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Hypertension 2008

Berlin, Germany / June 14-19, 2008

Current guidelines recommend that hypertensive patients with diabetes mellitus should be treated to systolic blood pressure (SBP) of less than 130 mm Hg and diastolic blood pressure (DBP) less than 80 mm Hg. It has been suggested that rather than focusing on specific BP targets, increasing the use and effectiveness of BP-lowering treatment by using fixed-dose combinations of agents might be more effective in diabetic patients with potentially fewer side effects. Agents that block the renin-angiotensin system are particularly recommended as part of first-line treatment based on evidence that they reduce the risk of development of progression of diabetic nephropathy.

The ADVANCE Trial

The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) randomized trial was the largest-ever study of treatments for type 2 diabetes mellitus, involving 11,140 patients recruited worldwide. ADVANCE was designed to determine the effects on major vascular complications of routine BP-lowering treatment using a fixed-dose combination regimen consisting of the ACE inhibitor perindopril plus the thiazide-like diuretic indapamide. Following a factorial design, patients were also randomized to intensive treatment for glucose control (target hemoglobin A1c [HbA1c] <u><</u>6.5%) with the sulfonylurea, modified-release (MR) gliclazide. All patients recruited to ADVANCE had diabetes plus at least one additional risk factor for cardiovascular (CV) disease.

BP-lowering treatment in ADVANCE consisted of daily treatment with a fixed combination tablet containing perindopril 2 mg and indapamide 0.625 mg vs. matching placebo in addition to current therapy. Doses of perindopril/indapamide were doubled after three months. The main results of ADVANCE (ADVANCE Collaborative Group. Lancet 2007; 370:829-40) showed that after a mean follow-up of 4.3 years, patients on perindopril/indapamide had reductions of 14% in total mortality, 18% in CV death, 9% in major vascular events, 14% in total coronary events, and 21% in total renal events. Benefits appeared to be independent of initial BP (similar in hypertensive and normotensive patients) and were similar in all major subgroups, and additional to other protective therapies. Active treatment was associated with a 5.6/2.2 mm Hg greater reduction in BP. Reviewing these results, co-principal investigator Dr. Steven MacMahon, The George Institute for International Health, University of Sydney, Australia, indicated that based on the ADVANCE findings, patients with type 2 diabetes should be considered routinely for treatment with combination ACE inhibitor/diuretic therapy.

New Data on Renoprotection

New analyses of the renal outcomes in ADVANCE suggest that the renoprotection produced by perindopril/indapamide can preserve diabetic renal function, autonomy, and quality of life, while potentially reducing the need for dialysis and kidney transplants. Co-principal investigator Dr. John Chalmers, The George Institute for International Health, reported that the primary outcome for this analysis, all renal events, was reduced by 21% (P<0.0001) with perindopril/indapamide compared with placebo. This composite end point included new-onset microalbuminuria (urinary albumin: creatinine ratio [UACR] 30-300 µg/mg); new-onset nephropathy (UACR >300 µg/mg); doubling of serum creatinine >200 µmol/L (2.3 mg/dL) and a requirement for renal replacement therapy; or renal death. Active treatment also reduced progression of albuminuria by 22% (P<0.0001) and increased regression of albuminuria by 16% (P=0.002).

The benefits of active treatment were consistent across subgroups defined by baseline SBP (from <120 to <u>></u>160 mm Hg) or DBP (from <70 to <u>></u>90 mm Hg). A continuous association was seen between renal events and achieved SBP, with a 6.8% relative risk (RR) reduction per 10 mm Hg reduction in SBP (P<0.0001) (Figure 1). This association was seen down to SBP 106 mm Hg, beyond the BP levels recommended in current guidelines, Dr. Chalmers observed.

Figure 1. ADVANCE: Renal Events by Systolic BP Achieved During Follow-Up*

Commenting on the new data, senior investigator Dr. Mark E. Cooper, Baker Memorial Research Institute, Melbourne, Australia, told delegates that ADVANCE showed that fixed-dose perindopril/indapamide can achieve the same reduction in albuminuria seen in many other antihypertensive combination studies. The reduction in albuminuria seen in ADVANCE could potentially translate to CV benefits and overall benefits on mortality, he added, but that four- to five-year studies in this setting might not be long enough to see the ultimate benefits of preventing microalbuminuria and reducing renal disease.

Glucose Control

In the ADVANCE intensive blood glucose control study, intensive glucose control was achieved with gliclazide MR plus any additional therapy to achieve target HbA1c, which was compared with standard control therapy consisting of any other sulfonylurea plus additional therapy, according to standard local guidelines. The results of the ADVANCE intensive blood glucose control study were recently presented at the annual meeting of the American Diabetes Association (ADA) and published simultaneously (The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-72). After a median follow-up of five years, the intensive-control group achieved a mean HbA1c of 6.5% compared with 7.3% in the standard control group. Intensive glucose-lowering was safe and effective, Dr. Chalmers reported, and it produced significant reductions in microvascular complications of diabetes, mainly kidney disease (21% reduction in new or worsening nephropathy vs. standard control). This is a major benefit, Dr. Chalmers emphasized, since 20% of diabetic patients die of kidney disease. There was no significant benefit in macrovascular disease, however, which Dr. Chalmers noted was consistent with the findings of Action to Control Cardiovascular Risk in Diabetes (ACCORD) (The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-59) and the Veterans Affairs Diabetes Trial (VADT), both also reported at ADA 2008. Unlike ACCORD, however, there was no excess mortality associated with intensive glucose lowering in ADVANCE, nor any weight gain or excess of serious sequelae from hypoglycemia.

Asked whether there might be synergy between the BP and glucose-lowering treatments in ADVANCE, Dr. Chalmers revealed that early analysis for the primary outcome has shown that there is no interaction. “This does not imply synergy, nor does it imply a negative interaction,” he stated. He confirmed that the ADVANCE investigators expect to see a greater effect in patients who had both treatments (about 25% of the study population). The results of this analysis will be presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in Rome in September 2008.

New HYVET Data

The benefit of antihypertensive treatment of patients aged ³80 years of age has been unclear and this group is seldom mentioned in current hypertension guidelines. Before the Hypertension in the Very Elderly Trial (HYVET), there was a lack of clinical trial evidence in elderly people with regard to the safety and efficacy of BP lowering with medication. As a result, this population was consistently untreated or undertreated and has remained at very high risk of stroke and CV disease, remarked lead investigator Dr. Christopher J. Bulpitt, Imperial College London, UK. Epidemiological evidence suggested that patients in this age group taking antihypertensive medication might be at higher risk of mortality and a meta-analysis of <u>></u>80 year-olds who participated in trials suggested that the potential benefit of antihypertensive treatment in reducing strokes might be offset by an increase in all-cause mortality (Gueyffier et al. Lancet 1999;353:793-6). However, the main results of HYVET, presented at the 2008 annual meeting of the American College of Cardiology and published simultaneously (Beckett et al. N Engl J Med 2008;358:1887-98), showed that lowering BP in elderly patients with indapamide sustained-release (SR) with or without perindopril was safe. It reduced total mortality by one-fifth and the rate of CV events by one-third.

The trial, which was sponsored by Imperial College London and supported by the British Heart Foundation, involved 3845 patients with SBP 160 to 199 mm Hg and DBP <110 mm Hg enrolled in Europe, China, Australasia, and Tunisia. Patients were otherwise generally healthy, living independently and not taking any other antihypertensive medications, although 65% had been taking BP-lowering agents up to two months prior to the start of the study. Target pressure was <150/80 mm Hg. HYVET was stopped early on the recommendation of the independent trial data-monitoring and ethics committee after a planned interim analysis showed a significant reduction in the primary end point, fatal and nonfatal strokes, as well as in total mortality.

Mean follow-up in HYVET was 1.8 years and at two years, mean BP was 15/6 mm Hg lower in the active treatment group than in the placebo group. Benefits of treatment were apparent within the first year, indicated Dr. Bulpitt. He noted that by intention-to-treat analysis, active treatment was associated with a 21% reduction in total mortality (P=0.019) and a 30% reduction in all strokes (P=0.055). In a per protocol analysis, however, reductions in both total mortality and stroke were significant at 34% (P=0.03) and 28% (P=0.001), respectively. Heart failure was also reduced by 72% (P<0.001) and CV events by 37% (P<0.001). In the patients followed for two or more years, there were no significant differences between the two groups in changes in potassium, uric acid, glucose, or creatinine. Although serious adverse events are very common in the elderly, Dr. Bulpitt noted, fewer were reported in the active-treatment group (358 vs. 448 in the placebo group; P=0.001) and among these, only five, including three in the placebo group, were considered to have been related to the study drug.

Analysis of the main results in predefined subgroups, as presented by Dr. Nigel S. Beckett, Imperial College London, showed that statistically significant benefits or positive trends associated with BP reductions were seen in both men and women and in patients with and without previous CV disease, indicating that active treatment was effective as secondary prevention in these patients (Table 1). There were also no differences between groups defined by age (80 to 84.9 years vs. <u>></u>85 years) or initial SBP (160 to <u>></u>180 mm Hg).

Table 1. HYVET: Analysis of Total Mortality
edefined Subgroups

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Another substudy, HYVET-COG, presented by Dr. Ruth Peters, Imperial College London, investigated the incidence of dementia (vascular dementia and Alzheimer’s disease) and cognitive decline in 3336 HYVET patients (mean age 83.5 years), 1687 in the active treatment group and 1649 in the placebo group. Although there was no significant effect seen with antihypertensive treatment, Dr. Peters reported that the modest reduction seen in incident dementia cases with BP lowering was of clinical significance. Cognitive function was assessed at baseline and annually using the Mini-Mental State Exam (MMSE), which can be used in all countries because it is not language-specific, but it is not usually the most accurate way to diagnose dementia, she commented. A total of 263 cases of dementia were diagnosed. The hazard ratio (HR) for active treatment after adjustment for education, age, and geographic region was 0.85 (95% CI, 0.67-1.09; P=0.19). Neither strokes nor antihypertensive treatment during or prior to the trial had any impact on the results. Dr. Peters suggested that longer follow-up might be required to demonstrate a statistically significant impact on dementia.

A meta-analysis was conducted by adding the HYVET-COG results to those of three earlier placebo-controlled trials of antihypertensive agents that assessed incident dementia: the Systolic Hypertension in Europe (Syst-Eur), Systolic Hypertension in the Elderly Program (SHEP), and Protection Against Recurrent Stroke Study (PROGRESS) trials. Findings indicated a significant reduction of 13% in relative risk of incident dementia (RR 0.87 [95% CI, 0.76-1.00; P=0.045]).

Updating the Guidelines

Guidelines have already taken note of the ADVANCE results. The BP-lowering data have strengthened the recommendations of the Canadian Hypertension Education Program (CHEP) for managing BP in patients with diabetes and focused attention on the potential role of fixed-dose combination therapy as a first-line option. The HYVET data have yet to be incorporated into national recommendations. Commenting on HYVET, Dr. Bryan Williams, University of Leicester School of Medicine, UK, declared that he has no doubt that these “landmark” results will change clinical practice worldwide with regard to the treatment of hypertension in older patients. “The very elderly represent the fastest growing segment of the population and they are almost all hypertensive. These patients have isolated systolic hypertension and we needed reassurance that treatment of SBP and further lowering of DBP would be safe and well tolerated,” he told delegates. Describing the HYVET findings as “unequivocal,” he added, “We can now further improve the clinical outcomes of this important population with a simple intervention.” He concluded, “HYVET removes uncertainty about the benefits of treating BP in the very elderly and will clarify and change international treatment guidelines.”