Kenji Norimatsu

Efficacy and safety of a single-pill fixed-dose combination of high-dose telmisartan/hydrochlorothiazide in patients with uncontrolled hypertension

Objective: Many patients still have high blood pressure (BP) after treatment with high-dose angiotensin II type 1 receptor blockers (ARBs) or Preminent® (medium-dose of losartan (50 mg/day)/hydrochlorothiazide (HCTZ) (12.5 mg/day)). Therefore, we analyzed whether Micombi®BP (high-dose telmisartan (80 mg/day)/HCTZ (12.5 mg/day)) could provide better results with regard to efficacy and safety for patients with uncontrolled hypertension. Methods: In total, 44 hypertensive patients (22 males, age 71±14 years) who showed uncontrolled BP despite the use of high-dose ARBs or Preminent® were enrolled in this study. We used a changeover design in which the patients were switched from high-dose ARBs or Preminent® to Micombi®BP. We analyzed BP, heart rate (HR), and biochemical parameters before and after treatment for 3 months. Results: Systolic BP and diastolic BP significantly decreased (125±15/69±11 mmHg) and 85% of the patients achieved their target BP at 3 months after changeover. Patients who switched from ARBs and those who switched from Preminent® showed similar BP-lowering effects. In addition, the reductions in BP after 3 months in patients with or without chronic kidney disease and in those with or without metabolic syndrome (MetS) were also similar. There were no significant changes in HR during the study period. Although blood levels of potassium, hemoglobin A1c and uric acid (UA) significantly increased after 3 months for all of the patients, none of the patients showed serious adverse effects. Conclusion: High-dose telmisartan/HCTZ therapy was associated with a significant reduction in BP and helped patients achieve their target BP.

The Ratio of Low-Frequency to High-Frequency in Ambulatory Electrocardiographic Monitoring Immediately Before Coronary Angiography as a Predictor of the Presence of Coronary Artery Disease

Background There is considerable evidence that impaired autonomic control may be associated with the etiology of coronary artery disease (CAD). We hypothesized that the autonomic imbalance as assessed by measuring heart rate variability (HRV) and biological parameters before and after coronary angiography (CAG) may predict the presence of CAD. Methods Ambulatory electrocardiographic (ECG) examination using eHEART® (Parama-Tec) is a novel, rapid, and simple method with which we can measure HRV within 5 min. We selected patients (n = 78, 68 ± 10 y) who underwent CAG and analyzed their ambulatory ECGs and blood levels of neuropeptides at both 1 day and immediately before and after CAG. The patients were divided into the presence (n = 64, CAD group) and absence of CAD (n = 14, non-CAD group). Results Although the CAD group showed an increase in blood pressure immediately before CAG, the ratio of low-frequency to high-frequency (LF/HF) was significantly decreased in the CAD group, but not in the non-CAD group. On the other hand, there was no difference in a coefficient of variation of the R-R interval or pulse rate between the two groups. CAD was independently associated with hypertension (P = 0.011), dyslipidemia (P = 0.009), and LF/HF immediately before CAG (P = 0.046) by a logistic regression analysis. Conclusions These findings suggest that LF/HF immediately before CAG in addition to hypertension and dyslipidemia might predict the presence of CAD.

Associations between glycated albumin or hemoglobin A1c and the presence of coronary artery disease.

OBJECTIVE We investigated the associations between serum levels of glycated albumin (GA) or hemoglobin A1c (HbA1c) and the presence of coronary artery disease (CAD) in patients who underwent coronary computed tomography angiography (CTA). METHODS AND RESULTS The study consisted of 244 consecutive patients who underwent CTA and in whom we could measure the levels of both GA and HbA1c. Any narrowing of the normal contrast-enhanced lumen to >50% that could be identified in multiplanar reconstructions or cross-sectional images by CTA was defined as significant stenosis in CAD. We divided the patients into two groups: CAD group (n=72) and non-CAD group (n=172), as assessed by CTA. The CAD group showed significantly higher GA and HbA1c than the non-CAD group. GA and HbA1c showed a positive correlation (r=0.551, p<0.0001). A multivariate logistic regression analysis was performed to examine the associations between the presence of CAD and age, gender, body mass index, and coronary risk factors (hypertension, dyslipidemia, and smoking), in addition to GA and HbA1c. Age [odds ratio (OR): 1.04, p=0.02], gender (OR: 2.84 p=0.01), hypertension (OR: 3.20, p=0.01), and GA (OR: 1.16, p=0.03) were identified as significant independent variables that predicted the presence of CAD. In particular, GA (OR: 1.30, p=0.02) was the only predictor of the presence of CAD in the diabetes mellitus group by a multivariate logistic regression analysis. We defined the cut-off value of GA for the prediction of CAD in patients with diabetes as 17.9% (sensitivity 0.639, specificity 0.639) by a receiver-operating characteristic curve analysis. CONCLUSION GA may be superior to HbA1c as a marker for evaluating the presence of CAD.

Efficacy and Safety of Combination Therapy Consisting of Angiotensin II Type 1 Receptor Blocker, Calcium Channel Blocker and Hydrochlorothiazide in Patients With Hypertension

Background Many patients continue to have high blood pressure (BP) even after treatment with high-dose (H)-angiotensin II type 1 receptor blocker (ARB)/calcium channel blocker (CCB) or middle-dose (M)-ARB/CCB/hydrochlorothiazide (HCTZ). Methods Thirty-two hypertensive patients who had the use of H-ARB/CCB or M-ARB/CCB/HCTZ were enrolled in this study. We applied a changeover with a switch to H-ARB (telmisartan 80 mg/day)/CCB (amlodipine 5 mg/day or nifedipine CR 40 mg/day)/HCTZ (12.5 mg/day). Results Systolic BP (SBP) and diastolic BP (DBP) were significantly decreased in all patients and in the H-ARB/CCB and M-ARB/CCB/HCTZ groups after 3 months. Percentage (%) of patients who reached the target BP after 3 months (72%) in all patients was significantly higher than that at 0 months (19%). There were no serious adverse effects in any of the patients. Conclusions Combination therapy with H-ARB/CCB/HCTZ was associated with a significant reduction of BP.

Comparison of Efficacy and Safety of Azilsartan and Olmesartan in Patients With Essential Hypertension

Many patients still have high blood pressure (BP) after treatment with angiotensin II type 1 (AT1) receptor blockers (ARBs). We compared the efficacy and safety of azilsartan to those of olmesartan in a prospective randomized clinical trial. Sixty-four hypertensive patients who were treated with ARBs other than azilsartan and olmesartan were enrolled in this study. We randomly assigned patients to changeover from their prior ARBs to either azilsartan or olmesartan, and followed the patients for 3 months. Systolic BP (SBP) in the azilsartan group was significantly decreased at 3 months, and diastolic BP (DBP) and pulse rate (PR) in the olmesartan group showed significant reductions after 3 months. There were no significant differences in ΔSBP, ΔDBP, or ΔPR (Δ = the value at 3 months minus the value at 0 months) between the groups. Serum levels of creatinine (Cr), uric acid (UA), and potassium (K) in the azilsartan group significantly increased after 3 months. While the changes in Cr, UA, and K were within the respective normal ranges, ΔSBP was positively associated with ΔCr in the azilsartan group. In conclusion, there was no difference in the depressor effects of azilsartan and olmesartan, and there were no serious changes in biochemical parameters with azilsartan and olmesartan.

Association between the severity of coronary artery stenosis and the combination of the difference in blood pressure between arms and brachial-ankle pulse wave velocity

Abstract Background: A difference in systolic blood pressure (SBP) ≥10 mmHg between the arms is associated with an increased risk of coronary artery disease (CAD) and mortality in high-risk patients. Methods and results: Four hundred and fourteen patients were divided into three groups according to the percent most severe luminal narrowing of a coronary artery as diagnosed by coronary computed tomography angiography: no or mild coronary stenosis (0–49%), moderate stenosis (50–69%) and severe stenosis (≥70%) groups. The relative difference in SBP between arms in the severe group was significantly lower than those in the no or mild and moderate groups. The brachial-ankle pulse wave velocity (baPWV) significantly increased as the severity of coronary stenosis increased. We confirmed that severe coronary stenosis was independently associated with both the relative difference in SBP between arms and baPWV, in addition to age, gender, hypertension, dyslipidemia, diabetes mellitus and ankle-brachial index by a logistic regression analysis. The group with a relative difference in SBP between arms of <1 mmHg and baPWV ≥ 1613 cm/s showed a higher percentage of patients with severe coronary stenosis than groups that met neither or only one of these criteria. Conclusion: The combination of the relative difference in SBP between arms and baPWV may be a more effective approach for the non-invasive assessment of the severity of CAD.

Associations between parameters of flow-mediated vasodilatation obtained by continuous measurement approaches and the presence of coronary artery disease and the severity of coronary atherosclerosis

ABSTRACT We investigated the associations between the parameters of flow-mediated vasodilatation (FMD) obtained by continuous measurement approaches and the presence of coronary artery disease (CAD) and the severity of coronary atherosclerosis. The subjects consisted of 282 consecutive patients who underwent coronary angiography (CAG) and in whom we could measure FMD. Using continuous measurement approaches, we measured FMD as the magnitude of the percentage change from brachial artery diameter from baseline to peak (bFMD), the maximum FMD rate calculated as the maximal slope of dilation (FMD-MDR), and the integrated FMD response calculated as the area under the dilation curve during the 60- and 120 s dilation periods (FMD-AUC60 and FMD-AUC120). We divided the patients into two groups, the CAD group and the non-CAD group, and defined the severity of coronary atherosclerosis according to the Gensini score. The CAD group showed significantly lower %FMD, FMD-MDR, FMD-AUC60, and FMD-AUC120. Gender, smoking, dyslipidemia (DL), and diabetes mellitus (DM), in addition to FMD-AUC120, were identified as significant independent variables that predicted the presence of CAD by a multivariate logistic regression. In addition, a multiple regression analysis indicated that gender, DL, and hypertension, in addition to FMD-AUC120, were predictors of the Gensini score. Finally, we defined the cutoff value of FMD-AUC120 for the prediction of CAD in all patients as 11.1 (sensitivity 0.582, specificity 0.652) by a receiver-operating characteristic (ROC) curve analysis. In conclusion, FMD-AUC120 as assessed by continuous measurement approaches may be a superior marker for evaluating the presence of CAD and the severity of coronary atherosclerosis.

Efficacy and safety of combination therapy of high-dose losartan and hydrochlorothiazide in patients with hypertension

Objective: We analyzed the efficacy and safety of combination therapy of high-dose losartan (100 mg/day) and hydrochlorothiazide (HCTZ, 12.5 mg/day) compared with those of the combination of high-dose telmisartan (80 mg/day) and HCTZ (12.5 mg/day). Methods: Forty hypertensive patients who received a combination of high-dose telmisartan and HCTZ were enrolled. We applied a changeover strategy with switching from a combination of high-dose telmisartan and HCTZ to high-dose losartan and HCTZ. We divided the patients into two groups; those who achieved the target blood pressure (controlled group) and those who did not reach the target blood pressure (uncontrolled group) before the changeover and performed further analysis. Results: The uncontrolled group showed a significant decrease in systolic blood pressure (SBP) (143±12 mmHg to 126±11 mmHg at three months). In addition, serum uric acid significantly decreased in all subjects, and in each of the controlled and uncontrolled groups. There were no significant changes in other biochemical parameters, such as potassium and hemoglobin A1c, at three months after the changeover in all subjects. Conclusion: Combination therapy with high-dose losartan and HCTZ was superior to the combination of telmisartan and HCTZ with respect to significant decreases in systolic blood pressure and serum uric acid in hypertensive patients.

Contrast between innovator drug- and generic drug-induced renal dysfunction on coronary angiography (CONTRAST study)

Contrast-induced nephropathy (CIN) has gained increasing attention in clinical practice, particularly during coronary angiography (CAG). However, some “bioequivalent” generic (GE) drugs are less effective than the innovator (IN) drug. Therefore, the aim of this study was to compare contrast media (IN drug)-induced renal dysfunction with contrast media (GE drug)-induced dysfunction. We enrolled 44 patients who underwent elective CAG or percutaneous coronary intervention (PCI) and randomly divided them into two groups that received contrast media (Iohexol, nonionic and low-osmolality contrast agent) containing either IN drug (Omnipaque) or GE drug (Iopaque). Blood and urine sampling were performed before and after (24 and 48 h) CAG or PCI. Biochemical parameters in blood (serum creatinine, cystatin C, high-sensitivity C-reactive protein, and pentraxin-3) and urine (urinary albumin/Cr and liver-type fatty acid binding protein/Cr) were measured. There were no significant differences in the biochemical parameters at baseline between the groups. In addition, there were no differences in changes in biochemical parameters in blood and urine before and after CAG or PCI between the groups, although one patient in the GE group had CIN. The degree of contrast in Iopaque-induced renal dysfunction was comparable with that in Omnipaque-induced dysfunction.

Advanced glycation of high-density lipoprotein and the functionality of aldosterone release in type 2 diabetes.

Patients with type 2 diabetes mellitus (DM) exhibit modification of high-density lipoprotein (HDL), which is likely to have an important role in the development of atherosclerotic cardiovascular disease (ASCVD). Excess production of aldosterone (Ald) results in hypertension as well as ASCVD. However, the biological activity of modified HDL in steroidogenesis is not clear. We measured the accumulation of thiobarbituric acid-reactive substances (TBARSs) and Nɛ-(carboxymethyl)lysine (CML) levels (markers of oxidation and glycoxidation, respectively) in isolated HDL from 41 patients with type 2 diabetes mellitus (DM group) and 41 age- and gender-matched patients in a non-DM group. We quantified angiotensin II-sensitized and -nonsensitized Ald release using a validated living adrenocortical cell assay. TBARS levels in isolated HDL were similar between patients in the DM and non-DM groups, whereas the CML content of HDL in the DM group was lower than that in the non-DM group, irrespective of higher blood glucose and hemoglobin A1c levels. There was no difference in the HDL-induced ex vivo Ald release between the groups. Although sustained hyperglycemia was not a determinant of HDL-induced Ald release, the degree of HDL glycoxidation was inversely associated with HDL-induced Ald release (r=−0.40, P<0.001). In conclusion, in vivo advanced glycoxidation of HDL had an inverse effect on HDL-induced Ald release, independent of the prevalence of type 2 DM.