1. Lower LDL, Less Events? Not That
Ravi Parmar
Island Health Pharmacy Resident
Nephrology Rotation RJH Nov 2017

2. Learning Objectives
Review the epidemiology and pathophysiology of dyslipidemia & atherosclerosis
Explain traditional risks factors of CV events and explore how they may differ in CKD patients
Compare different cholesterol lowering agents for dyslipidemia treatment in a hemodialysis patient
Apply the evidence to a patient case

3. Meet Our Patient: WI ID
50 yo Caucasian male, 69.3 kg, cm, BMI: kg/m2 CC
End stage renal disease (ESRD) presenting for hemodialysis (HD)
HPI
Patient has been on HD since Oct.27th/2015, currently on renal transplant list
PMHx
Dyslipidemia – treated with ezetimibe 10 mg po daily since at least 2011
ESRD – secondary to diabetic nephropathy, receiving HD 3x/week
T1DM– diagnosed at age 25
IBS-D
History CVA (Jan 2011) & suspected TIA (Dec 2016)
Depression, hypertension, anemia, insomnia, restless legs syndrome (RLS), bone mineral disease

4. Meet Our Patient: WI Allergies Statins = myositis (CK 1300)
Ramipril = cough
Social History
25 pack year smoking history. Ø EtOH and illicit drug use
Functional Status
Lives with sister and brother-in-law who provide a strong support system
Independent with regard to his ADLs
Financial
Status
Cost is a concern for WI (supported through CPP); medications covered through BCPRA. Interested in decreasing medication burden.
States that he successfully quit smoking 5 months ago, but this is questionable.

5. Edmonton Symptom Assessment Scale (ESAS)
Sleep
9/10; difficulty sleeping 2˚ to RLS
RLS
7/10; ropinirole ineffective
Nausea/Diarrhea
6/10; experiencing both nausea & diarrhea occasionally
Drowsiness
6/10; feeling tired throughout the day

6. Review of Systems 08-Nov-2017
PRE HD VITALS
T: 35.9˚C, HR: 71, RR: 16, BP: 158/60
CNS
A&O x 4
CVS
Dec 2016: TG:0.59, LDL: 1.06, HDL: 1.60
Carotid Doppler Dec 2016: No significant plaque is seen in either internal carotid artery. Vertebral artery flow directions are normal. No carotid stenosis
Echo Oct 2017: Normal biventricular systolic function. Mild aortic valve sclerosis
RENAL
HbA1C: 7.6%, eGFR: 6 mL/min, SrCr: 864
Lytes
Na: 134, K: 5.5, Ca: 2.27, PO4: 2.10, Mg: 1.35
HEMATOLOGY
Hgb: 103, MCV: 96, Retic: 42, Tsat: 17%, Ferritin: 716

7. Gastric protection/uremic GI symptoms
Medication List
Dyslipidemia
Ezetimibe 10 mg po daily
Hypertension
Amlodipine 15 mg po daily
Losartan 50 mg po bid
Furosemide 80 mg po daily
Stroke Prevention
Clopidogrel 75 mg po daily
ASA 81 mg EC po daily
T1DM
Insulin lispro u SC tid ac
Insulin glargine 12u SC qam
IBS
Loperamide 2 mg po prn loose BM (max 16 mg/day)
RLS
Levodopa/carbidopa 100/25 mg 1-2 tabs qHD prn
Ropinirole 0.25 mg 1-3 tabs qHS prn
Depression
Escitalopram 20 mg po daily
Insomnia
Melatonin 3 mg 1-2 tabs qHS
Trazodone mg qhs prn
BMD
Alfacalcidol 0.25 mcg qweek
Aluminum hydroxide 600 mg 1 tab tid
CaCO3 (Tums) 500 mg 1 tab brkft, lunch, 2 tabs supper
Anemia
Darbepoetin 10 mcg IV qweek
Iron gluconate 125 mg IV twice/month
Gastric protection/uremic GI symptoms
Pantoprazole 40 mg po bid
Domperidone 10 mg qid prn
Other
Replavite 1 tab po daily
Zinc 50 mg po weekly

8. Drug Therapy Problems
Experiencing IBS-D flares and occasional nausea which may be 2˚ to ezetimibe therapy
At risk of recurrent CVA/TIA 2˚ to unclear efficacy of ezetimibe in the HD population
Experiencing uncontrolled RLS 2˚ to ineffective ropinirole therapy and would benefit from initiation of levodopa/carbidopa at home
At risk of experiencing symptoms of anemia (e.g. fatigue, tachycardia, SOB) 2˚to low transferrin saturation and would benefit from an iron gluconate load
At risk of experiencing cardiovascular calcification and worsening metabolic bone disease 2˚to hyperphosphatemia and would benefit from an increased dosage of Tums
At risk of experiencing symptoms of aluminum toxicity (e.g. bone & muscle pain, osteomalacia, encephalopathy) 2˚ to use of aluminum hydroxide phosphate binder and would benefit from re-assessment of therapy
At risk of increased adverse effects of amlodipine therapy (e.g. hypotension, fatigue, nausea, edema) 2˚ to high dose and would benefit from reduction of dose
At risk of TdP & cardiac arrhythmias 2˚ to QTc prolongation associated with multiple agents and would benefit from re-assessment of therapy
Osteomalacia is characterized by a very low rate of bone turnover, low number of bone-forming and bone-resorbing cells, a mineralization defect, and marked accumulation of unmineralized osteoid (bone matrix)

9. Goals of Therapy
Reduce risk of CVA/TIA recurrence and cardiovascular events
Reduce surrogate markers (e.g. LDL-C)
Prevent adverse drug reactions (e.g. continued diarrhea, worsening of IBS)
Improve quality of life

10. Dyslipidemia
Elevated total or low-density lipoprotein (LDL) cholesterol levels, or low levels of high-density lipoprotein (HDL) cholesterol
Results in atherosclerotic plaques; important risk factor for coronary heart disease & stroke
Affects ~45% of Canadians aged ( )
Cardiovascular disease (19.7%) and cerebrovascular disease (5.2%) are the 2nd and 3rd leading causes of death in Canada, respectively
Vessels that carry cholesterol. LDL (bad cholesterol) and HDL (good cholesterol). LDL takes cholesterol to arteries where it may collect and form plaques. HDL takes cholesterol to liver to be expelled from body ‘scavenger’.
Only behind cancer (29.8%)
Joffres et al. Can J Pub Health. 2013
Statistics Canada, CANSIM table

11. Dyslipidemia Pathophysiology
Earliest visible lesion of atherosclerosis is the fatty streak, which is an accumulation of lipid laden foam cells in the intimal layer of the artery
Atherosclerotic plaque formed of lipids, inflammatory and smooth muscle cells, and a connective tissue matrix that may contain thrombi in various stages of organization and calcium deposits
All stages of atherosclerosis considered an inflammatory response and mediated by specific cytokines
Plaques can be stable (regress, remain static, or grow slowly) but can also be unstable making them to vulnerable to spontaneous erosion, fissure, or rupture, causing acute thrombosis, occlusion, and infarction. Most clinical events result from unstable plaques.

12. Difference in HD Patients?
In the dialysis population, there may be competing mechanisms of cardiovascular disease in which vascular disease is dominated by vascular calcification, cardiomyopathy, hyperkalemia, and sudden cardiac death
Non-HD population, vascular disease dominated mainly by atherosclerosis. Especially, in Western culture (obesity epidemic). CVD leading cause of death in CKD ~10-30 fold higher than general population
Abnormal Ca and PO4 metabolism, vit D deficiency, chronic inflammation/endothelial dysfunction leads to arterial calcification, LVH, & sympathetic overactivity and death due to arrhythmia or HF.
- Hyperkalemia – failing kidneys cannot maintain potassium hemostasis. Certain medications may contribute (furosemide, ACE, ARB, spiro, etc.)
Palmer et al. Cochrane Review. 2013

13. Risk Factors for CVA Recurrence 
Uremia = complication of CKD in which urea and other waste products build up in the body because kidneys cannot eliminate. Results in fluid, electrolyte and hormone imbalances and metabolic abnormalities.
A number of substances with toxic effects, such as parathyroid hormone (PTH), beta2 microglobulin, polyamines, advanced glycosylation end products, and other middle molecules, are thought to contribute to the clinical syndrome
Patient has normal LV size

14. Therapeutic Alternatives
Considerations
Statin Re-challenge
Gold standard therapy in 2˚ prevention of CV events
Hx. of rhabdo 2˚to atorvastatin therapy
Ezetimibe
Current medication regimen
CCS: Ezetimibe 2nd line in patients with CVD if LDL-C target not achieved on maximally tolerated statin (Strong Recommendation; High Quality Evidence)
PCSK-9 Inhibitor
CCS: Suggest PCSK9 inhibitor in patients with CVD if LDL-C target not achieved on maximally tolerated statin +/- ezetimibe
Cost: $$$$
Bile Acid Sequestrant
CCS: Consider for LDL-C lowering in high-risk patients with levels above target despite statin treatment with or without ezetimibe therapy
Niacin
CCS: Do not recommend niacin + statin in patients who have achieved LDL-C target
Fibrate
CCS: Do not recommend fibrates + statin in patients who have achieved LDL-C target × × × ×
We know based on a multitude of large clinical trials that statins are the gold standard of therapy in both primary (CARDS, ASCOT) and secondary (4S, LIPID, CARE, TNT) prevention of CV morbidity and mortality
Ezetimibe is the patient’s current medication regimen. CCS recommends it as a second line agent, and it has been studied in the CKD population. Other agents have not, especially in HD.
BAS – recommended below ezetimibe because of less tolerability. Does have some CV benefit data from LRC-CPPT study (pre-dating statins) as monotherapy. × × × ×
Anderson et al. Can J Cardiol. 2016

15. Role of Statins in HD Patients?
Aurora (2009)
Design
Multicenter, double blind, RCT
Multicenter, double-blind, RCT
Population
T2DM patients undergoing HD, n=1255
Patients undergoing HD, age 50-80, n=2776
Interventions
Atorva 20 mg daily vs placebo
Rosuva 10 mg daily vs placebo
Outcomes
1° Composite: death cardiac causes, nonfatal MI, stroke
2°Total mortality
1° Composite: death cardiac causes, nonfatal MI, or nonfatal stroke
Results
1°RR: 0.92 ( ; P=0.37) NSS
2°RR: 0.93 ( ; P=0.33) NSS
1°HR: 0.96 ( ; P=0.59) NSS
2°HR: 0.96 ( ; P=0.51) NSS
Wanner et al. NEJM. 2005
Fellstrom et al. NEJM. 2009

16. Role of Statins in HD Patients?
KDIGO Guideline Statements:
2.3.1: In adults with dialysis-dependent CKD, we suggest that statins or statin/ezetimibe combination not be initiated (2A)
2.3.2: In adults already receiving statins or statin/ezetimibe combination at the time of dialysis initiation, we suggest that these agents be continued (2C)
Wanner, Tonelli. Internat Soc Neph. 2014

17. Ezetimibe - Approved in USA in 2002, in Canada in 2003
Inhibits the sterol transporter protein, Niemann-Pick C1 like 1 (NPC1L1), which causes inhibition of cholesterol absorption at the brush border of the small intestine. This leads to decreased delivery of cholesterol to the liver, reduction of hepatic cholesterol stores and an increased clearance of cholesterol from the blood. Decrease LDL, ApoB, TG, while increasing HDL.
Greater than 90% protein bound and metabolized hepatically. No concern on when to be given around dialysis.

18. Ezetimibe ENHANCE (2008) IMPROVE-IT (2015) Design Population
Multicenter, double-blind, RCT
Population
Patients with familial hypercholesterolemia, n=720
Patients hospitalized for ACS within preceding 10 d with LDL mmol/L if receiving lipid lowering therapy or mmol/L if not, n=18,144
Interventions
Simva 80 mg + placebo vs. Simva 80 mg + Ezetimibe 10 mg
Simva 40 mg + placebo vs. Simva 40 mg + Ezetimibe 10 mg
Outcomes
1°Change in mean carotid artery intima-media thickness
1°Composite: CV death, nonfatal MI, UA requiring rehospitalization, coronary revascularization (≤30 days after randomization), or nonfatal stroke
2°Total mortality
Results
1° / mm Simva only vs / mm Simva & Eze (P=0.29) NSS
1°HR: ( ; P=0.016) SS
2°HR: 0.99 ( ; P=0.78) NSS
Past studies have shown that ezetimibe can reliably reduce LDL-C by about 15-20%, but these were the first to look at cardiovascular outcomes with it (true clinical outcome data).
ENHANCE: Intima media thickness (IMT) is a validated surrogate marker and modest positive correlation has been shown between it and coronary atherosclerosis over a number of studies. Combo therapy trended towards more of an increase in thickness (more atherosclerosis), combo therapy also had non significant rises in CV events and death from CV causes. Minimal secondary prevention population represented.
IMPROVE-IT: Most benefit in decreased MI
Kastelein et al. NEJM. 2008
Cannon et al. NEJM. 2015

19. Clinical Question
Is ezetimibe an effective and safe therapy in the prevention of cardio/cerebro vascular events in HD patients? P
50 yo male with ESRD undergoing regular HD I
Ezetimibe C
Placebo O
Efficacy – any atherosclerotic event, total mortality
Safety – adverse events

20. Most Relevant Evidence
Literature Review
Databases
PubMed (1946-Present), EMBASE, Medline, Google Scholar
Search Terms
Ezetimibe, hemodialysis, dyslipidemia, atherosclerosis, secondary prevention
Results
1 RCT (included)
1 observational study
Most Relevant Evidence
Baigent et al. 2011
- Observational study not included because it looked at surrogates (LDL-C) in only 20 HD patients over 12 weeks. We know that eze can reduce the surrogates from past studies and are more interested in CV outcomes.

21. Baigent et al 2011 (SHARP Trial)
Baigent C, et al. ‘The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomized placebo-controlled trial. Lancet. 2011; 377:
Study Design
Multicenter, double blind, double dummy, RCT
Patient
Patients with CKD with no known history of MI or coronary revascularisation
N = 9,270 (3,023 on dialysis)
Intervention
Simvastatin 20 mg daily + Ezetimibe 10 mg daily
Comparator
Matching placebo
Outcomes
1°1st major atherosclerotic event (non-fatal MI or coronary death, non hemorrhagic stroke, or any arterial revascularisation procedure)
- Ideally, would have found study with ezetimibe monotherapy. However, it is very unlikely to have studies of this nature nowadays as it would be unethical with what we know about the risk reduction of CV morbidity and mortality with statins.
Baigent et al. Lancet. 2011

22. Baigent et al – Baseline Data
Simvastatin + Ezetimibe (n=4650)
Placebo (n=4620)
Previous Vascular Disease
711 (15%)
682 (15%)
Diabetes
1054 (23%)
1040 (23%)
Age at randomization (years)
62 (SD: 12)
Current Smoker
626 (13%)
608 (13%)
LDL Cholesterol (mmol/L)
2.77 (SD: 0.88)
2.78 (SD: 0.87)
Hemodialysis
1275 (27%)
1252 (27%)
Vascular disease = prev. stroke, angina, PVD
Baigent et al. Lancet. 2011

23. Baigent et al – Efficacy
Baigent et al. Lancet. 2011

24. Baigent et al – Efficacy
Baigent et al. Lancet. 2011

25. Baigent et al – Efficacy
Baigent et al. Lancet. 2011

26. Baigent et al – Safety
No difference in cancer incidence or cancer mortality between arms which was a concern with ezetimibe going into the trial
Otherwise, therapy appeared safe overall. No mention of GI side effects (nausea, diarrhea), but we know these are very common side effects with ezetimibe therapy
Does confirm that statin and ezetimibe therapy are generally safe in the CKD population
Baigent et al. Lancet. 2011

27. Baigent et al 2011 (SHARP Trial)
Strengths
RCT on an important, infrequently-studied population addressing an unanswered question
Large, sufficiently powered, and well-designed study; ITT analysis
Limitations
Funded in part by Merck/Shering-Plough (↑risk bias)
1˚ outcome results driven by patients with stage 3 & 4 CKD
1˚ composite endpoint definition changed during trial (↑risk bias)
No statin-only arm – unclear if ezetimibe truly added additional benefit apart from further LDL lowering
Sub-group analyses not sufficiently powered
Blinding likely not maintained secondary to LDL-C decline in treatment arm (↑risk bias)
Strengths – 90% power
Limitations- 1) Makers of vytorin (combo ezetimibe/simva)
Intention-to-treat analysis is a comparison of the treatment groups that includes all patients as originally allocated after randomization.
Per-protocol analysis is a comparison of treatment groups that includes only those patients who completed the treatment originally allocated.
Baigent et al. Lancet. 2011

28. Baigent et al – Author’s Conclusion
Baigent et al. Lancet. 2011

29. Baigent et al – My Conclusions
Although statins have been proven to reduce CV morbidity and mortality in those at high risk of CVD, the pathophysiology of CVD changes as CKD advances
Worsening eGFR appears to be associated with smaller risk reduction of lipid lowering therapy
Lack of a statin only arm makes it very difficult to distinguish what, if any, benefit that ezetimibe is providing
Statin therapy is warranted in CKD up to stage 4. In stage 5 and in dialysis patients, no statistically significant benefit is shown
Baigent et al. Lancet. 2011

30. Applying the Evidence to WI?
NECESSARY
At risk of recurrent CVA/TIA & cardiovascular events
Most recent lipid panel shows LDL well controlled at 1.06
Carotid doppler shows no significant plaque and no carotid stenosis
EFFECTIVE
Ezetimibe + statin therapy showed no benefit in reduction of atherosclerotic events or total mortality in HD patients
SAFETY
Ezetimibe may be contributing to worsening diarrhea in the setting of IBS-D and nausea
ADHERENCE
Patient interested in decreasing medication burden as much as possible X X X

31. Recommendations Discontinue ezetimibe 10 mg po daily
Other Recommendations
Discontinue ropinirole, initiate levodopa/carbidopa 100/25 mg 1-2 tabs qhs prn
Initiate iron gluconate 125 mg IV eight dose load
Increase CaCO3 (Tums) to 1000 mg po tid, consider discontinuing aluminum hydroxide therapy or setting an end date
Decrease amlodipine to 10 mg po daily
Decrease domperidone to 10 mg tid prn

32. Monitoring Parameters
Monitoring Plan
Monitoring Parameters
Monitored By
How Often
Psych
↑ QoL (↓ medication burden, ↓ stress about IBS-D)
Pt, family, RPh, MD, RN
Daily
CVS
Recurrent CVA/TIA, or new cardiac event
Lipid panel
MD, RPh
Annually GI
Improvement of IBS-D and nausea

33. What Actually Happened
Presented my suggestions to the nephrologist at weekly med rec meeting Nov.9th/2017
Nephrologist accepted recommendation to discontinue ezetimibe and will assess if patient’s IBS-D symptoms improve over next few months

34. Follow-Up Nov.20th/2017
Patient reports symptoms of nausea have improved and he has not had any diarrhea since being off of ezetimibe therapy
He also reports that his RLS has been under better control and he has been sleeping better 

35. Questions?
All images obtained via google images

36. Supplemental Materials

37. Ezetimibe

38. Ezetimibe

39. Who To Screen
Anderson et al. Can J Cardiol. 2016

40. How To Screen
Anderson et al. Can J Cardiol. 2016

41. Risk Stratification
Anderson et al. Can J Cardiol. 2016

42. Statin Indication
Anderson et al. Can J Cardiol. 2016

43. Statins

44. Management Algorithm
Anderson et al. Can J Cardiol. 2016

45. Lipid Targets
Anderson et al. Can J Cardiol. 2016

46. Lipid Targets

47. Lipid Targets - Elevated ApoB levels indicate increased risk of CVD
Anderson et al. Can J Cardiol. 2016

48. PCSK-9 Inhibitors Evolocumab Dose: 140 mg q2w sc or 420 mg sc monthly
No dosage adjustments provided in severe renal impairment (<30 mL/min) as it has not been studied in this population. However, dosage adjustment is unlikely to be required as monoclonal antibodies (mAbs) are not known to be renally eliminated
Adverse Effects: Nasopharyngitis (6-11%), hypertension (3%), nausea (2%), dizziness (4%), myalgia (4%)
Lexicomp: Evolocumab

49. PCSK-9 Inhibitors

50. PCSK-9 Inhibitors
Cost: $7844-$10,862 per year, currently under PharmaCare review

51. PCSK-9 Inhibitors & Ezetimibe
GAUSS-3 (2016)
FOURIER (2017)
Design
Two stage RCT
Multicenter, double blind, RCT
Population
Adult patients with uncontrolled LDL-C and history of intolerance to 2 or more statins
Patients with atherosclerotic CV disease and LDL cholesterol of ≥ 1.8 mmol/L who were receiving statin therapy
Interventions
Phase A: Atorva 20 mg daily vs placebo
Phase B: Randomization 2:1 to sc evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily)
Evolocumab sc (140 mg q2w or 420 mg monthly) vs matching placebo
Outcomes
1° Mean percent change in LDL-C level
1° Composite: CV death, MI, stroke, hospitalization UA, or coronary revascularization
2°Death from any cause
Results
1° Evolocumab decreased the LDL-C by 37.8% more than ezetimibe (between group difference)
1°HR: 0.85 ( ; P<0.001) SS
2°HR: 1.04 ( ; P=0.54) NSS

52. GAUSS-3

53. FOURIER
Severe renal or liver dysfunction excluded (no data in HD patients)

54. CKD

55. Rhabdomyolysis

56. Rhabdomyolysis Myositis = inflammation of muscles. ULN = 230 U/L
CK = enzyme that is a marker of muscle breakdown (damage in CK rich tissue = muscle)
Tsuyuki RT, Williams CD. Can PharmJ; 2009
Mancini GB et al. Can J Cardiol;2011