The Unit: A Cardiology Blog: diuretics

Showing posts with label diuretics. Show all posts

Saturday, November 23, 2013

TOPCAT: not purrfect, but a signal of benefit with spironolactone in heart failure with preserved ejection fraction

This entry is the second part of a series on late-breaking clinical trials from the American Heart Association Scientific Sessions 2013. For a list of all reviewed trials, click here.

Note: details of this trial have not yet been published, so the following has been compiled from ClinicalTrials.gov and results presented at AHA13.

Summary:
In the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, 3445 patients with heart failure with preserved ejection fraction (HFpEF) were randomized in a double-blind fashion to spironolactone (15 mg titrated to 30-45 mg per day) or placebo. Investigators defined HFpEF as the presence of at least one sign and symptom of heart failure and EF > 45%. Patients were also required to have controlled systolic blood pressure (SBP < 140 mmHg or < 160 mmHg if taking > 3 antihypertensive medications) and serum potassium < 5.0 mEq/L. The mean systolic blood pressure at enrollment was 129.2±14.0 mmHg and potassium was 4.3±0.4 mEq/L. Other notable characteristics at baseline included the presence of hypertension in 91% of patients and chronic kidney disease in 39%. Additionally, 84% of patients were taking an ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB), and 82% were taking a diuretic.

After an average follow-up of 3.3 years, spironolactone failed to reduce the primary endpoint, a composite of cardiovascular mortality, cardiac arrest, or heart failure hospitalizations (18.6% vs. 20.4%, HR 0.89 (95% CI 0.77-1.04), p = 0.138). Spironolactone was more effective at reducing heart failure hospitalizations alone (12.0% vs. 14.2% with placebo, HR 0.83 (95% CI 0.69-0.99), p = 0.042), but it also doubled the rate of hyperkalemia (defined as serum potassium > 5.5 mEq/L) (18.7% vs. 9.1% with placebo, p < 0.001) and increased the incidence of renal failure (data not available at the time of writing). In a post-hoc analysis of TOPCAT, regional variability was observed, as patients in the Eastern Hemisphere (primarily Russia and the Republic of Georgia) did not benefit from the addition of spironolactone while a slight benefit was observed among patients in the Americas (HR 0.82 (95% CI 0.69-0.98)).

Commentary:
The results of TOPCAT follow a consistent theme in patients with HFpEF – no therapies have been shown to have a substantial impact on disease progression and it remains an incredibly difficult condition to treat. Optimism for spironolactone had been high due in part to the results of Aldo-DHF, where its use resulted in improvements in left ventricular function, although no differences in clinical endpoints were observe [1]. Authors attributed this lack of benefit to the short duration of the study and its relatively young, healthy population. However, as TOPCAT revealed, spironolactone does not appear to confer significant benefit even when a larger and sicker population is followed for a longer period of time.

Several findings from TOPCAT are worth further comment. Although the results were largely negative, the fact that spironolactone reduced heart failure hospitalizations may be a signal of benefit in carefully selected patients, such as those who can be monitored closely for hyperkalemia and changes in renal function. Although some experts have heralded it as the first study to show a benefit in HFpEF, this is not entirely accurate, as candesartan demonstrated similar improvements in heart failure hospitalizations as a secondary endpoint of the CHARM-Preserved trial [2]. Nonetheless, it does represent another potential approach in a patient population with so few therapeutic options.

Some of the baseline characteristics of patients in TOPCAT also warrant further discussion. The vast majority had hypertension, which is not altogether unsurprising given its role in the pathophysiology of HFpEF. However, the fact that patients were required to have controlled hypertension may have limited the impact of spironolactone. I recognize this probably had to be done to assess whether the potential impact of spironolactone was independent of its effects on blood pressure. However, given the number of trials showing benefit with spironolactone in refractory hypertension (as well as the role of hypertension in HFpEF), perhaps spironolactone would have been better than the medication therapies patients were required to be on in order to meet inclusion criteria. For example, the incidence of hyperkalemia (and the results this may have had on the primary endpoint) may not have been so high had so many patients not been taking ACEi or ARB therapy.

The higher rate of renal failure observed in the spironolactone arm is also intriguing, as a similar result was observed in Aldo-DHF, but this finding is not consistent with trials of aldosterone antagonists in patients with heart failure with reduced ejection fraction (HFrEF). Many patients with HFpEF are notoriously preload dependent, which can complicate strategies for maintaining appropriate volume status. Spironolactone is a weak diuretic at the low doses commonly used in HFrEF and usually has only minimal impact on volume status in most patients, even when combined with loop diuretics. However, could it have had a more substantial impact in patients with HFpEF given the more tenuous nature of their volume status? In TOPCAT, 4 out of every 5 patients were already on a diuretic at baseline – could the addition of spironolactone have been enough to tip the balance toward hypovolemia and subsequent renal failure?

All in all, I would still consider spironolactone in select patients with HFpEF (i.e., those who can be monitored for changes in serum potassium concentrations and renal function). I would especially consider its use in patients with HFpEF and refractory hypertension as well as those for whom only minor diuresis is necessary to maintain volume status. That being said, I am definitely cautious about its use in combination with diuretics or ACEi or ARB therapy. In fact, given the lack of benefit shown with these other agents, I think it would be reasonable to consider spironolactone first based on its potential for reducing heart failure hospitalizations (and potential for adverse events when combined with other agents).

Bottom line:
Similar to the agents studied before it, spironolactone does not substantially impact clinical outcomes in patients with HFpEF. It appears to reduce heart failure hospitalizations, but does so at the expense of increased rates of hyperkalemia and renal failure. Accordingly, its use should only be considered in select patients.

References

Thursday, November 21, 2013

ROSE AHF: Mostly thorns for low-dose dopamine, nesiritide in acute decompensated heart failure and renal impairment

This entry is the first part of a series on late-breaking clinical trials from the American Heart Association Scientific Sessions 2013. For a list of all reviewed trials, click here.

Summary:
In the Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE AHF) trial [1], patients with acute decompensated heart failure (ADHF) and renal impairment were randomized in a double-blind fashion to 72 hours of low-dose dopamine (2 mcg/kg/min), low-dose nesiritide (0.005 mcg/kg/min), or placebo. Patients were eligible for enrollment if they had at least one sign and symptom of ADHF (irrespective of ejection fraction) and an estimated glomerular filtration rate (eGFR) of 15-60 mL/min/1.73 m². Baseline characteristics were similar between the three groups with a median systolic blood pressure of 115 mmHg, median ejection fraction (EF) of 33% (over two-thirds with EF < 50%), and eGFR of 42 mL/min/1.73 m².

Low-dose dopamine failed to produce a difference in the co-primary endpoints of cumulative urine output (UOP) or change in cystatin C at 72 hours compared to placebo (differences in UOP of 8254 mL and 8296 mL, respectively, p = 0.59). Drug discontinuation was similar between the two groups, although low-dose dopamine was more likely to be discontinued for tachycardia (7.2% vs. 0.9% with placebo, p < 0.001) while placebo was discontinued more frequently for hypotension (10.4% vs. 0.9% with low-dose dopamine, p < 0.001). Likewise, low-dose nesiritide also failed to confer significant differences in the co-primary endpoint (differences in UOP of 8574 mL and 8296 mL with placebo, p < 0.49). Compared to placebo, hypotension was more common in the low-dose nesiritide group (18.8% vs. 10.4% with placebo, p = 0.07). Results for the co-primary endpoints were similar across subgroups with the exception of EF. Compared to dopamine, patients with preserved EF tended to do better with placebo (p = 0.01 for interaction). In contrast, nesiritide appeared to benefit those with reduced EF, although this difference was not statistically significant. No differences in clinical endpoints (e.g., symptom relief, death, rehospitalization) were observed between any of the groups.

Commentary:
Those who follow my blog know that I am no fan of using low-dose dopamine for the purposes of renoprotection in ADHF (previous entries here and here). While I am not opposed to its use as a mixed inotrope/vasopressor (i.e., for patients in whom peripheral vasodilation from a traditional inotrope might compromise hemodynamics), the renoprotective properties of low-dose dopamine have been widely discredited [2]. Given the lack of benefit observed in ROSE AHF, hopefully this myth has been debunked once and for all. Importantly, dopamine not only failed to produce a significant difference in the co-primary endpoints; it also resulted in lower rates of hypotension and higher rates of tachycardia, indicating that even at doses as low as 2 mcg/kg/min, dopamine is not entirely selective for renal vascular beds.

Unfortunately, a signal of differential response between those with reduced versus preserved EF was observed (although not statistically significant), which may provide just enough justification to continue evaluating this approach in select subgroups. Although the inclusion of a low-dose nesiritide arm in this study was an interesting hypothesis, the fact that it did not produce a meaningful difference in outcomes is not altogether unsurprising.

Bottom line:
Neither low-dose dopamine nor low-dose nesiritide provide renoprotective effects in patients with ADHF and renal impairment.

References

Sunday, September 22, 2013

Should tolvaptan be used routinely for hyponatremia in patients with heart failure? Na.

One can hardly open a medical publication without seeing an advertisement for Otsuka's tolvaptan (Samsca^®), an oral vasopressin antagonist approved for the management of hyponatremia in the setting of heart failure. Despite only minimal improvements in clinical trials and new warnings issued by the US Food & Drug Administration (FDA), the use of tolvaptan remains a topic of interest.

Hyponatremia is common among hospitalized patients and is associated with poor prognosis among those with heart failure [1]. What is less clear, however, is whether this relationship is a result of cause-and-effect or merely correlation. The latter is worth investigating, as this has been observed with other surrogate markers that were once considered potential therapeutic targets, with hemoglobin being one of the most recent to be called into question [2].

To date, the available evidence suggests that, while serum sodium concentrations can be improved with vasopressin antagonist therapy, these changes do not appear to confer meaningful differences in clinical outcomes. In SALT, a trial evaluating the use of tolvaptan in patients with hyponatremia (a third of whom had heart failure), patients randomized to tolvaptan experienced improvements in urine output and serum sodium concentrations, but this only persisted while patients were on therapy; in less than a week after discontinuing tolvaptan, serum sodium concentrations returned to baseline [3]. In EVEREST, a trial specifically enrolling patients with acute decompensated heart failure (irrespective of serum sodium concentrations), those randomized to tolvaptan experienced greater reductions in body weight (although less than a kg difference versus placebo) and improvements in some but not all heart failure signs and symptoms [4]. Tolvaptan failed to impart any clinically meaningful differences in mortality, hospitalizations, worsening heart failure, or quality of life [5]. Serum sodium concentrations improved initially but these differences dissipated with time.

In other words, tolvaptan and other vasopressin antagonists appear to have no appreciable effect on the underlying pathophysiology of heart failure. While serum sodium concentrations can be improved, recurrence of hyponatremia should be expected following cessation of therapy if underlying causes (e.g., reduced renal perfusion, hypervolemia, etc.) are not addressed. Coupled with emerging evidence of liver injury that eventually prompted FDA to limit its use to less than 30 days (and avoid it altogether in patients with evidence of liver impairment), tolvaptan has only limited utility in patients with heart failure.

There are a couple of scenarios where a short course of tolvaptan may be considered:

Patients with symptomatic hyponatremia at any serum sodium concentration; or,
As a temporizing measure (i.e., up to 5 days or so) to stabilize critically low serum sodium concentrations (< 125 mEq/L, to prevent patients from becoming symptomatic) while underlying causes are corrected, i.e., discontinuation of potentially offending drugs (select antipsychotics and antidepressants, thiazide diuretics), optimization of standard heart failure therapies, addition of vasodilators or inotropes to improve renal perfusion, or aggressive diuresis to correct hypervolemia.

That being said, there is evidence that suggests small boluses of hypertonic saline can improve hyponatremia in these scenarios without worsening fluid balance [6].

In summary, routine use of tolvaptan should be avoided, as it both fails to improve long-term clinical outcomes and represents an incredibly expensive strategy for improving symptoms and/or treating a surrogate marker that has yet to be associated with improved clinical endpoints. Although the price of tolvaptan has likely come down since its introduction to the market, at one time its use represented spending about $50 for each mEq/L increase in serum sodium concentration per day, and about $3 for each additional mL of urine output per day.

Note: I borrowed the title for this entry from an old Chemistry Cat meme, so let me end by giving credit (or blame?) to whomever it is due.

References

Saturday, May 12, 2012

Chlorthalidone versus hydrochlorothiazide: maybe it matters after all

At a journal club meeting earlier this week, we discussed a recently published meta-analysis/systemic review comparing chlorthalidone and hydrochlorothiazide (HCTZ) for the reduction of major cardiovascular events in patients with hypertension [1]. Controversy surrounding the widespread use of HCTZ over chlorthalidone seems to be a favorite theme among advocates for evidence-based medicine -- after all, chlorthalidone (rather than HCTZ) was the agent featured in the landmark ALLHAT trial of patients with hypertension, where improvements in cardiovascular endpoints were observed when it was compared to amlodipine and lisinopril -- all at a fraction of the cost [2]. Although the efficacy of chlorthalidone has been extrapolated to HCTZ, use of the latter has become far more widespread, where prescriptions for HCTZ outnumber those for chlorthalidone by as much as 20-fold [1]. This is likely also the result of the minimal cost of HCTZ -- currently included on the Wal-Mart $4 list and other discount programs -- and its inclusion as a combination product with nearly every other antihypertensive on the market. However, as many have suspected for a long time, there may be merit to the use of chlorthalidone over HCTZ, despite the lower cost and convenience of HCTZ.

Because no trial has directly compared chlorthalidone and HCTZ, Roush, et al conducted a retrospective review of nine randomized trials (n > 50,000) as well as drug-adjusted and blood pressure-adjusted meta-analyses comparing these two agents in the management of hypertension. Compared to HCTZ, chlorthalidone reduced the risk of cardiovascular events by 21% (95% CI 12-28%, p = 0.0001) and risk of heart failure by 23% (95% CI 2-39%, p = 0.032) -- results that were independent of actual blood pressure control. Impressively, the number-needed-to-treat to prevent a single cardiovascular event with chlorthalidone (compared to HCTZ) over a 5-year period was only 27. The investigators attribute these differences to several possible factors, including effects of chlorthalidone unrelated to its vasodilatory properties, as well as known pharmacokinetic differences between chlorthalidone and HCTZ.

Although there are usually other compelling indications that warrant the use of alternative anti-hypertensives in my patient population (e.g., ACE inhibitors in patients with established coronary artery disease, heart failure, diabetes, or chronic kidney disease), there are some instances where the decision to initiate either chlorthalidone or HCTZ arises (e.g., hypertensive urgency, uncontrolled hypertension on maximum doses of other therapies). In these scenarios, when cost or pill burden is not an issue, I recommend chlorthalidone over HCTZ, not so much for the academic purity of it but because of its pharmacokinetic advantages. Chlorthalidone has a terminal half-life of over 40 hours -- one of the longest of any anti-hypertensive currently available. Because patients with hypertension rarely "feel" the symptoms of their disease, daily compliance with anti-hypertensive medications can be a significant issue. With such a long terminal half-life, even if a patient remembers to take chlorthalidone every other day, they are likely to derive some anti-hypertensive benefit.

The only drawback with this strategy is cost and pill burden. Although chlorthalidone is generic and relatively inexpensive, it is not available on any of the retail discount programs (of which I am aware). The only exception is in a combination product with atenolol, but I usually have reasons for using an alternative beta blocker (e.g., metoprolol, carvedilol, etc), so this is not usually an option. Moreover, compliance decreases as the number of medications increases, so the limited number of combination products available makes chlorthalidone an entirely separate prescription to fill and another pill to take.

However, if neither of these issues is the case, it seems that the analysis conducted by Roush, et al, only adds further evidence to support the use of chlorthalidone over HCTZ.