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Simultaneous Use of Hypertonic Saline and IV Furosemide for Fluid Overload: A Systematic Review and Meta-Analysis.
Liu, C, Peng, Z, Gao, X, Gajic, O, Dong, Y, Prokop, LJ, Murad, MH, Kashani, KB, Domecq, JP
Critical care medicine. 2021;(11):e1163-e1175
Abstract
OBJECTIVES To evaluate the efficacy of the simultaneous hypertonic saline solution and IV furosemide (HSS+Fx) for patients with fluid overload compared with IV furosemide alone (Fx). DATA SOURCES Electronic databases (MEDLINE, EMBASE, CENTRAL, Cochrane Database of Systematic Reviews, PsycINFO, Scopus, and WOS) were searched from inception to March 2020. STUDY SELECTION Randomized controlled trials on the use of HSS+Fx in adult patients with fluid overload versus Fx were included. DATA EXTRACTION Data were collected on all-cause mortality, hospital length of stay, heart failure-related readmission, along with inpatient weight loss, change of daily diuresis, serum creatinine, and 24-hour urine sodium excretion from prior to post intervention. Pooled analysis with random effects models yielded relative risk or mean difference with 95% CIs. DATA SYNTHESIS Eleven randomized controlled trials comprising 2,987 acute decompensated heart failure patients were included. Meta-analysis demonstrated that HSS+Fx was associated with lower all-cause mortality (relative risk, 0.55; 95% CI, 0.46-0.67; p < 0.05; I2 = 12%) and heart failure-related readmissions (relative risk, 0.50; 95% CI, 0.33-0.76; p < 0.05; I2 = 61%), shorter hospital length of stay (mean difference, -3.28 d; 95% CI, -4.14 to -2.43; p < 0.05; I2 = 93%), increased daily diuresis (mean difference, 583.87 mL; 95% CI, 504.92-662.81; p < 0.05; I2 = 76%), weight loss (mean difference, -1.76 kg; 95% CI, -2.52 to -1.00; p < 0.05; I2 = 57%), serum sodium change (mean difference, 6.89 mEq/L; 95% CI, 4.98-8.79; p < 0.05; I2 = 95%), and higher 24-hour urine sodium excretion (mean difference, 61.10 mEq; 95% CI, 51.47-70.73; p < 0.05; I2 = 95%), along with decreased serum creatinine (mean difference, -0.46 mg/dL; 95% CI, -0.51 to -0.41; p < 0.05; I2 = 89%) when compared with Fx. The Grading of Recommendation, Assessment, Development, and Evaluation certainty of evidence ranged from low to moderate. CONCLUSIONS Benefits of the HSS+Fx over Fx were observed across all examined outcomes in acute decompensated heart failure patients with fluid overload. There is at least moderate certainty that HSS+Fx is associated with a reduction in mortality in patients with acute decompensated heart failure. Factors associated with a successful HSS+Fx utilization are still unknown. Current evidence cannot be extrapolated to other than fluid overload states in acute decompensated heart failure.
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Pivotal clinical trials, meta-analyses and current guidelines in the treatment of hyperkalemia.
Bianchi, S, Regolisti, G
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2019;(Suppl 3):iii51-iii61
Abstract
Hyperkalemia (HK) is the most common electrolyte disturbance observed in patients with advanced stages of chronic kidney disease (CKD), is a potentially life-threatening clinical condition due to an increased risk of fatal arrhythmias, and strongly impacts the quality of life and prognosis of CKD patients. Moreover, while renin-angiotensin-aldosterone system inhibitors (RAASIs) represent the most cardio-nephro-protective drugs used in clinical practice, the treatment with these drugs per se increases serum potassium (sK) values, particularly when heart failure and diabetes mellitus coexist. In fact, the onset or recurrence of HK is frequently associated with not starting, down-titrating or withdrawing RAASIs, and is an indication to begin renal replacement treatment in end-stage renal disease. Current strategies aimed at preventing and treating chronic HK are still unsatisfactory, as evidenced by the relatively high prevalence of HK also in patients under stable nephrology care, and even in the ideal setting of randomized clinical trials. Indeed, dietary potassium restriction, the use of sodium bicarbonate or diuretics, the withdrawal or down-titration of RAASIs, or the administration of old potassium binders, namely sodium polystyrene sulphonate and calcium polystyrene sulphonate, have limited efficacy and are poorly tolerated; therefore, these strategies are not suitable for long-term control of sK. As such, there is an important unmet need for novel therapeutic options for the chronic management of patients at risk for HK. The development of new potassium binders may change the treatment landscape in the near future. This review summarizes the current evidence on the treatment of chronic HK in cardio-renal patients.
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Interventions for preventing high altitude illness: Part 2. Less commonly-used drugs.
Gonzalez Garay, A, Molano Franco, D, Nieto Estrada, VH, Martí-Carvajal, AJ, Arevalo-Rodriguez, I
The Cochrane database of systematic reviews. 2018;(3):CD012983
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Abstract
BACKGROUND High altitude illness (HAI) is a term used to describe a group of mainly cerebral and pulmonary syndromes that can occur during travel to elevations above 2500 metres (˜ 8200 feet). Acute mountain sickness (AMS), high altitude cerebral oedema (HACE) and high altitude pulmonary oedema (HAPE) are reported as potential medical problems associated with high altitude ascent. In this second review, in a series of three about preventive strategies for HAI, we assessed the effectiveness of five of the less commonly used classes of pharmacological interventions. OBJECTIVES To assess the clinical effectiveness and adverse events of five of the less commonly used pharmacological interventions for preventing acute HAI in participants who are at risk of developing high altitude illness in any setting. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) in May 2017. We adapted the MEDLINE strategy for searching the other databases. We used a combination of thesaurus-based and free-text search terms. We scanned the reference lists and citations of included trials and any relevant systematic reviews that we identified for further references to additional trials. SELECTION CRITERIA We included randomized controlled trials conducted in any setting where one of five classes of drugs was employed to prevent acute HAI: selective 5-hydroxytryptamine(1) receptor agonists; N-methyl-D-aspartate (NMDA) antagonist; endothelin-1 antagonist; anticonvulsant drugs; and spironolactone. We included trials involving participants who are at risk of developing high altitude illness (AMS or HACE, or HAPE, or both). We included participants with and without a history of high altitude illness. We applied no age or gender restrictions. We included trials where the relevant medication was administered before the beginning of ascent. We excluded trials using these drugs during ascent or after ascent. DATA COLLECTION AND ANALYSIS We used the standard methodological procedures employed by Cochrane. MAIN RESULTS We included eight studies (334 participants, 9 references) in this review. Twelve studies are ongoing and will be considered in future versions of this review as appropriate. We have been unable to obtain full-text versions of a further 12 studies and have designated them as 'awaiting classification'. Four studies were at a low risk of bias for randomization; two at a low risk of bias for allocation concealment. Four studies were at a low risk of bias for blinding of participants and personnel. We considered three studies at a low risk of bias for blinding of outcome assessors. We considered most studies at a high risk of selective reporting bias.We report results for the following four main comparisons.Sumatriptan versus placebo (1 parallel study; 102 participants)Data on sumatriptan showed a reduction of the risk of AMS when compared with a placebo (risk ratio (RR) = 0.43, CI 95% 0.21 to 0.84; 1 study, 102 participants; low quality of evidence). The one included study did not report events of HAPE, HACE or adverse events related to administrations of sumatriptan.Magnesium citrate versus placebo (1 parallel study; 70 participants)The estimated RR for AMS, comparing magnesium citrate tablets versus placebo, was 1.09 (95% CI 0.55 to 2.13; 1 study; 70 participants; low quality of evidence). In addition, the estimated RR for loose stools was 3.25 (95% CI 1.17 to 8.99; 1 study; 70 participants; low quality of evidence). The one included study did not report events of HAPE or HACE.Spironolactone versus placebo (2 parallel studies; 205 participants)Pooled estimation of RR for AMS was not performed due to considerable heterogeneity between the included studies (I² = 72%). RR from individual studies was 0.40 (95% CI 0.12 to 1.31) and 1.44 (95% CI 0.79 to 2.01; very low quality of evidence). No events of HAPE or HACE were reported. Adverse events were not evaluated.Acetazolamide versus spironolactone (1 parallel study; 232 participants)Data on acetazolamide compared with spironolactone showed a reduction of the risk of AMS with the administration of acetazolamide (RR = 0.36, 95% CI 0.18 to 0.70; 232 participants; low quality of evidence). No events of HAPE or HACE were reported. Adverse events were not evaluated. AUTHORS' CONCLUSIONS This Cochrane Review is the second in a series of three providing relevant information to clinicians and other interested parties on how to prevent high altitude illness. The assessment of five of the less commonly used classes of drugs suggests that there is a scarcity of evidence related to these interventions. Clinical benefits and harms related to potential interventions such as sumatriptan are still unclear. Overall, the evidence is limited due to the low number of studies identified (for most of the comparison only one study was identified); limitations in the quality of the evidence (moderate to low); and the number of studies pending classification (24 studies awaiting classification or ongoing). We lack the large and methodologically sound studies required to establish or refute the efficacy and safety of most of the pharmacological agents evaluated in this review.
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Combination therapy of renin-angiotensin system inhibitors plus calcium channel blockers versus other two-drug combinations for hypertension: a systematic review and meta-analysis.
Lu, Z, Chen, Y, Li, L, Wang, G, Xue, H, Tang, W
Journal of human hypertension. 2017;(1):1-13
Abstract
Many randomized clinical trials (RCTs) have investigated the efficacy and safety of renin-angiotensin system inhibitors (RASIs) plus calcium channel blockers (CCBs), compared with other two-drug combinations, but systematic assessment in this aspect is still lacking. We carried out the present meta-analysis of randomized controlled trials to evaluate the long-term effect and safety of RASIs plus CCBs. Literatures were searched in MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials in September 2014. A fixed-effect model was used to estimate the pooled effect of trials identified. Thirty-four trials with 41 694 patients were included. Compared with RASIs plus diuretics, RASIs plus CCBs decreased total cardiovascular (CV) events (relative risk (RR) 0.82, 95% confidence interval (CI): 0.75, 0.91, adjusted RR (ARR) 1.7%) and withdrawals due to adverse effect (WDAE) (RR 0.87, 95% CI: 0.80, 0.94, ARR 1.3%). Compared with CCBs plus diuretics, RASIs plus CCBs decreased WDAE (RR 0.63, 95% CI: 0.45, 0.90, ARR 1.1%). Our meta-analysis indicates that RASIs plus CCBs provide a superior safety and prevention of CV events to RASIs plus diuretics, whereas this combination is also safer than CCBs plus diuretics. We also raise a new hypothesis. More high-quality RCTs focused on hard end points with CV, cerebrovascular and renal events are needed to confirm the hypothesis we have brought out.
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Renoprotective effects of renin-angiotensin system inhibitor combined with calcium channel blocker or diuretic in hypertensive patients: A PRISMA-compliant meta-analysis.
Cheng, Y, Huang, R, Kim, S, Zhao, Y, Li, Y, Fu, P
Medicine. 2016;(28):e4167
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Abstract
OBJECTIVES To conduct a meta-analysis of studies comparing the renoprotective effects of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) combined with either calcium channel blocker (CCB) or diuretic, but not both, in hypertensive patients. DATA SOURCES Pubmed, Embase, Medline, and Cochrane databases were searched to identify randomized controlled trials (RCTs) of blood pressure lowering treatments in patients with hypertension. STUDY SELECTION RCTs comparing the renoprotective effects of ACEI/ARB plus CCB with ACEI/ARB plus diuretic in hypertensive patients, with at least one of the following reported outcomes: urinary protein, estimated glomerular filtration rate/creatinine clearance (eGFR/CrCl), or serum creatinine. RESULTS Based on 14 RCTs with 18,125 patients, statistically significant benefits were found in ACEI/ARB plus CCB for maintaining eGFR/CrCl (standardized mean difference [SMD] = 0.36; 95% confidence interval [CI]: 0.20-0.53; P < 0.001), serum creatinine reduction (mean difference [MD] = -0.05 mg/dL; 95% CI: -0.07 to -0.03; P < 0.001). However, no statistical differences were found between the 2 therapeutic strategies in terms of urinary protein (MD = 7.48%; 95% CI: -6.13% to 21.08%; P = 0.28; I = 92%). CONCLUSIONS This meta-analysis concluded that ACEI/ARB plus CCB have a stronger effect on the maintenance of renal function in patients with hypertension than ACEI/ARB plus diuretic.
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Effects of limiting fluid intake on clinical and laboratory outcomes in patients with heart failure. Results of a meta-analysis of randomized controlled trials.
De Vecchis, R, Baldi, C, Cioppa, C, Giasi, A, Fusco, A
Herz. 2016;(1):63-75
Abstract
BACKGROUND The guidelines of the Scientific Societies of Cardiology recommend limiting fluid intake as a nonpharmacological measure for the management of chronic heart failure (HF). However, many patients with HF may suffer from severe thirst. A meta-analysis was performed to evaluate the effect of limiting fluid consumption based on various clinical and laboratory outcomes in patients with chronic HF. METHODS Only randomized controlled trials comparing liberal and restricted fluid oral intake in patients with HF were included. Primary outcomes were HF hospitalizations and all-cause mortality. Secondary outcomes were the sensation of thirst, the duration of therapy with intravenous diuretics, and the serum levels of creatinine, sodium, and B-type natriuretic peptide (BNP). RESULTS Six studies met the inclusion criteria. Significant heterogeneity was detected for the majority of outcomes. In 5 studies, patients with restricted fluid intake compared to patients with free consumption of beverages had similar rehospitalization and mortality rates. There were no differences regarding patients' sense of thirst (4 studies), duration of intravenous diuretic treatment (2 studies), serum creatinine levels (5 studies), and serum sodium levels (5 studies). Serum BNP levels were significantly higher in the group with free fluid intake (4 studies). CONCLUSION In patients with HF, liberal fluid consumption does not seem to exert an unfavorable impact on HF rehospitalizations or all-cause mortality. Further randomized controlled trials are warranted to definitively confirm the present findings.
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Effects of blood pressure-lowering treatment. 6. Prevention of heart failure and new-onset heart failure--meta-analyses of randomized trials.
Thomopoulos, C, Parati, G, Zanchetti, A
Journal of hypertension. 2016;(3):373-84; discussion 384
Abstract
BACKGROUND AND OBJECTIVES Relative effectiveness of blood pressure (BP)-lowering treatment on various outcomes was evaluated by meta-analyses restricted to randomized controlled trials (RCTs) measuring all major outcomes, and the question whether BP lowering and each class of antihypertensive agents prevent new-onset heart failure by meta-analyses limited to RCTs excluding baseline heart failure from randomization. METHODS Source of these meta-analyses are our databases of BP-lowering RCTs vs placebo or less-active treatment, and head-to-head comparisons of different antihypertensive classes. Risk ratios (RRs) and 95% confidence intervals of seven outcomes were calculated by a random-effects model. The relationships of outcome reductions to BP differences were investigated by meta-regressions. RESULTS First, 35 BP-lowering RCTs measured all outcomes, and heart failure [RR 0.63 (0.52-0.75)] and stroke [RR 0.58 (0.49-0.68)] were the outcomes most effectively prevented. Second, heart failure and stroke reductions were significantly related to SBP, DBP and pulse pressure reductions. Third, in 18 BP-lowering RCTs excluding baseline heart failure from recruitment, heart failure reduction ('new-onset' heart failure) [RR 0.58 (0.44-0.75)] was very similar to that in the entire set of RCTs. Fourth, in meta-analyses of head-to-head comparisons of different antihypertensive classes, calcium antagonists were inferior in preventing 'new-onset' heart failure [RR 1.16 (1.01-1.33)]. However, this inferiority disappeared when meta-analysis was limited to RCTs allowing concomitant use of diuretics, β-blockers or renin-angiotensin system blockers also in the calcium antagonist group [RR 0.96 (0.81-1.12)]. CONCLUSION BP-lowering treatment effectively prevents 'new onset' heart failure. It is suggested that BP lowering by calcium antagonists is effective as BP lowering by other drugs in preventing 'new-onset' heart failure, unless the trial design creates an unbalance against calcium antagonists.
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Diuretic antihypertensive drugs and incident dementia risk: a systematic review, meta-analysis and meta-regression of prospective studies.
Tully, PJ, Hanon, O, Cosh, S, Tzourio, C
Journal of hypertension. 2016;(6):1027-35
Abstract
OBJECTIVE Diuretic drugs have been a mainstay of hypertension treatment in the elderly however their dementia sparing effects are under-reported. The objective was to quantify dementia risk in relation to diuretic antihypertensive drugs. METHODS Electronic databases were searched until June 2015. ELIGIBILITY CRITERIA population, adults without dementia from primary care, community cohort, residential/institutionalized, or randomized controlled trial; exposure, diuretic antihypertensive drug; comparison, no diuretic drug, other or no antihypertensive drug, placebo-control; outcome, incident dementia diagnosed by standardized criteria. Adjusted hazard ratios (HR) with 95% confidence intervals (CI) were pooled in fixed-effects models with RevMan 5.3 (The Nordic Cochrane Centre, Copenhagen, Denmark) and the findings rated according to The Grading of Recommendations Assessment, Development and Evaluation criteria. RESULTS A total of 15 articles were included (52 599 persons, 3444 dementia cases, median age 76.1 years) and median follow-up was 6.1 years. Diuretics were associated with reduced dementia risk (HR 0.83; 95% CI 0.76-0.91, P < 0.0001, I = 0) and Alzheimer's disease risk (HR 0.82; 95% CI 0.71-0.94, P = 0.004, I = 0). Stratified analysis indicated a difference between potassium sparing, thiazide and loop diuretics (P = 0.01). Risk estimates were generally consistent comparing monotherapy vs. combination therapy, study design and follow-up. Meta-regression showed that demographics, stroke, heart failure, diabetes, liver disease, attrition, mortality rate, cognitive function, and apolipoprotein E allele did not moderate the results. CONCLUSION Diuretic antihypertensive drugs were associated with a consistent reduction in dementia risk without heterogeneity, pointing to generalizability of these findings. REGISTRATION PROSPERO [CRD42015023428].
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Effects of blood-pressure-lowering treatment in hypertension: 9. Discontinuations for adverse events attributed to different classes of antihypertensive drugs: meta-analyses of randomized trials.
Thomopoulos, C, Parati, G, Zanchetti, A
Journal of hypertension. 2016;(10):1921-32
Abstract
BACKGROUND Choice of antihypertensive drugs is also based on the expected burden of adverse events associated with each class of agents, and we have recently identified treatment discontinuation for adverse events as a measure of treatment tolerability frequently reported in randomized controlled trials (RCTs). OBJECTIVES To investigate whether all classes of blood pressure (BP) lowering drugs increase discontinuations for adverse events when compared with placebo and whether risk of discontinuation is similar for all classes when compared in head-to-head RCTs. METHODS RCTs of BP-lowering treatment were subdivided in groups according to class of drug compared with placebo or with other classes. Risk ratios and 95% confidence intervals of major cardiovascular events and of treatment discontinuations for adverse events were calculated (random-effects model). RESULTS Thirty-eight placebo-controlled RCTs (147 788 patients) and 37 head-to-head RCTs (242 481 patients) provided comparative information on discontinuations for adverse events. All classes of drugs significantly increased discontinuations for adverse events over those occurring on placebo: risk ratio diuretics 2.23 (1.32-3.76), beta-blockers 2.88 (1.58-5.28), calcium antagonists 2.03 (1.17-3.56), angiotensin-converting enzyme inhibitors 2.78 (1.37-5.47), central agents 1.74 (1.24-2.45), with the single exception of angiotensin receptor blockers, which did not significantly increase adverse events over placebo [risk ratio 1.13 (0.78-1.62)]. Similarly, in head-to-head comparison RCTs with other classes, angiotensin receptor blockers were the only class associated with a significantly lower risk of adverse events [risk ratio 0.71 (0.58-0.87)] when head-to-head compared with other classes. Regression analysis also shows that incidence of discontinuations for adverse events is proportional to the number of antihypertensive and other cardiovascular drugs, which accounts for the high incidence of this outcome often found in groups randomized to placebo. CONCLUSION Reduction of cardiovascular events by all classes of BP-lowering drugs is accompanied by increased treatment discontinuations for adverse events, except when angiotensin receptor blockers are used. Treatment discontinuations are also related to treatment often accompanying antihypertensive agents.
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Hypertonic saline with furosemide for the treatment of acute congestive heart failure: a systematic review and meta-analysis.
Gandhi, S, Mosleh, W, Myers, RB
International journal of cardiology. 2014;(2):139-45
Abstract
BACKGROUND Advanced congestive heart failure (CHF) therapies include intravenous inotropic agents, change in class of diuretics, and venous ultrafiltration or hemodialysis. These modalities have not been associated with improved prognosis and are limited by availability and cost. Compared to high-dose furosemide alone, concomitant hypertonic saline solution (HSS) administration has demonstrated improved clinical outcomes with good safety profile. METHODS A literature search was conducted for randomized controlled trials that investigated the use of HSS in patients admitted to hospital with acute CHF. RESULTS 1032 patients treated with HSS and 1032 controls, demonstrated decreased all-cause mortality in patients treat with HSS with RR of 0.56 (95% CI 0.41-0.76,p=0.0003). 1012 patients treated with HSS and 1020 controls, demonstrated decreased heart failure hospital readmission with RR of 0.50 (95% CI 0.33-0.76,p=0.001). Patients treated with HSS also demonstrated decreased hospital length of stay (p=0.0002), greater weight loss (p<0.00001), and preservation of renal function (p<0.00001). CONCLUSION The results of this meta-analysis demonstrate that in patients with advanced CHF concomitant hypertonic saline administration improved weight loss, preserved renal function, and decreased length of hospitalization, mortality and heart failure rehospitalization. A future adequately powered, multi-centre, placebo controlled, randomized, double dummy, blinded trial is needed to assess the benefit of hypertonic saline in patients with renal dysfunction, in diverse patient populations, as well using a patient population on optimal current heart failure treatment. Pending further validation, there is promise for hypertonic saline as an advanced therapy for the management of acute advanced CHF.