ADVANCE TRIAL SUPPORTS CURRENT RECOMMENDATIONS FOR BLOOD PRESSURE GOALS AND NOT THE USE OF ANY SPECIFIC COMBINATION OF ANTIHYPERTENSIVE AGENTS IN PATIENTS WITH TYPE 2 DIABETES
The Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends a blood pressure (BP) goal of <140/90 mm Hg in all patients with hypertension except those with adult‐onset diabetes mellitus (DM) or chronic kidney disease (CKD), for whom the recommended BP target is <130/80 mm Hg. The same recommendations in patients with DM have been made by the American Diabetes Association (ADA) and the American Heart Association (AHA). These recommendations are largely based on epidemiologic data and consensus opinion because, particularly among patients with DM, there are few trials that have randomized patients to specific BP targets. Debate also continues over the relative merits of various antihypertensive agents in persons with DM. Unless the patient with DM has underlying CKD, coronary heart disease (CHD), or heart failure (HF), JNC 7 recommends any 1 of 5 antihypertensive drug classes as initial therapy. The recent Action in Diabetes and Vascular Disease Preterax and Diamicron‐MR Controlled Evaluation (ADVANCE) trial attempted to determine whether there was a substantial benefit to using a combination of an angiotensin‐converting enzyme (ACE) inhibitor and a diuretic in patients with DM.
The ADVANCE trial was an industry‐sponsored trial conducted in conjunction with the National Health and Medical Research Council of Australia. This international multicenter trial was conducted at 215 centers in 20 countries throughout Asia, Australia, Europe, and North America. Patients were eligible if they had been diagnosed with DM no sooner than 30 years of age and were 55 years or older on entry into the study (mean age when diabetes was first diagnosed, 58 years). In addition, they had to have 1 or more of the following cardiovascular (CV) risk factors: a history of major CV disease (stroke [9%], myocardial infarction [MI] [12%], hospital admission for transient ischemic attack or unstable angina, coronary or peripheral revascularization, or amputation secondary to vascular disease) or at least 1 of the following: a history of major microvascular disease (microalbuminuria or macroalbuminuria, proliferative diabetic retinopathy, retinal photocoagulation therapy, macular edema, or blindness in 1 eye thought to be caused by diabetes), current cigarette smoking (15%), hypercholesterolemia, age 65 years or older on entry, or a diagnosis of DM at least 10 years before entry. The mean age of participants was 66 years (43% female), and approximately one‐third of those enrolled had a history of underlying CV disease. A second arm of the study, which is ongoing and will be stopped in mid‐March 2008, is assessing whether an intensive glucose‐lowering strategy will more favorably improve outcome compared with a standard glucose‐lowering strategy.
In the ADVANCE trial, a 6‐week run‐in period occurred in which 13.5% of eligible patients withdrew from the study. The remaining patients (n=11,140) took a fixed‐dose single combination antihypertensive tablet not approved in the United States that contained the ACE inhibitor perindopril, 2 mg (or 4 mg if previously on an ACE inhibitor at the investigator's discretion), and the indolene‐type diuretic indapamide, 0.65 mg. Patients who adhered to and tolerated the study drugs over the run‐in period were randomly assigned in a double‐blind fashion to combined perindopril (2 mg) and indapamide (0.625 mg) (n=5569) or matching placebo (n=5571). After 3 months, the doses of randomized therapy were doubled to 4 mg of perindopril and 1.25 mg of indapamide or matching placebo. The use of concomitant treatments during follow‐up, including background antihypertensive therapies, remained at the discretion of the treating physician, with 2 exceptions: the use of thiazide‐type diuretic therapy was not allowed, and open‐label perindopril (to a maximum of 4 mg/d) was the only ACE inhibitor allowed, ensuring that the maximum recommended dose of perindopril (8 mg) could not be exceeded by patients on active treatment. On entry, approximately 75% of patients enrolled in the study were being treated with antihypertensive drugs. In addition, 29% of the patients were taking statin therapy and 5% were taking antiplatelet therapy.
Participants were seen 3, 4, and 6 months after randomization, and subsequently every 6 months. At each visit, BP was recorded as the mean of 2 measurements made after the patient rested for at least 5 minutes in the seated position. In addition to BP values, blood glucose, glycated hemoglobin, and lipid levels and the occurrence of study outcomes were obtained. At the 2‐ and 4‐year follow‐up visits, a urinary albumin‐creatinine ratio, a formal retinal examination, a mini‐mental state examination, and a quality‐of‐life assessment were performed.
The primary end point was a composite of major macrovascular events including CV death, nonfatal MI or nonfatal stroke, and several types of microvascular events including new or worsening nephropathy (development of microalbuminuria, doubling of serum creatinine to a level of at least 200 µmol/L, need for kidney transplant, or death due to renal disease) or retinopathy (development of proliferative retinopathy, macular edema, diabetes‐related blindness, or retinal photocoagulation therapy). The secondary outcomes included all‐cause mortality, CV death, major coronary events (death due to CHD [including sudden death] and nonfatal MI), total coronary events (major coronary events, silent MI, coronary revascularization, or hospital admission for unstable angina), major cerebrovascular events (death due to cerebrovascular disease or nonfatal stroke), and total cerebrovascular events (major cerebrovascular events, transient ischemic attack, or subarachnoid hemorrhage). Other secondary outcomes were HF (death or hospitalization due to HF, or worsening HF), peripheral vascular disease, new or worsening nephropathy, new or worsening retinopathy, development of microalbuminuria, visual deterioration, new or worsening neuropathy, cognitive function, dementia, and hospitalizations.
The mean BP for all patients on study entry was 145/81 mm Hg. At the conclusion of the study, all patients in both groups were taking a mean of 1 or 2 antihypertensive drugs in addition to their randomized study medications. Adherence to antihypertensive therapy was similar: 73% vs 74%, study regimen and medications other than study drugs, respectively. Use of other therapies associated with improved CV outcomes including lipid‐lowering therapy, antiplatelet medication, and glucose‐lowering treatments (including insulin) were similar between the 2 groups. At the end of follow‐up, mean levels of glycated hemoglobin, fasting glucose, total cholesterol, and high‐density lipoprotein cholesterol were also similar between the randomized groups.
During a mean follow‐up of 4.3 years, the mean BP was 135/75 mm Hg in the active treatment arm and 140/77 mm Hg in the nonstudy arm (difference in BP, 5.6 mm Hg systolic/2.2 mm Hg diastolic). There was a significant reduction in the primary composite outcome of 9% (861 events in 15.5% of the actively treated patients and 938 events in 16.8% of the placebo group; hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.83–1.00; P=.04), an absolute difference of 1.3%. While not significant, a trend toward reductions in both macrovascular and microvascular events was noted (macrovascular HR, 0.92; 95% CI, 0.81–1.04; P=.16; microvascular HR, 0.91; 95% CI, 0.80–1.04; P=.16). The relative risk of death from CV disease was reduced by 18% (211 events in 3.8% of actively treated patients and 257 events in 4.6% of the placebo group; HR, 0.82; 95% CI, 0.68–0.98; P=.03), an absolute difference of 0.8%. Deaths from any cause were reduced by 14% (408 events in 7.3% of actively treated patients and 471 events in 8.5% of the placebo group; HR, 0.85; 95% CI, 0.75–0.98; P=.03), an absolute difference of 1.2%. In addition, significant reductions were seen in several secondary end points with active treatment including total coronary events (14%) and total renal events (21%).
The authors conclude that routine administration of a fixed combination of the ACE inhibitor perindopril and the diuretic indapamide to a broad range of patients with adult‐onset DM reduces the risks of major macrovascular and microvascular events, including death, irrespective of initial BP level or ancillary treatment. The study treatment was well tolerated and needed little monitoring or titration.—Patel A, MacMahon S, Chalmers J, et al, for the ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomized controlled trial. Lancet. 2007;370:829–840.
COMMENT
DM and its vascular complications are a global health concern. In patients with DM and hypertension, all the major classes of antihypertensive drugs appear to reduce the risk of stroke and CV disease, an effect often attributed to their overall benefit on BP reduction. In patients with DM who do not have concomitant CKD, CHD, or HF, specific antihypertensive medications have not received a unique endorsement from JNC 7, ADA, or AHA. Even in high‐risk patients, like the one‐third of all DM patients in the Heart Outcomes Prevention Evaluation (HOPE) study, the benefits of adding the ACE inhibitor ramipril compared with therapy that did not include the ACE inhibitor continues to be debated because of the additional BP reduction that occurred in the ramipril arm of the HOPE study, an effect that was most apparent in a small 24‐hour ambulatory BP‐monitoring substudy.
The present ADVANCE study found that the routine administration of a combination of the ACE inhibitor perindopril and the diuretic indapamide in addition to other medications in high‐risk DM patients reduces the risk of death and major macrovascular or microvascular complications. While the authors of the study suggest that a case can now be made for routinely considering such treatment in patients with DM, a more pressing question arises. Is it the specific combination of agents used in the study or the additional BP reduction achieved that is more likely responsible for the benefits seen?
Adequate BP control is essential in reducing the risk of CV events in diabetics. In the diabetic cohort of the Hypertension Optimal Treatment (HOT) study, for example, the lower the achieved diastolic BP (81 mm Hg vs 85 mm Hg), the greater the reductions in the risk of CV morbidity and mortality. In the United Kingdom Prospective Diabetes Study 38, significant reductions in the risks of any diabetes‐related end point, stroke, and microvascular disease were observed over the 9 years of the study in diabetic patients who achieved lower BP levels (mean BP of 144/82 mm Hg) compared with those who did not (mean BP of 154/87 mm Hg). Differing regimens of medication did not make a difference. Multiple past clinical trials have found that specific antihypertensive agents do not improve outcomes compared with other antihypertensive agents unless BP is at least as favorably reduced. The present ADVANCE trial, with a more favorable 5/2‐mm Hg BP reduction achieved in the ACE inhibitor/diuretic arm suggests it is the BP reduction rather than the specific antihypertensive agents used that led to the improvement in outcome. These results are similar to those seen in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), where more aggressive BP reduction in patients with a previous stroke or transient ischemic attack not only resulted in fewer recurrent cerebrovascular events but also fewer ischemic heart disease events. In PROGRESS, patients were randomized to the ACE inhibitor perindopril (with or without the diuretic indapamide) or to placebo, a similar randomization to that used in the ADVANCE trial. The final achieved BP in the perindopril plus indapamide group was similar to that seen in the ADVANCE study, around 135/80 mm Hg (a reduction in BP of 12/5 mm Hg from baseline). This more favorable BP lowering resulted in a 43% reduction in recurrent stroke (primary end point), a 40% reduction in major vascular events, and a 42% reduction in nonfatal MI. Of interest is that the ACE inhibitor‐alone regimen did not reduce events; these were only reduced in the ACE inhibitor‐diuretic groups.
The HOPE, PROGRESS, and ADVANCE trials are each limited by the use of a placebo control, which included other antihypertensive drugs rather than a specific active comparator group; this allowed a more favorable BP reduction in the active ACE inhibitor group. Given what we know about the importance of aggressive BP control, future studies that attempt to evaluate the merits of specific combinations of antihypertensive agents should use active treatment that would be expected to achieve similar reductions in BP, rather than placebo control. This is the approach that has been taken in the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial, which randomized patients to initial therapy with either a combination of an ACE inhibitor and a diuretic or an ACE inhibitor and calcium channel blocker. It is only by using an actively treated comparator and achieving similar BP that we can evaluate the relative merits of different antihypertensive combinations.
Other concerns with the ADVANCE trial include the 6‐week tolerability run‐in period in which only 1.8% of eligible patients dropped out of the study because of cough. This is a much lower rate than would normally be encountered in clinical practice and allowed the majority of the 43% of participants who were already taking an ACE inhibitor at run‐in to be randomized to perindopril. In addition, with more than one‐half of the patients assigned to placebo plus other drugs who were actually taking the active ACE inhibitor perindopril at the conclusion of the study, it is difficult to believe that a specific antihypertensive regimen used accounted for most of the outcome benefit. Rather than touting the merits of a specific antihypertensive regimen, the ADVANCE trial suggests that BP reduction appears to be the most important factor contributing to the improved vascular outcomes seen. The data from the ADVANCE trial suggest that in patients with DM, the BP goal should be <135/75 mm Hg. Whether further reductions in BP or the use of specific antihypertensive agents would have led to even greater reductions in vascular events cannot be determined based on the study methodology.
The ADVANCE trial shows us that reducing BP in diabetic patients is more important than the specific antihypertensive agents used, but more data are needed. To help us understand the incremental benefit in reducing systolic BP in DM, the results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial are anxiously awaited. Sponsored by the National Heart, Lung, and Blood Institute, ACCORD is comparing whether lowering systolic BP to a goal of <120 mm Hg will more favorably reduce CV disease risk compared with a systolic BP goal of <140 mm Hg in the setting of favorable blood glucose control. Until the results of the ACCORD trial are completed in 2009–2010, the ADVANCE trial moves us closer to supporting current guidelines that recommend a goal BP of <130/80 mm Hg in patients with DM. This will often require a combination of antihypertensive agents in addition to lifestyle modification.