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Current Problems in Cardiology Oct 2023Cardiovascular diseases are emerging as a major cause of death and hospitalization in the Western world. For many years, a number of medicines have been placed on the... (Review)
Review
Cardiovascular diseases are emerging as a major cause of death and hospitalization in the Western world. For many years, a number of medicines have been placed on the market, in well-established and safe use for antihypertensive therapy. The various classes of antihypertensives in established use include, ACE inhibitors, as monotherapy or in combination with diuretics or calcium antagonists, sartans, calcium antagonists, beta blockers, and diuretics. Among these medicines classes there are differences in mechanism of action, efficacy in reducing blood pression, tolerability, and cost. In fact, there are wide differences in the monthly cost of therapy within each class and among the classes themselves. In this analysis we describe an example about the prescribing trends of antihypertensive drugs at a European sample represented by an Italian health care company of about 1 million inhabitants. Aspects of pharmacoeconomics, pharmacoutilization, and pharmacological differences are described.
Topics: Humans; Antihypertensive Agents; Hypertension; Calcium; Angiotensin-Converting Enzyme Inhibitors; Adrenergic beta-Antagonists; Diuretics
PubMed: 37301491
DOI: 10.1016/j.cpcardiol.2023.101857 -
Cardiorenal Medicine 2024Increased renal sodium avidity is a hallmark feature of the heart failure syndrome. (Review)
Review
BACKGROUND
Increased renal sodium avidity is a hallmark feature of the heart failure syndrome.
SUMMARY
Increased renal sodium avidity refers to the inability of the kidneys to elicit potent natriuresis in response to sodium loading. This eventually causes congestion, which is a major contributor to hospital admissions and mortality in heart failure.
KEY MESSAGES
Important novel concepts such as the renal tamponade hypothesis, accelerated nephron loss, and the role of hypochloremia, the sympathetic nervous system, inflammation, the lymphatic system, and interstitial sodium buffers are involved in the pathophysiology of renal sodium avidity. A good understanding of these concepts is crucially important with respect to treatment recommendations regarding dietary sodium restriction, fluid restriction, rapid up-titration of guideline-directed medical therapies, combination diuretic therapy, natriuresis-guided diuretic therapy, use of hypertonic saline, and ultrafiltration.
Topics: Humans; Heart Failure; Sodium; Kidney; Natriuresis; Diuretics; Cardio-Renal Syndrome
PubMed: 38565080
DOI: 10.1159/000538601 -
Journal of the American College of... Sep 2023It is unknown how the efficacy and safety of mineralocorticoid receptor antagonists vary according to duration of heart failure with reduced ejection fraction (HFrEF).
BACKGROUND
It is unknown how the efficacy and safety of mineralocorticoid receptor antagonists vary according to duration of heart failure with reduced ejection fraction (HFrEF).
OBJECTIVES
In this study, we sought to evaluate the safety and efficacy of eplerenone according to duration of HFrEF.
METHODS
In the EMPHASIS-HF trial, 3 patient groups were created according to HFrEF duration: <1 year, 1 to <5 years, and ≥5 years. The primary outcome was the composite of heart failure (HF) hospitalization or cardiovascular death. Outcomes were adjusted for prespecified prognostic variables and examined with the use of Cox regression models.
RESULTS
The numbers of patients in each group were: 975, <1 year; 769, 1 to <5 years; and 988, ≥5 years. Patients with longer-standing HF were older and more frequently had cardiovascular and noncardiovascular comorbidities. The rate of the primary outcome (per 100 person-years) increased with HFrEF duration: 9.8 (95% CI: 8.4-11.4) for <1 year, 13.5 (95% CI: 11.6-15.7) for 1 to <5 years, and 17.6 (95% CI: 15.6-19.8) for ≥5 years. The benefits of eplerenone were consistent across HF duration: HRs for the primary outcome were 0.57 (95% CI: 0.42-0.79) for <1 year, 0.81 (95% CI: 0.60-1.10) for 1 to <5 years, and 0.61 (95% CI: 0.48-0.78) for ≥5 years; P = 0.24. The absolute benefit was greatest in the longest-duration group: the number needed to treat for the primary outcome was 14 for <1 year, 13 for 1 to <5 years, and 10 for ≥5 years duration.
CONCLUSIONS
Patients with longer-standing HFrEF had worse clinical status and a higher rate of events, but the benefit of eplerenone was consistent regardless of HFrEF duration. (A Comparison of Outcomes in Patients in NYHA Class II Heart Failure When Treated With Eplerenone or Placebo in Addition to Standard Heart Failure Medicines [EMPHASIS-HF]; NCT00232180).
Topics: Humans; Heart Failure; Mineralocorticoid Receptor Antagonists; Eplerenone; Stroke Volume; Hospitalization
PubMed: 37642608
DOI: 10.1016/j.jacc.2023.06.021 -
The American Journal of Medicine Jan 2024Apparent resistant hypertension, defined as uncontrolled office blood pressure despite ≥ 3 antihypertensive medications including a diuretic or use of ≥ 4... (Review)
Review
Apparent resistant hypertension, defined as uncontrolled office blood pressure despite ≥ 3 antihypertensive medications including a diuretic or use of ≥ 4 medications regardless of blood pressure, occurs in ≤ 15% of treated hypertensives. Apparent refractory hypertension, defined as uncontrolled office pressure despite use of 5 or more medications including a diuretic, occurs in ≤ 10% of resistant cases. Both are associated with increased comorbidity and enhanced cardiovascular risk. To rule out pseudo-resistant or pseudo-refractory hypertension, employ guideline-based methodology for obtaining pressure, maximize the regimen, rule out white-coat effect, and assess adherence. True resistant hypertension is characterized by volume overload and aldosterone excess, refractory by enhanced sympathetic tone. Spironolactone is the preferred agent for resistance, with lower doses. Spironolactone, potassium binders, or both, are preferred if the estimated glomerular filtration rate is below 45. If significant albuminuria, finerenone is indicated. The optimal treatment of refractory hypertension is unclear, but sympathetic inhibition (α-β blockade, centrally acting sympathoinhibitors, or both) seems reasonable. Renal denervation has shown minimal benefit for resistance, but its role in refractory hypertension remains to be defined.
Topics: Humans; Spironolactone; Hypertension; Antihypertensive Agents; Blood Pressure; Diuretics; Blood Pressure Monitoring, Ambulatory
PubMed: 37832756
DOI: 10.1016/j.amjmed.2023.09.015 -
The Lancet. Respiratory Medicine Jan 2024Mucociliary clearance is dysfunctional in people with primary ciliary dyskinesia, resulting in the accumulation of dehydrated mucus in the airways that is difficult to... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety and efficacy of the epithelial sodium channel blocker idrevloride in people with primary ciliary dyskinesia (CLEAN-PCD): a multinational, phase 2, randomised, double-blind, placebo-controlled crossover trial.
BACKGROUND
Mucociliary clearance is dysfunctional in people with primary ciliary dyskinesia, resulting in the accumulation of dehydrated mucus in the airways that is difficult to clear. We undertook a study to assess the benefit on lung function of treatment with a nebulised epithelial sodium channel (ENaC) blocker, idrevloride, with or without hypertonic saline, in people with primary ciliary dyskinesia.
METHODS
The CLEAN-PCD trial was a phase 2, randomised, double-blind, placebo-controlled crossover trial conducted at 32 tertiary adult and paediatric care centres and university hospitals in Canada, Denmark, Germany, Italy, the Netherlands, Poland, the UK, and the USA. People with a confirmed diagnosis of primary ciliary dyskinesia, aged 12 years or older, with a percentage of predicted FEV (ppFEV) in the range of 40% to <90%, were randomly assigned in a 2:2:1:1 ratio (block size=6), stratified by ppFEV at screening, to one of four sequences: (1) idrevloride in hypertonic saline in treatment period 1 then hypertonic saline in treatment period 2; (2) hypertonic saline in treatment period 1 then idrevloride in hypertonic saline in treatment period 2; (3) idrevloride in treatment period 1 then placebo in treatment period 2; and (4) placebo in treatment period 1 then idrevloride in treatment period 2. The idrevloride dose was 85 μg and hypertonic saline was 4·2% NaCl. 3 mL of each study treatment was nebulised twice daily for 28 days in treatment periods 1 and 2; the two 28-day treatment periods were separated by a 28-day washout period. The primary endpoint was absolute change from baseline in ppFEV after 28 days. Safety assessments and reports of adverse events were made at clinic visits during each treatment period and by a follow-up telephone call 28 days after the last dose of study drug. Additionally, adverse events could be reported at a follow-up telephone call 3 days after the start of dosing and as they arose. Participants who received at least one dose of study drug were included in the safety analyses (safety set), and those who also had spirometry data were included in the efficacy analyses (full analysis set). The completed study is registered (EudraCT 2015-004917-26; ClinicalTrials.govNCT02871778).
FINDINGS
Between Sep 14, 2016, and May 31, 2018, 216 patients were screened and 123 were randomly assigned to one of four crossover sequences. Across the two treatment periods, treatment with idrevloride in hypertonic saline was initiated in 80 patients and completed in 78 patients (all 78 had data available and were included in the analysis); hypertonic saline initiated in 81 patients and completed in 76 patients (75 had data available and were included in the analysis); idrevloride initiated in 37 patients and completed in 35 patients (34 had data available and were included in the analysis); and placebo initiated in 36 patients and completed in 34 patients (all 34 had data available and were included in the analysis). Greater absolute increases in ppFEV from baseline to 28 days of treatment were seen with idrevloride in hypertonic saline (least-squares mean absolute change from baseline 1·0 percentage points, 95% CI -0·4 to 2·4) than with hypertonic saline alone (least-squares mean absolute change from baseline of -0·5 percentage points, -2·0 to 0·9; difference 1·5 percentage points, 95% CI <0·1 to 3·0; p=0·044). There was no significant difference in ppFEV for the parallel comparison of idrevloride in hypertonic saline compared with placebo or the crossover comparison of idrevloride with placebo. Adverse events were similar across treatments (57 to 65% of patients). Cough occurred in a greater proportion of participants during treatments that contained idrevloride or hypertonic saline compared with placebo, and oropharyngeal pain occurred in a greater proportion of participants during idrevloride treatments than during treatment with hypertonic saline alone or placebo, whereas chest discomfort was more common during treatments that included hypertonic saline.
INTERPRETATION
In this phase 2 crossover study, idrevloride in hypertonic saline was safe and associated with improved lung function over a 28-day period in people with primary ciliary dyskinesia compared with hypertonic saline alone. Larger, longer clinical studies are warranted to explore the potential benefits of idrevloride in combination with hypertonic saline in people with primary ciliary dyskinesia.
FUNDING
Parion Sciences, under agreement with Vertex Pharmaceuticals.
Topics: Adult; Child; Humans; Cross-Over Studies; Epithelial Sodium Channel Blockers; Treatment Outcome; Mucociliary Clearance; Ciliary Motility Disorders; Double-Blind Method
PubMed: 37660715
DOI: 10.1016/S2213-2600(23)00226-6 -
European Journal of Internal Medicine Sep 2023The prevalence of arterial hypertension is approximately 47% in the United States and 55% in Europe. Multiple different medical therapies are used to treat hypertension... (Review)
Review
The prevalence of arterial hypertension is approximately 47% in the United States and 55% in Europe. Multiple different medical therapies are used to treat hypertension including diuretics, beta blockers, calcium channel blockers, angiotensin receptor blockers, angiotensin converting enzyme inhibitors, alpha blockers, central acting alpha receptor agonists, neprilysin inhibitors and vasodilators. However, despite the numerous number of medications, the prevalence of hypertension is on the rise, a considerable proportion of the hypertensive population is resistant to these therapeutic modalities and a definitive cure is not possible with the current treatment approaches. Therefore, there is a need for novel therapeutic strategies to provide better treatment and control of hypertension. In this review, our aim is to describe the latest developments in the treatment of hypertension including novel medication classes, gene therapies and RNA-based modalities.
Topics: Humans; United States; Antihypertensive Agents; Hypertension; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Adrenergic beta-Antagonists; Diuretics; Angiotensin Receptor Antagonists
PubMed: 37330317
DOI: 10.1016/j.ejim.2023.06.008 -
Current Heart Failure Reports Jun 2024To provide a contemporary overview of the pathophysiology, evaluation, and treatment of hyponatremia in heart failure (HF). (Review)
Review
PURPOSE OF REVIEW
To provide a contemporary overview of the pathophysiology, evaluation, and treatment of hyponatremia in heart failure (HF).
RECENT FINDINGS
Potassium and magnesium losses due to poor nutritional intake and treatment with diuretics cause an intracellular sodium shift in HF that may contribute to hyponatremia. Impaired renal blood flow leading to a lower glomerular filtration rate and increased proximal tubular reabsorption lead to an impaired tubular flux through diluting distal segments of the nephron, compromising electrolyte-free water excretion. Hyponatremia in HF is typically a condition of impaired water excretion by the kidneys on a background of potassium and magnesium depletion. While those cations can and should be easily repleted, further treatment should mainly focus on improving the underlying HF and hemodynamics, while addressing congestion. For decongestive treatment, proximally acting diuretics such as sodium-glucose co-transporter-2 inhibitors, acetazolamide, and loop diuretics are the preferred options.
Topics: Humans; Hyponatremia; Heart Failure; Diuretics; Disease Management
PubMed: 38411885
DOI: 10.1007/s11897-024-00651-3 -
European Journal of Heart Failure Aug 2023Diuretic response in heart failure is blunted when compared to healthy individuals, but the pathophysiology underlying this phenomenon is unclear. We aimed to... (Review)
Review
The blunted loop diuretic response in acute heart failure is driven by reduced tubular responsiveness rather than insufficient tubular delivery. The role of furosemide urine excretion on diuretic and natriuretic response in acute heart failure.
AIMS
Diuretic response in heart failure is blunted when compared to healthy individuals, but the pathophysiology underlying this phenomenon is unclear. We aimed to investigate whether the diuretic resistance mechanism is related to insufficient furosemide tubular delivery or low tubular responsiveness.
METHODS AND RESULTS
We conducted a prospective, observational study of 50 patients with acute heart failure patients divided into two groups based on previous furosemide use (furosemide naïve: n = 28 [56%] and chronic furosemide users: n = 22 [44%]). Each patient received a protocol-derived, standardized furosemide dose based on body weight. We measured diuretic response and urine furosemide concentrations. The furosemide naïve group had significantly higher urine volumes and natriuresis when compared to chronic users at all timepoints (all p < 0.05). Urine furosemide delivery was similar in furosemide naïve versus chronic users after accounting for differences in estimated glomerular filtration rate (28.02 [21.03-35.89] vs. 29.70 [18.19-34.71] mg, p = 0.87). However, the tubular response to delivered diuretic was dramatically higher in naïve versus chronic users, that is the urine volume per 1 μg/ml of urine furosemide at 2 h was 148.6 ± 136.1 versus 50.6 ± 56.1 ml (p = 0.005).
CONCLUSIONS
Patients naïve to furosemide have significantly better diuresis and natriuresis when compared to chronic furosemide users. The blunted diuretic response in patients with chronic loop diuretic exposure is driven by decreased tubular responsiveness rather than insufficient furosemide tubular delivery.
Topics: Humans; Furosemide; Diuretics; Sodium Potassium Chloride Symporter Inhibitors; Heart Failure; Prospective Studies; Observational Studies as Topic
PubMed: 37042083
DOI: 10.1002/ejhf.2852 -
Current Atherosclerosis Reports Dec 2023Chronic kidney disease (CKD) is increasingly prevalent worldwide and is associated with increased cardiovascular risk. New therapeutic options to slow CKD progression... (Review)
Review
PURPOSE OF REVIEW
Chronic kidney disease (CKD) is increasingly prevalent worldwide and is associated with increased cardiovascular risk. New therapeutic options to slow CKD progression and reduce cardiovascular morbidity and mortality have recently emerged. This review highlights recent evidence and gaps in knowledge in emerging CKD preventive strategies.
RECENT FINDINGS
EMPA-Kidney trial found that empagliflozin, a sodium-glucose co-transporter 2 inhibitor (SGLT2i) led to 28% lower risk of progression of kidney disease or death from cardiovascular causes, compared to placebo. This reinforced the previous findings from DAPA-CKD and CREDENCE trials and led to inclusion of SGLT2i as the cornerstone of CKD preventive therapy in both diabetic and non-diabetic CKD. Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, slowed diabetic kidney disease progression by 23% compared to placebo in a pool analysis of FIDELIO-DKD and FIGARO-DKD trials. Non-pharmacological interventions, including low protein diet, and early CKD detection and risk stratification strategies based on novel biomarkers have also gained momentum. Ongoing efforts to explore the wealth of molecular mechanisms in CKD, added to integrative omics modeling are well posed to lead to novel therapeutic targets in kidney care. While breakthrough pharmacological interventions continue to improve outcomes in CKD, the heterogeneity of kidney diseases warrants additional investigation. Further research into specific kidney disease mechanisms will facilitate the identification of patient populations most likely to benefit from targeted interventions.
Topics: Humans; Diabetes Mellitus, Type 2; Renal Insufficiency, Chronic; Kidney; Disease Progression; Diabetic Nephropathies; Sodium-Glucose Transporter 2 Inhibitors; Mineralocorticoid Receptor Antagonists
PubMed: 38038822
DOI: 10.1007/s11883-023-01172-5 -
Current Opinion in Nephrology and... Jul 2024Kidney stones are the most common condition affecting the kidney, and characterized by a high rate of recurrence. Thiazide and thiazide-like diuretics (thiazides) are... (Review)
Review
PURPOSE OF REVIEW
Kidney stones are the most common condition affecting the kidney, and characterized by a high rate of recurrence. Thiazide and thiazide-like diuretics (thiazides) are commonly prescribed to prevent the recurrence of kidney stones. This review offers a comprehensive up-to-date assessment of the evidence supporting the use of thiazides for kidney stone recurrence prevention, highlights potential harms associated with treatment, and identifies areas of knowledge that require further investigation.
RECENT FINDINGS
The clinical routine to prescribe thiazides for kidney stone prevention has recently been challenged by the findings of the large NOSTONE trial that failed to show superiority of hydrochlorothiazide at doses up to 50 mg daily over placebo in preventing a composite of clinical or radiological recurrence in patients at high risk of recurrence. Yet, adverse events such as new onset diabetes mellitus and gout were more common in patients receiving hydrochlorothiazide compared to placebo. As demonstrated by a novel meta-analysis presented in this review encompassing all randomized placebo-controlled trials with thiazide monotherapy, current trial evidence does not indicate that thiazide monotherapy is significantly better than placebo in preventing kidney stone recurrence.
SUMMARY
Given the limited efficacy and possible adverse effects, we advocate for a restrictive use of thiazides for kidney stone recurrence prevention. Clearly, there remains a high unmet medical need for effective, targeted therapies to prevent recurrence of kidney stones.
Topics: Humans; Kidney Calculi; Secondary Prevention; Recurrence; Sodium Chloride Symporter Inhibitors; Thiazides; Treatment Outcome; Hydrochlorothiazide
PubMed: 38606682
DOI: 10.1097/MNH.0000000000000990