Management of Hypertension and Hyperlipidemia in Hematopoietic Cell Transplant (HCT) patients

1. Management of Hypertension and Hyperlipidemia in Hematopoietic Cell Transplant (HCT) patients Joseph Bubalo PharmD, BCPS, BCOP Oncology Clinical Pharmacy Specialist OHSU Hospital & Clinics

2. Objectives • Discuss the unique needs of blood pressure and lipid management in the HCT population • Review selection and individualization of the different therapeutic options available for managing hypertension and hyperlipidemia

3. Patient Case • AA is a 27 year old male s/p a sibling donor HCT for his AML. He is currently day +125 and doing well. His recent cyclosporine taper was interrupted due to GVHD of the skin and bowel which have responded to treatment with prednisone and continuation of his cyclosporine at therapeutic levels. • His blood pressure has been slowly creeping up and today is 155/91.

4. Prevalence of Cardiac Risk • Autologous and allogeneic HCT experience higher mortality rates and 2.3 x the risk of cardiovascular (CV) death in adults • Similar reports for pediatrics • Higher rates of CV risk factors • Increased triglycerides (TG) • Decreased high-density lipoproteins (HDL) • Hypertension • Hyperglycemia (fasting) • Increased waist circumference Baker KS et al BMT 2012;47:619-25

5. Hypertension • Reported in 21-63% of patients • Solid organ transplant reports 65-100% incidence • Calcineurin inhibitors most likely cause • Cyclosporine (CSA) worse than tacrolimus (FK) • Sirolimus and mycophenolate less likely to cause hypertension • Corticosteroids mixed effects • At 2 years post transplant hypertension resolved in 2/3 of patient in one report Majhail NS, et al BBMT 2009;15:1100-07

6. Metabolic Syndrome • Insulin resistance – Primary driver • Also central obesity, glucose intolerance, dyslipidemia, hypertension, • Common among HCT survivors • Lead to Type II diabetes mellitus (DM) & atherosclerotic CV disease • Contribution of HCT related procedures and complications still unclear • TBI, high dose chemotherapy, calcineurin inhibitors, corticosteroids, GVHD, etc Baker KS et al BMT 2012;47:619-25

7. Screening Baker KS et al BMT 2012;47:619-25

8. Given the well documented increased cardiovascular risks of people post-HCT the next steps in the evolution of care is to identify those at risk early and to implement interventions to modify those risks or disease defining events Chow EJ et al Annals Internal Medicine 2011;155:21-32

9. Issues/Risk factors • Older age and cardiovascular disease, esp. arterial • Co-morbidities at time of HCT • Traditional risk factors (obesity, inactivity, smoking, etc) do not change • Allogeneic increased hypertension over autologous Baker KS et al Blood 2007;109(4): 1765-72 Tichelli A, et al Haematologica 2008;93(8):1203-10

10. Special patient groups • Highest risk patients • Diabetes • Abdominal aortic aneurysm • Carotid stenosis • Peripheral arterial disease

11. Treating Hypertension • Hypertension • Systolic > 140 and/or diastolic > 90 • Diabetics: systolic > 130 and/or diastolic > 80 • Calcineurin inhibitor (CI) -induced hypertension • Secondary to renal vasoconstriction and sodium retention • Corticosteroids – sodium retention • Other causes

12. Treating Hypertension • Dihydropyridine calcium channel blockers • Amlodipine, nifedipine (XL only), felodipine, NO nicardipine • Verapamil, diltiazem not preferred but may be useful for cardiac arrhythmias • Reverses acute vasoconstriction, may limit CI nephrotoxicity through preferential dilatation of afferent arteriole • Rare cases of increased CSA levels

13. Hypertension in NPO patients • Intravenous acute care options • Hydralazine • Metoprolol • Topical • Clonidine NPO – no oral intake

14. Alternate Antihypertensives • Beta blockers – for patients with prior CV history, monitor heart rate • Angiotensin converting enzyme inhibitors (ACE) inhibitors – drug of choice in diabetics, increased risk for nephrotoxicity, hyperkalemia • Angiotensin receptor blockers (ARB) – alternate to ACE inhibitors. Less nephrotoxic? • Diuretics • May be preferred depending on co-morbidities

15. Antihypertensive Dosing

16. Treating hyperlipidemia • Low density lipoproteins (LDL) primary target (treat if > 100) • HDL and TG secondary (treat <40 or >500) • Lifestyle modifications • Decreased saturated fats and cholesterol • Increased plant stanols/sterols and viscous fiber to lower LDL • Weight control and exercise Circulation 2002;106:3143-3421

17. Drug causes of hyperlipidemia • Glucocorticoids • affect metabolic pathways increasing weight, blood glucose, lipids • Cyclosporine • Inhibit bile acid synthesis, block LDL receptor • Tacrolimus • Less lipid effects than CSA • Sirolimus, everolimus • Increase triglycerides and lipids

18. Hyperlipidemia Treatment • LDL predominant • Statins • Bile acid binders • Cholesterol absorption inhibitors • Hypertriglyceridemia • Omega 3 fatty acids • Niacin • Fibrates

19. Statins • Not 3A4 metabolized Preferred • Fluvastatin 20-80 mg • Pravastatin 10-80 mg • Rosuvastatin 5-40 mg • 3A4 metabolized • Atorvastatin 10-80 mg • Lovastatin 20-80 mg • Simvastatin 20-80 mg • Avoid use if on azole • Decrease LDL and TG, Increase HDL • Monitor transaminases, myositis, rhabdomyolysis

20. Bile Acid Binders • Decrease LDL 15-30% • Colesevelam 3750 mg daily – preferred • Can dose as once or twice daily • Dose several hours away from other drugs • Monitor drug levels (CSA, FK) • Less absorption issues vs. colestipol or cholestyramine • Do not use if high TG

21. Cholesterol Absorption Inhibitors • Ezetimibe • Decrease LDL~15% • 10 mg daily • Less potent than statins • Second line agent • Do not stop but usually not a lot of value to starting it

22. Hypertriglyceridemia • Statins – decrease 7-30%, helpful in mild disease (<500) • Niacin - decrease 30-40% • Use ER dose forms to improve tolerance • Good choice if LDL high as well • No drug interactions • AE: flushing, GI intolerance, increase glucose, uric acid

23. Hypertriglyceridemia • Omega 3 fatty acids - decrease 35-45% • 2-4 gm daily in 2 doses • Decrease hepatic production of TG • Impair platelet aggregation • Doses > 3 gm/day • GI upset, diarrhea

24. Hypertriglyceridemia • Fibrates - decrease 20-50% • Use if > 500 mg/dl • Gemfibrozil 600-1200 mg daily, in 2 doses • Fenofibrate 45-200 mg daily – preferred • AE: cholelithiasis, GI upset, myopathy – increased with statins • Caution in renal impairment

25. Monitoring • Obtain fasting lipid profile pre-transplant • Start therapy if indicated • Post HSCT • Repeat fasting lipid profile 4-8 weeks post transplant then every 3 months if on immunosuppression • Stable patient at goal, check every 6-12 months • Patient without dyslipidemia every 1-2 years Griffiths ML et al Blood 2010;116(8):1197-1204

26. Monitoring • Challenging in acute care setting post HSCT • Effects of TPN • Intermittent lipids can give false results • GI chemo toxicity or GVHD may affect med selection and efficacy/absorption • Increased drug interaction issues • Long term follow up clinic more predictable results

27. Patient Case AA • Antihypertensive? • Fasting lipid panel, then follow up • Diet intervention vs. medication if indicated • Individual patient issues that need to be considered • Availability for follow-up

28. Summary • Management issues • Adherence • Side effects: • Cost • Monitoring • Drug interactions • Success – in general population <30% have both hypertension and high cholesterol controlled, since ATPIII < 20% success with dyslipidemia control Egan BM et al Circulation 2013;128:29-41