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MANAGEMENT OF ANGINA IN ESRD
April Jackson, PharmDFebruary 2, 2019
Disclosure Statement
I have had no financial relationship over the past 12 months with any commercial sponsor with a vested interest in this presentation
Objectives
■ Explain the basic pathophysiology of angina
■ Describe pathophysiological differences of coronary artery disease in ESRD patients
■ Identify common adverse effects of medications used in angina treatment in chronic kidney disease
■ Evaluate current guidelines and clinical trials of angina management in chronic kidney disease
Epidemiology and Statistics■ 14% of Americans have chronic kidney disease (CKD) with more than
100,000 progressing to dialysis-dependent CKD (CKD-5D) every year
■ 53% of the individuals who progress to CKD-5D will die of cardiovascular (CV) causes with 20% of these deaths being attributed to the consequence of coronary heart disease
■ Patients with ESRD appeared to have enhanced mortality from coronary artery disease (CAD) complications, particularly acute myocardial infarctions (MI)
Gregg, LP et al. Am J Kidney Disease. 2018.
Angina■ “Chest pain” = symptom Ischemic Heart Disease
– Stable vs Unstable
■ Main cause: atherosclerosis
■ Myocardial oxygen demand exceeds oxygen supplyàSpasm of heartàIschemia of heart muscle
Gregg, LP et al. Am J Kidney Disease. 2018.
Endothelium Damage
LDL Enters Artery Wall
WBC and LDL Build
Plaque
DiPiro, et al. Pharmacotherapy. 2014
PLAQUE FORMATION
ISCHEMIC HEART DISEASE
Stable Unstable
(Acute Coronary Syndrome)
ISCHEMIC HEART DISEASE
Stable Unstable
(Acute Coronary Syndrome)
Risk Factors in ESRDHypertension
Diabetes mellitus
Dyslipidemia
Obesity
Uremic Environment
C-Reactive Protein
Bhatti et al. J Am Heart Assoc. 2016.
How can ESRD lead to Heart Disease?
Anemia High Blood Pressure
High homocysteine levels
Unbalanced calcium-
phosphorous levels
Pathophysiology
General Population
•Intimal plaque atherosclerosis
CKD/ESRD
•Concentric stiffening of the arterial media•Calcium-phosphate product•Hyperparathyroidism
•Inflammation (high C-reactive protein)
•Uremia
Arterial Calcification■ Occurs in smooth muscle cells in the media or in the neointima of
atherosclerotic plaques à vascular stiffness
■ Intimal calcification and calcification of atheromatous plaques:– Possibly a healing response to the abnormal deposition of lipids
and oxidation products in the subendothelial space. ■ Medial calcification (Monckeberg’s sclerosis) associated with:
– Disturbances of Ca, P and vitamin D metabolism (ESRD) – LVH from increased left ventricular overload– Rhythm disturbances
Coronary Artery Calcification Score (CACS)■ Assessment of calcification■ Correlates with risk of CV event
0 – 10 Low Risk11 – 100 Intermediate Risk
>100 Disease progression>400 Highest risk
ANGINA MANAGEMENT
■ Beta blockers■ Calcium channel blockers■ Nitrates■ Antiplatelet therapy■ Statins■ ACE inhibitors or ARBs■ Diabetes management ■ Lifestyle Modifications
Goals1. Improve symptoms2. Prevent CV events3. Reduce mortality
Issues with traditional management ESRD…■ Unique triggers of angina (HD session, volume overload, anemia)■ Appropriate dosing
– Altered kinetics in kidney failure/dialytic removal – Blood pressure effects– Route of elimination
Evidence-based risk factor modification of CVD
General Population
• Lower BP• Low-dose aspirin for
primary and secondary prevention
• Lipid modification with statins
• Strict glycemic control in type 2 diabetes
NDD-CKD
• Lower BP to <140/90 or <130/90 if proteinuria
• RAAS blockage likely protective
• Low-dose aspirin cautiously used for secondary prevention
• Lipid modification with statin +/- ezetimibe
ESRD
•Lower BP•RAAS blockage may
be protective
Figure adapted from Gregg, LP et al. Am J Kidney Disease. 2018.
What we know from studies…
WHAT DO THE GUIDELINES
SUGGEST?
ACC/AHAKDIGOKDOQI
Risk Factor ACC/AHA KDIGO KDOQI
BP Target
--- Aggressively treat pre-dialysisSBP ≥ 200; only study published showed best outcome for home SBP 120-145
Pre-dialysis BP < 140/90Post-dialysis BP < 130/80
BP Medication Choice
--- No preference ACE inhibitors/ARB preferred (greater LVH regression; reduce sympathetic nerve activity and PWV; may improve endothelial function and reduce oxidative stress)
Aspirin --- --- ---
Lipid Management
--- Statins should not be initiated, but should be continued if the patient is already treated
Consider statin initiation if recent acute coronary event, young age or long life expectancy, or on transplant wait-list
Glycemic control--- --- Dialysis pts with DM should follow
ADA guidelines
Table adapted from Gregg, LP et al. Am J Kidney Disease. 2018.
Beta Blockers■ Cice et al (2003): Carvedilol vs Placebo: 114 HD patients with dilated
cardiomyopathy over 2 years – 71 all-cause deaths: HR 0.51 (0.32-0.82) – 55 CV deaths: HR 0.32 (0.18-0.57)– 1 MI: HR 0.81 (0.61-1.34)
Calcium Channel Blockers■ Tepel et al (2008): Amlodipine vs Placebo: 215 HD patients with hypertension over 4
years – CV event or all-cause deaths: HR 0.55 (0.31-0.97)
■ Other studies reported benefit from carvedilol or amlodipine over placebo in hemodialysis patients
Gregg, LP et al. Am J Kidney Disease. 2018.
Nitrates■ Cautious administration with preload is low (end of hemodialysis session), as these
states may potentiate the hypotensive effect of the drug
Gregg, LP et al. Am J Kidney Disease. 2018.
Aspirin■ Because patients with CKD are at increased baseline risk for both bleeding and
thrombosis, the use of aspirin for primary prevention deserves consideration.
■ The risks of aspirin may equal the benefits in NDD-CKD samples, and there are no trials testing aspirin in dialysis-dependent patients.
■ 2007 DOPPS nested-case control study: aspirin vs no aspirin in 28,320 HD patients over 1.9 years
– CV events: RR 1.08 (1.02- 1.14)– Fatal/nonfatal MI: RR 1.21 (1.06-1.38)– Stroke: RR 0.82 (0.69-0.98)– GI bleed: RR 1.01 (0.88-1.17)– Subdural hematoma: RR 0.56 (0.30-1.07)
Gregg, LP et al. Am J Kidney Disease. 2018.
Statins■ Lipid-lowering therapy improves CV outcomes in NDD-CKD, but not in dialysis-
dependent patients.
Study Intervention Comparator Duration Sample Outcome4D (2005) Atorvastatin 20
mg/dPlacebo 4 years 1,255 HD
pts with DM
Composite of CV death, MI, or stroke): RR 0.92 (0.77- 1.10)
AURORA (2009)
Rosuvastatin 10 mg/d
Placebo 5 years 2,776 HD pts
Composite of CV death, MI, or stroke): HR 0.96
SHARP (2011)
Simvastatin 20 mg/d + ezetimibe 10 mg/d
Placebo 5 years 3,023 CKD-5D pts (2,527 HD; 496 PD)
Composite of MI, coronary death, non-hemorrhagic stroke, or arterial revascularization) RRs: 0.90 (0.75-1.08) in CKD-5D0.95 (0.78-1.15) in HD 0.70 (0.46- 1.08) in PD
Gregg, LP et al. Am J Kidney Disease. 2018.
Blood Pressure Control■ Evidence in ESRD:
– Randomized trials: none– Observational studies: pre–dialysis session systolic BPs < 120
and >180 mm Hg associated with increased mortality risk– Meta-analysis: comparing antihypertensive treatments to lower
BP versus placebo or no treatment favored active treatment for decreasing CV events and deaths (mean decrease in BP of 4.5/2.3 mmHg)
■ Dose nocturnally to avoid significant antihypertensive effects during hemodialysis
■ Optimal blood pressure level has not yet been established
Gregg, LP et al. Am J Kidney Disease. 2018.
ACE Inhibitors and ARBs■ Secondary prevention of CAD with angiotensin converting enzyme (ACE) inhibitors
may have diminished clinical benefit in ESRD.
Gregg, LP et al. Am J Kidney Disease. 2018.
Study Intervention Comparator Duration Sample OutcomeFOSDIAL (2006)
Fosinopril Placebo 2 years 397 HD pts CV death, resuscitated death, stroke, CHF, MI, or revascularization): RR, 0.93 (0.68-1.26)
Takahashi et al (2006)
Candesartan --- 3 years 80 HD pts Sudden death, MI, unstable angina, CHF, or severe arrhythmia: OR, 0.23 (0.08-0.67)
Suzuki et al (2008)
Various ARBs --- 3 years 360 HD pts CV death, MI, stroke, CHF, or revascularization): HR, 0.51 (0.33-0.79)
Cice et al (2010)
Telmisartan Placebo 3 years 332 HD pttaking ACEI
All-cause death HR, 0.51 (0.32-0.82) CV death HR, 0.42 (0.38-0.61)
OCTOPUS (2013)
Olmesartan --- 3.5 years 469 HD pts Death, stroke, MI, or coronary revascularization): HR, 1.00 (0.71-1.40)
Diabetes Management
■ Hyperglycemia is associated with reduced coronary vasodilator function (opposes nitric oxide-mediated endothelial-dependent relaxation)
■ No trials investigating the efficacy of target glycemic control for CV event reduction in diabetic patients with ESRD.
■ Glucose goals: HbA1c of 7.0% (reduce microvascular events)
Gregg, LP et al. Am J Kidney Disease. 2018.
Unique Considerations■ Maintaining euvolemia
– Prolongation hemodialysis sessions– Modification of dosing regimens– Nocturnal medication dosing– Loop diuretics
■ Avoidance of large electrolyte shifts■ Anemia
■ Hyperphosphatemia
Anemia■ Goal: Increase oxygen supply ■ Treatment: ESA (erythropoietin stimulating agent)■ Indicated to keep hemoglobin > 9 g/dL with goal hemoglobin 11-
12 g/dL■ Goals higher than 12 g/dL associated with higher mortality
(Normal Hematocrit Study)
Hyperphosphatemia ■ Goal: decrease phosphorus (strong risk factor death from cardiovascular causes,
nonfatal myocardial infarction, or nonfatal stroke)
■ Treatment: calcium salts vs sevelamer
■ Block et al 2005 and 2007 outcomes: – Lowering Hyperphosphatemia: comparable – Hypercalcemia: calcium-containing binders more than sevelamer– Progressive coronary artery and aortic calcification: calcium-containing binders
quicker than sevelamer (P= 0.056 at 12 months, P= 0.01 at 18 months)– Mortality: calcium containing binders more than sevelamer with full multivariable
adjustment (P=0.016, hazard ratio 3.1, CI 1.23-7.61)
■ The Dialysis Clinical Outcomes Revisited trial (DCOR) reported a trend toward lower mortality in hemodialysis patients older than 65 years of age who were treated with sevelamer versus calcium-containing binders
Conclusion■ Comparable management approach to general population■ Special considerations for:
– ACEI/ARBs– Nitrates
■ Added management of:– Anemia – Hypophosphatemia
Post Assessment Question 1:
Which medication class may be associated with increased risk of bleeding in patients with chronic kidney disease? A. AntiplateletsB. ACE InhibitorsC. Statins
D. Nitrates
Post Assessment Question 1:
Which medication class may be associated with increased risk of bleeding in patients with chronic kidney disease? A. Antiplatelets
B. ACE InhibitorsC. Statins
D. Nitrates
Post Assessment Question 2:
Which of the following terms is often used interchangeably with “angina”?A. DizzinessB. Chest pain
C. Shortness of BreathD. Palpitations
Post Assessment Question 2:
Which of the following terms is often used interchangeably with “angina”?A. DizzinessB. Chest pain
C. Shortness of BreathD. Palpitations
Post Assessment Question 3:True / False: The Coronary Artery Calcium Score (CACS) has been shown to correlate with prevalence of angina.
Post Assessment Question 4:
Which medication class has trial evidence to support against its use in patients with ESRD?A. AntiplateletsB. ACE Inhibitors
C. StatinsD. Nitrates
Post Assessment Question 3:True / False: The Coronary Artery Calcium Score (CACS) has been shown to correlate with prevalence of angina.
Post Assessment Question 4:
Which medication class has trial evidence to support against its use in patients with ESRD?A. AntiplateletsB. ACE InhibitorsC. Statins
D. Nitrates
ReferencesBhatti NK, Karimi Galougahi K, Paz Y, et al. Diagnosis and Management of Cardiovascular Disease in Advanced and End-Stage Renal Disease. J Am Heart Assoc. 2016;5(8):e003648. Published 2016 Aug 4. doi:10.1161/JAHA.116.003648
Block GA, Raggi P, Bellasi A, Kooienga L, Spiegel DM. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int. 2007;71(5):438-441.
Block GA, Spiegel DM, Ehrlich J, et al,. Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int. 2005;68(4):1815-1824.
Gregg, L. Parker et al. Management of Traditional Cardiovascular Risk Factors in CKD: What Are the Data? Am J Kidney Dis. 2018 Nov;72(5):728-744. doi: 10.1053/j.ajkd.2017.12.007.