Major findings from ADVANCE:
blood pressure-lowering arm



by N. R. Poulter, United Kingdom


Neil R. POULTER, MBBS,
MSc, FRCP
International Centre for
Circulatory Health (ICCH)
Imperial College London
UNITED KINGDOM

Background: Although guidelines throughout the world recommend lower blood pressure (BP) treatment thresholds and lower BP targets for patients with type 2 diabetes, the evidence base for so-doing is limited.
Methods: As part of a 2_2 factorial design, the Action in Diabetes and Vascular disease: PreterAx and DiamicroN Controlled Evaluation (ADVANCE) trial randomized 11 140 patients with type 2 diabetes, and at least 1 other prespecified determinant of cardiovascular (CV) risk, to receive perindopril (4 mg)/indapamide (1.25 mg) or placebo, irrespective of whether other antihypertensive medication was being used and irrespective of BP level.
Results: During an average follow-up of 4.3 years, BP was lowered, on average, by 5.6/2.2 mm Hg among those on perindopril/indapamide compared with placebo, to a level of 135/75 mm Hg. This BP reduction was associated with a significant 9% reduction (95% confidence interval [CI], 0.83-1.00; P=0.04) in the primary end point (major macrovascular or microvascular events), an 18% (0.68-0.98) reduction in CV mortality and a 14% (0.75-0.98) reduction in all-cause mortality. New or worsening nephropathy was reduced by 18% (0.68-1.01), but no effects were apparent on retinopathy. CV benefits were apparent across all subgroups, and occurred irrespective of baseline BP and/or background use of angiotensin-converting enzyme inhibition.
Conclusion: Patients with type 2 diabetes should be routinely considered for the addition of the type of treatment used in the ADVANCE trial, irrespective of their baseline BP levels.

Medicographia. 2009;31:223-231 (see French abstract on page 231)

Background and rationale

Intervention on major cardiovascular (CV) risk factors has traditionally been based on the absolute levels of the risk factors in question (eg, fasting plasma glucose >7 mmol/L or systolic blood pressure >140 mm Hg). More recently, the concept of intervention being based on, or at least influenced by, an estimate of total CV risk has been introduced into guidelines.1,2

Prior to the conduct and publication of the Action in Diabetes and Vascular disease: PreterAx and DiamicroN Controlled Evaluation (ADVANCE) trial,3 two things relating to blood pressure (BP) among people with diabetes were clear. Firstly, there was a strong dose-response relationship between BP and risk of both macrovascular and microvascular events across the whole range of BP, irrespective of “hypertensive” status.4,5 Secondly, findings were consistent from randomized trial data (albeit rel- atively limited in size) that greater BP lowering was superior to lesser BP lowering in terms of preventing major CV events.6 Interestingly, whilst guidelines among the world vary on several key issues relating to optimal BP management, all guidelines are consistent in suggesting a lower BP target (<130/80 mm Hg) for patients with type 2 diabetes.1,2 Paradoxically, there are no good data, based on morbidity and mortality trials, to support these specifically lower BP levels recommended for diabetic patients and accepted throughout the world!

Figure 1
Figure 1. Trial design for the blood pressure–lowering arm of ADVANCE. The original power calculations were based on a total of 10 000 participants with type 2 diabetes, with an annual event rate of 3% and requiring an average follow-up of 4.5 years. All participants entered a preliminary 6-week open run-in phase, during which they received one tablet daily of perindopril 2 mg – indapamide 0.625 mg (Preterax).
Abbreviation: ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN Controlled Evaluation.

Modified from reference 12: ADVANCE Collaborative Group. Lancet. 2007;370:829-840. Copyright © 2007, Elsevier, Ltd.

Prior to the ADVANCE trial, data on BP lowering in diabetes were available from the results of the United Kingdom Prospective Diabetes Study (UKPDS),7 the Hypertension Optimal Treatment (HOT) trial,8 and the MIcroalbuminuria, Cardiovascular, and Renal Outcomes in the Heart Outcomes Prevention Evaluation (MICRO-HOPE) trial.9

UKPDS included a small BP-lowering limb comparing more versus less intensive BP lowering, but only among frankly hypertensive patients with diabetes. This trial also included a comparison of two different BP-lowering regimens, but it was underpowered and totally inadequate, and offered no useful information in this regard. In the small subgroup of diabetic hypertensive patients in HOT, a comparison of more versus less BP lowering (achieved with a regimen based on the dihydropyridine calcium channel blocker felodipine) showed a significant reduction in major CV events, despite only modest differential BP reduction. MICRO-HOPE compared the angiotensin- converting enzyme (ACE) inhibitor ramipril with placebo in a subgroup of about 3300 high-risk patients with type 2 diabetes.

ADVANCE extended these data in a larger database by adding additional BP-lowering therapy (with a single-pill combination of perindopril and indapamide) to whatever preventive therapies were being taken (including ACE inhibition). Other studies have shown that drugs which block the reninangiotensin system (RAS)—ACE inhibitors and angiotensin receptor blockers—appear to have beneficial effects on the development and progression of renal disease in patients with diabetes, and that these effects may be superior to those achieved by other BP-lowering agents for a similar level of BP reduction.10 These results, based on renal end points, are the major reason for the recommendation that a RAS-blocker should probably form part of whatever antihypertensive “cocktail” is provided for patients with diabetes.11

The ADVANCE trial set out to add to the currently available data by evaluating whether the addition of further BP lowering with perindopril and indapamide would reduce the risk of major macrovascular and microvascular disease in patients with type 2 diabetes, irrespective of their baseline BP or whether they were already taking background ACE inhibitor treatment or not.

Design

Details of the design of the ADVANCE trial have been published previously.3,12 However, in summary, ADVANCE had a 2_2 factorial design comparing additional active BP lowering versus placebo and comparing intensive versus standard glucose control (Figure 1).3

Patients with type 2 diabetes were eligible to join the trial if they were aged _55 years and had one or more of the following additional criteria for increased vascular risk—age _65 years, history of major macrovascular disease, history of major microvascular disease, diabetes diagnosed >10 years ago, or any other major risk factor (eg, current smoker, total cholesterol > 6.0 mmol/L, high-density lipoprotein [HDL] cholesterol <1.0 mmol/L). Following registration with the trial, potentially eligible participants underwent a 6-week runin treatment period with a single daily pill combination of perindopril 2 mg and indapamide 0.625 mg, which was added to whatever previous therapy was being taken. Patients with a compelling indication for an ACE inhibitor other than perindopril or for a thiazide/thiazide-like diuretic were ineligible. During the run-in period, these diuretics were withdrawn and ACE inhibitors other than perindopril were replaced by perindopril (up to 4 mg daily).

After the run-in period, those who had tolerated and adhered to trial therapy were randomized double-blind to receive either placebo or a single pill combination of perindopril 2 mg/indapamide 0.625 mg daily for 3 months, after which active therapy was doubled to perindopril 4mg/indapamide 1.25 mg daily. If, during the trial, a compelling indication to use a different ACE inhibitor and/or a thiazide/thiazide-like diuretic was found, open-label therapy was substituted for study treatment. Patients were seen at 3, 4, and 6 months after randomization and 6-monthly thereafter.

At each study visit, BP was recorded using standardized conditions and recording devices,3 and details of all/any end points were recorded. The primary outcome was major macrovascular disease (nonfatal stroke, nonfatal myocardial infarction [MI], or CV death) and/or major microvascular disease (new or worsening nephropathy or diabetic eye disease). Secondary outcomes included all those expected in a major trial of CV outcomes in diabetic patients.3 At 2 and 4 years of follow-up, a quality of life assessment, a mini mental state examination, and a retinal examination were made, and a urinary albumin-creatinine ratio was measured.

The trial was originally designed to detect a _16% greater reduction in macrovascular and in microvascular events, with 90% power at the “5% level,” between the active BP lowering and placebo groups. However, due to lower than expected event rates after approximately half the expected follow- up period had elapsed, it was agreed to extend the BP-lowering arm by an extra year and to evaluate macrovascular and microvascular events both jointly and separately.

Results

Of the 12 877 men and women from Europe, Canada, Asia, the Indian Subcontinent, and Australasia registered for the trial, 11 140 were randomized into the main trial. Baseline characteristics of those randomized are shown in Table I.

Table I
Table I. Baseline characteristics of randomized patients in ADVANCE.
Modified from reference 12: ADVANCE Collaborative Group. Lancet. 2007;370:829-840. Copyright © 2007, Elsevier, Ltd.

BP was lowered, on average, by 5.6/2.2 mm Hg with perindopril/ indapamide, compared with placebo. The combined primary outcome was significantly reduced by 9% (95% confidence interval [CI], 0% to 17%) in favor of active BP lowering (Figure 2).12 Major macrovascular and microvascular events were nonsignificantly reduced by 8% (-4% to 19%) and 9% (–4% to 20%), respectively. The biggest single contributor to the beneficial effect of perindopril/indapamide on the primary outcome was a significant 18% (2% to 32%) reduction in cardiovascular death, which when allied to an absence of adverse effect on noncardiovascular death generated a 14% (2% to 25%) significant reduction in all-cause mortality.

Figure 2
Figure 2. Results on the combined primary outcome in ADVANCE (major macro- or microvascular events) for perindopril/indapamide versus placebo.
Modified from reference 12: ADVANCE Collaborative Group. Lancet. 2007;370:829-840. Copyright © 2007, Elsevier, Ltd.

Interestingly, nonfatal stroke and MI were unaffected by additional BP lowering as was new or worsening eye disease, whilst new or worsening nephropathy showed an 18% (–1% to 32%) reduction. A summary of the outcomes is shown in Figure 312 and the use of concomitant medications at baseline and by the end of follow-up are shown in Table II. When subgroups of patients were considered in relationship to the primary composite outcome (Figure 4, page 228)12 or the development of microalbuminuria (Figure 5, page 229), no sign of heterogeneity was apparent.

Two critical findings among these subgroup analyses were that the benefits of perindopril/indapamide were equally large whether patients were receiving background ACE in- hibition or not, and that the benefits of BP lowering were equally large whether “hypertensive” or not and regardless of whether initial systolic BP was above or below 140 mm Hg. Indeed, the impact of baseline BP level, considered as a continuous variable, on the beneficial effects of perindopril/indapamide, was further and more robustly evaluated, and no sign of any interaction was apparent. That is to say, that right across the BP range, additional BP lowering generated similar relative benefits.

Figure 3
Figure 3. Efficacy of perindopril/indapamide versus placebo on primary and secondary end points in ADVANCE.
Modified from reference 12: ADVANCE Collaborative Group. Lancet. 2007;370:829-840. Copyright © 2007, Elsevier, Ltd.

Table II
Table II. Drug treatment being received by patients at registration visit* and end of follow-up in ADVANCE.
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BP, blood pressure; MR, modified release.
Modified from reference 12: ADVANCE Collaborative Group. Lancet. 2007;370:829-840. Copyright © 2007, Elsevier, Ltd.

ADVANCE in the context of previous trials

Table III shows that ADVANCE was larger than all previous relevant trials. In addition, by virtue of the inclusion criteria and, to a larger extent, the greater use of in-trial concomitant medications, the CV event rates experienced were much lower in ADVANCE than in UKPDS and MICROHOPE. This reflects the fact that current management of high-risk diabetic patients currently usually involves the use of ACE inhibition, statins, and aspirin—a situation which did not prevail at the time UKPDS or MICRO-HOPE were conducted. Importantly, the BP level achieved (136/73 mm Hg) is the lowest level achieved in any of the relevant trials— though some way short of the target level of <130/80 mm Hg recommended in all the world’s guidelines! While a “the lower, the better” approach for BP in patients with diabetes seems appropriate, it must be acknowledged that current recommendations are not truly evidence-based.

Table III
Table III. ADVANCE in context: comparative patient profiles for UKPDS, MICRO-HOPE, and ADVANCE.
Abbreviations: ACE, angiotensin-converting enzyme; BP, blood pressure; CV, cardiovascular; MICRO-HOPE, MIcroalbuminuria, Cardiovascular, and Renal Outcomes in the Heart Outcomes Prevention Evaluation; UKPDS, United Kingdom Prospective Diabetes Study.
Based on data from references 3, 7, 9, and 12.

Figure 4
Figure 4. Subgroup efficacy analysis on the primary composite end point in ADVANCE.
Modified from reference 12: ADVANCE Collaborative Group. Lancet. 2007;370:829-840. Copyright © 2007, Elsevier, Ltd.

Figure 5
Figure 5. Subgroup analysis of microalbuminuria events by age, sex, blood pressure, and HbA1c in ADVANCE.
Modified from reference 12: ADVANCE Collaborative Group. Lancet. 2007;370:829-840. Copyright © 2007, Elsevier, Ltd.

If the results of the effect of BP lowering on the individual macrovascular components evaluated in ADVANCE are compared with those predicted by the Blood Pressure Lowering Treatment Trialists’ Collaboration,13 some effects (eg, on stroke) are apparently rather smaller than what might be expected whilst others (CV mortality and total mortality), are larger than expected. Nevertheless, the observed effect sizes are all essentially compatible with those predicted. The small effect on fatal and nonfatal stokes (2% [–17% to 20%]) is, at first sight, surprising. It may be that the significantly greater in-trial use of calcium channel blockers (CCBs) in the placebo group—which was 10% higher—may have contributed to the relatively greater stroke protection in this group, which is in keeping with previous analyses that suggest CCBs may provide stroke protection beyond that expected by BP reduction alone.14 However, it should be remembered that in the Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS)15 and Poststroke Antihypertensive Treatment Study (PATS)16 trials, perindopril/indapamide and indapamide, respectively, have been shown to prevent stroke significantly, and hence chance along with differential CCB use may have contributed to the apparently small effect size in ADVANCE.

The lack of impact on the hard end points relating to new or worsening nephropathy (development of proliferative retinopathy, macular edema, retinal photocoagulation therapy, or diabetes-related blindness) is in sharp contrast to the results of UKPDS,7 in which large benefits of BP lowering were apparent (mainly regarding retinal photocoagulation). These disparities may reflect differences in terms of duration of the diabetes diagnosis (new-onset in UKPDS) or, more likely, the much lower BP levels at play in the 2 trials, and the much greater use of other CV protective agents in ADVANCE (Table III)

Implications of the ADVANCE results

The number needed to treat (NNT) for 5 years associated with the use of perindopril/indapamide in the context of the ADVANCE population was 66 to prevent 1 major macro- or microvascular event and 79 to prevent 1 death. Allied with the fact that the active BP-lowering therapy was tolerated as well as the placebo (adherence rates were 73% and 74%, respectively), a blanket policy to apply additional BP lowering to all patients with type 2 diabetes, irrespective of their BP level, seems reasonable. Two critical caveats need to be considered first, however.

Firstly, is it affordable? Cost-benefit analyses are in the process of being published, but given the massive health burden associated with the CV sequelae of type 2 diabetes, it is likely that the approach practiced in ADVANCE is costeffective.

Secondly, were the beneficial effects observed due to BP lowering alone, to the use of an ACE inhibitor plus a diuretic, or to the specific combination used? Prior prejudice determines the answers given by individuals to this question, and there is no definitive “true” answer. However, evidence is mounting that not all hypertensive agents are equal in terms of associated outcomes for any level of BP reduction,14,17 and, pending evidence to the contrary, we should try to stick with the evidence base arising from relevant trials.

Clinicians and research workers are variably influenced by the effect of interventions on various surrogate renal end points, such as microalbuminuria. However, most diabetologists and renal physicians will be suitably impressed by the large benefits of perindopril/indapamide on microalbuminuria observed in ADVANCE. Various measures of proteinuria are undoubtedly associated with CV events (as was the case in ADVANCE), presumably reflecting generalized endothelial dysfunction and increased cardiovascular risk. The greater effect on these end points observed in ADVANCE compared with the size of effect on individual macrovascular events (except CV mortality) may well reflect a time lag which prevents the realization of CV benefits in the relatively short follow-up period of less than 5 years.

Conclusions

The BP-lowering arm of the ADVANCE trial provides the best evidence to date that modest BP lowering is beneficial in terms of reducing the risk of critical CV events and renal end points in a broad range of patients with established type 2 diabetes, irrespective of their baseline BP levels. The significant 9% reduction in major vascular events and 18% reduction in CV mortality, plus an 18% reduction in new or worsening nephropathy and a 14% reduction in coronary events, were apparent in all major subgroups of patients, whether already taking ACE inhibitors or not, and irrespective of being hypertensive or not. Critically, for a potentially generalizable recommendation, the agents used to lower BP in ADVANCE were very well tolerated and NNTs to prevent major CV events or deaths were modest.

It therefore seems reasonable to conclude that all patients with type 2 diabetes should be considered for treatment with the type of intervention used in ADVANCE, ie, the combination of perindopril and indapamide, in addition to whatever other agents are already being taken and irrespective of the patient’s BP level.

Neil Poulter was the North European Regional Principal Investigator of the ADVANCE trial.

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