Intensive or standard blood pressure control in patients with a history of ischemic stroke: RESPECT post hoc analysis.

The Recurrent Stroke Prevention Clinical Outcome (RESPECT) Study and its pooled analysis showed that intensive blood pressure (BP) lowering reduced recurrent stroke risk by 22% in patients with a history of stroke. Here, we report the effect of intensive BP lowering on the risk of recurrent stroke subtypes in patients with a history of ischemic stroke. RESPECT was a randomized clinical trial among 1280 people with a history of cerebral infarction or intracerebral hemorrhage. Participants were assigned to the intensive blood pressure control group (blood pressure < 120/80 mmHg) or standard blood pressure control group (blood pressure < 140/90 mmHg). In this post hoc analysis, we analyzed 1074 patients with a history of cerebral infarction. The mean BP at baseline was 140.7/81.4 mmHg. Throughout the follow-up period, the mean BP was 133.4/77.5 (95% CI, 132.7-134.1/76.9-78.2) mmHg in the standard group and 126.7/74.1 (95% CI, 126.0-127.4/73.5-74.8) mmHg in the intensive group. During a mean follow-up of 3.9 years, 78 first recurrent strokes occurred. Intensive treatment tended to reduce overall annual stroke recurrence (1.74% in intensive vs. 2.17% in standard; P = 0.351 by log-rank test) and did not change the risk of ischemic stroke (1.74% vs. 1.75%, P = 0.999) but markedly reduced the risk of hemorrhagic stroke (0.00% vs. 0.39%, P = 0.005). Beneficial effects of intensive BP control were observed for the risk of hemorrhagic stroke in patients with a history of ischemic stroke. The findings of this study indicate the benefit of intensive BP control for patients with a history of ischemic stroke at high risk of hemorrhagic stroke.

Effects of an Antihypertensive Combination in Japanese Hypertensive Outpatients Based on the Long-acting Calcium Channel Blocker Benidipine on Vascular and Renal Events: A Sub-analysis of the COPE Trial

BACKGROUND: In the trial known as COPE (Combination Therapy of Hypertension to Prevent Cardiovascular Events), three benidipine (a Calcium Channel Blocker; CCB) regimens were compared. Hypertensive Japanese outpatients aged 40-85 years (n=3,293) who did not achieve the target blood pressure of <140/90 mmHg with benidipine 4 mg/day were treated with the diuretic thiazide (n=1,094) or a ß-blocker (n=1,089) or an additional Angiotensin Receptor Blocker (ARB; n=1,110). A significantly higher incidence of hard cardiovascular composite endpoints and of fatal or non-fatal strokes was observed in the benidipine-ß-blocker group compared to the benidipine-thiazide group. OBJECTIVE AND METHODS: We further evaluated the treatment effects of the three benidipine-based regimens on vascular and renal events in a sub-analysis of the COPE patients. RESULTS: A total of 10 vascular events (0.8 per 1,000 person-years) including one aortic dissection (0.1 per 1,000 person-years) and nine cases of peripheral artery disease (0.8 per 1,000 person-years) were documented, as was a total of seven renal events (0.6 per 1,000 person-years). No significant differences in vascular and renal events were revealed among the three treatment groups: vascular events, p=0.92; renal events, p=0.16, log-rank test. CONCLUSION: Blood pressure-lowering therapy with benidipine combined with an ARB, ß-blocker, or thiazide was similarly effective in the prevention of vascular and renal events in hypertensive outpatients, although there are not enough events to compare the difference in the three treatment groups.

Effect of Standard vs Intensive Blood Pressure Control on the Risk of Recurrent Stroke: A Randomized Clinical Trial and Meta-analysis.

IMPORTANCE: The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that a systolic blood pressure (BP) target less than 120 mm Hg was superior to less than 140 mm Hg for preventing vascular events. This trial excluded patients with prior stroke; therefore, the ideal BP target for secondary stroke prevention remains unknown. OBJECTIVE: To assess whether intensive BP control would achieve fewer recurrent strokes vs standard BP control. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial (RCT) of standard vs intensive BP control in an intent-to-treat population of patients who had a history of stroke. Patients were enrolled between October 20, 2010, and December 7, 2016. For an updated meta-analysis, PubMed and the Cochrane Central Library database were searched through September 30, 2018, using the Medical Subject Headings and relevant search terms for cerebrovascular disease and for intensive BP lowering. This was a multicenter trial that included 140 hospitals in Japan; 1514 patients who had a history of stroke within the previous 3 years were approached, but 234 refused to give informed consent. INTERVENTIONS: In total, 1280 patients were randomized 1:1 to BP control to less than 140/90 mm Hg (standard treatment) (n = 640) or to less than 120/80 mm Hg (intensive treatment) (n = 640). However, 17 patients never received intervention; therefore, 1263 patients assigned to standard treatment (n = 630) or intensive treatment (n = 633) were analyzed. MAIN OUTCOMES AND MEASURES: The primary outcome was stroke recurrence. RESULTS: The trial was stopped early. Among 1263 analyzed patients (mean [SD] age, 67.2 [8.8] years; 69.4% male), 1257 of 1263 (99.5%) completed a mean (SD) of 3.9 (1.5) years of follow-up. The mean BP at baseline was 145.4/83.6 mm Hg. Throughout the overall follow-up period, the mean BP was 133.2/77.7 (95% CI, 132.5-133.8/77.1-78.4) mm Hg in the standard group and 126.7/77.4 (95% CI, 125.9-127.2/73.8-75.0) mm Hg in the intensive group. Ninety-one first recurrent strokes occurred. Nonsignificant rate reductions were seen for recurrent stroke in the intensive group compared with the standard group (hazard ratio [HR], 0.73; 95% CI, 0.49-1.11; P = .15). When this finding was pooled in 3 previous relevant RCTs in a meta-analysis, the risk ratio favored intensive BP control (relative risk, 0.78; 95% CI, 0.64-0.96; P = .02; absolute risk difference, -1.5%; 95% CI, -2.6% to -0.4%; number needed to treat, 67; 95% CI, 39-250). CONCLUSIONS AND RELEVANCE: Intensive BP lowering tended to reduce stroke recurrence. The updated meta-analysis supports a target BP less than 130/80 mm Hg in secondary stroke prevention. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01198496.

Features of and preventive measures against hypertension in the young.

The Japanese hypertension guidelines report that essential hypertension is detected in 1-3% of upper elementary and high school students during blood pressure (BP) screenings. Hypertension in these age groups is an emerging public health concern mainly attributed to the rising rate of pediatric obesity. Considering the existence of BP tracking phenomenon, early preventive education and instruction are necessary, especially for male students with moderately elevated BP showing a tendency toward obesity, despite the low prevalence of hypertension in high school students. Students with a positive family history of hypertension and those born with low birth weight need the same measures. Lifestyle habits, such as increased alcohol intake, dramatically change once students begin university; thus, early education and instruction regarding the factors influencing BP are necessary. In particular, for male students with higher BP during high school, caution regarding increased body weight is required irrespective of their level of obesity. Young adults aged <40 years should be educated about the association between body weight and hypertension. Particular caution surrounding lifestyle habits, including drinking and smoking, is warranted in male hypertensive subjects because hypertension at a young age is strongly associated with obesity. BP monitoring and the management of obesity should be considered efficient approaches to the detection and treatment of hypertension. For the lifetime prevention of hypertension, it is essential to be aware of one's health status and learn about healthy lifestyles beginning in childhood. BP measurement may be an appropriate means to achieve this goal.

Effects of Calcium-Channel Blocker Benidipine-Based Combination Therapy on Cardiac Events　- Subanalysis of the COPE Trial.

BACKGROUND: The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial was conducted to compare the effects of regimens combining the dihydropyridine calcium-channel blocker benidipine with each of 3 secondary agent types (an angiotensin-receptor blocker (ARB), a ß-blocker and a thiazide) in Japanese hypertensive outpatients who did not achieve target blood pressure (<140/90 mmHg) with benidipine 4 mg/day alone. The analysis included 3,293 patients (ARB, 1,110; ß-blocker, 1,089; thiazide, 1,094) with a median follow-up of 3.61 years. The main results of the COPE trial demonstrated that the incidences of hard cardiovascular composite endpoints and fatal or non-fatal strokes were significantly higher in the benidipine/ß-blocker group than in the benidipine/thiazide group.Methods and Results:We further evaluated the treatment effects on different cardiac events among the 3 benidipine-based regimens.We observed a total of 50 cardiac events, 4.2 per 1000 person-years. The incidences of total cardiac events and each cardiac event were similarly low among the 3 treatment groups. Unadjusted and multi-adjusted hazard ratios for total cardiac events showed no significant difference among the 3 treatment groups. CONCLUSIONS: This subanalysis of the COPE trial demonstrated that blood pressure-lowering regimens combining benidipine with an ARB, ß-blocker or thiazide diuretic were similarly effective for the prevention of cardiac events in Japanese hypertensive outpatients.

On-Treatment Blood Pressure and Cardiovascular Outcomes in Older Adults With Isolated Systolic Hypertension.

Our aim was to assess optimal on-treatment blood pressure (BP) at which cardiovascular disease (CVD) and all-cause mortality risks are minimized in Japanese older adults with isolated systolic hypertension. We used data from the VALISH study (Valsartan in Elderly Isolated Systolic Hypertension) that recruited older adults (n=3035; mean age, 76 years) with systolic BP (SBP) of ≥160 mm Hg and diastolic BP of <90 mm Hg. Patients were treated by valsartan. Patients were also categorized into 3 groups based on achieved on-treatment SBP of <130 mm Hg (n=317), 130 to <145 mm Hg (n=2025), or ≥145 mm Hg (n=693). The primary outcome was composite CVD (coronary heart disease, stroke, heart failure, cardiovascular deaths, other vascular diseases, and kidney diseases) with secondary outcome being all-cause mortality. Cox proportional hazards models were used to assess the CVD risk for each group. Over a median 3-year follow-up (8022 person-years), 93 CVD events and 52 deaths occurred. Using the on-treatment SBP of 130 to <145 mm Hg as reference stratum, the multivariable-adjusted hazard ratios and 95% confidence intervals of CVD and all-cause mortality risks for those with SBP<130 mm Hg were 2.08 (1.12-3.83) and 2.09 (0.93-4.71) and for those with SBP≥145 mm Hg were 2.29 (1.44-3.62) and 2.51 (1.35-4.66), respectively. On-treatment diastolic BP yielded no relationships with CVD or all-cause mortality risk. In conclusion, among Japanese older adults with isolated systolic hypertension, SBP in the range between 130 and 144 mm Hg was associated with minimal adverse outcomes and a reduction in CVD and all-cause mortality. The BP range will need to be confirmed in randomized controlled trials. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00151229.

Effects of calcium channel blocker benidipine-based combination therapy on target blood pressure control and cardiovascular outcome: a sub-analysis of the COPE trial.

We compared three benidipine-based regimens-that is, benidipine plus angiotensin receptor blocker (ARB), ß-blocker (BB) or thiazide-and found that the benidipine-BB combination was less beneficial in reducing the risk of stroke than the benidipine-thiazide combination. This sub-analysis sought to compare the effects of reaching a target blood pressure (BP) (<140/90 mm Hg) on the cardiovascular outcomes among the three benidipine-based treatment groups in the Combination Therapy of Hypertension to Prevent Cardiovascular Events trial. This sub-analysis included 3001 subjects to evaluate the achievement of target BP at a minimum of three points at 6-month intervals of clinical BP measurements during the study period. After randomization, the patients were categorized into two groups on the basis of achieved on-treatment target BP: a good control (GC) group achieving a BP⩾66.7% of the target and a poor control (PC) group with a BP <66.6% of the target. For each of the two control groups, outcomes were compared among the three treatment groups. The event rates for cardiovascular composite endpoints, stroke and hard cardiovascular events were higher in the PC group than the GC group (P=0.041, P=0.042 and P=0.038, respectively). Within the PC group, hazard ratios for the incidence of cardiovascular events were lower in the benidipine-thiazide group than in the benidipine-BB group (composite cardiovascular events: 2.04, P=0.033; stroke: 4.14, P=0.005; and hard cardiovascular events: 3.52, P=0.009). Within the GC group, the incidence of cardiovascular events was not different among the three treatment regimens. The benidipine-thiazide combination may provide better cardiovascular outcomes than the benidipine-BB combination even in patients with poor BP control.

Effects of calcium channel blocker-based combinations on intra-individual blood pressure variability: post hoc analysis of the COPE trial.

Visit-to-visit blood pressure (BP) variability is an important predictor of stroke. However, which antihypertensive drug combination is better at reducing visit-to-visit BP variability and therefore at reducing stroke incidence remains uncertain. We have previously reported that the dihydropyridine calcium channel blocker benidipine combined with a ß-blocker appeared to be less beneficial in reducing the risk of stroke than a combination of benidipine and thiazide. Here, we further compare the visit-to-visit BP variability among three benidipine-based regimens, namely angiotensin receptor blocker (ARB), ß-blocker and thiazide combinations. The present post hoc analysis included 2983 patients without cardiovascular events or death during the first 18 months after randomization. We compared the BP variability (defined as the s.d. and the coefficient of variation (CV)), maximum systolic BP (SBP) and diastolic BP (DBP) of the clinic mean on-treatment BPs obtained at 6-month intervals, starting 6 months after the treatment initiation, among the 3 treatments (ARB, n=1026; ß-blocker, n=966; thiazide, n=991). During the first 6-36 months after randomization, both the s.d. and CV-BPs were lower in the benidipine-thiazide group than in the benidipine-ß-blocker group (s.d.-SBP, P=0.019; s.d.-DBP, P=0.030; CV-SBP, P=0.012; CV-DBP, P=0.022). The s.d. and CV in the ARB group did not reach statistical significance compared with the other two groups. The maximum BPs did not differ among the three treatments. These findings suggest that the benidipine-thiazide combination may reduce visit-to-visit BP variability more than the benidipine-ß-blocker combination.

Preferable effects of olmesartan/calcium channel blocker to olmesartan/diuretic on blood pressure variability in very elderly hypertension: COLM study subanalysis.

OBJECTIVE: The aims of this subanalysis of the COLM trial [NCT00454662] were to compare visit-to-visit variability (VVV) of blood pressure (BP) between age groups and between two treatment combinations, that is, the angiotensin II receptor blocker, olmesartan combined with a calcium channel blocker (CCB), or a diuretic and to investigate the effect of VVV of BP on cardiovascular events in elderly hypertensive patients. METHODS: Hypertensive patients ages 65-84 years with a history of and/or risk factors for cardiovascular disease were randomized to receive treatment with olmesartan along with either a CCB or a diuretic for at least 3 years. This subanalysis comprised 4876 patients who had their office BP measured at least three occasions (median nine occasions) during the follow-up period. VVV of BP was defined by several metrics including the within-individual standard deviation of every visit during the follow-up period. RESULTS: VVV of SBP was larger in the very elderly group (75-84 years) than in the elderly group (65-74 years). VVV of SBP was smaller in the olmesartan along with CCB group than in the olmesartan along with diuretic group, especially in very elderly patients and also isolated systolic hypertensive patients. The incidence rate of primary endpoint increased along with an increment in the SD of SBP in all of the age and treatment groups. CONCLUSION: VVV of SBP may mediate the preferable effect of combination of angiotensin II receptor blocker along with CCB on cardiovascular events in the very elderly and also isolated systolic hypertensive patients.

Comparison of olmesartan combined with a calcium channel blocker or a diuretic in elderly hypertensive patients (COLM Study): safety and tolerability.

The cardiovascular effects of combined therapy with the angiotensin receptor blocker (olmesartan) and a dihydropyridine calcium channel blocker (CCB) or a diuretic were compared in high-risk elderly Japanese hypertensive patients by performing a randomized, open label, blinded-endpoint study of morbidity and mortality (the COLM study). Here we report the results obtained with respect to safety and tolerability. High-risk hypertensive patients aged 65-84 years were enrolled and were randomized to receive olmesartan combined with either a CCB (amlodipine or azelnidipine) or a low-dose diuretic for at least 3 years. The primary endpoint was a composite of fatal and non fatal cardiovascular events, whereas adverse events (AEs) and the percentage of patients who discontinued the allocated treatment were evaluated as secondary endpoints. A total of 5141 patients were randomized. Both combination regimens achieved a similar reduction of cardiovascular morbidity and mortality. The incidences of AEs, serious AEs, drug-related serious AEs and discontinuation due to serious AEs were lower in the olmesartan plus CCB group than in the olmesartan plus diuretic group. Serum levels of uric acid and creatinine were significantly higher in the olmesartan plus diuretic group than in the olmesartan plus CCB group. Olmesartan combined with a CCB was significantly superior to olmesartan plus a diuretic with regard to the frequency of AEs and discontinuation of treatment.

Combination therapy of hypertension in the elderly: a subgroup analysis of the Combination of OLMesartan and a calcium channel blocker or diuretic in Japanese elderly hypertensive patients trial.

Combination of OLMesartan and a calcium channel blocker or a diuretic in Japanese elderly hypertensive patients (COLM) trial demonstrated that olmesartan combinations with a CCB or diuretic have similar effects on reducing cardiovascular risk in elderly hypertensive patients. However, the safety profiles suggest that olmesartan combined with CCB may be preferable to olmesartan combined with diuretic. In this subgroup analysis, we further evaluated the effects and safety of these combinations in elderly (65-74 years old (y.o.)) and very elderly (75-84 y.o.) hypertensive patients. In the COLM trial, 5141 patients (2918 elderly and 2223 very elderly) were randomly assigned to receive olmesartan-based therapy with either CCB or diuretic. The hazard ratios and 95% confidence intervals, respectively, in the elderly age group and in the very elderly group were: 1.04 (0.72-1.50; olmesartan plus CCB vs. olmesartan plus diuretic, P = 0.85) and 0.71 (0.51-0.99, P = 0.045) for the primary composite end point, and 1.07 (0.67-1.72, P = 0.77) and 0.64 (0.42-0.98, P = 0.036) for the composite of hard end points. The hazard ratios for stroke (fatal and non-fatal) were 1.48 (0.88-2.48; olmesartan plus CCB vs. olmesartan plus diuretic, P = 0.13) and 0.63 (0.39-1.02, P = 0.059) (interaction-P = 0.019). Withdrawal rates from the trial, withdrawal due to serious adverse event and the incidence of any adverse event were higher in the olmesartan plus diuretic group than in the olmesartan plus CCB group in both age groups. In conclusion, angiotensin receptor blocker (ARB) and CCB combination may be preferable to an ARB and diuretic combination in the very elderly hypertensive patients for the reduction of cardiovascular risk, particularly for the reduction in stroke risk.

A randomised controlled trial for the evaluation of risk for type 2 diabetes in hypertensive patients receiving thiazide diuretics: Diuretics In the Management of Essential hypertension (DIME) study.

OBJECTIVES: Thiazide diuretics are one of the first choice antihypertensives but not optimally utilised because of concerns regarding their adverse effects on glucose metabolism. The Diuretics In the Management of Essential hypertension (DIME) study was designed, for the first time, to assess the risk for type 2 diabetes mellitus in patients with essential hypertension during antihypertensive treatment with low-dose thiazide diuretics compared to those not treated with diuretics. DESIGN: Multicentre, unblinded, pragmatic, randomised, controlled trial with blinded assessment of end points and intention-to-treat analysis that was started in 2004 and finished in 2012. SETTING: Hypertension clinics at 106 sites in Japan, including general practitioners' offices and teaching hospitals. PARTICIPANTS: Non-diabetic patients with essential hypertension. INTERVENTIONS: Antihypertensive treatment with low-dose thiazide diuretics at 12.5 mg/day of hydrochlorothiazide or equivalent (Diuretics group) or that without thiazide diuretics (No-diuretics group). MAIN OUTCOME: The primary outcome was new onset of type 2 diabetes diagnosed according to WHO criteria and the criteria of Japanese Society of Diabetes. RESULTS: 1130 patients were allocated to Diuretics (n=544) or No-diuretics group (n=586). Complete end point information was collected for 1049 participants after a median follow-up of 4.4 years. Diabetes developed in 25 (4.6%) participants in the Diuretics group, as compared with 29 (4.9%) in the No-diuretics group (HR 0.93; 95% CI 0.55 to 1.58; p=0.800). CONCLUSIONS: Antihypertensive treatment with thiazide diuretics at low doses may not be associated with an increased risk for new onset of type 2 diabetes. This result might suggest safety of use of low doses of thiazide diuretics. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00131846.

Combinations of olmesartan and a calcium channel blocker or a diuretic in elderly hypertensive patients: a randomized, controlled trial.

OBJECTIVE: The aim of the present study was to compare the cardiovascular effects of olmesartan, an angiotensin II receptor blocker, combined with a calcium channel blocker (CCB) or a diuretic, in a prospective, randomized, open-label, blinded endpoint trial. METHODS: Japanese hypertensive patients aged at least 65 to less than 85 years with SBP at least 140 mmHg and/or DBP at least 90 mmHg with antihypertensive treatment, or SBP at least 160 mmHg and/or DBP at least 100 mmHg without antihypertensive treatment were randomized to receive olmesartan with either a dihydropyridine CCB or a low-dose diuretic. If SBP and/or DBP remained at least 140 and/or at least 90 mmHg, the other antihypertensive drug was added. The primary endpoint was a composite of fatal and nonfatal cardiovascular events. The median follow-up time was 3.3 years. RESULTS: Blood pressure decreased similarly in both groups. The primary endpoint occurred in 116/2568 patients (4.5%) in the olmesartan plus CCB group and in 135/2573 patients (5.3%) in the olmesartan plus diuretic group [hazard ratio 0.83, 95% confidence interval (CI) 0.65-1.07, P = 0.16]. Rates of all-cause death and cardiovascular deaths were similar. Among patients aged at least 75 years, the incidence of stroke tended to be lower in the olmesartan plus CCB group than in the olmesartan plus diuretic group (hazard ratio 0.63, 95% CI 0.38-1.02, P = 0.059, interaction P = 0.019). Fewer patients in the olmesartan plus CCB group (8.2%, 211/2568) than in the olmesartan plus diuretic group (9.8%, 253/2573; P = 0.046) experienced serious adverse events. CONCLUSION: Despite no significant difference in cardiovascular events, the different safety profiles suggest that the combination of olmesartan and CCB may be preferable to that of olmesartan and diuretic.

Rho-kinase contributes to pressure-induced constriction of renal microvessels.

Renal afferent arterioles (AFF) regulate glomerular capillary pressure through two main mechanisms: the myogenic response (MYO) and tubuloglomerular feedback (TGF). Because Rho-kinase and nitric oxide synthase (NOS) are established factors that modulate vascular tone, we examined the role of these factors in pressure-induced AFF tone in Wistar-Kyoto rats and in spontaneously hypertensive rats (SHR) using an intravital CCD camera. Elevated renal perfusion pressure elicited marked AFF constriction that was partially inhibited by gadolinium, furosemide and fasudil, which inhibit MYO, TGF and Rho-kinase, respectively; however, this AFF constriction was completely blocked by combined treatment with fasudil+gadolinium or fasudil+furosemide. S-methyl-L-thiocitrulline (SMTC) partially reversed the fasudil-induced inhibition of TGF-mediated, but not that of MYO-mediated, AFF constriction. In SHR, the pressure-induced AFF response was enhanced, and MYO- and TGF-induced constriction were exaggerated. In the presence of gadolinium, SMTC partially mitigated the fasudil-induced inhibition of TGF-mediated AFF constriction. Immunoblot analyses demonstrated that both Rho-kinase activity and neuronal NOS were augmented in SHR kidneys. In conclusion, Rho-kinase contributes to MYO- and TGF-mediated AFF responses, and these responses are enhanced in SHR. Furthermore, neuronal NOS-induced nitric oxide modulates the TGF mechanism. This mechanism constitutes a target for Rho-kinase in TGF-mediated AFF constriction.

Renal thrombotic microangiopathy in a patient with septic disseminated intravascular coagulation.

BACKGROUND: The mechanism for the development of thrombotic microangiopathy (TMA) during sepsis has only been partially elucidated. TMA is recognized as a disease caused by various factors, and may be involved in the emergence of organ damage in severe sepsis. Here we report a case of TMA that followed disseminated intravascular coagulation (DIC) due to severe infection in a patient with a reduced ADAMTS-13 activity level. CASE PRESENTATION: An 86-year-old Japanese woman was admitted to our hospital because of low back pain and fever. A careful evaluation led to a diagnosis of acute obstructive pyelonephritis due to a ureteral stone. Proteus mirabilis was isolated from both blood and urine cultures. The patient developed systemic inflammatory response syndrome and DIC, and was treated with antibiotics and daily continuous hemodiafiltration. Although infection and the coagulation abnormalities due to DIC were successfully controlled, renal failure persisted and her consciousness level deteriorated progressively in association with severe thrombocytopenia and microangiopathic hemolytic anemia. We therefore suspected the presence of TMA and started plasma exchange, which resulted in an impressive improvement in consciousness as well as the laboratory abnormalities. The ADAMTS-13 activity was 44% and the patient tested negative for the ADAMTS-13 inhibitor prior to the initiation of plasma exchange. A renal biopsy was performed to determine the etiology of acute renal injury, which revealed findings that were interpreted to be compatible with the sequelae of TMA. The follow-up studies performed after the successful treatment of TMA showed that her plasma ADAMTS-13 activity level remained persistently low. It is surmised that septic DIC occurring in the presence of preexisting reduced ADAMTS-13 activity have led to the development of secondary TMA in the present case. CONCLUSION: The present case suggests that TMA can be superimposed on sepsis-induced DIC, and plasma exchange is expected to be beneficial in such situations. Clinicians should consider the possibility of secondary TMA that follows sepsis-induced DIC in certain indicative clinical settings.

Comparison of efficacy and safety between bisoprolol transdermal patch (TY-0201) and bisoprolol fumarate oral formulation in Japanese patients with grade I or II essential hypertension: randomized, double-blind, placebo-controlled study.

TY-0201 (TY) is a new drug absorbed by the transdermal delivery system developed for the treatment of hypertension, which contains the free base of bisoprolol fumarate that is widely used. An 8-week randomized, double-blind, placebo-controlled study was conducted in hypertensive patients to evaluate the superiority of TY 8 mg to placebo and the noninferiority of TY 8 mg to bisoprolol fumarate oral formulation (BO) 5 mg. Changes in diastolic blood pressure (BP) (primary endpoint) from baseline in the TY 8 mg group, the BO 5 mg group, and the placebo group were -12.2 mm Hg, -11.8 mm Hg, and -3.7 mm Hg, respectively, with TY 8 mg demonstrating superiority to placebo and noninferiority to BO 5 mg. Changes from baseline for systolic BP and pulse rate produced significant reductions compared with placebo. TY is expected to serve as a new treatment approach for hypertensive patients.

Effects of a benidipine-based combination therapy on the risk of stroke according to stroke subtype: the COPE trial.

The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial compared the dihydropyridine T/L-type calcium channel blocker benidipine-based therapies when combined with an angiotensin receptor blocker (ARB), a ß-blocker (BB) or a thiazide diuretic (TD). The results suggested that benidipine combined with a BB appeared to be less beneficial in reducing the risk of stroke compared with the benidipine-TD combination (hazard ratio (HR): 2.31, P=0.0109). We further evaluated the treatment effects on different stroke subtypes among the three benidipine-based regimens. The COPE trial was an investigator-initiated, multicenter study with PROBE design. Patients with atrial fibrillation or flutter were excluded from the study. All stroke events were subclassified with the Trial of Org 10,172 in Acute Stroke Treatment (TOAST) criteria. The total incidence of stroke was 4.7, hemorrhagic stroke was 1.6 and ischemic stroke was 2.5 per 1000 person-years. The incidence of lacunar stroke was 1.1, large-artery stroke was 0.6, cardioembolic stroke was 0.3, unknown ischemic type was 0.6 and transient ischemic attack was 0.6 per 1000 person-years. Although few differences in stroke subtypes were observed among the three treatment groups, multi-adjusted HRs for the incidence rates of all types of stroke, hemorrhagic stroke and ischemic stroke were significantly higher with the benidipine-BB regimen than with the benidipine-TD regimen. The incidence of both hemorrhagic and ischemic stroke in the benidipine-ARB regimen was not different compared with the other two treatment regimens. This prespecified sub-analysis suggested that a blood pressure-lowering therapy with a benidipine-TD regimen might be beneficial for hypertensive patients to prevent both hemorrhagic and ischemic stroke.

Combination therapy for hypertension in patients with CKD: a subanalysis of the Combination Therapy of Hypertension to Prevent Cardiovascular Events trial.

The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial was a multicenter, randomized, three-arm comparative study (N=3293) undertaken to determine the optimal combination therapy, based on the occurrence of cardiovascular events in patients treated with an angiotensin II receptor blocker (ARB), a ß-blocker (BB) or a thiazide diuretic (TD) in addition to the calcium antagonist benidipine as baseline medication. This subanalysis was conducted to compare the efficacy of three combination therapies in a subset of 834 patients with chronic kidney disease (CKD) (287 patients treated with benidpine-ARB, 283 patients treated with benidipine-BB and 264 patients treated with benidipine-TD). The incidence of composite cardiovascular events as the primary end point did not differ among these three groups. The incidence of hard end points and cerebrovascular events among these groups did not differ either, although the incidence among all patients in the COPE trial was lower in the benidipine-TD group than in the benidipine-BB group. The incidence of new-onset diabetes mellitus was higher in the benidipine-TD group than in the benidipine-ARB group among patients with CKD. The estimated glomerular filtration rate (eGFR) was maintained even after 12 months of treatment in patients with a baseline eGFR <60 ml min(-1) per 1.73 m(2) regardless of the treatment group, although the eGFR decreased over time in all patients in the three groups. In conclusion, in patients with CKD, all of the tested combination therapies demonstrated comparable efficacy in terms of prevention of cardiovascular events as well as maintenance of eGFR.

[Current status of and regional differences in CKD management and medical cooperation in Japan: from the results of a nationwide questionnaire survey for primary care physicians].

OBJECTIVE: The goal of this study was to figure out the current status of and regional differences in CKD management and medical cooperation in Japan. METHODS: We conducted a nationwide questionnaire survey on CKD management for primary care physicians (PCPs) from December 2012 to March 2013. The questionnaire included 36 items about CKD management and medical cooperation. In order to compare the current status of CKD care and cooperation, we divided the country into 11 areas; Hokkaido, Tohoku, Kanto, Koshin-etsu, Hokuriku, Chubu-Tokai, Kinki, Chugoku, Shikoku, Kyushu and Okinawa. RESULTS: 28,200 sets of questionnaires were delivered to PCPs throughout Japan, and 2,287 (8.1%) doctors responded. Doctors at clinics accounted for 86.5%, and 90.9% were non-nephrologists. Regional differences were evident in the following items regarding CKD management; urinalysis at the first examination, measurement of urinary protein/albumin excretion, frequency of blood testing, counselling with eGFR, prescription of erythropoiesis stimulating agents (ESA). Urinalysis at the first examination was relatively rare in Koshin-etsu and Kanto (p < 0.01), and counseling with eGFR was relatively rare in Tohoku, Shikoku and Koshin-etsu (p = 0.05). Regional differences regarding medical cooperation were evident in the following items; functional level of cooperation, critical path, presence of consulting nephrologist, personal relationship, satisfaction with the nephrologists' reaction to referral, CKD involvement in Specific Medical Checkup/Specific Medical Guidance. Functional level of cooperation was higher in Chugoku, Okinawa, Chubu-Tokai and Hokuriku, and lower in Shikoku, Koshin-etsu and Kinki (p < 0.05). Serum creatinine measurement in the Specific Medical Checkup was involved more frequently in Okinawa, Shikoku, Kanto, Chubu-Tokai, Kyushu and Hokuriku, and less frequently in Tohoku, Chugoku and Kinki (p < 0.01). CONCLUSION: We elucidated the current status of CKD management by PCPs and medical cooperation in Japan. Effective actions to improve CKD care must be proposed on the basis of these data, especially the existing regional differences.