aaa bedside assistance: pharmaceutical … final.pdfaaa bedside assistance: pharmaceutical...

©2017 MFMER | slide-1

AAA Bedside Assistance: Pharmaceutical Management of Abdominal Aortic AneurysmsJanelle O. Poyant, PharmD, BCPSPGY2 Critical Care Pharmacy Resident

Pharmacy Grand RoundsJanuary 31, 2017


Presentation Objectives• Review the pathophysiology of abdominal aortic

aneurysms• Discuss the optimal hemodynamic goals in the

management of acute abdominal aortic aneurysms

• Describe the pharmaceutical management approach for both acute and chronic abdominal aortic aneurysms


Kent KC, Solomon CG. N Engl J Med 371.22(2014): 2101-108

Higher aortic wall

stress

Decreased aortic wall strength

Progressive aortic

expansionAortic

dilation

AAA Pathophysiology

Immune response

Oxidative stressThrombosis

Inflammation


Risk Factors

Development• Advanced age • Male gender• Caucasian race• Smoking• Family history• Other aneurysms• Atherosclerosis• Genetics

Expansion• Size >5.5 cm• Rate >0.5 cm in 6

months• Female gender• HTN• Elevated wall stress• Recent surgery• Smoker

Aggarwal S, et al. Exp Clin Cardiol;2011:16(10):11-15HTN: hypertension


Aortic Arch

Descending Aorta

Suprarenal

Infrarenal

Pararenal

Diaphragm

Ascending Aorta

Aortic Root

AAA Pathophysiology

≥3 cm


Aortic Dissection

Acute AD Subacute AD Chronic AD<14 days 15-90 days >90 days

Erbel R, et al. Eur Heart J 2014;35(41):2873-2926Image: http://www.mayoclinic.org/diseases-conditions

• Intramural bleeding• Separation of aortic

wall layers• Intimal layer tears

• Propagation of dissection

• High mortality if untreated


Classification Systems of Aortic Dissection

Erbel R, et al. Eur Heart J 2014;35(41):2873-2926Thrumurthy SG, et al. BMJ 2011;344:d8290

StanfordA: Ascending aorta affectedB: Ascending aorta not affected

DeBakeyI: Originates in ascending aortaII: Originates in and is confined to ascending aortaIII: Originates in descending aorta and extends distally


The pathophysiology of aortic aneurysms is characterized by mechanisms leading to higher aortic wall stress

A. TrueB. False


Patient JL• 54 year old male with sudden onset of pain and

numbness of his legs

• HTN• No home medicationsPMH

• One ppd cigarettes• One case of beer per daySH

PMH: past medical historySH: social historyPPD: pack per dayBP: blood pressureHR: heart rate

BP HR Respiratory Rate Temperature Saturation218/166 mmHg 118 bpm 22 bpm 37.2°F 97% RA


Erbel R, et al. Eur Heart J 2014;35(41):2873-2926Golledge J, Eagle KA. Lancet 2008;372:55-66

Clinical Presentation

Acute AD

Chest pain

Radiation to the back and/or abdomen

Chronic AAAPain and tenderness

on palpitation

Incidental finding


• Aortic regurgitation• Cardiac tamponade• Malperfusion of:

• Brain• Coronary artery

• Malperfusion of:• Spinal cord• Legs• Liver• Bowel• Kidneys

Image adapted from: Golledge J, Eagle KA. Lancet 2008;372:55-66

Clinical Presentation of Aortic Dissection


Patient JL

• Hypertensive emergency

CTA Chest/AbdomenStanford type B aortic dissection extends from just distal to the origin of the left subclavian artery through the abdominal aorta and iliac arteries bilaterally

HR 118218/166 mmHg

First-line intervention

HR 70166/100 mmHg

Second-line intervention

CTA: computed tomography angiogram

GOAL


Cerebral Autoregulation and BP Lowering• Intrinsic capacity of resistance vessels to dilate

and constrict in response to pressure changes

Ruland S, Aiyagari V. Hypertension 2007;49:977-978CBF: cerebral blood flowMAP: mean arterial pressure


Acute AD: Medical Management

Marik PE, Varon J. Chest 2007;131;1949-1962Stayer et al. Current Cardiology Revi

• Decrease aortic wall stress then SBP• A vasodilator alone is not ideal

Shear stress SBPdp

dtHR


Acute AD: Medical Management

HR 60-70 bpm

SBP 110-120 mmHg

MAP 60-80 mmHg

Marik PE, Varon J. Chest 2007;131;1949-1962

• Control of pain and anxiety • Hydromorphone, fentanyl


Ideal Pharmaceutical Agent• Short-acting• Continuous infusion• Titratable • Avoid

• Oral• Sublingual• Intramuscular



Acute management of AD

Heart rate >70 bpm

Initiate beta-blockade (e.g., esmolol or labetalol)

SBP >120mmHg despite beta-blockade

Nicardipine Clevidipine Sodium nitroprusside


Clevidipine • Third generation dihydropyridine CCB• Reduces afterload without

• affecting cardiac filling pressures • causing reflex tachycardia

• Rapid onset and offset of action

Rhoney D, Peacock WF AJHP 2009;66:1343-52Marik PE, Varon J. Chest 2007;131;1949-1962

No bolusInfusion

1-2 mg/hrMaximum 21 mg/hr

CCB: calcium channel blocker


Agents to Avoid in Initial Management• Nitroglycerin

• Reflex tachycardia• Reduction in preload and cardiac output

• Hydralazine• Prolonged and unpredictable

antihypertensive effects• Inability to titrate



JL presents with a BP of 218/166 mmHg with HRs in110s. A Type B AAA is found on CT. JL has a PMH of HTN, HL and DM. What is the best method to optimize JL’s hemodynamics at this time?

A. Reduce DBP by 10-15% over 30-60 minutesB. Reduce DBP to ~110 mmHg over 30-60

minutesC. Reduce HR to <60 then reduce SBP to <120

mmHg as quickly as possibleD. Reduce SBP to <180 mmHg over <20

minutes while reducing HR to <80HL: hyperlipidemiaDM: diabetes mellitus


What do you recommend for JL’s initial pharmacologic therapy?

A. NicardipineB. NitroprussideC. ClevidipineD. Esmolol


Postoperative Pearls• Spinal drains

• Reduce the rate of paraplegia• Continued 72 hours postoperatively

• Increased MAP goals• 80-90 mmHg

• ATN• Reinitiation of thromboembolism prophylaxis is

surgeon-dependent

Erbel R, et al. Eur Heart J 2014;35(41):2873-2926Bethel SA. J Vasc Nurs 1999;17(3):53-58

Crawford ES, et al. J Vasc Surg 1986;3:389-404CSF: cerebrospinal fluidATN: acute tubular necrosis


Transitioning to Oral Agents

• Overlap IV therapy with oral• Utilize higher doses and multiple mechanisms

HR 60-70 bpm

SBP 110-120 mmHg

MAP 60-80 mmHg


Chronic AAA: Medical Management • Open repair versus surveillance

• No statistically significant effect of intervention on survival

• Surgery reserved for complicated AAAs• International Registry of Aortic Dissection (IRAD)

• 73% managed medically• Survival at ten years is ~40-45%

• Options for pharmaceutical stabilization?

Suzuki T, et al. Circulation 2003;108(S1):II312-7Tsai Ttet al. Circulation.2005;112:3802–13

Doroghazi RM, et al. J Am Coll Cardiol. 1984;3:1026 –1034Filardo G. Mayo Clin Proc 2013;88(9):910-919


Role of β-Blockers

Leach SD, et al. Arch Surg 1988;123:606-9Gadowski GR, et al. J Vasc Surg 1994;19(4):727-31

AAA Expansion Rate: Effect of Size and β–adrenergic Blockade

Design Prospective, observational, cohort studyPrimary endpoint AAA expansion rateInclusion criteria Patient with AAA <5 cm or contraindications to surgery

Demographics β-blocker (n=83)

No β-blocker (n=38) p-value

Age* (years) 67 ± 10 68 ± 8 0.56Male 74% 71% 0.97Initial size* (cm) 4.0 ± 0.8 4.0 ± 0.7 1.0SBP* (mmHg) 154 ± 18 151 ± 20 0.43

*mean ± SD


Role of β-Blockers

Gadowski GR, et al. J Vasc Surg 1994;19(4):727-31

Result β-blocker No β-blocker p-valueExpansion rate* 0.38 ± 0.44**Expansion rate* 0.30 ± 0.3** 0.44 ± 0.42** NSLarge AAA expansion rate* 0.36 ± 0.20** 0.68 ± 0.64** < 0.02Rupture rate 5% 13% NS

• Significantly faster expansion with aneurysms >5.0 cm without β-blockers

00.10.20.30.40.50.60.7

3.0-3.9 4.0-4.9 ≥5

Gro

wth

Rat

e (c

m/y

r)

Aneurysm Diameter (cm)

β-blockerNo β-blocker

p<0.05

p<0.02

*mean ± SD**cm/year


Role of β-Blockers: Application to Practice• β-blockers reduce wall shear stress and

subsequently reduce AAA growth • Potential benefit in cohort studies• Not confirmed in three RCTs

• Pooled growth rate difference: -0.005 cm/yr, 95% CI -0.016 to 0.005

Erbel R, et al. Eur Heart J 2014;35(41):2873-2926Guessous I, et al. PLoS One 2008;3:e1895

Rughani G, et al. Cochrane Database Syst Rev 2012;9:CD009536

It is reasonable to reduce BP with β-blockers to the lowest point patients can

tolerate without AE

AE: adverse effects


Role of ACE-I• Suggested benefit

• Case control study for rupture prevention (OR 0.82; 95% CI 0.74-0.90)

• Possible harm• Prospective cohort study indicating

significant increase in aneurysm growth rate • Guidelines

• Conflicting and moderate quality evidence

Hackem DJ. Lancet 2006;368:659-65Sweeting MJ. J Vasc Surg 2010;52:1-4ACE-I: angiotensin-converting-enzyme inhibitor


Role of ACE-I

Aortic aneurysmal regression of dilation: value of ACE-inhibition on risk (AARDVARK)

Design Multicenter, single-blind, randomized, three arm, placebo-controlled

Primary endpoint Aneurysm growth rate

Intervention Perindopril 10mg, amlodipine 5mg or placebo

Population

Inclusion: Patients ≥55 years, AAA diameter 3.0-5.4 cm and SBP <150 mmHg

Exclusion: ACE-I, ARB, known renal artery stenosis , SCr > 2, unable to complete 3–6 monthly surveillance

SCr: serum creatinine Bicknell CD. Eur Heart Jour 2016;37:3213-3221


Role of ACE-I

• Perindopril and amlodipine effectively lowered SBP but did not affect AAA growth

• Perindopril did not affect the overall growth rate of AAAs during 2 years of follow up

Comparison Difference in average growth rate p-value

Perindopril vs. Placebo 0.8 cm NSAmlodipine vs. Placebo 1.2 cm NS

Bicknell CD. Eur Heart Jour 2016;37:3213-3221


ACE-I Application to Practice• Excellent follow-up• Drug compliance assessed (and excellent)• Limitations

• Lack of generalizability • Intra- and inter-observer variability

It is reasonable to reduce BP with ACE-I to the lowest point patients

can tolerate without AEBicknell CD. Eur Heart Jour 2016;37:3213-3221


Role of Statins• Chronic AAA

• May inhibit expansion of aneurysms• Small observational studies

• Post-AAA repair• Association with improved survival

• 3x reduction in the risk of CV death• The use of statins may be considered to reduce

aortic complications in patients with small AAAs

Erbel R, et al. Eur Heart J 2014;35(41):2873-2926Jovin IS, et al. Am J Cardiol 2012;109:1050-54Stein LH, et al. Am J Cardiol 2013;112:1240-45De Bruin, et al. J Vasc Surg 2014;59:p39-44e1

CV: cardiovascular


Other Potential OptionsDrug Pathologic Target Outcome Result

DoxycyclineMatrix metalloproteinases and inflammation

AAA growth Faster in intervention group

Pemirolast Mast cell inhibitor AAA growth NSAmlodipine HTN AAA growth NS

Cyclosporine A Inflammation, matrixremodelling AAA growth Recruiting

Ticagrelor AAA thrombus, inflammation AAA growth Ongoing

ValsartanAngiotensin II, inflammation, matrix remodelling

AAA growth Ongoing

Golledge, et al. J Vasc Surg 2017;65:225-35Clinicaltrials.gov/NCT02225756Clinicaltrials.gov/NCT02070653Clinicaltrials.gov/NCT01904981


Chronic Management• Stringent control of risk factors

• Smoking cessation• Moderate physical activity

• Optimization of comorbid conditions• Strict BP and HR control

• 110-120 mmHg• 60-70 bpm

• Serial imaging

Erbel R, et al. Eur Heart J 2014;35(41):2873-2926Aggarwal S, et al Exp Clin Cardiol 2011;16(1):11-15

Tsai Ttet al. Circulation.2005;112:3802–13


Acute AD

HR 60-70 bpm and

SBP 110-120 mmHg

Surgical intervention

IV β-blocker then IV

vasodilator

Chronic AAA

Chronic Medical

Management

HR 60-70 bpm and

SBP 110-120 mmHg

β-blocker, ACE-inhibitor

Thrumurthy SG, et al. BMJ 2011;344:d8290Erbel R, et al. Eur Heart J 2014;35(41):2873-2926


Conclusion• Mechanisms leading to aortic aneurysms

surround higher wall stress• No RCTs have been reported to guide acute

management of acute AD• Acute management should be focused on

HR control then BP lowering• Pharmaceutical stabilization of AAA is an unmet

medical need


Questions & Discussion

[email protected]


Esmolol• β1-adrenergic antagonist• Rapid onset with a short duration of action• Caution in decompensated heart failure and

reactive airway disease


Bolus 500 mcg/kg

Infusion50 mcg/kg/min

Maximum300 mcg/kg/min


Labetalol• α1- and nonselective β-adrenergic antagonist• Increased β receptor activity in IV formulation• Quick onset with short duration of action• Caution in reactive airway disease, COPD, HF,

and second or third decree AV block

Rhoney D, Peacock WF AJHP 2009;66:1343-52Kitiyakara C, et al. J Am Soc Nephrol 1998;9:133-42


Bolus 20 mg

Incremental20-80 mg

Infusion0.5-4 mg/min

COPD: chronic obstructive pulmonary diseaseHF: heart failureAV: atrioventricular


Nicardipine• Second generation dihydropyridine CCB• Quick onset with moderate duration of action• Dosage is independent of weight• Reduces cardiac and cerebral ischemia


No bolus Starting rate

5 mg/hrInfusion

5-15 mg/hr

CCB: calcium channel blocker


Nitroprusside• Arterial and venous vasodilator• Coronary steal• Contains 44% cyanide by weight

• Adequate liver and renal function required• Limit duration and dosage


No bolusInfusion

0.5-2 mcg/kg/minMaximum

2 mcg/kg/min

aaa bedside assistance: pharmaceutical … final.pdfaaa bedside assistance: pharmaceutical...

Documents