Managing High‐Risk Patients With Hypertension: Focus on the Renin‐Angiotensin System

Abstract

The goal of treating hypertension has evolved from merely lowering blood pressure to an emphasis on the more important objective of decreasing morbidity and mortality. Recent trials have emphasized, however, that the major benefit in outcome relates to the level of blood pressure achieved. Hypertension associated with other risk factors, such as age, diabetes, nephropathy, and left ventricular hypertrophy, places patients at high risk of myocardial infarction, stroke, renal failure, and cardiovascular death. In numerous studies, reductions in end points were usually achieved with combination therapy. The Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) reaffirmed the value of diuretics in treating high‐risk hypertension and reducing morbidity, but it also confirmed the necessity of combination drug therapy. Agents that block the effects of angiotensin II are an important component of antihypertensive therapy because of their proven ability to lower the incidence of cardiovascular and renal events in high‐risk hypertensive patients.

The past year has witnessed the publication of a number of important, large‐scale clinical trials of antihypertensive agents in high‐risk patients. The Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), ¹ the largest antihypertensive trial to date, was designed to compare the relative merits of a calcium channel blocker, an angiotensin‐converting enzyme (ACE) inhibitor, or an α blocker with a diuretic as first‐line pharmacologic treatment. Other landmark trials have demonstrated the effectiveness of angiotensin receptor blockers (ARBs) in the treatment of high‐risk patients with hypertension complicated by diabetic nephropathy or left ventricular hypertrophy (LVH).

These and other studies currently under way focus attention on the role of the renin‐angiotensin system in the genesis of cardiovascular complications of hypertension and the importance of blocking the effects of angiotensin II in high‐risk groups. This review places the results of recent trials in that context and discusses optimal treatment strategies in specific high‐risk populations. In certain subgroups of patients with both hypertension and comorbidities, clinical evidence points to the treatment benefits of a renin‐angiotensin‐system blocker plus a low‐dose diuretic. The review also highlights the importance of ongoing clinical trials, the results of which could affect the future course of preferred clinical therapy.

THE “GREAT QUESTION” IN ANTIHYPERTENSIVE THERAPY

The results of ALLHAT have engendered a great deal of discussion. ALLHAT was predicated on finding the answer to the great question: “What is the best first‐line drug for hypertension?” ALLHAT randomized 42,448 patients, aged 55 years and older, of whom 33,357 were followed for a mean of 4.9 years. ¹ All patients had hypertension and were considered at high risk of cardiovascular disease due to the presence of documented vascular disease, diabetes, or at least one other risk factor for cardiovascular morbidity. The trial was designed to determine whether the occurrence of fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI) is lower for hypertensive patients treated with newer agents—a calcium channel blocker (amlodipine 2.5–10 mg/d), an ACE inhibitor (lisinopril 10–40 mg/d), or an α blocker (ARBs were not included)—compared with a diuretic (chlorthalidone 12.5–25 mg/d), because, based upon earlier studies, diuretics were considered the gold standard. The mean age of participants was 67 years; 35% were black, 19% were Hispanic, and 36% had diabetes mellitus. ¹

For the primary outcome, the trial failed to demonstrate a significant difference between chlorthalidone and amlodipine or lisinopril in preventing MI or death from CHD (Figure 1). ¹ The α‐blocker arm of the study had been terminated early because of a 25% increased risk for combined cardiovascular outcomes, particularly heart failure, compared with chlorthalidone. ² The results differed for secondary end points, however. Compared with chlorthalidone, amlodipine‐treated patients had a 38% higher risk for heart failure (p<0.001), and lisinopril‐treated patients had a 19% higher risk for heart failure (p<0.001) and a 15% higher risk for stroke (p=0.02). ¹ The ALLHAT investigators concluded that, based on the superiority of thiazide diuretics in preventing one or more forms of cardiovascular disease, and taking cost into account, diuretics should be first‐choice drugs for antihypertensive therapy. ¹

Figure 1.

The Antihypertensive Lipid Lowering to Prevent Heart Attack Trial (ALLHAT) primary end point: coronary heart disease death and nonfatal myocardial infarction. CI=confidence interval. Adapted from ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. JAMA. 2002;288:2981–2997. ¹

ALLHAT cannot be considered a definitive comparative trial, as equivalent blood pressure (BP) reductions were not achieved in all groups. If the BPs are unequal, drug comparisons are of questionable validity because BP exerts such a potent effect on the development of cardiovascular end points, particularly stroke. In the study overall, systolic BP (SBP) was 2 mm Hg higher in the lisinopril group than in the diuretic group, but it was 4 mm Hg higher for black patients in the lisinopril group than in the diuretic group. ¹ This subgroup accounted for the excess stroke risk in patients receiving lisinopril.

Additionally, BP regimens were somewhat limited in ALLHAT. By protocol, a second drug added to achieve target BP could not be one of the comparator study drugs, which excluded commonly used combination therapy regimens. For example, patients given lisinopril could not be given a diuretic to achieve further BP lowering, ordinarily a logical choice, ³ although about 20% of patients in this group actually ended up on a diuretic. In most recent trials of ACE inhibitors and ARBs, most patients received diuretics in addition to study drugs.

Importantly, only 26% of patients in ALLHAT achieved BP control with monotherapy; this percentage is consistent with results of most clinical trials, signaling that the selection of add‐on or combination therapy is an important therapeutic consideration. Further, one third of patients in ALLHAT had diabetes. Using the current, lower BP targets for diabetic patients (<130/<80 mm Hg), it is estimated that >80% of the total ALLHAT population would require combination therapy to achieve goal BP. ALLHAT tried to identify the best single first‐line drug for hypertension, but that question may be obsolete. Although ALLHAT established that first‐line therapy with diuretics is as effective than ACE inhibitors or calcium channel blockers, multiple‐drug therapy may be necessary for a large majority of hypertensive patients.

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) ⁴ recognizes that most patients, except perhaps those with mild stage 1 hypertension, require two or more antihypertensive agents for effective BP control (<140/<90 mm Hg or <130/<80 mm Hg for patients with diabetes or renal disease). If monotherapy is inadequate to control BP to goal levels, a diuretic should generally be included in a multidrug regimen. ⁴ The question remains: “What is the ideal combination for most high‐risk hypertensive patients?” As this review will illustrate, the evidence clearly points to the use of a low‐dose diuretic plus a renin‐angiotensin‐system blocker.

In contrast to ALLHAT, BP reductions were equivalent in both treatment groups in the Second Australian National Blood Pressure Study (ANBP2). ⁵ This office‐based study had a relatively homogeneous population (6083 men and women aged 65–84 years, 95% of whom were white). Hypertension was virtually the only entry criterion. Under the guidance of family practitioners, patients received an ACE inhibitor (enalapril) or a diuretic (hydrochlorothiazide) with the addition of a calcium channel blocker, β blocker, or α blocker, as needed, to achieve BP goals. ⁵ The majority of patients received combination therapy.

At Year 5, BPs had decreased by 26/12 mm Hg in both groups. ⁵ The primary end point, all cardiovascular events or all‐cause mortality, decreased 11% more in the ACE‐inhibitor treatment group than with the diuretic (p=0.05). The treatment benefit was significant in men (17% reduction, p=0.02) but not in women, a result that probably reflects the lack of statistical reliability of subgroup analyses as well as the relatively small overall difference between the two treatments. The ACE‐inhibitor group also achieved a 32% reduction in the incidence of first nonfatal MI (p=0.05) and a 14% reduction in the incidence of first nonfatal cardiovascular event (p=0.03). The rate of fatal strokes, however, was significantly higher in ACE‐inhibitor‐treated patients (p=0.04), although the total number of strokes was similar between groups. Thus, in the family practice setting where most older patients receive their health care, the ACE inhibitor showed an outcome advantage compared with the diuretic in male patients. Investigators attributed this finding to a reduction in the effects of angiotensin II. ⁵ In comparison with ALLHAT, it should be noted that ANBP2 was not blinded, enrolled far fewer patients, and its findings are no more definitive.

THE RENIN‐ANGIOTENSIN SYSTEM AND CARDIOVASCULAR RISK

Angiotensin II has numerous effects on the acute and long‐term regulation of systemic BP and also exerts important effects on cardiovascular structure. In addition to its vasoconstrictive properties; angiotensin II increases platelet aggregation; promotes smooth muscle proliferation, myocardial hypertrophy and fibrosis; stimulates production of procoagulant plasminogen activator inhibitor‐1; and directly causes endothelial dysfunction (Figure 2). ⁶

Figure 2.

The hypertensive continuum: role of angiotensin II (Ang II). LVH=left ventricular hypertrophy; MI=myocardial infarction; ESRD=end‐stage renal disease; HF=heart failure

The Heart Outcomes Prevention Evaluation (HOPE) ⁷ was not specifically a hypertension trial—though many study subjects had hypertension—but was designed to evaluate the effects on vascular events of a renin‐angiotensin‐system blocker. Patients in HOPE were at high cardiovascular risk: 55% were aged 65 years and older, 88% had cardiovascular disease, 47% had hypertension, 38% had diabetes, and 8%–9% had LVH on electrocardiogram. Only patients with heart failure or a known left ventricular ejection fraction <40% were excluded. ⁷

Compared with placebo (i.e., usual therapy), 5‐year treatment with ramipril 10 mg/d (in addition to usual therapy) decreased the relative risk of cardiovascular‐related deaths by 25% (p<0.001), MI by 20% (p<0.001), stroke by 31% (p<0.001), and heart failure by 22% (p<0.001). ⁷ The benefits of ramipril were incremental over established treatments (e.g., aspirin, β blockers, and lipid‐lowering drugs) and were largely independent of BP reduction.

The mean reduction in BP was 3/2 mm Hg. ⁷ The between‐group difference in BPs was similar to that in ALLHAT, which has led some commentators to suggest that the benefits seen in HOPE derived from lower BP. In a small subgroup of patients who underwent ambulatory BP monitoring, the between‐group difference in BP was significantly greater than that of the main study, and questions have been raised regarding the methodology of BP determination and the fact that the study drug was given at night. ⁸ Still, the consensus seems to be that HOPE showed a specific effect of blocking the renin‐angiotensin system in reducing vascular events, which was particularly marked in patients with diabetes in the MIcroalbuminuria, Cardiovascular, and Renal Outcomes (MICRO)‐HOPE substudy. ⁹

PATIENTS WITH HIGH‐RISK HYPERTENSION: CONCOMITANT RISK FACTORS AND COMORBID CARDIOVASCULAR DISEASE

Hypertension is a major and independent contributor to cardiovascular events, increasing the risk of CHD, heart failure, and stroke from two‐ to four‐fold. ¹⁰ In most patients, hypertension does not occur in isolation, and persons with hypertension and multiple risk factors or concomitant disorders are at heightened risk of cardiovascular events. ¹⁰ , Table I lists the conditions that place hypertensive patients at high risk for complications.

Table I.

Factors or Concomitant Disorders That Place Hypertensive Patients at Increased Risk for Cardiovascular Complications

Multiple Risk Factors
Older age, men >55 years, women >65 years
Diabetes mellitus
Renal disease/proteinuria
Left ventricular hypertrophy
Established vascular disease
Coronary heart disease
Cerebrovascular disease
Peripheral vascular disease

Age as a Risk Factor

Increasing age is the most potent factor in the Framingham risk score. ¹¹ Both BP levels and overall cardiovascular risk increase with age. ¹² The population aged ≥65 years combines highest rates of hypertension (more than two thirds of this age group have hypertension) with the lowest rates of BP control. ⁴ Older patients with hypertension are at higher risk than younger patients, so treating older patients gives a greater benefit from antihypertensive therapy.

Because diastolic BP decreases while SBP increases with age, the majority (two thirds) of older hypertensive patients have isolated SBP elevation. Indeed, isolated systolic hypertension might be used as a surrogate for increased risk in elderly patients. Isolated systolic hypertension is a strong risk factor for cardiovascular mortality and is the most prevalent precursor to heart failure in the elderly population. ¹³ Treatment of isolated systolic hypertension has been shown to decrease the incidence of stroke, MI, heart failure, and kidney failure in a number of clinical trials in older patients, summarized in Table II. ⁴ , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ Notably, in the Swedish Trial in Old Patients with Hypertension (STOP‐Hypertension), ¹⁷ the benefits of treatment were observed throughout the patient age range of 70–80 years. Further, the majority of patients in this study received combination therapy. ¹⁷ No differences in outcome were observed between patient groups receiving β blockers and/or diuretics and patient groups treated with ACE inhibitors and/or calcium channel blockers. Compared with calcium channel blockers, however, ACE inhibitor‐treated patients experienced fewer MIs and heart failure.

Table II.

Benefits of Treating Hypertension in Older Persons

	End‐Point Reduction Compared With Placebo (%)
Trial Patient Ages in Years (Entry BP)	Stroke	HF	CHD	All CVD
SHEP ≥60 (mean 72) (170/77 mm Hg)	36*	—	27	32
STOP‐Hypertension 70–84 (195/102 mm Hg)	47*	51*	13*	40*
MRC 65–74 (160–209/≤114 mm Hg)	25*	—	19	17*
Syst‐Eur ≥60 (mean 70) 174/86 mm Hg	42*	29	30 (MI)	31*
BP=blood pressure; HF=heart failure; CHD=coronary heart disease; CVD=cardiovascular disease; MI=myocardial infarction; SHEP=Systolic Hypertension in the Elderly Program study; STOP‐Hypertension=Swedish Trial in Old Patients with Hypertension study; MRC=Medical Research Council trial; Syst‐Eur=Systolic Hypertension in Europe study; *statistically significant

Diabetes Mellitus

Diabetes affects a growing proportion of persons in the United States. Between 1994 and 2002, the age‐adjusted prevalence of diabetes among US adults increased by 54%, from 4.8% to 7.3%. ¹⁸ The annual incidence of newly diagnosed diabetes is 1 million adults ≥20 years of age. ¹⁹ In 2000, 17 million people had diabetes, 90%–95% of whom had type 2 diabetes. ¹⁹

Diabetes is a potent risk factor for cardiovascular morbidity and mortality. ¹¹ The overall incidence of cardiovascular disease averages two‐fold higher for men and three‐fold higher for women compared with their nondiabetic counterparts. ¹¹ By 45 years of age, approximately 40% of persons with type 2 diabetes will also have hypertension, further increasing their cardiovascular risk. ²⁰ At the same level of BP, diabetes has a great impact on risk, and antihypertensive treatment is particularly effective in reducing cardiovascular events in diabetic patients.

Lowering BP in patients with diabetes decreases both microvascular and macrovascular complications, as the series of reports from the United Kingdom Prospective Diabetes Study (UKPDS) showed. ²⁰ , ²¹ UKPDS 33 ²¹ compared the effects of intensive blood‐glucose control (goal fasting plasma glucose, <6 mmol/L) with conventional treatment on the risk of diabetes‐related complications in patients with type 2 diabetes. Although intensive blood‐glucose control reduced microvascular complications by 25%, it did not lower the risk of macrovascular end points (e.g., MI, stroke, heart failure).

A second study, UKPDS 38, ²⁰ targeted BP rather than blood glucose in 1148 patients with type 2 diabetes and hypertension; the mean entry BP was 160/94 mm Hg. Patients were randomly allocated to tight BP control or to less‐tight control. Despite only a 10‐mm Hg difference in SBP (p<0.0001) and a 5‐mm Hg difference in diastolic BP, 154/87 mm Hg compared to 144/82 mm Hg, between the two groups, the risk of any diabetes‐related end point was reduced by 24% in the tight‐control patients (p=0.0046), and the risk of fatal and nonfatal stroke was reduced by 44% (p=0.013). Diabetes‐related deaths were decreased by 32% in the tight‐control group (p=0.019); the majority due to a decline in fatal cardiovascular events. The risk reduction in the tight‐control group for combined MI, sudden death, stroke, and peripheral vascular disease was 34% (p=0.019). ²⁰ Of note, the reduction in BP also decreased microvascular complications, such as retinopathy (by 34%, p=0.004), which are often thought of as being directly related to glucose control. The reductions associated with intensive BP control were greater than those achieved with tight blood‐glucose control, indicating that aggressive treatment of hypertension in patients with diabetes pays a high rate of return. ²⁰ , ²¹ It is of interest that patients on a β‐blocker based regimen and those on an ACE‐inhibitor based treatment program demonstrated comparable risk reductions, probably reflecting the fact that both of these drug classes inhibit the renin‐angiotensin‐system.

The JNC 7 guidelines ⁴ and the recommendations of the American Diabetes Association (ADA) ²² and National Kidney Foundation ²³ all support lower hypertension goals in patients with diabetes or renal disease (<130/<80 mm Hg) and suggest that combination therapy will be needed to achieve the lower BP goal. ²² Numerous drugs—thiazide diuretics, β blockers, calcium channel blockers, ARBs, and ACE inhibitors—have proven effective in reducing the rates of stroke and cardiovascular disease in patients with diabetes and hypertension. ⁴ Treatment with ARBs and ACE inhibitors, which both target angiotensin II, has been particularly beneficial in slowing the progression of diabetic nephropathy and in reducing albuminuria and microalbuminuria in patients with diabetes. ⁴ , ²⁴ The ADA suggests that an ACE inhibitor is a reasonable first‐choice agent in most patients with diabetes, based on a track record of reducing microvascular and macrovascular complications in both type 1 and type 2 diabetes. In patients with type 2 diabetes and microalbuminuria or clinical nephropathy, ARBs and ACE inhibitors are considered first‐line therapy. ²² It should be remembered, however, that in all of the ACE inhibitor‐ or ARB‐based studies, it was necessary to also give a diuretic in a large percentage of patients to achieve goal BP.

Renal Disease

The prevalence of end‐stage renal disease (ESRD) in the United States more than doubled in the decade between 1991 and 2001, affecting almost 400,000 patients, and diabetes is the leading cause of ESRD. ²⁵ Between 1997 and 2001, diabetes was the primary diagnosis for nearly 200,000 patients with ESRD. Type 2 diabetes alone accounted for 39.3% of cases, and type 1 diabetes accounted for 5.3%. ²⁵

Hypertension is a major determinant of the rate of progression of ESRD. ²⁶ A cohort of previously untreated male veterans with hypertension was followed >15 years to examine factors associated with ESRD. Compared with SBP <165 mm Hg, the relative risk with a systolic pressure of 165–180 mm Hg was 1.9; with a systolic pressure >180 mm Hg, relative risk reached 4.6. ²⁶

Several studies have examined the effects of the renin‐angiotensin‐system inhibition on renal disease progression. Captopril was evaluated in a trial of patients with type 1 diabetes, urinary protein excretion ≥500 mg/d, and serum creatinine concentration ≤2.5 mg/dL. ²⁷ The primary end point was doubling of the baseline serum creatinine concentration. At study entry, approximately 60% of patients in both treatment groups were receiving antihypertensive medication. After 3 years, captopril‐treated patients (many of whom were receiving other medications, including diuretics) had a 48% risk reduction for doubling of serum creatinine concentration compared with the group receiving other medications that did not include an ACE inhibitor (25 vs. 43 patients; p=0.007). The combined risk of death, dialysis, and kidney transplantation was reduced by 50% in the captopril patients compared with placebo (p=0.006). The use of captopril plus other medications significantly slowed the progression of nephropathy independent of the small disparity in on‐study BP between the two groups. ²⁷

Another clinical trial of patients with type 2 diabetes and nephropathy, the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial ²⁸ had as a primary end point a composite of time to doubling of the baseline serum creatinine concentration, ESRD, or death. In addition to standard antihypertensive agents, (calcium channel blockers, β blockers, diuretics), patients received losartan (titrated to 100 mg/d) or placebo toward a goal trough pressure of <140/<90 mm Hg. Losartan lowered the risk of the primary composite end point by 16% vs. standard therapy (p=0.02). Although RENAAL is often described as placebo controlled, the majority of patients in both groups received combination therapy, including diuretics (>80% of patients) and/or calcium channel blockers (>77% of patients). ²⁸

Considering end points individually, the incidence of a doubling of the serum creatinine concentration was reduced by 25% (p=0.006), progression to ESRD was reduced by 28% (p=0.002), and the level of proteinuria was reduced by 35% (p<0.001). ²⁸ The mortality rate did not differ significantly between groups. It normally takes about 7 years from the time patients develop frank proteinuria to the time they develop ESRD. Extrapolating from the duration of the trial and the lowered risk of ESRD, the RENAAL investigators calculated that the use of an ARB delayed the need for dialysis or transplantation by 2 years compared with a conventional regimen. The significant improvement in renal outcomes in the losartan‐treated patients was not explained by more favorable BP control. Statistical analysis confirmed that renal protection by the ARB exceeded that attributable to the small BP differences between the two treatment groups. ²⁸

The Irbesartan Diabetic Nephropathy Trial (IDNT)— which also studied patients with hypertension, type 2 diabetes, and nephropathy—showed that the risk of a doubling of the serum creatinine concentration was 33% lower in patients treated with irbesartan 300 mg/d plus other medications compared with usual‐treatment patients (p=0.003), (that did not contain an ACE inhibitor or ARB) and 37% lower than in patients receiving amlodipine 10 mg/d (p<0.001). ²⁹ This measure, which approximates halving of the glomerular filtration rate, reflects the rate of progression of nephropathy. The overall risk of ESRD was 23% lower in the irbesartan group than in the amlodipine or placebo groups (both, p=0.07); amlodipine was essentially no different than placebo. Again, as BP was equally well controlled in the active‐treatment groups, BP lowering did not appear to account for the renoprotective benefits of irbesartan. ²⁹ Neither was there an independent renal protective effect from the calcium channel blocker, though this effect was demonstrated with both ARBs in RENAAL and IDNT. Another irbesartan study, the Irbesartan MicroAlbuminuria type 2 diabetes mellitus in hypertensive patients study (IRMA‐2) ³⁰ measured time to overt nephropathy in patients with microalbuminuria, hypertension, and type 2 diabetes. In the 24‐month study, the risk reductions vs. placebo were 44% for irbesartan 150 mg/d (p=0.05) and 68% for irbesartan 300 mg/d (p<0.001). At the end of the study, nearly half of patients in both irbesartan groups were also taking either a diuretic, β blocker, and/or calcium channel blocker. ²⁹ , ³⁰

A BP‐independent antiproteinuric effect of ARBs was demonstrated again in patients with type 2 diabetes and microalbuminuria in the MicroAlbuminuria Reduction With VALsartan (MARVAL) trial. ²⁴ At 24 weeks, urinary albumin excretion (a surrogate for progression of renal disease) in the valsartan 80 mg/d (ARB) group was reduced by 44%, which contrasted with the much more modest 8% reduction in the amlodipine 5 mg/d (calcium channel blocker) group (p<0.001). BP in the two groups was lowered almost identically (−11.2/6.6 mm Hg for valsartan and −11.6/6.5 mm Hg for amlodipine). Moreover, 30% of patients treated with the ARB were restored to normoalbuminuria compared with 15% of patients receiving the calcium channel blocker. ²⁴

Left Ventricular Hypertrophy

The prevalence of LVH in patients with hypertension has been estimated at 40%–62%, ³¹ and it can be considered a harbinger of major cardiovascular risk. In one study of a middle‐aged (≥40 years and older) Framingham population free of clinical cardiovascular disease, LVH assessed by echocardiography predicted an increased risk of incident CHD, stroke, heart failure, and intermittent claudication. Except for age, left ventricular mass was the only variable consistently related to all the cardiovascular events in this study. ³²

Angiotensin II plays a major role in the development and maintenance of LVH. ³¹ Increased wall stress activates the local cardiac renin‐angiotensin system and promotes cardiac hypertrophy and interstitial fibrosis. ARBs and ACE inhibitors are particularly effective in causing regression of LVH; other antihypertensive agents (including diuretics, calcium channel blockers and, to a lesser extent, β blockers ³³ ) are also effective. The effect of an ARB on cardiovascular morbidity and mortality in a high‐risk population with LVH was studied in the Losartan In hypertension For End‐point reduction (LIFE) trial. ³⁴ In LIFE, 9193 patients aged 55–80 years with electrocardiographic signs of LVH and hypertension were randomized to either losartan (mean dose, 82 mg) or atenolol (mean dose, 79 mg); hydrochlorothiazide and then other antihypertensive medications were added as needed to achieve target BR About 90% of patients in LIFE were on combination therapy. ³⁴

The primary end point was a composite of cardiovascular death, stroke, and MI. ³⁴ Compared with atenolol, losartan significantly reduced the risk of the primary end point by 13% (p=0.021), which was due entirely to a 25% reduction in the risk of fatal or non‐fatal stroke (p=0.001). Both drugs achieved substantial reductions in BP (mean BP at last visit: 144.1/81.3 mm Hg for losartan and 145.4/80.9 for atenolol), and adjustment for minor differences did not affect the results. The 25% reduction in stroke occurrence was regarded as an incremental benefit above and beyond the well‐established effects of β blockade in the treatment of cardiovascular disease. ³⁴

The results of LIFE, demonstrated protection against stroke with angiotensin receptor blockade. ³⁴ Both the HOPE and LIFE trials reported reductions in the risk of new‐onset diabetes with RAS blockade: ramipril by 34% (p<0.001) in the HOPE trial, losartan by 25% (p=0.001) in the LIFE trial. ⁷ , ³⁴

Whereas LIFE investigated the use of an ARB in patients with LVH, and both RENAAL and IDNT evaluated the use of ARBs in patients with diabetes and proteinuria, an ongoing trial, Valsartan Antihypertensive Long‐term Use Evaluation (VALUE) trial ³⁵ , ³⁶ is investigating cardiovascular end points in high‐risk hypertensive patients, comparing an ARB (valsartan 80–160 mg/d) based treatment program with a regimen based on a calcium channel blocker (amlodipine). Interim results indicate that VALUE has thus far succeeded in equalizing BP reduction between groups. ³⁷ More than 60% of patients are on two or more antihypertensive medicines. ³⁷ Results of the VALUE study will likely be reported in 2004.

CONCLUSIONS

Long‐accepted concepts in the treatment of hypertension are continuing to evolve. Clinical trials in hypertension have changed their focus from evaluating the BP‐lowering ability of various pharmacologic agents to testing the comparative efficacy of different antihypertensive regimens on reducing cardiovascular risk although BP lowering itself may account for a great deal of the benefit derived from treatment, there does appear to be some difference in outcome with different medications. The focus of drug therapy has changed from monotherapy to the use of multiple drugs to control hypertension. A major question in hypertension treatment is not “Which is the best first‐line drug?” but rather “Which is the best combination therapy?” Blocking the effects of angiotensin II, via either ACE inhibition or ARBs, has come to be seen as an essential component of treatment for high‐risk hypertensive patients—those with diabetes, renal disease, established vascular disease, or LVH.