Showing papers by "Luis M. Ruilope published in 2015"

Effect of finerenone on albuminuria in patients with diabetic nephropathy : a randomized clinical trial

Abstract: Importance Steroidal mineralocorticoid receptor antagonists, when added to a renin-angiotensin system blocker, further reduce proteinuria in patients with chronic kidney disease but may be underused because of a high risk of adverse events. Objective To evaluate the safety and efficacy of different oral doses of the nonsteroidal mineralocorticoid receptor antagonist finerenone, given for 90 days to patients with diabetes and high or very high albuminuria who are receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Design, Setting, and Participants Randomized, double-blind, placebo-controlled, parallel-group study conducted at 148 sites in 23 countries. Patients were recruited from June 2013 to February 2014 and the study was completed in August 2014. Of 1501 screened patients, 823 were randomized and 821 received study drug. Interventions Participants were randomly assigned to receive oral, once-daily finerenone (1.25 mg/d, n = 96; 2.5 mg/d, n = 92; 5 mg/d, n = 100; 7.5 mg/d, n = 97; 10 mg/d, n = 98; 15 mg/d, n = 125; and 25 mg/d, n = 119) or matching placebo (n = 94) for 90 days. Main Outcomes and Measures The primary outcome was the ratio of the urinary albumin-creatinine ratio (UACR) at day 90 vs at baseline. Safety end points were changes from baseline in serum potassium and estimated glomerular filtration rate. Results The mean age of the participants was 64.2 years; 78% were male. At baseline, 36.7% of patients treated had very high albuminuria (UACR ≥300 mg/g) and 40.0% had an estimated glomerular filtration rate of 60 mL/min/1.73 m 2 or lower. Finerenone demonstrated a dose-dependent reduction in UACR. The primary outcome, the placebo-corrected mean ratio of the UACR at day 90 relative to baseline, was reduced in the finerenone 7.5-, 10-, 15-, and 20-mg/d groups (for 7.5 mg/d, 0.79 [90% CI, 0.68-0.91; P = .004]; for 10 mg/d, 0.76 [90% CI, 0.65-0.88; P = .001]; for 15 mg/d, 0.67 [90% CI, 0.58-0.77; P P Conclusions and Relevance Among patients with diabetic nephropathy, most receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, the addition of finerenone compared with placebo resulted in improvement in the urinary albumin-creatinine ratio. Further trials are needed to compare finerenone with other active medications. Trial Registration clinicaltrials.gov Identifier:NCT1874431

First Report of the Global SYMPLICITY Registry on the Effect of Renal Artery Denervation in Patients With Uncontrolled Hypertension

Abstract: This study aimed to assess the safety and effectiveness of renal denervation using the Symplicity system in real-world patients with uncontrolled hypertension (NCT01534299). The Global SYMPLICITY Registry is a prospective, open-label, multicenter registry. Office and 24-hour ambulatory blood pressures (BPs) were measured. Change from baseline to 6 months was analyzed for all patients and for subgroups based on baseline office systolic BP, diabetic status, and renal function; a cohort with severe hypertension (office systolic pressure, ≥160 mm Hg; 24-hour systolic pressure, ≥135 mm Hg; and ≥3 antihypertensive medication classes) was also included. The analysis included protocol-defined safety events. Six-month outcomes for 998 patients, including 323 in the severe hypertension cohort, are reported. Mean baseline office systolic BP was 163.5±24.0 mm Hg for all patients and 179.3±16.5 mm Hg for the severe cohort; the corresponding baseline 24-hour mean systolic BPs were 151.5±17.0 and 159.0±15.6 mm Hg. At 6 months, the changes in office and 24-hour systolic BPs were −11.6±25.3 and −6.6±18.0 mm Hg for all patients ( P P 70% and 5 cases of hospitalization for a hypertensive emergency. In clinical practice, renal denervation resulted in significant reductions in office and 24-hour BPs with a favorable safety profile. Greater BP-lowering effects occurred in patients with higher baseline pressures. Clinical Trial Registration— URL: www.clinicaltrials.gov. Unique identifier: NCT01534299

Proceedings from the European clinical consensus conference for renal denervation: considerations on future clinical trial design.

Abstract: Approximately 8–18% of all patients with high blood pressure (BP) are apparently resistant to drug treatment.1,2 In this situation, new strategies to help reduce BP are urgently needed but the complex pathophysiology of resistant hypertension makes this search difficult. Not surprisingly in this context, the latest non-drug treatment which triggered controversy is catheter-based renal denervation (RDN).3,4 The method uses radiofrequency energy, or alternatively ultrasound or chemical denervation, to disrupt renal nerves within the renal artery wall, thereby reducing sympathetic efferent and sensory afferent signalling to and from the kidneys.5,6 Various experimental models of hypertension strongly support this concept7,8 and available evidence also suggests that sympathetic nervous system activation contributes to the development and progression of hypertension and subsequently to target organ damage.7–11 Historical observations have shown that surgical sympathectomy can reduce BP as well as morbidity and mortality in patients with uncontrolled hypertension.12,13 However, the clinical evidence in support of RDN as an effective interventional technique in patients with resistant hypertension is conflicting. A number of observational studies and three randomized, controlled trials (Symplicity HTN-2, Prague-15, and DENERHTN) support both safety and efficacy of this new therapy14–22 but some smaller studies and the large, single-blind, randomized, sham-controlled symplicity HTN-3 trial failed to show superiority of RDN when compared with medical therapy alone.23–25 Whatever the shortcomings of individual trials may be, the possibility remains that the observed BP responses were due to placebo response, the Hawthorne effect, regression to the mean, unknown co-interventions or other bias.26 The design, conduct, and interpretation …

Role of neprilysin inhibitor combinations in hypertension: insights from hypertension and heart failure trials

Abstract: Neprilysin is a neutral endopeptidase and its inhibition increases bioavailability of natriuretic peptides, bradykinin, and substance P, resulting in natriuretic, vasodilatatory, and anti-proliferative effects. In concert, these effects are prone to produce a powerful ventricular unloading and antihypertensive response. LCZ696 (Valsartan/sacubitril) is a first-in-class angiotensin II-receptor neprilysin inhibitor. LCZ696 is a novel drug not only for the treatment of heart failure but it is also likely to be a useful antihypertensive drug and may have a preferential effect on systolic pressure. This review discusses (i) the mechanism of action, pharmacokinetics, and pharmacodynamics of this novel drug, (ii) the efficacy, safety, and tolerability of LCZ696 in treatment of hypertension from the available trials, (iii) evidence from other contemporary trials on combined Neprilysin inhibitors, (iv) future trials and areas of research to identify hypertensive patient populations that would most benefit from LCZ696.

Ethnic Differences in the Degree of Morning Blood Pressure Surge and in Its Determinants Between Japanese and European Hypertensive Subjects Data From the ARTEMIS Study

Abstract: Morning blood pressure (BP) surge has been reported to be a prognostic factor for cardiovascular events. Its determinants are still poorly defined, however. In particular, it is not clear whether ethnic differences play a role in determining morning surge (MS) size. Aim of our study was to explore whether differences exist in the size of MS between Japanese and Western European hypertensive patients. We included 2887 untreated hypertensive patients (age 62.3±8.8 years) from a European ambulatory BP monitoring database and 811 hypertensive patients from a Japanese database (Jichi Medical School Ambulatory Blood Pressure Monitoring WAVE1, age 72.3±9.8 years) following the same inclusion criteria. Their 24-hour ambulatory BP monitoring recordings were analyzed focusing on MS. Sleep-trough MS was defined as the difference between mean systolic BP during the 2 hours after awakening and mean systolic BP during the 1-hour night period that included the lowest sleep BP level. The sleep-trough MS was higher in Japanese than in European hypertensive patients after adjusting for age and 24-hour mean BP levels (40.1 [95% confidence interval 39.0-41.2] versus 23.0 [22.4-23.5] mm Hg; P<0.001). This difference remained significant after accounting for differences in night-time BP dipping. Age was independently associated with MS in the Japanese database, but not in the European subjects. Our results for the first time show the occurrence of substantial ethnic differences in the degree of MS. These findings may help in understanding the role of ethnic factors in cardiovascular risk assessment and in identifying possible ethnicity-related differences in the most effective measures to be implemented for prevention of BP-related cardiovascular events.

Impact of Ambulatory Blood Pressure Monitoring on Reclassification of Hypertension Prevalence and Control in Older People in Spain.

Abstract: Ambulatory blood pressure monitoring (ABPM) accurately classifies blood pressure (BP) status but its impact on the prevalence and control of hypertension is little known. The authors conducted a cross-sectional study in 2012 among 1047 individuals 60 years and older from the follow-up of a population cohort in Spain. Three casual BP measurements and 24-hour ABPM were performed under standardized conditions. Approximately 68.8% patients were hypertensive based on casual BP (≥140/90 mm Hg or current BP medication use) and 62.1% based on 24-hour ABPM (≥130/80 mm Hg or current BP medication use) (P=.009). The proportion of patients with treatment-eligible hypertension who met BP goals increased from 37.4% based on the casual BP target to 54.1% based on the 24-hour BP target (absolute difference, 16.7%; P<.01). These results were consistent across alternative BP thresholds. Therefore, compared with casual BP, 24-hour ABPM led to a reduction in the proportion of older patients recommended for hypertension treatment and a substantial increase in the proportion of those with hypertension control.

KLK1 and ZG16B proteins and arginine-proline metabolism identified as novel targets to monitor atherosclerosis, acute coronary syndrome and recovery.

Abstract: We pursued here the identification of specific signatures of proteins and metabolites in urine which respond to atherosclerosis development, acute event and/or recovery. An animal model (rabbit) of atherosclerosis was developed and molecules responding to atherosclerosis silent development were identified. Those molecules were investigated in human urine from patients suffering an acute coronary syndrome (ACS), at onset and discharge. Kallikrein1 (KLK1) and zymogen granule protein16B (ZG16B) proteins, and l-alanine, l-arabitol, scyllo-inositol, 2-hydroxyphenilacetic acid, 3-hydroxybutyric acid and N-acetylneuraminic acid metabolites were found altered in response to atherosclerosis progression and the acute event, composing a molecular panel related to cardiovascular risk. KLK1 and ZG16B together with 3-hydroxybutyric acid, putrescine and 1-methylhydantoin responded at onset but also showed normalized levels at discharge, constituting a molecular panel to monitor recovery. The observed decreased of KLK1 is in alignment with the protective mechanism of the kallikrein-kinin system. The connection between KLK1 and ZG16B shown by pathway analysis explains reduced levels of toll-like receptor 2 described in atherosclerosis. Metabolomic analysis revealed arginine and proline metabolism, glutathione metabolism and degradation of ketone bodies as the three main pathways altered. In conclusion, two novel urinary panels of proteins and metabolites are here for the first time shown related to atherosclerosis, ACS and patient's recovery.

Trends in Hypertension Control Among the Older Population of Spain From 2000 to 2001 to 2008 to 2010 Role of Frequency and Intensity of Drug Treatment

Abstract: Background—The use of antihypertensive medication and hypertension control has significantly increased during recent decades in some developed countries, but the impact of improved drug treatment on blood pressure (BP) control in the population is unknown. Methods and Results—Data were taken from 2 surveys representative of the population aged ≥60 years in Spain conducted with the same methodology in 2000 to 2001 and in 2008 to 2010. BP was measured 6×. The first BP reading was discarded, and the average of the remaining 3 to 5 BP readings was taken for analysis. Hypertension prevalence was 68.7% in 2000 to 2001 and 66.0% in 2008 to 2010. Between both time periods there was an improvement in hypertension awareness (63.6%–67.7%), drug treatment among those aware (84.5%–87.5%), and BP control among treated hypertensives (30.3%–42.9%). Overall, BP control among all hypertensives increased from 16.3% to 25.4%. After adjustment for age, sex, education, hypertension duration, smoking, alcohol consumption, body ...

An update of the blockade of the renin angiotensin aldosterone system in clinical practice

Abstract: Introduction: Cardiovascular disease (CVD) is the leading cause of death worldwide. Blockade of this system is commonly used in the treatment of cardiovascular (CV) and renal disease.Areas covered: Data from multiple clinical trials have provided good evidence about the benefit of blocking the system as a therapeutic target to reduce CV and renal events. We have reviewed all the tested combinations of different drugs counteracting the effects of the renin–angiotensin–aldosterone system.Expert opinion: Monotherapy with an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB) remains valid in all the guidelines, whereas their dual combination has been discarded due to the absence of proven benefits in high CV risk patients and in patients with chronic kidney disease (CKD). The combination of the standard therapy with an ACEi or an ARB with a mineralocorticoid receptor blocker is a valid option, but has the inconvenience of frequent hyperkalemia in patients with CKD. Simi...

Ambulatory Blood Pressure Monitoring in the Diagnosis, Prognosis, and Management of Resistant Hypertension: Still a Matter of our Resistance?

Abstract: Resistant hypertension, commonly described as the failure to achieve goal blood pressure (BP) despite an appropriate regimen of three antihypertensive drugs at the maximal tolerated doses, one of which is diuretic, is increasingly recognized as an important problem of public health. Large population studies with office measurements suggest that the prevalence of resistance hypertension is approximately at 6-12 % of the general hypertensive population and 8-28 % of treated hypertensives. However, these estimations do not take into account factors of pseudo-resistance, most importantly, the white-coat effect that can be effectively ruled out with ambulatory blood pressure monitoring (ABPM). Recent studies have clearly shown that when ABPM is used, at least 30-35 % of patients labeled as "resistant hypertensives" turn out to have well-controlled BP on ambulatory basis, a finding changing entirely the estimates of prevalence of resistance hypertension and actual patient handling. Furthermore, current evidence suggests that ABPM is a much more accurate predictor of cardiovascular events in resistant hypertension compared to office BP and thus can offer a better risk stratification for these high-risk individuals. Finally, ABPM offers the potential of a better evaluation of the effect of pharmacologic and non-pharmacologic therapeutic interventions. This review attempts to summarize recent evidence on the advantages of ABPM in the diagnosis, prognosis, and management of resistant hypertension.

Factors influencing return-to-work after cerebrovascular disease: the importance of previous cardiovascular risk:

Abstract: BackgroundThe role of prior cardiovascular risk (CVR) in the multifactorial process of returning to work after a cerebrovascular event has not been adequately investigated. Therefore, the objective of the present study was to analyse the association between previous CVR level, cardiovascular risk factors (CVRFs) and return-to-work (RTW) following cerebrovascular disease.DesignThis was a prospective observational study.MethodsWe analysed a cohort of 348 patients who had experienced an episode of cerebrovascular disease-related work absence. These individuals were selected from the ICARIA study (Ibermutuamur CArdiovascular RIsk Assessment). Global CVR was assessed using the SCORE system. We investigated the association between demographics, work-related variables, CVRFs and RTW following a cerebrovascular event.ResultsWe found that a total of 254 individuals (73.0%; 95% CI: 68.3–77.7) returned to work after cerebrovascular disease. Also, we observed a median loss of 12 working years due to disability. Moreo...

Cardiorenal protection during chronic renin-angiotensin-aldosterone system suppression: evidences and caveats.

Abstract: Blocking the renin-angiotensin-aldosterone system (RAAS) has widely shown to be good for the protection of both cardiovascular and renal systems. A large number of trials have demonstrated clear benefits of using angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) to treat patients with established cardiovascular and renal disease during the last decades. Even more, simultaneous protection of cardiovascular and renal system with RAAS blockade has also been shown. However, some caveats of this therapy as the effectiveness lack in long-term, hyperkalaemia risk in patients with chronic kidney disease or aldosterone and albuminuria breakthrough limit their use, lead that new therapeutic strategies are needed for the RAAS blockade. At this time, new horizons are opened to manage the RAAS blockade in the cardiorenal disease through using the positive combination of an ACEi or an ARB plus and aldosterone antagonist, renin inhibitors, or other forms of blockade using new members as LCZ696.

3d.02: blood pressure variability increases with advancing chronic kidney disease stage. a cross-sectional analysis of 14,382 hypertensive patients from spain.

Abstract: Objective: Increased blood pressure (BP) variability has been related to cardiovascular morbidity and mortality in hypertensive patients. We aimed to assess short-term BP variability by means of ambulatory BP monitoring (ABPM) according to renal function status. Design and method: We conducted a cross-sectional analyses with data from 14 382 hypertensives included in the Spanish ABPM Registry. Performance of ABPM was standardized according to guideline recommendations. Kidney function was graded according to current KDIGO definitions for chronic kidney disease (CKD) staging. Estimated glomerular filtration rate was calculated by the CKD-EPI equation. Short-term (reading-to-reading) BP variability was assessed by standard deviation (SD) of mean daytime and nighttime systolic BP (SBP) and diastolic BP (DBP). Results: Mean age of the population was 61.0 ± 13.9 years and 52.6% of patients were male. Distribution according to renal function status was: 8,689 (60.4%) with no CKD, 765 (5.3%) with stage 1 CKD, 494 (3.4%) with stage 2 CKD, 3893 (27.1%) with stage 3 CKD, 413 (2.9%) with stage 4 CKD, and 128 (0.9%) with stage 5 CKD. SD of daytime SBP was higher at more advanced CKD stage (13.6 in CKD-free patients, and 15.7, 16.7, 15.7, 17.5, and 19.0 mmHg in stage 1 to 5 CKD patients respectively, p-trend < 0.001). SD of nighttime SBP also increased with progressive CKD stage, with the change being proportionally higher than that observed for daytime SBP (15.1 in CKD-free patients, and 17.5, 18.8, 17.7, 20.1, and 23.8 mmHg in stage 1 to 5 CKD patients respectively, p-trend < 0.001). SD of daytime DBP and nighttime DBP also increased as renal function worsened but with only marginal statistical significance. Conclusions: Increased short-term BP was significantly associated with progressive CKD stages in a large sample of hypertensive patients. This association was stronger for SBP than for DBP, and for nighttime than for daytime BP. We suggest that increased SBP variability, particularly at night, may partially explain the sharp elevation of cardiovascular risk with worsening renal function.

Ambulatory Blood Pressures in Hypertensive Patients Treated With One Antihypertensive Agent: Differences Among Drug Classes and Among Drugs Belonging to the Same Class

Abstract: The authors investigated the differences in office and ambulatory blood pressure (BP) among major antihypertensive drug classes and among frequently used drugs in each class in 22,617 patients treated with monotherapy from the Spanish ABPM Registry. Using thiazides as the reference group, patients treated with calcium channel blockers have significantly (P<.01) elevated ambulatory BP and less ambulatory control after adjusting for confounders. Inside each class, no significant differences were observed among thiazides or angiotensin receptor blockers. Atenolol and bisoprolol among β-blockers, amlodipine among calcium channel blockers, and lisinopril and enalapril among angiotensin-converting enzyme inhibitors exhibited lower ambulatory BP and better control than other agents. Differences exist among antihypertensive drug classes and among different compounds in each class with respect to ambulatory BP control. This can help physicians choose among drug classes and among compounds in each class if BP reduction is the main objective of treatment.

Aldosterone Antagonists and Renal Denervation: Friends or Foes?

Abstract: See related article, pp 407–413 Activation of the sympathetic nervous system plays an important role in the development and disease progression of hypertension and its comorbidities.1 Antihypertensive treatment approaches have focused on abrogation of activated neurohormonal systems associated with these conditions, including the renin–angiotensin–aldosterone system and the sympathetic nervous system. Despite the availability of effective antihypertensive drugs, certain patients remain uncontrolled to target blood pressure (BP) values.2 For these patients with uncontrolled hypertension, new device-based treatments have been developed, such as surgically implanted baroreceptor stimulators and catheter-based renal denervation.3 The available evidence suggests that renal denervation reduces renal sympathetic activity and office BP, as well as ambulatory BP in open-label registries and randomized, controlled trials in certain patients, but not in all patients.4 The BP-lowering effect of intensified drug treatment, with special focus on aldosterone antagonist treatment, compared with catheter-based renal denervation has not been investigated in detail. In this issue, the prospective, randomized, open-label multicenter PRAGUE-15 trial by Rosa et al5 investigated the efficacy and safety of catheter-based renal denervation (using Medtronic’s Symplicity device) versus intensified pharmacological treatment, including spironolactone in patients with mild to moderate resistant hypertension (office systolic BP [SBP] at the baseline, >140 mm Hg; 24-hour BP at the baseline, >130 mm Hg). The adherence of patients was confirmed by plasma toxicological analyses at the beginning (but unfortunately not after 6 months), and secondary causes of hypertension were excluded systematically. The study provides interesting insights about the efficacy and safety of intensified drug treatment and catheter-based renal denervation in patients with resistant hypertension. The significant BP change (24-hour SBP, −8.1 mm Hg; P =0.001 and office SBP, −14.3 mm Hg; P <0.001) in the intensified drug treatment group of PRAGUE-15 was mostly driven by patients in whom spironolactone was added and …

Ambulatory and home blood pressure monitoring in people with chronic kidney disease. Time to abandon clinic blood pressure measurements

Abstract: PURPOSE OF REVIEW: There is currently much interest in the usefulness of out-of-office blood pressure (BP) for the diagnosis and the management of hypertension in patients with chronic kidney disease (CKD). This is not to suggest that office BP should be disregarded and we will take the opportunity to stress how it could be improved. RECENT FINDINGS: Arterial hypertension constitutes a very relevant cardiovascular and renal risk factor in patients with CKD. To assess this risk, the best tool is ambulatory BP monitoring (ABPM), as it allows the detection of masked hypertension, masked untreated hypertension (MUCH) and nondipping pattern, conditions known to be associated with target organ damage that further contributes to increased risk to the patient. Home BP monitoring (HBPM) cannot fully substitute for ABPM because of the absence of BP data during the night. Despite this, there are good reasons to use HBPM systematically in patients with CKD during long-term follow-up. SUMMARY: In the individual patient office, BP may significantly differ from out-of-office measurements. This shortcoming can be attenuated by repeated measurement at every visit, but even if office BP is considered normal, it is still highly desirable to obtain out-of-office data.

4a.01: long-term effects of renal artery denervation in real world patients with uncontrolled hypertension from the global symplicity registry.

Abstract: Objective:The Global SYMPLICITY Registry (GSR) provides real world experience regarding the effects of radiofrequency denervation of the renal artery nerves in patients with uncontrolled hypertension. These data in hypertensive patients with a high proportion of concomitant conditions also character

8b.04: renal artery denervation for treatment of hypertensive patients with or without obstructive sleep apnea and resistant hypertension: results from the global symplicity registry.

Abstract: Objective:Obstructive sleep apnea (OSA) is associated with sympathetic nervous system activation and the development of hypertension. The Global SYMPLICITY Registry is prospectively enrolling real world patients with uncontrolled hypertension including patients with OSA. This analysis compares basel

Quantitative Electrocardiographic Analysis in Relation to Renal Function in a Geriatric Population

Abstract: Background: There is a frequent association between renal insufficiency and patients with cardiovascular disease, suggesting a common pathogenic mechanism. The electrocardiogram (ECG) is a quick and cheap tool that can detect early cardiac abnormalities. The aim of this study was to quantitatively analyze ECG alterations in relation to renal function of a population of 65 years or older. Methods: A population sample of 1,536 patients aged 65 or older (45.4% male; mean age 75.6±6.0 years) from the judicial district of Toledo, Spain, who had undergone a general medical checkup including an ECG were included. In 996 patients (64.8%) renal function (plasma creatinine and estimated glomerular filtration rate) was assessed and the relationship between ECG alterations and renal function was subsequently evaluated. Results: Only 36% of the ECGs analyzed were considered normal. Significant correlations of heart rate, QRS complex duration, and the frontal plane QRS-T angle with reduced renal function were observed. Other ECG parameters such as voltage, QRS and T wave axes, and QTc interval showed no correlation with renal function. Conclusions: In patients aged 65 years or older with impaired renal function there was a relationship of renal function with certain ECG parameters, which may constitute early markers of renal and cardiac pathology and suggest a common pathogenic mechanism.