Cardiology , Practical Techniques from the NAVC INSTITUTE

Beyond Furosemide: The Role of Diuretics in Congestive Heart Failure Part 2 – Spironolactone

Beyond Furosemide: The Role of Diuretics in Congestive Heart Failure Part 2 – Spironolactone
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Marisa K. Ames, DVM, Diplomate ACVIM (Cardiology), Colorado State University 
Clarke E. Atkins, DVM, Diplomate ACVIM (Internal Medicine & Cardiology) North Carolina State University

Each year, the NAVC Institute takes place in Orlando, Florida, and top specialists in select areas of veterinary medicine provide hands-on, one-on-one continuing education to the Institute attendees.

Practical Techniques from the NAVC Institute—brought to you by the NAVC and Today’s Veterinary Practice—provides the opportunity for you to experience the excellent education provided at the Institute within the pages of this journal.

This article reviews information from the session, Cardiology Without Intimidation, presented at the NAVC Institute 2014. The NAVC Institute 2016 takes place in Orlando, Florida, May 15 to 20; visit navc.com/institute for further information.

Diuretics are a critical component of the pharmacotherapy of congestive heart failure (CHF). In humans with heart failure, 90% receive at least one diuretic.1 Of these, loop diuretics—furosemide, bumetanide, and torsemide—are the most potent and commonly used diuretics. When a single drug is administered in humans, furosemide is given 87% of the time.1

Furosemide has been, and remains, the diuretic of choice for acute and chronic management of CHF in both humans and animals since its release in 1966. However, other interesting options are now available, including:

  • Torsemide, a loop diuretic that can be used as an adjunct or alternative to furosemide
  • Spironolactone, a weak, potassium-sparing diuretic and mineralocorticoid receptor (MR) blocker that is used primarily for additional blockade of the renin–angiotensin–aldosterone system (RAAS). In heart failure, it typically accompanies a more potent diuretic, such as furosemide.

This article, the second in a 2-part series, discusses spironolactone. Read Part 1: Torsemide (January/February 2016) at tvpjournal.com.

ACTIVITY & ADMINISTRATION

Spironolactone is a synthetic 17-lactone drug and competitive aldosterone receptor (mineralocorticoid receptor) blocker (MRB). This antagonism of the MR in distal renal tubule cells results in an increase in urinary sodium and water excretion and decrease in potassium excretion.

In the dog, spironolactone is relatively quickly absorbed through the gastrointestinal tract into the plasma; then converted to several active metabolites.2,3 The bioavailability of spironolactone in dogs is highest when it is administered with food, reaching 80% to 90%.4

Using an experimental model of hyperaldosteronism, mimicking that in heart failure (see Heart Failure: Effects of Hyperaldosteronism), Guyonnet and colleagues found that the spironolactone dosage of 2 mg/kg PO Q 24 H restored the urinary sodium:potassium ratio to near normal via increased urinary sodium excretion and decreased urinary potassium excretion.4 On the basis of this result, and analysis of pharmacokinetic and pharmacodynamic data, the optimal dosage of spironolactone in dogs appears to be 2 mg/kg PO Q 24 H. The dosage established by this preclinical trial has been used in subsequent clinical trials.a,5 Of note, in this study, spironolactone was administered with food.

Heart Failure: Effects of Hyperaldosteronism

In animals with heart failure, chronic exposure to high concentrations of aldosterone:

  • Results in excessive sodium retention, with expansion of extracellular volume
  • Favors potassium and magnesium wasting
  • Inhibits myocardial norepinephrine reuptake
  • Diminishes heart rate variability (a sign of cardiac health)
  • Produces cardiac arrhythmias
  • Decreases baroreceptor sensitivity
  • Contributes to endothelial dysfunction and vascular inflammation.

High concentrations of aldosterone are also independently associated with renal, vascular, and cardiac remodeling and heart failure.

An earlier study found that spironolactone had no effect on urinary sodium and water excretion in normal dogs when it was administered at dosages of 1, 2, 4, and 8 mg/kg PO Q 24 H for 8 days.6 Urinary potassium excretion, however, did decrease significantly at dosages of 1 and 2 mg/kg. These results—when compared to the results of the study by Guyonnet and colleagues—may be explained by the lack of hyperaldosteronism and administration of spironolactone to fasted dogs. While differences in timing of blood sampling for one of spironolactone’s active metabolites (canrenone) does not allow for direct comparison between studies, blood canrenone concentrations were apparently higher in dogs that received spironolactone with food.

RATIONALE FOR USE

Spironolactone was initially used to provide sequential nephron blockade and combat hypokalemia that resulted from the use of loop and thiazide diuretics. In the past 3 decades, the understanding of the consequences of excessive and prolonged aldosterone secretion in the progression and perpetuation of chronic cardiovascular and renal disease has grown significantly.7,8

Specifically, aldosterone has been implicated in the pathologic remodeling—inflammation, hypertrophy, fibrosis—of cardiovascular and renal tissues. Therefore, the primary rationale for adding spironolactone as adjunctive therapy for heart failure is now MR (specifically, aldosterone) blockade.

RAAS BLOCKADE

In Humans

Spironolactone and another synthetic MRB, eplerenone, have recently been evaluated in humans with mild to severe heart failure and low ejection fraction.9-11 The positive results of these studies showed that the addition of spironolactone or eplerenone to standard heart failure therapy—an angiotensin-converting enzyme inhibitor (ACEI) and a loop diuretic, with or without beta-blockers and with or without digoxin—led to a significant reduction in morbidity and mortality when compared with standard therapy alone.

These studies showed a significant benefit when additional blockade of the RAAS—in the form of MR blockade—was added to preexisting RAAS blockade with an ACEI. MR blockade is now considered the standard of care in humans with heart failure and low ejection fraction.12,13 The benefit seen with additional RAAS blockade in heart failure supports the concept of aldosterone breakthrough (see Aldosterone Breakthrough).

In Dogs

A similar study was performed in 212 dogs with naturally occurring myxomatous mitral valve disease (MMVD) and heart failure. This study demonstrated a 69% reduction in risk for cardiac morbidity and mortality when spironolactone was added to standard therapy (ACEI and furosemide, with or without digoxin) as compared with standard therapy alone (Figure).5

FIGURE. Kaplan–Meier plot of percentage of dogs remaining in the study5 over time. Of 212 dogs, 102 were treated with spironolactone in addition to standard therapy and 110 were treated with standard therapy alone. Dogs with myxomatous mitral valve disease treated with spironolactone remained in the study for a significantly longer time period. Adapted from Bernay F, Bland JM, Häggström J, et al. Efficacy of spironolactone on survival in dogs with naturally occurring mitral regurgitation caused by myxomatous mitral valve disease. J Vet Intern Med 2010; 24:331-341

FIGURE. Kaplan–Meier plot of percentage of dogs remaining in the study5 over time. Of 212 dogs, 102 were treated with spironolactone in addition to standard therapy and 110 were treated with standard therapy alone. Dogs with myxomatous mitral valve disease treated with spironolactone remained in the study for a significantly longer time period. Adapted from Bernay F, Bland JM, Häggström J, et al. Efficacy of spironolactone on survival in dogs with naturally occurring mitral regurgitation caused by myxomatous mitral valve disease. J Vet Intern Med 2010; 24:331-341.

A separate safety analysis of dogs involved in the aforementioned study demonstrated that, when compared with dogs receiving placebo and standard therapy (loop diuretic, ACEI, and pimobendan), those receiving spironolactone in addition to standard therapy14:

  • Were not at higher risk for adverse events, such as death from renal disease and variations in serum sodium, potassium, urea nitrogen, and creatinine
  • Had lower mortality associated with cardiac disease, kidney disease, or both
  • Of most importance, did not have a greater incidence of hyperkalemia.

In a study of Doberman pinschers with occult dilated cardiomyopathy (DCM), significant increases in serum potassium concentration (compared to each dog’s baseline values) were seen in those receiving both spironolactone and an ACEI.15 Although we deemed these changes clinically insignificant, in 50% of dogs, the serum potassium concentration exceeded the reference interval. Therefore, regular monitoring of serum electrolytes and renal values (as often as every 3 months) was recommended for Doberman pinschers receiving spironolactone and an ACEI.

Overall, regular monitoring of serum electrolytes and renal values is prudent in all animals receiving vasodilators and diuretics, including spironolactone and ACEIs. Finally, spironolactone in combination with ACEI therapy appears to be safe when used to treat dogs with naturally occurring asymptomatic MMVD, as well as those with occult DCM without preexisting azotemia.15,16

Read the ACVIM Guidelines for the Diagnosis and Treatment of Canine Chronic Valvular Heart Disease at http://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.2009.0392.x/full.

INDICATIONS

Dogs with MMVD

The 2009 consensus statement from the American College of Veterinary Internal Medicine defines the stages of heart disease and failure (Table) and provides guidelines for therapy of dogs with MMVD.17

  • The guidelines recommend spironolactone as an adjunctive therapy in dogs with ACVIM stage D2 (refractory heart failure managed on outpatient basis) MMVD.
  • A majority of panelists used spironolactone to treat ACVIM stage C2 (heart failure managed on outpatient basis) MMVD, although consensus (100% agreement) was not reached.
  • A minority of panelists advocated the use of spironolactone in dogs with ACVIM stage B2 MMVD.

Spironolactone is approved within the European Union as adjunctive therapy for canine heart failure, secondary to MMVD. Clinical trials are currently evaluating the effects of spironolactone in combination with an ACEI in the treatment of dogs with stage B2 and C MMVD.a,18

T1605C10Table

Dogs with DCM & Congenital Heart Disease

There are currently no consensus statements regarding the use of spironolactone in other diseases, such as DCM, heartworm disease, and congenital heart disease. Logic supports spironolactone’s utility and its history, along with research data, support its safety.

Heart Failure with HFpEF

The role of spironolactone in the treatment of heart failure due to ventricular diastolic dysfunction and preserved systolic function (heart failure with preserved ejection fraction [HFpEF]) is an area of ongoing research.

The association between hyperaldosteronism and development of myocardial fibrosis in human and experimental animal models of hypertension is well established.19 Small studies in humans with HFpEF have shown that MR blockade with spironolactone improved diastolic function.20,21

However, in a recently completed large study in humans with HFpEF, the addition of spironolactone to existing heart failure therapy did not result in a significant survival benefit or reduction in hospitalization for heart failure, although there were substantial geographic differences in patient response.22 The incidence of hospitalization for heart failure was lower in the spironolactone group.

Cats with HCM

Hyperaldosteronism and activation of the RAAS, in particular, are implicated in the pathologic ventricular remodeling and diastolic myocardial dysfunction in hypertrophic cardiomyopathy (HCM) in humans.23

Aldosterone is elevated in Maine coon cats with asymptomatic HCM,24 and use of spironolactone (2 mg/kg PO Q 24 H for 4 months) for asymptomatic HCM in cats has been evaluated.25 Unfortunately, this study did not show reduction in left ventricular mass or improvement in an echocardiographic parameter of diastolic function, and 4 of the 13 cats treated with spironolactone developed ulcerative facial dermatitis.

A double-blinded, placebo-controlled clinical trial has evaluated the use of spironolactone (1.7–3.3 mg/kg PO Q 24 H) in cats with heart failure due to cardiomyopathy (the majority of cats had HCM).26 All cats were also receiving furosemide and benazepril. The results of this study demonstrated an improved survival rate of 15 months in cats receiving spironolactone when compared to those receiving placebo. Also, at interim analysis27 (n = 16 cats enrolled), no cat receiving spironolactone had experienced ulcerative facial dermatitis.

Aldosterone Breakthrough

The positive results from studies of MRBs in patients with heart failure and low ejection fraction support the existence of aldosterone breakthrough (ABT): the phenomenon in which RAAS blockade with an ACEI—with or without an angiotensin-receptor blocker (ARB)—is incomplete and aldosterone levels rise despite RAAS suppressive therapy.

UAldo:C Ratio
We use the urine aldosterone-to-creatinine (UAldo:C) ratio, which correlates to 24-hour urine aldosterone excretion,28 to assess RAAS activation in clinical patients and experimental RAAS activation,29-35 and propose a cutoff value of 1 mcg/g. This value is the mean +2 standard deviation of the UAldo:C ratio in a population of young (1–2 years of age) normal dogs from North Carolina State University Veterinary Hospital and Colorado State University Veterinary Hospital.36

Definition
There is no consensus regarding the definition (and, therefore, incidence), mechanism, and clinical implications of ABT in humans with chronic cardiovascular or renal disease, although its existence and importance are uniformly accepted.37 However, we suggest 2 definitions for ABT—based on UAldo:C ratio:

  1. UAldo:C ratio that increases relative to baseline values, despite therapy with ACEI or ARB or
  2. UAldo:C ratio that exceeds an absolute cutoff value.

Incidence
Preliminary data from our clinics suggest that ABT occurs in dogs with heart failure due to naturally occurring heart disease, with an incidence of approximately 40%. This percentage is similar to that found in our model of RAAS activation as well as the incidence of ABT in humans receiving an ACEI. ABT also appears to occur early in the disease course.37

Monitoring the UAldo:C ratio may, therefore, help optimize an individual patient’s pharmacotherapy and determine whether spironolactone should be added as an adjunctive therapy to improve RAAS blockade.

IN SUMMARY

Based on clinical and research data, we use spironolactone in almost all instances in which ACEIs are used, which includes dogs with the following:

  • ACVIM stage B2 MMVD: Cardiac enlargement, but before onset of heart failure (pulmonary edema)
  • ACVIM stage C2 and D2 MMVD: At-home therapy of CHF
  • Systemic hypertension
  • Occult and symptomatic DCM
  • Proteinuric renal disease.

Although preliminary data are promising, we do not feel there is yet adequate evidence for routine use of spironolactone in cats.

Spironolactone: Key Points

  • The optimal dosage of spironolactone in dogs appears to be 2 mg/kg PO Q 24 H.
  • Spironolactone in combination with ACEI therapy appears to be safe when used to treat dogs with naturally occurring asymptomatic MMVD or occult DCM without preexisting azotemia.
  • Bioavailability of spironolactone in dogs is highest when it is administered with food.
  • Regular monitoring of serum electrolytes and renal values is prudent in all animals receiving vasodilators and diuretics, including spironolactone and ACEIs.
  • Monitoring the UAldo:C ratio may help optimize an individual patient’s pharmacotherapy and determine whether spironolactone should be added as an adjunctive therapy to improve RAAS blockade.

ABT = aldosterone breakthrough; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker; CHF = congestive heart failure; DCM = dilated cardiomyopathy; HCM = hypertrophic cardiomyopathy; HFpEF = heart failure with preserved ejection fraction; MMVD = myxomatous mitral valve disease; MR = mineralocorticoid receptor; MRB = mineralocorticoid receptor blocker; RAAS = renin–angiotensin–aldosterone system; UAldo:C = urine aldosterone-to-creatinine

Footnote

a. Unpublished data from the ongoing Ceva Animal Health LLC, BESST: Benazepril Spironolactone Study.

References

  1. Bikdeli B, Strait KM, Dharmarajan K, et al. Dominance of furosemide for loop diuretic therapy in heart failure: time to revisit the alternatives? J Am Coll Cardiol 2013; 61:1549-1550.
  2. Sadee W, Riegelman S, Jones SC. Plasma levels of spirolactones in the dog. J Pharm Sci 1972; 61:1129-1132.
  3. Karim A, Kook C, Zitzewitz DJ, et al. Species differences in the metabolism and disposition of spironolactone. Drug Metab Dispos 1976; 4:547-555.
  4. Guyonnet J, Elliott J, Kaltsatos V. A preclinical pharmacokinetic and pharmacodynamic approach to determine a dose of spironolactone for treatment of congestive heart failure in dog. J Vet Pharmacol Therap 2009; 33:260-267.
  5. Bernay F, Bland JM, Häggström J, et al. Efficacy of spironolactone on survival in dogs with naturally occurring mitral regurgitation caused by myxomatous mitral valve disease. J Vet Intern Med 2010; 24:331-341.
  6. Jeunesse E, Woehrle F, Schneider M, et al. Effect of spironolactone on diuresis and urine sodium and potassium excretion in healthy dogs. J Vet Cardiol 2007; 9:63-68.
  7. Ovaert P, Elliott J, Bernay F, et al. Aldosterone receptor antagonists – how cardiovascular actions may explain their beneficial effects in heart failure. J Vet Pharmacol Therap 2010; 33:109-117.
  8. Hezzell M, Boswood A, Chang Y-M, et al. Associations among serum N-terminal procollagen type III concentration, urinary aldosterone-to-creatinine ratio, and ventricular remodeling in dogs with myxomatous mitral valve disease. Am J Vet Res 2012; 73:1765-1774.
  9. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341:709-717.
  10. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348:1309-1321.
  11. Zannad F, McMurray J, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011; 364:11-21.
  12. McMurray J, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur J Heart Fail 2012; 14:803-896.
  13. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guidelines for the management of heart failure. Circulation 2013; 128:e240-e327.
  14. Lefebvre HP, Ollivier E, Atkins CE, et al. Safety of spironolactone in dogs with chronic heart failure because of degenerative valvular disease: A population-based, longitudinal study. J Vet Intern Med 2013; 27:1083-1091.
  15. Thomason JD, Rapoport G, Fallaw T, Calvert CA. The influence of enalapril and spironolactone on electrolyte concentrations in Doberman pinschers with dilated cardiomyopathy. Vet J 2014; 202(3):573-577.
  16. Thomason JD, Rockwell JE, Fallaw TK, Calvert CA. Influence of combined angiotensin-converting enzyme inhibitors and spironolactone on serum K+, Mg2+, and Na+ concentrations in small dogs with degenerative mitral valve disease. J Vet Cardiol 2007; 9:103-108.
  17. Atkins C, Bonagura J, Ettinger S, et al. Guidelines for the diagnosis and treatment of canine chronic valvular heart disease. J Vet Intern Med 2009; 23:1142-1150.
  18. Borgarelli M. Pre-clinical chronic degenerative mitral valve disease in the dog. ACVIM Proc 2011.
  19. Jansen PM, Danser AH, Imholz BP, et al. Aldosterone-receptor antagonism in hypertension. J Hypertens 2009; 27:680-691.
  20. Mottram PM, Haluska B, Leano R, et al. Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circ 2004; 110:558-565.
  21. Edelmann F, Wachter R, Schmidt AG, 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. J Am Med Assoc 2013; 309:781-791.
  22. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014; 370:1383-1392.
  23. Tsybouleva N, Zhang L, Chen S, et al. Aldosterone, through novel signaling proteins, is a fundamental molecular bridge between the genetic defect and the cardiac phenotype of hypertrophic cardiomyopathy. Circ 2004; 109:1284-1291.
  24. MacDonald KA, Kittleson MD, Larson RF, et al. The effect of ramipril on left ventricular mass, myocardial fibrosis, diastolic function, and plasma neurohormones in Maine coon cats with familial hypertrophic cardiomyopathy without heart failure. J Vet Intern Med 2006; 20:1093-1105.
  25. MacDonald KA, Kittleson MD, Kass PH. Effect of spironolactone on diastolic function and left ventricular mass in Maine coon cats with familial hypertrophic cardiomyopathy. J Vet Intern Med 2008; 22:335-341.
  26. James RA, Guillot E, Gilmour J, et al. Efficacy of spironolactone (SP) following oral administration of SP in cats with heart failure: Final results of the SEISICAT study. Proc Eur Coll Vet Intern Med Congress, http://www.vin.com/doc/?id=6922093 (2015).
  27. James RA, Gilmour J, Cobb M, et al. Safety of oral administration of spironolactone in cats with heart failure: interim results of the SEISICAT study (abst). J Vet Intern Med 2013; 27:638.
  28. Gardner SY, Atkins CE, Rausch WP, et al. Estimation of 24-h aldosterone secretion in the dog using the urine aldosterone:creatinine ratio. J Vet Cardiol 2007; 9:1-7.
  29. Lantis AC, Ames MK, Atkins CE, et al. Aldosterone breakthrough with benazepril in furosemide-activated renin-angiotensin-aldosterone system in normal dogs. J Vet Pharmacol Therap 2015; 38:65-73.
  30. Lantis AC, Ames MK, Werre S, Atkins CE. The effect of enalapril on furosemide-activated renin-angiotensin-aldosterone system in healthy dogs. J Vet Pharmacol Therap 2015; 38:513-517.
  31. Atkins CE, Rausch WP, Gardner SY, et al. The effect of amlodipine and the combination of amlodipine and enalapril on the renin-angiotensin-aldosterone system in the dog. J Vet Pharmacol Therap 2007; 30:394-400.
  32. Sayer MB, Atkins CE, Fujii Y, et al. Acute effects of pimobendan and furosemide on the circulating renin-angiotensin-aldosterone system in healthy dogs. J Vet Intern Med 2009; 23:1003-1006.
  33. Ames MK, Atkins CE, Lantis AC, Werre SR. Effect of furosemide and high-dosage pimobendan administration on the renin-angiotensin-aldosterone system in dogs. Am J Vet Res 2013; 74:1084-1090.
  34. Ames MK, Atkins CE, Lee S, et al. Effects of high doses of enalapril and benazepril on the pharmacologically activated renin-angiotensin-aldosterone system in clinically normal dogs. Am J Vet Res 2015; 76:1041-1050.
  35. Lantis AC, Atkins CE, DeFrancesco TC. Effects of furosemide and the combination of furosemide and the labeled dosage of pimobendan on the circulating renin-angiotensin-aldosterone system in clinically normal dogs. Am J Vet Res 2011; 72:1646-1651.
  36. Ames MK, Atkins CE, Webb K. The urine aldosterone to creatinine ratio (UALDO:C) determined by radioimmunoassay (RIA) in normal dogs greater than 5 years of age. J Vet Intern Med 2015; 29:1148.
  37. Bomback AS, Klemmer PJ. The incidence and implications of aldosterone breakthrough. Nat Clin Pract Nephrol 2007; 3:486-492.

Author_M-AmesMarisa K. Ames, DVM, Diplomate ACVIM (Cardiology), is an assistant professor at Colorado State University College of Veterinary Medicine. Dr. Ames received her DVM from Ohio State University. She completed a cardiology residency and the Jane Lewis Seaks postdoctoral fellowship at North Carolina State University. Her research interests include neurohormonal activation in heart failure, specifically the pharmacologic blockade of the renin–angiotensin–aldosterone system (RAAS).

 

 

Author_C-AtkinsClarke E. Atkins, DVM, Diplomate ACVIM (Internal Medicine & Cardiology), is the Jane Lewis Seaks Distinguished Professor Emeritus of Companion Animal Medicine at North Carolina State University. He is also a member of the Today’s Veterinary Practice Editorial Peer Review Board and American Heartworm Society’s Executive Board. Dr. Atkins’ research involves canine and feline heartworm disease and pharmacologic therapies for cardiac disease. He received the 2004 Norden Award for excellence in teaching.

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aria-required="true"/> <label for='input_6_10_1' id='input_6_10_1_label' >Street Address</label> </span><span class='ginput_full address_line_2' id='input_6_10_2_container' > <input type='text' name='input_10.2' id='input_6_10_2' value='' /> <label for='input_6_10_2' id='input_6_10_2_label' >Address Line 2</label> </span><span class='ginput_left address_city' id='input_6_10_3_container' > <input type='text' name='input_10.3' id='input_6_10_3' value='' aria-required="true"/> <label for='input_6_10_3' id='input_6_10_3_label' >City</label> </span><span class='ginput_right address_state' id='input_6_10_4_container' > <input type='text' name='input_10.4' id='input_6_10_4' value='' aria-required="true"/> <label for='input_6_10_4' id='input_6_10_4_label' >State / Province / Region</label> </span><span class='ginput_left address_zip' id='input_6_10_5_container' > <input type='text' name='input_10.5' id='input_6_10_5' value='' aria-required="true"/> <label for='input_6_10_5' id='input_6_10_5_label' >ZIP / Postal Code</label> </span><span class='ginput_right address_country' id='input_6_10_6_container' > <select name='input_10.6' id='input_6_10_6' aria-required="true"><option value='' selected='selected'></option><option value='Afghanistan' >Afghanistan</option><option value='Åland Islands' >Åland Islands</option><option value='Albania' >Albania</option><option value='Algeria' >Algeria</option><option value='American Samoa' >American Samoa</option><option value='Andorra' >Andorra</option><option value='Angola' >Angola</option><option value='Anguilla' >Anguilla</option><option value='Antarctica' >Antarctica</option><option value='Antigua and Barbuda' >Antigua and Barbuda</option><option value='Argentina' >Argentina</option><option value='Armenia' >Armenia</option><option value='Aruba' >Aruba</option><option value='Australia' >Australia</option><option value='Austria' >Austria</option><option value='Azerbaijan' >Azerbaijan</option><option value='Bahamas' >Bahamas</option><option value='Bahrain' >Bahrain</option><option value='Bangladesh' >Bangladesh</option><option value='Barbados' >Barbados</option><option value='Belarus' >Belarus</option><option value='Belgium' >Belgium</option><option value='Belize' >Belize</option><option value='Benin' >Benin</option><option value='Bermuda' >Bermuda</option><option value='Bhutan' >Bhutan</option><option value='Bolivia' >Bolivia</option><option value='Bonaire, Sint Eustatius and Saba' >Bonaire, Sint Eustatius and Saba</option><option value='Bosnia and Herzegovina' >Bosnia and Herzegovina</option><option value='Botswana' >Botswana</option><option value='Bouvet Island' >Bouvet Island</option><option value='Brazil' >Brazil</option><option value='British Indian Ocean Territory' >British Indian Ocean Territory</option><option value='Brunei Darussalam' >Brunei Darussalam</option><option value='Bulgaria' >Bulgaria</option><option value='Burkina Faso' >Burkina Faso</option><option value='Burundi' >Burundi</option><option value='Cambodia' >Cambodia</option><option value='Cameroon' >Cameroon</option><option value='Canada' >Canada</option><option value='Cape Verde' >Cape Verde</option><option value='Cayman Islands' >Cayman Islands</option><option value='Central African Republic' >Central African Republic</option><option value='Chad' >Chad</option><option value='Chile' >Chile</option><option value='China' >China</option><option value='Christmas Island' >Christmas Island</option><option value='Cocos Islands' >Cocos Islands</option><option value='Colombia' >Colombia</option><option value='Comoros' >Comoros</option><option value='Congo, Democratic Republic of the' >Congo, Democratic Republic of the</option><option value='Congo, Republic of the' >Congo, Republic of the</option><option value='Cook Islands' >Cook Islands</option><option value='Costa Rica' >Costa Rica</option><option value='Côte d&#039;Ivoire' >Côte d&#039;Ivoire</option><option value='Croatia' >Croatia</option><option value='Cuba' >Cuba</option><option value='Curaçao' >Curaçao</option><option value='Cyprus' >Cyprus</option><option value='Czech Republic' >Czech Republic</option><option value='Denmark' >Denmark</option><option value='Djibouti' >Djibouti</option><option value='Dominica' >Dominica</option><option value='Dominican Republic' >Dominican Republic</option><option value='Ecuador' >Ecuador</option><option value='Egypt' >Egypt</option><option value='El Salvador' >El Salvador</option><option value='Equatorial Guinea' >Equatorial Guinea</option><option value='Eritrea' >Eritrea</option><option value='Estonia' >Estonia</option><option value='Eswatini (Swaziland)' >Eswatini (Swaziland)</option><option value='Ethiopia' >Ethiopia</option><option value='Falkland Islands' >Falkland Islands</option><option value='Faroe Islands' >Faroe Islands</option><option value='Fiji' >Fiji</option><option value='Finland' >Finland</option><option value='France' >France</option><option value='French Guiana' >French Guiana</option><option value='French Polynesia' >French Polynesia</option><option value='French Southern Territories' >French Southern Territories</option><option value='Gabon' >Gabon</option><option value='Gambia' >Gambia</option><option value='Georgia' >Georgia</option><option value='Germany' >Germany</option><option value='Ghana' >Ghana</option><option value='Gibraltar' >Gibraltar</option><option value='Greece' >Greece</option><option value='Greenland' >Greenland</option><option value='Grenada' >Grenada</option><option value='Guadeloupe' >Guadeloupe</option><option value='Guam' >Guam</option><option value='Guatemala' >Guatemala</option><option value='Guernsey' >Guernsey</option><option value='Guinea' >Guinea</option><option value='Guinea-Bissau' >Guinea-Bissau</option><option value='Guyana' >Guyana</option><option value='Haiti' >Haiti</option><option value='Heard and McDonald Islands' >Heard and McDonald Islands</option><option value='Holy See' >Holy See</option><option value='Honduras' >Honduras</option><option value='Hong Kong' >Hong Kong</option><option value='Hungary' >Hungary</option><option value='Iceland' >Iceland</option><option value='India' >India</option><option value='Indonesia' >Indonesia</option><option value='Iran' >Iran</option><option value='Iraq' >Iraq</option><option value='Ireland' >Ireland</option><option value='Isle of Man' >Isle of Man</option><option value='Israel' >Israel</option><option value='Italy' >Italy</option><option value='Jamaica' >Jamaica</option><option value='Japan' >Japan</option><option value='Jersey' >Jersey</option><option value='Jordan' >Jordan</option><option value='Kazakhstan' >Kazakhstan</option><option value='Kenya' >Kenya</option><option value='Kiribati' >Kiribati</option><option value='Kuwait' >Kuwait</option><option value='Kyrgyzstan' >Kyrgyzstan</option><option value='Lao People&#039;s Democratic Republic' >Lao People&#039;s Democratic Republic</option><option value='Latvia' >Latvia</option><option value='Lebanon' >Lebanon</option><option value='Lesotho' >Lesotho</option><option value='Liberia' >Liberia</option><option value='Libya' >Libya</option><option value='Liechtenstein' >Liechtenstein</option><option value='Lithuania' >Lithuania</option><option value='Luxembourg' >Luxembourg</option><option value='Macau' >Macau</option><option value='Macedonia' >Macedonia</option><option value='Madagascar' >Madagascar</option><option value='Malawi' >Malawi</option><option value='Malaysia' >Malaysia</option><option value='Maldives' >Maldives</option><option value='Mali' >Mali</option><option value='Malta' >Malta</option><option value='Marshall Islands' >Marshall Islands</option><option value='Martinique' >Martinique</option><option value='Mauritania' >Mauritania</option><option value='Mauritius' >Mauritius</option><option value='Mayotte' >Mayotte</option><option value='Mexico' >Mexico</option><option value='Micronesia' >Micronesia</option><option value='Moldova' >Moldova</option><option value='Monaco' >Monaco</option><option value='Mongolia' >Mongolia</option><option value='Montenegro' >Montenegro</option><option value='Montserrat' >Montserrat</option><option value='Morocco' >Morocco</option><option value='Mozambique' >Mozambique</option><option value='Myanmar' >Myanmar</option><option value='Namibia' >Namibia</option><option value='Nauru' >Nauru</option><option value='Nepal' >Nepal</option><option value='Netherlands' >Netherlands</option><option value='New Caledonia' >New Caledonia</option><option value='New Zealand' >New Zealand</option><option value='Nicaragua' >Nicaragua</option><option value='Niger' >Niger</option><option value='Nigeria' >Nigeria</option><option value='Niue' >Niue</option><option value='Norfolk Island' >Norfolk Island</option><option value='North Korea' >North Korea</option><option value='Northern Mariana Islands' >Northern Mariana Islands</option><option value='Norway' >Norway</option><option value='Oman' >Oman</option><option value='Pakistan' >Pakistan</option><option value='Palau' >Palau</option><option value='Palestine, State of' >Palestine, State of</option><option value='Panama' >Panama</option><option value='Papua New Guinea' >Papua New Guinea</option><option value='Paraguay' >Paraguay</option><option value='Peru' >Peru</option><option value='Philippines' >Philippines</option><option value='Pitcairn' >Pitcairn</option><option value='Poland' >Poland</option><option value='Portugal' >Portugal</option><option value='Puerto Rico' >Puerto Rico</option><option value='Qatar' >Qatar</option><option value='Réunion' >Réunion</option><option value='Romania' >Romania</option><option value='Russia' >Russia</option><option value='Rwanda' >Rwanda</option><option value='Saint Barthélemy' >Saint Barthélemy</option><option value='Saint Helena' >Saint Helena</option><option value='Saint Kitts and Nevis' >Saint Kitts and Nevis</option><option value='Saint Lucia' >Saint Lucia</option><option value='Saint Martin' >Saint Martin</option><option value='Saint Pierre and Miquelon' >Saint Pierre and Miquelon</option><option value='Saint Vincent and the Grenadines' >Saint Vincent and the Grenadines</option><option value='Samoa' >Samoa</option><option value='San Marino' >San Marino</option><option value='Sao Tome and Principe' >Sao Tome and Principe</option><option value='Saudi Arabia' >Saudi Arabia</option><option value='Senegal' >Senegal</option><option value='Serbia' >Serbia</option><option value='Seychelles' >Seychelles</option><option value='Sierra Leone' >Sierra Leone</option><option value='Singapore' >Singapore</option><option value='Sint Maarten' >Sint Maarten</option><option value='Slovakia' >Slovakia</option><option value='Slovenia' >Slovenia</option><option value='Solomon Islands' >Solomon Islands</option><option value='Somalia' >Somalia</option><option value='South Africa' >South Africa</option><option value='South Georgia' >South Georgia</option><option value='South Korea' >South Korea</option><option value='South Sudan' >South Sudan</option><option value='Spain' >Spain</option><option value='Sri Lanka' >Sri Lanka</option><option value='Sudan' >Sudan</option><option value='Suriname' >Suriname</option><option value='Svalbard and Jan Mayen Islands' >Svalbard and Jan Mayen Islands</option><option value='Sweden' >Sweden</option><option value='Switzerland' >Switzerland</option><option value='Syria' >Syria</option><option value='Taiwan' >Taiwan</option><option value='Tajikistan' >Tajikistan</option><option value='Tanzania' >Tanzania</option><option value='Thailand' >Thailand</option><option value='Timor-Leste' >Timor-Leste</option><option value='Togo' >Togo</option><option value='Tokelau' >Tokelau</option><option value='Tonga' >Tonga</option><option value='Trinidad and Tobago' >Trinidad and Tobago</option><option value='Tunisia' >Tunisia</option><option value='Turkey' >Turkey</option><option value='Turkmenistan' >Turkmenistan</option><option value='Turks and Caicos Islands' >Turks and Caicos Islands</option><option value='Tuvalu' >Tuvalu</option><option value='Uganda' >Uganda</option><option value='Ukraine' >Ukraine</option><option value='United Arab Emirates' >United Arab Emirates</option><option value='United Kingdom' >United Kingdom</option><option value='United States' >United States</option><option value='Uruguay' >Uruguay</option><option value='US Minor Outlying Islands' >US Minor Outlying Islands</option><option value='Uzbekistan' >Uzbekistan</option><option value='Vanuatu' >Vanuatu</option><option value='Venezuela' >Venezuela</option><option value='Vietnam' >Vietnam</option><option value='Virgin Islands, British' >Virgin Islands, British</option><option value='Virgin Islands, U.S.' >Virgin Islands, U.S.</option><option value='Wallis and Futuna' >Wallis and Futuna</option><option value='Western Sahara' >Western Sahara</option><option value='Yemen' >Yemen</option><option value='Zambia' >Zambia</option><option value='Zimbabwe' 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