Journal Club Eastern Virginia Medical School
Resident: Jessica Cartoski Date: 5/20/11 CITATION: Felker MG, Diuretic strategies in patients with acute decompensated
heart failure. N England J Med 2011; 364: 797-805

DOSING STRATEGIES OF LASIX IN ACUTE DECOMPENSATED HEART FAILURE Investigate safety and efficacy of optimal dosing and route of administration of lasix in patients with ADHF Prospective, randomized, double-blind, double-dummy, 2x2 factorial design 9 sites, in US and Canada 308 patients randomized to 1 of 4 arms with 2 independent variables each with 2 levels: Low dose (home lasix dose) vs high dose (2.5 X home dose) Continuous vs bolus IV dosing Double dummy- all patients received both IV boluses q12 hours and a continuous infusion, one of which contained furosemide and the other saline placebo All patients evaluated at 48 hours (still blinded) and physicians chose: increase dose by 50%, maintain same strategy, or discontinue IV treatment for oral diuretics At 72 hours all treatment open- label/at discretion of treating physician followed/evaluated at 60 days for biomarker levels and recording of Presented within previous 24 hours ADHF: diagnosed on one symptoms and one sign Symptom: dyspnea, orthopnea, or edema Sign: rales, peripheral edema, ascites, or pulmonary vascular congestion on chest xray ADDITIONALLY: History of CHF and at least 1 month prior to hospitalization on 80-240mg lasix or an equivalent dose of a different loop diuretic (1mg bumetanide, 20mg torsemide) Thiazides were permitted if had been on long term No specification of EF for inclusion (though compared in group characteristics) Systolic blood pressure <90mmhg Serum creatinine level >3.0mg/dl IV vasodilators ionotropic agents (excluding digoxin) Low dose (home lasix dose) vs high dose (2.5 X home dose) Continuous vs bolus IV dosing Efficacy evaluation: subjective “global assessment of symptoms”/GAS, patients asked to mark their general well being on a 10cm vertical line with top labeled “best you have ever felt” and bottom “worst you have ever felt”, this quantified on scale 0 to 100 by measuring the distance in mm from the bottom of the line to their mark. Groups compared by mean area under the Curve of the GAS visual analogue scale Safety evaluation: Creatinine, cystatin C, pro-BNP taken at baseline, 72 hours, and 60 days Significance considered pvalue <0.025 PRESPECIFIED Secondary endpoints: Patient reported dyspnea, changes in body weight/net fluid los, proportion patients free from congestion (JVP<8cm and no orthopnea and trace or no peripheral edema at 72hrs), worsening renal function (creatinine increase>0.3mg/dl), changes in biomarkers at 72hours, day 7 or discharge, and day 60, and clinical end points- composite of death, rehospitalization, or ED visit within 60 days and number of days hospitalized during the 60 days of follow up Significance considered pvalue <0.05 II. Are the results of the study valid?
Randomly assigned in a 1:1:1:1 ratio to low vs high and bolus vs continuous dosing Randomization with permuted blocks, stratified according to clinical site Permuted blocks: a random number sequence is generated from a statistical textbook or computer. Each possible permuted block (a grouping of treatment vs control- in this study varying treatment options) is assigned a number. Using each number in the random number sequence in turn selects the next block, determining the next participant allocations. Numbers in the random number sequence greater than the number of permuted block combinations are not used to select blocks. 2. Were all patients who entered the trial properly accounted for and attributed at its No chart or data of those who left the study mentioned- but couldn’t find these when I got the journal article online either 4. Were patients, health workers and study 5. Were study groups similar at the start of Table 1- baseline characteristics, appear to similar in terms of: age, sex, race, daily lasix, EF’s , SBP’s/HR, DM, CHF disease modifying drugs, initial creatinine/BNP/sodium, and exacerbation symptomatology described- at discretion of caring physicians III. What were the results?
(difference between treatment and control No statistical difference found for both the primary safety and efficacy end points or in the secondary end points when comparing continuous versus bolus dosing Less total lasix dosed in continuous group Bolus dosing more likely to require a dose increase at 48 hours, but no difference in switch to oral dosing between bolus and continuous dosing No significant difference in the efficacy end point in low vs high dosing- but note a nonsignificant trend toward greater improvement in the high dosing- this coincides with the secondary end points that were significantly better with high dosing-that of fluid loss, weight loss, and relief from dyspnea. No significant difference in low and high dosing in the primary safety end point (overall difference between groups-change in creatinine) though there was a higher proportion of patients who met the prespecified secondary safety end point (rise in creatinine level of more than 0.3mg/dl at any time during the 72 hours of randomization)- no difference in creatinine at 60 days. And noted in adverse events- overall more cases of renal failure with continuous (vs bolus) dosing and in the LOW dose (vs high dose) strategy. Though not powered to find significant events between groups- overall fewer patients with SAE in high vs low dosing. No difference in the median length of hospital stay. No difference in the composite end point (death, rehospitalization, or Ed visit within 60 days) or in total number of days alive out of hospital (to total of 60 days) between any groups. 2. What was the estimated treatment effect There was no real treatment effect, as no significant difference in primary end points between any of the 4 treatment modes. No CI’s were given- p values only. CI for the nonsignificant hazard ratio’s were listed. IV. Will the results help me in caring for population chosen has relatively high lasix requirement already and so the study findings can’t be applied to patients with new onset CHF who are lasix naive or taking <80mg lasix daily or its equivalent in an alternative. Did find, in contradiction to prior studies, that continuous dosing was not associated with a lesser degree of renal dysfunction. and that perhaps that increased doses of lasix associated with worse outcomes in patients- was confounded by the disease severity. Study contents applicable for several points. Symptomatic dyspnea is one of the focuses of our primary treatment in the Ed. So, in patients requiring BIPAP/ those with severe dyspnea and CHF with fluid overload, more aggressive lasix dosing may decrease their time necessitating BiPap and thus risk of failing and leading to intubation, etc. And it may do this with only a short term bump in creatinine- and this study used doses of lasix I’ve personally never seen given. I’m not sure I’d give someone 500mg bolus lasix in the Ed because their home dose is 200mg. The study provides a reference to guide dosing in very lasix dependent patients- and that because of loop diuretic “braking phenomenon” this patient population very well may require very high doses of lasix for the same effect as prior low doses. Also have to keep in mind that there was a significant bump in creatinine >0.03mg/dl in the high dose group, and there is no data to determine whether this has a long term effect on outcome. 1. Were all clinically important outcomes Raw adverse event data poorly presented- blind statement of less hospitalization/SAE’s, etc. A study powered to determine significant event rates between groups would be helpful. Again, unsure exact increased risk of harm. Difficult as this disease process itself is a higher dosing can symptomatically relieve dyspnea more quickly and reduce short term risk of intubation and the risks that it poses to this patient population- it’s worth a transient bump in creatinine.
Hazard ratio: ratio of hazard rates; assumes constant ratio of events in two groups over
time. Trial split into distinct time intervals, at each time interval the probability of
surviving or not having certain events is calculated and these probabilities are multiplied
to give the “probability” of survival/etc up to a given time point.
Unlike RRR, not just a rate in certain time period and so can be taken over time periods-
allowing for some leeway with patients lost to follow up.
1=equal treatments
2= at any given time, two times as many patients in active group are having an event
compared with the compared group
Kaplan meier curve : The Kaplan-Meier curve displays a statistical estimate of the
percent of people receiving a given therapeutic regimen who, at each observation point
after entering a trial, continue to do acceptably well on their assigned therapy. Plotting
the curves for a trial's different treatment arms on the same chart yields a comparison of
the various regimens.
ie Graphical display of the estimates (based on Kaplan-Meier methodology) of the
probability of survival, or not experiencing a particular event such as disease progression,
at any time over the period of study.
An important advantage of the Kaplan–Meier curve is that the method can take into
account some types of censored data, particularly right censoring, which occurs if a
patient withdraws from a study, i.e. is lost from the sample before the final outcome is
observed. On the plot, small vertical tick-marks indicate losses, where a patient's survival
time has been right-censored.
Braking phenomenon: progressively diminishing response to diuretic therapy with
ongoing treatment. Due to multiple mechanisms. Ex: chronic loop diuretic therapy leads
to structural changes in the kidney itself, including hypertrophy of the epithelial cells in
the distal tubules, which enhance distal reabsorbtion of sodium and limits sodium
excretion and diuresis. Heart failure itself shifts dose response curve for loop diuretics
down and to the right, requiring higher starting dose to achieve same level of sodium
(felker et al- Loop Diuretics in ADHF: Necessary? Evil? A Necessary Evil?)

Source: http://emjournalclub.com/uploads/Felker_Cartoski.pdf

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