A clinical conversation on … Managing the CVD patient with multi-organ dysfunction Panel

1. A clinical conversation on…Managing the CVD patient with multi-organ dysfunction Panel Dr. Raffy Castillo ( Chair ) Dr. Albert Chua Dr. Oscar Cabahug

2. The cardiovascular patient with multi-organ dysfunction Myocardial infarction and stroke Remodelling Atherosclerosis and left ventricular hypertrophy Ventricular dilation/cognitive dysfunction CV High-Risk Congestive heart failure/secondary stroke Hyper-tension HF Risk factors Death Death Angiotensin II Adapted from Dzau VJ, et al. Circulation2006;114:2850–2870; Figure adapted from Dzau V, Braunwald E. Am Heart J 1991;121:1244–1263; Yusuf S, et al. Lancet2004;364:937–952 Image reproduced with kind permission of Professor Böhm

3. Case • For the first time, you see a 55 year old, male, smoker for 30 pack years, non-alcoholic, with hypertension for 20 yrs and abnormal renal function for the past 2 years . He was prescribed medications which he erratically took. • Patient complains of episodes of dizziness, easy fatigue, orthopnea and bipedal edema for the past 2 weeks.

4. Physical exam BP = 150/100, HR = 95/min, RR = 25, Wt = 90kg, obese, WC = 43 inches   Awake, coherent, oriented Positive bilateral carotid bruit, distended neck veins with bibasal crackles. Apex beat 6th ICS LMCL, irregularly irregular rhythm, no murmurs Liver span is 12 cm, no fluid wave noted Grade 2 bipedal edema         

5. This patient likely has a: A. Primary cardiac problem B. Primary kidney problem C. Primary liver problem

6. Cardiorenal interaction may include: A. Acute decompensated heart failure leading to acute kidney injury B. Chronic CHF leading to CKD C. Combined heart and kidney dysfunction due to a systemic cause D. All of the above JACC 2008 52 (19)

9. Question Which of the following statements regarding CVD risk in CKD patients is correct: A. CKD is a risk factor for CVD B. Urine albumin level does not predict CV events C. CVD risk starts to increase with CKD stage 3 D. CV mortality is the # 3 cause of death among dialysis patients

10. In healthy individuals –risk of CV death starts to rise at GFR 90 ml/min eGFR (ml/min/1.73m2) CV mortality standardized rate/ 1000 person years Hazard Ratio adjusted (95%CI) < 75.6 2.57 2.46 (1.27-4.78) 75.6 - 89.4 2.61 2.62 (1.34-5.14) 89.4 -104.3 1.9 1.9(0.93-3.86) > 104.3 0.99 1 van Biesen, Europ.Heart J.(2007) 28:478 8913 randomly selected apparently healthy individuals, 10 year follow-up

11. Prevalence of Cardiovascular Diseases in Renal Patients CAD LVH (Echo) General Population 5 – 12 % 20 % Chronic Kidney Disease 16 - 35 % 25 – 50 % Dialysis Patients 50 % 75 % At start of HD, only about 16 % have normal 2DEcho Heart failure seen in about 40 % of Dialysis Patients Presence of HF associated with increase risk of death by 93 % CV Mortality accounts for about 50 % of deaths in dialysis patients ( ranks # 1 ) AHA Statement 2003: Kidney Disease is a Risk Factor for CVD

12. Cardiovascular Risk Factors in CKD Traditional Risk Factors Age Gender Hypertension Diabetes mellitus Hyperlipidemia LVH Physical inactivity Smoking Kidney Disease related risk factors Albuminuria Dyslipidemia Ca x P product  PTH  Vascular calcification Fibrinogen  Homocysteine  CRP  Increased oxidative stress Volume overload Hyperuricemia Insulin resistance Anemia Nephr Dial Trans 2000

13. What work-up will you request to evaluate renal function: A. Urinalysis and Urine Albumin/Creatinine ratio B. Serum creatinine C. Kidney ultrasound D. All of the above

14. Cockcroft-Gault Formula eGFR = Case: 55 y/o male, Wt= 90Kg, Creat = 3 mg/d eGFR = 35.4 ml/min CKD Stage 3b A3 (140 – Age ) X Wt in kgs ______________________ 72 X Serum Cr in mgs/dl * Multiply result by 0.85 for female

15. Revised CKD Classification KDIGO 2009

16. What work-up will you request for the hepatomegaly? A. Liver enzymes (ALP, AST, ALT) B. Protime C. Liver ultrasound D. All of the above

17. Lab results of the patient: • Hgb = 10 gm/dl   Uric Acid = 8 mg/dl  • FBS = 105 mg/dl Creatinine = 3 mg/dl • Na = 138 meq/L  K = 4.8 meq/L           • Cholesterol = 240 mg/dl LDL = 155 mg/dl   • HDL 35mg/dl Triglycerides = 190 mg/dl • ALT = 80 U/L     AST = 100 U/L • ALP = 110 U/L • Albumin = 3.1 gm/dl INR = 1.1 • Urinalysis: +2 protein • Urine Protein/Creatinine = 1800 mg/gm      

18. Lab results of the patient: • Ultrasound = Hepatomegaly with fatty infiltration, •        Normal gallbladder, biliary tree and spleen, •                Bilateral diffuse renal parenchymal disease   • ECG: Atrial fibrillation with moderate ventricular response, IVCD, Non-specific ST TWC • Chest x-ray: Cardiomegaly (CTr = 0.6) with pulmonary congestion • 2D Echo: Eccentric LVH with diffuse hypokinesia; EF= 34 % ; mild mitral / tricuspid regurgitation 20

19. Will you refer this patient for coronary angiogram? A. Yes B. No

20. Contrast-Induced Nephropathy Risk Score Mehran R, Nikolsky E, et al Kidney Int 2006;69

21. You’d preferably prescribe this patient for his cardiovascular problem the following drugs EXCEPT? A. RAAS blocker B. Beta-blocker once Heart Failure is stabilized C. Loop diuretics D. Verapamil or Diltiazem for rate control

22. Impact of RAAS Blockade on Progression of CKD CV event Death Normal Micro albuminuria Overt Proteinuria ESRD Ravid 1998 BENEDICT 2004 ROADMAP 2011 Ravid 1993 UKPDS 1998 CALM 2000 MICRO-HOPE 2000 MARVAL 2001 IRMA 2001 DETAIL 2004 ADVANCE 2010 RENAAL 2001 IDNT 2001 ADVANCE 2010 FOSIDIAL 2006 Cooperative CV Project 2003 Candesartan 2006

23. Prevention of Chronic Kidney Disease Progression in the Candesartan Antihypertensive Survival Evaluation in Japan (Case-J) Trial T Saruta, et alHypertens Res  2009 Jun Subgroup analysis of CASE-J trial showed that in Hypertensives with CKD, Candesartan, and Amlodipine, are equally effective in controlling blood pressure and reducing the incidence of cardiovascular events, but Candesartan is more effective in preventing deterioration of renal function Events Candesartan Amlodipine HR P value CV 61 (7.3%) 74 (9.3%) 0.780 0.140 Renal 10 (1.2%) 22 (2.8%) 0.430 0.022

24. Question What is the target Blood Pressure level for this patient ? A. < 140 / 90 B. < 130 / 80 C. < 120 / 75 D. < 110 / 70 Case: CKD stage 3b A3

25. UK National Institute for Health and Clinical Excellence (NICE) 2008 CKD Guidelines

26. What is the risk of this patient to develop ischemic stroke? A. Low risk B. Intermediate risk C. High-risk

27. 0 1 2 3 CHADS2 total score 4 5 6 0 5 10 15 20 25 30 Risk of stroke, %/year* Risk of stroke according to CHADS2 Error bars = 95% confidence intervals; *Theoretical rates without therapy ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354 & Eur Heart J 2006;27:1979–2030; Gage BF et al. JAMA 2001;285:2864–70

28. To prevent cardioembolic problems, what would you prescribe this patient? A. Aspirin B. Clopidogrel C. Anticoagulant

29. AF-RELATED STROKE IS PREVENTABLE • Effective stroke prevention is a priority for patients with AF1 • Two-thirds of strokes due to AF are preventable with appropriate anticoagulant therapy2 • A meta-analysis of 29 trials in 28,044 patients showed that the vitamin K antagonist (VKA) warfarinreduces the risk of stroke and all-cause mortality2 • 64% reduction in stroke and 24% reduction in all-cause mortality compared with placebo • Aspirin also reduced the risk of stroke, but less effectively than warfarin (19% reduction compared with placebo) • However, VKAs are associated with complications, such as increased bleeding risk • Guidelines for antithrombotic therapy in AF recommend Aspirin or VKA depending on the presence of risk factors for stroke1 1. Fuster V, et al. Circulation 2006;114:e257–354. 2. Hart RG, et al. Ann Intern Med 2007;146:857-867.

30. What will be your management of choice to lower the cholesterol level? A. Low cholesterol diet initially B. Lowest possible dose of statin C. Ezetimibe plus statin D. Gemfibrozil plus statin

31. Ezetimibe 10 mg

32. SHARP TRIAL: Study of Heart and Renal ProtectionLancet June 2011RCT, 9438 CKD patients, 1/3 on dialysis, ffup 4.9 yrs There was no difference in the progression to ESRD between treated grp (33.9%) and placebo (34.6%)

33. CLINICAL GUIDELINES: CVD in CKDUK Renal Association 2011 Guideline 1.6 - Statins Statins should be considered for primary prevention in all CKD Stages 1-4 and transplant patients Guideline 1.7 – Target Lipid level Total cholesterol of <4 mmol/l or 25% reduction from baseline or fasting LDL of <2 mmol/l Guideline 1.8 – Statins in dialysis patients Statins should not be withdrawn from patients in whom they were previously indicated and should continue when such patients start renal replacement therapy

34. CLINICAL GUIDELINES: CVD in CKDUK Renal Association 2011 Guideline on Secondary prevention of CV risk CKD patients with a history of chronic stable angina, acute coronary syndrome, myocardial infarction, stroke, peripheral vascular disease, or who undergo surgical or angiographic coronary revascularisation, should receive: Aspirin, ACE-inhibitor, Beta-blocker and Statins unless contraindicated

35. What would be your next step in the management of the fatty liver of this patient? A. Observe liver transaminases with the cholesterol lowering agents B. Initiate therapy with essential phospholipids / silymarin C. Check for hepatitis B or C for possible interferon therapy D. Check serum insulin level for possible metformin therapy

36. Therapy for NAFLD • Anti-oxidants - vitamin E – based on 2 small open label studies but refuted by an RCT • Ursodeoxycholic acid - initial results also refuted by an RCT

37. Therapy for NAFLD • Insulin sensitizer • - use of metformin proved improvement of the liver enzymes and amount of steatosis but improvement of inflammation is equivocal - pioglitazone and rosiglitazone shows promise in terms of improvement of inflammation but some patients develop greater elevation of transaminase levels

38. Therapy for NAFLD • Lipid lowering drugs • - gemfibrozil and statin show promise but no RCTs yet • TNF- blockade - TNF- contributes to insulin resistance - use of pentoxifylline and adiponectin and its effect on TNF- should be investigated • Liver transplantation - 60 – 100% recurrence of steatosis

39. Renoprotective strategies in this patient includes use of: A. RAAS blocker B. Oral Bicarbonate C. Allopurinol D. All of the above

40. Measures to Prevent Progression of CKD • Lifestyle modification • Glycemic control • Blood pressure control • Renin Angiotensin Aldosterone System blockade • Reduction of proteinuria • Protein restriction – LPD, VLPD+KAA • Lipid lowering • Correct hyperuricemia, acidosis, anemia • Avoid nephrotoxic agents, infections, etc - Tao-Li. Kidney International, April 2005

41. Correction of Acidosis JASN 2009 – De Brito et al RCT of oral sodium bicarbonate in 134 adults with CKD Stage 4 and serum bicarbonate 16 -20 mmol / l. 2 years ff-up, 22 patients in control group vs 4 in bicarbonate group progressed to dialysis (33% vs 6.5%) Bicarbonate group less likely to experience rapid progression Kidney International 2010 - Mahajan et al 5-year, RCT on oral sodium bicarbonate vs NaCl vs placebo 120 patients with early CKD w/o acidosis GFR at the end of the study was significantly higher in the bicarbonate-treated group, by about 5 ml /min. Urine albumin excretion and NAG excretion were both significantly reduced.

42. Hyperuricemia in CKD Hyperuricemia is an independent risk factor for renal and CV disease Goicoechea, M. et al. Effect of Allopurinol in CKD progression and cardiovascular risk. Clin. J. Am. Soc. Nephrol. 2010 showed that Allopurinol slowed progression of renal disease and reduced the risk of CV events in patients with CKD.

43. June 24, 2011 Bardoxolone grp have mean increase in eGFR of 10 mL/min. 73% of Bardoxolone grp have improvement in eGFR vs 2% of placebo grp (P<.001)

44. What should we advise for the diet in this patient? A. High protein diet to prevent muscle atrophy B. Liberal sodium to prevent hyponatremia C. Force oral fluids to reduce azotemia D. Restrict potassium and phosphorus sources

45. Fouque D et al,:. 2006. Low protein diets for chronic renal failure in nondiabetic adults Cochrane Database Syst. Rev. CD001892 Favors LPD Courtesy Professor Anders Alvestrand 2009

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