management of angina in esrd 1.16.18 xx - starchapter · gregg, lp et al. am j kidney disease....

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


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


Nitrates■ Cautious administration with preload is low (end of hemodialysis session), as these

states may potentiate the hypotensive effect of the drug


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)


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


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


ACE Inhibitors and ARBs■ Secondary prevention of CAD with angiotensin converting enzyme (ACE) inhibitors

may have diminished clinical benefit in ESRD.


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)


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


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


Which of the following terms is often used interchangeably with “angina”?A. DizzinessB. Chest pain

C. Shortness of BreathD. Palpitations


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.


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.


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.

management of angina in esrd 1.16.18 xx - starchapter · gregg, lp et al. am j kidney disease....

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