ISH/ESH Late-Breaking Trial Results: ANBP2, PHYLLIS, LIFE, ELSA, Eplerenone, STOP-NIDDM, HYVET-Pilot, OCTAVE

Disclosures Peter Sleight, MD The 1st Joint Meeting of the International and European Societies of Hypertension (ISH/ESH) took place in Prague, the Czech Republic, June 23-27, 2002. Among the many presentations given before this large international audience, the following clinical trial and trial substudy results were among the most interesting and important.

Second Australian National Blood Pressure (ANBP2) Study

Of the trial results presented at the ISH/ESH meeting, perhaps the most important new data came from the Second Australian National Blood Pressure Study (ANBP2), presented by Professor Lindon Wing, MD (Flinders University of South Australia, Adelaide, Australia). [1] The signal design feature of this trial was that it was conducted in a general practice setting. A total of 6083 newly diagnosed or untreated patients aged 65-84 years with hypertension (systolic blood pressure [SBP] >/= 160 mm Hg and/or diastolic blood pressure [DBP] >/= 90 mm Hg) and no recent cardiovascular morbidity were randomized to receive either ACE inhibitor- or diureticbased open-label treatment (3044 and 3039 patients, respectively), with whichever diuretic or angiotensin-converting enzyme (ACE) inhibitor the general practitioner (GP) preferred. The patients were then followed for a median of 4.1 years, with the end point evaluation blinded as to the allocated group. BP reduction was impressive and similar in both treatment groups, averaging 26/12 mm Hg for SBP/DBP, respectively. End point evaluation, however, revealed superiority for the ACE inhibitor-based treatment over that with a diuretic. There were 692 cardiovascular events or deaths from any cause (55.8%) in the ACE inhibitor group vs 732 (59.5%) in the diuretic group, a risk reduction of 11% (P = .05). The results were more marked in males (17% reduction, P = . 02) vs females -- but was that possibly a play of chance? These results were augmented by one of the poster presentations, by another Australian group, at the University of Melbourne (presented by Trefor O. Morgan, MD, and colleagues). [2] This group presented new data from comparative ambulatory BP monitoring (ABPM) in placebo-controlled studies showing that in elderly patients (aged >/=60 years) with essential hypertension, angiotensin AT1 receptor blocker (losartan or candesartan) and ACE inhibitor treatment (perindopril -- both used at full dose to achieve very similar daytime BP values) reduced nighttime BP significantly more (almost double) than did beta-blocker (atenolol) or calcium channel blocker (felodipine) treatment; all drugs were taken at 8 AM.

Plaque Hypertension Lipid-Lowering Italian Study (PHYLLIS) Substudy

The results of a substudy of PHYLLIS, conducted as another ABPM study, were presented by Professor Giuseppe Mancia, MD (University of Milan-Biocca, Ospedale San Gerardo, Monza). [3] PHYLLIS was the first large hypertension trial to conduct office ABPM yearly in all patients. The main study -- a multicenter, prospective, double-blind, randomized, controlled trial conducted over a period of 3 years -- randomized 508 mildly hypertensive patients to a 2 X 2 factorial design treatment protocol. Patients were assigned to 1 of 4 treatments: an ACE inhibitor (fosinopril 20 mg once daily), a diuretic (hydrochlorothiazide 12.5 mg once daily), diet plus a statin (pravastatin 40 mg once daily), or diet plus placebo (n = approx. 120 patients on each of the 4 treatment arms). At baseline, office BP was around 160/100 mm Hg, whereas ABPM was (as expected) lower, at around 122/72 mm Hg. Both of these values were reduced on treatment, to 140/82 and 135/70 mm Hg, respectively.

There were essentially no differences in the BP reduction (about 8/6 mm Hg) between the ACE inhibitor and the diuretic; the addition of a statin did not further reduce BP in any group (mean changes in SBP were -8.7 mm Hg and -7.1 mm Hg without and with statin, respectively, and mean changes in DBP were -6.2 mm Hg and -5.5 mm Hg without and with statin, respectively). This replicates the finding in the much larger Heart Protection Study, [4] where there was similarly no fall in BP with simvastatin, despite other reports to the contrary. The ABPM reduction of BP was similar on diuretic or ACE inhibitor. The main end points of the PHYLLIS study, carotid wall thickening and atheroma, were subsequently presented by Professor Alberto Zanchetti, MD. [5]

Role of LV Mass in the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Echo Substudy and in the European Lacidipine Study on Atherosclerosis (ELSA)
The results of the recently completed Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study were initially presented at the 2002 annual meeting of the American College of Cardiology and subsequently published in The Lancet.[6] These results demonstrated a clear superiority of the angiotensin II AT1 receptor blocker (ARB) losartan over the beta-blocker atenolol for reducing major events, particularly in the high-risk population of hypertensive patients with left ventricular hypertrophy (LVH). Since this result appeared to go against the evidence from previous drug comparisons, it has been subjected to considerable scrutiny, in order to determine whether the BP reduction was indeed identical for the 2 drug regimens. It was in this context that similar concerns were raised when Richard Devereux, MD (Cornell Medical Center, New York, NY, USA), presented new echocardiographic data from the LIFEEcho substudy.[7] For the LIFE-Echo substudy, the core lab read 4677 echocardiograms in 460 patients, attempting to demonstrate whether reduction of the LV mass index predicted clinical outcomes. The study found that for those patients with increased LV mass index, incidence of cardiovascular mortality and stroke was increased, with a nonsignificant trend toward increased occurrence of myocardial infarction. Furthermore, the predictive value of the LV mass index held true even after baseline LV mass, BP, or treatment choice was allowed for. However, since in-trial BP is such a strong predictor of LV mass, Dr. Devereux was questioned as to whether there were differences between the 2 drugs' effects on BP. Another important study on the prognostic value of LV mass was presented by Professor Enrico Agabati-Rosei, MD (University of Brescia, Italy), on behalf of the European Lacidipine Study on Atherosclerosis (ELSA) investigators.[8] This study enrolled over 2000 patients, mean age 55, with mild hypertension (BP 162/100 mm Hg), to study the possible correlation of LV mass with carotid intima media thickening (IMT). Four Italian centers randomized 503 patients to either the calcium channel blocker lacidipine or the beta-blocker atenolol. At baseline there was a weak (but highly significant) correlation between LV mass and carotid IMT. There were no baseline differences between the atenolol and lacidipine groups, nor were there differences in LV mass index at 4 years. However, lacidipine showed reduced progression in IMT, despite identical 24-hour ABPM change (-6/-5 mm Hg for both drugs). The change in IMT was not explained by carotid diameter differences on the 2 drugs. So this study, unlike LIFE (with losartan), showed LV mass change was equivalent between atenolol and the calcium channel blocker. LV mass change and IMT thickening appear to respond to different mechanisms, not just BP alone.

Eplerenone

Eplerenone is the first of a potential new class of drugs, the selective aldosterone blockers (SABs), which are similar to spironolactone, the surprisingly effective agent in the Randomized Aldactone Evaluation Study (RALES) study. William B. White, MD (University of Connecticut Health Center, Farmington, Connecticut, USA), presented updated information culled from recent trials with eplerenone, giving a general overview of several past and ongoing studies. [9] Although most of these studies were relatively short-term, Dr. White noted that the incidence of spironolactone's unwanted side effects -- eg, gynecomastia and sexual dysfunction -- appears to be much reduced with this new compound, which has 100 and 1000 times less affinity for the progestogen and androgen receptors, respectively. He also emphasized the safety profile, with eplerenone being associated with a low incidence of hyperkalemia, except in black patients with renal impairment due to diabetes, where the incidence of serum potassium > 5 mmol was as high as 10%. Based on clinical experience in over 2000 patients, the recommended dose of eplerenone should be 25-200 mg daily (usually 50-100 mg/day). In terms of efficacy, the studies showed equal or better BP control with eplerenone than with amlodipine, based on ABPM studies, with microalbuminuria reduced more in diabetic patients and LV mass regressed more in hypertensive patients. Importantly, there was equal efficacy in low vs normal renin hypertensive patients, and in old vs young. These results, if confirmed by larger and longer trials, suggest that eplerenone will have a useful place in the treatment of hypertension, especially with the growing evidence that an important proportion of patients with resistant hypertension will respond to an aldosterone antagonist.

The Study to Prevent NIDDM (STOP-NIDDM)

Professor Jean-Louis Chiasson, MD (Centre Hospitalier de l'Universit de Montral, Htel-Dieu, Montral, Canada), addressed the importance of halting the growing epidemic of diabetes mellitus with the novel compound acarbose, an alpha-glucosidase inhibitor that decreases the rise in postprandial glucose, decreases insulin resistance, and downregulates the insulin receptor.[10] In the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM), 1429 patients with impaired glucose tolerance were randomized to acarbose 100 mg 3 times daily (n = 715) vs placebo (n = 714).[11] The primary end point was development of diabetes on the basis of a yearly oral glucose tolerance test (OGTT). Based on intent-to-treat analysis, there was a 25% relative risk reduction for the development of new diabetes in patients on acarbose ( P = .0015), which represents an absolute risk reduction of 9%. The results were independent of age, gender, or body mass index (BMI). Cox proportional analysis showed that acarbose significantly increased the likelihood of reversion of impaired glucose tolerance to normal by 41% ( P < .0001). Perhaps the most interesting and unexpected findings were highly significant reductions in the risk of hypertension (34%, P = .0059) and in the risk of cardiovascular events, a composite end point including myocardial infarction, stroke, congestive heart failure, coronary bypass, angioplasty, and new cases of angina (40%, P = .0265). The downside of the treatment was an increased withdrawal due to flatulence and diarrhea. There were only 2 deaths, one each in the placebo and the active groups. Based on these data, it is possible to calculate that treating 9 to 10 patients for 3 years would stop 1 new case of type 2 diabetes.

The Hypertension in the Very Elderly Trial Pilot Study (HYVET-Pilot)

Professor Christopher Bulpitt, MD (Imperial College School of Medicine, Hammersmith Hospital, London, UK), gave the results of the Hypertension in the Very Elderly Trial Pilot Study (HYVET-

Pilot), which is the only trial designed to address the risks vs benefits of antihypertensive treatment in the very elderly (>/= 80 years). [12] He presented a meta-analysis of previous trials, which showed a reduction in stroke but a nonsignificant increase in total mortality. [13] This was also seen in the open-label HYVET-Pilot study, which compared placebo, bendrofluazide (2.5 increasing to 5 mg, plus add-on diltiazem), and lisinopril (2.5 increasing to 5 mg, plus add-on diltiazem), in 1283 subjects (average age 84 years, sitting BP 180/100 mmHg). With the need for commercial funding, the diuretic-alone arm will unfortunately be dropped from the final HYVET trial, which will continue instead with Servier's combination of perindopril and indapamide. Analysis of the deaths in the pilot study shed no light on any particular cause of the nonsignificant excess in total mortality on active treatment (which of course may not be real).

Omapatrilat Cardiovascular Treatment Assessment vs Enalapril OCTAVE

John Kostis, MD (UMDNJ - Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA), gave the results of the OCTAVE trial, which tested the novel vasopeptidase inhibitor omapatrilat vs enalapril in 25,267 patients recruited from 3298 sites in 12 countries. [14] OCTAVE consisted of 3 separate arms: In 9292 previously untreated patients, randomization was between omapatrilat and enalapril. In 11,224 previously untreated, mildly hypertensive (stage 1) patients, omapatrilat or enalapril was substituted for former therapy; In 4751 stage 2 hypertensive patients, omapatrilat or enalapril was added on to previous therapy. The BP target was < 140/90 mm Hg, to be achieved by stepped increases of 10/5 to 20/10 to 40/20 to 80/40 mm Hg for omapatrilat/enalapril, respectively, by week 8, when add-on treatment was allowed. The results revealed that 8% more patients in the omapatrilat arm achieved target BP level, despite the use of more add-on drugs in the enalapril arm. The main interest of the presentation was the incidence of angioedema, which usually occurred early. This was significantly higher on omapatrilat than on enalapril (2.17% vs 0.68%). It was also higher in blacks (5.54 vs 1.62%) and smokers (3.93% vs 0.81%). About half the cases of angioedema needed no action except antihistamines and drug cessation. No patient died of this feared complication, and apart from angioedema, the side effects on omapatrilat were similar to those with enalapril. Thus, the conclusion of the OCTAVE trial suggests that we now may have a more effective drug, but with a serious, albeit low-incidence, complication.

References
1. Wing LMH, Reid CM, Bellin LJ, et al. Second Australian National Blood Pressure Study (ANBP2). Program of Hypertension Prague 2002 - Joint 19th Scientific Meeting of the International Society of Hypertension and 12th European Meeting on Hypertension, June 23-27, 2002, Prague, Czech Republic. Plenary session LCT1. 2. Morgan TO, Morgan O, Anderson AE. ACE inhibitors and AT1 receptor blocking drugs cause a greater pressure than other antihypertensive agents. Abstracts of Hypertension Prague 2002 - Joint 19th Scientific Meeting of the International Society of Hypertension and 12th European Meeting on Hypertension, June 23-27, 2002, Prague, Czech Republic. Abstract P0107.

3. Mancia G, Crepaldi G, Gallus G, et al, on behalf of the PHYLLIS investigators. Long-term statin administration and ambulatory blood pressure in the mild hypertensive and hypercholesterolemic patients of the PHYLLIS study. Regression of hypertensive left ventricular hypertrophy: Abstracts of Hypertension Prague 2002 - Joint 19th Scientific Meeting of the International Society of Hypertension and 12th European Meeting on Hypertension, June 23-27, 2002, Prague, Czech Republic. Abstract O013. 4. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002,360:7-22. Available at http://www.ctsu.ox.ac.uk/~hps/. Accessed July 15, 2002. 5. Zanchetti A, Crepaldi G, Bond G, on behalf of PHYLLIS Investigators. The Plaque Hypertension Lipid Lowering Italian Study (PHYLLIS). Principal results. Program of Hypertension Prague 2002 - Joint 19th Scientific Meeting of the International Society of Hypertension and 12th European Meeting on Hypertension, June 23-27, 2002, Prague, Czech Republic. Plenary session LCT3. 6. Dahlf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet. 2002;359:995-1003. 7. Devereux RB, Wachtell K, Gerdts E, et al. Regression of hypertensive left ventricular hypertrophy: Treatment effects and prognostic implications in the LIFE trial. Abstracts of Hypertension Prague 2002 - Joint 19th Scientific Meeting of the International Society of Hypertension and 12th European Meeting on Hypertension, June 23-27, 2002, Prague, Czech Republic. Abstract O014. 8. Agabiti Rosei E, Muiesan ML, Trimarco B, et al. Changes of LV mass and ABPM during long-term antihypertensive treatment in ELSA. Abstracts of Hypertension Prague 2002 Joint 19th Scientific Meeting of the International Society of Hypertension and 12th European Meeting on Hypertension, June 23-27, 2002, Prague, Czech Republic. Abstract O015. 9. White WB. Clinical profile of eplerenone - a novel selective aldosterone blocker for the treatment of hypertension. Abstracts of Hypertension Prague 2002 - Joint 19th Scientific Meeting of the International Society of Hypertension and 12th European Meeting on Hypertension, June 23-27, 2002, Prague, Czech Republic. Abstract O017. 10. Chiasson J-L, for the STOP-NIDDM Trial Research Group. Alpha-glucosidase inhibitor in the prevention of diabetes and cardiovascular disease: The STOP-NIDDM trial. Abstracts of Hypertension Prague 2002 - Joint 19th Scientific Meeting of the International Society of Hypertension and 12th European Meeting on Hypertension, June 23-27, 2002, Prague, Czech Republic. Abstract O018.. 11. Chiasson J-L, Josse RG, Gomia R, et al, for The STOP-NIDDM Trial Research Group. Acarbose for prevention of type 2 diabetes mellitus: The STOP-NIDDM randomised trial. Lancet. 2002;359:2072-2077. 12. Bulpitt CJ, Beckett NS, Cooke J, on behalf of the HYVET Investigators. Results of the pilot study for the Hypertension in the Very Elderly Trial (HYVET-PILOT). Abstracts of Hypertension Prague 2002 - Joint 19th Scientific Meeting of the International Society of Hypertension and 12th European Meeting on Hypertension, June 23-27, 2002, Prague, Czech Republic. Abstract O016. 13. Gueyffier F, Bulpitt C, Boissel J-P, et al, for the INDANA Group. Antihypertensive drugs in very old people: a subgroup meta-analysis of randomised controlled trials. Lancet. 1999;353:793-796. 14. Kostis JB. Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril (OCTAVE). Abstracts of Hypertension Prague 2002 - Joint 19th Scientific Meeting of the International Society of Hypertension and 12th European Meeting on Hypertension, June 23-27, 2002, Prague, Czech Republic. Abstract O018a