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DIFFERING EFFECTS OF RAMIPRIL ON AM-BULATORY AND OFFICE BLOOD PRESSUREMAY FURTHER EXPLAIN THE BENEFITSSEEN IN THE HOPE STUDYThe Heart Outcomes Prevention Evaluation(HOPE) study found that treatment with the an-giotensin-converting enzyme (ACE) inhibitor,ramipril, (plus other medications) reduced the riskof myocardial infarction, stroke, and cardiovascu-lar death, as well as total mortality, in high-riskpatients compared to a regimen that did not in-clude ramipril. Although only 46% of the patientson entry were hypertensive (baseline blood pres-sure 138/79 mm Hg), the mean reduction in officeblood pressure (OBP) in the ramipril group was3/2 mm Hg greater than in those on placebo. Itshould be remembered that many of the other pa-tients were taking antihypertensive drugs. Al-though the trial investigators suggested that mostof the benefit could be explained by factors otherthan the achieved differences in blood pressure,this has remained a major point of controversy.

In the HOPE study, ramipril was given once dailyat bedtime, with blood pressure measured during theday. Accordingly, the actual 24-hour reduction inblood pressure may have been underestimated basedsolely on OBP. Therefore, a HOPE substudy was per-formed using 24-hour ambulatory blood pressure(ABP) measurement to determine if the degree ofblood pressure reduction based on OBP may havebeen an underestimation.

Thirty-eight Scandinavian patients (19 men;mean age, 71 years), all of whom had peripheralarterial disease within the HOPE study and wereassigned to ramipril, underwent ABP and sittingOBP measurement both before and 1 year afterrandomization. Ramipril (mean dose, 8.1 mg) re-

duced OBP (8/2 mm Hg) and daytime ABP (6/2mm Hg) after 1 year on therapy. Twenty-four-hour ABP, however, was more favorably reducedat the end of 1 year (10/4 mm Hg), mainly be-cause of a more pronounced nocturnal decline(17/8 mm Hg) and a more favorable night/dayratio. Although previous studies assessing treat-ment effects have used OBP in assessing cardiovas-cular outcome, the favorable effects seen in theHOPE study may be related more to ramipril’s ef-fect on 24-hour ABP and its effect at night thanpreviously realized.—Svensson P, de Faire U,Sleight P, et al. Comparative effects of ramipril onambulatory and office blood pressures. A HOPEsubstudy. Hypertension. 2001;38:228–232.

CommentThe HOPE investigators have stated that the majorbenefit of ramipril in improving survival and pre-venting recurrent ischemic vascular disease was duemainly to interruption of the renin-angiotensin sys-tem and its subsequent benefit of improving endothelial function, as well as reducing atheroscle-rosis and thrombogenesis. In fact, they have statedthat the modest blood pressure-lowering effects wit-nessed in the trial account for, at most, one third ofthe benefit seen. The hypertension community hasbeen at odds with this interpretation and has criti-cized the study on several accounts.

Although the trial has not been promoted as a hy-pertension trial, the interpretation of blood pressureresults has occurred even though there was no appro-priate standardization for the measurement of bloodpressure and it was measured only five times duringthe entire mean 3.4 years of the study. Furthermore,although ramipril has a 24-hour blood pressure-lower-ing effect and can be taken once daily, its peak effectoccurs 3–6 hours after administration. Measuringmorning OBP several hours after dosing of ramipril atnight, as performed in the overall HOPE trial, mayhave underestimated the actual blood pressure-lower-ing effects of ramipril.

Based on the findings of this small, several-sitestudy from one geographic area, the greater reduction

Jan Basile, MD

From the Ralph H. Johnson VA Medical Center, Division of General Internal Medicine/Geriatrics, Medical University of South Carolina, Charleston, SCAddress for correspondence:Jan Basile, MD, Ralph H. Johnson VA Medical Center,1090 Bee Street, Charleston, SC 29403

A n a l y s i s o f R e c e n t P a p e r s i n H y p e r t e n s i o nJ a n B a s i l e , M D , S e c t i o n E d i t o r

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in ABP when compared to OBP, as well as themore favorable reduction in night/day blood pres-sure, may further help explain the contribution ofblood pressure reduction to the favorable effectsnoted. As stated by the authors, all of the patientsin this small substudy had peripheral vascular dis-ease (19% in the entire HOPE study), were older(mean age, 71 years vs. 66 years in the HOPEstudy), and had higher baseline blood pressures(151/81 mm Hg vs. 139/79 mm Hg). Further evi-dence for a lack of comparability between the twogroups involves the use of different additionalblood pressure-lowering agents. This may accountfor the findings of the substudy and not allow gen-eralization to the entire HOPE study population.

Nevertheless, the way in which blood pressureis measured and the timing of measurement appearto be important factors in assessing the effect ofblood pressure on clinical outcomes. Until furtherstudies can be performed, both the hypertensionand vascular biology communities will continue todebate the reasons for benefit in the HOPE study.Regardless, the use of ramipril at 10 mg given atnight appears to improve outcome in high-risk pa-tients with underlying cardiovascular disease. Onlythrough future clinical trials, where blood pressureis repeatedly and reliably measured, such as theAntihypertensive and Lipid-Lowering Treatment toPrevent Heart Attack Trial (ALLHAT), in whichthe diuretic chlorthalidone is directly compared tothe ACE inhibitor lisinopril and to a calcium chan-nel blocker, amlodipine, will we be better able todifferentiate between the benefits of blood pressurereduction and those related to specific pharmaco-logic therapies.

ANGIOTENSIN RECEPTOR BLOCKERS ARE RENOPROTECTIVE IN TYPE 2 DIABETICS WITH NEPHROPATHY: THREE LANDMARK TRIALSThe RENAAL StudyAngiotensin-converting enzyme (ACE) inhibitorsare currently the drugs of choice for patients withheart failure, renal dysfunction, and type 1 dia-betes with proteinuria, regardless of the presenceor absence of hypertension. Although ACE in-hibitor therapy slows the progression of renal dis-ease both in type 1 diabetes and in nondiabeticswith nephropathy, their use in patients with type2 diabetes has not been as well studied. Althoughthere are theoretical reasons to believe angiotensinII type 1 receptor blockers (ARBs) would be asrenoprotective as ACE inhibitors in type 2 dia-betes, their ability to retard progressive renal dis-ease has not been previously studied. Accordingly,

the renoprotective effects of two ARBs, losartanand irbesartan, in type 2 diabetic nephropathywere evaluated in three recent landmark trials.

The Reduction of Endpoints in Non-Insulin-De-pendent Diabetes Mellitus With the Angiotensin IIAntagonist Losartan (RENAAL) study was a double-blind, randomized, placebo-controlled trial in 1513type 2 diabetics with at least 300 mg of urinary pro-tein (mean, 1.8 g albumin/g creatinine) and a baselineserum creatinine of 1.3–3.0 (mean, 1.9) mg/dL. Rang-ing from 31–70 years of age (mean age, 60), they wererandomized to receive from 50 mg (27% of patients)to 100 mg (71% of patients) of losartan (mean dose,79 mg) or placebo (medications that did not includean ACE inhibitor or another ARB). Although theycould not be treated with either ACE inhibitor or ARBtherapy, they received other antihypertensive therapy,including diuretics, calcium channel blockers, β block-ers, and α blockers, to achieve a blood pressure<140/90 mm Hg. Baseline blood pressure was 152/82mm Hg. The final blood pressure achieved was140/74 mm Hg in each treatment arm over a new du-ration of 3.4 years. The composite primary end pointincluded a doubling of the baseline serum creatinineconcentration, end-stage renal disease, or death. Sec-ondary end points included a composite of morbidityand mortality from cardiovascular causes, includingheart failure leading to hospitalization, as well as pro-teinuria and the rate of progression of renal disease.

Treatment with losartan resulted in a 16% reduc-tion in the composite primary end point. The individ-ual risk for doubling of serum creatinine was reducedby 25%, the likelihood of reaching end-stage renaldisease was reduced by 28%, and there was a 20% re-duction in end-stage renal disease or death. Losartanreduced the rate of first hospitalization for heart fail-ure by 32%, although death due to cardiovascular dis-ease and overall mortality was not reduced.

Losartan improves renal outcomes in type 2 diabet-ic patients with established nephropathy. The benefitsof losartan are noted in patients who are already re-ceiving antihypertensive drug therapy.—Brenner BM,Cooper ME, De Zeeuw D, et al. Effects of losartan onrenal and cardiovascular outcomes in patients withtype 2 diabetes and nephropathy. N Engl J Med.2001;345:861–869.

The IDNTThe international, multi-center Irbesartan DiabeticNephropathy Trial (IDNT) was a prospective,randomized, double-blind trial comparing the ef-fects of irbesartan, amlodipine, and placebo onthe progression of nephropathy in type 2 diabetes.A total of 1715 male and female hypertensive type2 diabetic patients with at least 900 mg of pro-

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teinuria were enrolled in 210 centers in 20 coun-tries. They were randomized to receive irbesartan150 or 300 mg in addition to baseline antihyper-tensive agents (primarily diuretics, β blockers, andcentrally acting agents). Irbesartan and placebowere compared to amlodipine of up to 10 mg.Follow-up was 2.6 years. Baseline blood pressureaveraged 159/87 mm Hg; the final blood pressureaveraged 140/77 mm Hg in the irbesartan group,141/77 mm Hg in the amlodipine group, and144/80 mm Hg in the placebo group. The goals oftherapy had been set at lower levels.

The primary end point of the study was the com-posite of a doubling of the baseline serum creati-nine, the onset of end-stage renal disease, or deathfrom any cause. Irbesartan use was associatedwith a 20% lower risk for the primary end point,compared to placebo, and a 23% reduction whencompared to amlodipine treatment, independentlyof its effects on blood pressure. In the irbesartangroup, the risk of a doubling of the serum creati-nine was 33% and 37% lower than in the placeboand amlodipine groups, respectively. There wasno difference in the rates of death from any causeor in the cardiovascular composite end point.

Irbesartan, independently of blood pressure re-duction, was effective in protecting against pro-gressive nephropathy in the hypertensive type 2diabetic, and more effective than amlodipine.—Lewis EJ, Hunsicker LG, Clarke WR, et al. Renopro-tective effect of the angiotensin-receptor antagonistirbesartan in patients with nephropathy due to type 2diabetes. N Engl J Med. 2001;345:851–860.

The IRMA StudyThe Irbesartan in Patients with Type 2 Diabetes andMicroalbuminuria (IRMA)-2 study was a multina-tional, multi-center, randomized, double-blind,placebo-controlled study to determine if irbesartanwould delay or prevent the development of clinicalproteinuria in 590 hypertensive type 2 diabetic pa-tients with microalbuminuria and normal renalfunction (serum creatinine, 1.3 mg/dL for men and1.1 mg/dL for women). The patients were 30–70years of age (mean age, 58), mostly male (68%) andwhite (97%), and had persistent microalbuminuria,defined as an albumin excretion rate of 20–200µg/min in consecutive overnight urine samples.Baseline blood pressure was 153/90 mm Hg. Theywere randomized to receive irbesartan 150 mg, irbe-sartan 300 mg, or placebo once daily for 2 years.Additional antihypertensive agents, including diuret-ics, β-blockers, calcium channel blockers (except di-hydropyridines) and α blockers were allowed.

Excluded from use were ACE inhibitors or otherARBs. The primary end point of the study was thetime to development of overt nephropathy, definedas a urinary albumin excretion rate greater than 200µg/min and at least 30% higher than at baseline.

Final blood pressure averaged 144/83 mm Hg inthe placebo group, 143/83 mm Hg in the 150-mgirbesartan group, and 141/83 mm Hg in the 300-mg irbesartan group. There was a 70% clinical dif-ference for the primary end point only in the 300mg irbesartan-treated group. In addition, restora-tion of normoalbuminuria at the time of the lastvisit, a secondary end point, was also more com-mon in the 300-mg irbesartan group than in theplacebo group. Serious adverse events were less fre-quent among those treated with irbesartan. The au-thors conclude that irbesartan at 300 mg per dayslows the development of overt nephropathy, inde-pendently of its blood pressure-lowering effect intype 2 diabetics and its effect on microalbuminuria.This benefit appears to be dose-dependent and isassociated with regression to normoalbumiuria in34% of patients. Irbesartan should be considered intreating early nephropathy in patients with hyper-tension and type 2 diabetes.—Parving HH,Lenhert H, Brochner-Mortensen J, et al. The ef-fect of irbesartan on the development of diabeticnephropathy in patients with type 2 diabetes. NEngl J Med. 2001;345:870–878.

CommentThe sixth report of the Joint National Committee onthe Prevention, Detection, Evaluation, and Treatmentof High Blood Pressure recommends ARBs when ACEinhibitors are contraindicated or side effects occurfrom their use. The studies cited above in type 2 dia-betics with hypertension show that the addition ofirbesartan, at 300 mg per day, is effective in prevent-ing the development of overt nephropathy and reduc-ing the progression of microalbuminuria, compared toa regimen that does not include an ACE inhibitor oranother ARB. In addition, both losartan and irbesar-tan reduce the progression of established renal diseasein type 2 diabetics with hypertension. Even thoughblood pressure was not reduced to the current systolicgoal of 130 mm Hg (chronic renal insufficiency andsignificant proteinuria), the authors of the studies sug-gest that these favorable effects were independent ofblood pressure reduction.

What common theme arises from these studies?First, there appears to be a dose-response benefitthat occurs, as increasing doses of the ARBs wereassociated with more favorable effects on renalfunction. Second, although there were small bloodpressure differences between the active therapy and

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control groups, the majority of benefit occurredwithout reaching the current goals for blood pres-sure reduction (<130/80 mm Hg). This suggests thatantagonism of the renin-angiotensin-aldosteroneaxis seen with ARB therapy may account for thebenefit noted. Third, the recent African AmericanStudy of Kidney Disease (AASK) trial suggests that aramipril-based regimen affords better renoprotec-tion than an amlodipine-based regimen in nondia-betic blacks with hypertensive nephrosclerosis.There were few African Americans enrolled in thesecurrent studies (these individuals constitute up to30% of all those on dialysis in this country).

It is unknown whether ACE inhibitors induce thesame degree of renoprotection as ARBs in hyperten-sive patients with type 2 diabetes and nephropathy.This has led the American Diabetes Association to en-dorse ARBs as recommended therapy for the type 2diabetic with hypertension and any degree of protein-uria. It is known, however, that ACE inhibitors slowthe progression of nephropathy in type 1 diabetes, andthey were observed to decrease the progression of pro-teinuria in those with type 2 diabetes and microalbu-minuria in a substudy of the Heart OutcomesPrevention Evaluation (MICRO-HOPE) trial. There-fore, until we have direct comparative trials betweenthese two classes of drugs, we remain unsure of whichclass provides the most renal and cardiovascular pro-tection in the type 2 diabetic with hypertension.

THE BEST DIAGNOSTIC TEST FOR EVALUAT-ING RENAL ARTERY STENOSIS IN PATIENTSSUSPECTED OF HAVING RENOVASCULAR HY-PERTENSION IS STILL UNCLEARThe prevalence of renal artery stenosis (RAS) as theetiology of renovascular hypertension (RVH) variesbetween 1% and 5% of all hypertensives and is ashigh as 40% in those referred to a hypertension clinic.Although arteriography remains the gold standard fordiagnosing RAS, it is invasive and may be associatedwith serious complications. Clinicians continue tosearch for the most accurate noninvasive test to makethis diagnosis. It has been difficult to compare variousreports because of differences in case mix, test charac-teristics, and definitions of what constitutes a positivetest. Accordingly, researchers from the Netherlandsperformed a meta-analysis of the literature that com-pared arteriography with computed tomographic an-

giography (CTA), gadolinium-enhanced three-dimen-sional magnetic resonance angiography (MRA), cap-topril renal scintigraphy (CRS), ultrasonography, andthe captopril test for the detection of RAS.

In their analysis, the investigators included 55studies with more than 4000 patients suspected ofhaving RVH. Studies were included if 1) arteriogra-phy was used as the gold standard; 2) suspicion ofRVH was the reason for referral; 3) criteria for a pos-itive test were specifically defined; and 4) the absolutenumber of true-positive, false-negative, true-negative,and false-positive results were stated or could be ob-tained from the data. They summarized the sensitivityand specificity across the range of test results, rankingtheir order from best to worst, and found that bothCTA and gadolinium-enhanced MRA performedequally better than non-gadolinium-enhanced MRA,CRS, ultrasonography, and the captopril test.

Although CTA and MRA appear superior for thedetection of RAS, the tests continue to have theirgreatest use in those with a high pretest probabilityof RVH. Because only a limited number of pub-lished studies on these tests could be included in thismeta-analysis, the authors recommend that furtherresearch be performed.—Vasbinder GBC, NelemansPJ, Kessels AGH, et al. Diagnostic tests for renalartery stenosis in patients suspected of having reno-vascular hypertension: a meta-analysis. Ann InternMed. 2001;135:401–411.

CommentAlthough arteriography is considered the goldstandard for RAS, it is an anatomic test that con-veys nothing about functional significance, is inva-sive, and is associated with increased risk. Theideal, less invasive test for the diagnosis of RAScontinues to be debated within the hypertensioncommunity. From this meta-analysis of a relativelysmall number of studies, both CTA and MRA, ap-pear to be the best tests that we have to offer ourpatients and are associated with less risk. Whetherthese tests, which measure the degree of anatomicobstruction within the renal artery, will better pre-dict who will respond to treatment compared tosuch tests as CRS, which measures functionalblood flow to the kidney, remains unclear. Furtherstudy will better define the best way to screen for,as well as detect, RAS.