US2021038636A1PendingUtilityA1

Potassium binding polymers for treating hypertension and hyperkalemia

70
Assignee: VIFOR INT LTDPriority: Oct 8, 2012Filed: Oct 26, 2020Published: Feb 11, 2021
Est. expiryOct 8, 2032(~6.2 yrs left)· nominal 20-yr term from priority
Inventors:Gerrit KlaernerLance Berman
A61K 33/24A61K 31/78A61P 3/12A61P 13/12A61K 33/06A61K 31/7004A61P 9/12B01J 39/20A61P 9/04A61P 13/02A61K 9/14A61P 7/00A61P 3/10A61P 7/08
70
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Claims

Abstract

The present invention generally relates to methods of treating hypertension (HTN) in patients in need thereof wherein the patient optionally further suffers from chronic kidney disease (CKD) or Type II diabetes mellitus (T2DM). The invention also relates to methods of treating hyperkalemia in a patient in need thereof, wherein the patient suffers from CKD, T2DM or HTN and are optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent. The invention also relates to methods of treating kidney disease in a patient in need thereof, wherein the patient is optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent. The methods can comprise administering an effective amount of a potassium-binding polymer to the patient to lower the patient's blood pressure and/or increase or stabilize the patient's kidney function.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method of treating hypertension in a patient in need thereof, the method comprising administering an effective amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form to the patient. 
     
     
         2 . The method of  claim 1  wherein the 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form is administered chronically. 
     
     
         3 . The method of  claim 1  or  2  wherein the patient's systolic blood pressure is reduced by 5, 6, 7, 8 mm Hg or more after 4 weeks of treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form as compared to the patient's systolic blood pressure before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         4 . The method of  claim 1  or  2  wherein the patient's systolic blood pressure is reduced by 9, 10, 11, 12, 13, 14, 15, 16, 17 mm Hg or more after 4 weeks of treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form as compared to the patient's systolic blood pressure before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         5 . The method of any one of  claims 1  to  4  wherein the patient's diastolic blood pressure is reduced by 2, 3, 4, 5, 6 mm Hg as compared to the patient's diastolic blood pressure before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         6 . The method of any one of  claims 1  to  4  wherein the patient's diastolic blood pressure is reduced by 7, 8, 9, 10, 11, 12, 13 mm Hg or more as compared to the patient's diastolic blood pressure before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         7 . The method of any one of  claims 1  to  6  wherein the patient's systolic blood pressure is reduced by at least 6, 7, 8, 9, 10, 11, 12, or more percent as compared to the patient's systolic blood pressure before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         8 . The method of any one of  claims 1  to  7  wherein the patient's diastolic blood pressure is reduced by at least 8, 9, 10, 11, 12, 13, 14, 15, or more percent as compared to the patient's diastolic blood pressure before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         9 . The method of any one of  claims 1  to  8  wherein the patient had a systolic blood pressure of from 130 mmHg to 200 mm Hg before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         10 . The method of any one of  claims 1  to  8  wherein the patient had a systolic blood pressure of from 135 mmHg to 200 mm Hg before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         11 . The method of any one of  claims 1  to  8  wherein the patient had a systolic blood pressure of from 140 mmHg to 200 mm Hg before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         12 . The method of any one of  claims 1  to  8  wherein the patient had a systolic blood pressure of from 143 mmHg to 200 mm Hg before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         13 . The method of any one of  claims 1  to  8  wherein the patient had a systolic blood pressure of from 145 mmHg to 180 mmHg before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         14 . The method of any one of  claims 1  to  8  wherein the patient had a systolic blood pressure of from 148 mmHg to 180 mmHg before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         15 . The method of any one of  claims 1  to  14  wherein the systolic blood pressure of the patient is maintained below 130 mm Hg over at least 90% of the period of treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         16 . The method of any one of  claims 1  to  16  wherein the diastolic blood pressure of the patient is maintained at below 80 mm Hg over at least 90% of the period of treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         17 . The method of any one of  claims 1  to  16  wherein the patient is not being treated with an aldosterone antagonist. 
     
     
         18 . The method of any one of  claims 1  to  17  wherein the patient does not have another condition that causes hypertension. 
     
     
         19 . The method of  claim 18  wherein the patient does not have Type 2 diabetes. 
     
     
         20 . The method of  claim 18  wherein the patient does not have Class II or Class III heart failure (HF). 
     
     
         21 . The method of any one of  claims 1  to  20  wherein the patient is not being treated with a heart failure therapy. 
     
     
         22 . The method of  claim 21  wherein the heart failure therapy is an angiotensin converting enzyme inhibitor (ACEI), an angiotensin receptor blocker (ARB), a beta blocker (BB), or a combination thereof. 
     
     
         23 . The method of any one of  claims 1  to  22  wherein the patient is not being treated with an antihypertensive agent comprising a diuretic, a calcium channel blocker, an alpha blocker, a nervous system inhibitor, a vasodilator, an angiotensin converting enzyme inhibitor (ACEI), an angiotensin receptor blocker (ARB), a beta blocker (BB), or a combination thereof. 
     
     
         24 . The method of any one of  claims 1  to  23  wherein the patient is normokalemic. 
     
     
         25 . A method of treating hypertension in a chronic kidney disease patient in need thereof, the patient optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent, the method comprising administering an effective amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form to the patient. 
     
     
         26 . A method of treating hypertension in a heart failure patient in need thereof, the patient optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent, the method comprising administering an effective amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form to the patient. 
     
     
         27 . A method of treating hypertension in a type 2 diabetes mellitus patient in need thereof, the patient optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent, the method comprising administering an effective amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form to the patient. 
     
     
         28 . The method of  claim 25  wherein the patient further suffers from heart failure and type 2 diabetes mellitus. 
     
     
         29 . The method of  claim 26  or  27  wherein the patient further suffers from chronic kidney disease. 
     
     
         30 . The method of  claim 27  wherein the patient further suffers from heart failure. 
     
     
         31 . The method of any one of  claims 25  to  30  wherein the patient's systolic blood pressure is reduced by 5, 6, 7, 8 mm Hg as compared to the patient's systolic blood pressure before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         32 . The method of any one of  claims 25  to  30  wherein the patient's systolic blood pressure is reduced by 9, 10, 11, 12, 13, 14, 15, 16, 17 mm Hg or more as compared to the patient's systolic blood pressure before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         33 . The method of any one of  claims 25  to  32  wherein the patient's diastolic blood pressure is reduced by 2, 3, 4, 5, 6 mm Hg as compared to the patient's diastolic blood pressure before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         34 . The method of any one of  claims 25  to  32  wherein the patient's diastolic blood pressure is reduced by 7, 8, 9, 10, 11, 12, 13 mm Hg or more as compared to the patient's diastolic blood pressure before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         35 . The method of any one of  claims 25  to  30  and  32  to  34  wherein the patient's systolic blood pressure is reduced by at least 6, 7, 8, 9, 10, 11, 12, or more percent as compared to the patient's systolic blood pressure before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         36 . The method of any one of  claims 25  to  32 ,  34 , and  35  wherein the patient's diastolic blood pressure is reduced by at least 8, 9, 10, 11, 12, 13, 14, 15, or more percent as compared to the patient's diastolic blood pressure before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         37 . A method of treating hyperkalemia in a chronic kidney disease patient in need thereof optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent, the method comprising:
 administering an effective amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form to the patient and observing a decrease in the patient's serum creatinine level as compared to the patient's serum creatinine level before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form indicating an increase or stabilization of the patient's kidney function.   
     
     
         38 . A method of treating hyperkalemia in a chronic kidney disease patient in need thereof optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent, the method comprising:
 administering an effective amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form to the patient and observing a decrease in the time to progression of end stage renal disease as compared to a chronic kidney disease patient optionally treated with a RAAS agent but not treated with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form indicating an increase or stabilization of the patient's kidney function.   
     
     
         39 . A method of treating hyperkalemia in a chronic kidney disease patient in need thereof optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent, the method comprising:
 administering an effective amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form to the patient and observing an increase in survival as compared to a chronic kidney disease patient optionally treated with a RAAS agent but not treated with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form indicating an increase or stabilization of the patient's kidney function.   
     
     
         40 . A method of treating hyperkalemia in a chronic kidney disease patient in need thereof optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent, the method comprising:
 administering an effective amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form to the patient and observing an increase or stabilization of estimated glomerular filtration rate (eGFR) as compared to the patient's eGFR before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form indicating an increase or stabilization of the patient's kidney function.   
     
     
         41 . A method of treating chronic kidney disease in a patient in need thereof optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent, the method comprising:
 administering an effective amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form to the patient to increase or stabilize the patient's kidney function by decreasing the patient's serum creatinine level as compared to the patient's serum creatinine level before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form.   
     
     
         42 . A method of treating chronic kidney disease in a patient in need thereof optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent, the method comprising:
 administering an effective amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form to the patient to increase or stabilize the patient's kidney function by decreasing the time to progression of end stage renal disease as compared to a chronic kidney disease patient optionally treated with a RAAS agent but not treated with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form.   
     
     
         43 . A method of treating chronic kidney disease in a patient in need thereof optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent, the method comprising:
 administering an effective amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form to the patient to increase or stabilize the patient's kidney function by increasing survival as compared to a chronic kidney disease patient optionally treated with a RAAS agent but not treated with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form.   
     
     
         44 . A method of treating chronic kidney disease in a patient in need thereof optionally being treated with an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent, the method comprising:
 administering an effective amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form to the patient to increase or stabilize the patient's kidney function by increasing or stabilizing estimated glomerular filtration rate (eGFR) as compared to the patient's eGFR before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form.   
     
     
         45 . The method of any one of  claims 41  to  44  further comprising treating hyperkalemia in a patient in need thereof. 
     
     
         46 . The method of any one of  claims 25  to  45  wherein the treatment period is 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, or more weeks. 
     
     
         47 . The method of any one of  claims 25  to  46  wherein the patient has a baseline estimated glomerular filtration rate (eGFR) of from about 15 mL/min/1.73 m 2  to about 44 mL/min/1.73 m 2 . 
     
     
         48 . The method of any one of  claims 25  to  47  wherein the patient's eGFR after treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form is not significantly different from the patient's eGFR before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         49 . The method of any one of  claims 25  to  47  wherein the patient's eGFR is increased after 2, 3, 4, 5, 6 months or more of treatment as compared to the patient's eGFR before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         50 . The method of  claim 49  wherein the patient's eGFR after treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form increased by at least 4, 5, 6 mL/min/1.73 m 2  or more as compared to the patient's eGFR before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         51 . The method of any one of  claims 25  to  50  wherein the patient's serum potassium level is decreased after 1, 2, 3, 4, 5, 6, 7 days or more of treatment as compared to the patient's serum potassium level before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         52 . The method of any one of  claims 25  to  51  wherein the patient's urine albumin:creatinine ratio (ACR) is not significantly different after 2, 3, 4, 5, 6 months or more of treatment as compared to the patient's urine ACR before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         53 . The method of any one of  claims 25  to  52  wherein the patient's systolic and diastolic blood pressure is decreased after 1, 2, 3, 4, 5, 6, 7 days or more of treatment as compared to the patient's systolic and diastolic blood pressure before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         54 . The method of  claim 53  wherein the patient's systolic blood pressure is reduced by 5, 6, 7, 8 mm Hg or more as compared to the patient's systolic blood pressure before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         55 . The method of  claim 53  wherein the patient's systolic blood pressure is reduced by 9, 10, 11, 12, 13, 14, 15, 16, 17 mm Hg or more as compared to the patient's systolic blood pressure before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         56 . The method of any one of  claims 53  to  55  wherein the patient's diastolic blood pressure is reduced by 2, 3, 4, 5, 6 mm Hg as compared to the patient's diastolic blood pressure before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         57 . The method of any one of  claim 53  or  55  wherein the patient's diastolic blood pressure is reduced by 7, 8, 9, 10, 11, 12, 13 mm Hg or more as compared to the patient's diastolic blood pressure before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         58 . The method of any one of  claims 53  and  55  to  57  wherein the patient's systolic blood pressure is reduced by at least 6, 7, 8, 9, 10, 11, 12, or more percent as compared to the patient's systolic blood pressure before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         59 . The method of any one of  claims 53  to  55 ,  57 , and  58  wherein the patient's diastolic blood pressure is reduced by at least 8, 9, 10, 11, 12, 13, 14, 15, or more percent as compared to the patient's diastolic blood pressure before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         60 . The method of any one of  claims 1  to  59  wherein the patient's serum aldosterone level is decreased after four weeks or more of treatment as compared to the patient's serum aldosterone level before treatment with 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form. 
     
     
         61 . The method of any one of  claims 1  to  60  wherein the effective amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form comprises up to a maximum daily dose of 60 grams. 
     
     
         62 . The method of  claim 61  wherein the effective amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form comprises a daily dose of from 10 grams to 60 grams. 
     
     
         63 . The method of  claim 61  wherein the effective amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form comprises a daily dose of from 20 grams to 60 grams. 
     
     
         64 . The method of any one of  claims 1  to  63  further comprising:
 administering an effective amount of a renin-angiotensin-aldosterone system (RAAS) agent to the patient; 
 determining the serum potassium level in the patient; and 
 increasing the amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form subsequently administered to the patient based on the serum potassium level if greater than or equal to 5.1 mEq/L. 
 
     
     
         65 . The method of  claim 64  wherein the amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form was increased by 5 g per day. 
     
     
         66 . The method of  claim 64  wherein the amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form was increased by 10 g per day. 
     
     
         67 . The method of any one of  claims 64  to  66  further comprising decreasing the amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form subsequently administered to the patient based on the serum potassium level if less than 4.0 mEq/L. 
     
     
         68 . The method of  claim 67  wherein the amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form was decreased by 5 g per day. 
     
     
         69 . The method of  claim 67  wherein the amount of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form was decreased by 10 g per day. 
     
     
         70 . The method of any one of  claims 1  to  69  wherein 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form is in the salt form. 
     
     
         71 . The method of  claim 70  wherein the salt form comprises the sodium, calcium, magnesium, ammonium, or a combination thereof. 
     
     
         72 . The method of  claim 71  wherein the salt form comprises the calcium salt form. 
     
     
         73 . The method of any one of  claims 70  to  72  wherein the 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt form is stabilized with a linear polyol. 
     
     
         74 . The method of  claim 73  wherein the 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt form is stabilized with sorbitol. 
     
     
         75 . The method of any one of  claims 25  to  74  wherein the 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form is administered chronically. 
     
     
         76 . The method of any one of  claims 1  to  75  wherein the 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form exhibits long-term tolerability in the patient. 
     
     
         77 . The method of any one of  claims 1  to  76  wherein the 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form exhibits long-term safety in the patient. 
     
     
         78 . The method of any one of  claims 1  to  77  wherein the 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form exhibits long-term efficacy in the patient. 
     
     
         79 . The method of any one of  claims 1  to  78  wherein the 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form is administered to the patient daily for more than 8 weeks. 
     
     
         80 . The method of any one of  claims 1  to  78  wherein the 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form is administered to the patient daily for more than one year. 
     
     
         81 . The method of any one of  claims 1  to  16 ,  18  to  20  and  24  to  80  wherein the patient is being treated or further treated with an effective amount of a RAAS agent, the RAAS agent being an angiotensin converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), an aldosterone antagonist (AA), an aldosterone synthase inhibitor, or a combination thereof. 
     
     
         82 . The method of  claim 81  wherein the RAAS agent is the ACE inhibitor, the ARB, or a combination thereof. 
     
     
         83 . The method of  claim 81  or  82  wherein the effective amount of the RAAS agent comprises up to a maximum daily tolerated dose. 
     
     
         84 . The method of any one of  claims 81  to  83  wherein the RAAS agent comprises fosinopril, ramipril, captopril, lisinopril, trandolapril, moexipril, quinapril, enalapril, benazepril, perindopril, eprosartan, olmesartan, losartan, telmisartan, valsartan, candesartan, irbesartan, azilsartan medoxomil, spironolactone, eplerenone, or a combination thereof. 
     
     
         85 . The method of  claim 84  wherein the RAAS agent comprises fosinopril and the maximum daily tolerated dose is 40 mg/day. 
     
     
         86 . The method of  claim 84  wherein the RAAS agent comprises ramipril and the maximum daily tolerated dose is 20 mg/day. 
     
     
         87 . The method of  claim 84  wherein the RAAS agent comprises captopril and the maximum daily tolerated dose is 300 mg/day. 
     
     
         88 . The method of  claim 84  wherein the RAAS agent comprises lisinopril and the maximum daily tolerated dose is 40 mg/day. 
     
     
         89 . The method of  claim 84  wherein the RAAS agent comprises trandolapril and the maximum daily tolerated dose is 4 mg. 
     
     
         90 . The method of  claim 84  wherein the RAAS agent comprises moexipril and the maximum daily tolerated dose is 30 mg/day. 
     
     
         91 . The method of  claim 84  wherein the RAAS agent comprises quinapril and the maximum daily tolerated dose is 80 mg/day. 
     
     
         92 . The method of  claim 84  wherein the RAAS agent comprises enalapril and the maximum daily tolerated dose is 40 mg/day. 
     
     
         93 . The method of  claim 84  wherein the RAAS agent comprises benazepril and the maximum daily tolerated dose is 40 mg/day. 
     
     
         94 . The method of  claim 84  wherein the RAAS agent comprises perindopril and the maximum daily tolerated dose is 8 mg/day. 
     
     
         95 . The method of  claim 84  wherein the RAAS agent comprises eprosartan and the maximum daily tolerated dose is 800 mg/day. 
     
     
         96 . The method of  claim 84  wherein the RAAS agent comprises olmesartan and the maximum daily tolerated dose is 40 mg/day. 
     
     
         97 . The method of  claim 84  wherein the RAAS agent comprises losartan and the maximum daily tolerated dose is 100 mg/day. 
     
     
         98 . The method of  claim 84  wherein the RAAS agent comprises telmisartan and the maximum daily tolerated dose is 80 mg/day. 
     
     
         99 . The method of  claim 84  wherein the RAAS agent comprises valsartan and the maximum daily tolerated dose is 320 mg/day. 
     
     
         100 . The method of  claim 84  wherein the RAAS agent comprises candesartan and the maximum daily tolerated dose is 32 mg/day. 
     
     
         101 . The method of  claim 84  wherein the RAAS agent comprises irbesartan and the maximum daily tolerated dose is 300 mg/day. 
     
     
         102 . The method of  claim 84  wherein the RAAS agent comprises azilsartan medoxomil and the maximum daily tolerated dose is 80 mg/day. 
     
     
         103 . The method of  claim 84  wherein the RAAS agent comprises spironolactone and the maximum daily tolerated dose is 200 mg/day. 
     
     
         104 . The method of  claim 84  wherein the RAAS agent comprises eplerenone and the maximum daily tolerated dose is 50 mg/day. 
     
     
         105 . The method of any one of  claims 1  to  20  and  24  to  104  wherein the patient is further being treated with an effective amount of a beta-adrenergic blocking agent. 
     
     
         106 . The method of  claim 105  wherein the beta-adrenergic blocking agent comprises betaxolol, bisoprolol, atenolol, metoprolol, nebivolol, metoprolol, esmolol, acebutolol, propranolol, nadolol, carvedilol, labetalol, sotalol, timolol, carteolol, penbutolol, pindolol, or a combination thereof.

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