|Year : 2021 | Volume
| Issue : 1 | Page : 3-11
Role of spironolactone in patients with resistant hypertension: A narrative review
Geeta Sheth1, Kavita Joshi2
1 Department of Nephrology, Grant Government Medical College and Sir J. J. Group of Hospitals, Mumbai, Maharashtra, India
2 Department of Medicine, Seth G. S. Medical College and KEM Hospital, Mumbai, Maharashtra, India
|Date of Submission||15-Oct-2020|
|Date of Decision||09-Feb-2021|
|Date of Acceptance||25-Feb-2021|
|Date of Web Publication||30-Mar-2021|
Dr. Geeta Sheth
Department of Nephrology, Grant Government Medical College and Sir J. J. Group of Hospitals, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Treatment-resistant hypertension (RH) is defined as uncontrolled blood pressure (BP) despite use of at least three different antihypertensive agents (including angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, calcium channel blocker, and a diuretic) at their optimal doses. It is important to properly diagnose and treat RH because patients are at high risk of end-organ damage. Activated renin-angiotensin-aldosterone system, increased renal sympathetic nervous system activity (increase sodium and water reabsorption and thus increase in extracellular fluid volume), and increased arterial stiffness become the main reason for hypertension. Therefore, a controlled BP can be achieved by the use of mineralocorticoid receptor blockers as add-on treatment to the first-line triple-drug combination therapy. In this review, we provide evidences from various studies comparing spironolactone treatment with other comparators (diuretics or other mineralocorticoid receptor blockers) or placebo signifying spironolactone is beneficial for controlling BP in patients with RH. Furthermore, there is a greater need to increase the use of mineralocorticoid receptor blocker, spironolactone, as fourth-line medication add-on to three drug therapy in patients with RH.
Keywords: Aldactone, mineralocorticoid receptor blocker, resistant hypertension, spironolactone, uncontrolled blood pressure
|How to cite this article:|
Sheth G, Joshi K. Role of spironolactone in patients with resistant hypertension: A narrative review. Heart India 2021;9:3-11
| Introduction|| |
Resistant hypertension (RH) is defined as uncontrolled blood pressure (BP), that is office BP >140/90 or 130/80 mmHg, despite the use of at least three different antihypertensive agents (including a diuretic) at optimal doses. RH should be diagnosed using good BP measuring technique excluding the factors responsible for pseudoresistance, which include poor patient adherence to prescribed medications, diet and lifestyle changes (obesity, dietary salt intake, and alcohol consumption), insufficient doses or incorrect antihypertensive drug combinations, and white-coat effect. While the etiology of RH is multifactorial, the important secondary causes of RH are drug-induced hypertension, obesity, obstructive sleep apnea, primary aldosteronism (rise in aldosterone synthesis independent of renin-angiotensin-aldosterone system), chronic kidney disease, diabetes, and Cushing's syndrome.,, There is a crucial role played by renin-angiotensin-aldosterone system to understand the development of treatment RH. Activated renin-angiotensin-aldosterone system, increased renal sympathetic nervous system activity stimulates the production of aldosterone. High levels of aldosterone result in increased sodium and water reabsorption (consequent loss of potassium) from distal nephron, and thus increase in extracellular fluid volume. Aldosterone also becomes the reason for ventricular hypertrophy, cardiac fibrosis, and increased arterial stiffness, thereby resulting in hypertension. All these effects together raise BP contributing end-organ damage in patients with hypertension with high aldosterone explaining the treatment resistance in patients with severe hypertension. If the first-line three drug combination treatment for hypertension has not reduced BP, then a clinical evaluation to determine the potential pathogenic mechanisms is recommended and an add-on drug therapy is suggested to treat RH.,,
Renal venin renin (RVR) analysis is an important diagnostic tool that enables to rationalize the treatment strategy for identifying the etiology of hypertension through the detection of renal artery obstruction and renin-producing tumors leading to unilateral kidney. The measurement of renal vein renin enables to establish the indication of nephrectomy and decide whether revascularization of a kidney is essential in patients with renal artery stenosis. A 12-year prospective study demonstrated that RVR measurement was more beneficial for determining nephrectomy in patients with renal artery occlusion and different cutoff values were needed for nonoccluded and occluded renovascular hypertension.
Although the exact prevalence is unknown, it is estimated that nearly 10%–15% of hypertensive patients have RH.,,, The Antihypertensive Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) reported that after 5 years of treatment, 34% patients with hypertension remained uncontrolled and 27% patients remained on ≥3 drugs. Observations from a most recent eight National Health and Nutrition Examination Surveys (NHANES; 1999 to 2014), 46% patients had uncontrolled hypertension, whereas 27% patients despite being treated for hypertension remained uncontrolled.
Patients with RH have high risk of end-organ damage and cardiovascular events as seen by the prevalence of left ventricular hypertrophy, myocardial infarction, chronic kidney disease, congestive heart failure, stroke, and ischemic heart event when compared to patients with easily controlled hypertension.,,,,
This narrative review provides a comprehensive analysis from the available literature with an aim to show that the use of spironolactone is beneficial in controlling BP of resistant hypertensive patients when compared to placebo or other active comparators.
| Methods|| |
Articles were searched from PubMed database using the search term “Resistant hypertension and spironolactone.” The filters applied were clinical trials, meta-analyses, observational studies, and randomized controlled trials for article type, 2001–2019 for publication date, English language, and human species. From the results, the articles that studied safety and/or efficacy of spironolactone alone or versus placebo or other active drug comparators in patients with RH were only selected for this manuscript. Conditions other than RH and comparators other than drugs were excluded.
An inappropriately high aldosterone (primary aldosteronism) is one of the major factors responsible for uncontrolled RH. As reported from various studies, there is a 17%–23% prevalence of primary aldosteronism in patients with RH.,,,,,, Thus, a mineralocorticoid antagonist blocking aldosterone action on mineralocorticoid receptors is effective in treating RH.,, Various guidelines for the treatment of hypertension also suggest spironolactone as effective treatment for treatment RH. According to the NICE guidelines, treatment for hypertension should include three different classes of antihypertensive drugs such as angiotensin-converting enzyme (ACE) inhibitor (or an angiotensin receptor blocker), a calcium channel blocker, and a diuretic at their optimal doses (A + C + D). A greater BP reduction is achieved by combining medications from different classes at lower doses than a high dose of a single-class antihypertensive. The NICE guidelines recommend a mineralocorticoid receptor blocker, low-dose spironolactone therapy, as a fourth-line agent in hypertensive patients with blood potassium of ≤4.5 mmol/L. The JNC8 guidelines also suggest the similar approach as first-line treatment with A + C + D low doses, and second- and third-line treatments with their higher doses or combinations and then moving on to later-line alternatives which include beta-blockers, alpha-blockers, adrenergic agonists, direct vasodilators, loop diuretics, and aldosterone antagonists., The ASH and ISH guidelines too suggest the A + C + D therapy alone or combination followed by mineralocorticoid receptor blockers. Among the available mineralocorticoid receptor antagonists (spironolactone, eplerenone, and canrenone), spironolactone is the most effective add-on fourth medication for the treatment of patients with RH (who are on triple regimen of A + C + D)., The ESH/ESC guidelines also suggests the use of mineralocorticoid receptor blockers, spironolactone (at low doses 25–50 mg/day) or eplerenone, the alpha-1-blocker doxazosin and maximize diuretic dose, loop diuretic replacing thiazides or chlorthalidone if renal function is impaired. ESH/ESC guidelines also suggest using amiloride as add-on to thiazide or thiazide like diuretic, although the levels of potassium needs close monitoring.
Renin assessment in patients with resistant hypertension
Renin-angiotensin system (RAS) regulates BP and renin activity enables the measurement of RAS activity. The knowledge of RAS activity helps in clinical decision-making and guides in the selection of therapeutic intervention. It is also useful to locate rare tumors such as reninomas that causes severe hypertension. However, a retrospective study of 244 who underwent RVR (n = 123) and percutaneous renal artery angioplasty (n = 121). Improved BP control was observed in 72% with abnormal RVR analysis and 66% of the 121 patients without RVR measurements (P > 0.1). The findings also showed that the very low negative predictive value significantly limited the application of RVR analysis in elderly patients with the prevalence of mild renal impairment and bilateral renal artery stenosis.
About one-third of hypertensives has low renin and respond to sodium volume-depleting natriuretic agents. Patients those with high renin are more prevalent and responds very well to drugs including ACE inhibitors, angiotensin receptor blockers, and β-blockers, all of which block plasma renin activity. Evidences suggest that higher renin levels favors better response to atenolol, resulting in mean decreases in systolic BP of 10–12 mmHg but only 6–7 mmHg with hydrochlorothiazide. Approximately a twofold difference occurs in mean systolic BP reduction that would be higher if more potent renin blocker is administered and reverse is expected in low renin spectrum, with greater efficiency observed with hydrochlorothiazide.,
Aldosteronism which is the most prevalent cause of RH occurs due to several conditions such as tumor of adrenal gland, obesity, sleep apnea, or genetically acquired. The aldosterone/renin ratio is an effective screening test, but high ratio has low specificity for the detection of primary aldosteronism. Renal hypertension presents with high renin/high aldosterone levels and is best treated with angiotensin receptor antagonists, whereas primary aldosteronism having low renin/high aldosterone is best treated with aldosterone antagonists such as spironolactone.
Spironolactone is a competitive receptor antagonist of aldosterone, acting at aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule, increasing the excretion of sodium and water, and retaining potassium. Thus, it is effective in lowering systolic and diastolic BP in patients with RH where BP is uncontrolled with the use of first-line medication.
Evidences for spironolactone treatment
A number of studies were conducted to evaluate the efficacy and safety of spironolactone versus placebo or other medications as add-on treatment to standardized three-drug regimen for RH. Here, we summarized the results from various studies where patients with RH were given treatment with spironolactone, reporting the improvements in BP compared to baseline as well as with other treatments. [Table 1] represents the summary of effects of spironolactone from various studies for the treatment of RH.
|Table 1: Summary of effects of spironolactone from various studies for treatment of resistant hypertension|
Click here to view
The first study to assess effects of low-dose spironolactone (25 mg once daily) was a double-blind ASPIRANT trial where there was significant reduction in systolic BP (−5.4 mm Hg, P = 0.024) after 8 weeks of treatment with spironolactone versus placebo. Spironolactone reduced ambulatory daytime systolic BP by 9.3 mm Hg ± 12.6 while nighttime systolic BP by −11.2 ± 17.6 mm Hg. Although it reduced diastolic BP from baseline, there was no significant difference seen between spironolactone and placebo groups. Though there was a slight increase in mean serum potassium levels (4.15 to 4.52 mmol/L) after 8 weeks of spironolactone treatment, no patients were excluded because of hyperkalemia. 54.5% patients reached goal office systolic BP, whereas 69.1% patients reached goal diastolic BP in spironolactone treated group. The adverse events were comparable in both spironolactone and placebo groups.
Spironolactone versus other active treatments
The landmark study PATHWAY-2 assessed for the first-time add-on treatment of spironolactone 25 to 50 mg versus α-blocker doxazosin 5 to 10 mg, β-blocker bisoprolol 5 to 10 mg or placebo for RH. This was a double-blind four-way cross-over study reporting data of 314 patients for a treatment period of 3 months. Spironolactone significantly reduced home systolic BP compared to active treatments, doxazosin (−4.03 mm Hg) and bisoprolol (−4.48 mm Hg) and placebo (−8.7 mm Hg; all P < 0.0001). Fifty-eight percent patients had a BP control in spironolactone group while 41.5% in doxazosin group, 43.3% in bisoprolol group, 23.9% in placebo group (P < 0.001 for all groups). There was a small statistically significant increase in mean serum potassium levels by 0.43 mmol/L in spironolactone treated group, whereas the increase was less in doxazosin (0.08 mmol/L), bisoprolol (0.15 mmol/L), and placebo (0.03 mmol/L) groups. Neither gynecomastia nor hyperkalemia was reported in spironolactone group. There was a significant increase in serum potassium and creatinine with a change from baseline of 0.43 mmol/L and 8.43μmol/L, respectively, (P < 0.001 for both) in spironolactone group. An increase in estimated glomerular filtration rate was also seen with a change from baseline of 10.02 (P = 0.004). One of the PATHWAY-2 sub study indicated that in RH, there was excess fluid retention, mediated by excess aldosterone. In such cases of high aldosterone-renin ratio, spironolactone is beneficial in patients with RH to reverse aldosterone induced fluid retention. This study also reported amiloride to be an effective alternative substitute treatment for RH. Lane Da et al. reported amiloride, a potassium sparing diuretic (at a dose of 10 mg), to be less effective than spironolactone (at a dose of 25 mg) in patients with RH who were given a multidrug regime including an angiotensin-blocking agent. Another study which compared the reductions of BP after treatment with spironolactone versus doxazosin reported that both the drugs were beneficial in patients with RH. In this study, spironolactone significantly reduced mean systolic and diastolic BP by 28 mm Hg and 12 mm Hg while doxazosin reduced by 16 mm Hg and 7 mm Hg of corresponding BP values. When compared between the treatment groups, there was significant reduction in spironolactone group versus doxazosin group. Similarly, 39% patients with spironolactone achieved BP control versus 23% in doxazosin (P = 0.02). It was also reported that there was small but significant increase in serum potassium levels and reduction in glomerular filtration rate in spironolactone group while no changes were seen in doxazosin group. Parthasarathy et al. compared the antihypertensive effect of two different mineralocorticoid receptor blockers, eplerenone, and spironolactone. Patients with hypertension and primary aldosteronism were randomized to either groups in double-blinded fashion, and results showed spironolactone to be more effective in reducing the diastolic BP from respective baseline values (−5.6 mmHg for eplerenone vs. −12.5 mmHg for spironolactone) with a significant difference between the groups (-6.9 mmHg, P < 0.001) favoring spironolactone. However, male gynecomastia was seen in more patients with spironolactone than eplerenone (21.2% vs. 4.5%). As per the ReHOT study, clonidine was not superior to spironolactone; hence, the latter was preferred than clonidine. The BP control during office measurement and 24-h ambulatory BP monitoring was similar between the two groups (around 21% patients). However, spironolactone showed greater decrease than clonidine in 24-h systolic and diastolic BP and diastolic daytime ambulatory BP. The rates of adverse effects were low for both drugs. No cases of gynecomastia related to spironolactone were reported. However, the creatinine levels in spironolactone group were more (1.12 ± 0.38 mg/dL) compared to that of clonidine group (0.98 ± 0.35 mg/dL; P = 0.01) and also 14.3% patients from spironolactone group had hyperkalemia compared to 2.6% patients in clonidine group (P = 0.010). Another study reported effectiveness of add-on spironolactone treatment (12.5 to 25 mg) versus other most commonly used calcium channel blocker or α-blocker or β-blocker or ACE inhibitor or thiazide diuretic or a combination of these. After the spironolactone treatment, the systolic and diastolic BP was significantly reduced from baseline. Between the groups, there was significant reduction of BP by 23.2/12.5 mm Hg in spironolactone versus 7.6/5.8 mm Hg in other add-on therapy groups. A total of 50% patients reached systolic and diastolic BP control in patients with spironolactone versus 24% in patients with other add-on treatments. There was increase in mean serum potassium levels by 0.5 in spironolactone group, whereas it remained same in another add-on therapy group.
In an observational study, ASCOT, with 1411 patients receiving spironolactone for RH, the mean systolic BP was reduced by 21 mm Hg and diastolic BP by 9.5 mm Hg compared to baseline values (both P < 0.001). There was a small statistically significant increase in mean serum potassium levels by 0.41 mmol/L. This study reported that 6% patient discontinued spironolactone treatment because of adverse events. Furthermore, gynecomastia was the most frequent adverse event reported in 114 male patients (6%), leading to treatment discontinuation in 52 (3%) patients (all men). Lane et al. reported a significant fall in mean systolic and diastolic BP (21.7 mm Hg and 8.5 mm Hg, both P < 0.001) by the addition of spironolactone 25 mg. A mean increase of 0.3 mmol/L of serum potassium was observed and overall two patients discontinued spironolactone because of rise in serum potassium >6.0 mmol/L. Furthermore, there was a rise in serum potassium levels from an average of 3.7 mmol/L to 4.1 mmol/L, and hence, 4.1% of patients discontinued spironolactone because of hyperkalemia in another retrospective study. Furthermore, 5.2% of males reported gynecomastia. However, this study showed significant reduction of BP after 1, 3, and 6 months of add-on spironolactone.
Two separate meta-analyses were conducted by Liu et al. and Wang et al. to analyze spironolactone from the results of various randomized controlled trials. Both the analyses reported similar results thus favoring the addition of spironolactone as the fourth drug in the treatment of RH.,
Nishizaka et al. reported that add-on spironolactone therapy in patients with RH showed similar benefits in patients with and without primary aldosteronism. After 6 months follow-up, there was a mean decrease of systolic (25 ± 20 mm Hg) and diastolic BP (12 ± 12 mm Hg). The numbers of prescribed anti-hypertensive medications were also reduced in both patients with and without primary aldosteronism. However, patients with primary aldosteronism were more likely to be titrated up to spironolactone 50 mg/d and had a higher mean dosage compared to patients without primary aldosteronism. This study reported that 4% patients (10% of male patients) had gynecomastia and two patients had hyperkalemia with serum potassium >5.5 mEq/L. These both patients had chronic kidney disease with a calculated creatinine clearance <60 mL/min. Another recent study, Gaddam et al. also reported spironolactone to be effective in reducing hypertension in patients with hyperaldosteronism. After the addition of spironolactone, the clinic systolic and diastolic BP was reduced at 6 months' follow-up in both patients with normal aldosterone and high aldosterone in spite of withdrawing nearly 1.5 antihypertensive medications. In addition, spironolactone significantly reduced left ventricular, right ventricular end diastolic volumes in both normal aldosterone and high aldosterone patients. Hence, mineralocorticoid receptor blockade is more useful in RH patients irrespective of aldosterone status when intracardiac volume is increased in spite of use of conventional thiazide like diuretic. Another similar study of spironolactone (doses of 25 to 100 mg/day) reported a significant reduction of ambulatory systolic and diastolic BP of 16 mm Hg and 9 mm Hg in addition to reductions of office systolic BP (14 mm Hg) and diastolic BP (7 mm Hg). 48% patients achieved control of ambulatory BP. In this study, ambulatory BP measured after 15 months also confirmed the persistent efficacy of spironolactone. Gynecomastia was seen in seven patients (4%), increase of serum creatinine levels in two patients and asymptomatic hyperkalemia in two patients. Alvarez-Alvarez et al. also reported ambulatory BP reductions by the use of spironolactone in patients who were on double blockade of renin-angiotensin-aldosterone system after 1-month washout period. The ABPM systolic and diastolic BP dropped significantly (7.1 ± 13.4 mm Hg and 3.4 ± 6.2 mm Hg) when patients were on dual blockade. After spironolactone treatment, BP was reduced in office (32.2 ± 20.6/10.9 ± 11.6 mmHg) and ABPM (20.8 ± 14.6/8.8 ± 7.3 mmHg; P < 0.001) Spironolactone and dual blockade treatment resulted in BP control by ABPM in 56.4% and 20.5% patients, respectively. The office systolic and diastolic BPs and percentage of patients whose BP was controlled also favored spironolactone treatment over dual blockade of RAAS in RH.
In RH patients with moderately severe chronic kidney disease (stage 2 and 3), Abolghasmi et al. reported a significant reduction in BP with use of low dose spironolactone. In this study, 41 patients were grouped to either placebo (n = 22) or spironolactone 25 to 50 mg/day (n = 19). After 12 weeks of spironolactone treatment, the mean decrease in systolic and diastolic BPs were 36 ± 10 mm Hg and 12 ± 2 mmHg (P < 0.05), respectively, while there was no change in the BP in the control group. Hyperkalemia (serum potassium >5.5 meq/L) was observed in one subject in the spironolactone group. Another study retrospectively assessed the long-term effectiveness and safety of spironolactone and eplerenone as add-on treatment to pre-existing BP lowering medication in patients with RH associated with stage 3 chronic kidney disease. Thirty-two patients with spironolactone (mean dose 23.6 ± 10.5 mg/day) and four patients with eplerenone (60.4 ± 33.9 mg/day) were followed up for a median of 312 days. A significant decrease in SBP from 162 ± 22 to 138 ± 14 mm Hg (P < 0.0001) and in DBP from 87 ± 17 to 74 ± 12 mm Hg (P < 0.0001) with mean number of BP lowering agents increased from 4.9 ± 1.6 at baseline to 5.4 ± 1.5 (MRA included) at the last follow-up visit (P < 0.01). A significant increase in serum potassium from 4.0 ± 0.5 at baseline to 4.4 ± 0.5 mEq/L (P =0.0001) during follow-up was observed. Overall, eight patients (22%) developed hyperkalemia with serum potassium >5.0 mEq/L. Two patients discontinued spironolactone because of acute renal failure in one, symptomatic hypotension in another which was resolved after spironolactone withdrawal. Because of elevated serum potassium levels, one patient discontinued spironolactone and one patient dose was reduced from 25 mg to 12.5 mg daily. Two patients were switched to eplerenone because of the breast tenderness due to spironolactone. From the above two studies, spironolactone can also be used in chronic kidney disease stage 3 patients with RH although potassium levels needs close monitoring. Yang et al. also reported from his long-term study of spironolactone that the mineralocorticoid receptor antagonist could be promising treatment option for preventing progression of chronic kidney disease to end-stage renal disease provided hyperkalemia is treated strategically. Tseng et al. conducted a nation-wide population study in Taiwan and reported that spironolactone had higher risks for all-cause and infection-related mortality and hospitalization for heart failure in pre-dialysis stage 5 chronic kidney disease patients compared to nonusers of spironolactone.
A recent study phase 2, randomized, placebo-controlled study conducted in patients with RH and chronic kidney disease and were randomly assigned (1:1) to receive either placebo or patiromer (8·4 g once daily), with add on spironolactone (starting at 25 mg once daily). At week 12, 66% and 86% of patients from placebo and patiromer group remained on spironolactone (between-group difference 19·5%, 95% confidence interval 10·0–29·0; P < 0·0001). Furthermore, adverse events reported in placebo (53%) and patiromer (56%) group were mild or moderate in intensity. Overall findings suggest that spironolactone has beneficial effect with patiromer in terms of less hyperkalemia in patients with RH and chronic kidney disease. Spironolactone decreases testosterone production, increases conversion of testosterone to estradiol, and displaces estradiol from sex hormone-binding globulin, thus resulting in gynecomastia. From the above studies of effect of spironolactone in patients with RH, the most frequent adverse events reported were gynecomastia, hyperkalemia, increase in serum creatinine, and decrease in estimated glomerular filtration rate. In generak, discontinuing spironolactone resolves gynecomastia. A close monitoring is mandatory of serum creatinine and serum potassium levels in patients using spironolactone for the treatment of RH, who have chronic kidney disease stage 3, 4 and 5, to limit the risk of drug-related adverse events.
| Conclusion|| |
In conclusion, based on the above evidences of studies comparing spironolactone treatment with other comparators (diuretics or other mineralocorticoid receptor blockers) or placebo, spironolactone is beneficial for controlling BP in patients with RH. However, potassium levels and renal function need to be closely monitored in patients receiving spironolactone. We suggest that there is a greater need to increase the use of mineralocorticoid receptor blocker, spironolactone, as fourth-line medication add-on to three drug therapy in patients with RH.
Both the authors contributed to concept, design, writing, critical review and final approval of the paper. GS additionally contributed to literature search.
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Conflicts of interest
There are no conflicts of interest.
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