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- Patients and methods
Chronic systolic heart failure (CHF) is a major healthcare cost across the world . Diuretic therapy is a routine part the management of the majority of patients with CHF . Diuretics have variable effects on the neurohormonal responses of heart failure , and have the potential either to reduce readmission rates  or to generate iatrogenic morbidity through renal dysfunction [5, 6]. Minor changes can induce large fluctuations in haemodynamic status . Despite this, many patients manipulate diuretic therapy in response to symptoms and/or body weight , although the impact of this has not been defined in controlled circumstances . The decompensation of CHF resulting in hospital admission is a complex process  but may in part involve changes in diuretics. Episodes of diuretic resistance  might explain some episodes of hospitalization . Equally, non-adherence with diuretic treatment could also play a part in this process. The natriuretic response to furosemide can be defined by relating the urinary concentration of drug to the sodium excretion in the same sample of urine. There are no data examining how furosemide responsiveness varies chronically over time in CHF patients. It is not clear whether increased doses used in patients with CHF or decompensation are associated with a proportionately higher response to furosemide, although diuretic resistance is a marker of poor outcome .
In this study we report longitudinal patterns of within- and between-patient furosemide responses in CHF over a 2-year follow-up period. We examine the incidence of non-adherence to furosemide, poor bioavailability of furosemide and variability in furosemide responsiveness over time for a link between these factors and hospital admissions. We also wished to see if non-adherence with furosemide occurred at the same time as the patients were non-adherent with their ACE inhibitor, and finally if diuretic resistance was simply related to the counter-regulatory effect of aldosterone.
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- Patients and methods
The clinical pharmacology of furosemide is well defined and the most important determinant of response is the amount of drug reaching the renal tubule . Drug effect can be quantified by the ratio of sodium excretion relative to urinary diuretic concentration . Nearly all patients with significant left ventricular (LV) systolic dysfunction will require loop diuretic treatment as part of standard therapy. Attempts at diuretic withdrawal are successful only in a small minority in this patient group  and this is often complicated by short-term antinatriuresis. Despite this role, there are no data on the longitudinal impact of chronic loop diuretic therapy despite the repeated assumption that many CHF re-admissions are due to disease-related fluid retention or to problems with non-adherence and/or resistance to diuretic therapy [13, 23].
In this study we observed the community-based use of furosemide in otherwise stable CHF. Individual reasons for hospital referral and admission in the CHF population can be very variable and many admissions are not directly due to cardiac decompensation  but may represent intercurrent illness social instability or practical problems surrounding drug therapy. In the same way, death can come suddenly without warning in the community or be related to differing factors in the CHF population hospitalized prior to their final illness . In this project we attempted primarily to gain insight into whether the factors of diuretic resistance, poor diuretic absorption and/or diuretic non-adherence were linked to outcome. Importantly, patients in the study were not aware of the pattern of drug monitoring and were managed routinely by their community physician. This remains the main management paradigm for the vast majority of CHF patients and is therefore by far the most appropriate setting to complete such a study.
Within the follow-up period there was a progressive rise in prescribed daily dose of diuretic. Quality of life and symptom indices (MLHF scores) were static between outcome groups and unaffected by this change (Figure 1). Diuretic responsiveness within an individual patient remained constant despite variation in prescribed dose and regardless of outcome. Patients who died during follow-up (Group 2) were in general treated with higher doses and these doses were reaching their site of action as shown by the higher urine furosemide levels. However, this failed to produce a proportionately greater natriuresis or kaliuresis. This suggests that diuretic resistance (impaired sodium excretion per unit drug reaching the tubule) was present. Poor furosemide absorption might still have had a role, as double the prescribed furosemide dose in Group 2 led to only a 35% increase in mean urinary furosemide. It has been known for many years that furosemide is erratically absorbed in CHF . Thus, the effectiveness of upward titration of dose in these patients is blunted.
Higher prescribed doses were associated with poorer renal function in those who died during follow-up. One would ordinarily presume that this renal deterioration occurs because of diuretic-induced volume depletion, but in this study a higher dose did not produce a proportionally higher delivery of either furosemide or sodium into the urine. While it seems unlikely that volume depletion alone was the cause of the decreased renal function, it may equally also be a surrogate for the severity of the patient's overall disease [6, 13].
Non-adherence to prescribed therapy is an important and practical fact of clinical response, yet is little studied. We have examined this issue before in CHF using different techniques in relation to ACE inhibitor therapy . There are no perfect answers in this area as to how to define the problem. We feel our assumption that minimal 24-h urine furosemide excretion on the same dose with continued treatment equates to gross non-adherence, is a reasonable deduction and is valid. We are not able to exclude partial non-adherence without detailed pharmacokinetic modelling or by utilizing techniques such as computerized caps that register when a medication container is opened. The latter are not fool proof and easily open to manipulation. Our surrogate was gross non-adherence (nominally < 10% of average 24-h urinary furosemide excretion), and this is a degree of non-adherence that would be expected to have clinical significance. Excretion rates of furosemide at this level will have no meaningful diuretic effect and are associated if anything with antinatriuresis. Overall, we found the frequency of such events during repeated measurements to be reassuringly rare. Clearly, by point sampling we may have missed important episodes. Diuretic non-adherence could be expected to have important effects on clinical state through missed doses, rebound antinatriuretic effects  and also important effects on the diuretic interaction with ACE inhibition .
The patients in this study were not being instructed to vary either their dose of diuretic (or ACE inhibitor) informally , which is an increasingly common yet formally untested pattern . The fact that the isolated episodes of non-adherence with furosemide and non-adherence with an ACE inhibitor did not appear to correspond is intriguing. One simple explanation is that patients stop taking whichever supply has run out in their bathroom cabinet. Alternatively, it may be that they dislike the diuretic effect of furosemide and deliberately omit only their diuretic when they are likely to be away from home. Our visits were all done in the patients’ homes to avoid this being a complicating factor. Non-adherence with diuretic treatment from previous work does not appear to relate to social class .
While much is made of the lack of controlled trial evidence of efficacy for diuretic therapy reducing morbidity and mortality in CHF, there are some encouraging data that suggest diuretic strategies may be more important than previously anticipated . The use of spironolactone in severe heart failure is complex , but some workers have suggested that at least some of the benefits are mediated by improved diuresis . In our small study, non-adherence did not seem to relate to outcome. Thus, its importance might be overestimated. However, the data here show that while episodes of gross furosemide non-adherence are quite rare, this non-adherence occurs at a different time from non-adherence with an ACE inhibitor and could have a potentially vital impact on both the efficacy of hormone suppression and also on the net diuresis [32, 33]. Our data raise the notion that patients could have periods of time when they will be taking furosemide without the ACE inhibitor, and vice versa. The variability in natriuresis created by this could easily lead to fluid retention and hospitalization. This possibility should be examined in a larger prospective group and with samples secured rapidly on admission and before pulsed diuresis.
Loop diuretics have long been accepted to have a powerful stimulant effect on renin and aldosterone  and elevations in aldosterone would be expected to limit the natriuretic response to furosemide. Because of this we were keen to examine the relationship between diuretic responsiveness and endogenous aldosterone. Using repeated measures from the whole patient sample, there appeared to be a positive rather than the expected negative relationship between aldosterone and furosemide responsiveness. This implies that the effect of furosemide is sufficient to overwhelm the sodium retaining effect of aldosterone. While it remains likely that aldosterone does in part restrain the natriuretic effect of a loop diuretic, our data suggest that the furosemide can overcome this despite the fact that raising the diuretic dose probably further elevates aldosterone.
In summary, this community-based project following stable patients under routine conditions shows the response to chronic furosemide varies greatly between individuals but is reasonably constant within an individual subject. Non-adherence with treatments among CHF patients seems to be a selective process and is overall rare. We found non-adherence was, if anything, less common among those who died. While patients who died were prescribed higher furosemide doses and had greater furosemide excretion, they had no greater level of sodium excretion. Diuretic resistance is likely to be a key factor. We did not find the level of aldosterone to be a major cause of diminished diuretic response. Our data did not suggest that occasional gross non-adherence was a factor in determining outcome in CHF.