News from the 2007 Congress of the European Society of Cardiology, Vienna, September 1-5

Cardiology Review® OnlineOctober 2007
Volume 24
Issue 10

Blood pressure-lowering improves outcomes in type 2 diabetes

Aggressive blood pressure reduction reduces the risk of complications from type 2 diabetes by approximately one fifth, according to results from the largest study ever conducted in the treatment of diabetes.

In the double-blind study, patients with type 2 diabetes who were randomized to treatment with an angiotensin converting enzyme (ACE) inhibitor and thiazide-type diuretic in a single pill (perindopril/indapamide) had significant reductions in their risk of all-cause mortality, cardiovascular death, and major macro and microvascular events compared with a group randomized to placebo, said Stephen MacMahon, PhD, lead investigator of the trial.

The study's findings suggest that all patients with diabetes, regardless of their blood pressure, should receive antihypertensive therapy, said Dr MacMahon, principal director, The George Institute for International Health, and professor of cardiovascular medicine and epidemiology at the University of Sydney in Australia.

"We added treatment to everybody irrespective of blood pressure and with no blood pressure goals," he said. "The critical issue is to get every patient on treatment." He said the study supports current guidelines that recommend a blood pressure target of less than 130/80 mm Hg in patients with diabetes, for which no prior evidence existed.

In the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE), 11,140 patients with type 2 diabetes who were older than 55 years and considered at high risk of cardiovascular disease were randomized to placebo or perindopril/indapamide (initiated at 2.0 mg/0.625 mg daily and then titrated to 4.0 mg/1.25 mg daily after 3 months) in addition to existing therapies, and followed for a mean of 4.3 years.

The average systolic blood pressure during the study's follow-up was reduced by 5.6 mm Hg and the average diastolic blood pressure was reduced by 2.2 mm Hg in the patients allocated to perindopril/indapamide compared with placebo.





The primary endpoint—the combined incidence of macrovascular and microvascular events&mdash;was reduced by 9% ( = .041) in the group randomized to perindopril/indapamide compared with placebo. Active treatment was associated with a 14% relative reduction in all-cause mortality ( = .025), an 18% relative reduction in cardiovascular death ( = .027), and a 21% relative reduction in the incidence of renal events ( < .001).

"These benefits were achieved in a population with good control of risk factors," said Dr MacMahon. At the first visit, 75% were on antihypertensive drug therapy (in addition to the study drug). Antiplatelet drugs and statins were also being taken by many of the subjects.

There was no reduction in the risk of cerebrovascular events or new or worsening microvascular eye disease in participants assigned to perindopril/indapamide versus placebo.

"The trial is important in my thinking," commented Sidney Smith, MD, in that it confirms the importance of blood pressure lowering in the diabetic population, although the optimal blood pressure target in this population remains undefined.

The relative importance of the chosen drug combination studied to the overall effect is already being debated. The favorable effects of ACE inhibitors in patients with diabetes is presumed but more evidence is required before ACE inhibitors can be said to have protective effects on the vasculature independent of blood pressure lowering, said Dr Smith, professor of medicine and director of the Center for Cardiovascular Science and Medicine at the University of North Carolina, Chapel Hill.

In an editorial to accompany the online publication of the study in The Lancet, Norman M. Kaplan, MD, wrote, "…I believe that other drugs—if they lower blood pressure as much and do not have metabolic side effects&mdash;would be as protective as this combination treatment. Lowering blood pressure is what counts, not the way by which it is lowered." Dr Kaplan is professor of internal medicine, University of Texas Southwestern Medical Center, Dallas.

PAD is deadly even without symptoms

Even asymptomatic peripheral arterial disease (PAD) increases the risk of death and cardiovascular mortality, a German epidemiologic study has found. In fact, asymptomatic PAD identified using the ankle-brachial index (ABI) carried the same risks for mortality as symptomatic PAD.

For this reason, all older adults should be screened for PAD, said the study's lead investigator, Curt Diehm, MD.

"PAD is too important to leave to specialists only. You'll die 10 years earlier if you have symptomatic or asymptomatic PAD," said Dr Diehm, professor of internal medicine/vascular medicine, Clinic Karlsbad-Langensteinbach in Germany. "The ABI is quick, easy, noninvasive, and cost-effective, and can be learned in 15 minutes by primary care physicians and nurses."

Started in 2001, the German Epidemiological Trial on Ankle-Brachial Index (getABI) study sought to determine if screening older patients for PAD using the ABI could identify it early, and if so, the future risk associated with PAD.

The study included 6880 unselected patients aged 65 years or older from primary care offices in Germany, who underwent ABI testing. Asymptomatic PAD was defined as an ABI <0.9 as determined by standard Doppler sonography. Peripheral arterial disease was considered symptomatic if the patient had intermittent claudication or had undergone a PAD-related amputation or revascularization procedure.

"Asymptomatic and symptomatic patients show no difference in terms of mortality," said Dr Diehm.



The 5-year mortality rates were 9.4% in the subjects without PAD, 19.1% in those with asymptomatic PAD, and 23.9% in those with symptomatic PAD. These mortality rates correspond to a 60% increased risk with asymptomatic PAD compared with no PAD ( < .001) and an 80% increased risk with symptomatic PAD compared with an absence of PAD ( < .001).

As the ABI decreased, mortality increased: the worst survival was observed in patients with an ABI < 0.5.

Although the American Heart Association (AHA) recommends using the higher of the systolic pressures obtained at the left and right posterior tibial and tibial anterior arteries, Dr Diehm says that this method will result in missed diagnoses. "The AHA needs to change; using the higher of the 2 pressures will miss distal occlusions in the other artery…you miss disease," he said.

When found, PAD deserves secondary prevention along the standards of coronary artery disease. Unfortunately, therapies likely to be beneficial in reducing mortality in PAD are underused, said Dr Diehm. In Germany, only about half of PAD patients are receiving antiplatelet drugs and only about one fourth are being treated with statins or beta blockers. The treatment percentages are similar in the United States, he indicated.

Patients who deserve screening for PAD are those 70 years or older or 50 to 69 years old with cardiovascular risk factors. Others include a 10-year risk of cardiovascular events of 10% to 20% based on their Framingham risk score.

According to Don Poldermans, MD, professor in the department of vascular surgery at Erasmus University in Rotterdam, the Netherlands, most PAD patients will have unrecognized disease in multiple vascular beds. In patients with PAD, "screen for asymptomatic poly-vascular disease," he recommended. Such screening should include aortic aneurysm screening using ultrasound, as well as screening for cerebrovascular and coronary artery disease.

Silent CAD is common in men with ED

About 1 in 6 men with vasculogenic erectile dysfunction (ED) has documented asymptomatic coronary artery disease (CAD), according to Charalambos Vlachopoulos, MD.

"ED is sometimes the first manifestation of a generalized disease before CAD has become clinically evident," he said. "Studies have shown that ED and CAD often co-exist, as up to 75% of patients with CAD have some degree of ED."

He and colleagues evaluated angiographically the incidence of asymptomatic CAD in 182 consecutive men, aged 38 to 77 years, with ED of vascular origin. All of the men had an exercise treadmill test and stress echocardiography.

Cardiovascular risk factors were common: 59% had hypertension, 53% were smokers, 51% had hyperlipidemia, 19% had diabetes, and 11% had a family history of premature vascular disease. Twenty-one percent of the men had either a positive exercise treadmill test or stress echocardiogram, or both.Three patients suffered a myocardial infarction (MI) before completing the noninvasive investigation, said Dr Vlachopoulos, department of cardiology, Athens Medical School, Hippokration Hospital, Greece.

Coronary angiography was performed in 33 of the men in whom the noninvasive testing was positive and the 3 patients with acute MI. Five patients who had positive noninvasive tests refused to undergo angiography.Twenty-five of the 177 (14%) men had angiographically documented silent CAD. Six had 3-vessel disease, 7 had 2-vessel disease, and 12 had single-vessel disease. Six men had coronary ectasias.

The 14% rate of silent CAD in men with ED in this study is greater than the 4% found in a previous study of the general population, noted Dr Vlachopoulos.

The men who had CAD confirmed by angiography were older, had a higher prevalence of diabetes, a longer duration of ED, and more significant ED as estimated by penile color Doppler ultrasonography than the men without evidence of CAD.

"The mean ED duration in our patients was relatively long—a mean of 29 months in patients with angiographically documented CAD&mdash;thus allowing time for disease progression," he said.

"ED should raise suspicions about early atherosclerosis, even in men who would not otherwise be considered at high risk," he advised.

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