Showing posts with label hypertension. Show all posts
Showing posts with label hypertension. Show all posts
Thursday, December 26, 2013
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
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
- Edelmann F, Wachter R, Schmidt AG, Kraigher-Krainer E, Colantonio C, Kamke W, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA J Am Med Assoc. 2013 Feb 27;309(8):781–91.
- Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. The Lancet. 2003 Sep;362(9386):777–81.
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Sunday, February 3, 2013
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.
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.
- Roush GC, Holford TR, Guddati AK. Chlorthalidone Compared With Hydrochlorothiazide in Reducing Cardiovascular Events: Systematic Review and Network Meta-Analyses. Hypertension. 2012 Apr 23.
- ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002 Dec 18;288(23):2981-97.
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