Comparison of Oral Thiazides vs Intravenous Thiazides vs Tolvaptan in Combination With Loop Diuretics for Diuretic Resistant Decompensated Heart Failure
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Weight Change Over 48 Hours
研究概览
简要总结
Broad Objectives: To determine the comparative efficacy of commonly employed strategies to overcome loop diuretic resistance when added to concomitant loop diuretics in hospitalized decompensated heart failure patients with hypervolemia
Specific Aims:
- Compare the 48-hour weight change of either intravenous chlorothiazide or oral tolvaptan compared to standard-of-care oral metolazone when combined with standardized loop diuretic dosing for diuretic resistance in decompensated heart failure
- Compare the adverse effects of electrolyte depletion and renal function changes between intravenous chlorothiazide or oral tolvaptan compared to standard-of-care oral metolazone when combined with standardized loop diuretic dosing for diuretic resistance in acute heart failure
- Pharmacoeconomic analysis of the direct costs of intravenous chlorothiazide or oral tolvaptan compared to standard-of-care oral metolazone when combined with standardized loop diuretic dosing for diuretic resistance in acute heart failure
The investigators will conduct a dual center, randomized, double-blind, double-dummy, parallel design trial comparing: oral metolazone, intravenous chlorothiazide, or oral tolvaptan, in combination with loop diuretics in 60 patients hospitalized for hypervolemic decompensated heart failure and displaying loop diuretic resistance.
详细描述
Background:
The investigators aim to evaluate the optimal regimen for restoring diuretic efficacy in patients with decompensated heart failure demonstrating loop diuretic resistance, for which guideline-based recommendations are weak secondary to a lack of evidence. By comparing the efficacy, cost, and adverse effects of currently recommended therapies and testing a novel diuretic combination, the investigators will augment the dearth of data that exists regarding this clinical challenge.
Current heart failure guidelines recommend addition of a thiazide diuretic, listing either oral metolazone or intravenous chlorothiazide, to loop diuretic therapy as strategy to overcome loop diuretic resistance. At equipotent doses, these two therapies differ 250 fold in cost. To date, no prospective trial has compared the efficacy of these two commonly utilized therapies.
Tolvaptan, an oral vasopressin 2 receptor antagonist, could restore diuretic efficacy when used in combination with loop diuretics. While the safety of this combination has been established in the EVEREST trials, tolvaptan has been formally studied in a limited capacity as combination therapy to restore loop diuretic resistance. Hypokalemia is a common adverse effect of combining a thiazide and loop diuretic, increasing the risk of atrial and ventricular arrhythmias in a population who is already at high risk. Hypokalemia as not been reported with the combination of tolvaptan and loop diuretics, likely due to tolvaptan's distinctive mechanism of action. This potential benefit could provide tolvaptan a unique advantage for combination diuretic therapy in environments when electrolyte monitoring cannot be routinely performed or in patients with frequent arrhythmic events.
Methods:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •age of 18 years or older
- •hospital admission for hypervolemic decompensated heart failure complicated by loop diuretic resistance
- •24 hour telemetry monitoring on an inpatient ward
- •basic metabolic panel laboratory assessment twice daily during the study period
- •Hypervolemia will be diagnosed by the admitting provider as either (i) pulmonary artery catheterization with a pulmonary capillary wedge pressure greater than 19mmHg plus a systemic physical exam finding of hypervolemia (peripheral edema, ascites, or pulmonary edema on auscultation) or (ii) in the absence of pulmonary artery catheterization data 2 of the following signs or symptoms: peripheral edema ascites, jugular venous pressure > 10mmHg, or pulmonary edema on chest x-ray.
- •Loop diuretic resistance is defined as a provider decision to pursue combination diuretic therapy because of failure to reach provider defined adequate diuresis (can not exceed urine output of 2 L in past 12 hours) despite receipt of an intravenous loop diuretic dose of a furosemide equivalent of at least 240mg/day over at least the past 12 hours (40mg furosemide = 20mg torsemide = 1mg bumetanide).
排除标准
- •decision to pursue hemodialysis by a nephrologist
- •estimated glomerular filtration rate by the MDRD equation < 15ml/min/m2
- •systolic blood pressure < 85mmHg
- •pregnancy
- •serum potassium < 3.0mEq/L
- •serum sodium > 145mEq/L or < 130mEq/L
- •severe malnutrition
- •advanced liver disease
- •inability to perform standing weights
- •inability to collect and measure urine with either a foley catheter or urine collection containers
- •concomitant therapy with strong CYP3A4 inhibitors/inducers (systemic ketoconazole, clarithromycin, itraconazole, telithromycin, saquinavir, nelfinavir, ritonavir, nefazodone, rifampin, rifabutin, rifapentine, phenytoin, phenobarbital, carbamazepine, St. John's Wort)
- •concomitant therapy with p-glycoprotein inhibitors (cyclosporine, erythromycin, tacrolimus, dronedarone, quinidine, or verapamil)
- •non-study diuretics (spironolactone doses >75mg/day, eplerenone > 75mg/day, non-study thiazides or loop diuretics, or systemic acetazolamide, triamterene, or amiloride therapy)
- •thiazides administration in the previous 24 hours prior to randomization
研究组 & 干预措施
Metolazone
Metolazone 5mg tablet orally twice daily for 48 hours.
干预措施: Metolazone (Drug)
Chlorothiazide
Chlorothiazide 500mg intravenous infusion over 30 minutes twice daily for 48 hours
干预措施: Chlorothiazide (Drug)
Tolvaptan
Tolvaptan 30mg tablet orally once daily for 48 hours
干预措施: tolvaptan (Drug)
结局指标
主要结局
Weight Change Over 48 Hours
时间窗: 48 hours
The primary outcome will be 48-hour standing scale weight change (kg) from enrollment among the metolazone, intravenous chlorothiazide, and tolvaptan arms, using metolazone group as the comparator group for all other groups.
次要结局
- Mean Change in Serum Creatinine(48 hours)
- Mean Change in Glomerular Filtration Rate at Discharge(hospital discharge an average of 5 days)
- Change in eGFR From Baseline to 48 Hours(48 hours)
- Number of Patients With Hypokalemia(48 hours)
- Number of Patients With Escalation of Loop Diuretic Therapy(24 hours)
- Number of Patients With Cardiac Arrhythmias(48 hours)
- Number of Patients With Symptomatic Hypotension(48 hours)
- Mean Change in Serum Sodium(48 hours)
- Net Urine Output(48 hours)
- Mean Change in Serum Potassium(48 hours)
- Potassium Supplementation(48 hours)
研究者
Zachary L. Cox
Associate Professor, Lipscomb University College of Pharmacy
Vanderbilt University