Further information: Endocrine Disorders and the Heart (see p2295) and Cardiovascular Complications of Obesity and the Metabolic Syndrome (see p2693) from Cardiovascular Medicine, 3rd Edn*

Although published in the two separate papers listed above, the effects of Valsartan and Nateglinide were studied in the same trial entitled, “Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR)” [1, 2]. The double-blind, randomized clinical trial with a two-by-two factorial design was conducted from January 2002 through January 2004, with recruitment occurring at 806 centers in 40 countries. Eligible patients had impaired glucose tolerance, a fasting plasma glucose level of at least 95 mg/dl, but less than 126 mg/dl, and one or more cardiovascular risk factors or known cardiovascular disease, and 9306 participants were enrolled. Patients were randomized to receive either nateglinide, up to 60 mg three times a day, or a matching placebo, and valsartan, up to 160 mg daily, or a matching placebo. In addition, patients were required to participate in a lifestyle program, and a goal was set to maintain a 5% weight loss, an increase in physical activity to an average of 30 min five days a week, and adherence to a low-fat diet. Valsartan, an angiotensin-receptor blocker (ARB), is used to treat high blood pressure, heart failure (HF), and long-term consequences of a heart attack. Valsartan was selected for this trial to evaluate the use of an ARB in the delay or prevention of diabetes and to determine the possibility of its helping the cardiovascular system. In the valsartan group, the cumulative incidence of diabetes was 33.1%, as compared with 36.8% in the placebo group (hazard ratio (HR) with valsartan, 0.86; 95% confidence interval [CI], 0.80–0.92; P<0.001). Compared with placebo, valsartan did not significantly reduce the incidence of either the extended CV outcome (14.5% vs. 14.8%; hazard ratio [HR], 0.96; 95% CI, 0.86–1.07; P=0.43) or the core CV outcome (8.1% vs. 8.1%; HR, 0.99; 95% CI, 0.86–1.14; P=0.85). Although nateglinide is in a class of drugs previously shown to lower post prandial glycemia, the hoped-for effect did not occur in NAVIGATOR, nor was the incidence of cardiovascular disease reduced. Nateglinide compared with placebo did not reduce cumulative incidence of diabetes (36% and 34% respectively; HR, 1.07; 95% CI, 1.00–1.15; P=0.05), the core composite CV outcome (7.9% and 8.3% respectively; HR, 0.94, 95% CI, 0.82–1.09; P=0.43), or the extended composite CV outcome (14.2% and 15.2%, respectively; HR, 0.93%, 95% CI, 0.83–1.03; P=0.16).

In an accompanying editorial [3], the author opined that effective lifestyle interventions should be used to combat the current diabetes epidemic, a critical public health concern, but for now, neither drug evaluated in the NAVIGATOR should be used.

[1] The NAVIGATOR study group.Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med 2010;362(16):1477-90

[2] The NAVIGATOR study group.Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med 2010;362(16):1463-76

[3] Navigating the choices for diabetes prevention. Nathan DM. N Engl J Med 2010;362:1533-35

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* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.

Further information: Percutaneous Coronary Intervention for Acute Myocardial Infarction (see p1021) and  Drug-Eluting Coronary Stents (see p1031) from Cardiovascular Medicine, 3rd Edn*

Current guidelines for patients who have undergone percutaneous coronary intervention (PCI) recommend that patients who are not at risk of bleeding should be given clopidogrel (anti-platelet therapy), 75 mg daily, for 12 months following their procedure. However, the length of time that anti-platelet therapy should be further extended beyond 12 months has not been determined. The current study [1] evaluated data from two concurrent, randomized, clinical trials that compared continuation and discontinuation of clopidogrel: Correlation of Clopidogrel Therapy Discontinuation in Real-world Patients Treated with Drug-Eluting Stent Implantation and Late Coronary Arterial Thrombotic Events (REAL-LATE) and Evaluation of the Long-Term Safety after Zotarolimus-Eluting Stent, Sirolimus-Eluting Stent, or Paclitaxel-Eluting Stent Implantation for Coronary Lesion-Late Coronary Arterial Thrombotic Events (ZEST-LATE). Enrollment occurred from July 2007 through September 2008 in 22 cardiac centers in South Korea, and the two trials enrolled a total of 2701 patients who were free of major adverse cardiac or cerebrovascular events and major bleeding for at least 12 months after PCI. The group who had aspirin only and for whom clopidogrel was discontinued was assigned 1344 patients, and in the group for whom clopidogrel plus aspirin were continued, there were 1357 patients. The primary end point was the first occurrence of myocardial infarction (MI) or death from cardiac causes after group assignment. Secondary end points were death from any cause, MI, stroke, stent thrombosis, repeat revascularization, composite of MI or death from any cause, and major bleeding.

Cumulatively, the risk of primary outcome at 2 years was 1.8% with clopidogrel plus aspirin, as compared with 1.2% with aspirin alone (hazard ratio [HR], 1.65; 95% confidence interval [CI], 0.80–3.36; P=0.17). There was a non-significant difference in primary individual risks between the two groups, and there was a nonsignificant increase in composite risks in the group having both clopidogrel and aspirin.

The investigators concluded that the extended use of dual antiplatelet therapy (clopidogrel and aspirin) for more than 12 months after PCI was not significantly more effective than the use of aspirin alone to reduce risk of MI or death from cardiac causes.

[1] Park SJ, Park DW, Kim YH, et al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. N Engl J Med 2010;362:1374-82

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* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.

Further information: Hypertension (see p1833) and Endocrine Disorders and the Heart (see p2295) from Cardiovascular Medicine, 3rd Edn*

This review features two studies focusing on patients with diabetes mellitus that were recently presented at the American College of Cardiology Scientific Sessions in Atlanta. Both segments of the ACCORD trial are summarized here.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) [1] was conducted in diabetic patients who were at high-risk of cardiovascular (CV) events to determine if a combination therapy that included a fibrate to raise HDL cholesterol and to lower triglyceride levels and a statin to lower LDL cholesterol was more effective than treatment with statin therapy alone. Between January 11, 2001 and October 29, 2005, 5518 patients in 77 clinical sites who were already being treated with open-label simvastatin were randomized to also receive either masked fenofibrate or placebo. Prespecified primary outcome was the first occurrence of a major CV event, including nonfatal myocardial infarction (MI), nonfatal stroke, or death from CV causes. Secondary outcomes were a combination of the primary outcome plus revascularization or hospitalization for congestive heart failure (HF), a combination of a fatal CV event, nonfatal MI, or unstable angina; nonfatal MI; fatal or nonfatal stroke; death from any cause or from CV causes; and CV death due to HF. The average follow-up for patients who did not have an event was 5.6 years. There were no significant differences in the primary outcome for either the fenofibrate group (annual rate, 2.2%) or the placebo group (annual rate, 2.4%), with hazard ratio (HR) in fenofibrate group, 0.92; 95% confidence interval (CI), 0.79–1.08; P=0.32. There were also no significant differences in secondary outcomes. Annual rates of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (HR, 0.91; 95% CI, 0.75–1.10; P=0.33). ACCORD investigators concluded that combination therapy did not reduce CV risk in high-risk patients with type 2 diabetes.

This study [2] draws from the same cohort of patients with type 2 diabetes mellitus as the previous paper; however, the focus of this study was to determine if lowering the systolic blood pressure (BP) to less than 120 mm Hg was more effective in reducing CV events than the current target strategy of lowering systolic BP to below 135–140 mmHg. The 4733 patients with type 2 diabetes were randomly assigned to receive intensive therapy that would target a systolic pressure of less than 120 mmHg, or a standard therapy of pressure less than 140 mmHg. The same primary and secondary outcomes were in effect for both ACCORD trials. In the intensive therapy group after one year, the mean systolic BP was 119.3 mm Hg, and in the standard therapy group, mean systolic BP was 133.5 mmHg. In the intensive therapy group, the annual rate of outcome was 1.87%, and it was 2.09% in the standard therapy group (HR with intensive therapy, 0.88; .95% CI, 0.73–1.06; P=0.20). There were no significant differences in annual rates of death. The annual rates of stroke were 0.32% in intensive therapy patients and 0.53% in the standard therapy patients. Of the 2362 patients in the intensive therapy group, 77 had serious adverse events related to antihypertensive treatment (3.3%), as did 30 of 2371 patients in the standard therapy group (1.3%). Investigators concluded that targeting a systolic BP of less than 120 mmHg did not reduce risk of CV events in patients with type 2 diabetes.

[1] The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010 (10.1056/NEJMoa1001282)

[2] The ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010 (10.1056/NEJMoa1001286)

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* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.