Single‐pill combination of cilnidipine,an L‐/N‐type calcium channel blocker,and valsartan effectively reduces home pulse pressure in patients with uncontrolled hypertension and sympathetic hyperactivity: The HOPE‐Combi survey

The home blood pressure (BP) control by a single‐pill combination of cilnidipine (an L‐/N‐type calcium channel blocker; CCB) and valsartan (HOPE‐Combi) survey is a multicenter, post‐marketing, prospective observational study of a single‐pill combination of cilnidipine 10 mg and valsartan 80 mg (SPC of Cil/Val) in patients with uncontrolled hypertension. We examined the effects of the SPC of Cil/Val on morning home systolic BP (MHSBP) and morning home pulse pressure (MHPP) of 1036 patients with hypertension over 12 months. MHSBP decreased by 14.0 mm Hg (P < .01), and MHPP decreased by 6.6 mm Hg (P < .01). Moreover, morning home pulse rate (MHPR) decreased by 2.1 bpm (P < .01). A more progressive and greater decrease in MHSBP (−17.2 vs −10.3 mm Hg, P < .01) and MHPP (−7.6 vs −4.9 mm Hg, P < .01) was observed in patients with higher MHPR (≥70 bpm) than in those with lower MHPR (<70 bpm) over the treatment period. In particular, in patients with a wide MHPP (≥70 mm Hg), the difference in the MHPP reduction was greater in patients with higher MHPR than in those with lower MHPR (−17.9 vs −13.6 mm Hg, P < .01). These results suggested that the SPC of Cil/Val, which possesses the unique sympatholytic characteristics of an L‐/N‐type CCB, was particularly effective in patients with uncontrolled hypertension and sympathetic hyperactivity.     

Comparative effects of valsartan plus cilnidipine or hydrochlorothiazide on nocturnal home blood pressure

We tested our hypothesis that, in hypertensive patients with higher nocturnal home systolic blood pressure (HSBP) at baseline, a valsartan/cilnidipine (80/10 mg) combination would reduce nocturnal HSBP more markedly than a valsartan/hydrochlorothiazide (80/12.5 mg) combination. Patients measured their nocturnal HSBP over three nights prior to study randomization and at the end of treatment. Sixty‐three and 66 patients comprised the valsartan/cilnidipine and valsartan/hydrochlorothiazide groups; their respective baseline nocturnal HSBP values were 124.3 ± 15.6 and 125.8 ± 15.2 mm Hg (P = .597). Nocturnal HSBPs were significantly reduced from baseline in both groups. Although the valsartan/hydrochlorothiazide group exhibited a significantly greater reduction in nocturnal HSBP compared to the valsartan/cilnidipine group (−5.0 vs. −10.0 mm Hg, P = .035), interaction between the treatment groups and the baseline nocturnal HSBP levels for the changes in nocturnal HSBP after the treatment periods was significant (P = .047). The BP‐lowering effect of valsartan/cilnidipine was more dependent on baseline nocturnal HSBP than that of valsartan/hydrochlorothiazide.     

Prognostic significance of day‐by‐day in‐hospital blood pressure variability in COVID‐19 patients with hypertension

Hypertension is the most common comorbidity in patients with coronavirus disease 2019 (COVID‐19) and increases in‐hospital mortality. Day‐by‐day blood pressure (BP) variability (BPV) is associated with clinical outcomes in hypertensive patients. However, little information is available on the association of BPV with the outcomes of COVID‐19 patients with hypertension. This study aimed to demonstrate whether day‐by‐day in‐hospital BPV had prognostic significance in these patients. The authors included 702 COVID‐19 patients with hypertension from Huoshenshan Hospital (Wuhan, China), who underwent valid in‐hospital BP measurements on at least seven consecutive days. Day‐by‐day BPV was assessed by standard deviation (SD), coefficient of variation (CV), and variation independent of mean (VIM). Overall, patients with severe COVID‐19 and non‐survivors had higher BPV than moderate cases and survivors, respectively. Additionally, higher BPV was correlated with greater age and higher levels of C‐reactive protein, procalcitonin, high‐sensitive cardiac troponin I, and B‐type natriuretic peptide. In multivariable Cox regression, SD of systolic BP (SBP) was predictive of mortality [hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.05–1.30] as well as acute respiratory distress syndrome (ARDS) (HR 1.09, 95% CI 1.01–1.16). Similar trends were observed for CV and VIM of SBP, but not indices of diastolic BP variability. The authors demonstrated that day‐by‐day in‐hospital SBP variability can independently predict mortality and ARDS in COVID‐19 patients with hypertension. And high BPV might be correlated with severe inflammation and myocardial injury. Further studies are needed to clarify whether early reduction of BPV will improve the prognosis of these patients.     

Comparative effects of valsartan plus either cilnidipine or hydrochlorothiazide on home morning blood pressure surge evaluated by information and communication technology–based nocturnal home blood pressure monitoring

The authors tested the hypothesis that a valsartan/cilnidipine combination would suppress the home morning blood pressure (BP) surge (HMBPS) more effectively than a valsartan/hydrochlorothiazide combination in patients with morning hypertension, defined as systolic BP (SBP) ≥135 mm Hg or diastolic BP ≥85 mm Hg assessed by a self‐measuring information and communication technology–based home BP monitoring device more than three times before either combination''s administration. This was an 8‐week prospective, multicenter, randomized, open‐label clinical trial. The HMBPS, which is a new index, was defined as the mean morning SBP minus the mean nocturnal SBP, both measured on the same day. The authors randomly allocated 129 patients to the valsartan/cilnidipine (63 patients; mean 68.4 years) or valsartan/hydrochlorothiazide (66 patients; mean 67.3 years) combination groups, and the baseline HMBPS values were 17.4 mm Hg vs 16.9 mm Hg, respectively (P = .820). At the end of the treatment period, the changes in nocturnal SBP and morning SBP from baseline were significant in both the valsartan/cilnidipine and valsartan/hydrochlorothiazide groups (P < .001): −5.0 vs −10.0 mm Hg (P = .035) and −10.7 vs −13.6 mm Hg (P = .142), respectively. HMBPS was significantly decreased from baseline in both groups (P < .001), but there was no significant difference between the two groups: 14.4 mm Hg vs 14.0 mm Hg, respectively (P = .892). Valsartan/cilnidipine could not significantly suppress HMBPS compared with valsartan/hydrochlorothiazide. Large‐scale randomized controlled studies are needed to assess how reducing HMBPS will affect future cardiovascular outcomes. The information and communication technology–based home BP monitoring device may become an alternative to ambulatory BP monitoring, which has been a gold standard to measure nocturnal BP and the morning BP surge.     

A double‐blind,placebo‐controlled trial on the antihypertensive treatment effect of a quadruple single‐pill combination

In a randomized, double‐blind, placebo‐controlled trial, we investigated antihypertensive treatment effect of a quadruple single‐pill combination of reserpine 0.1 mg, dihydralazine 12.5 mg, hydrochlorothiazide 12.5 mg, and triamterene 12.5 mg, and changes in plasma levels of monoamine neurotransmitters (serotonin, norepinephrine, and dopamine) in patients with grade 1 hypertension. Eligible patients with a systolic/diastolic blood pressure (BP, average of six readings at two clinic visits during a 4‐week run‐in period) of 140‐159/90–99 mmHg were randomly assigned to the quadruple combination (n = 30) or placebo (n = 30). The randomized patients were instructed to take a pill of the combination or placebo once daily and followed up at 4, 8, and 12 weeks, respectively. Monoamine neurotransmitters were measured at baseline and 12 weeks of follow‐up. After 12‐week treatment, systolic/diastolic BP significantly (p ≤ .0001) decreased from 140.8 ± 7.9/89.5 ± 7.5 mmHg at baseline by 9.8 ± 1.8/6.4 ± 1.3 mmHg in the combination group. The corresponding values in the placebo group were 141.3 ± 7.9/90.3 ± 7.3 mmHg and 5.2 ± 1.8/0.4 ± 1.3 mmHg, respectively. The between‐group differences in systolic/diastolic BP changes were −4.6/−6.0 mmHg (95% CI, −9.7 to 0.6/−9.7 to −2.2 mmHg, p ≤ .08). The control rate of hypertension was higher in the combination than placebo group (63.3% vs. 16.7%, p = .0002). Plasma serotonin, but not norepinephrine or dopamine, changed in both treatment and placebo groups (p ≤ .01). Nonetheless, plasma norepinephrine tended to decrease in the treatment group (−34.4 pg/ml, p = .09). Adverse events occurred in 5 (16.7%) and 3 (10.0%) patients in the combination and placebo groups, respectively. Our study showed that the quadruple combination reduced BP and caused some changes in plasma neurotransmitters.     

Day‐by‐day blood pressure variability in hospitalized patients with COVID‐19

In a retrospective analysis, the authors investigated day‐by‐day blood pressure variability (BPV) and its association with clinical outcomes (critical vs. severe and discharged) in hospitalized patients with COVID‐19. The study participants were hospitalized in Tongji Hospital, Guanggu Branch, Wuhan, China, between February 1 and April 1, 2020. BPV was assessed as standard derivation (SD), coefficient of variation (CV), and variability independent of mean (VIM). The 79 participants included 60 (75.9%) severe patients discharged from the hospital after up to 47 days of hospitalization, and 19 (24.1%) critically ill patients transferred to other hospitals for further treatment (n = 13), admitted to ICU (n = 3) or died (n=3). Despite similar use of antihypertensive medication (47.4% vs. 41.7%) and mean levels of systolic/diastolic blood pressure (131.3/75.2 vs. 125.4/77.3 mmHg), critically ill patients, compared with severe and discharged patients, had a significantly (p ≤ .04) greater variability of systolic (SD 14.92 vs. 10.84 mmHg, CV 11.39% vs. 8.56%, and VIM 15.15 vs. 10.75 units) and diastolic blood pressure (SD 9.38 vs. 7.50 mmHg, CV 12.66% vs. 9.80%, and VIM 9.33 vs. 7.50 units). After adjustment for confounding factors, the odds ratios for critical versus severe and discharged patients for systolic BPV were 3.41 (95% confidence interval [CI] 1.20‐9.66, p = .02), 4.09 (95% CI 1.14‐14.67, p = .03), and 2.81 (95% CI 1.12‐7.05, p = .03) for each 5‐mmHg increment in SD, 5% increment in CV, and 5‐unit increment in VIM, respectively. Similar trends were observed for diastolic BPV indices (p ≤ .08). In conclusion, in patients with COVID‐19, BPV was greater and associated with worse clinical outcomes.     

Clinical effectiveness and safety of amlodipine/losartan‐based single‐pill combination therapy in patients with hypertension: Findings from real‐world,multicenter observational databases

Various single‐pill combinations (SPCs) have been introduced to improve drug compliance and clinical efficacy. However, there is a lack of real‐world evidence regarding the effectiveness of these SPCs for hypertension. This study evaluated the real‐world clinical efficacy and safety of amlodipine/losartan‐based SPC therapies in patients with hypertension in a real‐world setting. A total of 15 538 patients treated with amlodipine/losartan‐based SPCs [amlodipine + losartan (AL), amlodipine + losartan + rosuvastatin (ALR), and amlodipine + losartan + chlorthalidone (ALC)] were selected from the database of three tertiary hospitals in Korea. The efficacy endpoints were target blood pressure (BP) and low‐density lipoprotein cholesterol (LDL‐C) achievement rates. Safety was evaluated based on laboratory parameters. Drug adherence was defined as the proportion of medication days covered (PDC). The target BP attainment rate was above 90% and was similar among the three groups. Although many patients in the AL and ALC groups took statins, the target LDL‐C attainment rate was significantly higher in the ALR group than in the AL and ALC groups. Safety endpoints were not significantly different among the groups, except serum uric acid level and incidence rate of new‐onset hyperuricemia, which were significantly lower in the AL and ALR groups than in the ALC group. The PDC was > 90% in all groups. In the real‐world hypertensive patients, amlodipine/losartan‐based SPC therapy demonstrated good target BP achievement rates. Especially, rosuvastatin‐combination SPC showed better target LDL‐C goal achievement rate compared to the other SPCs. All three amlodipine/losartan‐based SPC had excellent drug adherence.     

Impact of home blood pressure variability on cardiovascular outcome in patients with arterial stiffness: Results of the J‐HOP study

This study sought to investigate whether the relation between increased blood pressure (BP) variability and increased arterial stiffness confers a risk for cardiovascular disease (CVD) events. We analyzed 2648 patients from a practitioner‐based population (mean ± SD age 64.9 ± 11.4 years: 75.8% taking antihypertensive medication) with at least one cardiovascular risk factor who underwent home BP monitoring in the Japan Morning Surge‐Home Blood Pressure Study. The standard deviation (SD_SBP), coefficient of variation (CV_SBP), and average real variability (ARV_SBP) were assessed as indexes of day‐by‐day home systolic BP (SBP) variability. The authors assessed arterial stiffness by brachial‐ankle pulse wave velocity (baPWV) and divided patients into lower (< 1800 cm/s, n = 1837) and higher (≥1800 cm/s, n = 811) baPWV groups. During a mean follow‐up of 4.4 years, 95 cardiovascular events occurred (8.1 per 1000 person‐years). In Cox proportional hazard models adjusted for traditional cardiovascular risk factors including average home SBP, the highest quartiles of SD_SBP (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.23‐4.32), CV_SBP (HR, 2.89; 95%CI, 1.59‐5.26) and ARV_SBP (HR, 2.55; 95%CI, 1.37‐4.75) were predictive of CVD events compared to the other quartiles in the higher baPWV group. Moreover, 1SD increases in SD_SBP (HR, 1.44; 95%CI, 1.13‐1.82), CV_SBP (HR, 1.49; 95%CI, 1.16‐1.90) and ARV_SBP (HR, 1.37; 95%CI, 1.09‐1.73) were also predictive of CVD events. These associations remained even after N‐terminal pro‐brain natriuretic peptide was added to the models. However, these associations were not observed in the lower baPWV group. We conclude that arterial stiffness contributes to the association between home BP variability and CVD incidence.