Vaptans
Patients with HF have raised vasopressin (AVP), which causes water re-absorption in the collecting ducts of the nephrons. Vaptans block the action of vasopressin on its receptors, thus leading to loss of water alone without a natriuresis – a so-called aquaresis. In 142 patients with severe HF symptoms, and compared with placebo, a single intravenous dose of conivaptan (20 or 40 mg) significantly reduced pulmonary capillary wedge pressure and right atrial pressure during the first hours following administration, also increasing urine output at a dose-dependent amount.51 However, in the EVEREST trial,52 the use of tolvaptan was associated with no change in clinical outcomes in a population of over 4,000 patients who were admitted with acute HF. Enthusiasm for the routine use of vaptans has thus waned, but they could certainly be helpful in patients who have hyponatraemia. Gheorghiade and colleagues showed that tolvaptan at different doses (30, 45 or 60 mg/day) for 25 days was effective in decreasing oedema, and also normalised serum sodium in hyponatremic patients compared with placebo.53
It is possible that vaptans might be better than a loop diuretic as standard care. In a recent study, 83 patients treated on optimal medical treatment, with severe HF and clinical congestion, were randomised to placebo, monotherapy with tolvaptan 30 mg/day or furosemide 80 mg or both tolvaptan 30 mg and furosemide 80 mg once daily for 7 days after a 2-day run-in period of low-sodium diet (2 mg/ day). Tolvaptan, or tolvaptan plus furosemide, were well tolerated and produced a similar increase in urine output, greater than furosemide or placebo, without affecting blood pressure or other electrolytes apart from sodium, which increased (although within normal values).54
The role of vaptans in routine practice is still uncertain, but several trials are on the way. At the moment, European Society of Cardiology (ESC) guidelines only recommend that tolvaptan may be used for patients with acute HF and resistant hyponatraemia; in the US, vasopressin antagonists have a class IIb recommendation for the short treatment of acute HF with congestion and persistent severe hyponatremia, at risk of (or having) active cognitive symptoms.
Other Drugs
ACE-inhibitors are the first-line treatment for chronic HF patients with reduced systolic function, unless contraindicated. They have a wide range of effects including the promotion of diuresis and the renal excretion of sodium, principally by blocking the effects of angiotensin II in the kidney and angiotensin II-mediated aldosterone secretion. In turn, ACE-inhibitors reduce the circulating blood volume, and both venous and arterial pressures; moreover, they not only improve the peak oxygen consumption but also decrease NP plasma levels in symptomatic55 or asymptomatic patients.56 The effect of ACE-inhibitors on NPs is independent of co-administration of beta-blockers.57
In a trial that pre-dates modern therapy, patients whose symptoms and congestion were well-controlled were unable to maintain clinical stability for long periods on diuretics alone. The risk of clinical decompensation was decreased when diuretics were combined with digoxin or an ACE-I.58 The addition of a direct renin-inhibitor to an ACE-I might further enhance diuresis and decrease NP levels,59 but whether this translates into an improved long-erm outcome is not known yet; results for the ongoing ATMOSPHERE trial are expected soon.
LCZ 696 combines angiotensin receptor blockade (with valsartan) and inhibition of neprilysin, an enzyme that degrades NPs, with sacubitril. LCZ 696 decreases the risk of death and hospitalisation for HF in patients with stable chronic HF compared with enalapril. The drug increases circulating active NP, as shown by higher urinary levels of cycling guanosine monophosphate (GMP), the NP’s second messenger, suggesting that it may have some role in reducing congestion.60
It has long been known that digoxin used alone in patients with severe congestion – particularly those with atrial fibrillation – can cause a profound diuresis. The effect is presumably secondary to the improvement in haemodynamics induced by both heart rate slowing and by digoxin’s positive inotropic effect, but there does appear to be a modest direct renal effect of digoxin.61 Since the introduction of loop diuretics, digoxin is very rarely used only for its diuretic effects.
Levosimendan causes vasodilation of the coronary arteries and systemic resistance vessels, decreasing preload and afterload. Some recent reports suggest that short, intermittent courses of intravenous levosimendan might decrease NPs and possibly HF hospitalisation.62,63 Larger trials are ongoing, evaluating the efficacy of this novel approach (LAICA: NCT00988806 and ELEVATE NCT01290146).
Other Factors
The long-term education of patients with HF is of fundamental importance, to emphasise medication adherence and monitor symptoms indicating progression of disease. It might be that some patients remain congested just because they do not take their prescribed medications. Around 25 % of patients have difficulties in keeping their follow-up appointments or taking their drugs,64 and this proportion increases over time after diagnosis.65 A substantial proportion of patients continue to smoke despite the adverse diagnosis.64 Nurses, physicians and other members of a multidisciplinary team, including a pharmacist,66 can provide education to patients, increase their compliance and, more importantly, improve quality of life, decrease readmissions rate and alleviate the economic burden of this increasingly common disease.67
During times of severe fluid retention, simple interventions, such as continuous bed rest, might enhance diuresis and significantly reduce body weight compared with bed rest during night only;68 also diurnal postural changes might influence the diuretic action, which is enhanced by supine position compared to the erect.69 Although fluid restriction is an intervention mentioned by current guidelines for patients with HF, a recent meta-analysis including five studies suggests this therapy has no benefit compared with liberal fluid intake on mortality, admission or thirst in patients with HF.70
The role of sodium restriction is not clear, although part of the traditional management of HF and recommended in guidelines (albeit with an acknowledged low grade of evidence to support the recommendations).71 In acute HF and congestion, the only effect of sodium restriction appears to be to increase the sensation of thirst.72 In patients with chronic HF, a normal sodium diet is associated with better outcomes, albeit on the background of very high loop diuretic dose.73 It seems sensible to suggest to patients that they should not add large quantities of salt to their diet, but excessive restriction has no role.
Newer technologies, such as home-telemonitoring, can be used to educate patients further but also to allow health care professionals to monitor patients’ symptoms and physiological variables. Early studies of telemonitoring suggested that it was helpful, but more recent studies are less convincing, perhaps because the ‘standard care’ limb of trials has improved markedly.74
Treating Congestion in Heart Failure and Normal Ejection Fraction
In patients with HF and HeFNEF, there is no clear evidence that ACEinhibitors affect NP levels.75 In a study that enrolled 150 patients with HeFNEF randomised to diuretics alone (either furosemide or thiazides, depending on the level of congestion) or diuretics plus irbesartan or ramipril, all treatments improved quality of life quickly (after 12 weeks). Plasma NT-proBNP fell after 12 months in the three groups, but the fall only reached statistical significance in the irbesartan (–124 (SD 302) pg/ml; p=0.01) and ramipril (-173 (SD 415) pg/ml; p=0.03) groups, suggesting a synergistic effect between the renin–angiotensin system inhibitors and diuretics.76
In patients with HeFNEF, and compared with valsartan, LCZ 696 was effective in reducing NT-proBNP after 12 weeks of treatment in the PARAMOUNT trial although the difference between treatment groups was no longer significant after 36 weeks of follow-up.77 Whether this translates into outcome benefits is currently under investigation in the large PARAGON trial, which should complete in 2019.
Ultrafiltration and Home Abdominal Paracentesis
In the most severe cases of HF, renal dysfunction and diuretic resistance often occur, and limit the available therapeutic resources to decrease congestion. While ultrafiltration is an invasive solution usually reserved for patients with severe acute HF, peritoneal dialysis (PD) is a home-based, intermittent, therapeutic option in which the removal of the excess fluid takes place using the peritoneum as a filter. Two recent studies of patients with advanced HF complicated by renal failure have reported that PD is feasible, and that it might decrease body weight, and improve symptoms and functional status.78,79 A recent systematic review of 21 studies (n=673 patients) suggests that PD improves ventricular function and decreases the number of days spent in hospital with little risk of peritonitis (14 %/year).80