Chapter 63 Spironolactone: A Grossly Undervalued and Underutilized Drug

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1 Chapter 63 Spironolactone: A Grossly Undervalued and Underutilized Drug VIVEKANAND GUPTA JOSHUA C. VOGT GURPREET S. SANDHU RAJIV AGARWAL INTRODUCTION Spironolactone is a mineralocorticoid receptor antagonist (MRA) approved for the treatment of heart failure (HF) and resistant hypertension (RHTN). The RALES trial published in 1999 clearly demonstrated the mortality benefit of spironolactone in patients with systolic HF. Also, various trials including the recent PATHWAY-2 trial have defined the role of spironolactone in patients with RHTN. Despite its proven clinical benefit in these conditions, this drug is being underused as demonstrated in various studies. The primary reason for this is its adverse side effect profile, although other factors are also important. This chapter will highlight the physiologic basis for spironolactone use, review the clinical evidence underpinning its efficacy, and explore the possible causes and corrective measures for spironolactone underuse in the clinical setting. PHYSIOLOGY Aldosterone has effect on various tissues and organ systems principally as a MRA. Table 63-1 outlines the effects of aldosterone on the cardiac, vascular and renal systems. In the kidney, aldosterone acts at the level of the distal convoluted tubule and collecting duct to promote sodium and water retention at the expense of potassium excretion. In addition, aldosterone excess promotes macrophage adhesion, inflammation, oxidative stress and fibrosis via varied genomic and nongenomic mechanisms. In the vasculature, aldosterone increases tissue angiotensin converting enzyme (ACE) activity, inhibits nitric oxide (NO) release and increases vasoconstriction 1. Beyond altering the vascular neurohormonal response, aldosterone decreases arterial compliance by enhancing profibrotic gene expression, promoting the formation of reactive oxygen species, and increasing the expression of pro-inflammatory transcription factors 2, 3. Tissue immune response and inflammation are also enhanced by MR-dependent transcription of cellular adhesion molecules: intercellular adhesion molecule-1 (ICAM-1) and vascular cellular adhesion molecule (VCAM-1) 2. Through similar genomic and nongenomic mechanisms, intramyocardial activation of the MR has been TABLE 63-1 THE PHYSIOLOGIC EFFECTS OF ALDOSTERONE ON THE CARDIAC, VASCULAR AND RENAL SYSTEMS, AND SUMMARY OF THE UNDERLYING MECHANISMS Effects Mechanisms Heart a Vasculature Kidney (Early) Perivascular inflammation (Late) Interstitial fibrosis h Profibrotic gene expression PAI-1, TGF- 1, CTGF h Pro-inflammatory transcription factors NF-K, AP-1 h Reactive oxygen species Decreased vascular compliance Vasoconstriction h Tissue ACE g NO synthesis h Profibrotic gene expression PAI-1, TGF- 1, CTGF h Reactive oxygen species Sodium and water retention Potassium excretion Acts at the distal convoluted tubule of the nephron and the collecting duct: h Sodium chloride cotransporter activity h Epithelial sodium channel Notes : See text for references. AP-1, activator protein-1; CTGF, connective tissue growth factor; NF-K, nuclear factor kappa beta; PAI-1, plasminogen activator inhibitor-1; TGF- 1, tissue growth factor-beta 1. a The effects of aldosterone on the heart listed here are those in response to chronic aldosterone excess. 531

2 532 SECTION VII Heart Failure implicated in myocardial fibrosis and myocyte hypertrophy 2, 3. By virtue of all these effects, aldosterone plays a key role in the pathophysiology of HF and hypertension and MRAs are crucial in management of these conditions. Spironolactone and eplerenone are the two major MRAs available in India and other newer drugs are in the developmental phase. Spironolactone is a nonselective, competitive MRA that is structurally similar to progesterone and metabolized in the liver to active metabolites. Eplerenone, a chemical derivative from spironolactone, is more selective for the MR with markedly lower cross-reactivity for the androgen and progesterone receptors, resulting in the absence of sexually related side effects. CLINICAL EVIDENCE FOR THE USE OF SPIRONOLACTONE HEART FAILURE WITH REDUCED EJECTION FRACTION (HFrEF) Antagonism of the renin angiotensin aldosterone system (RAAS) is crucial to the treatment of HFrEF and aldosterone mediates many of the adverse effects of an overactive RAAS. Angiotensin converting enzyme inhibitors (ACEI) initially act to depress aldosterone levels, but these tend to rise back to baseline or even higher on prolonged use of these drugs. This phenomenon, known as aldosterone escape 4, explains why additional MR antagonism is often required over and above ACEI or angiotensin receptor blockers (ARBs). American and European guidelines recommend adding MRAs (spironolactone or eplerenone) as the third agent in patients with HFrEF with NYHA class II IV symptoms after use of ACEI (or ARB) and beta blockers. This recommendation is based on several key trials which demonstrated a substantial morbidity and mortality benefit. In the RALES trial, a large randomized control trial published in 1999 (see ref 5 ), spironolactone (25 50 mg/day) was added to prevailing optimal medical therapy in patients of HFrEF (LVEF 35%) with NYHA class III IV symptoms. Patients were followed up for a period of 2 years. A significant mortality benefit was demonstrated for spironolactone (35% mortality in the spironolactone group vs. 46% in the placebo group). Secondary outcomes including death or hospitalization for cardiac causes and the combined incidence of these two were also lower with spironolactone. It may be noted that this trial was conducted in the era before the widespread use of beta blockers in HF. The role of spironolactone as the third drug in patients with HF who were on beta blocker and ACEI therapy was substantiated in a meta- analysis conducted by Bangalore and colleagues 6. It was observed that adding ARBs or direct renin inhibitors was not useful. Rather ARB addition to ACEI caused increased rate of hyperkalaemia, renal failure and hypotension. Adding MRA to the regimen, however, resulted in reduced mortality, HF hospitalization and cardiovascular death while hyperkalaemia was recorded less as compared to the ARBs. Given that eplerenone had a mortality benefit in acute MI patients with LV dysfunction in the EPHESUS trial 7, more recently, spironolactone was studied in patients with acute MI regardless of the presence of HF or LV dysfunction (92% Killip Class I) in the Early Aldosterone Blockade in Acute Myocardial Infarction (ALBATROSS) trial published in In this trial including 1603 patients, spironolactone had no effect on the composite outcome of death, resuscitated cardiac arrest, ventricular arrhythmia, indication for implantable defibrillator, or new or worsening HF at 6 months 8. These results suggest that the mortality benefit of mineralocorticoid antagonism, at least in MI, may be more applicable in the setting of LV dysfunction. The effects of MRA on ventricular remodelling have been tested. Tsutamoto et al. evaluated the effect of spironolactone on remodelling in 37 patients with nonischaemic cardiomyopathy, NYHA II III HF and EF 45% 8. LVEF, LV mass index and LV volume index were each significantly improved at 4 months compared to placebo. Plasma BNP and procollagen type 3 aminoterminal peptide (PIIINP), a marker of collagen turnover and fibrosis, were each significantly reduced compared to placebo 9. Other studies show conflicting results with no change in LVEF or volumetric parameters despite decreases in BNP and PINP 10. In summary, therapy with spironolactone has a significant mortality benefit in mild to severe HFrEF. MR antagonist therapy also reduces serum BNP and may improve parameters of ventricular remodelling, although the data are conflicting in this regard. HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFpEF) Aldosterone stimulates myocardial fibrosis, which plays a key role in diastolic dysfunction. This accounts for the interest in using MRAs in cases of HFpEF. Studies have shown that use of spironolactone results in improved LV relaxation and filling pattern in hypertensive patients 11. In patients with

3 Chapter 63 Spironolactone: A Grossly Undervalued and Underutilized Drug 533 HFpEF, along with improving diastolic function it also prevented increase in collagen turnover 12, 13. However, despite improved echo and biochemical markers, significant improvement in clinical status has not been proven. In the Aldo-DHF trial, patients with preserved LVEF of 50%, having diastolic dysfunction on echocardiography and in NYHA class II or III, patients randomized to spironolactone had improvements in diastolic parameters, reduced LV mass index, and reduced NT-proBNP 14. However, HF symptoms, quality of life, hospitalizations and peak VO 2 were not improved over 12 months of follow-up. Similarly, in the TOPCAT trial conducted in patients with HfpEF, spironolactone use did not result in significant reduction in death from cardiovascular causes, aborted cardiac arrest or hospitalization for HF 15. However, controversy surrounds the TOPCAT trial results, as significant regional variation in the treatment effect of spironolactone was observed between patients enrolled in North and South America compared with Russia and Georgia 16. Furthermore, in a biorepository substudy, 30% of patients from Russia/Georgia assigned to spironolactone had undetectable levels of a spironolactone metabolite at 12 months compared to 3% from patients in North and South America. This suggests that the role of MRAs in patients with HFpEF still needs further exploration. RESISTANT HYPERTENSION RHTN is defined as BP that remains above goal, despite the concurrent use of three antihypertensive agents of different classes, one of which should be a diuretic. Patients whose blood pressure is controlled with four or more medications are also considered to have RHTN 17. Spironolactone has been found useful in cases of RHTN. One of the earliest studies to suggest a role for spironolactone in the treatment of RHTN was by Ouzan et al. in The addition of spironolactone in patients with RHTN, who were already on three to four drugs, resulted in control of BP in 23 out of 25 patients at 1 month and in all 25 patients by 3 months. Along with this, the average number of antihypertensive drugs used was also decreased. In the Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm (ASCOT-BPLA), addition of spironolactone in a dose of mg daily as a fourth line agent in 1400 patients with uncontrolled BP after the use of study medications, resulted in reduction in mean SBP by 21.9 and DBP by 9.5 mm Hg 19. The Addition of Spironolactone in Patients with Resistant Arterial Hypertension (ASPIRANT) trial compared low-dose spironolactone (25 mg/day) with placebo in patients of RHTN, given for 8 weeks. Ambulatory BP monitoring was performed in this study. The study was stopped early because of a significant reduction in SBP in spironolactone group as compared to placebo (8.6 mm Hg vs. 5.4 mm Hg) 20. Strong evidence for spironolactone comes from the recent PATHWAY-2 trial which was conducted in order to find the best fourth line add-on drug in patients with RHTN. This study compared the addition of spironolactone, bisoprolol, doxazosin and placebo, each given for 12 weeks. Best hypertension control was obtained with spironolactone (a reduction of 8.70 mm Hg, P.001) as compared to doxazosin (a reduction of 4.03 mm Hg), and bisoprolol (a reduction of 4.48 mm Hg) 21. SPIRONOLACTONE UNDERUSE Despite being such a useful drug with clinically proven significant mortality and morbidity benefit, spironolactone is underutilized in clinical practice. Studies suggest that only 25% of the eligible patients hospitalized with HF receive an MRA 22. Even in patients admitted with acute decompensated HF who are otherwise eligible for MRA, it was found to be underutilized 23. The underutilization of MRA has also been documented in large registries. A study by Albert et al. 24 analysed data from 43,625 patients admitted with HF in 241 hospitals between January 2005 and December 2007 and found that out of 12,565 patients eligible for aldosterone antagonist therapy, only 4087 (32.5%) received the drug at discharge. According to the authors, multiple factors including overestimation of side effects, lack of clinician familiarity, lack of recent marketing and deferring initiation to the outpatient setting contributed to spironolactone underuse. Dev et al. 25 also recently described the patient-, provider- and system-based barriers to adoption of MRAs in patients with HFrEF. We have outlined the six major factors for spironolactone underuse: (1) Hyperkalaemia Hyperkalaemia has been reported in 2% 10% of the patients on spironolactone therapy in clinical trials 5, 26, 27. A higher prevalence of hyperkalaemia in clinical practice (up to 15%) may be due to inappropriate patient selection or suboptimal potassium and renal

4 534 SECTION VII Heart Failure monitoring 28. Spironolactone should not be initiated in patients with an estimated GFR 30 ml/min/1.73 m 2 or potassium 5.0 mmol/l 29. The risk of subsequent hyperkalaemia can be minimized by ensuring that potassium and creatinine are checked following drug initiation at baseline, within 1 week, and monthly for 3 months, then every 3 months. If hyperkalaemia develops, the dose should be reduced for K mmol/l or held for K 6.0 mmol/l with laboratory rechecks similar to those outlined for drug initiation. Patients should be educated to follow a lowpotassium diet, discontinue potassium supplementation and avoid NSAIDs. (2) Other adverse effects Sexually related side effects of spironolactone occur as a result of cross-reaction with androgen and progesterone receptors and include breast tenderness and gynaecomastia. It has been reported in 6.9% 10% of men in various clinical trials, the effect usually occurs at higher doses (50 mg/day) 5. Erectile dysfunction in men and menstrual irregularity in women may also be seen. The presence of these side effects can result in noncompliance 30. Drug discontinuation or replacement with eplerenone, which has lower affinity for the sex steroid receptor, can result in reversal of these side effects 31. (3) Patient polypharmacy and comorbidities Many patients take multiple medications for several chronic health conditions. Physicians may be hesitant to add an MRA because they believe patients already have difficulty adhering to their current prescriptions. They also avoid using it in conditions like diabetes and renal failure, as it can potentially worsen these conditions. (4) Difficulty in patient monitoring Limited laboratory service availability, lack of patient adherence to the laboratory tests or lack of proper follow-up planning also constitute an important reason for underuse of these drugs. (5) Lack of familiarity or experience with MRA use While cardiologists may be aware of the appropriate guidelines for the use of MRAs, noncardiology providers, especially primary care physicians may have less familiarity with prescribing MRAs or may believe that only a cardiologist should prescribe an MRA. This may lead to underprescribing or insufficient laboratory monitoring. (6) Position in therapy Guidelines recommend that patients with HFrEF are to be given maximally tolerated doses of beta blockers and ACEI or ARBs before initiating MRA therapy. This leads to a tendency to defer a decision on MRA initiation even though target beta blocker and ACEI/ARB doses have been reached. MEASURES TO IMPROVE THE USE OF SPIRONOLACTONE Health systems need to implement multimodal strategies that target all relevant barriers to the adoption of spironolactone where indicated. They need to improve knowledge of MRAs among clinicians, including resident and primary care physicians. Knowledge about the proper indications, adverse effect profile, when to modify the dose and stop the drug, would improve patient selection and mitigate side effects. Improving laboratory access and simplifying the logistics of arranging follow-up will improve patient safety at the health system level. Further safety can be promoted by adopting automatic laboratory reminder systems and pharmacist-run high-risk medication initiation and titration clinics. Patient education about the need to avoid high-potassium foods and potassium supplements while prescribing MRAs would also minimize the incidence of hyperkalaemia. Finally, development of newer MRAs which can provide similar cardiovascular benefits with a decreased risk of hyperkalaemia will be helpful in expanding the target population. CONCLUSION Spironolactone has strong randomized clinical trial data supporting a mortality benefit in HFrEF, efficacy in RHTN, and echocardiographic and biomarker improvement in HFpEF, yet MRAs remain underutilized in clinical practice. This may be due to lack of prescriber familiarity, an overestimation of side effects and an underestimation of benefit in clinical practice. All measures should be adopted to promote the rational use of spironolactone where clinically indicated. REFERENCES 1. Farquharson, C. A., & Struthers, A. D. ( 2000 ). Spironolactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure. Circulation, 101,

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