- ment ( P < .01) in cognitive functional impair- ment (P < 0.01).60 Overall, the message that

antihypertensive therapy causes side effects should be superseded by newer information suggesting actual benefit with appropriate antihypertensive agents in terms of quality of life and cognitive function.

FUTURE PHARMACOLOGIC AGENTS

There have been no recent additions to major classes of antihypertensive agents within the year 2000 other then new formulations of older medications and the additions of low dose diuretics to various ARBS.

Omapatrilat (Vasopeptidase Inhibitor)

Vasopeptidase inhibitors have now been synthesized with human testing begun. The prototype, omapatrilat, inhibits not only neutral endopeptidase, but also ACE, both cell surface metalloproteases with structural similarities at their active ~ i t e s . ~ Omapatrilat seems to cause extracellular volume reduction and vasodilation through blocking the effects of AT I1 and increasing levels of atrial and brain natriuretic peptides and bradykinin. Preliminary data suggest benefit regardless of low- or high-renin status or ethni~ity.~ There seems to be the potential for angioedema as previously reported with ACE inhibitor^.^ Omapatrilat, given once daily produces dose- dependent significant reductions in blood pres~ure.~, 75 This agent may be useful for the long-term treatment of heart failure and hypertension.

Bosentan (Endothelin-1 Antagonist)

Endothelin-1 is a powerful vasoconstrictor peptide originally isolated from supernatants of cultured endothelial cells. Endothelin-1 stimulates specific receptors, ETA and ETB, which are widely distributed in the cardiovascular system with ETA as the primary vasoconstrictor. Plasma levels of endothelin-1 are elevated in various pathophysiologic states, including hypertension, atherosclerosis, MI, and CHF. Bosentan, a combined ETA/ ETB receptor antagonist, lowers blood pres-

292 FERDINAND

sure without reflex sympathetic stimulation and may potentially benefit hypertension and heart failure.39 The proper dose, indication, and safety of bosentan and other endothelin- 1 antagonists need to be established by long- term clinical trials.

SUMMARY

Initial pharmacologic therapy for hypertension is low-dose thiazide diuretics, P-blockers, and ACE inhibitors. Increasing data have confirmed that ACE inhibitors have specific benefit in patients with diabetes, atherosclerosis, left ventricular dysfunction, and renal insufficiency. CCBs are alternative agents for ISH in the elderly and appear to decrease stroke with perhaps less protection against progression of renal insufficiency and proteinuria, CAD mortality and new onset heart failure versus other initial agents, especially ACE inhibitors. ARBS are well tolerated and effective blood pressure lowering agents but have not been confirmed as effective as ACE inhibitors for reducing renal progression, clinical events, or mortality from heart failure. Effective pharmacologic antihypertensive therapy may avoid disabling and undetected cerebrovascular disease, cognitive dysfunction, and disturbing symptoms of elevated blood pressure. Vasopeptidase inhibitor, such as omapatrilat, and endothelin-1 antagonist, such as bosentan, may become future agents approved for the reduction of morbidity and mortality with hypertension. The ALLHAT trial continues to examine the potential benefits and harms of amlodipine versus chlorthalidone and lisinopril in a diverse high-risk population. Based on ALLHAT data, however, doxazosin is no longer an acceptable initial pharmacological agent. Intensive pharmacologic treatment with blood pressure lowering to less than 130/85 mm Hg is recom- mended with diabetes, renal insufficiency, and heart failure with additional goal of less than 125/75 mm Hg with renal failure and proteinuria greater than 1 g/24 h, based on multiple outcome studies.

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2(2):132-133, 2000

SHEP. JAMA 265~3255-3264, 1991

325:293-302, 1991

Address reprint requests to Keith C. Ferdinand, MD

Department of Clinical Pharmacology Xavier University

College of Pharmacy and The Heartbeats Life Center 1201 Poland Avenue

New Orleans, LA 70117

e-mail: [email protected]

update in pharmacologic treatment of hypertension

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