Methods

The rationale, design, and principal findings of the NHS have been described previously. Briefly, the study was an investigator-initiated, prospective, randomized, open-labeled, blinded end points design trial that enrolled 1,150 participants aged 30 to 75 years with hypertension and glucose intolerance (type 2 diabetes mellitus or impaired glucose tolerance). Participants were recruited exclusively by 171 cardiologists from 46 Board-certified medical centers and hospitals of the Japanese Circulation Society from October 2004 to January 2009. This study was approved by the ethical review committees of the Nagoya University School of Medicine and participating institutions.

Hypertension was defined as having received any antihypertensive drug already or blood pressure (BP) of ≥140/90 mm Hg. Type 2 diabetes mellitus was defined as having received any antidiabetic agent or a plasma glucose level of ≥7.0 mmol/L in the fasting state or ≥11.1 mmol/L in the nonfasting state or 2 hours after glycemic load in a 75 g oral glucose tolerance test. Impaired glucose tolerance was defined by a plasma glucose level of <7.0 mmol/L in the fasting state and 7.8 to 11.0 mmol/L as the 2-hour value in a 75 g oral glucose tolerance test.

Main exclusion criteria were patients with previous CVD within 6 months, taking CCB for angina pectoris, left ventricular ejection fraction <40%, secondary or severe hypertension (≥200/110 mm Hg), and serum creatinine level ≥221 μmol/L.

The primary outcome was a composite of acute myocardial infarction, stroke, admission due to heart failure, coronary revascularization, or sudden cardiac death. All reported adverse events were strictly adjudicated by an independent Endpoint Evaluation Committee in a blinded manner as for the assigned treatments.

Enrolled patients were randomly assigned in accordance with the minimization method using 5 factors (age, gender, medication for dyslipidemia, current smoking status, and type 2 diabetes mellitus or impaired glucose tolerance) to the valsartan-based or the amlodipine-based treatment group. Patients were instructed to take the allocated medication (valsartan 80 mg/day or amlodipine 5 mg/day), and the dose was doubled after 4 weeks if the target BP of ≤130/80 mm Hg could not be achieved. Blood glucose control was performed according to the treatment guidelines issued from the Japan Diabetes Society.

In this subanalysis, the study population was divided into 2 groups according to the history of CVD at baseline.

Data were analyzed on the basis of the intention-to-treat principle. Only the first cardiovascular event was analyzed as a primary outcome in case of multiple events observed in a single patient. Cumulative incidence of cardiovascular events was estimated by the Kaplan-Meier method. The crude hazard ratios and 95% confidence intervals were calculated by the Cox proportional hazards model. Interactions of hazard ratios between treatment arms and previous CVD groups were also assessed by the Cox proportional hazards model with interaction terms. Repeated measure analysis of variance was used to compare the changes of BP throughout the follow-up. Categorical data were compared between groups with Fisher’s exact test or chi-square test, and continuous data were compared between groups using t test. All statistical analyses were 2 sided, and p value <0.05 was considered statistically significant.

Results

In the present analysis, 1,150 patients were randomized to valsartan- or amlodipine-based treatment arm; 818 patients did not have a CVD history, of whom 417 received valsartan-based treatment and 401 amlodipine-based treatment, and 332 patients had a CVD history, of whom 158 received valsartan-based treatment and 174 amlodipine-based treatment. The median follow-up was 3.2 years, and a total of 1,116 patients (97%) completed the follow-up throughout the study ( Figure 1 ).

Flow diagram of this subanalysis of the NAGOYA HEART Study.

Baseline characteristics for all enrolled patients are listed in Table 1 . The patients without previous CVD had lesser mean age and fewer were men compared with those with previous CVD. Baseline characteristics between the valsartan-based and the amlodipine-based treatment arms did not differ in both patients with and without previous CVD. Although the patients without previous CVD showed significantly higher mean systolic and diastolic BPs at baseline than those with CVD (p <0.001, respectively), there was no significant difference of systolic and diastolic BPs during the follow-up period among the 4 groups ( Figure 2 ). At 42 months, mean BPs were reduced to 132.4 ± 14.3/75.1 ± 7.9 mm Hg in the valsartan-based treatment arm and 131.6 ± 14.1/74.8 ± 9.2 mm Hg in the amlodipine-based treatment arm in the patients without previous CVD and 131.3 ± 16.5/73.0 ± 10.9 mm Hg in the valsartan-based treatment arm and 130.9 ± 12.7/72.3 ± 8.6 mm Hg in the amlodipine-based treatment arm in the patients with CVD.

Changes in BP throughout the study. ANOVA = analysis of variance; DBP = diastolic blood pressure; SBP = systolic blood pressure.

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